DE102005024493A1 - Use of pyrazolopyrimidines - Google Patents

Abstract

The invention relates to the use of pyrazolopyrimidines for the preparation of medicaments for the treatment of cardiovascular diseases.

Description

The The invention relates to the use of pyrazolopyrimidines for the preparation of medicines for the treatment of cardiovascular diseases.

inhibition of phosphodiesterases modulates levels of cyclic nucleotides 5'-3 'cyclic adenosine monophosphate (cAMP) or 5'-3 'cyclic guanosine monophosphate (CGMP). These cyclic nucleotides (cAMP and cGMP) are important second messengers and therefore play a central role in the cellular signal transduction cascades. Both activate, among other things, but not exclusively, respectively again protein kinases. The cAMP activated protein kinase becomes Protein kinase A (PKA), the cGMP-activated protein kinase is called protein kinase G (PKG). Activated PKA or PKG can turn a series of cellular Phosphorylate effector proteins (e.g., ion channels, G protein-coupled receptors, Structural proteins). That way, the second messengers cAMP and cGMP the most diverse physiological processes in the control various organs. The cyclic nucleotides can but also act directly on effector molecules. For example, e.g. known, that cGMP directly on ion channels act and thereby influence the cellular ion concentration can (overview in: Wei et al., Prog. Neurobiol., 1998, 56: 37-64). A control mechanism, about the activity of cAMP and cGMP and thus these physiological processes in turn to control are the phosphodiesterases (PDE). PDEs hydrolyze the cyclic monophosphates to the inactive monophosphates AMP and GMP. At least 21 PDE genes have now been described (Exp. Opin Investig Drugs 2000, 9, 1354-3784). Leave these 21 PDE genes divide into 11 PDE families due to their sequence homology (Nomenclature proposal see http://depts.washington.edu/pde/Nomenclature.html.). Individual PDE genes within a family are identified by letters differentiated (e.g., PDE1A and PDE1B). If still different Splice variants within a gene will occur through an additional Numbering is indicated after the letter (e.g., PDE1A1).

The human PDE9A was cloned and sequenced in 1998. The amino acid identity to other PDEs is a maximum of 34% (PDE8A) and a minimum of 28% (PDE5A). With a Michaelis-Menten constant (Km value) of 170 nM, PDE9A is highly affine for cGMP. In addition, PDE9A is selective for cGMP (Km value for cAMP = 230 μM). PDE9A has no cGMP binding domain suggestive of allosteric enzyme regulation by cGMP. In a Northern blot analysis, PDE9A has been shown to be expressed in human, inter alia, in the testes, brain, small intestine, skeletal muscle, heart, lungs, thymus and spleen. The highest expression has been found in brain, small intestine, heart and spleen (Fisher et al., J. Biol. Chem., 1998, 273 (25): 15559-15564). The gene for human PDE9A is located on chromosome 21q22.3 and contains 21 exons. To date, 20 alternative splice variants of PDE9A have been identified (Guipponi et al., Hum. Genet., 1998, 103: 386-392, Wang et al., Gene, 2003, 314: 15-27, Rentero et al., Biochem. Biophys Res. Commun., 2003, 301: 686-692). Classic PDE inhibitors do not inhibit human PDE9A. For example, IBMX, dipyridamole, SKF94120, rolipram and vinpocetine do not inhibit the isolated enzyme at concentrations up to 100 μM. For zaprinast an IC ₅₀ value of 35 μM was detected (Fisher et al., J. Biol. Chem., 1998, 273 (25): 15559-15564).

Mouse PDE9A was described by Soderling et al. (J. Biol. Chem., 1998, 273 (25): 15553-15558) and sequenced. Like the human form, this is highly affine for cGMP with a Km of 70 nM. In the mouse, a particularly high expression in the kidney, brain, lung and heart was found. The mouse PDE9A is also not inhibited by IBMX in concentrations below 200 μM; the IC ₅₀ value for zaprinast is 29 μM (Soderling et al., J. Biol. Chem., 1998, 273 (19): 15553-15558). In the rat brain, it has been shown that PDE9A is strongly expressed in some brain regions. These include the olfactory bulb, hippocampus, cortex, basal ganglia and basal forebrain (Andreeva et al., J. Neurosci., 2001, 21 (22): 9068-9076). In particular, hippocampus, cortex and basal forebrain play an important role in learning and memory processes.

As mentioned above, PDE9A is characterized by a particularly high affinity for cGMP. Therefore, PDE9A is in contrast to PDE2A (Km = 10 μM, Martins et al., J. Biol. Chem., 1982, 257: 1973-1979), PDE5A (Km = 4 μM, Francis et al., J. Biol. Chem., 1980, 255: 620-626), PDE6A (Km = 17 μM, Gillespie and Beavo, J. Biol. Chem., 1988, 263 (17): 8133-8141) and PDE11A (Km = 0.52 μM, Fawcett et al., Proc. Nat. Acad Sci., 2000, 97 (7): 3702-3707) already at low physiological concentrations. In contrast to PDE2A (Murashima et al., Biochemistry, 1990, 29: 5285-5292), the catalytic activity of PDE9A is not enhanced by cGMP, as there is no GAF domain (cGMP binding domain, via which the PDE Ab allosteric activity) (Beavo et al., Current Opinion in Cell Biology, 2000, 12: 174-179). PDE9A inhibitors may therefore increase the basal cGMP concentration.

Out WO 04/099211, WO 04/099210, WO 04/026876, WO 04/018474 and there cited literature and US 2004/022018 are pyrazolopyrimidines and their use for the preparation of medicaments for treatment already known from various diseases.

in welcher
R¹ C₁-C₈-Alkyl, C₂-C₆-Alkenyl, C₂-C₆-Alkinyl oder C₃-C₈-Cycloalkyl,
wobei C₁-C₈-Alkyl gegebenenfalls mit Oxo substituiert ist, und
wobei C₁-C₈-Alkyl, C₂-C₆-Alkenyl, C₂-C₆-Alkinyl und C₃-C₈-Cycloalkyl gegebenenfalls mit bis zu 3 Resten unabhängig voneinander ausgewählt aus der Gruppe C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, Cyano, Amino, Nitro, Hydroxy, C₁-C₆-Alkylamino, Halogen, Trifluormethyl, Trifluormethoxy, C₆-C₁₀-Arylcarbonylamino, C₁-C₆-Alkylcarbonylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₆-C₁₀-Arylaminocarbonyl, Heteroarylaminocarbonyl, Heteroarylcarbonylamino, C₁-C₆-Alkylsulfonylamino, C₁-C₆-Alkylsulfonyl, C₁-C₆-Alkylthio substituiert sind,
wobei
C₁-C₆-Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₆-C₁₀-Arylcarbonylamino, C₁-C₆-Alkylcarbonylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₆-C₁₀-Arylaminocarbonyl, Heteroarylaminocarbonyl, Heteroarylcarbonylamino, C₁-C₆-Alkylsulfonylamino, C₁-C₆-Alkylsulfonyl und C₁-C₆-Alkylthio gegebenenfalls mit ein bis drei Resten unabhängig voneinander ausgewählt aus der Gruppe Hydroxy, Cyano, Halogen, Trifluormethyl und Trifluormethoxy
substituiert sind,
R² Phenyl oder Heteroaryl, wobei Phenyl mit 1 bis 3 Resten und Heteroaryl gegebenenfalls mit 1 bis 3 Resten jeweils unabhängig voneinander ausgewählt aus der Gruppe C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, Cyano, Trifluormethyl, Trifluormethoxy, Amino, Nitro, Hydroxy, C₁-C₆-Alkylamino, Halogen, C₆-C₁₀-Arylcarbonylamino, C₁-C₆-Alkylcarbonylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₆-C₁₀-Arylaminocarbonyl, Heteroarylaminocarbonyl, Heteroarylcarbonylamino, C₁-C₆-Alkylsulfonylamino, C₁-C₆-Alkylsulfonyl, C₁-C₆-Alkylthio substituiert sind,
wobei C₁-C₆-Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₆-C₁₀-Arylcarbonylamino, C₁-C₆-Alkylcarbonylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₆-C₁₀-Arylaminocarbonyl, Heteroarylaminocarbonyl, Heteroarylcarbonylamino, C₁-C₆-Alkylsulfonylamino, C₁-C₆-Alkylsulfonyl und C₁-C₆-Alkylthio gegebenenfalls mit ein bis drei Resten unabhängig voneinander ausgewählt aus der Gruppe Hydroxy, Cyano, Halogen, Trifluormethyl, Trifluormethoxy und einer Gruppe der Formel -NR³R⁴,
wobei
R³ und R⁴ unabhängig voneinander Wasserstoff oder C₁-C₆-Alkyl,
oder
R³ und R⁴ zusammen mit dem Stickstoffatom, an das sie gebunden sind, 5- bis 8-gliedriges Heterocyclyl bedeuten,
substituiert sind,
bedeuten, sowie deren Salze, Solvate und/oder Solvate der Salze, zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.The present invention relates to the use of compounds of the formula

in which
R ^{1 is} C ₁ -C ₈ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl,
wherein C ₁ -C ₈ alkyl is optionally substituted with oxo, and
where C ₁ -C ₈ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl and C ₃ -C ₈ -cycloalkyl optionally having up to 3 radicals are selected independently of one another from the group C ₁ -C ₆ - Alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, cyano, amino, nitro, hydroxy, C ₁ -C ₆ -alkylamino, halogen, trifluoromethyl, trifluoromethoxy, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ - Alkylthio are substituted,
in which
C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₆ -C ₁₀ arylaminocarbonyl, heteroarylaminocarbonyl, Heteroarylcarbonylamino, C ₁ -C ₆ alkylsulfonylamino, C ₁ -C ₆ alkylsulfonyl and C ₁ -C ₆ alkylthio optionally with one to three radicals independently selected from the group hydroxy, cyano, halogen, trifluoromethyl and trifluoromethoxy
are substituted
R ^{2 is} phenyl or heteroaryl, where phenyl having 1 to 3 radicals and heteroaryl optionally having 1 to 3 radicals are each independently selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, Trifluoromethoxy, amino, nitro, hydroxy, C ₁ -C ₆ -alkylamino, halogen, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylthio are substituted,
wherein C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally having one to three radicals independently of one another selected from the group hydroxy, cyano, halogen, trifluoromethyl, trifluoromethoxy and a group of the formula -NR ³ R ⁴ ,
in which
R ³ and R ⁴ independently of one another are hydrogen or C ₁ -C ₆ -alkyl,
or
R ³ and R ^4, together with the nitrogen atom to which they are attached, denote 5- to 8-membered heterocyclyl,
are substituted
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (I)
in which
R ^{1 is} C ₁ -C ₈ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl, which are optionally selected with up to 3 radicals independently of one another from the group C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxycarbonyl, cyano, amino, nitro, hydroxy, C ₁ -C ₆ alkylamino, halogen, C ₆ -C ₁₀ arylcarbonylamino, C ₁ -C ₆ alkylcarbonylamino, C C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, Hete roarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylthio are substituted,
in which
C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₆ -C ₁₀ arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally with a radical selected from the group Hydroxy, cyano and halogen
are substituted
R ^{2 is} phenyl or heteroaryl, where phenyl having 1 to 3 radicals and heteroaryl optionally having 1 to 3 radicals are each independently selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, Amino, nitro, hydroxy, C ₁ -C ₆ -alkylamino, halogen, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylthio are substituted,
wherein C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally with a radical selected from the group Hydroxy, cyano, halogen and a group of the formula -NR ³ R ⁴ ,
in which
R ³ and R ⁴ independently of one another are hydrogen or C ₁ -C ₆ -alkyl,
or
R ³ and R ^4, together with the nitrogen atom to which they are attached, denote 5- to 8-membered heterocyclyl,
are substituted
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (I)
in which
R ^{1 is} C ₁ -C ₅ -alkyl or C ₃ -C ₆ -cycloalkyl, which are optionally selected with up to 3 radicals independently of one another from the group C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl, hydroxycarbonyl , Cyano, amino, hydroxy, C ₁ -C ₄ -alkylamino, fluorine, chlorine, bromine, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ Alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₄ -alkylsulfonylamino, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₄ -alkylthio,
wherein C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy optionally having a radical selected from the group hydroxy, cyano, fluorine, chlorine and bromine
are substituted
R ^{2 is} phenyl, pyrimidyl, N-oxidopyridyl or pyridyl, wherein phenyl having 1 to 3 radicals and pyrimidyl, N-oxidopyridyl and pyridyl optionally having 1 to 3 radicals each independently selected from the group C ₁ -C ₄ alkyl, C ₁ C ₄ alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, hydroxy, C ₁ -C ₄ alkylamino, fluoro, chloro, bromo, C ₆ -C ₁₀ arylcarbonylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C _4- alkylaminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₄ -alkylsulfonylamino, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₄ -alkylthio are substituted,
where C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy optionally have a radical selected from the group consisting of hydroxyl, cyano, fluorine, chlorine, bromine and a group of the formula -NR ³ R ⁴ ,
in which
R ³ and R ⁴ independently of one another are hydrogen or C ₁ -C ₄ -alkyl,
or
R ³ and R ^4, together with the nitrogen atom to which they are attached, denote 5- to 6-membered heterocyclyl,
are substituted
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (I)
in which
R ^{1 has} the meanings given above, and
R ^{2 is} phenyl, N-oxidopyridyl or pyridyl, where phenyl having 1 to 3 radicals and pyridyl and N-oxidopyridyl optionally having 1 to 3 radicals are each independently selected from the group of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, Fluorine and chlorine are substituted,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for Be treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (I)
in which
R ^{1 is} C ₁ -C ₅ -alkyl or C ₅ -C ₆ -cycloalkyl, which are optionally selected with up to 3 radicals independently of one another from the group C ₁ -C ₄ -alkyl, fluorine, trifluoromethyl, hydroxy, phenylcarbonylamino, C ₁ - C ₄ alkylcarbonylamino, C ₁ -C ₄ alkylaminocarbonyl or phenylaminocarbonyl are substituted, and
R ^{2 is} phenyl, N-oxidopyridyl or pyridyl, where phenyl having 1 to 3 radicals and pyridyl and N-oxidopyridyl optionally having 1 to 3 radicals are each independently selected from the group of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, Fluorine and chlorine are substituted,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (I)
in which
R ^{1 is} C ₁ -C ₅ -alkyl or C ₅ -C ₆ -cycloalkyl, which are optionally selected with up to 3 radicals independently of one another from the group C ₁ -C ₄ -alkyl, fluorine, trifluoromethyl, hydroxy, phenylcarbonylamino, C ₁ - C ₄ alkylcarbonylamino, C ₁ -C ₄ alkylaminocarbonyl or phenylaminocarbonyl are substituted, and
R ^{2 is} phenyl, N-oxidopyridyl or pyridyl wherein phenyl is substituted with one radical and pyridyl and N-oxidopyridyl optionally substituted with one independently selected from the group of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluoro and chloro are,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

In the context of the present invention, the substituents, unless specified otherwise, in the context of the formula (I) have the following meaning:
C ₁ -C ₈ -alkyl is a straight-chain or branched alkyl radical having 1 to 8, preferably 1 to 6, particularly preferably 1 to 5 carbon atoms. Preferred examples include methyl, ethyl, n-propyl, isopropyl, 2-butyl, 2-pentyl and 3-pentyl.

C ₂ -C ₆ -alkenyl is a straight-chain or branched alkenyl radical having 2 to 6, preferably 2 to 4 and particularly preferably 2 to 3 carbon atoms. Preferred examples include vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl.

C ₂ -C ₆ -alkynyl represents a straight-chain or branched alkynyl radical having 2 to 6, preferably 2 to 4 and particularly preferably 2 to 3 carbon atoms. Preferred examples include ethynyl, n-prop-1-yn-2-yl, n-prop-1-yn-3-yl and n-but-2-yn-1-yl.

C ₁ -C ₆ -alkoxy stands for a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably having 1 to 3 carbon atoms. Preferred examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

C ₁ -C ₆ -alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Preferred examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

C ₁ -C ₆ -alkylamino represents a straight-chain or branched mono- or dialkylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Preferred examples include methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-t-butylamino, di-n-pentylamino, Di-n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino and n-hexyl-i-pentylamino.

C ₁ -C ₆ -alkylcarbonylamino is an alkylcarbonyl radical linked via an amino group, where the alkyl radical can be straight-chain or branched and contains 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3, carbon atoms. Preferred examples include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.

C ₁ -C ₆ -alkylaminocarbonyl is a mono- or dialkylamino radical linked via a carbonyl group, where the alkyl radicals may be identical or different, straight-chain or branched, and because 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3 carbon atoms. Preferred examples include methylaminocarbonyl, ethylaminocarbonyl, n -propylaminocarbonyl, isopropylaminocarbonyl, tert -butylaminocarbonyl, n -pentylaminocarbonyl, n-hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, di-t-butylaminocarbonyl, di-n-pentylaminocarbonyl, di -n-hexylaminocarbonyl, ethylmethylaminocarbonyl, isopropylmethylaminocarbonyl, n-butylethylaminocarbonyl and n-hexyl-i-pentylaminocarbonyl. Furthermore, in the case of a dialkylamino radical, the two alkyl radicals together with the nitrogen atom to which they are attached may form a 5- to 8-membered heterocyclyl.

C ₆ -C ₁₀ -arylaminocarbonyl is an arylamino radical linked via a carbonyl group. Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.

C ₆ -C ₁₀ -arylcarbonylamino is an arylamino radical linked via an amino group. Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.

C ₁ -C ₆ -alkylsulfonylamino represents a straight-chain or branched alkylsulfonylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3, carbon atoms. Preferred examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.

C ₁ -C ₆ -alkylsulfonyl is a straight-chain or branched alkylsulfonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Preferred examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

C ₁ -C ₆ -alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Preferred examples include methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

halogen stands for Fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, especially prefers fluorine and chlorine.

heteroaryl stands for an aromatic, mono- or bicyclic radical having 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. Preferred are 5- to 6-membered heteroaryls containing up to 4 heteroatoms. Of the Heteroaryl may be over be bound to a carbon or nitrogen atom. Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, Tetrazolyl, pyridyl, N-oxidopyridyl, pyrimidinyl, pyridazinyl, indolyl, Indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl.

heteroarylaminocarbonyl stands for one over linked a carbonyl group Heteroarylamino radical. Preferred examples include thienylaminocarbonyl, furylaminocarbonyl, Pyrrolylaminocarbonyl, thiazolylaminocarbonyl, oxazolylaminocarbonyl, Imidazolylaminocarbonyl, tetrazolylaminocarbonyl, pyridylaminocarbonyl, Pyrimidinylaminocarbonyl, pyridazinylaminocarbonyl, indolylaminocarbonyl, Indazolylaminocarbonyl, benzofuranylaminocarbonyl, benzothiophenylaminocarbonyl, Quinolinylaminocarbonyl and isoquinolinylaminocarbonyl.

heteroarylcarbonylamino stands for one over linked an amino group Heteroarylcarbonyl radical. Preferred examples include thienylcarbonylamino, Furylcarbonylamino, pyrrolylcarbonylamino, thiazolylcarbonylamino, Oxazolylcarbonylamino, imidazolylcarbonylamino, tetrazolylcarbonylamino, Pyridylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, Indolylcarbonylamino, indazolylcarbonylamino, benzofuranylcarbonylamino, Benzothiophenylcarbonylamino, quinolinylcarbonylamino and isoquinolinylcarbonylamino.

3 to 8-membered cycloalkyl represents saturated and partially unsaturated non-aromatic Cycloalkyl radicals having 3 to 8, preferably 3 to 6 and particularly preferably 5 to 6 carbon atoms in the cycle. Preferred examples include Cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

5- to 8-membered heterocyclyl is a mono- or polycyclic, heterocyclic radical having 5 to 8 ring atoms and up to 3, preferably 2 heteroatoms or hetero groups from the series N, O, S, SO, SO ₂ . Mono- or bicyclic heterocyclyl is preferred. Particularly preferred is monocyclic heterocyclyl. As heteroatoms, N and O are preferred. The heterocyclyl radicals can be saturated or partially un be saturated. Saturated heterocyclyl radicals are preferred. Particularly preferred are 5- to 7-membered heterocyclyl radicals. Preferred examples include oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl.

If Residues in the compounds of the invention are optionally substituted is, unless otherwise specified, a substitution with up to three identical or different substituents prefers.

The Compounds of the formula (I) and their preparation are known from WO 04/099211 known.

in welcher
R⁵ Phenyl, Pyridyl oder Thiophenyl, welche gegebenenfalls mit bis zu 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, Cyano, Trifluormethyl, Amino, Nitro, Hydroxy, C₁-C₆-Alkylamino, Halogen, C₆-C₁₀-Arylcarbonylamino, C₁-C₆-Alkylcarbonylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₆-C₁₀-Arylaminocarbonyl, Heteroarylaminocarbonyl, Heteroarylcarbonylamino, C₁-C₆-Alkylsulfonylamino, C₁-C₆-Alkylsulfonyl, C₁-C₆-Alkylthio substituiert sind,
wobei C₁-C₆-Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₆-C₁₀-Arylcarbonylamino, C₁-C₆-Alkylcarbonylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₆-C₁₀-Arylaminocarbonyl, Heteroarylaminocarbonyl, Heteroarylcarbonylamino, C₁-C₆-Alkylsulfonylamino, C₁-C₆-Alkylsulfonyl und C₁-C₆-Alkylthio gegebenenfalls mit einem Rest ausgewählt aus der Gruppe Hydroxy, Cyano, Halogen, Hydroxycarbonyl und einer Gruppe der Formel -NR⁷R⁸,
wobei
R⁷ und R⁸ unabhängig voneinander Wasserstoff oder C₁-C₆-Alkyl,
oder
R⁷ und R⁸ zusammen mit dem Stickstoffatom, an das sie gebunden sind, 5- bis 8-gliedriges Heterocyclyl bedeuten,
substituiert sind,
R⁶ Phenyl oder Heteroaryl, wobei Phenyl mit 1 bis 3 Resten und Heteroaryl gegebenenfalls mit 1 bis 3 Resten jeweils unabhängig voneinander ausgewählt aus der Gruppe C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, Cyano, Trifluormethyl, Amino, Nitro, Hydroxy, C₁-C₆-Alkylamino, Halogen, C₆-C₁₀-Arylcarbonylamino, C₁-C₆-Alkylcarbonylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₆-C₁₀-Arylaminocarbonyl, Heteroarylaminocarbonyl, Heteroarylcarbonylamino, C₁-C₆-Alkylsulfonylamino, C₁-C₆-Alkylsulfonyl, C₁-C₆-Alkylthio substituiert sind,
wobei C₁-C₆-Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₆-C₁₀-Arylcarbonylamino, C₁-C₆-Alkylcarbonylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₆-C₁₀-Arylaminocarbonyl, Heteroarylaminocarbonyl, Heteroarylcarbonylamino, C₁-C₆-Alkylsulfonylamino, C₁-C₆-Alkylsulfonyl und C₁-C₆-Alkylthio gegebenenfalls mit einem Rest ausgewählt aus der Gruppe Hydroxy, Cyano, Halogen, Hydroxycarbonyl und einer Gruppe der Formel -NR⁷R⁸,
wobei R⁷ und R⁸ die oben angegebenen Bedeutungen aufweisen,
substituiert sind,
bedeuten, sowie deren Salze, Solvate und/oder Solvate der Salze, zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.A further embodiment of the invention relates to the use of compounds of the formula (II),

in which
R ^{5 is} phenyl, pyridyl or thiophenyl, which are optionally selected with up to 3 substituents independently selected from the group C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy, C C ₁ -C ₆ -alkylamino, halogen, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl , Heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylthio,
wherein C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally with a radical selected from the group Hydroxy, cyano, halogen, hydroxycarbonyl and a group of formula -NR ⁷ R ⁸ ,
in which
R ⁷ and R ⁸ independently of one another are hydrogen or C ₁ -C ₆ -alkyl,
or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, denote 5- to 8-membered heterocyclyl,
are substituted
R ^{6 is} phenyl or heteroaryl, where phenyl having 1 to 3 radicals and heteroaryl optionally having 1 to 3 radicals are each independently selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, Amino, nitro, hydroxy, C ₁ -C ₆ -alkylamino, halogen, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylthio are substituted,
wherein C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally with a radical selected from the group Hydroxy, cyano, halogen, hydroxycarbonyl and a group of formula -NR ⁷ R ⁸ ,
where R ⁷ and R ^{8 have} the meanings given above,
are substituted
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (II),
in which
R ^{5 is} phenyl, pyridyl or thiophenyl, which are optionally selected from the group C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, hydroxy, C ₁ - independently of one another with up to 3 radicals independently of one another C ₄ alkylamino, fluoro, chloro, bromo, C ₆ -C ₁₀ arylcarbonylamino, C ₁ -C ₄ alkylcarbonylamino, C ₁ -C ₄ alkylaminocarbonyl, C ₁ -C ₄ alkoxycarbonyl, C ₆ -C ₁₀ arylaminocarbonyl , Heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₄ -alkylsulfonylamino, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₄ -alkylthio,
wherein C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy optionally having a radical selected from the group hydroxy, Cy ano, fluorine, chlorine, bromine, hydroxycarbonyl and a group of the formula -NR ⁷ R ⁸ ,
in which
R ⁷ and R ^{8 are} independently hydrogen or C ₁ -C ₄ alkyl, or
R ⁷ and R ^8, together with the nitrogen atom to which they are attached, denote 5- to 6-membered heterocyclyl,
are substituted
R ^{6 is} phenyl, pyrimidyl or pyridyl, where phenyl having 1 to 3 radicals and pyrimidyl and pyridyl optionally having 1 to 3 radicals are each independently selected from the group consisting of C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, hydroxycarbonyl, Cyano, trifluoromethyl, amino, hydroxy, C ₁ -C ₄ -alkylamino, fluoro, chloro, bromo, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C _4- alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₄ -alkylsulfonylamino, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₄ -alkylthio,
where C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy optionally have a radical selected from the group consisting of hydroxyl, cyano, fluorine, chlorine, bromine, hydroxycarbonyl and a group of the formula -NR ⁷ R ⁸ ,
where R ⁷ and R ^{8 have} the meanings given above,
are substituted
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (II),
in which R ^{5 has} the meanings given above and
R ^{6 is} phenyl or pyridyl, phenyl having 1 to 2 radicals and pyridyl optionally having 1 to 2 radicals each independently selected from the group consisting of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (II),
in which
R ^{5 is} phenyl, pyridyl or thiophenyl, which are optionally selected from the group C ₁ -C ₄ -alkyl, fluorine, chlorine, trifluoromethyl, hydroxy, phenylcarbonylamino, C ₁ -C ₄ -alkylcarbonylamino, C ₁ -, optionally with up to 2 radicals independently of one another C ₄ alkylaminocarbonyl or phenylaminocarbonyl are substituted,
R ^{6 is} phenyl or pyridyl, phenyl having 1 to 2 radicals and pyridyl optionally having 1 to 2 radicals each independently selected from the group consisting of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine,
and their salts, solvates and / or solvates of the salts for the preparation of medicaments for the treatment of cardiovascular diseases.

In the context of the present invention, the substituents, unless specified otherwise, in the context of the formula (II) have the following meaning:
C ₁ -C ₆ -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Preferred examples include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

C ₁ -C ₆ -alkyl is a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms. Preferred examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and n-hexyl.

halogen stands for Fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, especially prefers fluorine and chlorine.

C ₁ -C ₆ -alkylamino represents a straight-chain or branched mono- or dialkylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Preferred examples include methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino and n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-t-butylamino, di-n-pentylamino, di -n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino and n-hexyl-i-pentylamino.

C ₁ -C ₆ -alkylcarbonylamino is an alkylcarbonyl radical linked via an amino group, where the alkyl radical can be straight-chain or branched and contains 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3, carbon atoms. Preferred examples include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, t-butylcarbonylamino, n-pentylcarbonylamino and n-hexylcarbonylamino.

C ₁ -C ₆ -alkylaminocarbonyl is a mono- or dialkylamino radical linked via a carbonyl group, where the alkyl radicals may be identical or different, straight-chain or branched, and in each case 1 to 6, preferably 1 to 4, and particularly preferably 1 to Contain 3 carbon atoms. Preferred examples include methylaminocarbonyl, ethylaminocarbonyl, n -propylaminocarbonyl, isopropylaminocarbonyl, tert -butylaminocarbonyl, n -pentylaminocarbonyl, n-hexylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, di-t-butylaminocarbonyl, di-n-pentylaminocarbonyl, di -n-hexylaminocarbonyl, ethylmethylaminocarbonyl, isopropylmethylaminocarbonyl, n-butylethylaminocarbonyl and n-hexyl-i-pentylaminocarbonyl. Furthermore, in the case of a dialkylamino radical, the two alkyl radicals together with the nitrogen atom to which they are attached may form a 5- to 8-membered heterocyclyl.

C ₆ -C ₁₀ -arylaminocarbonyl is an arylamino radical linked via a carbonyl group. Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.

C ₆ -C ₁₀ arylcarbonylamino represents an arylcarbonyl radical linked via an amino group. Preferred examples include phenylcarbonylamino and naphthylcarbonylamino.

C ₁ -C ₆ -alkylsulfonylamino represents a straight-chain or branched alkylsulfonylamino radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3, carbon atoms. Preferred examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.

C ₁ -C ₆ -alkylsulfonyl is a straight-chain or branched alkylsulfonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Preferred examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

C ₁ -C ₆ -alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Preferred examples include methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio and n-hexylthio.

heteroaryl stands for an aromatic, mono- or bicyclic radical having 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. Preferred are 5- to 6-membered heteroaryls containing up to 4 heteroatoms. Of the Heteroaryl may be over be bound to a carbon or nitrogen atom. Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, Tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, Benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl.

heteroarylaminocarbonyl stands for one over linked a carbonyl group Heteroarylamino radical. Preferred examples include thienylaminocarbonyl, Furylaminocarbonyl, pyrrolylaminocarbonyl, thiazolylaminocarbonyl, Oxazolylaminocarbonyl, imidazolylaminocarbonyl, tetrazolylaminocarbonyl, Pyridylaminocarbonyl, pyrimidinylaminocarbonyl, pyridazinylaminocarbonyl, Indolylaminocarbonyl, indazolylaminocarbonyl, benzofuranylaminocarbonyl, Benzothiophenylaminocarbonyl, quinolinylaminocarbonyl and isoquinolinylaminocarbonyl.

heteroarylcarbonylamino stands for one over linked an amino group Heteroarylcarbonyl radical. Preferred examples include thienylcarbonylamino, Furylcarbonylamino, pyrrolylcarbonylamino, thiazolylcarbonylamino, Oxazolylcarbonylamino, imidazolylcarbonylamino, tetrazolylcarbonylamino, Pyridylcarbonylamino, pyrimidinylcarbonylamino, pyridazinylcarbonylamino, Indolylcarbonylamino, indazolylcarbonylamino, benzofuranylcarbonylamino, Benzothiophenylcarbonylamino, quinolinylcarbonylamino and isoquinolinylcarbonylamino.

5- to 8-membered heterocyclyl is a mono- or polycyclic, heterocyclic radical having 5 to 8 ring atoms and up to 3, preferably 2 heteroatoms or hetero groups from the series N, O, S, SO, SO ₂ . Mono- or bicyclic heterocyclyl is preferred. Particularly preferred is monocyclic heterocyclyl. As heteroatoms, N and O are preferred. The heterocyclyl radicals may be saturated or partially unsaturated. Saturated heterocyclyl radicals are preferred. Particularly preferred are 5- to 7-membered heterocyclyl radicals. Preferred examples include oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahy drofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl.

6-membered Heteroaryl stands for an aromatic residue with 6 ring atoms and up to 2 nitrogen atoms. The heteroaryl radical is over bound a carbon atom. Preferred examples include pyridyl, Pyrimidinyl, pyridazinyl and pyrazinyl.

If Residues in the compounds of the invention are optionally substituted is, unless otherwise specified, a substitution with up to three identical or different substituents prefers.

The Compounds of the formula (II) and their preparation are known from WO 04/099210 known.

The compounds of the formulas (I) and (II) according to the invention can also be present as tautomers, as shown by way of example below:

in welcher
R⁹ C₁-C₆-Alkyl, Trifluormethyl, Hydroxy, C₁-C₆-Alkoxy, -C(=O)OR¹³ oder -C(=O)NR¹⁴R¹⁵, wobei C₁-C₆-Alkyl gegebenenfalls mit 1 bis 3 Resten unabhängig voneinander ausgewählt aus der Gruppe Hydroxy, C₁-C₆-Alkoxy, Halogen, Trifluormethyl, Trifluormethoxy, -C(=O)OR¹³ oder -C(=O)NR¹⁴R¹⁵ substituiert ist, und
R¹³ für C₁-C₆-Alkyl,
R¹⁴ und R¹⁵ unabhängig voneinander für Wasserstoff, C₆-C₁₀-Aryl, C₁-C₆-Alkyl stehen,
oder
zusammen mit dem Stickstoffatom, an das sie gebunden sind, ein 4- bis 10-gliedriges Heterocyclyl bilden,
R¹⁰ Wasserstoff, C₁-C₆-Alkyl, Trifluormethyl, C₁-C₆-Alkoxy,
oder
R⁹ und R¹⁰ zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, C₃-C₈-Cycloalkyl, C₃-C₈-Cycloalkenyl oder 4- bis 10-gliedriges Heterocyclyl bilden, die gegebenenfalls mit bis zu 2 Substituenten aus der Gruppe C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxy, Oxo, -C(=O)OR¹⁶ substituiert sind, und
R¹⁶ für C₁-C₆-Alkyl oder Benzyl steht,
R¹¹ Wasserstoff oder C₁-C₆-Alkyl,
R¹² Pentan-3-yl, C₃-C₆-Cycloalkyl,
X Sauerstoff oder Schwefel,
bedeuten, sowie deren Salze, Solvate und/oder Solvate der Salze, zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.A further embodiment of the invention relates to the use of compounds of the formula (III)

in which
R ^{9 is} C ₁ -C ₆ -alkyl, trifluoromethyl, hydroxy, C ₁ -C ₆ -alkoxy, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ , where C ₁ -C ₆ -alkyl optionally substituted with 1 to 3 radicals independently of one another selected from the group hydroxyl, C ₁ -C ₆ -alkoxy, halogen, trifluoromethyl, trifluoromethoxy, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ , and
R ^{13 is} C ₁ -C ₆ -alkyl,
R ¹⁴ and R ¹⁵ independently of one another represent hydrogen, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkyl,
or
together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl,
R ^{10 is} hydrogen, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₁ -C ₆ -alkoxy,
or
R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl or 4- to 10-membered heterocyclyl optionally substituted by up to 2 substituents from the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, oxo, -C (= O) OR ^{16 are} substituted, and
R ^{16 is} C ₁ -C ₆ -alkyl or benzyl,
R ^{11 is} hydrogen or C ₁ -C ₆ -alkyl,
R ^{12 is} pentan-3-yl, C ₃ -C ₆ -cycloalkyl,
X oxygen or sulfur,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (III)
R ^{9 is} C ₁ -C ₆ -alkyl, hydroxy, C ₁ -C ₆ -alkoxy, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ , where C ₁ -C ₆ -alkyl optionally with Hydroxy, C ₁ -C ₆ alkoxy, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ , and
R ^{13 is} C ₁ -C ₆ -alkyl,
R ¹⁴ and R ¹⁵ independently of one another are hydrogen, C ₆ -C ₁₀ -aryl, C ₁ -C ₆ -alkyl, or
together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl,
R ^{10 is} hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy,
or
R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl or 4- to 10-membered heterocyclyl optionally substituted by up to 2 substituents from the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy, oxo, -C (= O) OR ^{16 are} substituted, and
R ^{16 is} C ₁ -C ₆ -alkyl or benzyl,
R ^{11 is} hydrogen or C ₁ -C ₆ -alkyl,
R ^{12 is} pentan-3-yl, C ₄ -C ₆ -cycloalkyl,
X oxygen or sulfur,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (III)
R ^{9 is} C ₁ -C ₄ -alkyl, trifluoromethyl, hydroxy, C ₁ -C ₄ -alkoxy, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ where C ₁ -C ₄ -alkyl is optionally substituted with hydroxy, C ₁ -C ₄ alkoxy, trifluoromethyl, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ , and
R ^{13 is} C ₁ -C ₄ -alkyl,
R ¹⁴ and R ¹⁵ independently of one another represent hydrogen, phenyl, C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl,
R ^{10 is} hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl,
or
R ⁹ and R ^10, together with the carbon atom to which they are attached, form C ₅ -C ₆ -cycloalkyl, C ₅ -C ₆ -cycloalkenyl or 5- to 6-membered heterocyclyl, optionally substituted by up to 2 substituents from the group Group C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, oxo, -C (= O) OR ^{16 are} substituted, and
R ^{16 is} C ₁ -C ₄ -alkyl or benzyl,
R ^{11 is} hydrogen,
R ^{12 is} pentan-3-yl, C ₅ -C ₆ -cycloalkyl,
X oxygen or sulfur,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (III)
R ^{9 is} methyl, ethyl, isopropyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl or -C (= O) NR ¹⁴ R ¹⁵ , wherein methyl is optionally substituted by methoxycarbonyl or ethoxycarbonyl, and
R ^{14 is} phenyl and
R ^{15 is} hydrogen,
R ^{10 is} hydrogen, methyl, trifluoromethyl, or
R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form cyclopentyl, cyclohexyl, cyclopentenyl or tetrahydrofuryl, where cyclohexyl is optionally substituted by methyl, and
R ^{11 is} hydrogen,
R ^{12 is} pentan-3-yl, C ₅ -C ₆ -cycloalkyl,
X oxygen or sulfur,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (III)
R ^{9 is} methyl, ethyl, isopropyl, methoxycarbonyl, ethoxycarbonyl or -C (= O) NR ¹⁴ R ¹⁵ , wherein methyl is optionally substituted with methoxycarbonyl or ethoxycarbonyl, and
R ^{14 is} phenyl and
R ^{15 are} hydrogen,
R ^{10 is} hydrogen, methyl, or
R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form cyclopentyl, cyclohexyl, cyclopentenyl or tetrahydrofuryl, where cyclohexyl is optionally substituted by methyl, and
R ^{11 is} hydrogen,
R ^{12 is} pentan-3-yl, C ₅ -C ₆ -cycloalkyl,
X oxygen,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

In the context of the present invention, the substituents, unless specified otherwise, in the context of the formula (III) have the following meaning:
C ₁ -C ₆ -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

C ₁ -C ₆ -alkyl is a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, tert -butyl, n -pentyl and n -hexyl.

C ₆ -C ₁₀ aryl is phenyl or naphthyl.

C ₃ -C ₈ -cycloalkyl represents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl may be mentioned as preferred.

C ₃ -C ₈ -cycloalkenyl represents partially unsaturated, non-aromatic cycloalkyl radicals which contain one or more multiple bonds, preferably double bonds. Non-limiting examples include cyclopentenyl, cyclohexenyl and cycloheptenyl.

halogen stands for Fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, especially prefers fluorine and chlorine.

4- to 10-membered heterocyclyl is a mono- or polycyclic, heterocyclic radical having 4 to 10 ring atoms and up to 3, preferably 1 heteroatoms or hetero groups from the series N, O, S, SO, SO ₂ . 4- to 8-membered heterocyclyl is preferred. Mono- or bicyclic heterocyclyl is preferred. As heteroatoms, N and O are preferred. The heterocyclyl radicals may be saturated or partially unsaturated. Saturated heterocyclyl radicals are preferred. The heterocyclyl radicals can be bonded via a carbon atom or a heteroatom. Particular preference is given to 5- to 7-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the series O, N and S. Examples which may be mentioned are: oxetan-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl , Pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl.

If Residues in the compounds of the invention are optionally substituted is, unless otherwise specified, a substitution with up to three identical or different substituents prefers.

The compounds of the formula (III) according to the invention can also be present as tautomers, as shown by way of example below:

The Compounds of formula (III) and their preparation are from WO 04/026876 known.

in welcher
R¹⁷ Phenyl, welches mit 1 bis 5 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Halogen, C₁-C₆-Alkyl, Trifluormethyl, Trifluormethoxy, Cyano, Hydroxy, Nitro und C₁-C₆-Alkoxy substituert ist,
R¹⁸ Pentan-3-yl, C₄-C₆-Cyeloalkyl,
X Sauerstoff oder Schwefel,
bedeuten,
sowie deren Salze, Solvate und/oder Solvate der Salze, zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.A further embodiment of the invention relates to the use of compounds of the formula (IV)

in which
R ^{17 is} phenyl which is substituted by 1 to 5 substituents independently of one another selected from the group consisting of halogen, C ₁ -C ₆ -alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro and C ₁ -C ₆ -alkoxy,
R ^{18 is} pentan-3-yl, C ₄ -C ₆ -cycloalkyl,
X oxygen or sulfur,
mean,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formula (IV)
R ^{17 is} phenyl which is substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, bromine, C ₁ -C ₄ -alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro and C ₁ -C ₄ -alkoxy,
R ^{18 is} pentan-3-yl, C ₅ -C ₆ -cycloalkyl,
X oxygen or sulfur,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

in welcher
R¹⁹ Wasserstoff oder Chlor,
R²⁰ Fluor, Chlor, Brom, Methyl, Trifluormethyl,
R¹⁸ Pentan-3-yl, Cyclopentyl,
X Sauerstoff oder Schwefel,
bedeuten, sowie deren Salze, Solvate und/oder Solvate der Salze. zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.A further embodiment of the invention relates to the use of compounds of the formula (IVa)

in which
R ^{19 is} hydrogen or chlorine,
R ^{20 is} fluorine, chlorine, bromine, methyl, trifluoromethyl,
R ¹⁸ pentan-3-yl, cyclopentyl,
X oxygen or sulfur,
and their salts, solvates and / or solvates of the salts. for the manufacture of medicaments for the treatment of cardiovascular diseases.

A further embodiment of the invention relates to the use of compounds of the formulas (IV) and (IVa),
in which
R ^{19 is} hydrogen or chlorine,
R ^{20 is} fluorine, chlorine, bromine, methyl, trifluoromethyl,
R ¹⁸ pentane-3-yl, cyclopentyl,
X oxygen,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

Unless otherwise specified, in the context of the present invention, the substituents in the context of formulas (IV) and (IVa) have the following meanings:
C ₁ -C ₆ -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms. Preferred examples are methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

C ₁ -C ₆ -alkyl is a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms. Preferred examples are methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

C ₄ -C ₆ - and C ₅ -C ₆ -cycloalkyl are saturated or partially unsaturated cycloalkyl radicals having 4 to 6, preferably 5 to 6 carbon atoms. Preferred examples are cyclobutyl, cyclopentyl and cyclohexyl.

halogen stands for Fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, especially prefers fluorine and chlorine.

If Residues in the compounds of the invention of the formulas (IV) and (IVa) are optionally substituted, Unless otherwise specified, substitution with up to three same or different substituents preferred.

The Compounds of formulas (IV) and (IVa) and their preparation are from WO 04/018474.

The compounds of the formulas (IV) and (IVa) according to the invention can also be present as tautomers, as shown by way of example below:

Compounds of the invention are the compounds of the formula (I), (II), (III), (IV) and (IVa) and their salts, solvates and solvates of salts; those of Formelm (I), (II), (III), (IV) and (IVa) included compounds of the following formulas and their salts, solvates and solvates of the salts and those of formulas (I), (II), (III), (IV) and (IVa), below as exemplary embodiments mentioned compounds and their salts, solvates and solvates of Salts, as far as those of formulas (I), (II), (III), (IV) and (IVa) did not already include the compounds listed below Salts, solvates and solvates of the salts.

The Compounds of the invention can dependent on of their structure in stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore relates to the enantiomers or Diastereomers and their respective mixtures. From such mixtures enantiomers and / or diastereomers can be the stereoisomer isolate uniform components in a known manner.

When Salts are physiologically acceptable salts in the context of the invention the compounds of the invention prefers.

physiological acceptable salts of the compounds of the formulas (I), (II), (III), (IV) and (IVa) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methane, Ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

Physiologically acceptable salts of the compounds of the formulas (I), (II), (III), (IV) and (IVa) also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (eg sodium and potassium salts), alkaline earth salts (eg. and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, Dehydroabietylamine, arginine, lysine, ethylene diamine and methylpiperidine.

When Solvates are in the context of the invention, such forms of compounds designated, which in solid or liquid state by coordination with solvent molecules one Complex form. Hydrates are a special form of solvate, at which is coordinated with water.

It also includes the present invention also prodrugs of the compounds of the invention. Of the Term "prodrugs" includes compounds, which may themselves be biologically active or inactive, but during their Residence time in the body to compounds of the invention be implemented (for example, metabolically or hydrolytically).

The Compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic spectrum of activity. They stand out in particular by inhibition of PDE9A.

Surprisingly has been found that the compounds of the invention for the preparation of Medicines suitable for the treatment of cardiovascular diseases are.

The Compounds of the invention can due to their pharmacological and pharmacokinetic properties alone or in combination with other medicines for treatment used by cardiovascular diseases.

she can therefore in medicines for the treatment of cardiovascular diseases such as for the treatment of hypertension and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic disorders and ischemia such as myocardial infarction, stroke, transitory and ischemic Attacks, peripheral circulatory disorders, prevention of restenosis as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA), Bypass and for the treatment of arteriosclerosis, asthmatic diseases and diseases of the genitourinary system such as prostatic hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension, portal hypertension, ischemic kidney disease, Renal stenosis, renal insufficiency, acute renal failure, metabolic Syndrome, gastroparesis and incontinence are used.

Examples the compounds of the invention are from WO 04/018474, WO 04/026870, WO 04/099210 and WO 04/099211 known.

The In vitro activity of the compounds of the invention may be with the following biological assays are shown:

PDE Inhibition

recombinant PDE1C (GenBank / EMBL Accession Number: NM_005020, Loughney et al. J. Biol. Chem. 1996 271, 796-806), PDE2A (GenBank / EMBL Accession Number: NM_002599, Rosman et al., Gene 1997 191, 89-95), PDE3B (GenBank / EMBL Accession Number: NM_000922, Miki et al., Genomics 1996, 36, 476-485), PDE4B (GenBank / EMBL Accession Number: NM_002600, Obernolte et al. Genes. 1993, 129, 239-247), PDE5A (GenBank / EMBL Accession Number: NM_001083, Loughney et al. Gene 1998, 216, 139-147), PDE7B (GenBank / EMBL Accession Number: NM_018945, Hetman et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 472-476), PDE8A (GenBank / EMBL Accession Number: AF_056490, Fisher et al. Biochem. Biophys. Res. Commun. 1998 246, 570-577), PDE9A (Fisher et al., J. Biol. Chem, 1998, 273 (25): 15559-15564), PDE10A (GenBank / EMBL Accession Number: NM_06661, Fujishige et al. J Biol Chem. 1999, 274, 18438-45), PDE11A (GenBank / EMBL Accession Number: NM_016953, Fawcett et al. Proc. Natl. Acad. Sci. 2000, 97, 3702-3707) were synthesized using the pFASTBAC baculovirus expression system (GibcoBRL) expressed in Sf9 cells. PDE5 was purified from human platelets: After ultrasound digestion and Centrifugation was followed by ion exchange chromatography of the supernatant over a Mono Q 10/10 pillar (linear NaCl gradient, elution with 0.2-0.3 M NaCl in buffer (20 mM Hepes pH7.2 and 2mM MgCl2)). PDE1 (from bovine brain) was from Sigma.

The test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE9A. Typically, serial dilutions of 200 μM to 1.6 μM are prepared (resulting final concentrations in the assay: 4 μM to 0.032 μM). 2 μL each of the diluted substance solutions are placed in the wells of microtiter plates (Isoplate, Wallac Inc., Atlanta, GA). Subsequently, 50 μL of a dilution of the PDE9A preparation described above is added. The dilution of the PDE9A preparation is chosen such that during the later incubation less than 70% of the substrate is reacted (typical dilution: 1: 10,000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EDTA, 0.2% BSA). The substrate, [8- ³ H] guanosine 3 ', 5'-cyclic phosphate (1 μCi / μL; Amersham Pharmacia Biotech., Piscataway, NJ) is assayed 1: 2000 with assay buffer (50 mM Tris / HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EDTA) to a concentration of 0.0005 μCi / μL. By adding 50 μL (0.025 μCi) of the diluted substrate, the enzyme reaction is finally started. The test mixtures are incubated for 60 min at room temperature and the reaction is stopped by addition of 25 μl of a PDE9A inhibitor dissolved in assay buffer (eg the inhibitor from Preparation Example 1, 10 μM final concentration). Immediately thereafter, 25 μl of a suspension containing 18 mg / ml of Yttrium Scintillation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ) is added. The microtiter plates are sealed with a foil and allowed to stand at room temperature for 60 min. The plates are then measured for 30 s per well in a microbeta scintillation counter (Wallac Inc., Atlanta, GA). IC ₅₀ values are determined by plotting the concentration of the substance against the percent inhibition.

The in vitro effect of test substances on recombinant PDE3B, PDE4B, PDE7B, PDE8A, PDE10A and PDE11A is determined according to the test protocol described above for PDE9A with the following adaptations: As substrate, [5 ', 8- ³ H] adenosine 3', 5 ' cyclic phosphates (1 μCi / μL; Amersham Pharmacia Biotech., Piscataway, NJ). The addition of an inhibitor solution to stop the reaction is not necessary. Instead, following the incubation of substrate and PDE, the addition of the Yttrium Scintillation Proximity Beads is continued as described above, thereby stopping the reaction. For the determination of a corresponding effect on PDE1, PDE2A and PDE5, the protocol is additionally adapted as follows: For PDE1, additional calmodulin 10 ^-7 M and CaCl ₂ 3 mM are added to the reaction mixture. PDE2A is stimulated in the assay by addition of cGMP 1 μM and tested with a BSA concentration of 0.01%. For PDE1 and PDE2A 5'-cyclic phosphate is 'adenosine [, 8- ³ H 3 as the substrate 5]' (1 uCi / ul; Amersham Pharmacia Biotech, Piscataway, NJ.), For PDE5 [8- ³ H] guanosine 3 ', 5'-cyclic phosphate (1 μCi / μL; Amersham Pharmacia Biotech., Piscataway, NJ).

Vaso-relaxant effect in vitro

Rabbits are stunned and bled by a stroke of the neck. The saphenous artery is removed, detached from adherent tissue, divided into 3 mm wide rings and placed individually under pretension in 5 ml organ baths with 37 ° C warm, carbogen-fumigated Krebs-Henseleit solution of the following composition (mM): NaCl: 119; KCl: 4.8; CaCl ₂ × 2 H ₂ O: 1; MgSO ₄ .7H ₂ O: 1.4; KH ₂ PO _4: 1.2; _NaHCO3: 25; Glucose: 10. The force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on chart recorders. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is examined in each subsequent passage in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC ₅₀ ). The standard application volume is 5 μl, the DMSO content in the bath solution corresponds to 0.1%.

The results are shown in Table 1: TABLE 1 Vascular Relaxing Effect in vitro

Hemodynamics in anesthetized Rats.

Male Wistar rats weighing 300-350 g (Harlan Winkelmann, Borchen, Germany) were anesthetized with 100 mg kg ^-1 ip of thiopental " ^Nycomed® " (Nycomed, Munich, Germany). A tracheostomy was performed and catheters were used to measure blood pressure and heart rate (Gould pressure transducer and recorder, model RS 3400) introduced into the femoral artery and for substance application in the femoral vein. The animals were ventilated with room air and their body temperature controlled. Test substances were administered orally or intravenously.

Rabbit Model

adult, male Chinchilla rabbits weighing 3-5kg will be on delivery adapted for several days in individual housing. You have free access to water and can feed for two hours a day. The animals are in a 10/14 hour day-night rhythm (light on, from 8.00 Clock), the room temperature is 22-24 ° C.

Per Treatment group are used three to six animals and directly weighed before the start of the experiment. For the i.v. Gabe the substances in Transcutol (GATTEFOSSE GmbH) solved and in the ratio 3/7 with a 20% Cremophor solution (Cremophor (BASF), water). A volume of 0.5 ml / kg is injected into the ear vein. Water-soluble substances are in 0.9% saline injected.

For the oral Gabe the test substances in a mixture of glycerol: Water: Polyethylene glycol 6: 10: 9.69 dissolved and in a volume of 1 ml / kg with the gavage.

Under Rest conditions is not the rabbit penis in the pubic region visible and completely covered by penile skin. The erection is scored by looking at the length of the protruding penis with a sliding calliper. The measurement is performed 5, 10, 15, 30, 45, 60 and 120 minutes after substance administration, after oral administration in addition even after 3, 4, 5 and 6 hours. The animals become each Time out of the cage fetched, held on the neck fur and the hind legs, on the move turned and measured. Appropriate solvent controls are carried out. (See literature: E. Bischoff, K. Schneider, Int. J. of Impotence Res. 2001, 13, 230-235; E. Bischoff & Niewoehner, H. Haning, M. Es Sayed, T. Schenke, K.H. Schlemmer, The Journal of Urology, 2001, 165, 1316-1318; E. Bischoff Int. J. Impotence Res. 2001, 13, 146-148).

determination Pharmacokinetic parameters after intravenous and oral administration

The substance to be tested is administered intravenously to animals (e.g., mouse, rat, dog) as a solution which oral administration takes place as a solution or suspension over a gavage. After giving substance the animals are assigned to Blood is taken at times, this will be heparinized and subsequently derived from it by centrifugation plasma. The substance is in the Plasma over LC / MSMS analytically quantified. From the plasma concentration-time curves determined in this way the pharmacokinetic parameters by means of calculated from a validated pharmacokinetic calculation program.

Inhibition of cytochrome P450 enzymes

The Potential of inhibition of P-450 isoenzymes responsible for the metabolism important, is automatically analyzed in 96-well format. in this connection Two different assays are used.

Recombinant enzymes (eg CYP1A2, 2C8, 2C9, 2C19, 2D6 or 3A4) and substrates generally containing fluorescein or coumarin substructures are used in the assay for the formation of fluorescent metabolites. In each case a substrate concentration and 8 concentrations of the potential inhibitor are used. After incubation with the respective recombinant CYP enzyme, the extent of fluorescent metabolites in comparison with the control (without inhibitor) is determined by means of fluorescence reader and an IC ₅₀ value is calculated [Anal. Biochem. 248, 188 (1997)].

The second assay uses human liver microsomes as the enzyme source and phenacetin (CYP1A2), diclofenac (CYP2C9), dextromethorphan (CYP2D6) and midazolam (CYP3A4) as CYP isoform-selective substrates. The formation of the respective metabolite is measured by means of LC-MS / MS. Assuming competitive inhibition, K _i values are calculated from the reduction in metabolite formation compared to the control (1 substrate, 3 inhibitor concentrations).

Induction of cytochrome P450 enzymes in human liver cell cultures

To investigate the side effect potential of the substances according to the invention with respect to induction of cytochrome P450 enzymes, primary human hepatocytes with a cell density of 2.5 × 10 ⁵ cells between two layers of collagen in 24 well microtiter plates at 37 ° C at 5% CO _{2 for} 8 days cultivated. The cell culture medium is changed daily.

To 48 hours. in culture, the hepatocytes are in duplicate for 5 days compared with different concentrations of the test substances with the inducers rifampicin (RIF, 50 μM), omeprazole (OME, 100 μM) and phenobarbital (PB, 2mM). The final concentrations of the test substances are 0.01-10 μg / ml.

Of the cell cultures, the inductive effect of the test substances on the cytochrome (CYP) P450 enzymes 1A2, 2B6, 2C19 and 3A4 by addition of the substrates 7-ethoxyresorufin (CYP1A2), [ ¹⁴ C] -S-mephenytoin (CYP2B6 and 2C19) and [ ¹⁴ C] testosterone (CYP3A4) determined on day 8. From the thus measured enzyme activities CYP1A2, 2B6, 2C19 and 3A4 treated cells compared to untreated cells, the inductive potential of the test substances is determined.

Another The present invention relates to medicaments containing at least one compound of the invention and at least one or more further active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.

The Compounds of the invention can act systemically and / or locally. For this purpose they can 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.

For this Application routes can the compounds of the invention be administered in suitable administration forms.

For the oral Application are functioning according to the prior art rapidly and / or modifies the compounds according to the invention donating Application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, e.g. Tablets (uncoated or coated Tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, Capsules (for example hard or soft gelatine capsules), dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or Solutions.

The Parenteral administration can bypass a resorption step happen (e.g., intravenously, intraarterial, intracardiac, intraspinal or intralumbar) or involving absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates or sterile powders.

For the others Application routes are suitable, e.g. Inhalation medicines (i.a. Powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccally applied tablets, films / wafers or capsules, Suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (Lotions, shake mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, Implants or stents.

The Compounds of the invention can in the cited Application forms are transferred. This can be done in a conventional manner by mixing with inert, Non-toxic, pharmaceutically suitable excipients happen. Among these adjuvants include et al excipients (for example, microcrystalline cellulose, lactose, mannitol), solvent (e.g., liquid Polyethylene glycols), emulsifiers and dispersing or wetting agents (For example, sodium dodecyl sulfate, Polyoxysorbitanoleat), binder (For example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin), stabilizers (e.g., antioxidants such as for example ascorbic acid), Dyes (e.g., inorganic pigments such as iron oxides) and flavor and / or scent remedies.

Another The present invention relates to medicaments which are at least a compound of the invention, usually together with one or more inert, non-toxic, pharmaceutical contain suitable excipients, as well as their use to the previously mentioned purposes.

In general, it has proven to be advantageous for parenteral administration per day amounts of about 0.001 to 10 mg / kg of body weight to achieve effective results. When administered orally, the amount per day is about 0.005 to 3 mg / kg of body weight.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on of body weight, Route of administration, individual behavior towards the active substance, type of Preparation and time or interval to which the application he follows. So it can in some cases be sufficient, with less than the aforementioned minimum quantity to get along while in other cases exceeded the mentioned upper limit must become. In case of application of larger quantities it may be recommended be to distribute these in several single doses throughout the day.

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight, Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each on the volume.

The Compounds of the invention can as follows be converted into pharmaceutical preparations:

Tablet:

Summary:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate) 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

production:

The Mixture of compound according to the invention, Lactose and starch is with a 5% solution (m / m) of the PVP in water granulated. The granules will dry after drying mixed with the magnesium stearate for 5 minutes. This mixture will with a usual Pressed tablet press (format of the tablet see above). When Guideline for the compression is used a pressing force of 15 kN.

Orally administrable suspension:

Composition:

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

one Single dose of 100 mg of the compound of the invention correspond 10 ml oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound of the invention is fed to the suspension. While stirring the addition of the water takes place. Until the completion of the swelling of the rhododendron is stirred for about 6 h.

Orally administrable solution:

Summary:

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

production:

The inventive compound is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process will be up to the full resolution the compound of the invention continued.

iv Solution:

The inventive compound becomes in a concentration below the saturation solubility in a physiological acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%. The solution is sterile filtered and sterile and pyrogen-free injection containers refilled.

Intravenously administrable Solution:

Composition:

1 mg of the compound of the invention, 15 g of polyethylene glycol 400 and 250 g of water for injections.

production:

The inventive compound is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile-filtered (pore diameter 0.22 microns) and under raseptic conditions in heat-sterilized infusion bottles filled. These are with infusion stoppers and brim caps closed.

Claims (10)

Use of compounds of the formula

in which R ^{1 is} C ₁ -C ₈ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl, where C ₁ -C ₈ -alkyl is optionally substituted by oxo, and wherein C ₁ -C ₈ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkenyl and C ₃ -C ₈ cycloalkyl optionally having up to 3 radicals independently selected from the group C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkoxy, hydroxycarbonyl, cyano, amino, nitro, hydroxy, C ₁ -C ₆ alkylamino, halogen, trifluoromethyl, trifluoromethoxy, C ₆ -C ₁₀ arylcarbonylamino, C ₁ -C ₆ alkylcarbonylamino , C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -Alkylthio, wherein C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₆ -C ₁₀ arylcarbonylamino, C ₁ -C ₆ alkylcarbonylamino, C ₁ -C _6- alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbon yl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally substituted with one to three radicals independently of one another from the group hydroxy, cyano, halogen, trifluoromethyl and trifluoromethoxy substituted R ^{2 is} phenyl or heteroaryl, where phenyl having 1 to 3 radicals and heteroaryl optionally having 1 to 3 radicals are each independently selected from the group C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, cyano, Trifluoromethyl, trifluoromethoxy, amino, nitro, hydroxy, C ₁ -C ₆ -alkylamino, halogen, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ - Alkoxycarbonyl, C ₆ -C ₁₀ arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ alkylsulfonylamino, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylthio, wherein C ₁ -C ₆ alkyl, C C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamines no, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C _6- alkylthio optionally having one to three radicals independently of one another selected from the group consisting of hydroxyl, cyano, halogen, trifluoromethyl, trifluoromethoxy and a group of the formula -NR ³ R ⁴ , where R ³ and R ⁴ independently of one another are hydrogen or C ₁ -C ₆ -alkyl, or R ³ and R ⁴ together with the nitrogen atom to which they are bonded, denote 5- to 8-membered heterocyclyl, and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases. Use of compounds of the formula (II),

in which R ^{5 is} phenyl, pyridyl or thiophenyl, which may optionally have up to 3 substituents independently selected from the group C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy , C ₁ -C ₆ -alkylamino, halogen, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl , Heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylthio, wherein C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally with a radical selected from the group hydroxy, cyano, halogen, hydroxycarbony l and a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 are} independently hydrogen or C ₁ -C ₆ alkyl, or R ⁷ and R ⁸ together with the nitrogen atom to which they are attached, 5- to 8-membered heterocyclyl, are substituted, R ^{6 is} phenyl or heteroaryl, where phenyl having 1 to 3 radicals and heteroaryl optionally having 1 to 3 radicals each independently selected from the group C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy, C ₁ -C ₆ alkylamino, halo, C ₆ -C ₁₀ arylcarbonylamino, C ₁ -C ₆ alkylcarbonylamino, C ₁ -C ₆ alkylaminocarbonyl, C C ₁ -C ₆ -alkoxycarbonyl, C ₆ -C ₁₀ -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylthio are substituted, wherein C ₁ -C _6- alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₆ -C ₁₀ -arylcarbonylamino, C ₁ -C ₆ -alkylcarbonylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₆ -C ₁₀ arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally with a radical selected from the group hydroxy , Cyano, halogen, hydroxycarbonyl and a group of the formula -NR ⁷ R ⁸ , wherein R ⁷ and R ^{8 have} the meanings given above, and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases. Use of compounds of the formula (III),

in which R ^{9 is} C ₁ -C ₆ -alkyl, trifluoromethyl, hydroxy, C ₁ -C ₆ -alkoxy, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ , where C ₁ -C ₆ Alkyl optionally substituted with 1 to 3 radicals independently of one another selected from the group hydroxy, C ₁ -C ₆ alkoxy, halogen, trifluoromethyl, trifluoromethoxy, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ substituted and R ^{13 is} C ₁ -C ₆ alkyl, R ¹⁴ and R ¹⁵ are each independently hydrogen, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkyl, or together with the nitrogen atom to which they are attached R ^{10 is} hydrogen, C ₁ -C ₆ -alkyl, trifluoromethyl, C ₁ -C ₆ -alkoxy, or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form a 4- to 10-membered heterocyclyl are C ₃ -C ₈ -cycloalkyl, C ₃ -C ₈ -cycloalkenyl or form 4- to 10-membered heterocyclyl, optionally with up to 2 substituents from the group C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkoxy, hydroxy, oxo, -C (= O) OR ¹⁶ , and R ^{16 is} C ₁ -C ₆ alkyl or benzyl s R ^{11 is} hydrogen or C ₁ -C ₆ -alkyl, R ^{12 is} pentan-3-yl, C ₃ -C ₆ -cycloalkyl, X is oxygen or sulfur, and their salts, solvates and / or solvates of the salts, to Production of medicines for the treatment of cardiovascular diseases. Use of compounds of the formula (IV),

in which R ^{17 is} phenyl which is substituted by 1 to 5 substituents independently of one another selected from the group consisting of halogen, C ₁ -C ₆ -alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro and C ₁ -C ₆ -alkoxy, R ¹⁸ Pentan-3-yl, C ₄ -C ₆ -cycloalkyl, X is oxygen or sulfur, and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases. Use of compounds of the general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of hypertension. Use of compounds of the general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of stable and unstable angina pectoris. Use of compounds of the general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of renal insufficiency. Use of compounds of the general formula (I-IV) according to claims 1 to 4 for the manufacture of medicaments for the treatment of acute renal failure. Use of compounds of the general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of ischemic Kidney disease and ischemia. Use of compounds of the general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of heart failure and venous Diseases.