Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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

Definitions

• the present application relates to novel substituted 2-amino-3-cyanopyridines, processes for their preparation, their use for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of cardiovascular disease.
• Chronic heart failure is one of the most common medical conditions whose incidence and prevalence increase with age [Redfield MM, N Engl J Med 347: 1442-1444; 2002]. Despite improved pharmacological therapy, especially in the ⁇ III-TV stadiums, the mortality of heart failure patients is very high at up to 50% per year [Hoppe UC & Erdmann E, Z Kardiol 90: 218-237; 2001].
• Functional and structural remodeling processes initially triggered by, for example, a myocardial infarction, a chronic pressure or volume burden and / or inflammatory processes.
• NCX1 Mammalian sarcolemmal sodium-calcium exchangers (Na + / Ca 2+ exchangers, NCX) are encoded by a family of three genes (NCX1, NCX2, and NCX3).
• NCX1 SLC8A1 gene on chromosome 2p22.1
• NCX2 and NCX3 which have only 68-75% sequence homology with NCX1 [Schulze DH et al., Ann NY Acad Sci 976: 187-196, 2002], are restricted to nerve cells and skeletal muscle cells [Lytton J, Biochem J 406: 365-382, 2007].
• NCX1 alternative splicing of the six exons A, B, C, D, E, and F
• NCX 1.1 exons ACDEF
• NCX are transmembrane proteins which transport Na + and Ca 2+ ions in the opposite direction (antiport) across the membrane in a stoichiometric ratio of 3: 1.
• the antiport occurs in forward mode (Ca 2+ - outward transport) or in reverse mode (Ca 2+ inward transport).
• the myocardial NCX1 thus influences the membrane potential (depolarization), the intracellular Ca 2+ equilibrium (contraction / relaxation) and the Ca 2+ signaling in cardiomyocytes [Levi AJ et al., Am J Physiol 266: H1422-H1433 , 1994].
• NCX1 thus plays an essential role in the electromechanical Coupling, ie NCXl affects the electrical excitability (action potential) and its conversion into mechanical work (contraction / relaxation) in the heart.
• the mechanism of electromechanical coupling in the heart is based on temporally and spatially limited oscillations of the intracellular calcium concentration.
• calcium flows via the voltage-dependent L-type calcium channels into the cell interior during the action potential.
• This transmembrane calcium influx activates the spatially proximate ryanodine receptors and induces calcium release from the sarcoplasmic reticulum into the cytosol.
• This increase in the intracellular calcium concentration stimulates the contractile proteins and induces systolic strength development in the heart.
• the stimulability of the contractile proteins diminishes until complete relaxation of the heart muscle cell.
• the removal of calcium from the cytosol occurs mainly via the SERCA (sarcoplasmic reticulum Ca 2+ - ATPase) back into the sarcoplasmic reticulum and via the sarcolemmal NCXl into the extracellular space.
• SERCA sarcoplasmic reticulum Ca 2+ - ATPase
• NCX1 The central role of myocardial NCX1 in the above-mentioned processes could be demonstrated in mouse models with cardiac-specific NCX1 overexpression or knockout.
• NCX1 overexpression led to a disturbed electromechanical coupling with progressive cardiac hypertrophy and finally to impaired heart failure (cause of death) [Reuter et al., J Physiol 554.3: 779-789, 2003].
• mice with cardiac-specific NCX1 overexpression [Pott C et al., Ann NYA 1099: 310-314, 2007] or knockout [Henderson SA et al., Circ. Res.
• NCX1 amino acid exchange inhibitory peptides, 10 and 30 ⁇
• NCX1 amino acid exchange inhibitory peptides, 10 and 30 ⁇
• NCX with KB-R7943 has a cardioprotective effect in rats (reduced ischemia / reperfusion-related myocardial damage to the heart) and that a single dose of 10 mg / kg KB-R7943 prior to induction of myocardial ischemia (transient Coronary artery ligation) reduced the experimental incidence of ventricular arrhythmias to cardiac death [Nagasawa Y et al. Eur J Pharmacol 506: 249-255, 2005].
• KB-R7943 is a nonspecific NCX inhibitor (NCX3 »NCX1> NCX2), which has a 20-fold higher affinity for reverse mode (IC 5 o 0.3 ⁇ ) than for forward mode (IC50 17 ⁇ ) of NCX, and, in addition, it influences the intracellular Na + and Ca 2+ oscillations unselectively in relation to other ion channels [Amran MS et al., Cardiovasc Drug Rev 21: 255-276, 2003].
• NCX with KB-R7943 has been demonstrated to be cardioprotective in rats (reduced ischemia / reperfusion myocardial damage to the heart) [Nagasawa Y et al., Eur J Pharmacol 506: 249-255, 2005].
• guinea pigs pretreated with KB-R7943 it has been shown that digitalis intoxication-induced extrasystoles, ventricular tachycardias, and fibrillation to cardiac arrest were less common [Watano T et al., BrJ Pharmacol 127: 1846-1850, 1999].
• SEA0400 blocks NCX with an affinity sequence of NCX1 >> NCX2 NCX3 and a higher preference for forward mode [Lee C et al., J Pharmacol Exp Ther 311: 748-757, 2004].
• SEA0400 blocked the NCX1 with an IC50 of 90 and 92 nM, while for KB-R7943 the IC50 values were 7 ⁇ and 9.5 ⁇ , respectively.
• substituted 2-aminopyridines are claimed as NO synthase inhibitors.
• WO 01/62233 describes substituted cyanopyridines and -pyrimidines as adenosine receptor modulators for the treatment of, for example, Alzheimer's and Parkinson's disease.
• EP-A 1302463 claims dicyanopyridines as potassium channel opener for the treatment of incontinence.
• WO 2004/055015 discloses aminocyanopyridines as MAP kinase inhibitors for the treatment of cancers.
• Variously substituted pyridines for the treatment of cancers are described in WO 2008/008059, US 2008/0280891 and US 2009/0093479.
• DE-A 102008053024 discloses substituted pyridines for controlling insects and mites.
• the object of the present invention was to provide novel compounds which act as selective inhibitors of the cellular sodium-calcium exchanger and are suitable as such, in particular for the treatment and / or prevention of cardiovascular diseases.
• the present invention relates to compounds of the general formula (I)
• n is the number 0 or 1
• p is the number 0, 1 or 2
• R 4 and R 5 independently of one another each represent hydrogen, (G-C 6) -alkyl or (C 3 -C 9) -cycloalkyl,
• (C 1 -C 6) -alkyl in which (C 1 -C 6) -alkyl in turn has 1 to 3 substituents selected independently from the group of fluorine, cyano, trifluoromethyl, (C 3 -C 9) -cycloalkyl, hydroxy, (C 1 -C 6) -alkoxy, trifluoromethoxy, (C 1 -C 4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamino, 4 to 8-membered heterocyclyl and or 6-membered heteroaryl and a group of the formula
• the 4- to 8-membered heterocycle in turn may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C6) alkyl, hydroxy, oxo and (Ci-C6) alkoxy, and wherein
• C # l represents a carbon atom of (C 1 -C 6) -alkyl
• Q is a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle
• R 4 and R 5 together with the atom (s) to which they are attached form a 4- to 8-membered heterocycle
• the 4- to 8-membered heterocycle in which the 4- to 8-membered heterocycle in turn contains 1 or 2 substituents independently of one another selected from the group consisting of cyano, trifluoromethyl, (C 1 -C 6) -alkyl, hydroxy, oxo, (C 1 -C 6) -alkoxy, trifluoromethoxy, C4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino and di (C 1 -C 4) -alkylamino may be substituted,
• R 6 is (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl
• q is a number 1, 2 or 3,
• R 2 is halogen, cyano, methyl or hydroxymethyl
• R 3 is phenyl
• phenyl having 1 or 2 substituents independently of one another can be substituted from the group halogen, cyano, difluoromethyl, trifluoromethyl, (C 1 -C 4) -alkyl, trifluoromethoxy, (C 1 -C 4) -alkoxy and pentafluorosulfanyl,
• 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 the compounds of formula (I) 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 of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
• the present invention therefore encompasses 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.
• 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 hereby used as a compound understood in which at least one atom is exchanged within the inventive compound for another atom of the same atomic number, but with a different atomic mass than the usual or predominantly occurring in nature atomic mass.
• 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.
• Certain isotopic variants of a compound of the invention may be useful, for example, to study the mechanism of action or distribution of drug 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.
• the incorporation of 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 of the invention may therefore optionally 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 here denotes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted into compounds according to the invention (for example metabolically or hydrolytically).
• alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2 Methylbutyl, 3-methylbutyl, n -hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,4-dimethylpentyl and 4,4 -Dimethylpentyl.
• Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 or 1 to 4 or 2 to 4 carbon atoms. Preference is given to a linear or branched alkoxy radical having 1 to 4 or 2 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isoproperoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
• Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group.
• Preferred is a linear or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group.
• methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl By way of example and preferably mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
• 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 by way of example include methylamino, ethylamino, propylamino, isopropylamino 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. Examples which may be mentioned are: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and N-tert-butyl-N-methylamino.
• Cycloalkyl or carbocycle in the context of the invention is a monocyclic, saturated alkyl radical having 3 to 8 or 3 to 6 carbon atoms. Examples which may be mentioned by way of example are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preference is given to a monocyclic, saturated alkyl radical having 3 to 6 carbon atoms.
• Heterocycle or heterocyclyl in the context of the invention is a saturated heterocycle having a total of 4 to 8 ring atoms which contains one or two ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally a ring nitrogen atom is linked.
• Examples which may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl.
• Preferred are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and morpholinyl.
• Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatics) having a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
• heterocycle monocyclic aromatic heterocycle (heteroaromatics) having a total of 5 or 6 ring atoms, which contains up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
• furyl examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
• furyl pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiadiazolyl, pyridyl.
• Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine and fluorine.
• An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
• the end point of the line where the symbol *, # 2 or # 1 stands does not stand for a carbon atom or a CFb group, respectively is part of the bond to the respective designated atom to which R 1 , R 3 or R 4 are bonded.
• treatment includes inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the course or progression of such conditions and / or the symptoms of such conditions.
• therapy is understood to be synonymous with the term “treatment”.
• prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
• the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
• 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. Particularly preferred is the substitution with one or two substituents.
• R 1 is phenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl or pyridyl,
• n is the number 0 or 1
• p is the number 2
• R 4 and R 5 independently of one another each represent hydrogen, (C 1 -C 6) -alkyl or (C 3 -C 5) -cycloalkyl,
• (C 1 -C 6) -alkyl in turn, having 1 to 3 substituents independently selected from the group fluorine, cyano, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxy, (Ci-C i) alkoxy, trifluoromethoxy, methoxycarbonyl, ethoxycarbonyl, amino, methyl - mino, ethylamino, dimethylamino, N-methyl-N-ethylamino, diethylamino, azetidinyl,
• azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl may in turn be substituted by 1 substituent selected from the group consisting of methyl, ethyl, hydroxy, oxo and methoxy,
• C # l represents a carbon atom of (C 1 -C 6) -alkyl
• Q is a cyclopropyl, cyclobutyl or cyclopentyl ring, or
• R 4 and R 5 together with the atom (s) to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl ring,
• azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl ring may in turn be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, methyl, ethyl, hydroxy, oxo, methoxy and ethoxy, R 6 is methyl or Ethyl stands,
• q is a number 1, 2 or 3,
• R 7 is chlorine, cyano, trifluoromethyl, (C 1 -C 4) -alkyl or trifluoromethoxy,
• R 8 is hydrogen, fluorine, chlorine or trifluoromethyl
• R 9 is chlorine
• R 10 is hydrogen or chlorine
• R 11 represents chlorine, cyano, trifluoromethyl, (C 1 -C 4) -alkyl or trifluoromethoxy,
• R 12 is chlorine or methyl
• # 2 represents the point of attachment to the 2-amino-3-cyanopyridine
• R 4 is hydrogen or (C 1 -C 6 ) -alkyl
• (C 1 -C 6) -alkyl having 1 or 2 substituents independently of one another can be substituted from the group cyano, trifluoromethyl, hydroxy, (C 1 -C 4) -alkoxy, trifluoromethoxy and a group of the formula c # 1 ,
• C # 1 represents a carbon atom of (C 1 -C 6) -alkyl
• R 7 is trifluoromethyl
• R 8 is hydrogen, fluorine or chlorine
• pyridyl may be substituted with 1 to 3 substituents independently of one another selected from the group fluorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -R 4 and -OR 4 ,
• R 4 is hydrogen or (C 1 -C 4 ) -alkyl
• (C 1 -C 4) -alkyl in turn may be substituted by 1 to 3 substituents independently of one another selected from the group cyano, trifluoromethyl, hydroxy, methoxy, ethoxy and trifluoromethoxy,
• R 2 is cyano
• R 3 is a group of the formula
• R 7 is trifluoromethyl
• R 8 is hydrogen, fluorine or chlorine
• # 2 represents the point of attachment to the 2-amino-3-cyanopyridine
• R 13 is fluorine, methyl, hydroxymethyl, methoxy, ethoxy, isopropoxy, dimethylamino, diethylamino, dimethylaminocarbonyl, diethylaminocarbonyl, morpholin-4-yl, or methylsulfonyl,
• R 14 is hydrogen, fluorine or methoxy
• R 15 is hydrogen, fluorine or methoxy
• R '2 stands for cyano
• R 7 is trifluoromethyl
• R 8 is hydrogen, fluorine or chlorine
• R 7 is trifluoromethyl
• R 8 is hydrogen or chlorine
• R 2 is cyano
• R 3 is a group of the formula
• R 7 is trifluoromethyl
• R 8 is hydrogen, fluorine or chlorine
• # 2 represents the point of attachment to the 2-amino-3-cyanopyridine
• n is the number 0 or 1
• p is the number 0, 1 or 2
• R 4 and R 5 independently of one another each represent hydrogen, (C 1 -C 6) -alkyl or (C 3 -C 6) -cycloalkyl,
• (C 1 -C 6) -alkyl in turn, having 1 to 3 substituents selected independently from the group fluorine, cyano, trifluoromethyl, (C3-Cg) -cycloalkyl, hydroxy, (Ci-C6) -alkoxy, trifluoromethoxy, (Ci-C4 ) Alkoxycarbonyl, amino, mono (Ci-C i) - alkylamino, di (Ci-C4) -alkylamino, 4- to 8-membered heterocyclyl and 5- or 6 eroaryl and a group of the formula
• the 4- to 8-membered heterocycle in turn may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C6) alkyl, hydroxy, oxo and (Ci-C6) alkoxy, and wherein
• C # l represents a carbon atom of (C 1 -C 6) -alkyl
• Q is a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle
• R 4 and R 5 together with the atom (s) to which they are attached form a 4- to 8-membered heterocycle
• the 4- to 8-membered heterocycle in which the 4- to 8-membered heterocycle in turn contains 1 or 2 substituents independently of one another selected from the group consisting of cyano, trifluoromethyl, (C 1 -C 6) -alkyl, hydroxy, oxo, (C 1 -C 6) -alkoxy, trifluoromethoxy, C4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino and di (C 1 -C 4) -alkylamino may be substituted,
• R 6 is (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl
• # 2 represents the point of attachment to the 2-amino-3-cyanopyridine
• R 16 is (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkoxy or aminosulfonyl,
• (Ci-C6) alkyl and (Ci-C6) alkoxy can be substituted with 1 or 2 substituents independently selected from the group hydroxy, methoxy and ethoxy, as well as their salts, solvates and solvates of the salts.
• Another object of the invention is a process for the preparation of the compounds of formula (I) according to the invention, characterized in that a V
• R is phenyl or C-linked 5- or 6-membered heteroaryl
• R is pyrazol-1-yl, pyrrol-1-yl, imidazol-1-yl or triazol-1-yl,
• T 1 is hydrogen or (Ci-C 4 ) -alkyl or
• R 1A , R 1B , R 2 and R 3 each have the meanings given above,
• n is the number 0 or 1
• p is the number 0, 1 or 2
• R 4 and R 5 independently of one another each represent hydrogen, (C 1 -C 6) -alkyl or (C 3 -C 8) -cycloalkyl,
• (C 1 -C 6) -alkyl in turn, having 1 to 3 substituents independently selected from the group fluorine, cyano, trifluoromethyl, (C3-Cg) -cycloalkyl, hydroxy, (Ci-Ce) -alkoxy, trifluoromethoxy, (Ci-C4 ) Alkoxycarbonyl, amino, mono (Ci-C4) - alkylamino, di- (Ci-C4) -alkylamino, 4- to 8-membered heterocyclyl and 5- or 6-eroaryl and a group of the formula
• the 4- to 8-membered heterocycle in turn may be substituted with 1 or 2 substituents independently selected from the group trifluoromethyl, (Ci-C6) alkyl, hydroxy, oxo and (Ci-C6) alkoxy, and wherein
• C # l represents a carbon atom of (C 1 -C 6) -alkyl
• Q is a 3- to 6-membered carbocycle or a 4- to 7-membered heterocycle
• the 4- to 8-membered heterocycle in which the 4- to 8-membered heterocycle in turn contains 1 or 2 substituents independently of one another selected from the group consisting of cyano, trifluoromethyl, (C 1 -C 6) -alkyl, hydroxy, oxo, (C 1 -C 6) -alkoxy, trifluoromethoxy, C4) -alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino and di (C 1 -C 4) -alkylamino may be substituted,
• R 6 is (C 1 -C 6 ) -alkyl or (C 3 -C 8 ) -cycloalkyl
• T 2 is (C 1 -C 4 ) -alkyl
• R 1A has the abovementioned meaning
• R 1A has the abovementioned meaning
• R 2A is chlorine
• R 2B is (C 1 -C 4 ) -alkyl
• R 1A , R 2A , R 2B and R 3 each have the meanings given above,
• the resulting compounds of the formulas (IA), (IB), (IC), (ID), (I-El) and (I-E2) separates into their enantiomers and / or diastereomers according to methods known in the art and / / or optionally with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.
• Suitable solvents for process step (II) + (III-A) -> (IA) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, Glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethoxyethane (DME), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), Pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to a
• Suitable bases for process step (II) + (III-A) -> (I-A) are customary inorganic bases.
• These include in particular alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali metal hydrogen phosphates such as disodium or dipotassium hydrogen phosphate.
• alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide
• alkali metal bicarbonates such as sodium or potassium bicarbonate
• alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
• alkali metal hydrogen phosphates such as disodium or dipotassium hydrogen phosphate.
• sodium bicarbonate or sodium carbonate is used.
• reaction (II) + (III-A) -> (I-A) are generally carried out in a temperature range of + 20 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C.
• Inert solvents for process steps (II) + (III-B) or (IV) + (III-B) -> (IB) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or di ethylene glycol dimethyl ethers, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), Dimethylsulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrol
• Suitable bases for the process steps (II) + (III-B) and (IV) + (III-B) -> (I-B) are customary inorganic see or organic bases.
• These preferably include alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide, or organic amines such as triethylamine, Af-methylmorpholine, V-methylpiperidine, A ⁇ -diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,4
• process steps (II) + (III-B) or (IV) + (III-B) -> (IB) are generally carried out in a temperature range from 0 ° C to + 150 ° C, in particular from + 20 ° C to + 50 ° C.
• the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
• Inert solvents for process step (IV) ⁇ (V) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-dimethylpropyl urea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile.
• alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or
• Suitable bases for process step (IV) -> (V) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1 , 5-diazabicyclo [4.3.0] - ⁇ -5-ene (DBN). Preferred is triethylamine.
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide
• alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate
• alkali hydrogen carbonates such as sodium or potassium bicarbonate
• alkali metal such as sodium or potassium
• the reaction (IV) -> (V) is generally carried out in a temperature range from 0 ° C to + 60 ° C, preferably from + 10 ° C to + 30 ° C.
• the reaction may be carried out at normal or elevated pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
• reaction (V) + (VI) -> (I-C) can be carried out in an inert solvent or else without solvent.
• the reaction preferably takes place without solvent.
• Inert solvents for this process step are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons, such as dichloromethane, trichloromethane, 1,2 Dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures
• Suitable acids for the reaction (V) + (VI) -> (I-C) are organic and inorganic acids such as formic acid, acetic acid, trifluoroacetic acid, para-toluenesulfonic acid, methanesulfonic acid or hydrochloric acid / hydrochloric acid, sulfuric acid or phosphoric acid.
• acetic acid is used.
• the reaction (V) + (VI) -> (I-C) is generally carried out in a temperature range of + 50 ° C to + 180 ° C, optionally in a microwave.
• the said reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).
• Inert solvents for process step (VII) + (VIII) -> (ID) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, Isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF),
• Suitable bases for the process step (VII) + (VIII) -> (ID) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine, triethylamine, pyridine, 1,5-diazabicyclo [4.3.0 ] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-en
• alkali metal hydroxides such as lithium, sodium or potassium hydroxide
• the process step (VII) + (VIII) -> (I-D) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 50 ° C to +100 ° C, optionally in a microwave.
• the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
• the process steps (VII) + (IX-B) (I-E2) and (VII) + (IX-A) (I-El) can be carried out with and without solvent.
• Inert solvents for this process step are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert.
• Butanol hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), Dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using n-butanol or xylene.
• the process step (VII) + (IX-B) -> (I-E2) is generally carried out in a temperature range from + 50 ° C to + 200 ° C, preferably at + 120 ° C to + 180 ° C, optionally in a microwave.
• the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).
• Inert solvents for the reaction (X) -> (XI) are, for example, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF ), Dimethyl sulfoxide
• Suitable bases for process step (X) -> (XI) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium methoxide, sodium ethylate, sodium or potassium hydroxide. tert.-butylate or alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide. Preference is given to using sodium methylate.
• alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide
• alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate
• alkali alcoholates such as sodium methoxide, sodium ethylate, sodium or potassium hydroxide.
• the process step (X) -> (XI) is generally carried out in a temperature range from -20 ° C to + 50 ° C, preferably at 0 ° C to + 10 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).
• Inert solvents for the reaction (XI) ⁇ (II-A) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol , n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or others Solvents such as acetone, dimethylformamide (
• the process step (XI) -> (II-A) is generally carried out in a temperature range of + 20 ° C to + 100 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).
• the compounds of the formula (VII) can be prepared by reacting malononitrile in an inert solution with a compound of the formula (XII)
• Inert solvents for process step (XII) -> (VII) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols, such as methanol, ethanol, n-propanol, isopropanol , n-butanol or tert-butanol, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as Dimethylformamide (DMF), di
• Suitable bases for process step (XU) -> (VII) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide, or organic amines such as triethylamine, N-methylmorpholine, V-methylpiperidine, NN- Diisopropylethylamine, piperdine, pyridine, l, 5-diazabicyclo [4.3.0] non-5-ene (DBN), l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 4-diazabicyclo [ 2.2.2] octane
• the process step (XII) -> (VII) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C, optionally in a microwave.
• the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
• the compounds according to the invention are potent and selective inhibitors of the cellular Na + / Ca 2+ exchanger and are therefore suitable for the treatment and / or prevention of cardiovascular diseases.
• the compounds according to the invention can be used as medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as acute and chronic heart failure, arterial hypertension, essential hypertension, therapy-resistant hypertension, coronary heart disease, acute coronary syndrome, acute coronary syndrome with ST elevation, acute coronary syndrome without ST Elevation, stable and unstable angina pectoris, Prinzmetal angina, persistent ischemic dysfunction (hibernating myocardium), transient post-ischemic dysfunction (stunned myocardium), tachycardia, atrial tachycardia, atrial fibrillation with normal left ventricular function, atrial fibrillation with impaired left ventricular function, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, rhythm disorders of the atria and ventricles, ventricular and supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, Chamber flutter, torsade de pointes tachycardia
• cardiac failure includes both acute and chronic manifestations of heart failure, as well as more specific or related forms of disease such as acute congestive heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart failure in heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure and acute ph the worse
• the compounds according to the invention are suitable for the reduction of the infarcted myocardium area and for the prevention of secondary infarcts, reperfusion damage after ischemia.
• Ischemias such as myocardial infarction, cardioprotection in coronary artery bypass graft surgery (CABG), primary PTCAs, PTCAs after thrombolysis, rescue PTCA, heart transplants, and open heart surgery. and organ protection in transplantation, bypass surgery, cardiac catheterization and other surgical procedures.
• Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
• the present invention furthermore relates to the use of the compounds according to the invention for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass grafting (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure , acute and chronic renal diseases as well as acute and chronic inflammatory diseases.
• CABG coronary artery bypass grafting
• PTAs percutaneous transluminal angioplasties
• PTCAs primary percutaneous transluminal coronary angioplasties
• acute and chronic heart failure acute and chronic renal diseases as well as acute and chronic inflammatory diseases.
• Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
• the present invention furthermore relates to the use of the compounds according to the invention for the manufacture of a medicament for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass grafting (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic renal diseases and acute and chronic inflammatory diseases.
• CABG coronary artery bypass grafting
• PTAs percutaneous transluminal angioplasties
• PTCAs primary percutaneous transluminal coronary angioplasties
• acute and chronic heart failure acute and chronic renal diseases and acute and chronic inflammatory diseases.
• Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
• the present invention further relates to a method for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass grafting (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic heart failure Chronic kidney disease and acute and chronic inflammatory diseases using an effective amount of at least one of the compounds of the invention.
• CABG coronary artery bypass grafting
• PTAs percutaneous transluminal angioplasties
• PTCAs primary percutaneous transluminal coronary angioplasties
• Another object of the present invention are the compounds of the invention for use in a method for the treatment and / or prophylaxis of cardiovascular diseases.
• the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of myocardial infarction, cardioprotection in coronary artery bypass operations (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic renal diseases, and acute and chronic inflammatory diseases.
• CABG cardioprotection in coronary artery bypass operations
• PTAs percutaneous transluminal angioplasties
• PTCAs primary percutaneous transluminal coronary angioplasties
• the present invention further relates to medicaments comprising at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of myocardial infarction, cardioprotection in coronary artery bypass surgery (CABG), percutaneous transluminal angioplasties (PTAs) and primary percutaneous -transluminal coronary angioplasties (PTCAs), acute and chronic heart failure, acute and chronic renal diseases, and acute and chronic inflammatory diseases.
• CABG cardioprotection in coronary artery bypass surgery
• PTAs percutaneous transluminal angioplasties
• PTCAs primary percutaneous -transluminal coronary angioplasties
• the compounds of the invention may be used alone or as needed in combination with other agents.
• Another object of the present invention are therefore 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, hypotensives, circulation-promoting and / or antithrombotic agents, antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists.
• Another object of the present invention are combinations of at least one of the compounds of the invention with one or more active ingredients independently selected from:
• Active substances which alter lipid metabolism such as by way of example and preferably from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, LDL receptor inducers, cholesterol Absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, MTP inhibitors, lipase inhibitors, LpL activators, fibrates, niacin, CETP inhibitors, PPAR-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,
• hypotensive agents by way of example and with preference from the group of calcium antagonists, angiotensin II ATI receptor antagonists, ACE inhibitors, renin inhibitors, beta-receptor blockers, alpha-receptor blockers, aldosterone antagonists, mineralocorticoid Receptor antagonists, ECE inhibitors, ACE / NEP inhibitors and also the vasopeptidase inhibitors, antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances, factor Xa inhibitors or vitamin K antagonists,
• Cyclooxygenase inhibitors such as, for example, meloxicam, rofecoxib and celecoxib
• Anti-inflammatory agents by way of example and preferably from the group of glucocorticosteroids, non-steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs (NSAIDs), beta-receptor blockers
• Diuretics such as by way of example and preferably loop diuretics, thiazides, potassium-sparing diuretics, or carbonic anhydrase inhibitors,
• organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO,
• cGMP cyclic guanosine monophosphate
• cAMP cyclic adenosine monophosphate
• PDE phosphodiesterases
• sildenafil vardenafil
• tadalafil tadalafil
• milrinone positive inotropic agents such as digitoxin, digoxin, epinephrine, norepinephrine, dobutamine and dopamine
• antiproliferative agents such as multikinase inhibitors and preferably sorafenib, imatinib, gefitinib and erlotinib
• cGMP cyclic guanosine monophosphate
• cAMP cyclic adenosine monophosphate
• PDE phosphodiesterases
• natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin; Agonists of the prostacyclin receptor (IP receptor), such as iloprost, beraprost, cicaprost; Inhibitors of the If (funny channel) channel, such as Ivabradine;
• Calcium sensitizers such as by way of example and preferably levosimendan
• Guanylate cyclase NO- and heme-independent activators in particular those described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510
• HNE human neutrophil elastase
• the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib; and or
• Anti-inflammatory agents by way of example and with preference from the group of glucocorticoids, in particular prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone;
• Vasopressin receptor antagonists such as, and preferably, conivaptan, tolvaptan, lipivaptan, mozavaptan, satavaptan, SR-121463, RWJ 676070 or BAY 86-8050;
• the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapol, torcetrapib, JTT-705 or CETP vaccine (CETi-1).
• a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapol, torcetrapib, JTT-705 or CETP vaccine (CETi-1).
• the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
• a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
• the compounds according to the invention are combined with an HMG-CoA reductase inhibitor from the class of statins, such as, for example and preferably, lovastatin, cerivastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavasatin administered.
• statins such as, for example and preferably, lovastatin, cerivastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavasatin administered.
• 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, RPR 107393 or TAK-475.
• a squalene synthesis inhibitor such as by way of example and preferably BMS-188494, RPR 107393 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, melinamide, pactimibe, eflucimibe, lecimibid, CP-113818 or SMP-797.
• an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757, CP-346086, AEGR-733, LAB678 or JTT-130.
• the compounds according to the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone, ciglitazone or rosiglitazone.
• a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone, ciglitazone or rosiglitazone.
• the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
• a PPAR-delta agonist such as by way of example and preferably GW 501516 or BAY 68-5042.
• 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, pamaqueside or colesevelam.
• the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
• a lipase inhibitor such as, for example and preferably, orlistat.
• the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, such as, by way of example and by way of preference, cholestyramine, colobrepol, colesolvam, cholesta gel or colestimide.
• ASBT IBAT
• AZD-7806 S-8921
• AK-105 AK-105
• BARI-1741 AK-105
• SC-435 SC-635.
• the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
• the compounds according to the invention are combined with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, nitrendipine, felodipine, lercanidipine, nimodipine, nicardipine, lacidipine, israpidine, nisoldipine, nilvadipine, manidipine, verapamil or Diltiazem administered.
• a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, nitrendipine, felodipine, lercanidipine, nimodipine, nicardipine, lacidipine, israpidine, nisoldipine, nilvadipine, manidipine, verapamil or Diltiazem administered.
• the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, by way of example and preferably prazosin, terazosin, dopazosin, trimazosin, and the non-selective blockers of the first generation phentolamine and phenoxybenzamine ,
• 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, e
• the compounds according to the invention are administered in combination with an angiotensin AT-1 receptor antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, eprosartan, olmesartan or embursatan.
• angiotensin AT-1 receptor antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, eprosartan, olmesartan or embursatan.
• the compounds according to the invention are administered in combination with an ACE inhibitor, by way of example and preferably enalapril, captopril, lisinopril, spirapril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• an ACE inhibitor by way of example and preferably enalapril, captopril, lisinopril, spirapril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, attresentan, ambrisentan or sitaxsentan.
• an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, attresentan, ambrisentan or sitaxsentan.
• the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600, SPP-800, SPP-1148, VTP-27999 or MK-8141.
• the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
• a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
• the compounds of the invention are used in combination with a loop diuretic, such as by way of example and preferably bumetanide, ethacrynic acid, toresemide or furosemide; in combination with thiazides, such as, by way of example and by way of illustration, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, metyclothiazide, metolazone or polythiazide; in combination with potassium-sparing diuretics, such as and preferably amiloride, eplerenone, spironolactone or triamterene, and / or in combination with carbonic anhydrase inhibitors such as, and preferably, acetazolamide, dichlophenamide or mathazolamide.
• a loop diuretic such as by way of example and preferably bumetanide, ethacrynic acid, toresemide or furosemide
• the compounds according to the invention are administered in combination with a vasopressin receptor antagonist, such as by way of example and preferably Tolvaptan.
• a vasopressin receptor antagonist such as by way of example and preferably Tolvaptan.
• the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as by way of example and preferably aspirin, clopidogrel, ticlopidine, prasugrel, tirofiban 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, dabigatran, melagatran, argatroban, bivalirudin, hirudin, lepirudin, desirudin or Clexane.
• a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, argatroban, bivalirudin, hirudin, lepirudin, desirudin or Clexane.
• the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as by way of example and preferably tirofiban or abciximab.
• the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, edoxaban, enoxaparin, otamixaban, fondaparinux, idraparinux, PMD-31 12, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
• a factor Xa inhibitor such as by way of example and preferably rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, edoxaban, enoxaparin, otamixaban, fondaparinux, idraparinux, PMD
• 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 by way of preference, warfarin, coumarin, acenocoumarol, phenprocoumone or dicumarol.
• a vitamin K antagonist such as, by way of example and by way of preference, warfarin, coumarin, acenocoumarol, phenprocoumone or dicumarol.
• compositions containing at least one of the compounds according to the 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 the energy metabolism of the heart affecting compounds, diuretics, beta-receptor blocker, organic nitrates and NO donors, blockers of the renin-angiotensin-aldosterone system, platelet aggregation inhibitors, anticoagulants, vasopressin receptor antagonists, glucocorticoids, NSAIDs and COX inhibitors, and their use for the treatment and / or prevention of the aforementioned disorders.
• further active compounds selected from the group consisting of the energy metabolism of the heart affecting compounds, diuretics, beta-receptor blocker, organic nitrates and NO donors, blockers of the renin-angiotensin-aldosterone system, platelet aggregation inhibitors, anticoagulants, vasopressin receptor antagonists, glucocorticoids, NSAIDs and COX inhibitor
• 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.
• compositions containing at least one compound of the invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
• the compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
• the compounds according to the invention can be administered in suitable administration forms.
• the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
• Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
• tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates
• capsules e.g. Soft gelatin capsules
• dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration can be accomplished by bypassing a ⁇ (e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
• a ⁇ e.g., intravenously, intraarterially, intracardially, intraspinally, or intralumbarally
• absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
• parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhalation medicaments including powder inhalers, nebulizers
• nasal drops solutions or sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or ophthalmic preparations
• vaginal capsules aqueous suspensions (lotions, shake mixtures)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (eg plasters)
• milk pastes, foams, powdered powders, implants or stents.
• excipients include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitanoleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g.
• excipients e.g., microcrystalline cellulose, lactose, mannitol
• solvents eg, liquid polyethylene glycols
• emulsifiers and dispersing or wetting agents e.g., sodium dodecyl sulfate, polyoxysorbitanoleate
• binders e.g., polyvinylpyrrolidone
• synthetic and natural polymers e.g.
• Albumin e.g antioxidants such as ascorbic acid
• dyes eg inorganic pigments such as iron oxides
• Instrument Micromass GCT, GC6890; Column: Restek RTX-35, 15 m x 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 ° C, 30 ° C / min 310 ° C (hold for 3 min).
• Instrument MS Waters ZQ 2000; Instrument HPLC: Agilent 1100, 2-column circuit, Autosampler: HTC PAL; Column: YMC-ODS-AQ, 50 mm x 4.6 mm, 3.0 ⁇ ; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A 0.2 min 95% A 1.8 min 25% A 1.9 min 10% A 2.0 min 5% A 3.2 min 5% A 3.21 min 100% A 3.35 min 100% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm. Method 6 (LC / MS:
• the compounds according to the invention can be prepared in salt form, for example as triflate. luoracetat incurred, formate or ammonium salt, provided that the compounds of the invention a sufficient basic or acidic functionality.
• a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
• An LDA solution was prepared by dropwise addition of 83 ml (133 mmol) of a 1.6N solution of n-butyllithium in hexane to 13.1 g (130 mmol) of diisopropylamine in 100 ml of THF at -78 ° C. and stirring for 30 min. Subsequently, 4.70 g (1 14 mmol) of acetonitrile were added dropwise as a solution in 70 ml of THF and 30 min. further stirred. Then 7.09 g (76.2 mmol) of 2-furanonitrile were added as a solution in 100 ml of THF. After 20 min. was warmed to RT and stirred overnight at this temperature.
• the crude product was purified by flash chromatography (silica gel 60, eluent: cyclohexane).
• the aqueous phase was extracted once with MTBE. Then the combined organic phases were washed three times with saturated aqueous sodium chloride solution and once with saturated aqueous ammonium chloride solution, dried over sodium sulfate and the solvent was removed in vacuo. The residue was stirred with petroleum ether, filtered off with suction and washed with petroleum ether. Yield: 71.2 g (85% of theory).
• An LDA solution was first prepared by adding 19.4 g (192 mmol) of diisopropylamine in 400 ml of THF at -70 ° C and dropping 65.5 ml (164 mmol) of a 2.5M solution of n-butyllithium in hexane and dropping for 10 min. allowed to stir. Then, 6.95 g (169 mmol) of acetonitrile was added as a solution in 50 ml of THF. The mixture was stirred for 30 min, resulting in a thick suspension.
• Example 39A 3-amino-3- (1-methyl-1 / pyrazol-4-yl) acrylonitrile from Example 36A with the respective benzylidenemalononitrile in the molar ratio 1: 1 in sulfolane as solvent (2 ml / mmol 36A ) were reacted at RT and the addition products listed in Table 1 were isolated.

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• 2013
  • 2013-03-27 WO PCT/EP2013/056493 patent/WO2013144191A1/fr not_active Ceased

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