EP2588454A1 - Dicyanopyridines substituées et utilisation desdites dicyanopyridines substituées - Google Patents

Dicyanopyridines substituées et utilisation desdites dicyanopyridines substituées

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Publication number
EP2588454A1
EP2588454A1 EP11737909.9A EP11737909A EP2588454A1 EP 2588454 A1 EP2588454 A1 EP 2588454A1 EP 11737909 A EP11737909 A EP 11737909A EP 2588454 A1 EP2588454 A1 EP 2588454A1
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Prior art keywords
hydrogen
formula
amino
compound
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP11737909.9A
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German (de)
English (en)
Inventor
Alexandros Vakalopoulos
Daniel Meibom
Peter Nell
Frank SÜSSMEIER
Barbara ALBRECHT-KÜPPER
Katja Zimmermann
Joerg Keldenich
Dirk Schneider
Ursula Krenz
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Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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Publication of EP2588454A1 publication Critical patent/EP2588454A1/fr
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present application relates to novel substituted dicyanopyridines, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, preferably for the treatment and / or prophylaxis of cardiovascular diseases.
  • Adenosine a purine nucleoside
  • Adenosine is present in all cells and is released from a variety of physiological and pathophysiological stimuli.
  • Adenosine is produced intracellularly in the degradation of adenosine 5'-monophosphate (AMP) and S-adenosyl homocysteine as an intermediate, but can be released from the cell and then functions as a hormone-like substance or neurotransmitter by binding to specific receptors.
  • AMP adenosine 5'-monophosphate
  • S-adenosyl homocysteine as an intermediate, but can be released from the cell and then functions as a hormone-like substance or neurotransmitter by binding to specific receptors.
  • adenosine Under normoxic conditions, the concentration of free adenosine in the extracellular space is very low. However, the extracellular concentration of adenosine in the affected organs increases dramatically under both ischemic and hypoxic conditions. For example, it is known that adenosine inhibits platelet aggregation and increases blood flow in the coronary arteries. It also affects blood pressure, heart rate, neurotransmitter release and lymphocyte differentiation. In adipocytes, adenosine is able to inhibit lipolysis and thus reduce the concentration of free fatty acids and triglycerides in the blood.
  • adenosine aim to increase the supply of oxygen in the affected organs or to reduce the metabolism of these organs in order to achieve an adaptation of the organ metabolism to the organ perfusion under ischemic or hypoxic conditions.
  • adenosine receptor-selective ligands are substances which bind selectively to one or more subtypes of the adenosine receptors and either mimic the action of adenosine (adenosine agonists) or block its action (adenosine antagonists) ,
  • adenosine receptors are mediated intracellularly by the messenger cAMP.
  • an activation of the membrane-bound adenylate cyclase leads to an increase of the intracellular cAMP, while the binding of adenosine to the AI or A3 receptors via adenylate cyclase inhibits a decrease in the adenylate cyclase intracellular cAMP content.
  • adenosine receptors In the cardiovascular system, the main effects of the activation of adenosine receptors are: bradycardia, negative inotropy and protection of the heart from ischemia (preconditioning) via AI receptors, dilation of the vessels via A2a and A2b receptors as well as inhibition of fibroblasts and smooth muscle cell proliferation via A2b receptors.
  • AI agonists coupled preferably via G; proteins
  • a decrease in the intracellular cAMP content is observed (preferably after direct pre-stimulation of adenylate cyclase by forskolin).
  • A2a and A2b agonists (coupling preferably via Gs proteins) to an increase and A2a and A2b antagonists to a decrease in cAMP concentration in the cells.
  • A2 receptors direct pre-stimulation of adenylate cyclase by forskolin is not helpful.
  • AI receptors by specific AI agonists leads to a frequency-dependent lowering of the heart rate in humans, without having any influence on the blood pressure.
  • Selective AI agonists could thus be suitable, inter alia, for the treatment of angina pectoris and atrial fibrillation.
  • the cardioprotective effect of AI receptors in the heart can be exploited, inter alia, by the activation of these AI receptors by specific AI agonists for treatment and organ protection in acute myocardial infarction, acute coronary syndrome, heart failure, bypass surgery, cardiac catheterization and organ transplantation.
  • A2b receptors by adenosine or specific A2b agonists leads to a blood pressure reduction via the dilation of vessels. Lowering blood pressure is accompanied by a reflex increase in heart rate. Heart rate increase can be reduced by activation of AI receptors by specific AI agonists.
  • adipocytes activation of AI and A2b receptors causes inhibition of lipolysis.
  • the selective or combined action of AI and Al / A2b agonists on lipid metabolism thus leads to a decrease in free fatty acids and triglycerides.
  • Lowering lipids reduces insulin resistance and improves symptoms in patients with metabolic syndrome and diabetics.
  • the above-mentioned receptor selectivity can be determined by the action of the substances on cell lines expressing the respective receptor subtypes after stable transfection with the corresponding cDNA (see in this regard the document ME Olah, H. Ren, J.
  • adenosine receptor-specific valid ligands are mainly derivatives based on the natural adenosine [S.-A. Poulsen and R.J. Quinn, "Adenosine Receptors: New Opportunities for Future Drugs", Bioorganic and Medicinal Chemistry 6 (1998), pages 619-641].
  • these adenosine ligands known from the prior art generally have the disadvantage that they are not really receptor-specific, are less potent than the natural adenosine, are only very weakly active after oral administration or have undesirable side effects on the central nervous system (CNS) ( AK Dhalla et al., Curr. Topics in Med.
  • CNS central nervous system
  • the object of the present invention is to provide novel compounds which act as potent and selective agonists of the adenosine AI receptor or selective dual agonists of the AI and A2b receptor, have the same or improved physicochemical and / or pharmacokinetic properties as well as an advantageous therapeutic and / or Pharmacological profile of action and are suitable as such for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of cardiovascular diseases.
  • the present invention relates to compounds of the formula (I)
  • A is oxygen or sulfur
  • G is CH or N
  • K is CH, CF or N
  • L is CR 6 or N
  • R 6 represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or (C 1 -C 4 -alkoxy, in which (C 1 -C 4 -alkoxy may be substituted by 1 or 2 substituents hydroxy, M is CR 7 or N, where
  • R 7 represents hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl or (C 1 -C 4 -alkoxy, in which (C 1 -C 4 -alkoxy may be substituted by 1 or 2 substituents hydroxy, with the proviso that a maximum of two of the groups K, L or M stands for N, R 1 is hydrogen or (C r C 4) -alkyl,
  • R 2 represents hydroxycarbonyl, aminocarbonyl, mono- (C 1 -C 4) -alkylaminocarbonyl, di- (C 1 -C 4) -alkylaminocarbonyl, (C 3 -C 7 ) -cycloalkylaminocarbonyl, aminosulfonyl, (C 1 -C 4) -alkylsulfonylamino or Phenylsulfonylamino, where mono- (C 1 -C 4) -alkylaminocarbonyl, di (C 1 -C 4) -alkylaminocarbonyl and (C 3 -C 7) -
  • Cycloalkylaminocarbonyl having 1 to 3 substituents independently of one another can be substituted from the group fluorine, hydroxy and amino,
  • R 3 is hydrogen, fluorine or methoxy
  • R 4 is hydrogen, fluorine, (C 1 -C 6) -alkoxy, mono- (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamino, (C 1 -C 4) -alkylcarbonylamino, mono (C 1 -C 4) alkylaminosulfonyloxy, di- (C 1 -C 4) -alkylaminosulfonyloxy or 2-oxopyrrolidin-1-yl, where (C 1 -C 6) -alkoxy having 1 to 3 substituents independently of one another selected from the group trifluoromethyl, hydroxy, C4) -alkoxy, amino, mono- (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamino, aminocarbonyl, mono- (C 1 -C 4) -alkylaminocarbonyl, di- (C 1 -C
  • R 10 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or isomers, or
  • R 5 is hydrogen or -NR 8 R 9 , where
  • R 8 is hydrogen or (C r C 4) alkyl
  • R 9 is hydrogen, (C r C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl, in which (C 1 -C 6 ) -alkyl having 1 or 2 substituents independently of one another selected from the group consisting of fluorine, difluoromethyl, trifluoromethyl, Hydroxy and (Ci-C-alkoxy may be substituted, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle having 1 or 2 substituents independently selected from the group of fluorine, hydroxy and 4- to 7-membered heterocycle may be substituted, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, with the exception of the compounds
  • Compounds according to the invention are the compounds of the formula (I) and their N-oxides, salts, solvates and solvates of N-oxides and salts, the compounds of the formulas below and their N-oxides, salts, solvates and compounds encompassed by formula (I) Solvates of N-oxides and salts as well as those of formula (I), hereinafter referred to as exemplary compounds and their N-oxides, salts, solvates and solvates of N-oxides and salts, as far as it is in the compounds of the formula (I) mentioned below are not already N-oxides, salts, solvates and solvates of N-oxides and salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds according to the invention may therefore possibly also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • alkyl is a linear or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
  • alkyl is a linear or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
  • Cycloalkyl in the context of the invention is a monocyclic, saturated carbocycle having 3 to 7 ring carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.
  • Di-alkylamino in the context of the invention represents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 4 carbon atoms.
  • Mono-alkylaminocarbonyl in the context of the invention represents an amino group which is linked via a carbonyl group and which has a linear or branched alkyl substituent having 1 to 4 carbon atoms.
  • Di-alkylaminocarbonyl is in the context of the invention an amino group which is linked via a carbonyl group and which has two identical or different linear or branched alkyl substituents each having 1 to 4 carbon atoms.
  • Cycloalkylaminocarbonyl in the context of the invention is an amino group which is linked via a carbonyl group and which forms a monocyclic, saturated carbocycle having 3 to 7 carbon atoms.
  • cyclopropylaminocarbonyl More particularly, and preferably, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl and cycloheptylaminocarbonyl.
  • Alkylcarbonylamino in the context of the invention represents an amino group having a linear or branched alkylcarbonyl substituent which has 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the nitrogen atom.
  • alkylcarbonylamino represents an amino group having a linear or branched alkylcarbonyl substituent which has 1 to 4 carbon atoms in the alkyl chain and is linked via the carbonyl group to the nitrogen atom.
  • Alkylsulfonylamino in the context of the invention represents an amino group having a linear or branched alkylsulfonyl substituent which has 1 to 4 carbon atoms and is linked via the sulfonyl group to the N-atom.
  • alkylsulfonylamino represents an amino group having a linear or branched alkylsulfonyl substituent which has 1 to 4 carbon atoms and is linked via the sulfonyl group to the N-atom.
  • -Butylsulfonylamino represents an amino group having a linear or branched alkylsulfonyl substituent which has 1 to 4 carbon atoms and
  • Mono-alkylaminosulfonyloxy in the context of the invention represents an aminosulfonyl group which is linked via an oxygen atom and which has a linear or branched alkyl substituent having 1 to 4 carbon atoms.
  • Examples which may be mentioned by way of example include: methylamino-sulfonyloxy, ethylaminosulfonyloxy, n-propylaminosulfonyloxy, isopropylaminosulfonyloxy, n-butylaminosulfonyloxy and tert. -Butylaminosulfonyloxy.
  • Di-alkylaminosulfonyl in the context of the invention represents an aminosulfonyl group which is linked via an oxygen atom and which has two identical or different linear or branched alkyl substituents each having 1 to 4 carbon atoms. Examples which may be mentioned are: N, N-dimethylaminosulfonyloxy, N, N-diethylaminosulfonyloxy, N-ethyl-N-methylaminosulfonyloxy, N-methyl-N-n-propylaminosulfonyloxy, N-n-butyl-N-methylaminosulfonyloxy and N-tert. Butyl-N-methylaminosulfonyloxy.
  • Heterocycle in the context of the invention is a saturated heterocycle having a total of 4 to 7 ring atoms, which contains one or two ring heteroatoms from the series N, O and / or S and is linked via a ring carbon atom or optionally a ring nitrogen atom.
  • Examples which may be mentioned are: azetidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.
  • azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl Particularly, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.
  • the side group of an ⁇ -amino acid in the meaning of R includes both the side groups of the naturally occurring ⁇ -amino acids and the side groups of homologues and isomers of these ⁇ -amino acids.
  • the ⁇ -amino acid can be present in both the L and the D configuration or else as a mixture of the L and D form.
  • side groups which may be mentioned are: methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl ( Isoleucine), butan-1-yl (norleucine), tert.
  • Preferred a-amino acid side groups in the meaning of R 3 are methyl (alanine), propan-2-yl (valine), 2-methylpropan-1-yl (leucine), benzyl (phenylalanine), imidazol-4-ylmethyl (histidine ), Hydroxymethyl (serine), 1-hydroxyethyl (threonine), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric acid), aminomethyl (2 , 3-diaminopropionic acid),
  • arginine 3-guanidinopropan-1-yl (arginine).
  • the L configuration is preferred in each case.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Most preferably, the substitution with one or two identical or different substituents.
  • Another object of the present invention is the use of the following compound for the treatment and / or prophylaxis of diseases in humans and animals: 4- ⁇ [(6-Amino-3,5-dicyano-4-phenylpyridin-2-yl) sulfane]
  • R 6 is hydrogen or fluorine
  • M is CR 7 or N, wherein is hydrogen, fluorine, chlorine, difluoromethyl, trifluoromethyl, methoxy or ethoxy, wherein ethoxy may be substituted with 1 or 2 substituents hydroxy, with the proviso that only one of the groups K, L or M stands for N,
  • R is hydrogen or methyl
  • R 2 is hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, cyclopropylammocarbonyl, cyclobutylammocarbonyl, aminosulfonyl, methylsulfonylamino, ethylsulfonylamino or phenylsulfonylamino, with ethylaminocarbonyl, cyclopropylammocarbonyl and cyclobutylammocarbonyl having 1 or 2 substituents independently selected from the group consisting of fluoro, hydroxy and amino can, R 3 is hydrogen or fluorine,
  • R for hydrogen, fluorine, Methylamino, ethylamino, dimethylamino, diethylamino, methylcarbonylamino, ethylcarbonylamino, dimethylaminosulfonyloxy, diethylaminosulfonyloxy or 2-oxopyrrolidin-1-yl, wherein (C 1 -C 3 -alkoxy having 1 to 3 substituents independently selected from among
  • R 10 is hydrogen, methyl, 2-methylpropan-1-yl, hydroxymethyl, 1-hydroxyethyl, 4-aminobutan-1-yl or 3-aminopropan-1-yl, or
  • R 5 is hydrogen or -NR 8 R 9 , where
  • R 8 is hydrogen, methyl or ethyl
  • R 9 is hydrogen, (C r C 6 ) -alkyl or (C 3 -C 6 ) -cycloalkyl, wherein (C 1 -C 6) -alkyl having 1 or 2 substituents independently of one another can be substituted from the group of fluorine, difluoromethyl, trifluoromethyl and hydroxy, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle wherein the 4- to 7-membered heterocycle having 1 or 2 substituents independently selected from the group of fluorine and hydroxy substituted and their salts, solvates and solvates of the salts, with the exception of the compounds
  • A is sulfur, G is N, K is CH, CF or N, L is CR 6 or N, wherein
  • R 6 is hydrogen or fluorine
  • M is CR 7 or N, where hydrogen, fluorine, trifluoromethyl, methoxy or 2-hydroxyethoxy, with the proviso that only one of the groups K, L or M is N, R 1 is hydrogen,
  • R 2 is hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl or cyclopropylaminocarbonyl,
  • R 3 is hydrogen
  • R 4 is hydrogen, fluorine or (C 1 -C 4 ) -alkoxy, where (C 1 -C 4 -alkoxy having 1 or 2 substituents independently of one another is selected from the group consisting of trifluoromethyl, hydroxy, amino and a group of the formula
  • R 10 is hydrogen or methyl, R 5 is hydrogen or -NR 8 R 9 , wherein
  • R 8 is hydrogen
  • R 9 is hydrogen, (Ci-C 6 ) -alkyl or cyclopropyl, or
  • A stands for sulfur
  • G is CH, K is CH, CF or N, L is CR 6 or N, where
  • R 6 is hydrogen or fluorine
  • M is CR 7 or N
  • R 7 is hydrogen, fluorine, trifluoromethyl, methoxy or 2-hydroxyethoxy, with the proviso that only one of the groups K, L or M is N, R 1 is hydrogen,
  • R 2 is hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl or cyclopropylaminocarbonyl,
  • R 3 is hydrogen
  • R 4 is hydrogen, fluorine or (C 1 -C 4 ) -alkoxy, where (C 1 -C 4 ) -alkoxy having 1 or 2 substituents independently of one another is selected from the group consisting of trifluoromethyl, hydroxy, amino and a group of the formula
  • R is hydrogen or methyl
  • R 5 is -NR 8 R 9 , wherein
  • R 8 is hydrogen
  • R 9 is hydrogen
  • R 2 is hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl or cyclopropylaminocarbonyl, and their salts, solvates and solvates of the salts.
  • G stands for CH, and R 2 is aminocarbonyl, and their salts, solvates and solvates of the salts.
  • R 2 is hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, aminosulfonyl, methylsulfonylamino, ethylsulfonylamino or phenylsulfonylamino, wherein ethylaminocarbonyl, cyclopropylaminocarbonyl and cyclobutylaminocarbonyl having 1 or 2 substituents independently selected from the group of fluoro, hydroxy and amino substituted and their salts, solvates and solvates of the salts.
  • R 2 is hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, aminosulfonyl, methylsulfonylamino, ethylsulfonylamino or phenylsulfonylamino, with ethylaminocarbonyl, cyclopropylaminocarbonyl and cyclobutylaminocarbonyl having 1 or 2 substituents independently selected from the group consisting of fluoro, hydroxy and amino and their salts, solvates and solvates of the salts.
  • K stands for CH
  • L stands for CR 6
  • R 6 is hydrogen
  • M is CR 7
  • R 7 is hydrogen
  • R 3 is hydrogen
  • R 4 is hydrogen or ethoxy, wherein ethoxy having 1 or 2 substituents independently selected from
  • R 8 is hydrogen
  • R 9 is (Ci-C 6 ) -alkyl or cyclopropyl, or R 8 and R 9 together with the nitrogen atom to which they are attached, one
  • Azetidinyl- form a pyrrolidonyl or a piperidinyl ring, and their salts, solvates and solvates of the salts.
  • R 5 is -NR 8 R 9 , where
  • Azetidinyl- form a pyrrolidonyl or a piperidinyl ring, and their salts, solvates and solvates of the salts.
  • K is CH
  • L is CR 6
  • R 6 is hydrogen
  • M is CR 7
  • R 7 is hydrogen
  • R 3 is hydrogen
  • R 4 is hydrogen or ethoxy, where ethoxy is substituted by 1 or 2 substituents independently of one another selected from the group hydroxy or methoxy,
  • G is CH or N
  • R is hydroxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl or cyclopropylaminocarbonyl,
  • A stands for S,
  • R 5 is -NR 8 R 9 , where
  • R 8 is hydrogen
  • R 9 is hydrogen, (Ci-C6) -alkyl or cyclopropyl, or
  • Azetidinyl- form a pyrrolidonyl or a piperidinyl ring, and their salts, solvates and solvates of the salts.
  • radical definitions given in detail in the respective combinations or preferred combinations of radicals are optionally replaced by radical definitions of other combinations, regardless of the particular combinations of radicals indicated.
  • Another object of the present invention is a process for the preparation of the compounds of formula (I) according to the invention, characterized in that
  • X 1 represents a suitable leaving group, preferably halogen, in particular chlorine, bromine or iodine, or represents mesylate, tosylate or triflate, or
  • R is amino, first with copper (II) chloride and isopentyl nitrite in a suitable solvent in a compound of formula (VI)
  • Suitable solvents for the reaction (II) + (III) -> ⁇ (I) are all organic solvents which are inert under the reaction conditions.
  • ketones such as acetone and methyl ethyl ketone
  • acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane
  • esters such as ethyl acetate or butyl acetate
  • hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane
  • chlorinated hydrocarbons such as dichloromethane, trichloromethane and chlorobenzene
  • solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidinone (NMP), acetonitrile or pyridine. It is likewise possible to use mixtures of the abovementioned solvents. Preference is given to using dimethylformamide.
  • Suitable bases for this reaction are the customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonate such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium methoxide, sodium or potassium ethoxide or Potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyllithium or phenyllithium, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8 Diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5- Diazabicyclo [4.3.0] non-5-ene (DBN).
  • alkali metal carbonates and bicarbonates such as potassium carbon
  • the base may in this case be used in an amount of 1 to 10 mol, preferably 1 to 5 mol, in particular 1 to 3 mol, based on 1 mol of the compound of the formula (II).
  • the reaction can be carried out at normal, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Suitable inert solvents for the reaction (IV) + (V) - > ⁇ (I) are in particular acyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, hydrocarbons such as benzene, Toluene, xylene, hexane and cyclohexane, or dipolar solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidinone (NMP) and pyridine. It is also possible to use mixtures of these solvents. Preference is given to using 1,2-dimethoxyethane.
  • Suitable bases for this reaction are, in particular, alkali metal alkoxides, such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium.
  • alkali metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide
  • amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organometallic compounds such as butyllithium or phenyllithium.
  • potassium tert-butoxide is used.
  • the base is in this case generally used in an amount of 1 to 1.25 mol, preferably in equimolar amount, based on 1 mol of the compound of formula (V).
  • the reaction (IV) + (V) -> (I) is generally carried out in a temperature range from -20 ° C to + 120 ° C, preferably at + 20 ° C to + 100 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
  • the process step (IA) -> (VI) is generally carried out with a molar ratio of 2 to 12 moles of copper (II) chloride and 2 to 12 moles of isopentyl nitrite based on 1 mole of the compound of formula (IA).
  • Suitable solvents for this process step are all organic solvents which are inert under the reaction conditions.
  • acyclic and cyclic ethers such as di- ethyl ether and tetrahydrofuran, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, 1, 2-dichloroethane and chlorobenzene, or other solvents such as dimethylformamide, acetonitrile or pyridine. It is also possible to use mixtures of these solvents. Preferred solvents are acetonitrile and dimethylformamide.
  • the reaction is generally carried out in a temperature range from -78 ° C to + 180 ° C, preferably in the range of + 20 ° C to + 100 ° C, in particular at + 20 ° C to + 60 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
  • the process step (VI) + (VII) -> (I-B) is generally carried out with a molar ratio of 1 to 8 mol of the compound of formula (VII) based on 1 mol of the compound of formula (XV).
  • Suitable solvents for this process step are all organic solvents which are inert under the reaction conditions. These include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate or Butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, 1, 2-dichloroethane and chlorobenzene, or other solvents such as dimethylformamide, acetonitrile, pyridine or dimethylsulfoxide. Water is also suitable as a solvent
  • the reaction is generally carried out in a temperature range from 0 ° C to + 180 ° C, preferably in the range of + 20 ° C to + 120 ° C, in particular at + 20 ° C to + 100 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
  • the compounds of the formula (II), (III) and (VII) are either commercially available, known to the person skilled in the art or can be prepared by customary methods.
  • the compounds of the formula (IV) can be prepared in analogy to processes described in the literature [cf. e.g. Kambe et al., Synthesis, 531-533 (1981); Elnagdi et al., Z. Naturforsch. 47b, 572-578 (1991); Reddy et al., J. Med. Chem. 49, 607-615 (2006); Evdokimov et al., Org. Lett. 8, 899-902 (2006)] or by reacting compounds of the formula (II) in which X is S, in analogy to processes described in the literature [cf. z. Fujiwara, H. et al., Heterocycles 1993, 36 (5), 1105-1113, Su et al., J. Med. Chem. 1988, 31, 1209-1215].
  • the alkali metal sulfide used is preferably sodium sulfide in an amount of from 1 to 10 mol, preferably from 1 to 8 mol, in particular from 1 to 5 mol, based on 1 mol of the compound of the formula (IV).
  • Suitable solvents for this process step are all organic solvents which are inert under the reaction conditions. These include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, ketones such as acetone and methyl ethyl ketone, acyclic and cyclic ethers such as diethyl ether, 1, 2-dimethoxyethane, tetrahydrofuran and dioxane, esters such as ethyl acetate or Butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, 1, 2-dichloroethane and chlorobenzene, or dipolar solvents such as acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide or N-methylpyrrolidin
  • the reaction is generally carried out in a temperature range from 0 ° C to + 180 ° C, preferably in the range of + 20 ° C to + 120 ° C, in particular at + 40 ° C to + 100 ° C, optionally in a microwave.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
  • reaction parameters previously described for the sequence (I-A) ⁇ (VI) ⁇ (I-B), such as solvents, reaction temperatures and molar ratios, are used analogously.
  • alkali hydroxide excess sodium or potassium hydroxide is preferably used.
  • Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol and mixtures thereof with water are particularly suitable as solvents.
  • the reaction is generally carried out in a temperature range from + 20 ° C to + 120 ° C, preferably at + 50 ° C to + 100 ° C.
  • This process step is generally carried out with a molar ratio of 2 to 5 mol of copper (II) chloride and 0.1 to 0.9 mol of isopentyl nitrite based on 1 mol of the compound of formula (II) or (IV).
  • 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 di- ethyl ether and tetrahydrofuran, esters such as ethyl acetate or butyl acetate, hydrocarbons such as benzene, toluene, xylene, hexane and cyclohexane, chlorinated hydrocarbons such as dichloromethane, 1, 2-dichloroethane and chlorobenzene, or other solvents such as dimethylformamide, acetonitrile or pyridine. It is also possible to use mixtures of these solvents. THF is preferred.
  • the reaction is generally carried out in a temperature range from -30 ° C to + 40 ° C, preferably in the range of 0 ° C to + 20 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example in the range from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular those listed under R 2 , R 4 , R 8 and R 9 , starting from the compounds of the formula (I) obtained by the above methods.
  • transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protection groups.
  • reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protection groups.
  • the compounds of the invention show an unpredictable, valuable pharmacological activity spectrum and are therefore particularly suitable for the prophylaxis and / or treatment of diseases.
  • the pharmaceutical activity of the compounds according to the invention can be explained by their action as potent, selective ligands on the adenosine AI and / or A2b receptors. They act as selective Al agonists or selective dual Al / A2b agonists.
  • the compounds of the invention show an advantageous therapeutic, pharmacological and / or physicochemical profile of action, such as improved solubility in aqueous media.
  • adenosine AI and / or A2b receptor selective ligands are understood to be those adenosine receptor ligands in which, on the one hand, a marked effect on the AI and / or A2b adenosine receptor subtypes and, on the other hand, no or a distinct one a weaker effect (factor 10 or higher) on A2a and A3 adenosine receptor subtypes can be observed, reference being made to the methods described in section Bl. described tests.
  • the compounds of the invention may function as full or as partial adenosine receptor agonists, depending on their particular structure.
  • Partial adenosine receptor agonists are defined herein as receptor ligands that elicit a functional response to adenosine receptors that is lower than full agonists (such as adenosine itself). As a result, partial agonists are less effective in receptor activation than full agonists. For test methods for receptor activation, see section B-6. and B-7. described tests.
  • the compounds of the formula (I) are suitable, alone or in combination with one or more other active substances, for the prophylaxis and / or treatment of various diseases, for example disorders of the cardiovascular system (cardiovascular diseases), cardioprotection for damage to the heart and metabolic disorders. and kidney disease.
  • cardiovascular system cardiovascular system
  • diseases of the cardiovascular system or cardiovascular diseases are to be understood as meaning, for example, the following diseases: hypertension, peripheral and cardiac vascular diseases, coronary heart disease, coronary restenosis, e.g. Peripheral blood vessel restenosis, myocardial infarction, acute coronary syndrome, acute coronary syndrome with ST elevation, acute coronary syndrome without ST elevation, stable and unstable angina pectoris, myocardial insufficiency, Prinzmetal angina, persistent ischemic dysfunction (hibernating myocardium), transient postischemic dysfunction (stunned Myocardium), heart failure, tachycardia, atrial tachycardia, arrhythmias, atrial and ventricular fibrillation, persistent atrial fibrillation, permanent atrial fibrillation, atrial fibrillation with normal left ventricular function, atrial fibrillation with impaired left ventricular function, Wolff-Parkinson-White syndrome, peripheral circulatory disorders, increased levels of fibrinogen and low-density L
  • cardiac insufficiency includes both acute and chronic manifestations of heart failure, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve failure, heart failure Heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders, diastolic and systolic heart failure and acute worsening heart failure episodes.
  • acute decompensated heart failure right heart failure, left heart failure
  • the compounds according to the invention are also suitable for the reduction of the myocardium affected by an infarct and for the prophylaxis of secondary infarcts.
  • the compounds of the invention for the prophylaxis and / or treatment of thromboembolic disorders, reperfusion injury after ischemia, micro- and macrovascular damage (vasculitis), arterial and venous thrombosis, edema, ischaemia such as myocardial infarction, stroke and transient ischemic attacks, for cardioprotection in coronary arteries Bypass surgery (CABG), primary PTCAs, PTCAs after thrombolysis, rescue PTCA, heart transplantation and open heart surgery, as well as organ protection in transplantation, bypass surgery, cardiac catheterization and other surgical procedures.
  • CABG coronary arteries
  • primary PTCAs PTCAs after thrombolysis
  • rescue PTCA heart transplantation and open heart surgery
  • organ protection in transplantation bypass surgery
  • cardiac catheterization and other surgical procedures.
  • the compounds according to the invention are, for example, the prophylaxis and / or treatment of diseases of the genitourinary area, such as, for example, Irritable bladder, erectile dysfunction and female sexual dysfunction, but also the prophylaxis and / or treatment of inflammatory diseases such.
  • inflammatory dermatoses psoriasis, acne, eczema, atopic dermatitis, dermatitis, keratitis, scarring, wart formation, chilblains
  • diseases of the central nervous system and neurodegenerative disorders stroke, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depression , Multiple sclerosis
  • pain cancer
  • cancer skin cancer, liposarcoma, carcinoma of the gastrointestinal tract, liver, pancreas, lung, kidney, ureter, prostate and genital tract
  • nausea and vomiting associated with cancer therapies as well as nausea and vomiting associated with cancer therapies.
  • Other indications include, for example, the prophylaxis and / or treatment of inflammatory and immune diseases (Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis) and respiratory diseases, such as chronic obstructive pulmonary disease (chronic bronchitis, COPD), asthma, emphysema , Bronchiectasis, cystic fibrosis (cystic fibrosis) and pulmonary hypertension, especially pulmonary arterial hypertension.
  • inflammatory and immune diseases Crohn's disease, ulcerative colitis, lupus erythematosus, rheumatoid arthritis
  • respiratory diseases such as chronic obstructive pulmonary disease (chronic bronchitis, COPD), asthma, emphysema , Bronchiectasis, cystic fibrosis (cystic fibrosis) and pulmonary hypertension, especially pulmonary arterial hypertension.
  • the compounds according to the invention also come for the prophylaxis and / or treatment of diabetes, in particular diabetes mellitus, gestational diabetes, insulin-dependent diabetes and non-insulin-dependent diabetes, of diabetic secondary diseases such as Retinopathy, nephropathy and neuropathy, metabolic disorders (metabolic syndrome, hyperglycemia, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance, obesity) and atherosclerosis and dyslipidaemias (hypercholesterolemia, hyperpriglyceridemia, increased levels of postprandial plasma triglycerides, Hypoalpha lipoproteinemia, combined hyperlipidaemias), in particular diabetes, metabolic syndrome and dyslipidaemias
  • diabetes mellitus gestational diabetes
  • insulin-dependent diabetes and non-insulin-dependent diabetes of diabetic secondary diseases such as Retinopathy, nephropathy and neuropathy
  • metabolic disorders metabolic syndrome, hyperglycemia, gestational diabetes, hyperinsulinemia, insulin resistance, glucose intolerance, obesity
  • the compounds according to the invention can also be used for the treatment and / or prophylaxis of thyroid disorders (hyperthyroidism), diseases of the pancreas (pancreatitis), liver fibrosis, viral diseases (HPV, HCMV, HIV), cachexia, osteoporosis, gout, incontinence and for wound healing and angiogenesis be used.
  • thyroid disorders hyperthyroidism
  • diseases of the pancreas pancreatitis
  • liver fibrosis fibrosis
  • viral diseases HPV, HCMV, HIV
  • cachexia osteoporosis
  • gout incontinence
  • incontinence for wound healing and angiogenesis
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction and atrial fibrillation.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of diabetes, metabolic syndrome and dyslipidaemias.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • Suitable combination active ingredients are: lipid metabolism-altering active substances antidiabetics, hypotensive agents, circulation-promoting and / or antithrombotic agents, antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics , PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB 4 receptor antagonists), analgesics such as aspirin, anti-depressants and other pesticides.
  • lipid metabolism-altering active substances antidiabetics, hypotensive agents, circulation-promoting and / or antithrombotic agents, antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists, anorectics , PAF-AH inhibitors, anti-inflammatory drugs (COX inhibitors, LTB 4 receptor antagonists), analgesics such as aspirin, anti-depressants and other pesticides.
  • the present invention relates, in particular, to combinations of at least one of the compounds according to the invention with at least one lipid metabolism-altering active ingredient, an antidiabetic agent, a hypotensive agent and / or an antithrombotic agent.
  • the compounds of the invention may preferably be with one or more
  • Lipid metabolizing agents 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 adsorber, bile acid reabsorption inhibitor, MTP
  • Inhibitors lipase inhibitors, LpL activators, fibrates, niacin, CETP inhibitors, PPAR-a, PPAR- ⁇ and / or PPAR-8 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 / radical scavengers;
  • Antidiabetic agents mentioned in the Red List 2004/11, Chapter 12, and by way of example and preferably those from the group of sulfonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors, inhibitors of dipeptidyl peptidase IV (DPP-IV inhibitors ), Oxadiazolidinones, thiazolidinediones, GLP 1 receptor agonists, glucagon antagonists, insulin sensitizers, CCK 1 receptor agonists, leptin receptor agonists, inhibitors of
  • the blood pressure-lowering active substances by way of example and preferably from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, renin inhibitors, beta-
  • Receptor blockers alpha-receptor blockers, aldosterone antagonists, mineralocorticoid Receptor antagonists, ECE inhibitors, ACE / NEP inhibitors and the vasopeptidase inhibitors; and or
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors or anticoagulants, diuretics;
  • cGMP cyclic guano sinmonophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • sildenafil adenosine monophosphate
  • Vardenafil adenosine monophosphate
  • PDE 3 inhibitors such as Milrinone
  • Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
  • ABP atrial natriuretic peptide
  • BNP B-type natriuretic peptide
  • CNP C-type natriuretic peptide
  • urodilatin urodilatin
  • IP receptor prostacyclin receptor
  • Inhibitors of the I f (funny channel) channel such as Ivabradine;
  • Calcium sensitizers such as by way of example and preferably levosimendan; ⁇ Potassium supplements;
  • NO-independent, but heme-dependent guanylate cyclase stimulators in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
  • Guanylate cyclase NO- and heme-independent activators in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510; • inhibitors of human neutrophilic ecstasy (HNE), such as Sivelestat and DX-890 (Reltran);
  • HNE human neutrophilic ecstasy
  • the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib; and / or ⁇ the energy metabolism of the heart affecting compounds such as etomoxir, dichloroacetate, Ranolazine and trimetazidine be combined.
  • 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-a agonists, PPAR- ⁇ agonists, PPAR-8 agonists, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, antioxidants / radical scavengers, and the cannabinoid receptor 1 antagonists.
  • HMG-CoA reductase inhibitors preferably compounds from the group of HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorption inhibitors, MTP inhibitors, lipase inhibitors, thyroid hormones and / or thyroid mimetics, niacin receptor Agonists, CETP inhibitor
  • 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 or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melamine, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melamine, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • the compounds according to the invention are administered in combination with a thyroid hormone and / or thyroid mimetic, such as by way of example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3).
  • a thyroid hormone and / or thyroid mimetic such as by way of example and preferably D-thyroxine or 3,5,3'-triiodothyronine (T3).
  • the compounds according to the invention are administered in combination with an agonist of the niacin receptor, such as by way of example and preferably niacin, Acipimox, Anatin or Radecol.
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the compounds according to the invention are administered in combination with a PPAR-y agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-8 agonist such as, by way of example and by way of preference, GW-501516 or BAY 68-5042.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • the compounds according to the invention are administered in combination with an antioxidant / free-radical scavenger such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
  • the compounds of the invention are administered in combination with a cannabinoid receptor 1 antagonist, such as by way of example and preferably rimonabant or SR-147778.
  • Antidiabetic agents are preferably understood as meaning insulin and insulin derivatives as well as orally active hypoglycemic agents.
  • Insulin and insulin derivatives here include both insulins of animal, human or biotechnological origin as well as mixtures thereof.
  • the orally active hypoglycemic agents preferably include sulphonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors and PPAR-gamma agonists.
  • the compounds according to the invention are administered in combination with insulin.
  • the compounds according to the invention are administered in combination with a sulphonylurea, such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
  • a sulphonylurea such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
  • the compounds according to the invention are administered in combination with a biguanide, such as by way of example and preferably metformin.
  • the compounds of the invention are administered in combination with a meglitinide derivative, such as by way of example and preferably repaglinide or nateglinide.
  • a meglitinide derivative such as by way of example and preferably repaglinide or nateglinide.
  • the compounds according to the invention are administered in combination with a glucosidase inhibitor, such as by way of example and preferably miglitol or acarbose.
  • a glucosidase inhibitor such as by way of example and preferably miglitol or acarbose.
  • the compounds of the invention are administered in combination with a DPP-IV inhibitor, such as by way of example and preferably sitagliptin and vildagliptin.
  • a DPP-IV inhibitor such as by way of example and preferably sitagliptin and vildagliptin.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone and rosiglitazone.
  • a PPAR-gamma agonist for example from the class of thiazolidinediones, such as, by way of example and by way of preference, pioglitazone and rosiglitazone.
  • the blood pressure lowering agents are preferably understood as meaning compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers and diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, valsartan, candesartan, embusartan, olmesartan or telmisartan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds according to the invention are administered in combination with an alpha-receptor B, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, Acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlor
  • the compounds according to the invention are administered in combination with an aldosterone or mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • an aldosterone or mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds according to the invention are administered in combination with a vasopressin receptor antagonist, such as by way of example and preferably Conivaptan, tolvaptan, lixivaptan or SR-121463.
  • a vasopressin receptor antagonist such as by way of example and preferably Conivaptan, tolvaptan, lixivaptan or SR-121463.
  • the compounds according to the invention are administered in combination with an organic nitrate or NO donor, such as by way of example and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, or in combination with inhaled NO.
  • an organic nitrate or NO donor such as by way of example and preferably sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1
  • a positive inotropically active compound such as by way of example and preferably cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, adrenaline, norepinephrine, dopamine or dobutamine.
  • the compounds according to the invention are administered in combination with antisympathotonics, such as reserpine, clonidine or alpha-methyl-dopa, with potassium channel agonists, such as minoxidil, diazoxide, dihydralazine or hydralazine, or with nitric oxide-releasing substances, such as glyceryl nitrate or nitroprusside sodium.
  • antisympathotonics such as reserpine, clonidine or alpha-methyl-dopa
  • potassium channel agonists such as minoxidil, diazoxide, dihydralazine or hydralazine
  • nitric oxide-releasing substances such as glyceryl nitrate or nitroprusside sodium.
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors or anticoagulants.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, dabigatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • a vitamin K antagonist such as by way of example and preferably coumarin.
  • Particularly preferred in the context of the present invention are combinations containing at least one of the compounds according to the invention and one or more further active compounds selected from the group consisting of HMG-CoA reductase inhibitors (statins), diuretics, beta-receptor blockers, organic nitrates and NO Donors, ACE inhibitors, angiotensin AII antagonists, aldosterone and mineralocorticoid receptor antagonists, vasopressin receptor antagonists, platelet aggregation inhibitors and anticoagulants, and their use for the treatment and / or prophylaxis of the aforementioned disorders.
  • statins HMG-CoA reductase inhibitors
  • diuretics beta-receptor blockers
  • organic nitrates and NO Donors organic nitrate
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the 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
  • the parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets to be applied films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous for example, antioxidants such ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A -> 3.0 min 5% A -> 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
  • Method 2 (LC-MS):
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm x 4 mm
  • Eluent A 1 l of water + 0.5 ml of 50% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min
  • Oven 50 ° C
  • UV detection 210 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm
  • Eluent A 1 l of water + 0.5 ml of 50% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min
  • Oven 50 ° C
  • UV detection 210 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2.5 ⁇ MAX-RP 100A Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A -> 3.0 min 5% A -> 4.0 min 5% A -> 4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
  • Method 6 Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50 x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A-> 0.1 min 90% A-> 1.5 min 10% A -> 2.2 min 10% A Furnace: 50 ° C; Flow: 0.33 ml / min; UV detection: 210 nm.
  • Method 7 (LC-MS):
  • Device Type MS Waters (Micromass) Quattro Micro
  • Device type HPLC Agilent 1 100 series
  • 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
  • Oven 50 ° C
  • Flow 2 ml / min
  • UV detection 210 nm
  • Method 9 LC-MS
  • Device Type MS Waters ZQ
  • Device type HPLC Waters Alliance 2795
  • Column Phenomenex Onyx Monolithic C18, 100 mm x 3 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 min 65% A-> 4.5 min 5% A -> 6 min 5% A
  • Flow 2 ml / min
  • Oven 40 ° C
  • UV detection 210 ⁇ m.
  • Device DSQ II; Thermo Fisher-Scientific; DCI with NH 3 , flow: 1.1 ml / min; Source temperature: 200 ° C; Ionization energy 70 eV; Heat DCI filament up to 800 ° C; Mass Range 80-900.
  • the product contains about 10% of the regioisomer 4- [( ⁇ S) -2- ⁇ [tert. Butyl (dimethyl) silyl] oxy ⁇ - 1-methylethoxy] benzaldehyde.
  • Example 10A The illustration was carried out as described in WO 03/053441 for Example 1 (1st stage).
  • Example 47A 0.1 g (0.268 mmol) of 4- [4- (2-hydroxyethoxy) phenyl] -2- (phenylthio) pyridine-3,5-dicarbonitrile (Example 47A) was initially charged in 1 ml of DMF. After addition with 73 mg (0.937 mmol) of sodium sulfide was stirred for 2 h at 80 ° C and stirred at RT overnight. The reaction mixture was added with 20 ml of 1N hydrochloric acid, the precipitate was filtered off and washed well with water.
  • Example 34A The examples listed in Table 2 were prepared analogously to Example 34A from the corresponding starting materials.
  • Example 40A 7.50 g (33.989 mmol) of 4- (hydroxymethyl) -N-methylpyridine-2-carboxamide hydrochloride hydrate (Example 40A) were initially charged in 90 ml of methanol, admixed with 23.64 g (271,915 mmol) of manganese dioxide and stirred at RT overnight. The reaction mixture was filtered through silica gel, the Silica gel / manganese dioxide mixture was stirred overnight with tetrahydrofuran / methanol 1: 1, then the silica gel / manganese dioxide mixture was filtered off and the filtrate was evaporated.
  • Example 36A 1.5 g (4.568 mmol) of Example 36A were initially charged in 20 ml of tetrahydrofuran. After addition of 61 mg (0.457 mmol) of copper (II) chloride and 1.6 g (13.703 mmol) of isopentyl nitrite, the reaction solution was stirred at RT overnight. For the first 8 hours, 61 mg (0.457 mmol) of copper (II) chloride were added to the reaction solution. The reaction mixture mixture was added with 9.1 ml of 1 N hydrochloric acid, extracted three times with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel 60 (eluent: toluene / ethyl acetate 50/1 -> 20/1).
  • Example 35A 5 g (12.872 mmol) of Example 35A were initially charged in 60 ml of tetrahydrofuran. After addition of 173 mg (1.287 mmol) of copper (II) chloride and 4.5 g (38.615 mmol) of isopentyl nitrite, the reaction solution was stirred at RT overnight. During the first 8 hours, 173 mg (1.287 mmol) of copper (II) chloride were added four times to the reaction solution. The reaction mixture mixture was added with 25.7 ml of 1 N hydrochloric acid, twice with ethyl acetate extracted.
  • Example 39A 3 g (8.368 mmol) of Example 39A were initially charged in 39 ml of tetrahydrofuran. After addition of 113 mg (0.837 mmol) of copper (II) chloride and 2.94 g (25.104 mmol) of isopentyl nitrite, the reaction solution was stirred for 2 days at RT. 113 mg (0.837 mmol) of copper (II) chloride were added four times in the course of the first day, and 226 mg (1.674 mmol) of copper (II) chloride were added twice to the reaction solution during the second day. The reaction solution mixture was added with 16.7 ml of 1 N hydrochloric acid, extracted twice with ethyl acetate.
  • Example 60A 5 g (27.75 mmol) of methyl 3- (1-hydroxyethyl) benzenecarboxylate (Example 60A) were initially charged in 100 ml of toluene. At 0 ° C., 0.98 g (36.07 mmol) of phosphorus tribromide were added dropwise and the mixture was stirred at RT for 45 min. The reaction solution was poured onto ice water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel 60 (eluent: cyclohexane: ethyl acetate 50: 1-> 40: 1).
  • Example 87A 650 mg (3.02 mmol) of rac-N- [3- (1-hydroxyethyl) phenyl] methanesulfonamide (Example 87A) were initially charged in 9 ml of dichloromethane. At 0 ° C., 1.08 g (9.07 mmol) of thionyl chloride was added dropwise to the reaction solution and the mixture was stirred at RT for 3 h. The reaction solution was evaporated.
  • Example 1 Exemplary embodiments: Example 1
  • Example 65A 150 mg (0.307 mmol) of methyl 3- [1- ( ⁇ 6-amino-3,5-dicyano-4- [4- (2-methoxyethoxy) phenyl] pyridin-2-yl ⁇ sulfanyl) ethyl] benzenecarboxylate (Example 65A) were dissolved in 7 ml of tetrahydrofuran. After adding 14.7 mg (0.61 mmol) of lithium hydroxide, it was stirred at RT overnight. The mixture was then stirred for 4 h at 40 ° C. The reaction solution was adjusted to pH 4 with 1N hydrochloric acid and the clear solution was purified by preparative HPLC (Chromasil, water / acetonitrile + 0.1% trifluoroacetic acid).
  • Example 74A The preparation was carried out as described for Example 23 from the corresponding starting material (Example 74A).
  • Example 58 rac-N- ⁇ 3- [1- ( ⁇ 6-Amino-3,5-dicyano-4- [4- (2,2,2-trifluoroethoxy) phenyl] pyridin-2-yl ⁇ sulfanyl) ethyl] phenyl ⁇ methanesulfonamide
  • Example 56 The preparation was carried out, as described in Example 56, from the corresponding starting compounds in Example 16A and Example 88A.
  • Example 17 The preparation was carried out as described in Example 60 from the corresponding starting compound (Example 17).
  • Example 57A The preparation was carried out as described in Example 57A from the corresponding educt (Example 15).
  • Example 75A 50 mg (0.12 mmol) of 4- ⁇ [(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl) sulfanyl] methyl ⁇ -N-methylpyridine-2-carboxamide.
  • Example 75A 19.6 mg (0.18 mmol) Azetidin-3-ol hydrochloride and 36.2 mg (0.36 mmol) of triethylamine were dissolved in 1 ml of tetrahydrofuran and stirred for 1 h at RT. To the reaction mixture was added so much water and tetrahydrofuran that a Solution was created. The solution was purified by preparative HPLC (Chromasil, water / acetonitrile + 0.1% trifluoroacetic acid).
  • Example 75A were initially charged in 1.26 ml of DMF. After Offset with 33.8 mg (0.45 mmol) of 2- (methylamino) ethanol was stirred for 1 h at RT. The reaction mixture was mixed with enough water and tetrahydrofuran to give a clear solution. The solution was purified by preparative HPLC (Chromasil, water / acetonitrile + 0.1% trifluoroacetic acid).
  • Example 81A presented in 1.5 ml of DMF. After being mixed with 26 mg (0.24 mmol) of azetidin-3-ol hydrochloride and 24 mg (0.24 mmol) of triethylamine, it was stirred at RT overnight. The reaction mixture was purified by preparative HPLC (Chromasil, water / acetonitrile).
  • Example 83A The preparation was carried out as described in Example 92 from the corresponding starting compound (Example 83A).
  • Example 84A presented in 1.5 ml of tetrahydrofuran. After addition of 26.6 mg (0.31 mmol) of (R) -3-pyrrolidinol, the mixture was stirred at RT for 30 min. The reaction mixture was mixed with enough water to form a clear solution. The solution was purified by preparative HPLC (Chromasil, water / acetonitrile + 0.1% trifluoroacetic acid).
  • Example 85A 50 mg (0.12 mmol) of 3- ⁇ [(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl) sulfanyl] methyl ⁇ -N-methylbenzenecarboxamide
  • Example 85A 50 mg (0.12 mmol) of 3- ⁇ [(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl) sulfanyl] methyl ⁇ -N-methylbenzenecarboxamide
  • Example 85A were initially charged in 1 ml of tetrahydrofuran. After adding 19.6 mg (0.18 mmol) of azetidin-3-ol hydrochloride and 24.2 mg (0.24 mmol) of triethylamine, the mixture was stirred at RT for 30 min. The reaction mixture was mixed with enough water to form a clear solution. The solution was purified by preparative HPLC (Chromasil, water / acetonitrile
  • Example 10 The preparation was carried out as described in Example 96 from the corresponding starting compound (Example 10).
  • Example 96 The preparation was carried out as described in Example 96 from the corresponding starting compound (Example 24).
  • Example 79A The preparation was carried out as described in Example 75 and Example 99 from the corresponding starting compound (Example 79A).
  • Example 57A were initially charged in 1 ml of dioxane. After adding 21.6 mg (0.6 mmol) of 4 N hydrochloric acid in dioxane, the mixture was stirred at RT overnight. The reaction mixture was evaporated. The residue was purified by preparative HPLC (Chromasil, water / acetonitrile).
  • Example 96 The preparation was carried out as described in Example 96 from the corresponding starting compound (Example 18).
  • Example 96 The preparation was carried out as described in Example 96 from the corresponding starting compound (Example 20).
  • 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, duration of culture and test incubation, forskolin concentration and medium composition.
  • test parameters such as cell density, duration of culture and test incubation, forskolin concentration and medium composition.
  • FCS fetal calf serum
  • 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).
  • 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 pipetted in a dilution series of 5 x 10 ⁇ u M to 3 x 10 "6 M (final concentration) to the test cultures (maximum DMSO final concentration in test mixture: 0.5%). 10 minutes later, forskolin to the AI cells are added and then all cultures are incubated for four hours at 37 ° C.
  • a solution consisting of lysis reagent (30 mM disodium hydrogenphosphate, 10% glycerol, 3% Triton X100) are added to the test cultures , 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 Shaken for about 1 minute and the luciferase activity measured with a camera system, the EC 5 o values, ie the concentrations at which the AI cell inhibits 50% of the luciferase response are determined.
  • lysis reagent 30 mM disodium hydrogenphosphate, 10% glycerol, 3% Triton X100
  • the reference compound used in these experiments is the adenosine-analogous compound NECA (5-N-ethylcarboxamido-adenosine), which binds with high affinity to all adenosine receptor subtypes and has an agonistic effect [Comparable pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells ", Naunyn Schmiedebergs Arch. Pharmacol. 357, 1-9 (1998)].
  • NECA adenosine-analogous compound
  • Table A lists the EC 5 o values of representative embodiments for the receptor stimulation on adenosine AI, A2a and A2b receptor subtypes:
  • the caudal artery is prepared and clamped in a conventional apparatus for measuring isolated vessels.
  • the vessels are perfused in a heat bath and contracted with phenylephrine.
  • the degree of contraction is determined by a contraction knife.
  • test substances are given and measured the decrease in the contraction of the vessels.
  • a decrease of the contraction corresponds to a dilatation of the Vessels.
  • the EC 5 o value of a test substance with regard to its relaxing properties is the concentration at which the contraction of the vessels is reduced by 50%.
  • Guards Claw monkeys carrying an internal transmitter which can permanently measure both blood pressure and heart rate (telemetric detection of hemodynamic parameters), test substances are administered orally in various concentrations. Subsequently, blood pressure and heart rate and their changes are recorded over 6-24 hours.
  • Wistar rats 250-300 g body weight; Fa. Harlan- Winkelmann
  • Wistar rats are kotjon nar- with 5% isoflurane ®.
  • the anesthesia is maintained with 2% isoflurane ® and compressed air in a anesthetic mask.
  • the carotid artery is dissected free and a tip catheter (Miliar micro-tip transducer, 2 French, HSE) is inserted and advanced into the left ventricle. Subsequently, a second catheter is inserted into the jugular vein. Placebo solution and test substance solutions are infused into the animals in ascending concentrations via this catheter.
  • cardiac function (such as heart rate, left ventricular pressure, contractility (dp / dt), left ventricular end-diastolic pressure) is measured through the left ventricular catheter.
  • cardiac function such as heart rate, left ventricular pressure, contractility (dp / dt), left ventricular end-diastolic pressure
  • the brain is removed from male Wistar rats and immediately transferred to an ice-cold 0.32 mol / l sucrose solution.
  • the tissue is minced with a glass Teflon homogenizer and then centrifuged (1000 x g for 10 minutes). The supernatant is then ultracentrifuged at 30,000 g for 30 minutes. The resulting pellet is resuspended in 10 ml of water and allowed to stand on ice for 30 minutes.
  • the membranes are resuspended in 50 mmol / l Tris-HCl buffer, pH 7.4 and incubated with 2 U / ml adenosine deaminase at 37 ° C for 30 min. This is followed by a protein determination according to Bradford. The membranes are frozen in small aliquots and stored at -80 ° C until use in the binding assay.
  • the filters are then washed three times with ice-cold Tris-HCl buffer 50 mM, pH 7.4.
  • the radioactivity on the filter is measured with the addition of 100 ⁇ l scintillation cocktail in a Microbeta TriLux beta counter (Perkin Elmer, Massachusetts, USA).
  • Table B lists values for the GTP shift of representative embodiments.
  • mice strain: CD1
  • running wheels Weber et al., Psychopharmacology 2008, in print
  • mice are caged and trained in cages with an impeller 2-3 weeks before the start of the experiment. 2 weeks before the start of the experiment, the movements of the mice in the impeller are recorded by a photocell by means of computer and different running parameters such. the daily running distance, the individual distances covered, but also your time distribution over the day.
  • the animals are randomized according to their natural running behavior in groups (8-12 animals) (control group and 1- multiple substance groups).
  • the animals are treated orally with the substances to be tested.
  • Single doses or ascending doses e.g., 0.3-1-3-10-30 mg / kg
  • Substances are tested in two independent experiments. There are at least 3 days between 2 experiments in which the animals do not receive any substances.
  • the running behavior of the animals is observed and recorded over 24 hours after the application.
  • the evaluation of the running intervals and the total running distance takes place over a period of several hours during the main activity time of the mice. Effects are specified as percent of the control value.
  • PBS buffer pH 6.5 90.00 g NaCl pa (for example from Merck, Item No. 1.06404.1000), 13.61 g KH 2 PO 4 pa (for example from Merck, Item No. 1,04873,1000) and 83.35 g of 1N sodium hydroxide solution (eg from Bernd Kraft GmbH, Item No. 01030.4000) are weighed into a 1 liter volumetric flask, made up to 1 liter with distilled water and stirred for 1 hour. Thereafter, the pH is adjusted to 6.5 with 1 N hydrochloric acid (for example from Merck, Item No. 1.09057.1000).
  • 1 N hydrochloric acid for example from Merck, Item No. 1.09057.1000.
  • PEG / water solution (30:70 v / v): 30 ml of polyethylene glycol 400 (for example from Merck, Art.
  • PEG / PBS buffer pH 6.5 80:20 v / v: 80 ml of polyethylene glycol 400 (eg Merck, Art. No. 8.17003.1000) and 20 ml of PBS buffer pH 6.5 are dissolved in a 100 ml Homogenized volumetric flask.
  • Dimethyl sulfoxide e.g., Baker, art. No. 71572500
  • distilled water
  • At least 4 mg of the test substance are accurately weighed into a wide-necked 10 mm Screw V-Vial (Glastechnik Gräfenroda GmbH, Art. No. 8004 ⁇ ⁇ - ⁇ / ⁇ 5 ⁇ ) with matching screw cap and septum in a pipetting robot with DMSO added to a concentration of 50 mg / ml and shaken for 10 minutes.
  • Preparation of the starting solution for calibration solutions (stock solution): Transfer 10 ⁇ of the original solution into a microtiter plate using a pipetting robot and make up to a concentration of 600 ⁇ g / ml with DMSO. The sample is shaken until completely dissolved.
  • Calibration solution 1 (20 g / ml): Mix 34.4 ⁇ of the stock solution with 1000 ⁇ DMSO and homogenize.
  • Calibration solution 2 (2.5 g / ml): 100 ⁇ of the calibration solution 1 are mixed with 700 ⁇ DMSO and homogenized. Preparation of the sample solutions:
  • Sample solution for solubility up to 5 g / liter in PBS buffer pH 6.5 Transfer 10 ⁇ of original solution into a microtiter plate and add 1000 ⁇ PBS buffer pH 6.5.
  • the sample solutions prepared in this way are shaken at 1400 rpm for 24 hours at 20 ° C. by means of a temperature-controlled shaker (for example Eppendorf Thermomixer comfort Art. No. 5355 000.011 with interchangeable block Art. No. 5362.000.019). Of these solutions, in each case 180 ⁇ are removed and transferred to Beckman Polyallomer Centrifuge Tubes (Art. No. 343621). These solutions are centrifuged for 1 hour at about 223,000 x g (e.g., Beckman Optima L-90K Ultracentrifuge with Type 42.2 Ti rotor at 42,000 rpm). From each sample solution, 100 ⁇ of the supernatant are removed and diluted to 1: 5 and 1: 100 with DMSO. Each dilution is bottled in a suitable vessel for HPLC analysis. analytics:
  • Agilent 1100 with DAD (G1315A), quat. Pump (Gl 31 1A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: Phenomenex Gemini C18, 50 mm x 2 mm, 5 ⁇ ; Temperature: 40 ° C; Eluent A: water / phosphoric acid pH 2; Eluent B: acetonitrile; Flow rate: 0.7 ml / min; Gradient: 0-0.5 min 85% A, 15% B; Ramp: 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; Ramp: 3.5-4 min 85% A, 15% B; 4-5 minutes 85% A, 15% B.
  • Agilent 1100 with DAD (G1315A), quat. Pump (Gl 31 1A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: VDSoptilab Kromasil 100 C18, 60 mm x 2.1 mm, 3.5 ⁇ ; Temperature: 30 ° C; Eluent A: water + 5 ml perchloric acid / liter; Eluent B: acetonitrile; Flow rate: 0.75 ml / min; Gradient: 0-0.5 min 98% A, 2% B; Ramp: 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; Ramp: 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.
  • Table C lists the solubility values for representative embodiments.
  • test compounds are incubated in vitro with liver microsomes or preferably with primary fresh hepatocytes of various animal species (eg from rat and dog) as well as of human origin to obtain metabolite profiles of a complete hepatic phase I and phase II metabolism to obtain and compare.
  • liver microsomes or preferably with primary fresh hepatocytes of various animal species (eg from rat and dog) as well as of human origin to obtain metabolite profiles of a complete hepatic phase I and phase II metabolism to obtain and compare.
  • test compounds are incubated at a concentration of 10-20 ⁇ .
  • stock solutions of the substances are prepared in a concentration of 1 -2 mM in acetonitrile and then pipetted with a 1: 100 dilution in the incubation.
  • Liver microsomes are incubated in 50 mM potassium phosphate buffer (pH 7.4) with and without NADPH-generating system consisting of 1 mM NADP + , 10 mM glucose-6-phosphate and 1 unit of glucose-6-phosphate dehydrogenase at 37 ° C incubated.
  • Primary hepatocytes are also incubated in suspension in Williams E medium at 37 ° C.
  • the incubation mixtures are stopped with acetonitrile (final concentration about 30%) and the protein is centrifuged off at about 15,000 ⁇ g. The thus stopped samples are either analyzed directly or stored at -20 ° C until analysis.
  • the analysis is carried out by high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS). For this, the supernatants of the incubation samples are chromatographed with suitable C18 reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution. The UV chromatograms in combination with mass spectrometric MS / MS data are used to identify and structure the metabolites.
  • HPLC-UV-MS / MS ultraviolet and mass spectrometric detection
  • test compounds are preferably dissolved in acetonitrile.
  • 96-well plates are incubated for a defined time at 37 ° C with pooled human liver microsomes. The reactions are stopped by addition of 100 ⁇ L acetonitrile, which is a suitable internal standard. Precipitated proteins are separated by centrifugation, the supernatants are pooled and analyzed by LC-MS / MS.
  • the substance to be examined is administered to animals (eg mouse, rat, dog) intravenously as a solution, the oral administration is carried out as a solution or suspension via a gavage. After substance administration, the animals are bled at fixed times. This is heparini-5 Siert, then it is obtained by centrifugation plasma. The substance is analytically quantified in the plasma via LC / MS-MS. From the plasma concentration-time curves determined in this way, the pharmacokinetic parameters such as AUC (area under the concentration-time curve), Cmax (maximum plasma concentration), Tl / 2 (half-life) and CL (clearance) are calculated by means of a validated pharmacokinetic calculation program.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • 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.
  • 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 at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution).
  • a physiologically acceptable solvent e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

L'invention concerne de nouvelles dicyanopyridines substituées, des procédés pour les préparer, leur utilisation pour le traitement et/ou la prévention de maladies, ainsi que leur utilisation pour fabriquer des médicaments destinés au traitement et/ou à la prévention de maladies, de préférence destinés au traitement et/ou à la prévention de pathologies cardiovasculaires.
EP11737909.9A 2010-06-30 2011-06-27 Dicyanopyridines substituées et utilisation desdites dicyanopyridines substituées Ceased EP2588454A1 (fr)

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US20130210795A1 (en) 2013-08-15
US9187428B2 (en) 2015-11-17
DE102010030688A1 (de) 2012-01-05
WO2012000945A1 (fr) 2012-01-05
CA2803971A1 (fr) 2012-01-05

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