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WO2009080242A1 - Acides 4-aminopyrimidine-5-carboxyliques substitués, et leur utilisation - Google Patents

Acides 4-aminopyrimidine-5-carboxyliques substitués, et leur utilisation Download PDF

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Publication number
WO2009080242A1
WO2009080242A1 PCT/EP2008/010691 EP2008010691W WO2009080242A1 WO 2009080242 A1 WO2009080242 A1 WO 2009080242A1 EP 2008010691 W EP2008010691 W EP 2008010691W WO 2009080242 A1 WO2009080242 A1 WO 2009080242A1
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Prior art keywords
hydrogen
formula
mmol
methyl
fluorine
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German (de)
English (en)
Inventor
Lars BÄRFACKER
Barbara ALBRECHT-KÜPPER
Peter Kolkhof
Yolanda Cancho Grande
Klemens Lustig
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Bayer Pharma AG
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Bayer Schering Pharma AG
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    • 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
    • C07D239/42—One nitrogen atom
    • 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

Definitions

  • the present application relates to novel substituted 4-aminopyrimidine-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.
  • JP 2001-89452 describes substituted pyrimidines for the treatment of autoimmune diseases.
  • WO 03/045941 discloses pyrimidines for the treatment of immunological and inflammatory diseases.
  • WO 2004/111014 claims substituted pyrimidines for the treatment of cystic fibrosis.
  • 4-aminopyrimidines are described in WO 2005/003099 as ion channel modulators for the treatment of pain, arthritis, migraine, epilepsy and incontinence described.
  • WO 2005/040133 claims aminopyrimidines for the treatment of inflammatory disorders.
  • WO 2005/110416 discloses 4,5-disubstituted 2-arylpyrimidines as C5a receptor ligands for the treatment of inflammatory, immunological and cardiovascular diseases. Inter alia, substituted pyrimidines for the treatment of cancer are described in WO 2006/124874.
  • 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 hydrogen or (C r C 3 ) -alkyl
  • R 2 is (C r C6) alkyl, (C 3 -C 6) alkenyl or (C 3 -C 7) cycloalkyl,
  • (C 1 -C 4 ) -alkyl having 1 or 2 substituents independently of one another can be substituted from the group of fluorine, trifluoromethyl, hydroxyl, (C 1 -C 4 ) -alkoxy, trifluoromethoxy and (C 3 -C 7 ) -cycloalkyl,
  • (C 3 -C 7 ) -cycloalkyl in turn having 1 or 2 substituents independently selected from the group fluorine, hydroxy, oxo, (C r C 4 ) alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C r C 4 ) alkoxy and trifluoromethoxy can be substituted, and
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring, which in turn is independently selected from the group of fluorine, trifluoromethyl, (C 1 -C 4 ) -alkyl by 1 or 2 substituents , Hydroxy, (C 1 -C 4 ) -alkoxy and trifluoromethoxy may be substituted,
  • R 3 is (C r C 4) -alkyl or cyclopropyl
  • R 4 is hydrogen or fluorine
  • R 5 is hydrogen, fluorine, chlorine or methyl
  • R 6 is hydrogen, halogen, nitro, cyano, trifluoromethyl, methyl, ethyl, trifluoromethoxy or methoxy,
  • R 7 is hydrogen, fluorine, chlorine or methyl
  • R 4 , R 5 , R 6 and R 7 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 from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms 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 from 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • Solvates in the context of the invention 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 themselves are biologically active or inactive may, however, be converted into compounds of the invention during their residence time in the body (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.
  • straight-chain or branched (C 1 -C 6 ) -alkyl esters in which the alkyl group is hydroxyl, Amino, mono- (Ci-C 4 ) -alkylamino and / or di- (C iC 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.
  • Alkenyl in the context of the invention is a straight-chain or branched alkenyl radical having 3 to 6 carbon atoms and one or two double bonds. Preference is given to a straight-chain or branched alkenyl radical having 3 or 4 carbon atoms and one double bond. By way of example and by way of preference: allyl, isopropenyl and n-but-2-en-1-yl.
  • 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.
  • 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.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Within the scope of the present invention It holds true that for all radicals which occur several times, their meaning is independent of one another. 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 hydrogen, methyl or ethyl
  • R 2 is (C 1 -C 6 ) -alkyl, cyclopropyl, cyclopentyl or cyclohexyl,
  • (C 1 -C 6 ) -alkyl may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, cyclopropyl, cyclopentyl and cyclohexyl,
  • cyclopropyl, cyclopentyl and cyclohexyl may themselves be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl,
  • cyclopropyl, cyclopentyl and cyclohexyl can be substituted by a substituent selected from the group consisting of fluorine, methyl, ethyl and trifluoromethyl,
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring, which in turn may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, methyl and ethyl,
  • R 3 is (C 1 -O-alkyl or trifluoromethyl
  • R 4 is hydrogen
  • R 5 is hydrogen or fluorine
  • R 6 is hydrogen, fluorine, chlorine, trifluoromethyl or methyl
  • R 7 is hydrogen or methyl
  • R 2 is ethyl, iso-propyl, cyclopropyl or cyclopropylmethyl
  • R 3 is methyl, ethyl or iso-propyl
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen, chlorine or methyl
  • R 7 is hydrogen or methyl
  • R 6 and R 7 are different from hydrogen
  • R 1 is hydrogen or ethyl
  • R 2 is ethyl, iso-propyl, iso-butyl or cyclopropylmethyl
  • R 3 is iso-butyl
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen, chlorine or methyl
  • R 7 is hydrogen or methyl
  • R 6 and R 7 are different from hydrogen
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, which comprises reacting a compound of the formula (II)
  • R 8 is (C 1 -C 4 ) -alkyl
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 each have the meanings given above,
  • the compounds of the formula (IV) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.
  • the compounds of the formula (II) can be prepared by reacting compounds of the formula (VI)
  • the reaction (II) -> (ET) is carried out without a solvent or optionally in an inert solvent which is suitable under the reaction conditions, for example hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, 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 (II) -> (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 reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for process step (IE) + (IV) ⁇ (V) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide , Dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone ( ⁇ MP), pyridine, acetone, 2-butanone or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using dimethylformamide or tetrahydrofuran.
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol
  • Suitable bases for process step (HT) + (IV) -> • (V) are customary inorganic and organic bases. These include in particular alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal hydrides such as sodium or potassium hydride, organometallic bases such as n-butyl lithium or tert. organic amines such as diisopropylethylamine or triethylamine. Preferred is triethylamine.
  • the base is used here in an amount of 1 to 5 mol, preferably in an amount of 1.2 to 3 mol, based on 1 mol of the compound of formula (IV).
  • the reaction (IH) + (FV) -> (V) is generally carried out in a temperature range from 0 0 C to +150 0 C, preferably at +20 0 C to +120 0 C.
  • the reaction can be at normal, elevated or be carried out at reduced pressure (eg from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the hydrolysis of the carboxylic acid esters in process steps (V) -> (I) by conventional methods, optionally in a microwave, by treating the esters in inert solvents with acids or bases, wherein the salts initially formed in the latter by subsequent treatment with acid be converted into the free carboxylic acids. In the case of 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 metal or alkaline earth metal hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali metal 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, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic 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, preferably from 0 0 C to +50 0 C.
  • the reaction may be at atmospheric, elevated or reduced pressure is performed (for example from 0.5 to 5 bar) ,
  • 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 suitable for primary and / or secondary prevention and treatment of cardiovascular diseases caused by Disturbances in fatty acid and glucose metabolism are caused. Such disorders include dyslipidaemias (hypercholesterolemia, hypertriglyceridemia, elevated levels of 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 (obesity) and diabetic sequelae such as retinopathy, nephropathy and neuropathy).
  • dyslipidaemias hypercholesterolemia, hypertriglyceridemia, elevated levels of postprandial plasma triglycerides, hypoalphalipoproteinemia, combined hyperlipidemias
  • arteriosclerosis and metabolic disorders (
  • the compounds according to the invention are also particularly suitable for primary and / or secondary prevention and treatment of cardiac insufficiency.
  • 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, valvular heart failure, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis , Tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure, and systolic heart failure.
  • diseases such as right heart failure, left heart failure, global insufficiency, hypertension-induced heart failure, ischemic cardiomyopathy,
  • the compounds of the invention may also be used for the treatment and / or prevention of cancers such as skin cancer, breast cancer, brain tumors, head and neck cancer, liposarcoma, carcinoma of the eye, gastrointestinal tract, thyroid, liver, pancreas of the respiratory organs, the kidney, the ureter, the prostate, the genital tract and their distant metastases as well as lyphomas, sarcomas and leukemias.
  • cancers such as skin cancer, breast cancer, brain tumors, head and neck cancer, liposarcoma, carcinoma of the eye, gastrointestinal tract, thyroid, liver, pancreas of the respiratory organs, the kidney, the ureter, the prostate, the genital tract and their distant metastases as well as 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 as well as venous thromboses, edema, diseases of the central nervous system and neurodegenerative disorders (stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression, multiple sclerosis), inflammatory diseases, immune diseases (Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis, asthma), chronic obstructive pulmonary diseases (chronic bronchitis, COPD), kidney disease (glomerulonephritis), thyroid disease (hyperthyroidism), diseases of the pancreas (pancreatitis), liver fibrosis, skin diseases (psoriasis, acne, eczema, atopic dermatitis, dermatitis, Keratitis, scarring, wart formation, chilblains), sepsis, viral diseases (vas
  • the effectiveness 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 erf ⁇ ndungswashen compounds for the manufacture of a medicament for the treatment and / or prevention of Erkran- kungen, 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 inventive compounds.
  • 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.
  • AIs suitable combination active ingredients are exemplary and preferably mentioned: fat metabolism-altering agents, antidiabetics, blood pressure lowering agents, circulation-promoting and / 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.
  • 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 Absorption inhibitors, 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 and the antioxidants / free radical scavengers;
  • hypotensive agents by way of example and preferably from the group of calcium antagonists, angiotensin Aue 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; • diuretics;
  • 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 the compounds 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, Gef ⁇ tinib 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 Abso ⁇ tionhemmer, 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 Abso ⁇ tionhemmer, MTP inhibitors, lipase inhibitors, thyroid hormones and / or thyroid mimetics, niacin receptor Agonists, CETP inhibitors,
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin ,
  • statins such as 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.
  • the compounds according to the invention are administered in combination with an antioxidant / radical catalyst such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
  • an antioxidant / radical catalyst 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 AQ 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 Aü antagonist, such as by way of example and preferably losartan, valsartan, candesartan, embusartan or telmisartan.
  • angiotensin Aü 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 / IIIa 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, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the inventive compounds rapidly and / or modified donating application forms containing the compounds of the invention 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 gelatine 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
  • rapidly disintegrating tablets or films / wafers, films / lyophilisates capsules (for example hard or soft gelatine capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • 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 2 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; 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 -» 4.01 min 90% A; Flow: 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
  • Example 2A 1.5 g (5.124 mmol) of Example 2A in 19.1 ml (204.971 mmol) of phosphorus oxychloride are stirred for 2 hours at reflux temperature. The reaction mixture is evaporated. The residue is treated with a 25% aqueous ammonium hydroxide solution, adjusted to pH 7 with 1N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. This gives 1.38 g (87% of theory) of the target compound.
  • Example 5A To a solution of 250 mg (0.803 mmol) of Example 5A in 4 ml of tetrahydrofuran is added 203 mg (2.01 mmol) of triethylamine and 71 mg (1.205 mmol) of isopropylamine. The reaction mixture is stirred overnight at 80 0 C. The mixture is concentrated by rotary evaporation and used without further workup. This gives 250 mg (91% of theory) of the target compound
  • Example 4A 1.5 g (about 2151 mmol) of Example 4A in 8 ml (86.041 mmol) of phosphorus oxychloride are stirred for 2 h at reflux temperature. The reaction mixture is evaporated. The residue is treated with a 25% aqueous ammonium hydroxide solution, adjusted to pH 7 with 1N hydrochloric acid and then extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. The residue is column chromatographed on silica gel (mobile phase: cyclohexane / ethyl acetate 50/1 ⁇ 20/1). , This gives 540 mg (55% of theory) of crude product in 74% purity (LC-MS), which is reacted without further purification operation.
  • LC-MS LC-MS
  • Example 5 A To a solution of 100 mg (0.321 mmol) of Example 5 A in 2 ml of tetrahydrofuran is added 1.8 ml (13,498 mmol) of triethylamine and 35 mg (0.482 mmol) of diethylamine. The reaction mixture is stirred at 80 0 C overnight. The mixture is concentrated by rotary evaporation and used without further workup. This gives 100 mg (90% of theory) of the target compound
  • Example 8A To a solution of 60 mg (about 0.131 mmol) of Example 8A in 0.8 ml of THF are added 9 mg (0.196 mmol) of ethylamine and 0.8 ml (5.498 mmol) of triethylamine. The reaction mixture is stirred overnight at 80 0 C. The reaction mixture is concentrated by rotary evaporation and the residue is reacted without further work-up. This gives 55 mg (100% Th.) Of the target compound in 90% - purity (LC-MS).
  • Example 8A To a solution of 60 mg (about 0.131 mmol) of Example 8A in 0.8 ml of THF are added 11 mg (0.196 mmol) of cyclopropanamine and 556 mg (5.498 mmol) of triethylamine. The reaction mixture is stirred overnight at 80 0 C. The mixture is purified by preparative HPLC without elution (eluent: acetonitrile / water, gradient 10/90 ⁇ 90/10). This gives 40 mg (85% Th.) Of the target compound.
  • Example 8A To a solution of 60 mg (about 0.131 mmol) of Example 8A in 0.8 ml of THF are added 0.09 ml (0.196 mmol) of methanamine solution (2M in THF) and 556 mg (5.498 mmol) of triethylamine. The reaction mixture is stirred overnight at 80 0 C. The mixture is purified by preparative HPLC without further workup (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gives 60 mg (100% Th.) Of the target compound.
  • Example 13A 1.38 g (4.47 mmol) of Example 13A is dissolved in 40 ml of tetrachloromethane and under argon atmosphere with 0.835 g (4.69 mmol) of N-bromosuccinimide, 0.054 mg (0.223 mmol).
  • Residue is purified by preparative MPLC (Biotage 4OM cartridge;
  • Example 15A 39 ul (0:46 mmol) of isopropylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted overnight at 80 0 C. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gives 42 mg (39% of theory) of the target compound.
  • Example 15A 35 ul (0:46 mmol) of allylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted overnight at 80 0 C. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gives 70 mg (66% of theory) of the target compound.
  • Example 15A 48 ul (0:46 mmol) of diethylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted overnight at 80 0 C. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gives 90 mg (81% of theory) of the target compound.
  • Example 15A 53 ul (0:46 mmol) of cyclohexylamine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted overnight at 80 0 C. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gives 43 mg (36% of theory) of the target compound.
  • Example 15 A 100 mg (0.31 mmol) of Example 15 A, 46 .mu.l (0.46 mmol) of piperidine and 107 .mu.l (0.77 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran and then reacted at 80 0 C overnight. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gives 123 mg (98% of theory) of the target compound.
  • preparative HPLC eluent: acetonitrile / water, gradient 10:90 -> 90:10
  • Example 21A 1.32 g (4.58 mmol) of Example 21A are dissolved in 40 ml of tetrachloromethane and treated under argon with 0.856 g (4.81 mmol) of N-bromosuccinimide, 0.055 mg (0.229 mmol) of dibenzoyl peroxide and 6.32 g (45.78 mmol) of potassium carbonate. The mixture is then stirred at reflux temperature for 30 minutes. After cooling, the batch is mixed with 100 ml of water and extracted with dichloromethane (3x). The combined organic phases are dried with magnesium sulfate. Then, the volatile components are separated by distillation under reduced pressure.
  • Example 22A 450 mg (1.60 mmol) of Example 22A and 5.96 ml of phosphoxyl chloride are added for 2 h
  • Example 23A 100 mg (0.328 mmol) of Example 23A, 51 ul (0.492 mmol) of diethylamine and 114 .mu.l (0.820 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted at 80 0 C for 3 h. Then the volatile components are separated on a rotary evaporator. The residue will be purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 -> 90:10). This gives 78 mg (66% of theory) of the target compound.
  • preparative HPLC eluent: acetonitrile / water, gradient 10:90 -> 90:10
  • Example 23A 100 mg (0.328 mmol) of Example 23A, 42 ul (0.492 mmol) of diethylamine and 114 .mu.l (0.820 mmol) of triethylamine are dissolved in 3 ml of tetrahydrofuran, and then reacted at 80 0 C for 2 h. Then the volatile components are separated on a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). This gives 68 mg (62% of theory) of the target compound.
  • preparative HPLC eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10
  • Example 26A A mixture of 5.02 g (-10.27 mmol) of Example 26A, 1.83 g (10.27 mmol) of N-bromosuccinimide, 497 mg (2.05 mmol) of dibenzoyl peroxide and 2.13 g (15.40 mmol) of ground potassium carbonate in 120 ml of dioxane is refluxed under argon atmosphere for 3 hours touched. After cooling, the mixture is treated with a saturated aqueous sodium thiosulfate solution and then concentrated. The aqueous phase is extracted with dichloromethane and the organic phase is washed first with water and then with a saturated aqueous sodium chloride solution. It is dried with sodium sulfate and concentrated.
  • Example 28 A To a solution of 60 mg (0.177 mmol) of Example 28 A in 1.2 ml of THF are added 12 mg (0.265 mmol) of ethylamine and 45 mg (0.442 mmol) of triethylamine. The mixture is stirred at 80 0 C overnight. The reaction mixture is concentrated by rotary evaporation and used further without further work-up. This gives 32 mg (53% of theory) of the target compound.
  • Example 28 A To a solution of 60 mg (0.177 mmol) of Example 28 A in 1.2 ml of THF are added 16 mg (0.265 mmol) of isopropylamine and 45 mg (0.442 mmol) of triethylamine. The mixture is stirred at 80 ° C. for 30 h. Then the volatile components are separated on a rotary evaporator. The residue is taken up in ethyl acetate and washed several times with water. The organic phase is dried over magnesium sulfate, the solvent is evaporated in vacuo and the crude product is purified by chromatography on silica gel (mobile phase: dichloromethane). This gives 35 mg (49% of theory) of the target compound.
  • Example 6A To a solution of 250 mg (0.749 mmol) of Example 6A in 15.6 ml of ethanol is added 7.5 ml (14.978 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture is stirred at 80 ° C. for 6 hours. For workup, the reaction mixture is adjusted to pH 1 with 1N hydrochloric acid and the volatile components are distilled off in vacuo. The resulting crystals are filtered off and dried under high vacuum. This gives 195 mg (74% of theory) of the target compound.
  • Example 7A To a solution of 100 mg (0.289 mmol) of Example 7A in 6 ml of ethanol is added 2.9 ml (5.783 mmol) of a 2M aqueous sodium hydroxide solution. The reaction mixture is stirred at 80 ° C. for 6 hours. For workup, the reaction mixture with 1N hydrochloric acid to pH. 1 placed and distilled off the volatile components in vacuo. The resulting crystals are filtered off and dried under high vacuum. This gives 83 mg (79% of theory) of the target compound.
  • Example 9A 100 mg (0.287 mmol) of Example 9A are taken up in 6 ml of ethanol and admixed with 2.8 ml (5.75 mmol) of a 2M aqueous sodium hydroxide solution. Min is then reacted at 140 0 C in a single Mojé microwave (Emrys Optimizer) 40th The mixture is concentrated to pH 1 with 1N hydrochloric acid and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10). This gives 15 mg (28% of theory) of the target compound.
  • Example 1OA 55 mg (about 0.142 mmol) of Example 1OA are taken up in 2 ml of ethanol and treated with 1.4 ml (2,846 mmol) of a 2M aqueous sodium hydroxide solution. It is then reacted at 140 ° C. for 20 minutes and then at 150 ° C. for 20 minutes in a single-mode microwave (Emrys Optimizer). The mixture is concentrated and the aqueous residue is taken up and adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off and dried under high vacuum. This gives 15 mg (27% of theory) of the target compound.
  • Emrys Optimizer single-mode microwave
  • Example I IA 80 mg (0.222 mmol) of Example I IA are taken up in 3 ml of ethanol and admixed with 2.2 ml (4.446 mmol) of a 2M aqueous sodium hydroxide solution. Min is then reacted at 140 0 C in a single ⁇ forfe microwave (Emrys Optimizer) 20th The mixture is concentrated and the aqueous residue is taken up and adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off and dried under high vacuum. This gives 82 mg (91% of theory) of the target compound.
  • Example 12A 60 mg (0.180 mmol) of Example 12A are taken up in 2 ml of ethanol and admixed with 1.8 ml (3.595 mmol) of a 2M aqueous sodium hydroxide solution. Min is then reacted at 140 0 C in a single Mwfe microwave (Emrys Optimizer) 20th The mixture is concentrated and the aqueous residue is taken up and adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off and dried under high vacuum. This gives 60 mg (97% of theory) of the target compound.
  • Example 16A 42 mg (0.121 mmol) of Example 16A are taken up in 5 ml of ethanol and admixed with 193 mg (4.83 mmol) of sodium hydroxide. After addition of a few drops of water is reacted for 2 hours at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigklareethyester (3x). Then the combined organic phases are dried with magnesium sulfate. The solvent is removed on a rotary evaporator and the residue is purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10). This gives 8 mg (21% of theory) of the target compound.
  • preparative HPLC eluent: acetonitrile / water, gradient 90:10
  • Example 17A 70 mg (0.202 mmol) of Example 17A are taken up in 5 ml of ethanol and admixed with 323 mg (8.10 mmol) of sodium hydroxide. After addition of a few drops of water is reacted for 2 hours at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigklareethyester (3x). Then the combined organic phases are dried with magnesium sulfate. The solvent is separated on a rotary evaporator. This gives 55 mg (86% of theory) of the target compound.
  • Example 18A 90 mg (0.249 mmol) of Example 18A are taken up in 5 ml of ethanol and admixed with 398 mg (9.95 mmol) of sodium hydroxide. After addition of a few drops of water is reacted overnight at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigklareethyester (3x). The combined organic phases are dried with magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is finally purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10). This gives 54 mg (65% of theory) of the target compound.
  • preparative HPLC eluent: acetonitrile / water, gradient 90:10
  • Example 19A 43 mg (0.111 mmol) of Example 19A are taken up in 5 ml of ethanol and admixed with 177 mg (4.43 mmol) of sodium hydroxide. After addition of a few drops of water is reacted overnight at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigklareethyester (3x): Then the combined organic phases are dried with magnesium sulfate and the solvent is removed on a rotary evaporator. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 90:10). This gives 7 mg (18% of theory) of the target compound.
  • preparative HPLC eluent: acetonitrile / water, gradient 90:10
  • Example 2OA 126 mg (0.337 mmol) of Example 2OA are taken up in 5 ml of ethanol and treated with 539 mg (13.48 mmol) of sodium hydroxide. After addition of a few drops of water is reacted overnight at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. It is then extracted with Essigklareethyester (3x) and the combined organic phases are dried with magnesium sulfate. Then the solvent is separated on a rotary evaporator. This gives 104 mg (87% of theory) of the target compound.
  • Example 24A 78 mg (0.228 mmol) of Example 24A are taken up in 3 ml of ethanol and admixed with 365 mg (9.14 mmol) of sodium hydroxide. It is then reacted overnight at reflux temperature. Since the conversion remains incomplete, 15 min at 140 0 C in a single-mode microwave (Emrys Optimizer) tempered. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. Then it is extracted with Essigklareethyester (3x). Then the combined organic phases are dried with magnesium sulfate. The solvent is separated on a rotary evaporator. Finally, it is dried in a high vacuum. This gives 60 mg (80% of theory) of the target compound.
  • Emrys Optimizer Emrys Optimizer
  • Example 25A 68 mg (0.208 mmol) of Example 25A are taken up in 3 ml of ethanol and admixed with 332 mg (8.31 mmol) of sodium hydroxide. After addition of a few drops of water is reacted overnight at reflux temperature. The mixture is concentrated, taken up with water and adjusted to pH 1 with 1N hydrochloric acid. It is then extracted with ethyl acetate (3x), The combined organic phases are dried with magnesium sulfate. Then the solvent is separated on a rotary evaporator. This gives 54 mg (87% of theory) of the target compound.
  • Example 30A 41 mg (0.109 mmol) of Example 30A are taken up in 1.2 ml of dioxane and admixed with 2.2 ml (4.64 mmol) of a 2M aqueous sodium hydroxide solution. The mixture is then reacted for 40 min at 150 0 C in a single ⁇ / brfe microwave (Emrys Optimizer). The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off, re-absorbed with water and extracted with Essigklareethyester (3x). The organic phase is concentrated. This gives 16 mg (36% of theory) of the target compound.
  • Example 31A 41 mg (0.106 mmol) of Example 31A are taken up in 1.2 ml of dioxane and admixed with 2.1 ml (4.23 mmol) of a 2M aqueous sodium hydroxide solution. It is then 40 min at 150 0 C in a single ⁇ / oJe microwave (Emrys Optimizer) implemented. The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off, re-absorbed with water and extracted with Essigklareethyester (3x). The organic phase is concentrated. This gives 21 mg (47% of theory) of the target compound.
  • Emrys Optimizer Emrys Optimizer
  • Example 32A 31 mg (0.089 mmol) of Example 32A are taken up in 1.0 ml of dioxane and admixed with 1.8 ml (3.565 mmol) of a 2M aqueous sodium hydroxide solution. Min is then reacted at 150 0 C in a single Aforfe microwave (Emrys Optimizer) 40th The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid posed. The resulting crystals are filtered off, re-absorbed with water and extracted with Essigklareethyester (3x). The organic phase is concentrated. This gives 15 mg (45% of theory) of the target compound.
  • Example 33A 30 mg (0.080 mmol) of Example 33A are taken up in 0.9 ml of dioxane and admixed with 1.6 ml (3.210 mmol) of a 2M aqueous sodium hydroxide solution. It is then 40 min at 150 0 C in a single-Mwfe microwave (Emrys Optimizer) implemented. The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off, re-absorbed with water and extracted with Essigklareethyester (3x). The organic phase is concentrated. This gives 16 mg (50% of theory) of the target compound.
  • Emrys Optimizer single-Mwfe microwave
  • Example 34A 33 mg (0.091 mmol) of Example 34A are taken up in 1.0 ml of dioxane and admixed with 1.8 ml (3.648 mmol) of a 2M aqueous sodium hydroxide solution. Min is then reacted at 150 0 C in a single Mocfe microwave (Emrys Optimizer) 40th The mixture is concentrated and the residue taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off with suction. This gives 24 mg (68% of theory) of the target compound.
  • Mocfe microwave Emrys Optimizer
  • Example 29A 36 mg (0.091 mmol) of Example 29A are taken up in 1.0 ml of dioxane and admixed with 1.9 ml (3.83 mmol) of a 2M aqueous sodium hydroxide solution. This is followed by 40 min 150 0 C and 40 min at 170 0 C in a single Afocfe microwave (Emrys Optimizer) implemented. The mixture is concentrated and residue is taken up in water. Then it is adjusted to pH 1 with 1N hydrochloric acid. The resulting crystals are filtered off with suction and purified by HPLC (Sunfire C 1, eluent acetonitrile / 0.2% aqueous TFA). This gives 0.6 mg (2% of theory) of the target compound.
  • HPLC Hydrochloric acid
  • 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 GAL4-PPAR ⁇ chimera and the luciferase reporter gene construct described above 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 microtitre 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 the apoprotein Al (ApoAl) and HDL-cholesterol (HDL-C) in the serum of transgenic mice transfected with the human ApoAl gene (hApoAl) .
  • the substances to be tested for their HDL-C increasing activity in vivo are orally administered to male transgenic hApoAl mice.
  • the substances are administered orally once a day for 7 days.
  • the test substances are dissolved in a solution of Solutol HS 15 + ethanol + saline (0.9%). in the ratio 1 + 1 + 8 or dissolved in a solution of Solutol HS 15 + saline (0.9%) in the ratio 2 + 8.
  • the application of the dissolved substances takes place in a volume of 10 ml / kg body weight with a gavage. Animals which are treated in the same way, but only the solvent (10 ml / kg body weight) without test substance, serve as a control group.
  • each mouse Before the first substance administration, each mouse is sampled for the determination of ApoAl, serum cholesterol, HDL-C and serum triglycerides (TG) by puncture of the retroorbital venous plexus (initial value). Subsequently, the animals are given the test substance for the first time with a gavage. 24 hours after the last substance application (on the 8th day after the start of treatment), each animal is again drawn by puncture of the retroorbital venous plexus to determine the same parameters.
  • the blood samples are centrifuged and, after recovery of the serum, TG, cholesterol, HDL-C and human ApoAl are incubated with a Cobas Integra 400 plus instrument (Cobas Integra, Roche Diagnostics GmbH, Mannheim) using the respective cassettes (TRIGL, CHOL2, HDL-C and APOAT).
  • HDL-C is purified by gel filtration and post-column derivatization with MEGA cholesterol reagent (Merck KGaA) analogously to the method of Garber et al. [J. Lipid Res. 4L, 1020-1026 (2000)].
  • the effect of the test substances on the HDL-C, hApoAl or TG concentrations is determined by subtracting the measured value of the first blood sample (pre-value) from the measured value of the second blood sample (after treatment).
  • the differences of all HDL-C, hApoAl and TG values of a group are averaged and compared with the mean of the differences of the control group.
  • the statistical evaluation is done with Student's t-test after checking the variances for homogeneity.
  • Substances which increase the HDL-C of the treated animals statistically significantly (p ⁇ 0.05) by at least 20% or decrease the TG statistically significantly (p ⁇ 0.05) by at least 25% compared to those of the control group are considered to be pharmacologically active .
  • DHA desoxycorticosterone acetate
  • Uninephrectomized SD rats receive 1% sodium chloride in drinking water and once weekly a subcutaneous injection of desoxycorticosterone acetate (dissolved in sesame oil, Sigma) injected between the shoulder blades (high dose: 100 mg / kg / week sc, normal dose: 30 mg / kg / week sc).
  • the substances that are to be tested for their protective effect in vivo are administered by gavage or via the feed (Ssniff) or drinking water.
  • the substances are administered once a day for 4-6 weeks by gavage, food or drinking water.
  • the placebo group used is animals that are treated in the same way, but which either only receive the solvent or the feed or drinking water without the test substance.
  • the effect of the test substances is determined by measuring hemodynamic parameters [blood pressure, heart rate, inotropy (dp / dt), relaxation time (tau), maximum left ventricular pressure, left ventricular end-diastolic pressure (LVEDP)], weight determination of heart, kidney and lung Protein excretion and by measuring the gene expression of biomarkers (eg ANP, Atrial Natriuretic Peptide, and BNP, Brain Natriuretic Peptide) by RT / TaqMan PCR after RNA isolation from cardiac tissue determined.
  • biomarkers eg ANP, Atrial Natriuretic Peptide, and BNP, Brain Natriuretic Peptide
  • the statistical evaluation is done with Student's t-test after checking the variances for homogeneity.
  • test compounds are incubated in vitro with liver microsomes or preferably with primary fresh hepatocytes of various animal species (eg from rat and dog) as well as of human origin to obtain metabolite profiles of a complete hepatic phase I and phase II metabolism and compare.
  • the test compounds are incubated at a concentration of 10-20 ⁇ M.
  • stock solutions of the substances are prepared in a concentration of 1-2 mM in acetonitrile and then pipetted with a 1: 100 dilution in the incubation mixture.
  • Liver microsomes are incubated in 50 mM potassium phosphate buffer (pH 7.4) with and without NADPH-generating system consisting of 1 mM NADP + , 10 mM glucose-6-phosphate and 1 unit of glucose-6-phosphate dehydrogenase at 37 ° C incubated.
  • Primary hepatocytes are also incubated in suspension in Williams E medium at 37 ° C. After an incubation period of 0-4 hours, the incubation approaches are stopped with acetonitrile (final concentration about 30%) and the protein is centrifuged off at about 15,000 ⁇ g. The thus-stopped samples are analyzed either directly or stored at -20 0 C until analysis.
  • the analysis is carried out by high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS). For this, the supernatants of the incubation samples are chromatographed with suitable C18 reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution. The UV chromatograms in combination with mass spectrometric MS / MS data are used to identify and structure the metabolites.
  • HPLC-UV-MS / MS ultraviolet and mass spectrometric detection
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • a single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • the compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

L'invention concerne : de nouveaux dérivés substitués d'acide 4-aminopyrimidine-5-carboxylique ; des procédés pour leur fabrication ; leur utilisation pour le traitement et/ou la prophylaxie de maladies et leur utilisation pour la fabrication de médicaments pour le traitement et/ou la prophylaxie de maladies, de préférence pour le traitement et/ou la prophylaxie de maladies cardiovasculaires, en particulier de dyslipidémies, d'artériosclérose et d'insuffisance cardiaque.
PCT/EP2008/010691 2007-12-20 2008-12-16 Acides 4-aminopyrimidine-5-carboxyliques substitués, et leur utilisation Ceased WO2009080242A1 (fr)

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WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN116496252A (zh) * 2022-04-29 2023-07-28 江苏亚虹医药科技股份有限公司 嘧啶类化合物、其制备方法及其医药用途

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US20100298143A1 (en) * 2009-05-19 2010-11-25 Dow Agrosciences Llc Compounds and methods for controlling fungi
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WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN116496252A (zh) * 2022-04-29 2023-07-28 江苏亚虹医药科技股份有限公司 嘧啶类化合物、其制备方法及其医药用途
CN116496252B (zh) * 2022-04-29 2025-07-22 江苏亚虹医药科技股份有限公司 嘧啶类化合物、其制备方法及其医药用途

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