Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
• • 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
• • 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
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/34—One oxygen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present application relates to novel substituted 2-phenylpyrimidine-5-carboxylic acid derivatives, 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, preferably for treatment and / or prophylaxis of cardiovascular diseases, especially dyslipidaemias, atherosclerosis and cardiac insufficiency.
• fibrates are currently the only treatment option for patients in these risk groups. They lower elevated triglycerides by 20-50%, lower LDL-C by 10-15%, change the LDL particle size from low density atherogenic LDL to normal dense and less atherogenic LDL and increase the HDL concentration by 10-15%.
• Fibrates act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) - ⁇ (Nature 1990, 347, 645-50).
• PPAR-alpha is a nuclear receptor that regulates the expression of target genes by binding to DNA sequences in the promoter region of these genes [also called PPAR response elements (PPRE)].
• PPREs have been identified in a number of genes that encode proteins that regulate lipid metabolism.
• PPAR-alpha is highly expressed in the liver, and its activation leads, inter alia, to decreased VLDL production secretion and reduced apolipoprotein CHI (ApoCIII) synthesis. In contrast, the synthesis of apolipoprotein Al (ApoAl) is increased.
• a disadvantage of previously approved fibrates is their weak interaction with the receptor (EC 50 in the ⁇ M range), which in turn leads to the relatively low pharmacological effects described above.
• WO 99/41253 discloses substituted pyrimidines for the treatment of viral infections.
• WO 2004/111014 claims substituted pyrimidines for the treatment of cystic fibrosis.
• WO 2005/049573 and WO 2005/049606 describe substituted Pyrimidincarbonklar as Syntheseintermediate without biological activity.
• WO 2005/110416 discloses 4,5-disubstituted 2-arylpyrimidines as C5a receptor ligands for the treatment of inflammatory, immunological and cardiovascular diseases.
• WO 2006/124874 are under described other substituted pyrimidines for the treatment of cancer.
• WO 2006/097220 claims 4-phenoxy-2-phenylpyrimidinecarboxylic acids and in WO 2008/031500 and WO 2008/031501 4-phenoxy- or 2-phenoxynicotinic acids as PPAR-alpha modulators for the treatment of dyslipidemias and arteriosclerosis.
• the present invention relates to compounds of the general formula (I)
• R 1 is (C 3 -C 10) -alkyl, (C 3 -C 7 ) -cycloalkyl or -OR A ,
• (C 3 -C O) alkyl having 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, hydroxy, (Ci-C 4) -alkoxy, trifluoromethoxy, and (C 3 -C 7) cycloalkyl may be substituted .
• R A is (C r C 10 ) -alkyl or (C 3 -C 7 ) -cycloalkyl
• (C 1 -C 10) -alkyl can be substituted by one substituent selected from the group consisting of hydroxyl, (C 1 -C 4 ) -alkoxy and (C 3 -C 7 ) -cycloalkyl,
• R 2 is (C 1 -C 4 ) -alkyl or cyclopropyl
• R 3 is hydrogen or fluorine
• R 4 is hydrogen, fluorine, chlorine, methyl or trifluoromethyl
• R 5 is hydrogen, halogen, nitro, cyano, trifluoromethyl, methyl, ethyl, trifluoromethoxy or methoxy,
• R 6 is hydrogen, fluorine, chlorine, methyl or trifluoromethyl
• R 3 , R 4 , R 5 and R 6 is different from hydrogen
• Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
• the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
• the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
• the present invention encompasses all tautomeric forms.
• Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of 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 and benzoic 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 customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
• customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
• 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 solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
• the present invention also includes prodrugs of the compounds of the invention.
• prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
• the present invention also includes hydrolyzable ester derivatives of the carboxylic acids of the formula (I).
• esters which can be hydrolyzed in physiological media and in particular in vivo enzymatically or chemically to the free carboxylic acids.
• esters are linear or branched (Ci-C 6) -alkyl, wherein the alkyl group by hydroxy, (Ci-C 4) alkoxy, amino, mono (C 1 -C 4) -alkylamino and / or di- (C 1 -C 4 ) -alkylamino may be substituted.
• Particularly preferred are the methyl or ethyl esters of the compounds of formula (I).
• alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
• alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
• Cycloalkyl in the context of the invention is a monocyclic, saturated alkyl radical having 3 to 7 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine. If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
• R 1 is (C 3 -C 8 ) -alkyl, cyclopropyl, cyclopentyl, cyclohexyl or -OR A ,
• (C 3 -C 8 ) -alkyl can be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, methoxy, ethoxy and trifluoromethoxy,
• cyclopropyl, cyclopentyl and cyclohexyl can be substituted with 1 or 2 substituents independently of one another selected from the group fluorine, hydroxyl, oxo, methyl, ethyl, trifluoromethyl and methoxy,
• R A is methyl, ethyl, (C 3 -C 8 ) -alkyl, cyclopropyl, cyclopentyl or cyclohexyl,
• methyl and ethyl are substituted by a substituent selected from the group cyclopropyl, cyclopentyl and cyclohexyl,
• Substituents independently of one another can be substituted from the group fluorine, hydroxyl, oxo, methyl, ethyl, trifluoromethyl and methoxy,
• (C 3 -C 8 ) -alkyl can be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxyl, methoxy and ethoxy,
• cyclopropyl, cyclopentyl and cyclohexyl can be substituted with 1 or 2 substituents independently of one another selected from the group fluorine, hydroxyl, oxo, methyl, ethyl, trifluoromethyl and methoxy,
• R 2 is (C 1 -C 4 ) -alkyl, trifluoromethyl or cyclopropyl,
• R 3 is hydrogen
• R 4 is hydrogen or fluorine
• R 5 is hydrogen, fluorine, chlorine, trifluoromethyl or methyl
• R 6 is hydrogen or methyl
• R 1 is (C 3 -C 6 ) -alkyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or -OR A ,
• R A is methyl, (C 3 -C 6 ) -alkyl, cyclopropyl, cyclopentyl or cyclohexyl,
• methyl is substituted by a substituent selected from the group cyclopropyl, cyclopentyl and cyclohexyl,
• CyI may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of hydroxy and methoxy,
• R 2 is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or cyclopropyl,
• R 3 is hydrogen
• R 4 is hydrogen or fluorine
• R 5 is hydrogen, chlorine or methyl
• R 6 is hydrogen or methyl
• R 1 is isopropyl, isobutyl, 1-methylpropyl, isopentyl, 1-methylbutyl or -OR A ,
• R A is isopropyl, iso-butyl, 1-methylpropyl, 1-methylbutyl or 3-methylbutyl,
• R 2 is methyl, ethyl or trifluoromethyl
• R 3 is hydrogen
• R 4 is hydrogen
• R 5 is hydrogen, chlorine or methyl
• R 6 is hydrogen or methyl
• R 5 and R 6 are other than hydrogen
• R 1 is isopropyl, isobutyl, 1-methylpropyl, isopentyl or 1-methylbutyl.
• R 1 is -OR A , where R A is isopropyl, isobutyl, 1-methylpropyl, 1-methylbutyl or 3-methylbutyl.
• Another object of the present invention is the compound 4-cyclopropyl-6- (methoxymethyl) -2- [4- (trifluoromethyl) phenyl] -pyrimidine-5-carboxylic acid for the prophylaxis and / or treatment of cardiovascular diseases.
• Another object of the present invention is the use of the compound 4-cyclopropyl-6- (methoxymethyl) -2- [4- (trifluoromethyl) phenyl] pyrimidine-5-carboxylic acid to
• the invention further provides a process for preparing the compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (II)
• R 2 , R 3 , R 4 , R 5 and R 6 each have the meanings given above,
• R 7 is (C 1 -C 4 ) -alkyl
• R ' A is -OR A
• R 1A , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each have the meanings given above,
• R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each have the meanings given above,
• R IB is (C 3 -C 10) -alkyl or (C 3 -C 7 ) -cycloalkyl
• (C 3 -C 10) -alkyl can be substituted by one or two substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, (CrQ) -alkoxy, trifluoromethoxy and (C 3 -C 7 ) -cycloalkyl,
• X 1 represents a group of the formula -B (OR 8 ) 2 or -ZnHaI
• Hal is halogen, in particular chlorine, bromine or iodine,
• R 8 is hydrogen or (C r C 4 ) alkyl
• both radicals R 8 together form a -C (CH 3 ) 2 -C (CH 3 ) 2 bridge
• R 1B , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each have the meanings given above,
• the compounds of the formula (II) can be prepared by reacting compounds of the formula (VI)
• R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each have the meanings given above,
• R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each have the meanings given above,
• the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention in which R 1 is R 1B in which R 1B has the abovementioned meanings, characterized in that a compound of the formula (X)
• R 1B has the abovementioned meaning
• R 1B , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each have the meanings given above,
• R 1B , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each have the meanings given above,
• the compound 4-cyclopropyl-6- (methoxymethyl) -2- [4- (trifluoromethyl) phenyl] pyrimidine-5-carboxylic acid can be prepared analogously to the above-described process [B] or as described in WO 2005/049573.
• the reaction (EI) -> (HI) is carried out without solvent or optionally in an inert solvent suitable under the reaction conditions such as hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone ( ⁇ MP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned.
• the reaction preferably takes place without solvent.
• the reaction (ET) -> (IH) is generally carried out in a temperature range from 0 0 C to +160 0 C, preferably at +20 0 C to +120 0 C, optionally in a microwave.
• the reaction can be carried out at normal, elevated or at reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.
• Transition metal catalysts, catalyst ligands and auxiliary bases for the coupling reactions (V) + (III-B) ⁇ (IV-B) are known from the literature [cf. e.g. J. Hassan et al., Chem. Rev. JO2, 1359-1469 (2002)] and commercially available. Preference is given to using palladium or nickel catalysts.
• tetrakis (triphenylphosphine) palladium (0) is preferably used as the catalyst.
• Diethylene glycol dimethyl ether such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, NN '
• DMPU Dimethylpropyleneurea
• ⁇ MP N-methylpyrrolidone
• pyridine pyridine
• acetonitrile acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using dimethylformamide or dioxane.
• the reactions can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar).
• triphenylphosphine or tri-n-butylphosphine, 1, 2-bis (diphenylphosphino) ethane (DPPE), diphenyl (2-pyridyl) phosphine (Ph2P-Py), (p-dimethylaminophenyl ) diphenylphosphine (DAP-DP), tris (4-dimethylaminophenyl) phosphine (tris-DAP) and a suitable dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, NNN'N ' -Tetramethylazodicarboxamide (TMAD), I, L '- (azodicarbonyl) - dipiperidine (ADDP) or 4,7-dimethyl-3,5,7-
• DPPE 1, 2-bis (diphen
• Inert solvents for the Mitsunobu reaction (ET) + (IQ-A) ⁇ (IV-A) are, for example, ethers such as tetrahydrofuran, diethyl ether, hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane or other solvents such as acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferably, THF is used.
• the Mitsunobu reaction (U) + (IH-A) -> • (IV-A) is generally carried out in a temperature range from -78 ° C to +180 0 C, preferably at 0 0 C to + 50 0 C, optionally in a microwave.
• the reactions can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar).
• the hydrolysis of the carboxylic acid esters in process steps (IV-A) - »(IA) and (IV-B) -> (IB) is carried out by customary methods, if appropriate in a microwave, by treating the esters in acids or bases with inert solvents , Where the salts initially formed in the latter are converted into the free carboxylic acids by subsequent treatment with acid.
• the tert-butyl ester ester cleavage is preferably carried out with acids.
• Suitable inert solvents for the hydrolysis of the carboxylic acid esters are water or the organic solvents customary for ester cleavage. These include in particular alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert. Butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, acetonitrile, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
• Suitable bases for the ester hydrolysis are the customary inorganic bases. These include in particular alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Preference is given to using sodium hydroxide or potassium hydroxide.
• Suitable acids for the ester cleavage are generally sulfuric acid, hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, Toluene sulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.
• the Esterspaltung is generally carried out in a temperature range of 0 0 C to +100 0 C, forthcoming Trains t at 0 0 C to +50 0 C.
• the reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar).
• R 1A is -H, triphenylphosphine, DIAD, room temperature].
• the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
• the compounds according to the invention are highly effective PPAR-alpha modulators and moreover have increased metabolic stability. They are particularly useful for primary and / or secondary prevention and treatment of cardiovascular disorders caused by disorders in fatty acid and glucose metabolism.
• cardiovascular disorders include dyslipidemias (hypercholesterolemia, hypertriglyceridemia, increased levels postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidemias), arteriosclerosis and metabolic disorders (metabolic syndrome, hyperglycemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance, obesity and diabetic Late effects such as retinopathy, nephropathy and neuropathy).
• the compounds of the invention are particularly suitable for primary and / or secondary prevention and treatment of heart failure.
• cardiac insufficiency also encompasses more specific or related forms of disease such as right heart failure, left heart failure, global insufficiency, hypertension-induced heart failure, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, valvular heart failure, cardiac insufficiency in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency , Tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure, and systolic heart failure.
• myocarditis chronic myocarditis, acute myocarditis, viral myo
• CAD-I independent cardiovascular disease risk factors
• hypertension ischemia, myocardial infarction, angina pectoris, myocardial insufficiency, restenosis, pulmonary hypertension, increased levels of fibrinogen and low density LDL, and elevated levels of plasminogen activator.
• Inhibitor 1 PAI-I
• the compounds according to the invention can also be used for the treatment and / or prevention of cancers such as, for example, skin cancer, breast cancer, brain tumors, head and neck tumors, liposarcomas, carcinomas of the eye, the gastrointestinal tract, the thyroid, the liver, the pancreas, the respiratory organs, the kidney, the ureter, the prostate, the genital tract and their distant metastases, and lyphomas, sarcomas and leukemias.
• cancers such as, for example, skin cancer, breast cancer, brain tumors, head and neck tumors, liposarcomas, carcinomas of the eye, the gastrointestinal tract, the thyroid, the liver, the pancreas, the respiratory organs, the kidney, the ureter, the prostate, the genital tract and their distant metastases, and lyphomas, sarcomas and leukemias.
• the compounds according to the invention can also be used for the treatment and / or prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thromboses, edema, diseases of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease).
• vasculitis micro- and macrovascular damage
• reperfusion damage arterial and venous thromboses
• edema diseases of the central nervous system and neurodegenerative disorders
• stroke Alzheimer's disease, Parkinson's disease.
• the activity of the compounds of the invention can be e.g. in vitro by the transactivation assay described in the Examples section.
• the efficacy of the compounds of the invention in vivo can be e.g. Check by the tests described in the example section.
• Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
• Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
• Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
• Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of dyslipidaemias, arteriosclerosis and heart failure.
• the compounds of the invention may be used alone or as needed in combination with other agents.
• Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
• Suitable combination active ingredients which may be mentioned by way of example are active substances which alter the metabolism of lipids, antidiabetics, blood pressure depressants, circulation-promoting and / or or antithrombotic agents and antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB 4 receptor antagonists), analgesics (Aspirin), antidepressants and other psychotropic drugs.
• active substances which alter the metabolism of lipids, antidiabetics, blood pressure depressants, circulation-promoting and / or or antithrombotic agents and antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB 4 receptor antagonists), analgesics (Aspirin),
• the present invention relates, in particular, to combinations of at least one of the compounds according to the invention with at least one lipid metabolism-altering active ingredient, an antidiabetic agent, a hypotensive agent and / or an antithrombotic agent.
• the compounds of the invention may preferably be with one or more
• the substances which modify the lipid metabolism by way of example and preferably from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, LDL receptor inducers, cholesterol Anti-absorption agents, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, MTP inhibitors, lipase inhibitors, LpL activators, fibrates, niacin, CETP inhibitors, PPAR- ⁇ and / or PPAR- ⁇ agonists, RXR modulators, FXR modulators , LXR modulators, thyroid hormones and / or thyroid mimetics, ATP citrate lyase inhibitors, Lp (a) antagonists, cannabinoid receptor 1 antagonists, leptin receptor agonists, bombesin receptor agonists, histamine receptor Agonists as well as the antioxidants / free radical scavengers;
• Antidiabetic agents mentioned in the Red List 2004 / ⁇ , Chapter 12, and by way of example and preferably those from the group of sulfonylureas, biguanides, meglitinide derivatives,
• Glucosidase inhibitors oxadiazolidinones, thiazolidinediones, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK 1 receptor agonists, leptin receptor agonists, inhibitors of liver enzymes that stimulate gluconeogenesis and / or glycogenolysis involved, modulators of glucose uptake and the potassium channel opener, such as those disclosed in WO 97/26265 and WO 99/03861;
• hypotensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers, ECE inhibitors and the vasopeptidase inhibitors;
• Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants;
• cGMP cyclic guanosine monophosphate
• cAMP cyclic adenosine monophosphate
• PDE phosphodiesterases
• sildenafil sildenafil
• Vardenafil tadalafil
• PDE 3 inhibitors such as milrinone
• Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
• ABP atrial natriuretic peptide
• BNP B-type natriuretic peptide
• CNP C-type natriuretic peptide
• urodilatin urodilatin
• Calcium sensitizers such as by way of example and preferably levosimendan
• NO-independent, but heme-dependent guanylate cyclase stimulators in particular those described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451
• Guanylate cyclase NO- and heme-independent activators in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
• HNE human neutrophil elastase
• the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib; and or
• lipid metabolism-changing active compounds are preferably compounds from the group of HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, lipase inhibitors, thyroid hormones and / or thyroid mimetics, niacin receptor Agonists, CETP inhibitors, PPAR-gamma agonists, PPAR delta agonists, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, antioxidants / radical scavengers, and the cannabinoid receptor 1 antagonists.
• HMG-CoA reductase inhibitors preferably compounds from the group of HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, lipase inhibitors, thyroid hormones and / or thyroid mimetics, niacin receptor Agonists, CETP inhibitors, PPAR-gam
• the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin ,
• an HMG-CoA reductase inhibitor from the class of statins, by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin ,
• the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
• a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
• the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably melinamide, pactimibe, eflucimibe or SMP-797.
• an ACAT inhibitor such as by way of example and preferably melinamide, pactimibe, eflucimibe or SMP-797.
• the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
• a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
• the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide or JTT-130.
• the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
• a lipase inhibitor such as, for example and preferably, orlistat.
• the compounds according to the invention are administered in combination with a thyroid hormone and / or thyroid mimetic, such as by way of example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3).
• a thyroid hormone and / or thyroid mimetic such as by way of example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3).
• the compounds according to the invention are administered in combination with an agonist of the niacin receptor, such as by way of example and preferably niacin, Acipimox, A mecanical or Radecol.
• an agonist of the niacin receptor such as by way of example and preferably niacin, Acipimox, A mecanical or Radecol.
• the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib, JTT-705 or CETP vaccine (Avant).
• the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone.
• a PPAR-gamma agonist such as by way of example and preferably pioglitazone or rosiglitazone.
• the compounds of the invention are administered in combination with a PPAR delta agonist such as, for example and preferably, GW-501516.
• a PPAR delta agonist such as, for example and preferably, GW-501516.
• the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• ASBT IBAT
• AZD-7806 S-8921
• AK-105 AK-105
• BARI-1741 AK-105
• SC-435 SC-635.
• the compounds according to the invention are administered in combination with an antioxidant / free-radical scavenger such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
• an antioxidant / free-radical scavenger such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
• the compounds of the invention are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant or SR-147778.
• a cannabinoid receptor 1 antagonist such as by way of example and preferably rimonabant or SR-147778.
• Antidiabetic agents are preferably understood as meaning insulin and insulin derivatives as well as orally active hypoglycemic agents.
• Insulin and insulin derivatives here include both insulins of animal, human or biotechnological origin as well as mixtures thereof.
• the orally active hypoglycemic agents preferably include sulphonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors and PPAR-gamma agonists.
• the compounds according to the invention are administered in combination with insulin.
• the compounds according to the invention are administered in combination with a sulphonylurea, such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
• the compounds according to the invention are administered in combination with a biguanide, such as by way of example and preferably metformin.
• the compounds of the invention are administered in combination with a meglitinide derivative, such as by way of example and preferably repaglinide or nateglinide.
• a meglitinide derivative such as by way of example and preferably repaglinide or nateglinide.
• the compounds according to the invention are administered in combination with a glucosidase inhibitor, such as by way of example and preferably miglitol or acarbose.
• a glucosidase inhibitor such as by way of example and preferably miglitol or acarbose.
• the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• a PPAR-gamma agonist for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• the blood pressure lowering agents are preferably understood as meaning compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers and diuretics.
• the compounds of the invention are administered in combination with a diuretic, such as by way of example and preferably a loop diuretic such as furosemide, bumetanide or torsemide, or a thiazide or thiazide-like diuretic such as chlorothiazide or hydrochlorothiazide.
• a diuretic such as by way of example and preferably a loop diuretic such as furosemide, bumetanide or torsemide, or a thiazide or thiazide-like diuretic such as chlorothiazide or hydrochlorothiazide.
• the compounds according to the invention are administered in combination with an aldosterone or mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
• an aldosterone or mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
• the compounds according to the invention are administered in combination with a vasopressin receptor antagonist, such as by way of example and preferably Conivaptan, tolvaptan, lixivaptan or SR-121463.
• a vasopressin receptor antagonist such as by way of example and preferably Conivaptan, tolvaptan, lixivaptan or SR-121463.
• the compounds according to the invention are used in combination with an organic nitrate or NO donor, such as by way of example and by way of example.
• an organic nitrate or NO donor such as by way of example and by way of example.
• the compounds according to the invention are used in combination with a positive inotropically active compound, such as by way of example and preferably cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, adrenaline, norepinephrine, dopamine or dobutamine, administered.
• a positive inotropically active compound such as by way of example and preferably cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, adrenaline, norepinephrine, dopamine or dobutamine, administered.
• the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
• a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
• the compounds according to the invention are administered in combination with an angiotensin AQ antagonist, such as by way of example and preferably losartan, valsartan, candesartan, embusartan or telmisartan.
• angiotensin AQ antagonist such as by way of example and preferably losartan, valsartan, candesartan, embusartan or telmisartan.
• the compounds according to the invention are administered in combination with an ACE inhibitor such as, for example and preferably, enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• an ACE inhibitor such as, for example and preferably, enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
• a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolo
• the compounds according to the invention are administered in combination with an alpha-receptor blocker, such as by way of example and preferably prazosin.
• the compounds according to the invention are used in combination with an antisympathotonicum, such as by way of example and preferably reserpine, clonidine or alpha-methyl-dopa, or in combination with a potassium channel agonist such as, for example and preferably, minoxidil, diazoxide, dihydralazine or hydralazine.
• an antisympathotonicum such as by way of example and preferably reserpine, clonidine or alpha-methyl-dopa
• a potassium channel agonist such as, for example and preferably, minoxidil, diazoxide, dihydralazine or hydralazine.
• Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors or anticoagulants.
• the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
• the compounds according to the invention are administered in combination with a thrombin inhibitor, such as by way of example and preferably ximelagarran, melagatran, bivalirudin or Clexane.
• a thrombin inhibitor such as by way of example and preferably ximelagarran, melagatran, bivalirudin or Clexane.
• the compounds according to the invention are administered in combination with a GPUb / IHa antagonist, such as by way of example and preferably tirofiban or abciximab.
• the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
• a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM
• the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
• LMW low molecular weight
• the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
• HMG-CoA reductase inhibitors statins
• diuretics beta-receptor blockers
• organic nitrates and NO Donors ACE inhibitors
• angiotensin Aü antagonists aldosterone and mineralocorticoid receptor antagonists
• vasopressin receptor antagonists platelet aggregation inhibitors and anticoagulants, and their use for the treatment and / or prevention of the aforementioned diseases.
• the compounds according to the invention can be used for the treatment and / or prophylaxis of cancers alone or as needed in combination with other anti-tumor agents.
• the present invention particularly relates to combinations of at least one of the compounds according to the invention with at least one other anti-tumor active ingredient selected from the group consisting of alkylating agents, antimetabolites, of Plant derived anti-tumor agents, hormone therapy agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, targeted drugs, antibodies, immunoconjugates, interferon and / or immunomodulators, antiangiogenic compounds, antisense RNA and RNA interference, and others Tumor medication.
• Alkylating agents such as chloromethine N-oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, ⁇ imustin, temozolomide, altretamine, apaciquin, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, mafosfamide and mitolactol;
• Platinum-coordinated alkylating agents such as, for example, cisplatin, carboplatin, eptaplatin, lobaplatin, ⁇ edaplatin, oxaliplatin and satraplatin;
• Antimetabolites such as methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone or in combination with leucovorin, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, Decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan, ⁇ elarabine, ⁇ olatrexed, ocfosfit, disodium
• Premetrexed pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, and vinorelbine;
• hormonal agents such as exemestane, lupron, anastrozole, doxercalciferol, fadrozole, formestan, 11-beta hydroxysteroid dehydrogenase-1 inhibitors, 17-alpha hydroxylase / 17,20 lyase inhibitors such as abiraterone acetate, 5-alpha reductase
• Inhibitors such as finasteride and epristeride, anti-estrogens such as tamoxifen citrate and fulvestrant, trelstar, toremifene, raloxifene, lasofoxifene, letrozole, anti-androgens such as bicalutamide, flutamide, mifepristone, ilutamide, Casodex and anti-progesterone, and combinations thereof;
• anti-estrogens such as tamoxifen citrate and fulvestrant, trelstar, toremifene, raloxifene, lasofoxifene, letrozole
• anti-androgens such as bicalutamide, flutamide, mifepristone, ilutamide, Casodex and anti-progesterone, and combinations thereof;
• plant-derived antitumor agents such as mitotic inhibitors such as epothilones (sagopilone, ixabepilone and epothilone B), vinblastine, vinflunine, docetaxel, and paclitaxel;
• mitotic inhibitors such as epothilones (sagopilone, ixabepilone and epothilone B), vinblastine, vinflunine, docetaxel, and paclitaxel;
• Cytotoxic topoisomerase inhibitors such as aclarubicin, doxorubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan, topotecan, edotecarin, epimbicin, etoposide, exatecan, germantcan, lurtotecan, mitoxantrone, pirambicin, pixantrone, Rubitecan, Sobuzoxan, Tafluposide, and combinations thereof; • Immunological agents exemplified and preferably from the group of interferons such.
• Ibritumomab Imiquimod, Lenograstim, Lentinan, Melanoma Vaccine (Corixa), Molgramostim, Sargramostim, Tasonermin, Tecleukin, Thymalasin, Tositumomab, Vimlizine, Epratuzumab, Mitumomab, Oregovomab, Pemtumomab and Proveng;
• Immunomodulators such as Krestin, Lentinan, Sizofiran, Picibanil, ProMun and Ubenimex;
• Antiangiogenic compounds such as, for example, acitretin, aflibercept, angiostatin, aplidine, asentar, axitinib, recentin, bevacizumab, brivanib alaninate, cilengtide, combretastatin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, rebarastat, Removab, Revlimid , Sorafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide, Ukrain and vitaxin;
• VEGF inhibitors such as sorafenib, DAST, bevacizumab, sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib, pazopanib, and ranibizumab;
• antibodies such as trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, orregovomab and alemtumab;
• EGFR (HERI) inhibitors such as cetuximab, panitumumab, vectibix, gefitinib, erlotinib and Zactima;
• HER2 inhibitors such as lapatinib, tratuzumab and pertuzumab;
• mTOR inhibitors such as temsirolimus, sirolimus / rapamycin and everolimus;
• CDK inhibitors such as roscovitine and flavopiridol; • Spindle assembly checkpoint inhibitors and targeted mitotic inhibitors such as PLK inhibitors, Aurora inhibitors (eg hesperadine), checkpoint kinase inhibitors and KSP inhibitors;
• HDAC inhibitors such as Panobinostat, Vorinostat, MS275, Belinostat and LBH589;
• Proteasome inhibitors such as bortezomib and carf ⁇ lzomib;
• Serine / threonine kinase inhibitors such as MEK inhibitors and Raf inhibitors such as sorafenib;
• Tyrosine kinase inhibitors such as dasatinib, nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate, brivanib alaninate, pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, vectibix, gefitinib, erlotinib , Lapatinib, tratuzumab, pertuzumab and c-kit inhibitors;
• Corticoids e.g. dexamethasone
• Thalidomide or thalidolide analogs e.g. lenalidomide
• Bcl-2 protein inhibitors such as Obatoclax, Oblimersen sodium and Gossypol;
• CD20 receptor antagonists such as rituximab
• Ribonucleotide reductase inhibitors such as gemcitabine
• Tumor necrosis apoptosis inducing ligand receptor 1 agonists such as Mapatumumab
• 5-hydroxytryptamine receptor antagonists such as rEV598, xaliprod, palonosetron hydrochloride, granisetron, zindol and AB-1001; • Integrin inhibitors including Alpha5-betal integrin inhibitors. E7820, JSM 6425, Volociximab and Endostatin;
• Androgen receptor antagonists including e.g. Nandrolone Decanoate, Fluoxymesterone, Android, Prost-Aid, Andromustine, Bicalutamide, Flutamide, Apo-cyproterone, Apo-Flutamide, Chlormadinone Acetate, Androcur, Tabi, Cyproterone Acetate and Nilutamide;
• aromatase inhibitors such as Anastrozole, letrozole, testolactone, exemestane, amino-glutethimide and formestane;
• the compounds of the invention may also be used to treat cancers associated with radiotherapy and / or surgery.
• compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
• the compounds according to the invention can act systemically and / or locally.
• they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
• the compounds according to the invention can be administered in suitable administration forms.
• the compounds of the invention rapidly and / or modified donating application forms containing the inventive compounds in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control of the compound according to the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• tablets uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control of the compound according to the invention
• Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
• a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
• absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
• parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhalation medicaments including powder inhalers, nebulizers
• nasal drops solutions or sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or ophthalmic preparations
• vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions
• Ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, scattering powders, implants or stents.
• the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• excipients for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
• binders for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• Stabilizers eg antioxidants such as ascorbic acid
• dyes eg inorganic pigments such as iron oxides
• flavor and / or odoriferous include, among others.
• Excipients for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium dodecyl
• the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
• UV ultraviolet spectrometry v / v volume-to-volume ratio (of a mixture)
• Method 1 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 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 3 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 100 x 4.6 mm; Eluent A: 1 liter of water + 0.5 ml of 50% formic acid; Eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 10% B-> 7.0 min 95% B-> 9.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min -> 7.0 min 2.0 ml / min-> 9.0 min 2.0 ml / min; UV detection: 210 nm
• Method 4 Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2.5 ⁇ MAX-RP 100A Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A ⁇ 3.0 min 5% A ⁇ »4.0 min 5% A -» 4.1 min 90% A; Flow: 2 ml / min; Oven: 50 ° C .; UV detection: 208-400 nm.
• Method 5 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ 20 x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A -> 0.2 min 100% A - »2.9 min 30% A -> 3.1 min 10% A -» 5.5 min 10% A; Oven: 50 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.
• Method 6 Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD l, 9 ⁇ 50 x lmm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A ⁇ 1.5 min 10% A - »2.2 min 10% A; Oven: 50 ° C; Flow: 0.33 ml / min; UV detection: 210 nm.
• Method 7 Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3 ⁇ 20 x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A ⁇ 3.0 min 10% A -> 4.0 min 10% A ⁇ 4:01 min 100% A (flow 2.5ml) -> 5:00 min 100% A furnace: 50 0 C; Flow: 2 ml / min; UV detection: 210 nm
• Example (150 mg, 0.448 mmol) of IA were taken up in 10 ml of benzene and 112 mg (0.493 mmol) of DDQ were added. The reaction was stirred overnight at reflux temperature. After cooling, the reaction was concentrated, taken up in water and then extracted with ethyl acetate. It was dried with magnesium sulfate and the solvent was removed by distillation under reduced pressure. The mixture was then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 107 mg (72% of theory) of the target compound.
• Example 4A A solution of 100 mg (about 0.342 mmol) Example 4A, 42 mg (0.478 mmol) of 3-methyl-1-butanol and 125 mg (0.478 mmol) of triphenylphosphine in 4 ml of THF was stirred for 20 minutes at room temperature. 96 mg (0.478 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred for 3 h at room temperature. The mixture was purified by preparative HPLC without elution (eluent: acetonitrile / water, 90:10, isocratic). This gave 41 mg (46% of theory) of the target compound.
• Example 4A A solution of 100 mg (about 0.342 mmol) of Example 4A, 50 mg (0.478 mmol) of 4-methoxybutan-2-ol and 125 mg (0.478 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature. 96 mg (0.478 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred for 3 h at room temperature. The mixture was purified by preparative HPLC without further work-up (eluent: acetonitrile / water 90:10, isocratic). 40 mg (43% of theory) of the target compound were thus obtained.
• Example 4A A solution of 100 mg (about 0.342 mmol) of Example 4A, 28 mg (0.478 mmol) of isopropanol and 125 mg (0.478 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature. 96 mg (0.478 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred for 3 h at room temperature. The mixture was purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 42 mg (51% of theory) of the target compound.
• Example 4A A solution of 100 mg (about 0.342 mmol) of Example 4A, 28 mg (0.478 mmol) of 3- (trifluoromethyl) cyclohexanol and 125 mg (0.478 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature. 96 mg (0.478 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was allowed to stand for 3 h Room temperature stirred. The mixture was purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 14 mg (13% of theory) of the target compound.
• Example 10A A solution of 92 mg (about 0.200 mmol) of Example 10A, 9 mg (0.201 mmol) of methanol and 74 mg (0.281 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature. Then 57 mg (0.281 mmol) of diisopropyl azodicarboxylate were added and the reaction mixture was further stirred for 1.5 h at room temperature. The mixture was purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 26 mg (39% of theory) of the target compound.
• Example 4A A solution of 100 mg (about 0.342 mmol) of Example 4A, 34 mg (0.478 mmol) of cyclopropylmethanol and 125 mg (0.478 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature. 96 mg (0.478 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred for 3 h at room temperature. The mixture was purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 68 mg (81% of theory) of the target compound.
• Example 13A 940 mg (2.93 mmol) Example 13A were taken up in 50 ml benzene and treated with 731 mg (3.22 mmol) DDQ. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gave 390 mg (41% of theory) of the target compound and 190 mg (21% of theory) of Example 7 directly by partial saponification.
• Example 15A were taken up in 40 ml benzene and treated with 784 mg (3.46 mmol) DDQ. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and then by means of preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 690 mg (58% of theory) of the target compound.
• Example 4A A solution of 100 mg (about 0.304 mmol) of Example 4A, 19 mg (0.426 mmol) of ethanol and 111 mg (0.426 mmol) of triphenylphosphine in 1.8 ml of THF was stirred for 20 minutes at room temperature. There were added 86 mg (0.426 mmol) of diisopropyl azodicarboxylate and then the reaction mixture was stirred for 2.5 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). 45 mg (58% of theory) of the target compound were thus obtained
• Example 4A A solution of 100 mg (about 0.304 mmol) of Example 4A, 36 mg (0.426 mmol) of (1-methylcyclopropyl) methanol and 111 mg (0.426 mmol) of triphenylphosphine in 1.8 ml of THF was stirred for 20 minutes at room temperature. 86 mg (0.426 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred at room temperature for 2.5 h. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). 53 mg (48% of theory) of the target compound were thus obtained
• Example 4A 1.5 g (5.124 mmol) of Example 4A in 19.1 ml (204.971 mmol) of phosphorus oxychloride were stirred at reflux temperature for 2 h. The reaction mixture was evaporated. The residue was treated with a 25% aqueous ammonium hydroxide solution, adjusted to pH 7 with 1N hydrochloric acid and then extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. This gave 1.38 g (87% of theory) of the target compound.
• Example 25A A solution of 60 mg (0.187 mmol) of Example 25A, 12 mg (0.262 mmol) of ethanol and 69 mg (0.262 mmol) of triphenylphosphine in 1.2 ml of THF was stirred for 20 minutes at room temperature. 53 mg (0.262 mmol) of diisopropyl azodicarboxylate were added and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water: 90/10, isocratic). This gave 35 mg (53% Th.) Of the target compound.
• Example 245 mg (0.706 mmol) of example 36A were taken up in 40 ml of benzene and 176 mg (0.777 mmol) of DDQ were added. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and the residue was taken up in about 5 ml of acetonitrile. The precipitate was filtered off and the remaining solution was then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 70 mg (26% of theory) of the target compound.
• Example 23A 100 mg (0.321 mmol) of Example 23A were dissolved in 2.5 ml of DMF. Subsequently, 1.28 ml (0.643 mmol) of 1-butylzinc bromide solution (0.5M in THF) and 18 mg (0.016 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. The reaction mixture was stirred at room temperature overnight and allowed to stand at room temperature over the weekend. The reaction mixture was purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10, isocratic) without further work-up. 20 mg (19% of theory) of the target compound were obtained.
• preparative HPLC eluent: acetonitrile / water, gradient 90:10, isocratic
• Example 23 A 100 mg (0.321 mmol) of Example 23 A were dissolved in 2.5 ml of DMF. Subsequently, 1.28 ml (0.643 mmol) of 2-butylzinc bromide solution (0.5M in THF) and 18 mg (0.016 mmol) of tetrakis (triphenylphosphine) palladium (0) were added. The reaction mixture was stirred at room temperature overnight and allowed to stand at room temperature over the weekend. The reaction mixture was purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10, isocratic) without further work-up. 8 mg (8% of theory) of the target compound were obtained.
• preparative HPLC eluent: acetonitrile / water, gradient 90:10, isocratic
• Example 10A A solution of 100 mg (about 0.143 mmol) of Example 10A, 17 mg (0.201 mmol) of cyclopentanol and 53 mg (0.201 mmol) of triphenylphosphine in 1.4 ml of THF was stirred for 20 minutes at room temperature. 41 mg (0.201 mmol) of diisopropyl azodicarboxylate were added and the reaction mixture was stirred at room temperature overnight. The mixture was without further Workup purified by preparative HPLC (eluent: acetonitrile / water: 90:10, isocratic). 54 mg (85% th.) Of the target compound were thus obtained.
• Example 10A A solution of 100 mg (about 0.143 mmol) of Example 10A, 157 mg (0.201 mmol) of cyclopropylmethanol and 53 mg (0.201 mmol) of triphenylphosphine in 1.4 ml of THF was stirred for 20 minutes at room temperature. 53 mg (0.262 mmol) of diisopropyl azodicarboxylate were added and the reaction mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC without elution (eluent: acetonitrile / water: 90/10, isocratic). This gave 28 mg (52% of theory) of the target compound.
• Example 1OA A solution of 100 mg (about 0.143 mmol) of Example 1OA, 12 mg (0.201 mmol) of isopropanol and 53 mg (0.201 mmol) of triphenylphosphine in 1.4 ml of THF was stirred for 20 minutes at room temperature. 53 mg (0.262 mmol) of diisopropyl azodicarboxylate were added and the reaction mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC without elution (eluent: acetonitrile / water: 90/10, isocratic). This gave 44 mg (85% th.) Of the target compound.
• Example 45A A solution of 200 mg (about 0.341 mmol) of Example 45A, 28 mg (0.478 mmol) of isopropanol and 125 mg (0.478 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature. 96 mg (0.487 mmol) of diisopropyl azodicarboxylate were added and the reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90/10, isocratic). This gave 11 mg (9% of theory) of the target compound.
• Example 45A A solution of 200 mg (about 0.328 mmol) of Example 45A, 15 mg (0.459 mmol) of methanol and 120 mg (0.459 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature. 96 mg (0.487 mmol) of diisopropyl azodicarboxylate were added and the reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 5 mg (5% of theory) of the target compound.
• Example 50A were taken up in 20 ml benzene and treated with 227 mg (1.002 mmol) DDQ. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and the residue was taken up in about 2 ml of acetonitrile. The precipitate was filtered off and the remaining solution was then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 190 mg (70% of theory) of the target compound.
• Example 234 mg (0.561 mmol) of example 52A were taken up in 20 ml of benzene and 140 mg (0.617 mmol) of DDQ were added. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and the residue was taken up in about 2 ml of acetonitrile. The precipitate was filtered off and the remaining solution then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). 111 mg (66% of theory) of the target compound were thus obtained.
• Example (87 mg, 0.235 mmol) of Example 54A was taken up in 20 ml of benzene and 59 mg (0.259 mmol) of DDQ were added. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and the residue was taken up in about 2 ml of acetonitrile. The precipitate was filtered off and the remaining solution was then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 50 mg (64% of theory) of the target compound.
• Example 56A 149 mg (0.837 mmol) of N-bromosuccinimide, 20.3 mg (0.084 mmol) of dibenzoyl peroxide and 173 g (1.26 mmol) of potassium carbonate were taken up under an argon atmosphere in 10 ml of dioxane and stirred overnight at reflux temperature. After cooling, the mixture was concentrated, the residue taken up in water and then extracted with ethyl acetate (2x). The combined organic phases were dried with magnesium sulfate and the volatile components were separated on a rotary evaporator. The mixture was then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 184 mg (66% of theory) of the target compound.
• preparative HPLC eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10
• Example 57A 90 mg (0.271 mmol) of Example 57A, 22 ⁇ l (0.284 mmol) of 2-propanol and 74.5 mg (0.284 mmol) of triphenylphosphine were taken up in 5 ml of THF and stirred for 20 minutes at room temperature. Subsequently, 55 ⁇ l (0.459 mmol) of diisopropyl azodicarboxylate were added and the
• Reaction mixture reacted for 2 h at room temperature.
• the volatile components were removed by distillation under reduced pressure and the crude product was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 66 mg (65% of theory) of the target compound.
• Example 57A 90 mg (0.271 mmol) of Example 57A, 26 ⁇ l (0.284 mmol) of cyclopentanol and 74.5 mg (0.284 mmol) of triphenylphosphine were taken up in 5 ml of THF and stirred at room temperature for 20 minutes. Subsequently, 55 ⁇ l (0.459 mmol) of diisopropyl azodicarboxylate were added and the
• Reaction mixture reacted for 2 h at room temperature.
• the volatile components were removed by distillation under reduced pressure and the crude product was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gave 75 mg (69% of theory) of the target compound.
• Example 45A A mixture of 200 mg (about 0.328 mmol) of Example 45A, 34 mg (0.459 mmol) of n-propanol and 120 mg (0.459 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature touched. Then, 93 mg (0.459 mmol) of diisopropyl azodicarboxylate was added and the reaction mixture was further stirred for 2 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 19 mg (17% of theory) of the target compound.
• Example 45A A mixture of 200 mg (about 0.328 mmol) of Example 45A, 34 mg (0.459 mmol) of 2-methyl-1-propanol and 120 mg (0.459 mmol) of triphenylphosphine in 2 ml of THF was stirred for 20 minutes at room temperature. Then, 93 mg (0.459 mmol) of diisopropyl azodicarboxylate was added and the reaction mixture was further stirred for 2 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 15 mg (13% of theory) of the target compound.
• aqueous phase was extracted with dichloromethane and the organic phase was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated.
• the crude product was mixed with acetonitrile and the resulting crystals were filtered off and dried under high vacuum to constant weight. This gave 1.47 g (40% of theory) of the target compound in 88% purity (LC-MS), which was reacted without further purification steps.
• Example 63 A A solution of 80 mg (about 0.219 mmol) of Example 63 A, 14 mg (0.307 mmol) of ethanol and 80 mg (0.307 mmol) of triphenylphosphine in 1.5 ml of THF was stirred for 20 minutes at room temperature. 62 mg (0.307 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred for a further 2.5 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 40 mg (52% of theory) of the target compound.
• Example 63A A solution of 80 mg (about 0.219 mmol) of Example 63A, 18 mg (0.307 mmol) of 2-propanol and 80 mg (0.307 mmol) of triphenylphosphine in 1.5 ml of THF was stirred for 20 minutes at room temperature. 62 mg (0.307 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred for a further 2.5 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 47 mg (59% of theory) of the target compound.
• Example 63A A solution of 80 mg (about 0.219 mmol) of Example 63A, 22 mg (0.307 mmol) of 2-methylpropanol and 80 mg (0.307 mmol) of triphenylphosphine in 1.5 ml of THF was stirred for 20 minutes at room temperature. 62 mg (0.307 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred for a further 2.5 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 47 mg (57% of theory) of the target compound.
• Example 63 A A solution of 80 mg (about 0.219 mmol) of Example 63 A, 22 mg (0.307 mmol) of cyclopropylmethanol and 80 mg (0.307 mmol) of triphenylphosphine in 1.5 ml of THF was stirred for 20 minutes at room temperature. 62 mg (0.307 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was further stirred at room temperature for 2.5 hours. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 42 mg (51% of theory) of the target compound.
• Example 63 A A solution of 80 mg (about 0.219 mmol) of Example 63 A, 23 mg (0.307 mmol) of 2-methoxyethanol and 80 mg (0.307 mmol) of triphenylphosphine in 1.5 ml of THF was stirred for 20 minutes at room temperature. 62 mg (0.307 mmol) of diisopropyl azodicarboxylate were added and then the reaction mixture was stirred for a further 2.5 h at room temperature. The mixture was concentrated by rotary evaporation and purified by preparative HPLC without elution (eluent: acetonitrile / water 90:10, isocratic). This gave 44 mg (53% of theory) of the target compound.
• Example 2A 100 mg (0.300 mmol) Example 2A were taken up in 5 ml of ethanol and admixed with 1.50 ml (3.00 mmol) of a 2M aqueous potassium hydroxide solution. It was stirred at reflux temperature. After cooling, the reaction was concentrated, taken up in water and acidified with 1N hydrochloric acid. It was then extracted with ethyl acetate. After drying with magnesium sulfate, the solvent was removed by distillation under reduced pressure and the crude material purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gave 73 mg (76% of theory) of the target compound.
• preparative HPLC eluent: acetonitrile / water, gradient 10:90 -> 90:10
• Example 5 A To a solution of 41 mg (0.113 mmol) of Example 5 A in 2 ml of ethanol was added 1.13 ml (2.260 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. overnight. For workup, the ethanol was removed on a rotary evaporator and the reaction mixture was adjusted to pH 1 with 1 N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried under high vacuum. 44 mg (64% of theory) of the target compound were obtained.
• Example 6A To a solution of 40 mg (0.105 mmol) of Example 6A in 2 ml of ethanol was added 1.05 ml (2.111 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. overnight. For workup, the ethanol was removed on a rotary evaporator and the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried under high vacuum. 25 mg (67% of theory) of the target compound were obtained.
• Example 7A To a solution of 42 mg (0.125 mmol) of Example 7A in 2 ml of ethanol was added 1.25 ml (2.509 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. overnight. For workup, the ethanol was removed on a rotary evaporator and the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried under high vacuum. 20 mg (52% of theory) of the target compound were obtained.
• Example 8A To a solution of 14 mg (0.031 mmol) of Example 8A in 2 ml of ethanol was added 0.316 ml (0.632 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 4 h. For workup, the ethanol was removed on a rotary evaporator and the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried under high vacuum. 9 mg (69% of theory) of the target compound were obtained.
• Example I IA To a solution of 26 mg (0.077 mmol) of Example I IA in 2 ml of ethanol was added 0.78 ml (1.553 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. overnight. For workup, the ethanol was removed on a rotary evaporator and the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried under high vacuum. 20 mg (84% of theory) of the target compound were obtained.
• Example 12A To a solution of 68 mg (0.196 mmol) of Example 12A in 2 ml of ethanol was added 1.96 ml (3.921 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the ethanol was removed on a rotary evaporator and the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried under high vacuum. 53 mg (85% of theory) of the target compound were obtained.
• Example 16A 690 mg (1.99 mmol) Example 16A were taken up in 25 ml dioxane and treated with 558 mg (9.95 mmol) potassium hydroxide. The reaction was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was concentrated on a rotary evaporator. Then the residue was taken up in water, acidified with 1N hydrochloric acid and washed with
• Example 17A To a solution of 43 mg (0.134 mmol) of Example 17A in 2 ml of ethanol was added 1.34 ml (2.687 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. Thirty mg (74% of theory) of the target compound were obtained.
• Example 18A To a solution of 50 mg (0.049 mmol) of Example 18A in 2 ml of ethanol was added 1.49 ml (2.987 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and in
• Example 19A To a solution of 76 mg (0.218 mmol) of Example 19A in 3 ml of ethanol was added 2.18 ml (4.357 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and in
• Example 2OA To a solution of 51 mg (0.141 mmol) of Example 2OA in 2 ml of ethanol was added 1.40 ml (2,810 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 0 C for 3h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 40 mg (86% of theory) of the target compound were obtained.
• Example 21A To a solution of 36 mg (0.100 mmol) of Example 21A in 1.5 ml of ethanol was added 1.00 ml (2,006 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C for 3h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 17 mg (52% of theory) of the target compound were obtained.
• Example 22A To a solution of 50 mg (0.134 mmol) of Example 22A in 2 ml of ethanol was added 1.34 ml (2.673 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 22 mg (48% of theory) of the target compound were obtained.
• Example 26A To a solution of 33 mg (0.095 mmol) of Example 26A in 1.5 ml of ethanol was added 0.95 ml (1.903 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 8O 0 C for 3h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid posed. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 29 mg (93% of theory) of the target compound were obtained.
• Example 27A To a solution of 33 mg (0.095 mmol) of Example 27A in 2 ml of ethanol was added 1.23 ml (2.469 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 34 mg (81% of theory) of the target compound were obtained.
• Example 28A To a solution of 40 mg (0.106 mmol) of Example 28A in 2 mL of ethanol was added 1.06 mL (2.123 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 32 mg (86% of theory) of the target compound were obtained.
• Example 29A To a solution of 41 mg (0.105 mmol) of Example 29A in 2 ml of ethanol was added 1.05 ml (2.093 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and in Drying oven dried overnight at 40 0 C. 31 mg (82% of theory) of the target compound were obtained.
• Example 30A To a solution of 68 mg (0.175 mmol) of Example 30A in 3 ml of ethanol was added 1.75 ml (3.497 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C for 3h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and in
• Example 31A To a solution of 68 mg (0.175 mmol) of Example 31A in 2 ml of ethanol was added 1.15 ml (2.293 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 6 h. For workup, the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid and the volatile components were distilled off in vacuo. The resulting crystals were filtered off with suction and dried under high vacuum. 23 mg (97% of theory) of the target compound were obtained.
• example 35A 270 mg (0.78 mmol) of example 35A were taken up in 14 ml of pyridine and 521 mg (3.89 mmol) of lithium iodide were added. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gave 121 mg (47% of theory) of the target compound.
• Example (70 mg, 0.203 mmol) of Example 37A was taken up in 5 ml of pyridine, and 136 mg (1.02 mmol) of lithium iodide were added. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gave 42 mg (59% of theory) of the target compound.
• Example 38A To a solution of 60 mg (0.159 mmol) of Example 38A in 2.8 ml of ethanol was added 1.59 ml (3.189 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 6 h. For workup, the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid and the volatile components were distilled off in vacuo. The resulting crystals were filtered off, dried under high vacuum and then purified by preparative HPLC (eluent: acetonitrile / water, gradient 50:50). This gave 15 mg (28% of theory) of the target compound.
• preparative HPLC eluent: acetonitrile / water, gradient 50:50
• Example 39A To a solution of 20 mg (0.060 mmol) of Example 39A in 2 ml of ethanol was added 0.60 ml (1.202 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 10 h and allowed to stand at room temperature over the weekend. For workup, the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The volatile components were then distilled off in vacuo. The resulting crystals were filtered off with suction and dried under high vacuum. This gave 12 mg (64% of theory) of the target compound
• Example 4OA To a solution of 9 mg (0.026 mmol) of Example 4OA in 1 ml of ethanol was added 0.26 ml (0.523 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 8O 0 C 10h and over the weekend at room temperature, allowed to stand. For workup, the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The volatile components were then distilled off in vacuo. The resulting crystals were filtered off with suction and dried under high vacuum. This gave 5 mg (59% of theory) of the target compound.
• Example 41A To a solution of 50 mg (0.129 mmol) of Example 41A in 2.4 ml of ethanol was added 1.28 ml (2.571 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 6 h. For workup, the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The volatile components were then distilled off in vacuo. The resulting crystals were filtered off with suction and dried under high vacuum. This gave 29 mg (60% of theory) of the target compound.
• Example 42A To a solution of 25 mg (0.067 mmol) of Example 42A in 1.2 ml of ethanol was added 0.67 ml (1334 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 6 h. For workup, the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The volatile components were then distilled off in vacuo. The resulting crystals were filtered off with suction and dried under high vacuum. This gave 23 mg (94% of theory) of the target compound.
• Example 43A To a solution of 40 mg (0.110 mmol) of Example 43A in 2.2 ml of ethanol was added 1.1 ml (2,205 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 6 h. For workup, the reaction mixture was adjusted to pH 1 with 1N hydrochloric acid. The volatile components were then distilled off in vacuo. The resulting crystals were filtered off with suction and dried under high vacuum. This gave 15 mg (38% of theory) of the target compound.
• Example 46A To a solution of 10 mg (0.029 mmol) of Example 46A in 0.6 ml of ethanol was added 0.29 ml (0.582 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. This gave 7.3 mg (75% of theory) of the target compound.
• Example 47A To a solution of 4.4 mg (0.014 mmol) of Example 47A in 0.3 ml of ethanol was added 0.14 ml (0.276 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 3 mg (69% of theory) of the target compound were obtained.
• Example 48A To a solution of 10 mg (0.030 mmol) of Example 48A in 0.64 ml of ethanol was added 0.30 ml (0.595 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the volatile components were distilled off in vacuo. The residue was taken up in water and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and in
• Example (184 mg, 0.617 mmol) of Example 51A was taken up in 5 ml of pyridine and 413 mg (3.08 mmol) of lithium iodide were added. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90-> 90:10). After drying under high vacuum, 59 mg (34% of theory) of the target compound were obtained.
• Example 47 mg (0.140 mmol) Example 55A were taken up in 5 ml pyridine and treated with 93 mg (0.70 mmol) lithium iodide. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). After drying under high vacuum, 21 mg (47% of theory) of the target compound were obtained.
• example 58A 65 mg (0.173 mmol) of example 58A were taken up in 4 ml of pyridine and admixed with 116 mg (0.867 mmol) of lithium iodide. The reaction was stirred overnight at reflux temperature. After cooling, the batch was concentrated on a rotary evaporator and then purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). After drying under high vacuum, 46 mg (74% of theory) of the target compound were obtained.
• preparative HPLC eluent: acetonitrile / water, gradient 10:90 -> 90:10
• Example 6OA To a solution of 19.2 mg (0.055 mmol) of Example 6OA in 1.1 ml of ethanol was added 0.55 ml (1.107 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the reaction mixture was distilled off in vacuo and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 15 mg (80% of theory) of the target compound were obtained.
• Example 61A To a solution of 15.4 mg (0.043 mmol) of Example 61A in 0.86 ml of ethanol was added 0.42 ml (0.854 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the reaction mixture was distilled off in vacuo and adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried in a drying oven at 40 0 C overnight. 11.5 mg (77% of theory) of the target compound were obtained.
• Example 65A To a solution of 45 mg (0.125 mmol) of Example 65A in 2.3 ml of methanol was added 1.25 ml (2.491 mmol) of 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the methanol was removed on a rotary evaporator and the reaction mixture was adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried under high vacuum overnight. 38 mg (87% of theory) of the target compound were obtained.
• Example 66A To a solution of 43 mg (0.114 mmol) of Example 66A in 2 ml of methanol was added 1.14 ml (2.277 mmol) of 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the methanol was removed on a rotary evaporator and the reaction mixture was adjusted to pH 2 with 1N hydrochloric acid. The resulting crystals were filtered off, washed with water and dried under high vacuum overnight. 20 mg (98% of theory) of the target compound were obtained.
• Example 67A To a solution of 40 mg (0.106 mmol) of Example 67A in 2 mL of methanol was added 1.06 mL (2.123 mmol) of 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the methanol was removed on a rotary evaporator, the reaction mixture was adjusted to pH 2 with 1N hydrochloric acid and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated. This gave 29 mg (73% of theory) of the target compound.
• Example 68A To a solution of 42 mg (0.111 mmol) of Example 68A in 2 ml of methanol was added 1.11 ml (2.212 mmol) of 2M aqueous sodium hydroxide solution. The reaction mixture was stirred at 80 ° C. for 3 h. For workup, the methanol was removed on a rotary evaporator, the reaction mixture was adjusted to pH 2 with 1N hydrochloric acid and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated. This gave 34 mg (85% of theory) of the target compound.
• a cellular assay is used to identify activators of the peroxisome proliferator-activated receptor alpha (PPAR-alpha).
• the GAL4-PPAR ⁇ expression construct contains the ligand binding domain of PPARa (amino acids 167-468), which is PCR amplified and cloned into the vector pcDNA3.1. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene).
• the reporter construct containing five copies of the GAL4 binding site upstream of a thymidine kinase promoter, expresses the firefly luciferase (Photinus pyralis) upon activation and binding of GAL4-PPAR ⁇ .
• CHO (Chinese hamster ovary) cells stably expressing the above-described GAL4-PPAR ⁇ chimera and the luciferase reporter gene construct are in the medium (Optimem, GIBCO), 2% activated charcoal-purified fetal calf serum (Hyclone) the day before the test. , 1.35 mM sodium pyruvate (GIBCO), 0.2% sodium bicarbonate (GIBCO) with 1 x 10 3 cells plated in 96-well microtiter plates and maintained in a cell incubator (96% humidity, 5% v / v CO 2 , 37 ° C).
• the substances to be tested are taken up in the above-mentioned medium, but without the addition of calf serum, and added to the cells.
• the luciferase activity is measured using a video camera.
• the measured relative light units give as a function of the substance concentration a sigmoidal stimulation curve.
• the EC 50 values are calculated using the computer program GraphPad PRISM (version 3.02).
• B-3 Test description for the discovery of pharmacologically active substances which increase or inhibit the apoprotein Al (ApoAl) and HDL-cholesterol (HDL-C) in the serum of transgenic mice transfected with the human ApoAl gene (hApoAl) .

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