EP1994031A1

EP1994031A1 - Use of adenosine a1 and/or dual a1/a2b agonists for production of medicaments for treating diseases

Info

Publication number: EP1994031A1
Application number: EP07711554A
Authority: EP
Inventors: Peter Nell; Barbara ALBRECHT-KÜPPER; Walter Hübsch; Martina Wuttke; Thomas Krahn; Nicole Diedrichs; Hilmar Bischoff
Original assignee: Bayer Healthcare AG
Current assignee: Bayer Pharma AG
Priority date: 2006-03-01
Filing date: 2007-02-16
Publication date: 2008-11-26
Also published as: KR20080099293A; CN101395153A; DE102006009813A1; AU2007222736A1; RU2008138649A; BRPI0708407A2; US20100048641A1; WO2007101531A1; JP2009528308A; CA2644166A1; MX2008011082A

Abstract

The invention relates to use of A1 and/or dual A1/A2b agonists of formula (IA) and (IB) for production of a medicament for treatment of dyslipidemia, metabolic syndrome and diabetes and dyslipidemia, metabolic syndrome and diabetes in connection with hypertonia and diseases of the cardiovascular system.

Description

USE OF ADENOSINE Al AND / OR DUAL A1 / A2B AGONISTS FOR THE MANUFACTURE OF MEDICAMENTS FOR THE TREATMENT OF ILLNESSES

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.

Over 180 million people in the US, Europe and Japan have hypertension. With increasing aging of the population, this proportion will increase even further. Of all patients with diagnosed hypertension, 65% also have dyslipidemia and 16% have diabetes. An even higher percentage has a precursor to these diseases, the Metabolic Syndrome. These patients have a high risk of developing cardiovascular diseases such as CHD, angina pectoris, arteriosclerosis and heart failure as a result of the additional illnesses. Despite multiple therapeutic successes, cardiovascular disease remains a serious public health problem. Treating these high-risk patients with a drug that not only lowers blood pressure or reduces heart rate, but also has a positive effect on these additional disorders would be of great benefit to the patient.

Adenosine, a purine nucleoside, 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.

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.

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. In the case of the binding of adenosine to the A2a or A2b receptors, an activation of the membrane-bound adenylate cyclase leads to an increase of intracellular cAMP, while the binding of adenosine to the A1 or A3 receptors via an inhibition of adenylate cyclase intracellular cAMP Keep the level low.

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.

The activation of 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.

The combined effect of selective Al / A2b agonists on the vascular system and heart rate thus results in a systemic lowering of blood pressure with a significantly reduced tendency for a reflex heart rate increase. With such a pharmacological profile, dual Al / A2b agonists for the treatment of e.g. of hypertension in humans.

In 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.

The known from the prior art, as "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]. However, 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.

It is therefore an object of the present invention to provide compounds which act as selective agonists of the adenosine A1 or selective dual agonist of the Al / A2b receptor and as such are useful in the treatment and / or prevention of dyslipidemia, metabolic syndromes and diabetes.

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)

in which

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

(C] _-C6) -alkoxycarbonyl,

in which alkyl and alkoxy may each themselves be substituted by up to five times with fluorine,

and

n is the number 0, 1, 2, 3, 4 or 5,

wherein in the event that the substituent R ³ occurs several times, its meanings may be the same or different,

and their salts, solvates and solvates of the salts for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes. 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.

Depending on their structure, 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.

If the compounds according to the invention can occur in tautomeric forms, 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.

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. In the context of the invention, 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.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "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).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

.. (C ₁ -CgVAlIcVl (C ₂ -CV) -alkyl (C ₁ -CaVAIkVl and (C ₂ -G.) - alkyl, in the context of the invention 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.

in the context of the invention are an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino. 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. Examples which may be mentioned are: 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.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Most preferably, the substitution with one or two identical or different substituents.

Preferred within the scope of the present invention is the use of compounds of the formula (IA)

in which

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,

in which alkyl and alkoxy may each themselves be substituted up to three times by fluorine,

and

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,

and their salts, solvates and solvates of the salts for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes.

Particularly preferred in the context of the present invention is the use of compounds of the formula (IA)

in which

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,

and

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,

The compounds of formula (IA) can be prepared by the following method.

Process, characterized in that compounds of the formula (H)

wherein R ¹ and R ² each have the meanings given above,

in an inert solvent in the presence of a base with a compound of formula (DI)

wherein R ³ and nj in each case have the meanings given above, and

X is a suitable leaving group, preferably halogen, in particular chlorine, bromine or iodine, or mesylate, tosylate or triflate,

implements

and optionally reacting the compounds of formula (IA) with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

The method described above can be explained by way of example by the following equation: Scheme 1

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.

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.

Compounds of the formula (II) in which R ^{1 is} hydrogen are known per se to the person skilled in the art or can be prepared by customary methods known from the literature. In particular, reference may be made to the following publications, the respective contents of which are incorporated by reference:

a) Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014-1017 (1997) and 34 (4), 557-563 (1998);

b) Dyachenko et al., Chemistry of Heterocyclic Compounds 34 (2), 188-194 (1998);

c) Qintela et al., European Journal of Medicinal Chemistry 33, 887-897 (1998);

d) Kandeel et al., Journal of Natural Science 42b, 107-111 (1987).

The compounds of the formula (H) in which R ^{1 is} hydrogen may also be prepared starting from compounds of the formula (IV)

wherein R ^{2 has} the meaning given above,

be prepared by reaction with a Alkalisulfϊd. This production method can be exemplified by the following formula scheme: Scheme 2

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.

The compounds of the formula (IV) can be prepared analogously to the compounds described in the following publications:

a) Kambe et al., Synthesis, 531-533 (1981);

b) Elnagdi et al., Z. Naturforsch. 47b, 572-578 (1991).

Compounds of the formula (H) in which R ^{1 is} not hydrogen can be prepared by first reacting compounds of the formula (TV) with copper (II) chloride and isoamyl nitrite in a suitable solvent in compounds of the formula (V)

wherein R ^{2 has} the meaning given above,

these are then reacted with a compound of the formula (VI)

R ' ^A -NH ₂ (VI),

wherein

R ^{1A has} the abovementioned meaning of R ¹ but does not stand for hydrogen,

to compounds of the formula (VU)

wherein R ^IA and R ² each have the meanings given above,

reacted and finally with sodium sulfide in compounds of formula (H) überfuhrt.

The method described above can be exemplified by the following equation: Scheme 3

R ^1A -NH,

The process step (TV) -> (V) is generally carried out with a molar ratio of 2 to 12 moles of copper (π) 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.

Compounds of the formula (ID) can be prepared from compounds of the formula (VTJI)

wherein R ³ and n have the meanings given above,

be prepared by reaction with a 1,3-dihaloacetone. This production method can be exemplified by the following formula scheme:

Scheme 4

(HI-A)

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). Preferably, the in situ production from 1,3-dichloroacetone and a compound of formula (VTS) in Dimethylfoπnamid 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.

Likewise provided by the present invention is the use of compounds of the formula (IB)

wherein

a number 2, 3 or 4 means

R ^{1 is} hydrogen or (C _r C ₄ ) alkyl

and

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-substituted phenyl may be substituted,

and their salts, hydrates, hydrates of the salts and solvates for the manufacture of a medicament for the treatment of dyslipidaemia, metabolic syndrome and diabetes.

Likewise preferred is the use of compounds of the formula (IB)

wherein n is the number 2,

R ^{1 is} hydrogen, methyl or ethyl

and

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,

Pyridyl, morpholinyl, piperidinyl, optionally substituted by methyl-substituted thiazolyl or optionally substituted up to three times by chlorine or methoxy-substituted phenyl,

Especially preferred is the use of compounds of formula (IB) wherein R ^{1 is} hydrogen or methyl for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes.

Also particularly preferred is the use of compounds of formula (IB) wherein

n is the number 2,

R ^{1 is} hydrogen or methyl

and

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,

Very particular preference is given to the use of the compound from Example 6 from WO 03/053441 having the following structure

The compounds of formula (BB), their preparation and explicitly mentioned examples are known from WO 03/053441. The teaching of WO 03/053441 is hereby expressly to be regarded as part of this disclosure.

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. Surprisingly, 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.

According to the invention, "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).

In the context of the present invention, "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.

For the purposes of the present invention, diseases of the cardiovascular system or cardiovascular diseases, for example in particular in addition to hypertension, 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.

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).

Another object of the present 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.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art working, 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). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example 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.

Preference is given to oral or parenteral administration, in particular oral administration.

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. These excipients include, among others, excipients (for example, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyols). 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 ) and flavor and / or odorants.

In general, it has proven to be advantageous to administer 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. When administered orally, 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.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. For example, in some cases it may be sufficient to make do with less than the minimum amount mentioned above, while in other cases this upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

A. Examples

Used abbreviations:

Example. Example

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide d. Th. Of theory (at yield)

EE ethyl acetate (ethyl acetate)

EI electron impact ionization (in MS)

ESI electrospray ionization (in MS)

Mp melting point sat. Saturated

H hour (s)

HPLC high pressure, high performance liquid chromatography conc. Concentrated

LC-MS liquid chromatography-coupled mass spectrometry

LDA lithium diisopropylamide

Literature (position)

Solution. Solution

Min minute (s)

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

RP-HPLC reverse phase HPLC

RT room temperature

R, retention time (by HPLC)

THF tetrahydrofuran dil. Dilute aq. Aqueous HPLC and LC-MS methods:

Method 1 (HPLC):

Instrument: Hewlett Packard Series 1050; Column: Symmetry ™ C18 3.9 x 150 mm; Flow: 1.5 ml / min; Eluent A: water, eluent B: acetonitrile; Gradient: -> 0.6 min 10% B → 3.8 min 100% B - »5.0 min 100% B → 5.5 min 10% B; Stop time: 6.0 min; Injection volume: 10 μl; Diode array detector signal: 214 and 254 nm.

Method 2 (LC-MSV

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2μ 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: 208-400 nm.

Method 3 TLC MSV

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ 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.

Method 4 (LC-MSV

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ 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.

Method 5 (LC-MSV

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 μl 50% formic acid / 1, eluent B: acetonitrile + 500 μl 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.

Method 6 (HPLC):

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml HClO _4/1 of water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B - »4.5 min 90% B → 9 min 90% B; Flow: 0.75 ml / min; Oven: 3O ⁰ C; UV detection: 210 nm.

Method 7 (HPLO:

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml HClO _4/1 of water, eluent B: acetonitrile; Gradient: 0 min 2% B - »0.5 min 2% B ¹ → 4.5 min 90% B → 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 30 ^° C; UV detection: 210 nm.

Starting compounds and intermediates:

Example IA

4 - [(2,2-dimethyl-l, 3-dioxolan-4-yl) methoxy] benzaldehyde

39.3 g (150 mmol) of triphenylphosphine are added to a solution of 13.2 g (100 mmol) of 1,2-O-isopropylideneglycerol in 250 ml of dry THF, and the batch is stirred at RT for 30 min. It is cooled to about 0 ⁰ C and are 12.2 g (100 mmol) of 4-hydroxybenzaldehyde and 31.9 g (150 mmol) of diisopropyl azodicarboxylate (DIAD) was added. The yellow reaction solution is stirred for 16 h at RT. The mixture is then concentrated on a rotary evaporator and the residue to 150 ml sat. Sodium bicarbonate solution. given. It is extracted with ethyl acetate (three times 150 ml each time) and the combined organic phases are dried over sodium sulfate. After removal of the solvent on a rotary evaporator, the crude product on silica gel 60 (mobile phase gradient cyclohexane -> cyclohexane / ethyl acetate 2: 1) is purified by chromatography.

Yield: 5.03 g (21% of theory)

LC-MS (Method 3): R, = 1.86 min; MS (ESIpos): m / z = 237 [M + H] ⁺ .

Example 2A

{4 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] benzylidene} malononitrile

0.13 g (1.98 mmol) of malononitrile, 0.45 g (1.90 mmol) of the compound from Example IA and 5.7 μl (0.06 mmol) of piperidine are dissolved in ethanol and the mixture is refluxed for 3.5 h. The reaction solution is concentrated and the residue is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane - »cyclohexane / ethyl acetate 2: 1).

Yield: 0.43 g (79% of theory)

¹ H-NMR (400 MHz, CDCl _3): δ = 7.91 (d, 2H), 7.65 (s, IH), 7:03 (d, 2H), 4:51 (m, IH) 4.19 (dd, IH), 4.14 ( dd, IH), 4.06 (dd, IH), 3.91 (dd, IH), 1.46 (s, 3H), 1.41 (s, 3H).

MS (DCI, NH _3): m / z = 302 [M + NH,] ^+.

Example 3A

2-Amino-4- {4 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] phenyl} -6-mercaptopyridine-3,5-dicarbonitrile

0.43 g (1.51 mmol) of the compound from Example 2A, 0.38 g (3.78 mmol) of cyanothioacetamide and 0.38 g (3.78 mmol) of 4-methylmorpholine are dissolved in 15 ml of ethanol and the mixture is stirred under reflux for 6 h. After cooling, the reaction solution is concentrated on a rotary evaporator and the residue is chromatographed on silica gel 60. After separation of secondary components (mobile phase gradient cyclohexane - »cyclohexane / ethyl acetate 1: 1), the product fractions are eluted (mobile phase gradient ethyl acetate -> ethyl acetate / methanol 20: 1). Subsequently, a fine purification is carried out by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm, mobile phase gradient: acetonitrile / water 10:90 → 95: 5).

Yield: 88 mg (15% of theory)

¹ H-NMR (400 MHz, DMSO-de): δ = 12.96 (br.s, IH), 7.90 (br.s, 2H), 7.46 (d, 2H), 7.12 (d, 2H), 4.44 (m , IH), 4.18-4.02 (m, 3H), 3.79 (m, IH), 1.37 (s, 3H), 1.32 (s, 3H). LC-MS (Method 3): R, = 1.76 min; MS (ESIpos): m / z = 383 [M + H] ⁺ .

Example 4A

4 - [(4- {[(6-Amino-3, 5-dicyano-4- {4 - [(2,2-dimethyl-1,3-dioxolan-4-yl) -methoxy] -phenyl} -pyridine-2-one yl) thio] methyl} -1,3-thiazol-2-yl) amino] benzoic acid

177 mg (0.90 mmol) of 4-carboxyphenylthiourea and 111 mg (0.87 mmol) of 1,3-dichloroacetone are dissolved in 3 ml of DMF and the reaction solution is stirred at 100 ^° C. for 60 min. After cooling, 230 mg (0.60 mmol) of the compound from Example 3A and 151 mg (1.80 mmol) of sodium bicarbonate are added and the mixture is stirred at RT for a further 16 h. The reaction mixture is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm, mobile phase gradient: acetonitrile / water 10:90-> 95: 5).

Yield: 134 mg (36% of theory)

¹ H-NMR (400 MHz, CDCl _3): δ = 12.5 (m, IH), 10.6 (s, IH), 8:07 (br. S, 2H), 7.86 (d, 2H), 7.67 (d, 2H) , 7.49 (d, 2H), 7.12 (d, 2H), 7.07 (s, IH), 4.50 (s, 2H), 4.44 (m, IH), 4.16-4.03 (m, 3H), 3.78 (dd, IH ), 1.37 (s, 3H), 1.31 (s, 3H).

LC-MS (Method 4): R, = 2.51 min; MS (ESIpos): m / z = 615 [M + H] ⁺ .

Example 5A

2-Arrimo-4- {4 - [(2,2-dimemyl-1,3-dioxolan-4-yl) methoxy] phenyl} -6 - [({2 - [(4-fluorohexyl) amino] -1, 3-thiazol-4-yl} methyl) thio] pyridine-3,5-dicarbonitrile

102 mg (0.6 mmol) of 4-fluorophenylthiourea and 73.6 mg (0.58 mmol) of 1,3-dichloroacetone are dissolved in 2.5 ml of ethanol and the mixture is stirred under reflux for 60 min. Allow to cool and concentrated on a rotary evaporator. The residue is taken up in 1.5 ml of DMF, 153 mg (0.4 mmol) of the compound from Example 3A and 101 mg (1.2 mmol) of sodium bicarbonate are added and the reaction solution is stirred at RT for a further 16 h. The reaction mixture is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm, mobile phase gradient: acetonitrile / water 10:90 -> 95: 5) chromatographically.

Yield: 62 mg (26% of theory)

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 10.24 (s, IH), 8.08 (br. S, 2H), 7.62 (dd, 2H), 7.47 (d, 2H), 7.13 (m , 4H), 6.97 (s, IH), 4.49-4.39 (m, 3H), 4.10 (m, 3H), 3.78 (dd, IH), 1.36 (s, 3H), 1.31 (s, 3H).

LC-MS (Method 2): R ₁ = 2.51 min; MS (ESIpos): m / z = 589 [M + H] ⁺ .

The examples listed in Table 1 are prepared from the corresponding starting compounds analogously to Example 5 A: Table 1

Example IIA

(5) -4 - [(2,2-dimethyl-l, 3-dioxolan-4-yl) methoxy] benzaldehyde

1.79 g (14.6 mmol) / »- hydroxybenzaldehyde are dissolved in absolute DMF (10 ml) and treated with 14.2 g (102.5 mmol) of potassium carbonate and 3.3 g (22.0 mmol) of (Ä) - (+) - 4-CbJoπnethyl-2,2 -dimethyl-l, 3- dioxolane added. The mixture is heated for 24 h at 150 ⁰ C. Subsequently, the batch on a rotary evaporator is concentrated and the residue partitioned between dichloromethane and water. It is extracted with dichloromethane (three times 20 ml each), washed with sat. Brine solution and the combined organic phases are dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the crude product is purified by chromatography on silica gel 60 (mobile phase: cyclohexane / ethyl acetate 5: 1).

Yield: 2.12 g (61% of theory)

LC-MS (method 2): R, = 1.97 min; MS (ESIpos): m / z = 237 [M + H] ⁺ .

Example 12A

(S) -2-Amino-4- {4 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] phenyl} -6-mercaptopyridine-3,5-dicarbonitrile

1.52 g (6.43 mmol) of the compound from Example IA, 1.29 g (12.9 mmol) of cyanothioacetamide and 1.3 g (12.9 mmol) of 4-methylmorpholine are dissolved in 15 ml of ethanol and the mixture is stirred at reflux for 3 h. Thereafter, the mixture is stirred for 18 h at RT. The reaction solution is concentrated on a rotary evaporator and the residue is chromatographed on silica gel 60 (mobile phase: dichloromethane / ethanol 10: 1).

Yield: 1.06 g (43% of theory)

LC-MS (Method 3): R, = 1.75 min; MS (ESIpos): m / z = 383 [M + H] ⁺ .

Example 13A

(S) -2-amino-4- {4 - [(2,2-dimethyl-l, 3-dioxolan-4-yl) methoxy] phenyl} -6 - [({2 - [(4-fluoφhenyl) - amino] -l, 3-thiazol-4-yl} methyl) thio] pyridine-3,5-dicarbonitrile

The synthesis is carried out analogously to Example 5A starting from the enantiomerically pure starting material from Example 12A.

Yield: 47% d. Th.

LC-MS (Method 3): R, = 2.58 min; MS (ESIpos): m / z = 589 [M + H] ⁺ .

The examples listed in Table 2 are prepared from the corresponding starting compounds analogously to Example 5 A or 13A or the corresponding enantiomer:

Table 2

Example 29A

2-Amino-4- [4- (2-hydroxyethoxy) phenyl] -6-phenylthio-pyridine-3,5-dicarbonitrile

0.765 g (11.6 mmol) of malononitrile, 1.28 g (11.6 mmol) of thiophenol and 2.48 g (11.6 mmol) of 2- [4- (2-hydroxyethoxy) ben2yliden] malononitrile [preparation according to WO 03/053441, Example 6 / Method 2, 1 Step] are dissolved in 15 ml of ethanol and treated with 0.03 ml of triethylamine. The mixture is stirred under reflux for 2 h. After cooling, the reaction mixture is filtered and the residue is washed with ethanol and dried.

Yield: 2.07 g (46% of theory)

¹ H-NMR (400 MHz, DMSO-d _ö ): δ = 7.76 (br.s, 2H), 7.60 (m, 2H), 7.51 (m, 5H), 7.12 (d, 2H), 4.93 (t, IH), 4.09 (t, 2H), 3.75 (m, 2H).

LC-MS (Method 3): R, = 2.02 min; MS (ESIpos): m / z = 389 [M + H] ⁺ .

Example 3OA

2-chloro-4- [4- (2-hydroxyethoxy) phenyl] -6-phenylthio-pyridine-3,5-dicarbonitrile

2.07 g (5.33 mmol) of the compound from Example 29A are dissolved in 11 ml of absolute DMF and admixed with 4.30 g (32.0 mmol) of anhydrous copper (II) chloride and 2.71 ml (32.0 mmol) of isoamyl nitrite. The mixture is stirred at 40 ^° C. for 18 h. The reaction solution is then concentrated on a rotary evaporator and the residue is added to 1 N hydrochloric acid. It is extracted three times with dichloromethane and the combined organic phases are washed with 1 N hydrochloric acid and brine. After drying over magnesium sulfate, the solvent is removed on a rotary evaporator. The crude product is purified by chromatography on silica gel 60 (eluent: dichloromethane / ethanol 20: 1).

Yield: 1.29 g (59% of theory)

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 7.60 (m, 7H), 7.20 (d, 2H), 4.12 (t, 2H), 3.76 (t, 2H).

LC-MS (Method 3): R, = 2.38 min; MS (ESIpos): m / z = 408 [M + H] ⁺ .

Example 31A

2- (2-hydroxyethoxy) amino-4- [4- (2-hydroxyethoxy) phenyl] -6-phenylthio-pyridine-3,5-dicarbonitrile

0.50 g (1.23 mmol) of the compound from Example 30A are dissolved in 1.5 ml of DMF and admixed with 0.16 ml (2.70 mmol) of 2-hydroxyethylamine. The mixture is stirred for 20 minutes and then 2 ml of methanol and 4 ml of water are added. The precipitate is filtered off, washed with methanol and dried.

Yield: 0.36 g (68% of theory)

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.94 (br.s, IH), 7.55 (m, 7H), 7.13 (d, 2H), 4.93 (t, IH), 4.49 (t, IH) , 4.09 (t, 2H), 3.75 (m, 2H), 3.09 (m, 2H), 3.00 (m, 2H).

LC-MS (Method 4): R, = 2.33 min; MS (ESIpos): m / z = 433 [M + H] ⁺ . Example 32A

2- (2-hydroxyethoxy) amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile

0.30 g (0.70 mmol) of the compound from Example 31A are dissolved in 2 ml of DMF and admixed with 0.19 g (2.43 mmol) of sodium sulfide. The mixture is stirred at 80 ^° C. for 2 h and then at RT for 12 h. Then 1N hydrochloric acid (10 ml) is added and the precipitate is filtered off.

Yield: 0.25 g (72% of theory)

LC-MS (Method 3): R, = 1.21 min; MS (ESIpos): m / z = 357 [M + H] ⁺ .

Example 33A

2-Aπuno-6- (benzyltmo) -4- {4- [2- (dimethylamino) ethoxy] phenyl} pyridine-3,5-dicarbonitrile

To a solution of 8.39 g (23.4 mmol) of 2-amino-6- (benzylthio) -4- (4-hydroxyphenyl) pyridine-3,5-dicarbonitrile [preparation according to WO 01/25210, Example A 383, from 2-amino -4- (4-hydroxyphenyl) -6-mercaptopyridine-3,5-dicarbonitrile and benzylbromide] in 105.5 ml of ethanol become 6.31 g (56.2 mmol) of potassium tert-butoxide was added. The mixture is stirred for 1 h at RT and then 4.05 g (28.1 mmol) of 2-dimethylaminoethyl chloride hydrochloride was added. Then it is stirred for 3 h at + 78 ° C. The reaction mixture is filtered after cooling and the filtrate is concentrated on a rotary evaporator. The residue is purified directly by preparative HPLC (column: Merck 210 g RP silica gel Gromsil 120 ODS-4 HR 10 μm, 50 mm × 200 mm, eluent A = water + 0.1% formic acid, eluent B = acetonitrile; gradient: 0 min 10% B → 5 min 10% B → 6 min 90% B → 22 min 90% B → 22 min 10% B → 28 min 10% B, flow rate: 110 ml / min, wavelength: 220 nm).

Yield: 3.55 g (35% of theory)

LC-MS (Method 3): R, = 1.57 min; MS (ESIpos): m / z = 430 [M + H] ⁺ .

Example 34A

2-amino-4- {4- [2- (dimethylamino) ethoxy] phenyl} -6-mercaptopyridine-3,5-dicarbonitrile

To a solution of 3.56 g (8.28 mmol) of the compound from Example 33A in 13 ml of dry DMF is added 0.97 g (12.41 mmol) of sodium sulfide. The reaction mixture is stirred at +80 ⁰ C for 2 h. After cooling to RT, the reaction mixture is mixed with 2 ml of 37% hydrochloric acid, with heating to 65 ° C occurs. After addition of 2.6 ml of water, the reaction mixture is cooled again to RT. After addition of a further 5 ml of water, it is washed with 5 ml of ethyl acetate and made alkaline by addition of 40% sodium hydroxide solution. There are yellow crystals, which are filtered off and washed with 10 ml of water and 10 ml of diethyl ether and then dried in vacuo. The filtrate is concentrated on a rotary evaporator and stirred with a little water. The resulting crystals are filtered off, washed with 10 ml of water and diethyl ether and dried in vacuo. Yield: 0.38 g (13% of theory)

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 10.77 (br.s, IH), 7.39 (d, 2H), 7.09 (d, 2H), 6.92 (br.s, 2H), 4.30 ( t, 2H), 3.21 (brs s, 2H), 2.64 (s, 6H).

LC-MS (Method 3): R, = 0.83 min; MS (ESIpos): m / z = 340 [M + H] ⁺ .

Example 35A

2- (4-Formylphenoxy) ethyl 4-methylphenylsulfonate

To a solution of 10.0 g (60.2 mmol) of 4- (2-hydroxyethoxy) benzaldehyde in 300 ml of dichloromethane at RT successively with stirring 12.6 ml (90.3 mmol) of triethylamine and a solution of 13.77 g (72.2 mmol) of toluene-4 sulfonyl chloride in 200 ml of dichloromethane was added dropwise. The reaction mixture is stirred for 12 h at RT. After addition of 0.15 g (1.2 mmol) of 4-NN-dimethylaminopyridine is stirred for a further 4 h at RT. Then, 250 ml of saturated aqueous sodium bicarbonate solution are added and the mixture is extracted three times with 100 ml of dichloromethane. The combined organic phases are dried over sodium sulfate. After removal of the solvent on a rotary evaporator, the crude product is purified by chromatography on silica gel 60 (mobile phase gradient cyclohexane -> ethyl acetate).

Yield: 12.34 g (64% of theory)

HPLC (Method 6): R, = 4.57 min; MS (ESIpos): m / z = 321 [M + H] ⁺ . Example 36A

4- (2-azidoethoxy) benzaldehyde

A solution of 5.0 g (15.61 mmol) of the compound from Example 35A and 2.03 g (31.22 mmol) of sodium azide in 100 ml of dry DMF is stirred at RT for 12 h. The reaction mixture is concentrated on a rotary evaporator and the residue is suspended with about 20 ml of water. After three extractions with 30 ml of diethyl ether, the combined organic phases are washed twice with 10 ml of water and once with 10 ml of saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed on a rotary evaporator.

Yield: 3.02 g (98% of theory)

HPLC (method 7): R, = 4.14 min; MS (DCI): m / z = 209 [M + NH,] *.

Example 37A

[4- (2-azidoethoxy) benzylidene] malononitrile

47 μl (0.47 mmol) of piperidine are added dropwise to a solution of 3.02 g (15.79 mmol) of the compound from Example 36A and 1.09 g (16.42 mmol) of malononitrile in 100 ml of ethanol, and the reaction mixture is stirred at + 78 ° C. for 3.5 hours. The solution turns orange-red. After cooling to RT, the solution is allowed to stand without stirring for 20 h. It forms a colorless precipitate. The crude suspension is reduced to half of the original volume on a rotary evaporator. The volume was concentrated and the crystallization completed with cooling in an ice bath. The resulting precipitate is filtered off with suction and washed twice with 20 ml of ethanol and twice with 20 ml of methyl-teΛt.-butyl ether.

Yield: 2.38 g (63% of theory)

MS (DCI): m / z = 257 PVH-NH ₄ J ⁺ .

Example 38A

2-Amino-4- [4- (2-azidoethoxy) phenyl] -6-mercaptopvridin-3,5-dicarbonitrile

A solution of 2.39 g (9.98 mmol) of the compound from Example 37A and 2.50 g (24.92 mmol) of cyanothioacetamide in 100 ml of ethanol is stirred at + 78 ° C for 6 h. After cooling to RT and 12 h further standing without stirring, the reaction mixture is concentrated on a rotary evaporator. The residue is recrystallized from about 30 ml of ethanol. The resulting precipitate is filtered off with suction and washed twice with 10 ml of methyl tert-butyl ether.

Yield: 2.04 g (61% of theory)

MS (DCI): m / z = 355 [M + NHJ ".

Example 39A

2-Amino-4- [4- (2-azidoemoxy) phenyl] -6 - [({2 - [(4-fluoro-phenyl) -amino] -l, 3-thiazol-4-yl} -methyl) -thio] -pyridine 3,5-dicarbonitrile

A solution of 74 mg (0.44 mmol) of 4-fluorophenylthiourea and 55 mg (0.44 mmol) of 1,3-dichloroacetone in 5 ml of ethanol is stirred at + 85 ° C. for 60 min. After removal of the solvent on a rotary evaporator, the residue is taken up in 5 ml of DMF, admixed with 105 mg (0.31 mmol) of the compound from Example 38A and 78 mg (0.93 mmol) of sodium bicarbonate and then stirred at RT for 20 h. The mixture is then added to 15 ml of saturated sodium bicarbonate solution. It is extracted with ethyl acetate (three times 15 ml each time) and the combined organic phases are dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the crude product is purified by chromatography on silica gel 60 (mobile phase gradient dichloromethane / ethanol 200: 1 → 20: 1).

Yield: 79 mg (47% of theory)

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 10.22 (s, IH), 8.27-7.86 (br, s, 2H), 7.66-7.58 (m, 2H), 7.50 (d, 2H) , 7.17-7.08 (m, 4H), 6.96 (s, IH), 4.46 (s, 2H), 4.31-4.22 (m, 2H), 3.74-3.67 (m, 2H).

LC-MS (Method 2): R, = 2.72 min; MS (ESIpos): m / z = 544 [M + H] ⁺ .

Example 4OA

4- (2-hydroxypropoxy) benzaldehyde

To a solution of 7.03 g (57.5 mmol) of p-hydroxybenzaldehyde and 6.80 g (71.9 mmol) of 1-chloro-2-propanol (techn., About 70%, isomer mixture with 2-chloro-1-propanol) in 125 ml of dry DMF are added 18.30 g (172.6 mmol) of sodium carbonate and the mixture for 20 h at +130 ⁰ C stirred. After cooling to RT, the mixture is treated with 100 ml of saturated sodium bicarbonate solution and extracted with ethyl acetate (three times 100 ml). The combined organic phases are dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the crude product is purified by chromatography on silica gel 60 (mobile phase gradient cyclohexane / ethyl acetate 5: 1 → 2: 1).

Yield: 4.60 g (44% of theory, mixture of isomers in the ratio 75:25)

LC-MS (Method 4): R, = 1.63 min; MS (ESIpos): m / z = 181 [M + H] ⁺ .

Example 41A

4- (2 - {[ter /.- butyl (dimethyl) silyl] oxy} propoxy) benzaldehyde

5.39 g (35.7 mmol) of tert.-butyldimethylsilyl chloride and 3.30 g (48.5 mmol) of imidazole are added successively to a solution of 4.60 g (25.5 mmol) of the compound from Example 4OA in 120 ml of dry dimethylformamide, and the mixture is stirred at RT for 20 h touched. Subsequently The reaction mixture is mixed with 100 ml of saturated sodium bicarbonate solution and extracted with diethyl ether (three times 100 ml). The combined organic phases are dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the crude product is purified by chromatography on silica gel 60 (mobile phase gradient cyclohexane / ethyl acetate 50: 1 → 10: 1).

Yield: 4.00 g (53% of theory, mixture of isomers in the ratio 86:14)

LC-MS (Method 2): R, = 3.29 min; MS (ESIpos): m / z = 295 [M + H] ⁺ .

Example 42A

2-Amino-4- [4- (2 - {[tert-butyl (dimethyl) silyl] oxy} propoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile

A solution of 1.77 g (5.99 mmol) of the compound from Example 41A and 1.26 g (12.59 mmol) of cyanothioacetamide in 25 ml of ethanol is stirred at + 78 ° C. for 6 hours. It is then cooled to RT and stirred for a further 20 h at this temperature. The precipitate is filtered off with suction and washed with cold diethyl ether. Further product is obtained from the concentrated filtrate solution by chromatographic purification on silica gel 60 (mobile phase gradient cyclohexane / ethyl acetate 1: 1 → 1: 4).

Yield: 0.25 g (9% of theory, mixture of isomers)

LC-MS (Method 3): R, = 2.71 min, 2.77 min; MS (ESIpos): m / z = 430 [M + H] ⁺ .

Example 43 A

2-AmmcH4- [4- (2 - {[tert -butyl (dimemyl) -silyl] oxy} -propoxy) -phenyl] -6 - [({2 - [(4-fluorophenyl) -amino] -l, 3-thiazole 4-yl} methyl) thio] pyridine-3,5-dicarbonitrile - -

A solution of 78.6 mg (0:46 mmol) of 4-Fluorphenylthioharnstoff and 56.0 mg (0:44 mmol) of 1,3-dichloroacetone in 2 ml of dry DMF is stirred for 3 hours at +80 ⁰ C. After cooling to RT, 370 mg (0.42 mmol) of the compound from Example 42 A are added and the mixture is subsequently stirred at RT for 20 h. The reaction mixture is purified directly by preparative HPLC twice (column: YMC GEL ODS-AQ S-5/15 μm, mobile phase gradient: acetonitrile / water 10:90 → 95: 5).

Yield: 0.44 g (14% of theory)

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 10.21 (s, IH), 8.18-7.93 (br. S, 2H), 7.60 (dd, 2H), 7.47 (d, 2H), 7.12 (t, 2H), 7.07 (d, 2H), 6.95 (s, IH), 4.44 (s, 2H), 4.21-4.12 (m, IH), 3.96 (dd, IH), 3.87 (dd, IH), 1.18 (i.e. , 3H), 0.87 (s, 9H), 0.08 (d, 6H).

LC-MS (Method 5): R. = 7.35 min; MS (ESIpos): m / z = 647 [M + H] ⁺ .

Ausffihrungsbeispiele:

example 1

2-Amino-6 - [({2 - [(3-chloro-phenyl) -amino] -l, 3-thiazol-4-yl} -methyl) -thio] -4- [4- (2,3-dihydroxypropoxy) -phenyl ] pyridine-3,5-dicarbonitrile

2 ml of glacial acetic acid and 90 mg (0.15 mmol) of the compound from Example 7A are added to 1 ml of water and the batch is stirred at RT for 16 h. The mixture is concentrated and the residue is chromatographed on silica gel 60 (eluent gradient dichloromethane - »dichloromethane / methanol 10: 1).

Yield: 30 mg (36% of theory)

Mp 192-194 ° C

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 10.42 (s, IH), 8.06 (br, s, 2H), 7.82 (s, IH), 7.45 (m, 3H), 7.30 (t , IH), 7.10 (d, 2H), 7.03 (s, IH), 6.97 (d, IH), 4.99 (d, IH), 4.68 (dd, IH), 4.49 (s, 2H), 4.09 (dd, IH), 3.95 (dd, IH), 3.82 (m, IH), 3.46 (dd, 2H).

LC-MS (Method 3): R, = 2.17 min; MS (ESIpos): m / z = 565 [M + H] ⁺ .

The examples listed in Table 3 are prepared from the corresponding starting compounds ^' analogously to Example 1: Table 3

- -

Example 8

2-Amino-6 - [({2 - [(4-fluorophenyl) amino] -1,3-thiazol-4-yl} methyl) thio] -4- [4- (2-hydroxyethoxy) phenyl] pyridine 3,5-dicarbonitrile

To a solution of 327 mg (1.92 mmol) of 4-fluorophenylthiourea in 8 ml of ethanol, 244 mg (1.92 mmol) of 1,3-dichloroacetone are added and the mixture is stirred under reflux for 1 h. The mixture is concentrated, the residue is dissolved in 4 ml of DMF, 429 mg (1.37 mmol) of 2-amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile are obtained (preparation see WO 03/053441, Example 6 / Method 1, 1st stage) and 346 mg (4.1 mmol) of sodium bicarbonate and stirred overnight at RT. After addition of water, the precipitate is decanted off and the residue triturated with dichloromethane. After chromatography on silica gel (mobile phase dichloromethane / methanol 50: 1), the title compound is obtained as a yellowish solid.

Yield: 316 mg (44% of theory)

HPLC (Method 1): R, = 4.24 min

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 10.23 (s, IH), 8.1 (br, s, 2H), 7.62 (dd, 2H), 7.47 (d, 2H), 7.12 (dd , 4H), 6.96 (s, IH), 4.92 (t, IH), 4.45 (s, 2H), 4.07 (t, 2H), 3.74 (q, 2H).

LC-MS (Method 2): R, = 2.39 min; MS (ESIpos): m / z = 519 [M + H] ⁺ .

Example 9

2-Ammo-6 - [({2 - [(4-chloro-phenyl) -nino] -l, 3-thiazol-4-yl} -methyl) -thio] -4- [4- (2-hydroxy-ethoxy) -phenyl] -pyridine 3,5-dicarbonitrile

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.

Yield: 60 mg (12% of theory)

HPLC (Method 1): R, = 4.44 min

¹ H-NMR (400 MHz, DMSO-dβ): δ = 10.37 (s, IH), 8.1 (br, s, 2H), 7.63 (d, 2H), 7.47 (d, 2H), 7.32 (d, 2H ), 7.11 (d, 2H), 6.99 (s, IH), 4.47 (s, 2H), 4.08 (t, 2H), 3.75 (q, 2H). LC-MS (Method 3): R, = 2.31 min; MS (ESIpos): m / z = 535 [M + H] ⁺ .

Example 10

2-Ammo-6 - [({2 - [(2,4-difluoro-phenyl) -amino] -l, 3-thiazol-4-yl} -methyl) -thio] -4- [4- (2-hydroxyethoxy) -phenyl] pyridine-3,5-dicarbonitrile

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.

Yield: 126 mg (36% of theory)

HPLC (Method 1): R, = 4.31 min

¹ H NMR (400 MHz, DMSOd ₆ ): δ = 9.97 (s, IH), 8.34 (dt, IH), 8.1 (br, s, 2H), 7.47 (d, 2H), 7.30 (dq, IH) , 7.10 (d, 2H), 7.04 (br t, IH), 6.99 (s, IH), 4.91 (t, IH), 4.45 (s, 2H), 4.06 (t, 2H), 3.74 (q, 2H ).

LC-MS (Method 3): R, = 2.21 min; MS (ESIpos): m / z = 537 [M + H] ⁺ .

Example 11

2-Aπimo-6 - [({2 - [(3-fluoro-phenyl) -amino] -l, 3-thiazol-4-yl} -methyl) -thio] -4- [4- (2-hydroxy-ethoxy) -phenyl] -pyridine 3,5-dicarbonitrile

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.

Yield: 80 mg (24% of theory)

HPLC (Method 1): R, = 4.36 min

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 10.46 (s, IH), 8.1 (br, s, 2H), 7.66 (dt, IH), 7.47 (d, 2H), 7.35-7.21 (m, 2H), 7.10 (t, 2H), 7.04 (s, IH), 6.74 (dt, IH), 4.92 (br s, IH), 4.48 (s, 2H), 4.07 (t, 2H), 3.74 (t, 2H).

LC-MS (Method 3): R ₁ = 2.20 min; MS (ESIpos): m / z = 519 [M + H] ⁺ .

Example 12

2-Ammo-6 - [({2 - [(2-fluoro-phenyl) -amino] -l, 3-thiazol-4-yl} -methyl) -thio] -4- [4- (2-hydroxy-ethoxy) -phenyl] -pyridine 3,5-dicarbonitrile

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.

Yield: 170 mg (51% of theory)

HPLC (Method 1): R, = 4.28 min

¹ H-MMR (400 MHz, DMSO-d *): δ = 9.99 (s, IH), 8.36 (t, IH), 8.1 (br, s, 2H), 7.46 (d, 2H), 7.22 (dd, IH), 7.16-7.08 (m, 3H), 7.02-6.96 (m, 2H), 4.90 (t, IH), 4.46 (s, 2H), 4.07 (t, 2H), 3.74 (t, 2H).

LC-MS (Method 3): R, = 2.16 min; MS (ESIpos): m / z = 519 [M + H] ⁺ .

Example 13

4 - ({4 - [({6-amino-3,5-dicyano-4- [4- (2-hydroxyethoxy) phenyl] pyridin-2-yl} thio) methyl] -1,3-thiazole-2 yl} amino) benzoic acid

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.

Yield: 45 mg (13% of theory)

HPLC (Method 1): R, = 3.81 min

¹ H-NMR (300 MHz, DMSOd ₆ ): δ = 12.6 (br.s, IH), 10.64 (s, IH), 8.1 (br, s, 2H), 7.87 (d, 2H), 7.68 (d, 2H), 7.49 (d, 2H), 7.13-7.06 (m, 3H), 4.45 (s, 2H), 4.07 (t, 2H), 3.74 (t, 2H).

LC-MS (method 2): R, = 1.97 min; MS (ESIpos): m / z = 545 [M + H] ⁺ .

As a minor component in this reaction arises 4 - ({4 - [({6-amino-3,5-dicyano-4- [4- (2-hydroxyemoxy) phenyl] pyrridin-2-yl} thio) methyl] -1, 3-thiazol-2-yl} amino) benzoic acid ethyl ester (see Example 14).

Example 14

4 - ({4 - [({6-amino-3,5-dicyano-4- [4- (2-hydroxyethoxy) phenyl] pyridin-2-yl} thio) methyl] -1,3-thiazole-2 yl} amino) benzoic acid ethyl ester

As described in Example 13, 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.

Yield: 59 mg (16% of theory)

HPLC (Method 1): R, = 4.32 min

¹ H NMR (300 MHz, DMSO- (I ₆ ): δ = 10.67 (s, IH), 8.1 (br, s, 2H), 7.88 (d, 2H), 7.68 (d, 2H), 7.47 (i.e. , 2H), 7.13-7.07 (m, 3H), 4.91 (br s, IH), 4.50 (s, 2H), 4.26 (q, 2H), 4.07 (t, 2H), 3.74 (t, 2H), 1.29 (t, 3H).

LC-MS (Method 2): R _t = 2.46 min; MS (ESIpos): m / z = 573 [M + H] ⁺ .

Example 15

2-Amino-4- [4- (2-hydroxyethoxy) phenyl] -6 - [({2 - [(4-nitrophenyl) amino] -1,3-thiazol-4-yl} methyl) thio] pyridine 3,5-dicarbonitrile

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.

Yield: 67 mg (19% of theory)

HPLC (Method 1): R, = 4.23 min

¹ H NMR (400 MHz, DMSO- (I ₆ ): δ = 11.03 (s, IH), 8.20 (d, 2H), 8.1 (br, s, 2H), 7.80 (d, 2H), 7.48 (i.e. , 2H), 7.20 (s, IH), 7.10 (d, 2H), 4.90 (t, IH), 4.52 (s, 2H), 4.07 (t, 2H), 3.74 (q, 2H).

LC-MS (Method 2): R, = 2.39 min; MS (ESIpos): m / z = 546 [M + H] ⁺ .

Example 16

2-Ammo-4- [4- (2-hydroxyemoxy) phenyl] -6 - {[(2 - {[3- (trifluoromethyl) phenyl] amino} -1,3-thiazol-4-yl) methyl] thio} pyridine-3,5-dicarbonitrile

44 mg (0.2 mmol) of 3-trifluoromethylthiourea are treated with a solution of 25.4 mg (0.2 mmol) of 1,3-dichloroacetone in 0.5 ml of DMF. The reaction mixture is stirred at 80 ^° C. for 3 h. After cooling, 62.5 mg (0.2 mmol) of 2-amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercapto-pyridine-3,5-dicarbonitrile in 0.2 ml of DMF and 67 mg (0.8 mmol) of sodium bicarbonate are added , After stirring at RT overnight, the reaction mixture is filtered and purified by preparative HPLC (column: GROMSIL 120 ODS-HE-4, 5 μm, 20 × 50 mm, UV detection: 220 nm, 700 μl injection volume, eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 0 min 10% B → 1.5 min 10% B → 5.5 min 90% B → 7 min 90% B → 7.1 min 10% B -> 8 min 10% B; 25 ml / min). The product-containing fractions are concentrated in vacuo.

Yield: 71.6 mg (63% of theory)

LC-MS (Method 2): R, = 2.56 min; MS (ESIpos): m / z = 569 [M + H] ⁺ .

¹ H NMR (400 MHz ₅ DMSO-de): δ = 10.6 (s, IH), 8.1 (s, IH), 8.1 (br, s, 2H), 7.8 (d, IH), 7.5 (m, 3H ), 7.25 (d, IH), 7.1 (m, 3H), 4.9 (t, IH), 4.5 (s, 2H), 4.1 (t, 2H), 3.75 (q, 2H).

Analogously to Example 16, 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

The examples listed in Table 5 are prepared from the corresponding starting compounds analogously to Example 1: Table 5

Analogously to Example 16, the examples listed in Table 6 are prepared from 2-amino-4- [4- (2-hydroxyethoxy) phenyl] -6-mercaptopyridine-3,5-dicarbonitrile: Table 6

Example 68

2- (2-Hydroxyethoxy) amino-6 - [({2 - [(4-fluoro-phenyl) -amino] -l, 3-thiazol-4-yl} -methyl) thio] -4- [4- (2-hydroxyethoxy) phenyl] pyridine-3,5-dicarbonitrile

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).

Yield: 30 mg (11% of theory)

¹ H-NMR (400 MHz, DMSO-de): δ = 10.24 (s, IH), 8.03 (t, IH), 7.61 (dd, 2H), 7.46 (d, 2H), 7.12 (m, 4H), 6.81 (s, IH), 4.91 (t, IH), 4.80 (t, IH), 4.50 (s, 2H), 4.07 (t, 2H), 3.74 (dt, 2H), 3.62 (t, 2H), 3.56 (m, 2H).

LC-MS (Method 3): R, = 2.10 min; MS (ESIpos): m / z = 563 [M + H] ⁺ .

Example 69

2-Ammo-6 - [({2 - [(4-cyanophenyl) animo] -1,3-tm ^' azol-4-yl} methyl) thio] -4- {4- [2- (dimethylamino) ethoxy ] phenyl} pyridine-3,5-dicarbonitrile

A solution of 26.6 mg (0.15 mmol) N- (4-cyanophenyl) thiourea and 19 mg (0.15 mmol) of 1,3-dichloroacetone in 0.4 ml DMF is stirred for 3 hours at +80 ⁰ C. After cooling to RT, a solution of 50.9 mg (0.15 mmol) of the compound from Example 34A in 0.2 ml of DMF and 50 mg (0.6 mmol) of sodium bicarbonate are added. The mixture is then stirred at RT for 12 h. The

Reaction mixture is filtered and purified directly by preparative HPLC (column: Macherey

Nail VP50 / 21 Nucleosil 100-5 Cl 8 Nautilus, 5 μm, 21 mm x 50 mm; Wavelength: 220 mn; Flow rate: 25 ml / min; Eluent A = water + 0.1% formic acid, eluent B = acetonitrile; Gradient:

0 min 10% B -> 2 min 10% B → 6 min 90% B -> 7 min 90% B → 7.1 min 10% B → 8 min 10% B) cleaned. The product-containing fractions are combined and concentrated on a rotary evaporator.

Yield: 50 mg (57% of theory)

¹ H-NMR (400 MHz, DMSO-dg): δ = 10.80 (s, IH), 8.17 (s, IH), 8.20-7.96 (br. S, 2H), 7.82-7.70 (m, 4H), 7.47 (d, 2H), 7.13 (d, 2H), 7.10 (s, IH), 4.50 (s, 2H), 4.16 (t, 2H), 2.73 (t, 2H), 2.30 (s, 6H).

LC-MS (Method 4): R, = 1.87 min; MS (ESIpos): m / z = 553 [M + H] ⁺ .

Example 70

2-Ammo-4- [4- (2-ammoethoxy) phenyl] -6 - [({2 - [(4-fluoro-phenyl) -amino] -l, 3-thiazol-4-yl} -methyl) -thio] -pyridine 3,5-dicarbonitrile hydrochloride

1000 mg (1.84 mmol) of the compound from Example 39A are dissolved in 100 ml of dioxane, treated with 150 mg (1.41 mmol) of palladium on activated carbon and hydrogenated at 3 bar with hydrogen. After 3 h, 4 ml of 2 M hydrochloric acid are added and hydrogenated for a further 20 h at 3 bar with hydrogen. The mixture is then filtered off with suction through Seitz Klärschichten filter, washed with 50 ml of dioxane and the filtrate mixed with 50 ml of toluene. After removal of the solvent on a rotary evaporator, the residue is taken up in a mixture of 50 ml of water and 50 ml of ethyl acetate. 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 μm, 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.

Yield: 57 mg (6% of theory)

¹ H-NMR (400 MHz, DMSOKI ₆ ): δ = 10.27 (s, IH), 8.08-7.97 (br. S, 2H), 7.67-7.59 (m, 2H), 7.51 (d, 2H), 7.20- 7.09 (m, 4H), 6.98 (s, IH), 4.47 (s, 2H), 4.25 (t, 2H), 3.31-3.21 (m, 2H).

LC-MS (Method 2): R, = 2.08 min; MS (ESIpos): m / z = 518 [M + H] ⁺ .

Example 71

2-Arnmo-6 - [({2 - [(4-fluoro-phenyl) -nino] -l, 3-thiazol-4-yl} -methyl) -thio] -4- [4- (2-hydroxy-propoxy) -phenyl] -pyridine 3, 5-dicarbonitrile

A solution of 43 mg (0.06 mmol) of the compound from Example 43A in 6 ml of methanol is mixed with 3 ml of 1 M hydrochloric acid and stirred at RT for 20 h. The reaction mixture is then treated with 10 ml of saturated sodium bicarbonate solution and extracted with ethyl acetate (three times 10 ml each). The combined organic phases are dried over magnesium sulfate. After removal of the solvent on a rotary evaporator, the crude product is purified by chromatography on silica gel 60 (mobile phase gradient dichloromethane / ethanol 100: 1 → 20: 1).

Yield: 0.34 g (96% of theory)

¹ H-NMR (400 MHz, DMSOKI ₆ ): δ = 10.22 (s, IH), 8.22-7.91 (br.s, 2H), 7.61 (dd, 2H), 7.47 (d, 2H), 7.18-7.06 ( m, 4H), 6.97 (s, IH), 4.91 (d, IH), 4.46 (s, 2H), 4.02-3.94 (m, IH), 3.94-3.83 (m, 2H), 1.17 (d, 3H) , LC-MS (Method 3): R, = 2.26 min; MS (ESIpos): m / z = 533 [M + H] ⁺ .

Experimental descriptions:

B. Evaluation of Pharmacological and Physiological Activity

The pharmacological and physiological action of the compounds according to the invention can be shown in the following assays:

Indirect determination of adenosine agonism via gene expression

Cells of the permanent line CHO (Chinese Hamster Ovary) 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. For pharmacological characterization of cells and for robot-assisted substance screening, the following test protocol is used:

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). The dissolved in 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. for four hours, after which 35 μl of a solution consisting of 50% lysing reagent (30 mM disodium hydrogen phosphate, 10% glycerol, 3% triton XIOO, 25 mM TrisHCl, 2 mM dithiothreitol (DTT), pH 7.8) and 50% luciferase substrate solution (2.5 mM ATP, 0.5 mM luciferin, 0.1 mM coenzyme A, 10 mM tricine, 1.35 mM magnesium sulfate, 15 mM DTT, pH 7.8 1 minute and the luciferase activity was measured with a camera system to determine the EC ₅ o values, ie the concentrations at which the luciferase activity was measured Al cell inhibits 50% of the luciferase response or in the A2b and A2a cells 50% of the maximum stimulability with the corresponding substance are reached. 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.Ν., 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)].

The following 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:

Table 1

Acute lipid lowering in the rat

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 μl of whole blood in EDTA tubes from Sarstedt, centrifugation for 10 min at 12000 rpm). In the plasma, the free fatty acids and triglycerides content is determined at any time using the Cobas Integra 400 ™ analyzer from Roche Diagnostics and expressed as a% change in relation to the value before the substance administration. As a positive control is an oral dose of acipimox (50 mg / kg, 100 mg / kg).

Chronic lipid lowering in the rat

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 μl 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 ™ analyzer, expressed as% change in relation to pre-drug value, as positive control by oral pioglitazone (10 mg / kg; bid).

Chronic lipid lowering in the fructose-fed rat

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 μl of whole blood in EDTA tubes from Sarstedt, centrifugation 10 min at 12000 rpm). In the plasma, the free fatty acids and triglycerides content is determined at any time using the Cobas Integra 400 ™ 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 ™ analyzer from Roche Diagnostics and expressed in ng of insulin per ml of plasma.

Exemplary embodiments of pharmaceutical compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows: - -

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

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). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 of the compound of the invention, 1000 mg of ethanol mg (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

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. - -

Orally administrable solution:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound according to the invention correspond to 20 g of oral solution.

production:

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.

iv solution:

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%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Combination with other medicines

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 erfϊndungsgemäßen compounds and one or more further active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.

Examples of 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.

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.

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-γ- and or PPAR-δ 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,

• Antidiabetics listed in the Red List 2004 / π, Chapter 12, and by way of example and preferably those from the group of sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, oxadiazolidinones, thiazolidinediones, GLP 1 receptor agonists,

Glucagon antagonists, insulin sensitizers, 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

be combined.

Among the 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.

In a preferred embodiment of the invention, 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 ,

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, 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).

In a preferred embodiment of the invention, 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, Acifran or Radecol. In a preferred embodiment of the invention, 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).

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR delta agonist such as, for example and preferably, GW-501516.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds of the present invention are used in combination with a bile acid reabsorption inhibitor, such as, by way of example and preferably, ASBT (= IBAT) inhibitors, e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with insulin. In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a biguanide, by way of example and preferably metformin.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.

In a preferred embodiment of the invention, 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.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors or anticoagulants.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of 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.

Claims

claims

1. Use of compounds of the formula (IA)

in which

R ^{1 is} hydrogen or (C ₁ -C ₆ ) -alkyl which may be substituted by hydroxyl, amino, mono- or di- (C 1 -C ₄ ) -alkylamino, pyrrolidino, piperidino, monochloro, piperazino or N'-methylpiperazino can

R ^{2 is} (C ₂ -C ₆ ) -alkyl which is monosubstituted or disubstituted by identical or different substituents selected from the group of hydroxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- and di- ( C ₁ -C ₄ ) -alkylamino is substituted,

R ^{3 is} a substituent selected from the group of halogen, cyano, nitro, (C ₁ -C ₆ ) -alkyl, hydroxy, (C 1 -C ₆ ) -alkoxy, amino, mono- and di- (C, -C ₆ ) -alkylamino, carboxyl and (C _r C ₆ ) -alkoxycarbonyl,

and

n is the number 0, 1, 2, 3, 4 or 5,

wherein in the event that the substituent R ³ occurs several times, its meanings may be the same or different, and their salts, solvates and solvates of the salts for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes.

2. Use of compounds of the formula (IA)

in which

R ^{1 is} hydrogen or (C ¹ -C ₄ ) -alkyl, which is represented by hydroxy, amino or

Dimethylamino may be substituted,

R ^{3 is} a substituent selected from the group of halogen, cyano, nitro,

(Ci-C ₄₎ alkyl, hydroxy, (C _r C ₄₎ alkoxy, amino, mono- and di- (C ₁ -C ₄₎ - alkylamino, carboxyl and (Ci-C ₄₎ alkoxycarbonyl is,

and

n is the number 0, 1 or 2,

3. Use of compounds of the formula (IA)

in which

R ^{1 is} hydrogen,

R ^{2 is} ethyl, n-propyl or iso-propyl, each one or two times, same or different, having substituents selected from the group of hydroxy,

Methoxy and amino are substituted, 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,

and

n is the number 0, 1 or 2,

4. Use of compounds of the formula (IB)

wherein

n is a number 2, 3 or 4,

R ^{1 is} hydrogen or (C ¹ -C ₄ ) -alkyl

and

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, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, N-

(C 1 -C ₄ ) -alkylpiperazinyl, pyrrolidinyl, oxazolyl, isoxazolyl, pyrimidinyl, Pyrazinyl, optionally substituted by (Ci-C ₄ ) alkyl-substituted thiazolyl or optionally substituted up to three times by halogen, (Ci-C ₄ ) alkyl or (Ci-C ₄ ) alkoxy-substituted phenyl,

and their salts, hydrates, hydrates of the salts and solvates for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and

Diabetes.

5. Use of compounds of the formula (IB)

wherein

n is the number 2,

R ^{1 is} hydrogen, methyl or ethyl

and

R ^{2 is} pyridyl or thiazolyl, which in turn is represented by methyl, ethyl, fluorine, chlorine,

Amino, dimethylamino, acetylamino, guanidino, 2-pyridylamino, 4-pyridylamino, thienyl, pyridyl, morpholinyl, piperidinyl, optionally methyl-substituted thiazolyl or optionally up to three times by chlorine or

Methoxy substituted phenyl may be substituted,

Use of compounds of formula (IB) wherein R ^{1 is} hydrogen or methyl for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes.

7. Use of compounds of the formula (IB), in which

n is the number 2,

R ^{1 is} hydrogen or methyl

and 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,

Use of the compound of the following structure

and their salts, hydrates, hydrates of the salts and solvates for the preparation of a

Drug for the treatment of dyslipidaemia, metabolic syndrome and diabetes.

Use of a combination of compounds as defined in any of claims 1 to 3 and 4 to 8 for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes in combination

Use of compounds as defined in any one of claims 1 to 3 and / or 4 to 8 for the manufacture of a medicament for the treatment of dyslipidemia, metabolic syndromes and diabetes associated with hypertension and cardiovascular disorders.

11. A medicament containing a compound as defined in any one of claims 1 to 3 and / or 4 to 8, in combination with an inert, non-toxic, pharmaceutically suitable excipient for the treatment of dyslipidemia, metabolic syndrome and diabetes.

12. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3 and / or 4 to 8, in combination with an inert, non-toxic, pharmaceutically suitable excipient for the treatment of dyslipidaemia, metabolic syndrome and diabetes associated with hypertension and Diseases of the cardiovascular system.

13. A medicament containing a compound as defined in any one of claims 1 to 3 and / or 4 to 8, in combination with another active ingredient selected from the group of antihypertensive drugs such as beta-blockers, calcium antagonists, diuretics, ACE inhibitors, ATl Antagonists and nitrates, aldosterone antagonists, renin inhibitors, mineral corticoid receptor antagonists, lipid metabolism-altering agents such as HMG-CoA reductase inhibitors, PPARα agonists, PPARγ agonists,

Fibrates, niacin, CETP inhibitors and the antidiabetic drugs mentioned in the 2004 / π Red List, Chapter 12.

14. Method for the treatment and / or prevention of dyslipidemia, metabolic

Syndromes and diabetes as a single disease and in association with hypertension and diseases of the cardiovascular system in humans and animals by administering an effective amount of at least one compound as defined in any one of claims 1 to 8 or a drug as claimed in any one of claims 11 to 13 defined.