Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to the use of Al and / or dual Al / A2b agonists of formulas (IA) and (IB) for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes and dyslipidemia, metabolic syndromes and diabetes associated with Hypertension and diseases of the cardiovascular system.
• Adenosine a purine nucleoside
• Adenosine is present in all cells and is released from a variety of physiological and pathophysiological stimuli.
• Adenosine is produced intracellularly in the degradation of adenosine 5'-monophosphate (AMP) and S-adenosyl homocysteine as an intermediate, but can be released from the cell and then functions as a hormone-like substance or neurotransmitter by binding to specific receptors.
• AMP adenosine 5'-monophosphate
• S-adenosyl homocysteine as an intermediate, but can be released from the cell and then functions as a hormone-like substance or neurotransmitter by binding to specific receptors.
• adenosine Under normoxic conditions, the concentration of free adenosine in the extracellular space is very low. However, the extracellular concentration of adenosine in the affected organs increases dramatically under both ischemic and hypoxic conditions. For example, it is known that adenosine inhibits platelet aggregation and increases blood flow to the coronary arteries. It also affects blood pressure, heart rate, neurotransmitter release and lymphocyte differentiation.
• adenosine In adipocytes, adenosine is able to inhibit lipolysis by activating specific adenosine receptors, thus reducing the concentration of free fatty acids and triglycerides in the blood. So far, it is known that the effect of adenosine is mediated via four specific receptors. So far, the subtypes Al, A2a, A2b and A3 are known. The effects of these adenosine receptors are mediated intracellularly by the messenger cAMP.
• adenosine receptors In the cardiovascular system, the main effects of the activation of adenosine receptors are: bradycardia, negative inotropy and protection of the heart from ischemia (preconditioning) via Al receptors, dilation of the vessels via A2a and A2b receptors as well as inhibition of fibroblasts and smooth muscle cell proliferation and migration via A2b receptors.
• A2b receptors by adenosine or specific A2b agonists leads to a blood pressure reduction via the dilation of vessels. Lowering blood pressure is often accompanied by a reflex heart rate increase.
• a tachycardia or a reflex heart rate increase can be treated or reduced by the activation of Al receptors by means of specific Al agonists.
• adipocytes activation of Al as well as A2b receptors causes inhibition of lipolysis.
• the singular as well as the combined effect of Al or Al / A2b agonists on the lipid metabolism thus leads to a lowering of free fatty acids and / or triglycerides.
• a reduction of the lipids or the free fatty acids in turn leads, e.g. in patients with metabolic syndrome and in diabetics to reduce insulin resistance and to improve the symptoms.
• adenosine receptor-specific valid ligands are mainly derivatives based on the natural adenosine [S.-A. Poulsen and RJ Quinn, "Adenosine receptors: new opportunities for future drugs” in Bioorganic and Medicinal Chemistry 6 (1998), pages 619-641].
• these adenosine ligands known from the prior art usually have the disadvantage that they are not really receptor-specific act, are less effective than the natural adenosine or after oral administration are only very weakly effective. Therefore, they are mainly used only for experimental purposes.
• WO 02/06237 discloses aryl substituted dicyanopyridines as calcium dependent potassium channel openers and their use in the treatment of diseases of the genitourinary tract. Furthermore, WO 01/25210 and WO 02/070485 describe substituted 2-thio-3,5-dicyano-4-aryl-6-amino-pyridines as adenosine receptor ligands for the treatment of diseases. WO 03/053441 discloses specifically substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines as selective ligands of the adenosine A1 receptor for the treatment of, in particular, cardiovascular diseases. WO 02/50071 describes aminothiazole derivatives as tyrosine kinase inhibitors for the treatment of various diseases.
• Another object of the invention is to provide compounds which act as selective agonists of the adenosine A1 or selective dual agonist of the Al / A2b receptor and, as such, for the treatment and / or prevention of dyslipidemia, metabolic syndromes and diabetes associated with Hypertension and diseases of the cardiovascular system are suitable.
• Another object of the invention is to provide compounds which act in combination as selective agonists of the adenosine A1 and selective dual agonists of the Al / A2b receptor and as such for the treatment and / or prevention of dyslipidemia, metabolic syndromes and diabetes and Dyslipidaemia, metabolic syndrome and diabetes are associated with hypertension and cardiovascular disease.
• the present invention relates to the use of compounds of the formula (IA)
• R 1 is hydrogen or (C 1 -C 6 ) -alkyl which is hydroxyl, amino, mono- or di- (C 1 -C 4 ) -alkylamino, pyrrolidino, piperidino, monochloro, piperazino or N'-methylpiperazino may be substituted
• R 2 is (C 2 -C 6 ) -alkyl which is monosubstituted or disubstituted, identical or different, with substituents selected from the group consisting of hydroxy, (C 1 -C 4 -alkoxy, amino, mono- and di (C 1 -C 6 ) -alkyl -C t ) - alkylamino is substituted,
• R 3 represents a substituent selected from the group consisting of halogen, cyano, nitro, (Ci-C 6) - alkyl, hydroxy, (Ci-C 6) alkoxy, amino, mono- and di- (Ci-C 6) - alkylamino, carboxyl and
• alkyl and alkoxy may each themselves be substituted by up to five times with fluorine
• n is the number 0, 1, 2, 3, 4 or 5
• Compounds according to the invention are the compounds of the formulas (IA) and (IB) and their salts, solvates and solvates of the salts, the compounds of formulas (IA) and (IB) of the formulas mentioned below or in WO 03/053441 and salts thereof , Solvates and solvates of the salts as well as the compounds of formulas (IA) and (IB) mentioned hereinafter or in WO 03/053441 as exemplary embodiments and their salts, solvates and solvates of the salts, as far as those of formers (IA ) and (IB), compounds mentioned below or in WO 03/053441 are not already salts, solvates and solvates of the salts.
• the compounds of the formulas (IA) and (IB) according to 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 which are preferred 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 which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
• a straight-chain or branched alkyl radical having from 1 to 6, 2 to 6, 1 to 4 or 2 to 4 carbon atoms is preferred, a straight-chain or branched alkyl radical having 1 to 4 or 2 to 4 carbon atoms being given by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.
• (C 1 -CgVAIkOXV and (C 1 -C) -alkoxy are in the context of the invention a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms.
• Preferred is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms.
• Exemplary and preferably are: methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.
• (C 1 -C 6) -AlkoxyVCaTbOnVl and (C 1 -C 4 -alkoxycarbonyl in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group.
• carbonyl radical having 1 to 4 carbon atoms in the alkoxy group by way of example and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
• Di-RQ-CfiValkylamino and di-fC ⁇ -C ⁇ alkylamino stand for the purposes of the invention for an amino group having two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 or 1 to 4 carbon atoms.
• Straight-chain or branched dialkylamino radicals having in each case 1 to 4 carbon atoms are preferred.
• N N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.
• 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. 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. Most preferably, the substitution with one or two identical or different substituents.
• R 1 is hydrogen or (C 1 -C 4 ) -alkyl which may be substituted by hydroxyl, amino or dimethylamino,
• R 2 is (C 2 -C 4 ) -alkyl which is monosubstituted or disubstituted by identical or different substituents selected from the group consisting of hydroxy, methoxy and amino,
• R 3 represents a substituent selected from the group consisting of halogen, cyano, nitro, (Ci-C4) - alkyl, hydroxy, (Ci-C 4) alkoxy, amino, mono- and di- (Ci-C4) - alkylamino, carboxyl and (C r C 4 ) alkoxycarbonyl,
• alkyl and alkoxy may each themselves be substituted up to three times by fluorine
• n is the number 0, 1 or 2, wherein, in the event that the substituent R 3 occurs twice, its meanings may be the same or different,
• R 1 is hydrogen
• R 2 is ethyl, n-propyl or isopropyl, each of which is monosubstituted or disubstituted by identical or different substituents selected from the group of hydroxy, methoxy and amino,
• R 3 is a substituent selected from the group of fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, mono- and dimethylamino, carboxyl, methoxycarbonyl and ethoxycarbonyl,
• n is the number 0, 1 or 2
• the compounds of formula (IA) can be prepared by the following method.
• R 1 and R 2 each have the meanings given above,
• X is a suitable leaving group, preferably halogen, in particular chlorine, bromine or iodine, or mesylate, tosylate or triflate,
• Suitable solvents for the process according to the invention are all organic solvents which are inert under the reaction conditions. These include alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether, tetrahydrofuran and dioxane, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane or cyclohexane, chlorinated hydrocarbons such Dichloromethane or chlorobenzene, or other solvents such as dimethylformamide, acetonitrile, pyridine or dimethyl sulfoxide. Water is also suitable as a solvent. It is likewise possible to use mixtures of the abovementioned solvents. Preferred as a solvent is dimethylformamide.
• Suitable bases are the customary inorganic or organic bases. These include preferably alkali metal hydroxides such as, for example, sodium or potassium hydroxide, alkali metal carbonates such as sodium, potassium or cesium carbonate, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene ( DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to alkali metal carbonates and bicarbonates.
• alkali metal hydroxides such as, for example
• the base may in this case be used in an amount of 1 to 10 mol, preferably from 1 to 5 mol, in particular from 1 to 4 mol, based on 1 mol of the compound of the formula (II).
• the reaction is generally carried out in a temperature range from -78 ° C to + 140 ° C, preferably in the range from -20 0 C to +60 0 C, especially at 0 0 C to +40 0 C.
• the reaction may be at atmospheric, increased or decreased pressure (eg in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• R 2 has the meaning given above
• the alkali metal sulfide used is preferably sodium sulfide in an amount of from 1 to 10 mol, preferably from 1 to 5 mol, in particular from 1 to 4 mol, based on 1 mol of the compound of the formula (TV).
• Suitable solvents are all organic solvents which are inert under the reaction conditions. These preferably include N, N-dimethylformamide, N-methylpyrrolidinone, pyridine and acetonitrile. It is likewise possible to use mixtures of the abovementioned solvents. Particularly preferred is N, N-dimethylformamide.
• the reaction is generally carried out in a temperature range from + 2O 0 C to + 140 0 C, preferably in the range of + 2O 0 C to +120 0 C, in particular at +60 0 C to +100 0 C.
• the reaction can be carried out under normal , increased or decreased pressure (eg in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• R 2 has the meaning given above
• R 1A has the abovementioned meaning of R 1 but does not stand for hydrogen
• R IA and R 2 each have the meanings given above,
• the process step (TV) -> (V) is generally carried out with a molar ratio of 2 to 12 moles of copper ( ⁇ ) chloride and 2 to 12 moles of isoamyl nitrite based on 1 mol of the compound of formula (TV).
• Suitable solvents for this process step are all organic solvents which are inert under the reaction conditions. These include acyclic and cyclic ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane or cyclohexane, chlorinated hydrocarbons such as dichloromethane, dichloroethane or chlorobenzene, or other solvents such as Dimethylformamide, acetonitrile or pyridine. It is likewise possible to use mixtures of the abovementioned solvents. Preferred solvents are acetonitrile and dimethylformamide.
• the reaction is generally carried out in a temperature range from -78 ° C to +180 0 C, forthcoming Trains t in the range of +20 0 C to +100 0 C, in particular at +20 0 C to +60 0 C.
• the reaction can be carried out at normal, elevated or reduced pressure (eg in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• the process step (V) + (VI) -> (VIT) is generally carried out with a molar ratio of 1 to 8 mol of the compound of formula (VT) based on 1 mol of the compound of formula (V).
• Suitable solvents for this process step are all organic solvents which are inert under the reaction conditions. These include alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane or cyclohexane, chlorinated hydrocarbons such as dichloromethane, Dichloroethane or chlorobenzene, or other solvents such as dimethylformamide, acetonitrile, pyridine or dimethyl sulfoxide. Water is also suitable as a solvent. It is likewise possible to use mixtures of the abovementioned solvents. Preferred solvent is dimethylformamide.
• the reaction is generally carried out in a temperature range from -78 ° C to +180 0 C, preferably in the range of +20 0 C to +160 0 C, in particular at +20 to +40 0 C.
• the reaction can be carried out under normal , increased or decreased pressure (eg in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• the process step (VII) -> (H) is generally carried out with a molar ratio of 1 to 8 moles of sodium sulfide based on 1 mole of the compound of formula (VII).
• Suitable solvents for this process step are all organic solvents which are inert under the reaction conditions. These include alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane or cyclohexane, chlorinated hydrocarbons such as dichloromethane, Dichloroethane or chlorobenzene, or other solvents such as dimethylformamide, acetonitrile, pyridine or dimethyl sulfoxide. It is also possible to mix to use the aforementioned solvent. Preferred solvent is dimethylformamide.
• the reaction is generally carried out in a temperature range from -78 ° C to +180 0 C, preferably in the range of +20 0 C to +160 0 C, in particular at +40 0 C to +100 0 C.
• the reaction can be carried out under normal , increased or decreased pressure (eg in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• the compounds of the formula (VI) are either commercially available, known to the person skilled in the art or can be prepared by customary methods.
• the compounds of the formula (IH-A) can be used either analogously to the literature [I. Simiti et al., Chem. Ber. 95, 2672-2679 (1962)] or they can be generated in situ and reacted further directly with a compound of formula (II).
• the in situ production from 1,3-dichloroacetone and a compound of formula (VTS) in Dimethylfo ⁇ namid or ethanol.
• the preparation is generally carried out in a temperature range of 0 0 C to +140 0 C, preferably in the range of +20 0 C to +120 0 C, in particular at +80 0 C to +100 0 C.
• the compounds of the formula (VIH) are either commercially available, known to the person skilled in the art or can be prepared by customary methods.
• R 1 is hydrogen or (C r C 4 ) alkyl
• R 2 is pyridyl or thiazolyl, which in turn is represented by (C 1 -C 4 ) -alkyl, halogen, amino, dimethylamino, acetylamino, guanidino, pyridylamino, thienyl, furyl, imidazolyl, pyridyl, polypholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N- ( C 1 -C 4 ) -alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, thiazolyl optionally substituted by (C 1 -C 4 ) -alkyl or optionally up to three times by halogen, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkyl. C 4 ) -alkoxy
• n is the number 2
• R 1 is hydrogen, methyl or ethyl
• R 2 is pyridyl or thiazolyl which in turn is substituted by methyl, ethyl, fluorine, chlorine, amino, dimethylamino, acetylamino, guanidino, 2-pyridylamino, 4-pyridylamino, thienyl,
• n is the number 2
• R 1 is hydrogen or methyl
• R 2 is pyridyl or thiazolyl, which is in turn denoted by methyl, chloro, amino, dimethylamino, acetylamino, guanidino, 2-pyridylamino, 4-pyridylamino, thienyl, pyridyl, morpholinyl, 2-methyl-thiazol-5-yl, phenyl, 4- Chlorophenyl or 3,4,5-trimethoxyphenyl can be substituted,
• Another and preferred subject of the invention is the use of compounds of the formula (IA) and (IB), their salts, solvates and solvates of the salts for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes.
• Another and preferred subject of the invention is the use of compounds of the formers (IA) and / or (IB), their salts, solvates and solvates of the salts for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndrome and diabetes associated with hypertension and Diseases of the cardiovascular system.
• the compounds of formula (IA) prove to be dual agonists of adenosine which act selectively on the A1 and A2b receptors.
• the compounds of formula (IB) are known as singular agonists of adenosine, which act selectively on the Al receptor.
• Specific Al agonists differ from the corresponding dual Al / A2b agonists in the form that specific Al agonists have a factor of> 10 agonistic effect on the Al receptor compared to the A2b receptor in the same species.
• the specificity can be determined in corresponding in vitro assays based on the concentration and / or in vivo experiments based on the corresponding dose.
• the compounds of the formulas (IA) and (IB) according to the invention show an unpredictable, valuable spectrum of pharmacological activity and are therefore especially useful for the prophylaxis and / or treatment of dyslipidemia, metabolic syndromes and diabetes and dyslipidemia, metabolic syndromes and diabetes associated with hypertension and Diseases of the cardiovascular system and for the manufacture of a medicament for the treatment of dyslipidaemia, metabolic syndrome and diabetes and dyslipidaemia, metabolic syndrome and diabetes associated with hypertension and diseases of the cardiovascular system suitable.
• the pharmaceutical activity of the compounds according to the invention can be explained by their action as selective ligands on adenosine A1 and A2b receptors.
• Compounds of formula (IB) act as singular Al agonists and the compounds of formula (IA) as dual Al / A2b agonists.
• adenosine receptor-selective ligands are those substances which bind selectively to one or more subtypes of the adenosine receptors and either mimic the action of the adenosine (adenosine agonists) or block its action (adenosine antagonists).
• “selective” refers to those adenosine receptor ligands in which, on the one hand, a marked effect on Al or Al / A2b adenosine receptor subtypes and, on the other hand, no or a significantly weaker effect (factor 10 or higher) A2a and A3 adenosine receptor subtypes can be observed.
• diseases of the cardiovascular system or cardiovascular diseases are to be understood as meaning the following diseases: Coronary restenosis, such as, for example, Restenosis after balloon dilatation, peripheral blood vessels, tachycardia, arrhythmias, peripheral and cardiac vascular diseases, stable and unstable angina pectoris, atrial and ventricular fibrillation and heart failure.
• Coronary restenosis such as, for example, Restenosis after balloon dilatation, peripheral blood vessels, tachycardia, arrhythmias, peripheral and cardiac vascular diseases, stable and unstable angina pectoris, atrial and ventricular fibrillation and heart failure.
• the present invention furthermore relates to a method for the prophylaxis and / or treatment of the aforementioned clinical pictures with the compounds of the formulas (IA) and (DB).
• compositions containing at least one compound of the invention are pharmaceutical 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. For this purpose, they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
• the compounds according to the invention can be administered in suitable administration forms.
• the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
• Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
• tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
• capsules e.g. Soft gelatin capsules
• dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
• a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
• absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
• 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, shaking mixtures)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (eg plasters)
• milk pastes, foams, powdered 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 include, among others, excipients (for example, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyols).
• ethylene glycols ethylene glycols
• emulsifiers and dispersing or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
• binders for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• stabilizers for example antioxidants such as ascorbic acid
• dyes for example inorganic pigments such as, for example, iron oxides
• flavor and / or odorants for example sodium dodecyl sulfate, polyoxysorbitanoleate
• binders for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• stabilizers for example antioxidants such as ascorbic acid
• dyes for example inorganic pigments such as, for example, iron oxides
• flavor and / or odorants for example inorganic pigments such as, for example, iron oxides
• parenteral administration amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective results.
• 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 body weight.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP 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 ⁇ 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.
• Device type MS Micromass ZQ
• Device type HPLC HP 1100 Series
• UV DAD Column: Phenomenex Synergi 2 ⁇ Hydro-RP 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
• 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.
• Device type MS Micromass ZQ
• Device type HPLC Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 100 mm x 4.6 mm; Eluent A: water + 500 ⁇ l 50% formic acid / 1, eluent B: acetonitrile + 500 ⁇ l 50% formic acid / 1; 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 5A The synthesis is carried out analogously to Example 5A starting from the enantiomerically pure starting material from Example 12A.
• Example 8 Analogously to Example 8, the title compound is obtained by reaction of 179 mg (0.96 mmol) of 4-chlorophenylthiourea with 122 mg (0.96 mmol) of 1,3-dichloroacetone in ethanol and subsequent reaction with 150 mg (0.48 mmol) of 2-amino 4- [4- (2-hydroxyethoxy) phenyl] -6-mercapto-pyridine-3, 5-dicarbonitrile.
• Example 8 Analogously to Example 8, the title compound is obtained by reaction of 169 mg (0.90 mmol) of 2,4-difluorophenylthiourea with 114 mg (0.90 mmol) of 1, 3-dichloroacetone in ethanol and subsequent reaction with 200 mg (0.64 mmol) of 2-amino 4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile.
• Example 8 Analogously to Example 8, the title compound is obtained by reaction of 153 mg (0.90 mmol) of 3-fluorophenylthiourea with 114 mg (0.90 mmol) of 1,3-dichloroacetone in ethanol and subsequent reaction with 200 mg (0.64 mmol) of 2-amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile.
• Example 8 Analogously to Example 8, the title compound is obtained by reaction of 153 mg (0.90 mmol) of 2-fluorophenylthiourea with 114 mg (0.90 mmol) of 1, 3-dichloroacetone in ethanol and subsequent reaction with 200 mg (0.64 mmol) 2-amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile.
• Example 8 Analogously to Example 8, the title compound is obtained by reaction of 176 mg (0.90 mmol) of 4- [(aminocarbonothioyl) amino] benzoic acid with 114 mg (0.90 mmol) of 1,3-dichloroacetone in ethanol and subsequent reaction with 200 mg (0.64 mmol). 2-Amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile.
• the title compound is obtained as a minor component in the reaction of 176 mg (0.90 mmol) of 4 - [(aminocarbonotbioyl) amino] benzoic acid with 114 mg (0.90 mmol) of 1,3-dichloroacetone in ethanol and subsequent reaction with 200 mg (0.64 mmol) 2-amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile.
• Example 8 Analogously to Example 8, the title compound is obtained by reaction of 177 mg (0.90 mmol) of 4-nitrophenylthiourea with 114 mg (0.90 mmol) of 1,3-dichloroacetone in ethanol and subsequent reaction with 200 mg (0.64 mmol) of 2-amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile.
• Examples 17 to 28 listed in Table 4 are prepared from 2-amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile (Examples 17 to 25) or from 2-Amino-4- [4- (2-methoxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile (preparation see WO 03/053441, Example 1 / 2nd stage) (Examples 26 to 28) prepared: Table 4
• Example 32A Analogously to Example 8, the title compound is obtained by reaction of 120 mg (0.70 mmol) of 4-fluorophenylthiourea with 89 mg (0.70 mmol) of 1,3-dichloroacetone in ethanol and subsequent reaction with 245 mg (0.50 mmol) of 2- (2-hydroxyethoxy ) amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile (Example 32A).
• Reaction mixture is filtered and purified directly by preparative HPLC (column: Macherey
• the pH is carefully adjusted to about pH 9 by addition of aqueous dilute sodium bicarbonate solution.
• the formed phases are separated. After drying the organic phase over magnesium sulfate, the solvent is removed on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 ⁇ m, mobile phase gradient: acetonitrile / water 10:90 ⁇ 95: 5, with addition of 0.5% concentrated hydrochloric acid).
• the product-containing fractions are combined and concentrated on a rotary evaporator.
• Cells of the permanent line CHO are stably transfected with the cDNA for the adenosine receptor subtypes Al, A2a and A2b.
• the adenosine Al receptors are cyclase coupled via Gj proteins, while the adenosine A2a and A2b receptors via G s proteins to adenylate. Accordingly, cAMP production in the cell is inhibited or stimulated. Via a cAMP-dependent promoter, the expression of the luciferase is then modulated.
• the luciferase test is optimized with the aim of high sensitivity and reproducibility, low variance and suitability for implementation on a robotic system by varying several test parameters, such as cell density, growing phase and test incubation, forskolin concentration and medium composition.
• test parameters such as cell density, growing phase and test incubation, forskolin concentration and medium composition.
• the stock cultures are grown in DMEM / F12 medium with 10% FCS (fetal calf serum) at 37 ° C under 5% CO 2 and split 1:10 each after 2-3 days.
• Test cultures are seeded at 2,000 cells per well in 384-well plates and grown at 37 ° C for approximately 48 hours. Then, the medium is replaced with a physiological saline solution (130 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 20 mM HEPES, 1 mM magnesium chloride hexahydrate, 5 mM sodium hydrogencarbonate, pH 7.4).
• DMSO substances to be tested are in a dilution series from 1.1 x 10 "11 M to 3 x 10 -6 M (final concentration) to the test cultures pipetted (maximum DMSO final concentration in test mixture: 0.5%). 10 minutes later is forskolin to All cultures are then incubated at 37 ° C.
• the reference compound used in these experiments is the adenosine-analogous compound NECA (5-N-ethylcarboxamidoadenosine), which binds with high affinity to all adenosine receptor subtypes and has an agonistic activity [Klotz, K. ⁇ ., Hessling, J , Hegler, J., Owman, C, KuIl, B., Fredholm, BB, Lohse, MJ, "Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells", Naunyn Schmiedebergs Arch. Pharmacol. 357, 1-9 (1998)].
• NECA adenosine-analogous compound
• Table 1 lists the EC 50 values of representative embodiments of compounds of the formula (IA) for the receptor stimulation on adenosine A1, A2a and A2b receptor subtypes:
• mice Male Sprague Dawley rats (10 per group, Harlan-Netherland, 200g) are placed on a liner-free diet overnight. Subsequently, the substance to be tested is orally administered to the animals in various dosages (1 mg / kg, 3 mg / kg, 10 mg / kg). An animal group is continued as a control group without substance. Before the administration of the substance and 2, 4 and 6 hours thereafter, the treated and control animals are bled and EDTA plasma is obtained (500 ⁇ l of whole blood in EDTA tubes from Sarstedt, centrifugation for 10 min at 12000 rpm).
• the free fatty acids and triglycerides content is determined at any time using the Cobas Integra 400 TM analyzer from Roche Diagnostics and expressed as a% change in relation to the value before the substance administration.
• a positive control is an oral dose of acipimox (50 mg / kg, 100 mg / kg).
• mice Male Sprague Dawley rats (15 per group, Harlan-Netherland, 200g) are treated orally with the substance to be tested in different doses (3 mg / kg, 10 mg / kg) twice a day for 24 days Prior to the administration of the substance and on days 10 and 24 during the treatment, blood is taken from the fasting animals and EDTA plasma is obtained (500 ⁇ l whole blood in EDTA tubes from Sarstedt, centrifugation at 12000 rpm for 10 min.) Fatty acids and triglycerides determined at any time by the Roche Diagnosics Cobas Integra 400 TM analyzer, expressed as% change in relation to pre-drug value, as positive control by oral pioglitazone (10 mg / kg; bid).
• mice Male Sprague Dawley rats (15 per group, Harlan-Winkelmann, 180-20Og) are put on a fructose (66%) diet for 26 days. After 15 days, the animals are treated orally for a further 10 days with the substance to be tested in various dosages (3 mg / kg, 10 mg / kg) twice a day. An animal group is continued as a control group without substance. Before the fructose diet, on day 12 of the diet (before the substance administration) and on day 26 (10 days after the start of the substance treatment), the animals are bled and EDTA plasma is obtained (500 ⁇ l of whole blood in EDTA tubes from Sarstedt, centrifugation 10 min at 12000 rpm).
• the free fatty acids and triglycerides content is determined at any time using the Cobas Integra 400 TM analyzer from Roche Diagnostics and expressed as a% change in relation to the value before the substance administration. Furthermore, the plasma insulin concentration is determined using the Cobas Integra 400 TM analyzer from Roche Diagnostics and expressed in ng of insulin per ml of plasma.
• 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 swelling of the Rhodigels swirling is about 6 h stirred. - -
• 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.
• 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 erf ⁇ ndungswashen compounds and one or more further active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
• Suitable combination active ingredients are lipid metabolism-changing active ingredients, hypoglycaemic agents (petidische and non-peptidische), means for the treatment of obesity and obesity, blood pressure lowering, circulation-promoting and / or antithrombotic acting agents and antioxidants, chemokine receptor Antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB / j receptor antagonists), analgesics (aspirin), antidepressants and other psychotropic drugs.
• hypoglycaemic agents petidische and non-peptidische
• chemokine receptor Antagonists e.glycaemic agents
• p38 kinase inhibitors p38 kinase inhibitors
• NPY agonists NPY agonists
• orexin agonists anorectics
• PAF-AH inhibitors anti-inflammatory 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-changing active substance, an antidiabetic (petidische and non-peptidische), for the treatment of obesity or obesity, an antihypertensive agent and / or an antithrombotic agent.
• at least one of the compounds according to the invention with at least one lipid metabolism-changing active substance, an antidiabetic (petidische and non-peptidische), for the treatment of obesity or obesity, an antihypertensive agent and / or an antithrombotic agent.
• the compounds of the invention may preferably be with one or more
• the lipid metabolism-changing active substances 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,
• Glucagon antagonists insulin sensitizers, CCK1 receptor agonists, leptin receptor agonists, potassium channel antagonists, liver enzyme inhibitors involved in the stimulation of gluconeogenesis and / or glycogenolysis, modulators of glucose uptake, and potassium channel openers, e.g. those disclosed in WO 97/26265 and WO 99/03861,
• Hypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers, diuretics, phosphodiesterase inhibitors, sGC stimulators, Enhancers of cGMP levels, aldosterone antagonists, mineralocorticoid receptor antagonists, ECE inhibitors and the vasopeptidase inhibitors, and / or
• Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants
• 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, anti-oxidants / radical scavengers, and the cannabinoid receptor 1 antagonists.
• 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 melamine, pactimibe, eflucimibe or SMP-797.
• an ACAT inhibitor such as by way of example and preferably melamine, pactimibe, eflucimibe or SMP-797.
• the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
• a cholesterol absorption inhibitor such as, for 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 by way of preference, pioglitazone or rosiglitazone.
• a PPAR-gamma agonist such as, by way of example and by way of preference, 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 of 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
• the compounds of 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 according to 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, by way of example and preferably metformin.
• the compounds according to 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 migolith or acarbose.
• the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example from the class of tbiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
• a PPAR-gamma agonist for example from the class of tbiazolidinediones, 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 Aü antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers and diuretics.
• 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 AII antagonist, such as by way of example and preferably losartan, valsartan, candesartan, embusartan, olmesartan or telmisartan.
• angiotensin AII antagonist such as by way of example and preferably losartan, valsartan, candesartan, embusartan, olmesartan or telmisartan.
• the compounds according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• an ACE inhibitor such as by way of 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, metabisole pranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol.
• 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 administered in combination with a diuretic, such as by way of example and preferably furosemide.
• the compounds according to the invention are administered in combination with antisympathotonics such as reserpine, clonidine or alpha-methyl-dopa, with potassium channel agonists such as minoxidil, diazoxide, dihydralazine or hydralazine, or with nitric oxide-releasing substances such as glyceryl nitrate or nitroprusside sodium.
• antisympathotonics such as reserpine, clonidine or alpha-methyl-dopa
• potassium channel agonists such as minoxidil, diazoxide, dihydralazine or hydralazine
• nitric oxide-releasing substances such as glyceryl nitrate or nitroprusside sodium.
• 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.
• 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 by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
• a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, 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 by way of preference, 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 DX-9065a, DPC 906, JTV 803, BAY 59-7939, DU-176b, fidexaban, razaxaban, fondaparinux, Idra- parinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, SSR-126512 or SSR-128428.
• a factor Xa inhibitor such as by way of example and preferably DX-9065a, DPC 906, JTV 803, BAY 59-7939, DU-176b, fidexaban, razaxaban, fondaparinux, Idra- parinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, SSR-126512 or SSR-128428.
• the compounds according to the invention
• the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

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