WO2006125548A1

WO2006125548A1 - Use of pyrazolopyrimidine against cardiovascular diseases

Info

Publication number: WO2006125548A1
Application number: PCT/EP2006/004591
Authority: WO
Inventors: Martin Hendrix; Frank Wunder; Adrian Tersteegen; Johannes-Peter Stasch; Martina Wuttke
Original assignee: Bayer Healthcare Ag
Priority date: 2005-05-27
Filing date: 2006-05-16
Publication date: 2006-11-30
Also published as: EP1888076A1; DE102005024493A1

Abstract

The invention relates to the use of pyrazolopyrimidine for producing drugs for treating cardiovascular diseases.

Description

USE OF PYRAZOLOPYRIMIDINES AGAINST HEART CIRCULATION DISEASES

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

Inhibition of phosphodiesterases modulates levels of cyclic nucleotides 5'-3 'cyclic adenosine monophosphate (cAMP) and 5'-3' cyclic guanosine monophosphate (cGMP), respectively. These cyclic nucleotides (cAMP and cGMP) are important second messengers and therefore play a central role in the cellular signal transduction cascades. Both activate, inter alia, but not exclusively, again protein kinases. The cAMP-activated protein kinase is called protein kinase A (PKA), and the cGMP-activated protein kinase is called protein kinase G (PKG). Activated PKA or PKG, in turn, can phosphorylate a variety of cellular effector proteins (e.g., ion channels, G protein-coupled receptors, structural proteins). In this way, the second messengers cAMP and cGMP can control the most diverse physiological processes in various organs. However, the cyclic nucleotides can also act directly on effector molecules. For example, e.g. It is known that cGMP can act directly on ion channels and thereby influence the cellular ion concentration (reviewed in: Wei et al., Prague Neurobiol., 1998, 56: 37-64). A control mechanism to control the activity of cAMP and cGMP, and thus these physiological processes, 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). These 21 PDE genes can be divided into 1 1 PDE families based on their sequence homology (for a nomenclature suggestion, see http://depts.washington.edu/pde/Nomenclature.html.). Individual PDE genes within a family are distinguished by letters (e.g., PDEIA and PDEIB). If there are still different splice variants within a gene, this is then indicated by an additional numbering after the letter (for example PDElAl).

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. Geriet., 1998, 103: 386-392, Wang et al., Gern, 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 PDEI IA (Km = 0.52 μM; Fawcett et al., Proc. Nat. Acad. Sci., 2000, 97 (7): 3702-3707) are active even 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 since there is no GAF domain (cGMP binding domain) through which PDE activity allosterically enhanced) (Beavo et al., Current Opinion in Cell Biology, 2000, 12: 174-179). PDE9A inhibitors may therefore increase the basal cGMP concentration.

WO 04/099211, WO 04/099210, WO 04/026876, WO 04/018474 and the literature cited therein and US 2004/022018 already disclose pyrazolopyrimidines and their use for the production of medicaments for the treatment of various diseases.

The present invention relates to the use of compounds of the formula

in which

R ^{1 is} C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl,

wherein Cj-Cg-alkyl is optionally substituted with oxo, and

where C _r Cg-alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl and C ₃ -C ₈ -cycloalkyl optionally having up to 3 radicals independently selected from the group Cj-Cβ-alkyl, Cp C ₆ alkoxy, hydroxycarbonyl, cyano, amino, nitro, hydroxy, Ci-C ₆ -alkylamino, halogen, trifluoromethyl, trifluoromethoxy, Cβ-Cio-arylcarbonylamino, C _r C ₆ alkyl carbonylamino, C _ö alkylaminocarbonyl, C _r C ₆ -alkoxycarbonyl, C ₆ -C 10 -arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C ₁ -C ₆ -alkylsulfonylamino,

CpC _ö alkylsulfonyl, Ci-Cό-alkylthio are substituted,

in which

Ci-C ₆ alkyl, Ci-C ₆ alkoxy, -C ₆ alkylamino, C ₆ -C ₀ -Arylcarbonylamino, C _r C ₆ alkyl carbonylamino, Ci-Cβ-alkylaminocarbonyl, Ci-C _δ alkoxycarbonyl, C ₆ - Cio-arylaminocarbonyl, heteroarylaminocarbonyl, Heteroarylcarbonylamino, Ci-Cβ-alkylsulfonylamino, Ci-Cβ-alkylsulfonyl and Ci-Cβ-alkylthio optionally having 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 each independently selected from the group Ci-Cβ-alkyl, CpC _ö alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, amino, nitro , hydroxy, Ci-Cβ alkylamino, halogen, C _δ -Cio-arylcarbonylamino, Ci-Cβ-alkyl carbonylamino, Ci-C _ö alkylaminocarbonyl, Ci-C ₆ alkoxycarbonyl, C ₆ -Cio arylamino-carbonyl, heteroarylaminocarbonyl , heteroarylcarbonylamino, Ci-Cβ-alkylsulfonylamino, CpC _ö alkylsulfonyl, Ci-C ₆ substituted alkylthio, wherein CpCβ alkyl, C _r C ₆ alkoxy, Ci-C ₆ -alkylamino, C _ö -C -Arylcarbonylamino, Cj-C ₆ - alkylcarbonylamino, Ci-COE-alkylaminocarbonyl, Ci-C ₆ alkoxycarbonyl, C ₆ - Cj _O - arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, Cj-C ₆ - alkylsulfonylamino, C _r C ₆ alkylsulfonyl and C _r C ₆ alkylthio optionally substituted with one to three radicals independently selected from the group of hydroxy,

Cyano, halogen, trifluoromethyl, trifluoromethoxy and a group of 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 ₆ -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 _r C ₆ - Alkyl, C

C _ö alkoxy, hydroxycarbonyl, cyano, amino, nitro, hydroxy, Ci-C ₆ -alkylamino, halogen, C ₆ -Cio-arylcarbonylamino, Ci-C _ö alkylcarbonylamino, Cj-Cβ-alkylaminocarbonyl, Ci-C _ö -alkoxycarbonyl , Q-C jo-arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, Ci-C _ö alkylsulfonylamino, Ci-Cβ alkylsulfonyl, C] _-C6 alkylthio tuiert substitutable,

in which

C _r C ₆ alkyl, CPCE alkoxy, C _r C ₆ alkylamino, C _ö -Cio-arylcarbonylamino, C) _-C6 alkyl carbonylamino, CpCβ-alkylaminocarbonyl, Ci-C ₆ alkoxycarbonyl, C ₆ - Cio Arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonyl amino, C | -C ₆ alkylsulfonylamino, Ci-C ₆ alkylsulfonyl and C _r C ₆ -alkylthio optionally substituted 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 each independently selected from the group Ci-C ₆ - alkyl, CpCβ-alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy , Ci-C ₆ -alkylamino, halogen, Cβ-Cio-arylcarbonylamino, Ci-Cβ-alkylcarbonylamino, C _r C ₆ alkylaminocarbonyl, Ci-C ₆ alkoxycarbonyl, C _ö -Cio-arylaminocarbonyl, heteroaryl, aminocarbonyl, heteroarylcarbonylamino, Ci C ₆ alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylthio are substituted,

wherein Ci-C _ό alkyl, Ci-C ₆ alkoxy, C _r C ₆ alkylamino, Cβ-Cio-arylcarbonylamino, C ₁ -C ₆ - alkylcarbonylamino, CRQ-alkylaminocarbonyl, Ci-C ₆ alkoxycarbonyl, C ₆ - Ci ₀ - arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, CpC ₆ - alkylsulfonylamino, C _r C ₆ -alkylsulfonyl and C _r 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

are substituted

and their salts, solvates and / or solvates of the salts, for the production of medicaments for the treatment of cardiovascular diseases.

in which R ¹ Ci-C ₅ alkyl or C ₃ -C ₆ cycloalkyl, which is optionally substituted by up to 3 radicals independently selected from the group dC ₄ alkyl, _Ci-C4 alkoxy, trifluoromethyl, hydroxycarbonyl, cyano, amino, hydroxy, C _r C ₄ alkylamino, fluorine, chlorine, bromine, C ₆ - Cio-arylcarbonylamino, _{Ci-C4-alkylcarbonylamino,} _{Ci-C4-alkylaminocarbonyl,} Ci-C ₄ - alkoxycarbonyl, C ₆ -C ₀ arylaminocarbonyl , ₄ alkylsulfonyl, CpC ₄ -alkylthio heteroarylaminocarbonyl, Heteroarylcarb- carbonylamino, C _r C ₄ alkylsulfonylamino, Ci-C,

where C 1 -C ₄ -alkyl and C 1 -C ₄ -alkoxy optionally having a radical selected from the group consisting of hydroxyl, cyano, fluorine, chlorine and bromine

are substituted

R ^{2 is} phenyl, pyrimidyl, N-oxidopyridyl or pyridyl, phenyl having 1 to 3 radicals and pyrimidyl, N-oxidopyridyl and pyridyl optionally having 1 to 3 radicals, each independently selected from the group consisting of C 1 -C ₄ -alkyl, C] - C ₄ alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, 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,

Ci-C ₄ alkoxycarbonyl, C ₆ -C ₁₀ arylaminocarbonyl, heteroarylaminocarbonyl, heteroaryl carbonylamino, C] _-C4 alkylsulfonylamino, C] -C ₄ alkylsulfonyl, C _r C ₄ -alkylthio,

where C 1 -C ₄ -alkyl and C 1 -C ₄ -alkoxy optionally having a radical selected from the group consisting of hydroxy, 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,

in which

R ^{1 is} Q-Cs-alkyl or Cs-Cβ-cycloalkyl, which are optionally selected with up to 3 radicals independently of one another from the group Ci-Ci-alkyl, fluorine, trifluoromethyl, hydroxy,

Phenylcarbonylamino, C 1 -C ₄ -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl or phenylaminocarbonyl, and

in which

R ^{1 is} C ¹ -C ₅ -alkyl or C ₅ -C ₆ -cycloalkyl which is optionally selected with up to 3 radicals independently of one another from the group consisting of C 1 -C ₄ -alkyl, fluorine, trifluoromethyl, hydroxy, Phenylcarbonylamino, C 1 -C ₄ -alkylcarbonylamino, C 1 -C ₄ -alkylaminocarbonyl or phenylaminocarbonyl, and

R ^{2 is} phenyl, N-oxidopyridyl or pyridyl, wherein phenyl having one radical and pyridyl and N-oxidopyridyl optionally having a radical each independently selected from the group of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and

Chlorine are substituted,

In the context of the present invention, the substituents, unless specified otherwise, in the context of the formula (I) have the following meaning:

Q-Cs-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? -Cyalkenyl is a straight-chain or branched alkenyl radical having 2 to 6, preferably 2 to 4 and particularly preferably having 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 4 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 -CyAlkoxy is 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 -alkoxy-carbonyl 1 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 tertbutoxycarbonyl.

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, diisopropyl amino, di-t-butylamino, di-n-pentylamino, di-n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino and n-hexyl-i-pentylamino.

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.

is a mono- or dialkylamino radical linked via a carbonyl group, where the alkyl radicals may be identical or different, are straight-chain or branched and contain in each case 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 can form a 5- to 8-membered heterocyclyl.

Cfi-Cio-arylaminocarbonyl is an arylamino radical linked via a carbonyl group. Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.

Cft-C _j n-arylcarbonylamino is an arylamino radical linked via an amino group. Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.

C 1 -C 12 -alkyl-sulfonylamino 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.

dVQs-alkylsulfonyl represents 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, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

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 is fluorine, chlorine, bromine and iodine. Preference is given to fluorine, chlorine, bromine, more preferably fluorine and chlorine.

Heteroaryl is 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. Preference is given to 5- to 6-membered heteroaryls having up to 4 heteroatoms. The heteroaryl group may be bonded via 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 represents a group linked via a carbonyl heteroarylamino radical. Preferred examples include Thienylaminocarbonyl, Furylaminocarbonyl, pyrrolyl aminocarbonyl, Thiazolylaminocarbonyl, Oxazolylaminocarbonyl, Imidazolylaminocarbonyl, tetra- zolylaminocarbonyl, pyridylaminocarbonyl, Pyrimidinylaminocarbonyl, Pyridazinylaminocarbonyl, Indolylaminocarbonyl, Indazolylaminocarbonyl, Benzofuranylaminocarbonyl, benzothiophenyl aminocarbonyl , Quinolinylaminocarbonyl and isoquinolinylaminocarbonyl.

Heteroarylcarbonylamino represents a heteroarylcarbonyl radical linked via an amino group. 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 more 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 may be saturated or partially unsaturated. Saturated heterocyclyl radicals are prefers. 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 radicals in the compounds according to the invention are optionally substituted, unless otherwise specified, a substitution with up to three identical or different substituents is preferred.

The compounds of the formula (I) and their preparation are known from WO 04/09921 1.

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 consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxyl, C ₆ alkylamino, halogen, C _ö -Cio-arylcarbonylamino, Ci-Cβ-alkylcarbonylamino, Ci-Cβ-alkylaminocarbonyl, Ci-C ₆ -

Alkoxycarbonyl, C _ό--Cio arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonyl amino, Ci-C ₆ alkylsulfonylamino, Ci-C ₆ alkylsulfonyl, C _r C ₆ substituted alkylthio,

wherein Ci-C _ö alkyl, _Ci-C6 alkoxy, Cj-Cβ alkylamino, Cβ-Cio-arylcarbonylamino, CpC ₆ - alkylcarbonylamino, Ci-C _ö alkylaminocarbonyl, Ci-C ₆ alkoxycarbonyl, C ₆ -C ] ₀ - arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, Cj-C ₆ -

Alkylsulfonylamino, C ₁ -C ₆ -alkylsulfonyl and CpCβ-alkylthio optionally with a radical selected from the group consisting of hydroxyl, cyano, halogen, hydroxycarbonyl and a group of the formula -NR ⁷ R ⁸ ,

in which

R ⁷ and R ⁸ are independently hydrogen or C _r 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 Ci-C ₆ -

Alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy,

CpCβ-alkylamino, halogen, Cβ-Cio-arylcarbonylamino, Cj-C _ö -alkylcarbonylamino,

Ci-C _δ alkylaminocarbonyl, C) -C ₆ alkoxycarbonyl, Q-Cio-arylaminocarbonyl, arylaminocarbonyl hetero-, heteroarylcarbonylamino Ci-C ₆ alkylsulfonylamino, Ci-C ₆ alkyl sulfonyl Ci-C substituted, ₆ -alkylthio are,

wherein Cj-Cβ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ -alkylamino, Cβ-Cio-arylcarbonylamino, CpC ₆ - alkylcarbonylamino, Ci-C _δ alkylaminocarbonyl, C _r C ₆ alkoxycarbonyl, C ₆ -C ₀ - arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, Ci-C ₆ - alkylsulfonylamino, Ci-C ₆ alkylsulfonyl, and Ci-C ₆ alkylthio optionally substituted with a radical selected from the group hydroxy, cyano, halogen, hydroxycarbonyl and a group of the formula -NR ⁷ R ⁸ ,

where R ⁷ and R ^{8 have} the meanings given above,

are substituted

in which

R ⁵ is phenyl, pyridyl, or thiophenyl, which are optionally substituted by up to 3 radicals independently selected from the group C _r C ₄ alkyl, Ci-Q-alkoxy, hydroxycarbonyl,

Cyano, trifluoromethyl, amino, hydroxy, Ci-Q-alkylamino, fluorine, chlorine, bromine, Cβ-Cio-Arylcarbonylamino, C ₁ -C ₄ -AllCy lcarbonylamino, Ci-C ₄ alkylaminocarbonyl, Ci-C ₄ -alkoxycarbonyl , Ce-Cio-arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C 1 -C ₄ -alkylsulfonylamino, C 1 -C ₄ -alkylsulfonyl, C 1 -C ₄ -alkylthio, where Ci-Q-alkyl and Ci-C ₄ -alkoxy optionally with a radical selected from the group hydroxy, cyano, 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 _r 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, wherein the phenyl by 1 to 3 groups and pyrimidyl and pyridyl optionally substituted with 1 to 3 groups each independently selected from the group Ci-C ₄ alkyl, C _r C ₄ -alkoxy, hydroxycarbonyl, cyano, Trifluoromethyl, amino,

Hydroxy, _{Ci-C4-alkylamino,} fluorine, chlorine, bromine, Cβ-Cio-arylcarbonylamino, C _r C ₄ alkyl carbonylamino, Cj-Q-alkylaminocarbonyl, Ci-C ₄ alkoxycarbonyl, C ₆ -C ₀ arylamino - carbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, _Ci-C4 alkylsulfonylamino, C, -C ₄ alkylsulfonyl, C _r C ₄ -alkylthio,

wherein C | -C ₄ alkyl and Ci-C ₄ alkoxy optionally substituted with a radical selected from the group hydroxy, 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

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.

in which

R ^{5 is} phenyl, pyridyl or thiophenyl, which optionally substituted with up to 2 radicals independently of one another from the group dC ₄ alkyl, fluorine, chlorine, trifluoromethyl, hydroxy, phenylcarbonylamino, Ci-Gj-alkylcarbonylamino, Ci-Gi-alkylaminocarbonyl or phenylaminocarbonyl substituted are,

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 _j -CFT-Alkoxy represents a straight or branched alkoxy group 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 5 -alkyl represents 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.

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 methylamine, 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. CVCU-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.

dVCV alkylaminocarbonyl is a mono- or dialkylamino radical linked via a carbonyl group, where the alkyl radicals may be identical or different, are straight-chain or branched and contain in each case 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 can form a 5- to 8-membered heterocyclyl.

Cfi-C _j n-arylaminocarbonyl represents a group linked via a carbonyl arylamino. Preferred examples include phenylaminocarbonyl and naphthylaminocarbonyl.

Cft-C _j n-arylcarbonylamino represents an arylcarbonyl radical linked via an amino group. Preferred examples include phenylcarbonylamino and naphthylcarbonylamino.

CVCU-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.

for 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, tertbutylthio, n-pentylthio and n-hexylthio. Heteroaryl is 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. Preference is given to 5- to 6-membered heteroaryls having up to 4 heteroatoms. The heteroaryl group may be bonded via 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 is a heteroaryl-amino radical linked via a carbonyl group. Preferred examples include thienylaminocarbonyl, furylaminocarbonyl, pyrrolylaminocarbonyl, thiazolylaminocarbonyl, oxazolylaminocarbonyl, imidazolylaminocarbonyl, tetrazolylaminocarbonyl, pyridylaminocarbonyl, pyrimidinylaminocarbonyl, pyridazinylaminocarbonyl, indolylaminocarbonyl, indazolylaminocarbonyl, benzofuranylaminocarbonyl, benzothiophenylaminocarbonyl, quinolinylaminocarbonyl and isoquinolinylaminocarbonyl.

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 of the

Row 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

Residues 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, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl.

6-membered heteroaryl is an aromatic radical having 6 ring atoms and up to 2 nitrogen atoms. The heteroaryl radical is bonded via a carbon atom. Preferred examples include pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

If radicals in the compounds according to the invention are optionally substituted, unless otherwise specified, substitution with up to three identical or different substituents is preferred. The compounds of the formula (II) and their preparation are known from WO 04/099210.

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

A further embodiment of the invention relates to the use of compounds of the formula (III)

in which

R ^{9 is} Ci-Cβ-alkyl, trifluoromethyl, hydroxy, C _r C ₆ alkoxy, -C (O) OR ¹³ or -C (= O) NR ¹⁴ R ¹⁵ , wherein C] -C ₆ -alkyl optionally with 1 to 3 radicals independently of one another are selected from the group consisting of hydroxy, 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 are independently hydrogen, C ₆ -C _0-aryl, Ci-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 _r C ₆ alkyl, trifluoromethyl, C _r C ₆ alkoxy,

or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form Ca-Cg-cycloalkyl, C ₃ -C ₈ -cycloalkenyl or 4- to 10-membered heterocyclyl, which may be substituted by up to 2 substituents from the group Ci -Cβ-alkyl, Ci-Cβ-alkoxy, hydroxy, oxo, -C (= O) OR ^{16 are} substituted, and

R ^{16 is} C 1 -C ₆ -alkyl or benzyl,

R ¹ 'is hydrogen or C _r C ₆ alkyl,

R ^{12 is} pentan-3-yl, C ₃ -C ₆ -cycloalkyl,

X oxygen or sulfur,

R ⁹ is C _r C ₆ alkyl, hydroxy, C, _-C6 alkoxy, -C (O) OR ¹³ or -C (= O) NR ^I4 R ^15, wherein CC ₆ - alkyl optionally substituted by hydroxy, C _r C _6- alkoxy, -C (O) OR ¹³ or -C (O) NR ¹⁴ R ¹⁵ , and

R ^{13 is} C, -C ₆ -alkyl,

R ¹⁴ and R ¹⁵ are each independently hydrogen, C _ö -Cio-aryl, Cj-Cβ-alkyl, or

together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl,

R ¹⁰ is hydrogen, C _r C ₆ alkyl, C, -C ₆ alkoxy,

or

R ⁹ and R ¹⁰ together with the carbon atom to which they are attached form C ₃ -Cg -cycloalkyl, C ₃ -C ₈ -cycloalkenyl or 4- to 10-membered heterocyclyl, which may optionally have up to 2 substituents the group Ci-Cβ-alkyl, Ci-Cβ-alkoxy,

Hydroxy, oxo, -C (O) OR ^{16 are} substituted, and

R ^{16 is} C _r 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,

R ⁹ Ci-C ₄ alkyl, trifluoromethyl, hydroxy, C _r C ₄ alkoxy, -C (O) OR ¹³ or -C (= O) NR ¹⁴ R ^15, wherein _Ci-C4 -alkyl optionally substituted by hydroxy, Ci-C ₄ -alkoxy, trifluoromethyl, -C (= O) OR ¹³ or -C (= O) NR ¹⁴ R ^{15 is} substituted, and

R ¹³ is C _r 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 _r C ₄ -AlkyI, Ci-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 Ci-C ₄ alkyl, CrQ 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,

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 "hydrogen,

R ^{12 is} pentan-3-yl, C ₅ -C ₆ -cycloalkyl,

X oxygen,

In the context of the present invention, the substituents, unless specified otherwise, in the context of the formula (IH) have the following meaning:

C ₁ -CyAlkoxy is 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 -CyAlkVl 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.

Cfi-O-aryl is phenyl or naphthyl.

C _r C 9 cycloalkyl is cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl may be mentioned as preferred.

Ci-Cg-Cycloalkenyl is partially unsaturated, non-aromatic cycloalkyl radicals containing one or more multiple bonds, preferably double bonds. Non-limiting examples include cyclopentenyl, cyclohexenyl and cycloheptenyl.

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. For example and preferably mention may be made of: oxetane 3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyranyl, piperidinyl, thiopyranyl, morpholinyl, perhydroazepinyl.

If radicals in the compounds according to the invention are optionally substituted, substitution with up to three identical or different substituents is preferred, unless otherwise specified.

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 the formula (III) and their preparation are known from WO 04/026876.

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,

R ^{17 is} phenyl which is substituted by 1 to 3 substituents independently of one another selected from the group fluorine, chlorine, bromine, C 1 -C ₄ -alkyl, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro and CpCrAlkoxy,

R ^{18 is} pentan-3-yl, C ₅ -C ₆ -cycloalkyl,

X oxygen or sulfur,

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 ^{ιs pentan} -3-yl, cyclopentyl,

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 formulas (IV) and (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,

In the context of the present invention, the substituents, unless specified otherwise, in the context of the formulas (FV) and (FVa) have the following meaning:

C _j -CyAlkoxy 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 _r C6-Alkyl is a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, more preferably 1 to 3 carbon atoms. Preferred examples are methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

C4 ~ Cg- and C5-Cg-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.

When radicals in the compounds of the formulas (IV) and (IVa) according to the invention are optionally substituted, unless otherwise specified, substitution with up to three identical or different substituents is preferred. The compounds of the formulas (IV) and (FVa) and their preparation are known from WO 04/018474.

The compounds of the formulas (FV) and (FVa) 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 formula (F), (II), (FII), (FV) and (FVa) and their salts, solvates and solvates of the salts; the compounds of the formulas (I), (II), (FFF), (FV) and (FVa) mentioned below of the following formulas and their salts, solvates and solvates of the salts and of the formulas (T), (ET), ( IFI), (FV) and (FVa), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as those of the formulas (I), (FF), (FFI), (FV) and (FVa), compounds mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

As salts, physiologically acceptable salts of the compounds according to the invention are preferred in the context of the invention.

Physiologically acceptable salts of the compounds of formulas (T), (II), (FFI), (FV) and (FVa) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, 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 (F), (FI), (FIF), (FV) and (FVa) 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 C 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, dehydroabietylamine, Arginine, lysine, ethylenediamine and methylpiperidine.

Solvates in the context of the invention are those forms of the compounds 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.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).

The compounds of the invention show an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum. They are characterized in particular by an inhibition of PDE9A.

Surprisingly, it has been found that the compounds according to the invention are suitable for the preparation of medicaments for the treatment of cardiovascular diseases.

Because of their pharmacological and pharmacokinetic properties, the compounds according to the invention can be used alone or in combination with other medicaments for the treatment of cardiovascular diseases.

They can therefore be used in medicaments for the treatment of cardiovascular diseases such as hypertension and cardiac insufficiency, acute heart failure, stable and unstable angina pectoris, peripheral and cardiovascular diseases, arrhythmias, for the treatment of thromboembolic disorders and ischemia such as myocardial infarction, stroke , transitory and ischemic attacks, peripheral circulatory disorders, prevention of restenosis such 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, nephrosis such as nephrotic syndrome, renal stenoses, renal insufficiency, acute renal failure, metabolic syndrome, gastroparesis, incontinence, liver fibrosis and cirrhosis.

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

The in vitro effect of the compounds of the invention can be demonstrated by the following biological assays:

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., Gene, 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 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), PDEI IA (GenBank / EMBL Accession Number : NM_016953, Fawcett et al., Proc Natl Acad., 2000, 97, 3702-3707) were synthesized using the p FASTBAC baculovirus expression system (GibcoBRL) expressed in Sf9 cells. PDE5 was purified from human platelets. After sonication and centrifugation, supernatant ion exchange chromatography was performed on a Mono Q 10/10 column (linear NaCl gradient, elution with 0.2-0.3 M NaCl in buffer (20 mM Hepes pH 7.2 and 2mM MgC12)). PDE 1 (from bovine brain) was from Sigma.

The test substances are dissolved in 100% DMSO and serially diluted to determine their in vitro effect on PDE 9A. 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; Ameram Pharmacia Biotech., Piscataway, NJ) is diluted 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 PDEI IA is determined according to the test protocol described above for PDE 9A with the following adaptations: The substrate used is [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 determining a corresponding effect on pdel, PDE2A PDE5 and the protocol is additionally adjusted as follows: In pdel Calmodulin ^{10 -7} M and CaCl ₂ are added 3 mM to the reaction mixture in addition. PDE2A is stimulated in the assay by addition of cGMP 1 μM and tested with a BSA concentration of 0.01%. For pdel and PDE2A as a substrate [5 ', 8- ³ H] adenosine 3', 5'-cyclic phosphate (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 harvested, detached from adherent tissue, divided into 3 mm wide rings and individually prestressed in 5 ml organ baths with 37 ° C warm, carbogen-fumigated Krebs-Henseleit solution following

Composition (mM) brought: 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 to the bath added cumulatively 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 relaxation 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 thiopental "Nycomed®" (Nycomed, Munich, Germany). A tracheostomy was performed and catheters were inserted into the femoral artery for measurement of blood pressure and heart rate (Gould Pressure Transducer and Recorder, Model RS 3400) and for substance administration into 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 - 5 kg are adapted for single days after delivery for several days. They have free access to water and can feed for two hours a day. The animals are kept in a 10/14 hour day-night rhythm (light on, from 8.00 clock), the room temperature is 22 - 24 ° C.

Three to six animals are used per treatment group and weighed immediately before the start of the experiment. For intravenous administration, the substances are dissolved in Transcutol (GATTEFOSSE GmbH) and diluted in a ratio of 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 injected in 0.9% saline. For oral administration, the test substances are dissolved in a mixture of glycerol: water: polyethylene glycol 6: 10: 9.69 and applied in a volume of 1 ml / kg with the gavage.

Under rest conditions, the rabbit penis is not visible in the pubic region and is completely covered by the penile skin. The erection is scored by measuring the length of the protruding penis with a calliper. The measurement is carried out 5, 10, 15, 30, 45, 60 and 120 minutes after substance administration, after oral administration also after 3, 4, 5 and 6 hours. Each time, the animals are taken out of the cage, held tight to the neck and hind legs, turned on their backs and measured. Corresponding solvent controls are carried out, (see literature: E. Bischoff, K. Schneider, Int. J. of Impotence Res. 2001, 13, 230-235, E. Bischoff, U. Niewoehner, H. Haning, M. Es Sayed, T. Schenke, KH Schlemmer, The Journal of Urology, 2001, 165, 1316-1318, E. Bischoff, Int., J. Impotence Res., 2001, 13, 146-148).

Diurcsc in anesthetized rats

Male Wistar rats weighing 300-350 g (Harlan Winkelmann, Germany) were anesthetized with 1-2.5% isofluoran in a nitrous oxide / C> ₂ (2: 1) mixture. To measure blood pressure and heart rate, a catheter was inserted into the femoral artery, the substance was administered via a femoral vein catheter and urine collection via a bladder catheter. After the operation, 5 ml / kg of phys. NaCl were given intravenously as a bolus for fluid compensation and the animals were infused continuously with physi. NaCl for 1 h at a rate of 100 μl / kg / min via the venous catheter. The body temperature of the animals was kept constant over a hot plate. After the first hour, the test substances along with ANP were continuously infused via the venous catheter at a rate of 100 μl / kg / min. Urine was collected every 15 min and the volume, cGMP content (RIA), and Na ⁺ and K ⁺ concentrations (flame photometry) were measured.

Determination of pharmacokinetic parameters after intravenous and oral administration

The substance to be examined is administered to animals (eg mouse, rat, dog) intravenously as a solution, the oral administration is carried out as a solution or suspension via a gavage. After substance administration, the animals are bled at fixed times, this is heparinized and then plasma is recovered therefrom by centrifugation. The substance is analytically quantified in the plasma via LC / MSMS. From the plasma Concentration time courses are the pharmacokinetic parameters calculated using a validated pharmacokinetic calculation program.

Inhibition of cytochrome P450 enzymes

The potential for inhibition of P-450 isoenzymes, which are important for metabolism, is being investigated automatically in 96-well format. Two different assays are used here.

Recombinant enzymes (eg CYP 1A2, 2C8, 2C9, 2CI9, 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 to the control (without inhibitor) is determined by means of fluorescence readers 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 (CYP 1A2), diclofenac (CYP2C9), dextromethorphan (CYP2D6) and midazolam (CYP3A4) as CYP isoform-selective substrates. The formation of the respective metabolite is measured by LC-MS / MS. Assuming competitive inhibition, Kj 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 the induction of cytochrome P450 enzymes, primary human hepatocytes with a cell density of 2.5 × 10 4 cells between two layers of collagen in 24 well microtiter plates are incubated at 37 ^° C. with 5% CO Cultivated ₂ days. The cell culture medium is changed daily.

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

From the cell cultures the inductive effect of the test substances on the cytochrome (CYP)

P450 enzymes 1A2, 2B6, 2C19 and 3A4 were determined by adding the substrates 7-ethoxyresorufin (CYP1A2), [ ¹⁴ C] -S-mephenytoin (CYP2B6 and 2C19) and [ ¹⁴ C] -testosterone (CYP3A4) at day 8. From the thus measured enzyme activities CYP 1A2, 2B6, 2Cl 9 and 3 A4 treated cells compared to untreated cells, the inductive potential of the test substances is determined.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention and at least one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.

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

For the oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as. 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), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules) in the oral cavity , Dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration are, for example, inhalant medicines (including powder inhalers, nebulizers), nasal drops, solutions, 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 (such as patches), milk, Pastes, foams, scattering powders, implants or stents. The compounds according to the invention can be converted into the mentioned administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. Such adjuvants 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, polyoxysorbitol oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g. Albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and flavor and / or odoriferous agents.

Another object of the present invention are pharmaceutical compositions containing at least one compound of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

In general, it has been found to be beneficial to administer parenteral administration per day amounts of about 0.001 to 10 mg / kg 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 to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight, solvent ratios, dilution ratios and concentration data of liquid / liquid solutions refer in each case to the volume.

The compounds according to the invention can be converted into pharmaceutical preparations as follows: 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 of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

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

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

production:

The rhodigel is suspended in ethanol, the compound of the invention is fed to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Summary:

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

production:

The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.

i.v.Lösung:

The compound of the invention is sterile at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5%, and / or PEG 400 solution.) The solution is sterile filtered and sterile and pyrogen-free injection wells are filled.

Intravenous solution:

Composition:

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

production:

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

Claims

claims

1. Use of compounds of the formula

in which

R ^{1 is} C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl or C ₃ -C ₈ -cycloalkyl, where C _r C ₈ -

Alkyl is optionally substituted with oxo, and

where CpCg-alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl and C ₃ -C ₈ -cycloalkyl optionally having up to 3 radicals independently selected from the group Ci-C ₆ alkyl, Ci-C ₆ alkoxy, hydroxycarbonyl, cyano, amino, nitro, hydroxy, CpC _ό alkylamino, halogen, trifluoromethyl, trifluoromethoxy, C _IO -C _east -

Arylcarbonylamino, Ci-Cβ-alkylcarbonylamino, Ci-Cβ-alkylaminocarbonyl, Ci- C _ö alkoxycarbonyl, Cβ-Cio-arylaminocarbonyl, heteroarylaminocarbonyl, hetero- arylcarbonylamino, Ci-Cβ-alkylsulfonylamino, Ci-C _ö alkylsulfonyl, C _I -C _Ö - alkylthio are substituted,

in which

Ci-C _ö alkyl, Ci-Cβ-alkoxy, Ci-Cβ alkylamino, C _ό -Cio-arylcarbonylamino, Ci-Ce-alkylcarbonylamino, Cj-Cβ-alkylaminocarbonyl, Ci-Cβ-alkoxy carbonyl, Cβ-CIO Arylaminocarbonyl, heteroarylaminocarbonyl, Heteroarylcarbonylamino, Cj-Cβ-alkylsulfonylamino, Ci-Ce- alkylsulfonyl and Ci-C ₆ alkylthio optionally with one to three

Independently selected from the group consisting of hydroxyl, 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, Ci-C ₆ -alkylamino, halogen, C ₆ -C ₀ - arylcarbonylamino, Ci-COE-alkylcarbonylamino, _Ci-C6 alkylaminocarbonyl, Cp Cβ-alkoxycarbonyl, Cβ-Cio-arylaminocarbonyl, heteroarylaminocarbonyl , hetero- arylcarbonylamino, Ci-Cό-alkylsulfonylamino, Ci-C ₆ alkylsulfonyl, C _I -C _Ö - alkylthio,

wherein Ci-C ₆ alkyl, Ci-C ₆ alkoxy, Ci-C ₆ -alkylamino, C6-Cio-arylcarbonyl amino, Ci-C _ό alkylcarbonylamino, Ci-C _ö alkylaminocarbonyl, Ci-Cβ- alkoxycarbonyl, Cβ-Cio-arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, C] -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 manufacture of medicaments for the treatment of cardiovascular diseases.

2. 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 from the group Ci-Cβ-alkyl, CpCö-alkoxy, Hydroxycarbonyl, cyano, trifluoromethyl, amino, nitro, hydroxy, CpC ₆ - alkylamino, halogen, C _δ -Cio-arylcarbonylamino, alkylcarbonylamino CpCβ, Q Coe-alkylaminocarbonyl, Ci-C ₆ alkoxycarbonyl, C ₆ -Cio-arylaminocarbonyl, Heteroarylaminocarbonyl, heteroarylcarbonylamino, C _r C ₆ -alkylsulfonylamino, Cp Cό-alkylsulfonyl, CpCβ-alkylthio are substituted,

wherein Ci-C ₆ alkyl, C _r C ₆ alkoxy, Ci-C ₆ -alkylamino, C ₆ -C ₁₀ amino -Arylcarbonyl-, CpCβ-alkylcarbonylamino, CpCö-alkylaminocarbonyl, CpC ₆ - alkoxycarbonyl, C _ό -Cio- Arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, CpCβ-alkylsulfonylamino, CpC ₆ -alkysilylsulfonyl and C _r C ₆ -alkylthio optionally with a radical selected from among

Group hydroxy, cyano, halogen, hydroxycarbonyl and a group of the formula -NR ⁷ R ⁸ ,

in which

R ⁷ and R ⁸ independently of one another are hydrogen or CpC 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

Phenyl or heteroaryl, wherein the phenyl by 1 to 3 groups and heteroaryl optionally substituted with 1 to 3 groups each independently selected from the group d-Cβ-alkyl, C _r C ₆ alkoxy, hydroxycarbonyl, cyano, trifluoromethyl,

Amino, nitro, hydroxy, CpCβ-alkylamino, halogen, C _δ -Cio-arylcarbonylamino,

Ci-C _ö alkylcarbonylamino, Ci-C _ö alkylaminocarbonyl, C _r C ₆ alkoxycarbonyl,

Cβ-Cio-arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylcarbonylamino, Ci-C ₆ alkylsulfonylamino, C _r C ₆ alkylsulfonyl, CpC _ö -alkylthio,

wherein Ci-Cβ alkyl, Ci-Cβ-alkoxy, Ci-C _ö alkylamino, Cβ-Cio-arylcarbonyl amino, Cj-Cβ-alkylcarbonylamino, Ci-Cβ-alkylaminocarbonyl, Cj-Ce-

Alkoxycarbonyl, Cβ-Cio-arylaminocarbonyl, heteroarylaminocarbonyl,

Heteroarylcarbonylamino, Ci-Cβ-alkylsulfonylamino, Ci-Cβ-alkylsulfonyl and Cj-C _ö alkylthio optionally having a radical selected from Group hydroxy, cyano, halogen, hydroxycarbonyl and a group of the formula -NR ⁷ R ⁸ ,

where R ⁷ and R ^{8 have} the meanings given above,

are substituted

3. Use of compounds of the formula (III),

in which

R ^{9 is} CpCe-alkyl, trifluoromethyl, hydroxy, C _r C ₆ -alkoxy, -C (O) OR ¹³ or

-C (O) NR ¹⁴ R ¹⁵ , wherein C 1 -C ₆ -alkyl optionally having 1 to 3 radicals independently selected from the group consisting of hydroxy, C 1 -C ₆ -alkoxy, halogen, trifluoromethyl, trifluoromethoxy, -C (O) OR ¹³ or -C (O) NR ¹⁴ R ^{15 is} substituted, and

R ^{13 is} C, -C ₆ -alkyl,

R ¹⁴ and R ^{15 are} independently hydrogen, C ₆ -C ₁₀ aryl, C _r C ₆ alkyl, or

together with the nitrogen atom to which they are attached form a 4 to 1 O-membered heterocyclyl,

R ¹⁰ is hydrogen, C _r C ₆ -AlkyI, trifluoromethyl, C _r 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 with up to 2 substituents selected from Group C _{r is} Ce-alkyl, C ₁ -C ₆ -alkoxy, hydroxy, oxo, -C (= O) OR ^{16 are} substituted, and

R ^{16 is} CC ₆ alkyl or benzyl,

R ^{1 1} is hydrogen or Ci-C ₆ alkyl,

R ^{12 is} pentan-3-yl, C ₃ -C ₆ -cycloalkyl,

X oxygen or sulfur,

4. Use of compounds of the formula (FV),

in which

R ^{17 is} phenyl which is selected from 1 to 5 substituents independently of the group halogen, C ₁ -C ₆ -alkyl, trifluoromethyl, trifluoromethoxy, cyano,

Hydroxy, nitro and Ci-Cβ-alkoxy is substituted,

R ^{18 is} pentan-3-yl, C ₄ -C ₆ -cycloalkyl,

X oxygen or sulfur,

mean,

5. Use of compounds of general formula (MV) according to claims 1 to 4 for the preparation of medicaments for the treatment of hypertension.

6. Use of compounds of general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of stable and unstable angina pectoris.

7. Use of compounds of general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of renal insufficiency.

8. Use of compounds of general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of acute renal failure.

9. Use of compounds of general formula (I-FV) according to claims 1 to 4 for the preparation of medicaments for the treatment of ischemic kidney diseases and ischaemias.

10. Use of compounds of general formula (I-IV) according to claims 1 to 4 for the preparation of medicaments for the treatment of heart failure, acute heart failure and venous diseases.