DE102005024494A1 - Use of cyanopyrimidines - Google Patents

Abstract

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

Description

The The invention relates to the use of cynoopyrimidines 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). These 21 PDE genes can be divided 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% (PDESA). 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), PDESA (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 04/113306 and the literature cited therein are cyanopyrimidines and their use for the preparation of medicaments for treatment already known from various diseases.

The US 5,002,949 discloses cyanopyrimidinones for inhibiting white thrombus formations.

In WO 02/06288 makes cyanopyrimidinones more antagonistic with mGluR Effect described.

In WO 95/10506 discloses cyanopyrimidinones for the treatment of depression and Alzheimer's Illness.

In EP 130735 Cyanopyrimidines are described as cardiotonic reagents.

US 5,256,668 and WO 99/41253 disclose cyanopyrimidines having antiviral activity.

in welcher
A C₁-C₈-Alkyl, C₃-C₈-Cycloalkyl, Tetrahydrofuryl oder Tetrahydropyranyl, welche gegebenenfalls mit bis zu 3 Resten unabhängig voneinander ausgewählt aus der Gruppe C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Hydroxycarbonyl, Cyano, Trifluormethyl, Trifluormethoxy, Amino, Hydroxy, C₁-C₆-Alkylamino, Halogen, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₁-C₆-Alkylcarbonyl, C₁-C₆-Alkylsulfonyl und C₁-C₆-Alkylthio substituiert sind,
wobei C₁-C₆-Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₁-C₆-Alkylcarbonyl, C₁-C₆-Alkylsulfonyl und C₁-C₆-Alkylthio gegebenenfalls mit einem oder mehreren Resten ausgewählt aus der Gruppe Hydroxy, Cyano, Halogen, Hydroxycarbonyl 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,
B Phenyl oder Heteroaryl, die gegebenenfalls mit bis zu 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, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₁-C₆-Alkylcarbonyl, C₁-C₆-Alkylsulfonyl und C₁-C₆-Alkylthio substituiert sind,
wobei C₁-C₆-Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₁-C₆-Alkylaminocarbonyl, C₁-C₆-Alkoxycarbonyl, C₁-C₆-Alkylcarbonyl, C₁-C₆-Alkylsulfonyl und C₁-C₆-Alkylthio gegebenenfalls mit einem Rest ausgewählt aus der Gruppe Hydroxy, Cyano, Halogen, Hydroxycarbonyl und einer Gruppe der Formel -NR³R⁴,
wobei
R³ und R⁴ 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.The present invention relates to compounds of the formula

in which
C ₁ -C ₈ -alkyl, C ₃ -C ₈ -cycloalkyl, tetrahydrofuryl or tetrahydropyranyl, which are optionally selected independently of one another from the group C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxycarbonyl with up to 3 radicals , Cyano, trifluoromethyl, trifluoromethoxy, amino, hydroxy, C ₁ -C ₆ -alkylamino, halogen, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ Alkylsulfonyl and C ₁ -C ₆ -alkylthio are substituted,
wherein C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally with one or more radicals selected from the group consisting of hydroxy, cyano, halogen, hydroxycarbonyl 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
B is phenyl or heteroaryl optionally with up to 3 radicals 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 C ₁ -C ₆ -alkylamino, halogen, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio are substituted .
wherein C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylaminocarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally having a radical selected from the group consisting of hydroxyl, cyano, halogen, hydroxycarbonyl and a group of the formula -NR ³ R ⁴ ,
in which
R ³ and R ^{4 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 compounds of the formula (I)
in which
A 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, hydroxycarbonyl, cyano, amino , Hydroxy, C ₁ -C ₄ -alkylamines no, fluorine, chlorine, bromine, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₄ -alkylsulfonyl and 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, hydroxycarbonyl 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
B is phenyl, thienyl or pyridyl, optionally with up to 3 radicals each independently selected from the group consisting of C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, hydroxycarbonyl, cyano, trifluoromethyl, trifluoromethoxy, amino, hydroxy, C C ₁ -C ₄ -alkylamino, fluorine, chlorine, bromine, C ₁ -C ₄ -alkylaminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -alkylcarbonyl, C ₁ -C ₄ -alkylsulfonyl and 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, hydroxycarbonyl and a group of the formula -NR ³ R ⁴ ,
in which
R ³ and R ^{4 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 compounds of the formula (I)
in which
A has the meanings given above, and
B is phenyl or pyridyl, which is optionally selected independently of one another from the group consisting of methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, ethoxy, fluorine and chlorine, with up to 3 radicals,
wherein one of the radicals on the phenyl or pyridyl is located in the ortho position relative to the point of attachment of the amino function,
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 compounds of the formula (I)
in which
A is C ₃ -C ₆ cycloalkyl and
B has 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.

A further embodiment of the invention relates to compounds of the formula (I)
in which
A is 2-methylpropyl, 2-butyl, 2-peethyl or 3-pentyl and
B has 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.

A further embodiment of the invention relates to compounds of the formula (I)
in which
A is C ₃ -C ₅ -alkyl or C ₅ -C ₆ -cycloalkyl,
B is phenyl, thienyl or pyridyl, optionally with up to 3 radicals each independently selected from the group C ₁ -C ₃ alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, cyano, dimethylamino, diethylamino, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, ethylcarbonyl , 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.

In the context of the present invention, the substituents of the compounds of the formula (I) according to the invention, unless otherwise specified, have the following meaning:
C ₁ -C ₈ -alkyl, C ₁ -C ₆ -alkyl, C ₁ -C ₅ -alkyl and C ₁ -C ₄ -alkyl represent a straight-chain or branched alkyl radical having 1 to 8, preferably 1 to 6, particularly preferably 1 to 5 and 1 to 4 carbon atoms. Preferred example Le include methyl, ethyl, n-propyl, isopropyl, 2-butyl, 2-pentyl and 3-pentyl.

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 -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-tert-butylamino, di-n-pentylamino , Di-n-hexylamino, ethylmethylamino, isopropylmethylamino, n-butylethylamino and n-hexyl-i-pentylamino.

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 ₁ -C ₆ -alkylcarbonyl is a straight-chain or branched alkylcarbonyl radical having 1 to 6 and preferably 1 to 4 carbon atoms. Examples which may be mentioned are: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. Particularly preferred are acetyl and ethylcarbonyl.

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, monocyclic radical having 5 to 6 ring atoms and up to 3 heteroatoms from the series S, O and / or N. are preferred 5- to 6-membered heteroaryls containing up to 2 heteroatoms. The heteroaryl radical can over be bound to a carbon or nitrogen atom. Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, Tetrazolyl, pyridyl, pyrimidinyl and pyridazinyl.

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 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.

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 formulas (I) and their preparation are known from WO 04/113306 known.

in welcher
D Phenyl, Heteroaryl oder eine Gruppe der Formel

wobei Phenyl und Heteroaryl gegebenenfalls mit bis zu 2 Resten unabhängig voneinander ausgewählt aus der Gruppe Heteroaryl, Halogen, C₁-C₆-Alkyl, C₁-C₆-Alkoxy, Trifluormethyl, Trifluormethoxy, Benzyloxy und Benzyl substituiert sind,
wobei C₁-C₆-Alkyl gegebenenfalls mit einer Gruppe der Formel -NR⁵R⁶, in welcher R⁵ C₁-C₆-Alkyl und R⁶ Wasserstoff oder C₁-C₆-Alkoxy(C₁-C₆)alkyl bedeuten, und
Heteroaryl gegebenenfalls mit C₁-C₆-Alkoxy substituiert ist,
R¹ C₃-C₈-Cycloalkyl, C₁-C₆-Alkyl, C₁-C₆-Alkoxy(C₁-C₆)alkyl, Benzyl oder eine Gruppe der

wobei C₃-C₈-Cycloalkyl gegebenenfalls mit Hydroxy, C₁-C₆-Alkyl oder Trifluormethyl,
C₁-C₆-Alkyl gegebenenfalls mit Heteroaryl, C₃-C₈-Cycloalkyl oder Hydroxy,
und Benzyl gegebenenfalls mit C₁-C₆-Alkoxy oder Halogen substituiert ist,
R² Wasserstoff,
oder
R¹ und R² zusammen mit dem Stickstoffatom, an dem sie gebunden sind, ein 5- bis 6-gliedriges Heterocyclyl bilden, welches gegebenenfalls mit bis zu 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe C₁-C₆-Alkyl, Hydroxy, Cyano, Oxo, Heteroaryl, Benzyl, Formyl, C₁-C₆-Alkylcarbonyl und einer der folgenden Gruppen

die über die beiden Sauerstoffatome an eines der Kohlenstoffatome im Heterocyclus gebunden sind, substituiert ist,
wobei C₁-C₆-Alkyl gegebenenfalls mit Hydroxy oder Heteroaryl substituiert ist,
bedeuten, sowie deren Salze, Solvate und/oder Solvate der Salze, zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.Another object of the present invention relates to compounds of the formula

in which
D is phenyl, heteroaryl or a group of the formula

where phenyl and heteroaryl are optionally substituted by up to 2 radicals independently of one another selected from the group consisting of heteroaryl, halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl,
where C ₁ -C ₆ -alkyl optionally with a group of the formula -NR ⁵ R ⁶ , in which R ^{5 is} C ₁ -C ₆ -alkyl and R ^{6 is} hydrogen or C ₁ -C ₆ -alkoxy (C ₁ -C ₆ ) alkyl, and
Heteroaryl is optionally substituted by C ₁ -C ₆ -alkoxy,
R ^{1 is} C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, benzyl or a group of

where C ₃ -C ₈ -cycloalkyl is optionally substituted by hydroxy, C ₁ -C ₆ -alkyl or trifluoromethyl,
C ₁ -C ₆ -alkyl optionally with heteroaryl, C ₃ -C ₈ -cycloalkyl or hydroxy,
and benzyl is optionally substituted by C ₁ -C ₆ -alkoxy or halogen,
R ^{2 is} hydrogen,
or
R ¹ and R ^2, together with the nitrogen atom to which they are attached, form a 5- to 6-membered heterocyclyl, optionally substituted with up to 2 substituents independently selected from the group C ₁ -C ₆ -alkyl, hydroxy, cyano , Oxo, heteroaryl, benzyl, formyl, C ₁ -C ₆ alkylcarbonyl and one of the following groups

which is substituted via the two oxygen atoms bound to one of the carbon atoms in the heterocycle,
where C ₁ -C ₆ -alkyl is optionally substituted by hydroxy or heteroaryl,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

wobei Phenyl und Heteroaryl gegebenenfalls mit bis zu 2 Resten unabhängig voneinander ausgewählt aus der Gruppe Heteroaryl, Halogen, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, Trifluormethyl, Trifluormethoxy, Benzyloxy und Benzyl substituiert sind,
wobei C₁-C₄-Alkyl gegebenenfalls mit einer Gruppe der Formel -NR³R⁴, in welcher R³ C₁-C₄-Alkyl und R⁴ Wasserstoff oder C₁-C₄-Alkoxy(C₁-C₄)alkyl bedeuten, und
Heteroaryl gegebenenfalls mit C₁-C₄-Alkoxy substituiert ist,
R¹ C₃-C₆-Cycloalkyl, C₁-C₄-Alkyl, C₁-C₄-Alkoxy(C₁-C₄)alkyl, Benzyl oder eine Gruppe der

wobei C₃-C₆-Cycloalkyl gegebenenfalls mit Hydroxy, C₁-C₄-Alkyl oder Trifluormethyl,
C₁-C₄-Alkyl gegebenenfalls mit Heteroaryl, C₃-C₆-Cycloalkyl oder Hydroxy,
und Benzyl gegebenenfalls mit C₁-C₄-Alkoxy oder Halogen substituiert ist,
R² Wasserstoff,
oder
R¹ und R² zusammen mit dem Stickstoffatom, an dem sie gebunden sind, ein 5- bis 6-gliedriges Heterocyclyl bilden, welches gegebenenfalls mit bis zu 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe C₁-C₄-Alkyl, Hydroxy, Cyano, Oxo, Heteroaryl, Benzyl, Formyl, C₁-C₄-Alkylcarbonyl und einer der folgenden Gruppen

die über die beiden Sauerstoffatome an eines der Kohlenstoffatome im Heterocyclus gebunden sind, substituiert ist,
wobei C₁-C₄-Alkyl gegebenenfalls mit Hydroxy oder Heteroaryl substituiert ist,
bedeuten, sowie deren Salze, Solvate und/oder Solvate der Salze, zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.Another embodiment of the invention relates to compounds of the formula (II) in which
A is phenyl, heteroaryl or a group of the formula

where phenyl and heteroaryl are optionally substituted by up to 2 radicals independently of one another selected from the group consisting of heteroaryl, halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl,
where C ₁ -C ₄ -alkyl is optionally substituted by a group of the formula -NR ³ R ⁴ , in which R ^{3 is} C ₁ -C ₄ -alkyl and R ^{4 is} hydrogen or C ₁ -C ₄ -alkoxy (C ₁ -C ₄ ) alkyl, and
Heteroaryl is optionally substituted by C ₁ -C ₄ -alkoxy,
R ^{1 is} C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy (C ₁ -C ₄ ) -alkyl, benzyl or a group of

where C ₃ -C ₆ -cycloalkyl is optionally substituted by hydroxy, C ₁ -C ₄ -alkyl or trifluoromethyl,
C ₁ -C ₄ -alkyl optionally with heteroaryl, C ₃ -C ₆ -cycloalkyl or hydroxy,
and benzyl is optionally substituted by C ₁ -C ₄ alkoxy or halogen,
R ^{2 is} hydrogen,
or
R ¹ and R ^{2 taken} together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl, optionally substituted with up to 2 substituents independently selected from the group C ₁ -C ₄ -alkyl, hydroxy, cyano , Oxo, heteroaryl, benzyl, formyl, C ₁ -C ₄ alkylcarbonyl and one of the following groups

which is substituted via the two oxygen atoms bound to one of the carbon atoms in the heterocycle,
where C ₁ -C ₄ -alkyl is optionally substituted by hydroxy or heteroaryl,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

wobei Phenyl und Thienyl gegebenenfalls mit bis zu 2 Resten unabhängig voneinander ausgewählt aus der Gruppe Pyridyl, Fluor, Chlor, Brom, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, Trifluormethyl, Trifluormethoxy, Benzyloxy und Benzyl substituiert sind,
wobei C₁-C₄-Alkyl gegebenenfalls mit einer Gruppe der Formel -NR³R⁴, in welcher R³ C₁-C₄-Alkyl und R⁴ Wasserstoff oder C₁-C₄-Alkoxy(C₁-C₄)alkyl bedeuten, und
Pyridyl gegebenenfalls mit C₁-C₄-Alkoxy substituiert ist,
R¹ C₃-C₆-Cycloalkyl, C₁-C₄-Alkyl, C₁-C₄-Alkoxy(C₁-C₄)alkyl, Benzyl oder eine Gruppe der

wobei C₃-C₆-Cycloalkyl gegebenenfalls mit Hydroxy, C₁-C₄-Alkyl oder Trifluormethyl,
C₁-C₄-Alkyl gegebenenfalls mit Pyridyl, C₃-C₆-Cycloalkyl oder Hydroxy,
und Benzyl gegebenenfalls mit C₁-C₄-Alkoxy, Fluor, Chlor oder Brom substituiert ist,
R² Wasserstoff,
oder
R¹ und R² zusammen mit dem Stickstoffatom, an dem sie gebunden sind, ein 5- bis 6-gliedriges Heterocyclyl ausgewählt aus der Gruppe Pyrrolidinyl, Piperidinyl, Piperazinyl und Morpholinyl bilden, welches gegebenenfalls mit bis zu 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe C₁-C₄-Alkyl, Hydroxy, Cyano, Oxo, Heteroaryl, Benzyl, Formyl, C₁-C₄-Alkylcarbonyl und einer der folgenden Gruppen

die über die beiden Sauerstoffatome an eines der Kohlenstoffatome im Heterocyclus gebunden sind, substituiert ist,
wobei C₁-C₄-Alkyl gegebenenfalls mit Hydroxy oder Pyridyl substituiert ist,
bedeuten, sowie deren Salze, Solvate und/oder Solvate der Salze, zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.Another embodiment of the invention relates to compounds of the formula (II) in which
A is phenyl, thienyl or a group of the formula

where phenyl and thienyl are optionally substituted by up to 2 independently selected from the group consisting of pyridyl, fluorine, chlorine, bromine, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl,
wherein C ₁ -C ₄ -alkyl optionally with a group of the formula -NR ³ R ⁴ , in which R ^{3 is} C ₁ -C ₄ -alkyl and R ^{4 is} or C ₁ -C ₄ alkoxy (C ₁ -C ₄ ) alkyl, and
Pyridyl is optionally substituted by C ₁ -C ₄ -alkoxy,
R ^{1 is} C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy (C ₁ -C ₄ ) -alkyl, benzyl or a group of

where C ₃ -C ₆ -cycloalkyl is optionally substituted by hydroxy, C ₁ -C ₄ -alkyl or trifluoromethyl,
C ₁ -C ₄ -alkyl optionally with pyridyl, C ₃ -C ₆ -cycloalkyl or hydroxy,
and benzyl is optionally substituted by C ₁ -C ₄ -alkoxy, fluorine, chlorine or bromine,
R ^{2 is} hydrogen,
or
R ¹ and R ² together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, optionally substituted with up to 2 substituents independently selected from the group C ₁ -C ₄ alkyl, hydroxy, cyano, oxo, heteroaryl, benzyl, formyl, C ₁ -C ₄ alkylcarbonyl and one of the following groups

which is substituted via the two oxygen atoms bound to one of the carbon atoms in the heterocycle,
where C ₁ -C ₄ -alkyl is optionally substituted by hydroxy or pyridyl,
and their salts, solvates and / or solvates of the salts, for the preparation of medicaments for the treatment of cardiovascular diseases.

wobei Phenyl gegebenenfalls mit bis zu 2 Resten unabhängig voneinander ausgewählt aus der Gruppe Pyridyl, Fluor, Chlor, Methyl, Methoxy, Ethoxy, Trifluormethyl, Trifluormethoxy, Benzyloxy und Benzyl substituiert ist,
wobei Methyl gegebenenfalls mit einer Gruppe der Formel -NR³R⁴, in welcher R³ Methyl und R⁴ Wasserstoff oder 2-Methoxyethyl bedeuten, und
Pyridyl gegebenenfalls mit Methoxy substituiert ist,
R¹ C₃-C₆-Cycloalkyl, Methyl, Ethyl, Propyl, 2-Methoxyethyl, Benzyl oder eine Gruppe der

wobei C₃-C₆-Cycloalkyl gegebenenfalls mit Hydroxy, Methyl oder Trifluormethyl, Methyl, Ethyl, Propyl gegebenenfalls mit Pyridyl, Cyclopropyl oder Hydroxy, und Benzyl gegebenenfalls mit Methoxy, Ethoxy, Fluor oder Chlor substituiert ist,
R² Wasserstoff,
oder
R¹ und R² zusammen mit dem Stickstoffatom, an dem sie gebunden sind, ein 5- bis 6-gliedriges Heterocyclyl ausgewählt aus der Gruppe Pyrrolidinyl, Piperidinyl, Piperazinyl und Morpholinyl bilden, welches gegebenenfalls mit bis zu 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Methyl, Ethyl, Propyl, tert.-Butyl, Hydroxy, Cyano, Oxo, Pyridyl, Benzyl, Formyl, Methylcarbonyl, Ethylcarbonyl, Propylcarbonyl und einer der folgenden Gruppen

die über die beiden Sauerstoffatome an eines der Kohlenstoffatome im Heterocyclus gebunden sind, substituiert ist,
wobei Methyl, Ethyl und Propyl gegebenenfalls mit Hydroxy oder Pyridyl substituiert sind,
bedeuten, sowie deren Salze, Solvate und/oder Solvate der Salze, zur Herstellung von Arzneimitteln zur Behandlung von Herz-Kreislauf-Erkrankungen.Another embodiment of the invention relates to compounds of the formula (II) in which
A is phenyl, thienyl or a group of the formula

where phenyl is optionally substituted by up to 2 independently selected from the group consisting of pyridyl, fluorine, chlorine, methyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl,
where methyl is optionally substituted by a group of the formula -NR ³ R ⁴ , in which R ^{3 is} methyl and R ^{4 is} hydrogen or 2-methoxyethyl, and
Pyridyl is optionally substituted with methoxy,
R ^{1 is} C ₃ -C ₆ -cycloalkyl, methyl, ethyl, propyl, 2-methoxyethyl, benzyl or a group of

where C ₃ -C ₆ -cycloalkyl is optionally substituted by hydroxy, methyl or trifluoromethyl, methyl, ethyl, propyl optionally with pyridyl, cyclopropyl or hydroxy, and benzyl is optionally substituted by methoxy, ethoxy, fluorine or chlorine,
R ^{2 is} hydrogen,
or
R ¹ and R ² together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, optionally substituted with up to 2 substituents independently selected from the group Methyl, ethyl, propyl, tert-butyl, hydroxy, cyano, oxo, pyridyl, benzyl, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl and one of the following groups

which is substituted via the two oxygen atoms bound to one of the carbon atoms in the heterocycle,
where methyl, ethyl and propyl are optionally substituted by hydroxy or pyridyl,
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 of the compounds of the formula (II) according to the invention, unless otherwise specified, have the following meaning:
C ₁ -C ₆ -alkyl is a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, carbon atoms. Preferred examples include methyl, ethyl, n-propyl, isopropyl, 2-butyl, tert-butyl, 2-pentyl, 3-pentyl and n-hexyl.

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 -alkoxy (C ₁ -C ₆ ) -alkyl is a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms which is attached to a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably with 2 to 3 carbon atoms is bound. Preferred examples include methoxymethyl, 2-methoxyethyl, ethoxymethyl and 2-ethoxyethyl.

C ₁ -C ₆ -alkylcarbonyl is a straight-chain or branched alkylcarbonyl radical having 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms. Preferred examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl.

3 to 8-membered cycloalkyl is saturated with cycloalkyl radicals 3 to 8, preferably 3 to 6 and more preferably 5 to 6 carbon atoms in the cycle. Preferred examples include cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl and cycloheptyl.

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, monocyclic radical having 5 to 6 ring atoms and up to 3 heteroatoms from the series S, O and / or N. are preferred 5- to 6-membered heteroaryls containing up to 2 heteroatoms. The heteroaryl radical can over be bound to a carbon or nitrogen atom. Preferred examples include thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, Pyridyl, pyrimidinyl and pyridazinyl.

5 to 6-membered heterocyclyl is a monocyclic, saturated or partially unsaturated heterocyclic Residue with 5 to 6 ring atoms and up to 2 heteroatoms from the series N, O, S. As heteroatoms, N and O are preferred. Preferred examples include pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothienyl, Pyranyl, thiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

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.

• [A] eine Verbindung der Formel
  
  zunächst mit einer Verbindung der Formel HNR¹R² (IV),in welcher R¹ und R² die oben angegebenen Bedeutungen aufweisen, bei erhöhter Temperatur in einem inerten Lösemittel oder auch in Abwesenheit eines Lösemittels in eine Verbindung der Formel
  
  in welcher R¹ und R² die oben angegebenen Bedeutungen aufweisen, überführt und diese dann in einem inerten Lösemittel in Gegenwart einer Base mit einer Verbindung der Formel
  
  in welcher D die oben angegebenen Bedeutungen aufweist, umsetzt oder in veränderter Reihenfolge der Reaktionspartner
• [B] eine Verbindung der Formel (III) zunächst mit einer Verbindung der Formel (VI) in einem inerten Lösemittel in Gegenwart einer Base in eine Verbindung der Formel
  
  in welcher D die oben angegebenen Bedeutungen aufweist, überführt und diese dann bei erhöhter Temperatur in einem inerten Lösemittel oder auch in Abwesenheit eines Lösemittels mit einer Verbindung der Formel (IV) umsetzt,

und die jeweils resultierenden Verbindungen der Formel (II) gegebenenfalls mit den entsprechenden (i) Lösemitteln und/oder (ii) Basen oder Säuren zu ihren Solvaten, Salzen und/oder Solvaten der Salze umsetzt.In addition, a process for the preparation of the compounds of the formula (II) according to the invention was found, characterized in that either

• [A] a compound of the formula
  
  first with a compound of the formula HNR ¹ R ² (IV), in which R ¹ and R ^{2 have} the meanings given above, at elevated temperature in an inert solvent or in the absence of a solvent in a compound of formula
  
  in which R ¹ and R ^{2 have} the meanings given above, and then these in an inert solvent in the presence of a base with a compound of formula
  
  in which D has the meanings given above, or reacted in an altered order of the reactants
• [B] a compound of formula (III) first with a compound of formula (VI) in an inert solvent in the presence of a base in a compound of formula
  
  in which D has the meanings given above, and then reacted at elevated temperature in an inert solvent or else in the absence of a solvent with a compound of the formula (IV),

and the respective resulting compounds of the formula (II), if appropriate, with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

The Compound of the formula (III) is known from the literature (R. Gompper, W. Toepfl, Chem. Ber. 1962, 95, 2861-2870). The compounds of the formulas (IV) and (VI) are commercially available, known from the literature or can be prepared in analogy to literature methods (see e.g. H. Gielen, C. Alonso-Alija, M. Hendrix, U. Niewöhner, D. Schauss, Tetrahedron Lett. 2002, 43, 419-421).

For the process step (III) + (IV) → (V) are high-boiling, inert organic solvents, which are among the Do not change reaction conditions. These include preferably toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide or sulfolane. It is also possible the reaction without solvent in the melt. Particularly preferred is a reaction without solvent or in dimethylformamide, acetonitrile or toluene.

The Reaction is generally carried out in a temperature range from + 70 ° C to + 200 ° C, preferably in a temperature range of + 100 ° C to + 150 ° C. The conversion can occur at normal, he heightened or at a reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

The Compound of formula (IV) is in this case in an amount of 1 to 2 mol, preferably in an equivalent Amount of 1 mole, based on 1 mole of the compound of formula (III), used.

For the process step (VII) + (IV) → (II) are usual organic solvents, which do not change under the reaction conditions. For this belong preferably dimethylformamide, dimethyl sulfoxide or acetonitrile. As well Is it possible, the reaction without solvent perform. Particularly preferred is a reaction without solvent or in acetonitrile.

The Reaction is generally carried out in a temperature range of + 50 ° C to + 150 ° C, preferably in a temperature range from + 70 ° C to + 100 ° C. The conversion can occur at normal, increased or at a reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

The Compound of formula (IV) is in this case in an amount of 1 to 10 mol, preferably in an excess from 3 to 10 mol, based on 1 mol of the compound of formula (VII), used.

For the process step (V) + (VI) → (II) or (III) + (VI) → (VII) are usual organic solvents, which do not change under the reaction conditions. For this belong preferably dimethylformamide, dimethyl sulfoxide, acetonitrile, dioxane or alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol or tert-butanol. It is also possible mixtures of the above solvent use. Particular preference is given to process step (V) + (VI) → (II) Dimethylformamide or acetonitrile and for process step (III) + (VI) → (VII) Ethanol.

The Reaction is generally carried out in a temperature range of + 50 ° C to + 150 ° C, preferably in a temperature range from + 70 ° C to + 100 ° C. The conversion can occur at normal, increased or at a reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

When Bases for the process step (V) + (VI) → (II) or (III) + (VI) → (VII) are suitable preferred are alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate or organic amine bases such as pyridine, triethylamine, Ethyldiisopropylamine, N-methylmorpholine or N-methylpiperidine. Particularly preferred is potassium carbonate or triethylamine.

The Base is in this case in an amount of 1.5 to 4 mol, preferably in an amount of 1.5 to 2 mol, based on 1 mol of the compound of the formula (V) or (III) used. The compound of the formula (VI) is used in an amount of 1 to 1.5 mol, preferably in an amount of 1.2 mol, based on 1 mol of the compound of formula (V) or (III).

• a) Ethanol, Triethylamin, 5-16 h Rückfluss; b) Acetonitril, 85-90°C, 1-7 Tage.

Schema II:

• X = Cl, Br
• a) 1. Toluol, Bortrifluorid-Etherat, RT, 30 min.; 2. Amin-Komponente R¹R²NH, 150°C, 16 h; oder: Schmelze der Ausgangsverbindungen bei 150°C, 1-16 h; b) DMF, Triethylamin, 100°C, 16 h oder DMF, Kaliumcarbonat, 90°C, 16 h.

The process according to the invention can be exemplified by the following equation schemes: Scheme I:

• a) ethanol, triethylamine, 5-16 h reflux; b) acetonitrile, 85-90 ° C, 1-7 days.

Scheme II:

• X = Cl, Br
• a) 1. Toluene, boron trifluoride etherate, RT, 30 min .; 2. Amine Component R ¹ R ² NH, 150 ° C, 16 h; or: Melting of the starting compounds at 150 ° C, 1-16 h; b) DMF, triethylamine, 100 ° C, 16 h or DMF, potassium carbonate, 90 ° C, 16 h.

Compounds of the invention are the compounds of formula (I) and (II) and their salts, solvates and solvates of salts; the compounds encompassed by formula (I) and (II) the following formulas and their salts, solvates and solvates the salts as well as those of formulas (I) and (II), hereinafter as exemplary embodiments mentioned compounds and their salts, solvates and solvates of Salts, as far as included in formulas (I) and (II), The following compounds are not already 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 according to the formulas (I) and (II) 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.

physiological acceptable salts of the compounds of formulas (I) and (II) also salts more usual Bases, such as by way of example and preferably alkali metal salts (e.g. Sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 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 methyl piperidine.

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 of the formula (I) are known from WO 04/113306.

Examples the compounds of the invention of the formula (II) are listed below.

Abbreviations:

DCI

direct chemical Ionization (in MS)

DMSO

dimethyl sulfoxide

d. Th.

the theory (at yield)

IT I

Electrospray ionization (in MS)

Mp.

melting point

H

Hour (s)

HPLC

High pressure, high performance liquid chromatography

LC-MS

Liquid chromatography-coupled mass spectroscopy

min

Minute (s)

MS

mass spectroscopy

NMR

Nuclear Magnetic Resonance Spectroscopy

R _f

Retention index (at DC)

RT

room temperature

R _t

Retention time (at HPLC)

LC-MS and HPLC methods:

Method 1:

• Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; Pillar: Grom-Sil 120 ODS-4 HE, 50 mm × 2.0 mm, 3 μm; Eluent A: 1 l of water + 1 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 1 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Method 2:

• Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; Pillar: Grom-Sil 120 ODS-4 HE, 50 mm × 2.0 mm, 3 μm; Eluent A: 1 l of water + 1 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 1 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A; Oven: 55 ° C; Flow: 0.8 ml / min; UV detection: 208-400 nm.

Method 3:

• Instrument: Micromass Platform LCZ with HPLC Agilent series 1100; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A, flow 1 ml / min → 2.5 min 30% A, flow 2 ml / min → 3.0 min 5% A, flow 2 ml / min → 4.5 min 5% A, flow 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 4:

• Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A, flow 1 ml / min → 2.5 min 30% A, flow 2 ml / min → 3.0 min 5% A, flow 2 ml / min → 4.5 min 5% A, flow 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.

Method 5:

• device type MS: Micromass ZQ; device type HPLC: Waters Alliance 2795; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A, flow 1 ml / min → 2.5 min 30% A, flow 2 ml / min → 3.0 min 5% A, flow 2 ml / min → 4.5 min 5% A, flow 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 6:

• device type MS: Micromass ZQ; device type HPLC: HP 1100 Series; UV DAD; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A, flow 1 ml / min → 2.5 min 30% A, flow 2 ml / min → 3.0 min 5% A, flow 2 ml / min → 4.5 min 5% A, flow 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.

Method 7:

• device type MS: Micromass ZQ; device type HPLC: HP 1100 Series; UV DAD; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2 mm, 3.0 μm; Eluent A: water + 500 μl 50% formic acid / 1, Eluent B: acetonitrile. + 500 μl 50% formic acid / 1; Gradient: 0.0 min 0% B → 2.9 min 70% B → 3.1 min 90% B → 4.5 min 90% B; Oven: 50 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 8:

• device type MS: Micromass ZQ; device type HPLC: Waters Alliance 2790; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2 mm, 3.0 μm; Eluent A: water + 500 μl 50% formic acid / 1, Eluent B: acetonitrile + 500 μl 50% formic acid / 1; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B → 5.5 min 90% B; Flow: 0.0 min 0.75 ml / min → 4.5 min 0.75 ml / min → 5.5 min 1.25 ml / min; Oven: 45 ° C; UV detection: 210 nm.

Method 9:

• device type MS: Micromass ZQ; device type HPLC: Waters Alliance 2790; Pillar: Grom-Sil 120 ODS-4 HE 50 mm × 2 mm, 3.0 μm; Eluent A: water + 500 μl 50% formic acid / 1, Eluent B: acetonitrile + 500 μl 50% formic acid / 1; Gradient: 0.0 min 0% B → 0.2 min 0% B → 2.9 min 70% B → 3.1 min 90% B → 4.5 min 90% B; Oven: 45 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 10:

• device type MS: Micromass ZQ; device type HPLC: Waters Alliance 2795; Pillar: Merck Chromolith SpeedROD RP-18e 50 mm × 4.6 mm; Eluent A: water + 500 μl 50% formic acid / 1, Eluent B: acetonitrile + 500 μl 50 % formic acid / 1; Gradient: 0.0 min 10% B → 3.0 min 95% B → 4.0 min 95% B; Oven: 35 ° C; Flow: 0.0 min 1.0 ml / min → 3.0 min 3.0 ml / min → 4.0 min 3.0 ml / min; UV detection: 210 nm.

Method 11:

• device type MS: Micromass ZQ; device type HPLC: Waters Alliance 2790; Pillar: Uptisphere C 18 50 mm × 2.0 mm, 3.0 μm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05 % Formic acid; Gradient: 0.0 min 5% B → 2.0 min 40% B → 4.5 min 90% B → 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min → 4.5 min 0.75 ml / min → 5.5 min 1.25 ml / min; UV detection: 210 nm.

Method 12

• Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ / l water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B; Flow: 0.75 ml / min; Temperature: 30 ° C; UV detection: 210 nm.

Method 13:

• Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 125 mm × 4 mm, 5 μm; Eluent A: 5 ml HClO ₄ / l water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B; Flow: 0.75 ml / min; Temperature: 30 ° C; UV detection: 210 nm.

Starting Compounds:

The for the required the following reactions Amidines are prepared from the corresponding nitriles or esters according to Gielen H., Alonso-Alija C., Hendrix M., Niewöhner U., Schauß D., Tetrahedron Lett. 43, 419-421 (2002).

Example 1A 2- (3,4-dichlorophenyl) ethanamidine hydrochloride

Under an argon atmosphere, 2.88 g (54 mmol) of ammonium chloride are suspended in 50 ml of toluene and cooled to 0 ° C. After dropwise addition of 27 ml of a 2 M trimethylaluminum solution in toluene, the mixture is warmed to room temperature and stirred for 1.5 h. 5 g (27 mmol) of 3,4-dichlorophenylacetonitrile are added and the batch is stirred overnight at 80.degree. After cooling to 0 ° C, 50 ml of methanol are added dropwise. The product is separated from the precipitated solid by suction and the filter cake washed several times with methanol. The combined filtrates are concentrated to dryness, the residue is then slurried in dichloromethane / methanol 10: 1 and again filtered off with suction. After concentration, the filtrate yields 6.2 g (77% of theory) of the title compound.
MS (ESIpos): m / z = 203 [M + H] ⁺ .

Example 2A 6-Methoxypyridin-3-ylboronic acid

1 g (5.32 mmol) of 5-bromo-2-methoxypyridine is dissolved in 10 ml of absolute tetrahydrofuran and cooled to -78 ° C. After addition of 0.4 g (6.38 mmol) of a 1.6 M n-butyllithium solution in hexane, a yellow solution is formed, which is stirred for 30 min at the given temperature. After adding 3 g (15.9 mmol) of triisopropyl borate, the mixture is stirred for a further hour, during which the solution is warmed to -20.degree. It is mixed with water and stirred overnight. The crude solution is acidified to pH 5 with 1 N hydrochloric acid and extracted twice with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated to give a tan solid, which is slurried with diethyl ether and filtered. 0.38 g (47% of theory) of the product are isolated.
MS (ESIpos): m / z = 154 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 3.83 (s, 3H), 6.76 (d, 1H), 8.0 (dd, 1H), 8.52 (s, 1H).

Example 3A Methyl [2- (6-methoxypyridin-3-yl) phenyl] acetate

1.35 g (5.89 mmol) of methyl (2-bromophenyl) acetate are charged with 1 g (6.55 mmol) of 6-methoxypyridin-3-ylboronic acid and 1.98 g (13.09 mmol) of cesium fluoride under argon in 20 ml of 1,2-dimethoxyethane. After addition of 0.22 g (0.19 mmol) of tetrakis (triphenylphosphine) palladium (0), the reaction mixture is stirred at 100 ° C. for 4 h. After cooling to room temperature, a mixture of ethyl acetate and water is added and extracted with ethyl acetate. After drying the organic phase over magnesium sulfate and removing the solvent in vacuo, the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 9: 1). 1.1 g (68% of theory) of the product are obtained.
LC-MS (Method 5): R _t = 2.1 min., MS (ESIpos): m / z = 258 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 3.51 (s, 3H), 3.63 (s, 2H), 3.9 (s, 3H), 6.89 (d, 1H), 7.26 (m, 1H) , 7.38 (m, 3H), 7.63 (dd, 1H), 8.08 (m, 1H).

Example 4A 2- [2- (6-Methoxypyridin-3-yl) phenyl] ethanimidamide Hydrochloride

Under an argon atmosphere, 1.14 g (21.37 mmol) of ammonium chloride are suspended in 20 ml of toluene and cooled to 0 ° C. After dropwise addition of 10.7 ml of a 2 M trimethylaluminum solution in toluene, the mixture is warmed to room temperature and stirred for 1.5 h. 1.1 g (4.27 mmol) of methyl [2- (6-methoxypyridin-3-yl) phenyl] acetate are added and the batch is stirred at 80 ° C. for two days. After cooling to 5 ° C, 50 ml of methanol are added dropwise. The product is separated from the precipitated solid by suction and the filter cake washed several times with methanol. The combined filtrates are concentrated to dryness, the residue is then slurried in dichloromethane / methanol 10: 1 and again filtered off with suction. After concentration, the filtrate gives 0.5 g (46% of theory) of the title compound.
LC-MS (Method 5): R _t = 0.94 min., MS (ESIpos): m / z = 242 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 3.79 (s, 2H), 3.9 (s, 3H), 6.89 (d, 1H), 7.31 (m, 2H), 7.46 (m, 2H) , 7.68 (dd, 1H), 8.12 (m, 1H), 8.72 (s, 1H), 8.8 (s, 2H).

Example 5A 2- [2- (6-Methoxypyridin-3-yl) benzyl] -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

0.55 g (1.96 mmol) of 2- [2- (6-methoxypyridin-3-yl) phenyl] ethanimidamide hydrochloride are treated with 0.4 g (1.96 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 0.79 g Triethylamine (7.81 mmol) dissolved in 20 ml of dioxane and stirred at 90 ° C overnight. Then the solvent is removed in vacuo to about 2 ml and the remaining solution with acetonitrile, whereupon the product precipitates. After filtration, it is washed with acetonitrile and methanol and the product is dried under high vacuum. 276 mg (38% of theory) of the title compound are obtained.
LC-MS (Method 5): R _t = 2.08 min., MS (ESIpos): m / z = 365 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 2.31 (s, 3H), 3.9 (s, 3H), 3.98 (s, 2H), 6.89 (d, 1H), 7.28 (m, 1H) , 7.39 (m, 3H), 7.63 (dd, 1H), 8.08 (m, 1H).

Example 6A 2-Benzyl-4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

100 mg (0.59 mmol) of 2-phenylethanamidine hydrochloride are dissolved in 2 ml of ethanol with 119 mg (0.59 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 237 mg (2.34 mmol) of triethylamine and left to stand for 5 h 70 ° C stirred. Then the solvent is removed in vacuo, the residue taken up in 50 ml of dichloromethane and washed with 2 M hydrochloric acid. After drying the organic phase over magnesium sulfate, the solvent is removed in vacuo and the residue flash-chromatographed on silica gel (eluent: dichloromethane / methanol 200: 1, 100: 1). 75 mg (50% of theory) of the title compound are obtained.
HPLC (Method 12): R _t = 4.2 min.
MS (ESIpos): m / z = 258 [M + H] ⁺ .

Example 7A 2- (3-Methylbenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

1.45 g (9.83 mmol) of 2- (3-methylphenyl) ethanamidine hydrochloride are treated with 2 g (9.83 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 2 g (19.67 mmol) of triethylamine in 40 ml of ethanol dissolved and stirred at 70 ° C for 5 h. Subsequently, the solvent is removed in vacuo and the residue purified by preparative HPLC. There are obtained 0.4 g (15% of theory) of the product.
LC-MS (Method 2): R _t = 2.83 min., MS (ESIpos): m / z = 272 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 2.25 (s, 3H), 2.50 (s, 3H), 3.91 (s, 2H), 7.19 (m, 4H).

Example 8A 2- (2-Methylbenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

3 g (16.45 mmol) of 2- (2-methylphenyl) ethanamidine hydrochloride are treated with 3.3 g (16.45 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 6.6 g (64.9 mmol) of triethylamine in 60 ml of dioxane dissolved and stirred overnight at 90 ° C. After filtering off the triethylammonium salts, the filtrate is concentrated and the residue triturated with dichloromethane. 3.6 g (81% of theory) of the product are obtained.
LC-MS (method 10): R _t = 2.13 min, MS (ESIpos):. M / z = 272 [M + H] ^+.

Example 9A 2- (2-Fluorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

3.5 g (18.5 mmol) of 2- (2-fluorophenyl) ethanamidine hydrochloride are treated with 3.8 g (18.5 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 7.5 g (74.2 mmol) of triethylamine in 50 ml of dioxane dissolved and stirred overnight at 90 ° C. After filtering off the triethylammonium salts, the filtrate is concentrated and the residue taken up in ethyl acetate. The product is precipitated by addition of 1 N hydrochloric acid and water. 3.8 g (75% of theory) of the title compound are obtained.
LC-MS (Method 10): R _t = 2.03 min., MS (ESIpos): m / z = 276 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 2.31 (s, 3H), 4.06 (s, 2H), 7.19 (m, 2H), 7.41 (m, 2H).

Example 10A 2- (2-Ethoxybenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

4.2 g (19.7 mmol) of 2- (2-ethoxyphenyl) ethanamidine hydrochloride are mixed with 4.0 g (19.7 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 7.9 g (78.7 mmol) of triethylamine in 80 ml of dioxane dissolved and stirred overnight at 90 ° C. After filtering off the triethylammonium salts, the filtrate is concentrated and the residue taken up in ethyl acetate. The product is precipitated by addition of 1 N hydrochloric acid and water. 5.3 g (90% of theory) of the title compound are obtained.
LC-MS (Method 3): R _t = 2.32 min., MS (ESIpos): m / z = 302 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.19 (t, 3H), 2.30 (s, 3H), 3.99 (q, 2H + s, 2H), 6.93 (m, 2H), 7.27 ( m, 2H).

Example 11A 2- (3-Chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 2A, 0.5 g (2.00 mmol) of 2- (3-chlorophenyl) ethanamidine hydrobromide with 0.41 g (2.00 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 0.81 g (8.01 mmol ) Reacted triethylamine to 0.5 g (86% of theory) of the title compound.
HPLC (Method 12): R _t = 4.4 min.
MS (DCI, NH _3): m / z = 292 [M + H] ^+, 309 [M + NH _4] ^+.

Example 12A 2- (4-Chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 2A, 10 g (48.8 mmol) of 2- (4-chlorophenyl) ethanamidine hydrochloride with 9.91 g (48.8 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 19.7 g (195 mmol ) Triethylamine was reacted to 7.00 g (49% of theory) of the title compound.
HPLC (Method 12): R _t = 4.35 min.
MS (ESIpos): m / z = 292 [M + H] ⁺ .

Example 13A 2- (3,4-Dichlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 2A, 1.00 g (4.17 mmol) of 2- (3,4-dichlorophenyl) ethanamidine hydrochloride are mixed with 0.85 g (4.17 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 1.69 g ( 16.7 mmol) of triethylamine to 0.6 g (44% of theory) of the title compound.
HPLC (Method 12): R _t = 4.7 min.
MS (DCI, NH _3): m / z = 343 [M + NH _4] ^+.

Example 14A 2- (3-Fluorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 2A, 100 mg (0.43 mmol) of 2- (3-fluorophenyl) ethanamidine hydrochloride with 87 mg (0.43 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 174 mg (1.72 mmol ) Triethylamine was reacted to 28 mg (24% of theory) of the title compound.
HPLC (Method 12): R _t = 4.2 min.
MS (ESIpos): m / z = 276 [M + H] ⁺ .

Example 15A 4- (Methylsulfanyl) -6-oxo-2- [3- (trifluoromethyl) benzyl] -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 2A, 0.5 g (2.10 mmol) of 2- [3- (trifluoromethyl) phenyl] ethanamidine hydrochloride with 0.43 g (2.10 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 0.85 g (8.38 mmol) of triethylamine to 0.4 g (59% of th.) Of the title compound.
HPLC (Method 12): R _t = 4.4 min.
MS (ESIpos): m / z = 326 [M + H] ⁺ .

Example 16A 4- (Methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 2A, 3.10 g (17.6 mmol) 2- (3-thienyl) ethanamidine hydrochloride with 3.57 g (17.6 mmol) of methyl 2-cyano-3,3-dimethylthioprop-2-enoate and 7.10 g (70.2 mmol ) Triethylamine was reacted to 2.19 g (47% of theory) of the title compound.
HPLC (Method 12): R _t = 4.1 min.
MS (ESIpos): m / z = 263.9 [M + H] ⁺ .

Example 17A Methyl (2E / Z) -2-cyano-3- (cyclohexylamino) -3-methylthio-prop-2-enoate

0.6 g (2.9 mmol) of methyl 3,3-bis (methylthio) -2-cyanoacrylate are stirred with 0.29 g (2.9 mmol) of cyclohexylamine in 20 ml of acetonitrile for 1 h at room temperature. The volatiles are removed in vacuo. There are obtained 0.74 g (98% of theory) of the product as a yellow oil.
HPLC (Method 12): R _t = 4.85 min.
MS (DCI, NH _3): m / z = 254.9 [M + H] ^+, 272 [M + NH _4] ^+.

Example 18A Methyl (2E / Z) -2-cyano-3- (cyclopentylamino) -3-methylthio-prop-2-enoate

0.3 g (1.47 mmol) of methyl 3,3-bis (methylthio) -2-cyanoacrylate are heated to 70 ° C. with 0.13 g (1.47 mmol) of cyclopentylamine in 3 ml of acetonitrile for 30 min. Subsequently, the volatiles are removed in vacuo. 0.35 g (98% of theory) of the product are obtained as a yellow oil.
HPLC (Method 12): R _t = 4.6 min.
MS (DCI, NH _3): m / z = 241 [M + H] ^+, 258 [M + NH _4] ^+.

• a) Ethanol, Triethylamin, 5-16 h Rückfluss; b) Acetonitril, 85-90°C, 1-7 Tage.

Beispiel 1 2-(3,4-Dichlorbenzyl)-6-oxo-4-(1-piperidinyl)-1,6-dihydropyrimidin-5-carbonitril

The following compounds are prepared by the general synthetic route shown in Scheme I: Scheme I:

• a) ethanol, triethylamine, 5-16 h reflux; b) acetonitrile, 85-90 ° C, 1-7 days.

Example 1 2- (3,4-Dichlorobenzyl) -6-oxo-4- (1-piperidinyl) -1,6-dihydropyrimidine-5-carbonitrile

100 mg (0.34 mmol) of 2- (3,4-dichlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine 5-carbonitrile are stirred with 261 mg (3.07 mmol) of piperidine at 85 ° C. for 16 h , After removal of the volatiles in vacuo, the residue is purified by preparative HPLC. 42 mg (38% of theory) of the title compound are obtained.
HPLC (Method 12): R _t = 4.8 min.
MS (ESIpos): m / z = 363 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.45-1.70 (m, 6H), 3.73-3.89 (m, 6H), 7.35 (dd, 1H), 7.57-7.66 (m, 2H), 11.1 (s, 1H). Example 2 2-Benzyl-6-oxo-4- (1-piperidinyl) -1,6-dihydropyrimidine-5-carbonitrile

43 mg (0.17 mmol) of 2-benzyl-4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile are suspended in 0.3 ml of acetonitrile and 42.7 mg (0.50 mmol) of piperidine at 85 ° C for 16 h touched. Subsequently, the resulting crude product is purified by preparative HPLC. 11 mg (22% of theory) of the title compound are obtained.
HPLC (Method 12): R _t = 4.3 min.
MS (ESIpos): m / z = 295 [M + H] ^+
1 H-NMR (CD ₃ OD, 300 MHz): δ = 1.59-1.77 (m, 6H), 3.83 (s, 2H), 3.93 (t, 4H), 7.24-7.34 (m, 5H).

Example 3 4- [4- (2-Hydroxyethyl) -1-piperidinyl] -2- (3-methylbenzyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

0.1 g (0.37 mmol) of 2- (3-methylbenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile are dissolved under argon with 0.142 g (1.16 mmol) of 2- (4-piperidinyl). ethan-1-ol in 3 ml acetonitrile heated to 90 ° C for seven days. After cooling to room temperature, the crude product is purified by preparative HPLC. There are obtained 0.047 g (36% of theory) of the title compound as a colorless solid.
LC-MS (Method 7): R _t = 3.01 min., MS (ESIpos): m / z = 353 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.05 (m, 2H), 1.36 (m, 2H), 1.69 (m, 3H), 2.25 (s, 3H), 2.89 (t, 2H) , 3.42 (t, 2H), 3.68 (s, 2H), 4.51 (d, 2H), 7.18 (m, 4H).

Example 4 4- (Cyclopentylamino) -2- (3-methylbenzyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

0.1 g (0.37 mmol) of 2- (3-methylbenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile are added under argon with 0.31 g (3.65 mmol) of cyclopentylamine in 3 ml of acetonitrile overnight heated to 90 ° C. After cooling to room temperature, the crude product is purified by preparative HPLC. There are 0.03 g (26 % d. Th.) Of the title compound as a colorless solid.
LC-MS (Method 10): R _t = 2.27 min., MS (ESIpos): m / z = 309 [M + H] ⁺ .

Example 5 4 - [(2S) -2- (Hydroxymethyl) -1-pyrrolidinyl] -2- (3-methylbenzyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

0.1 g (0.37 mmol) of 2- (3-methylbenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile are dissolved under argon with 0.11 g (1.1 mmol) of (S) - (+) 2-Pyrrolidinmethanol in 3 ml of acetonitrile heated to 90 ° C for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. There are obtained 0.035 g (29% of theory) of the title compound as a colorless solid.
LC-MS (Method 7): R _t = 2.91 min., MS (ESIpos): m / z = 325 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.94 (m, 4H), 2.28 (s, 2H), 3.76 (m, 3H), 3.70 (s, 2H), 3.81 (m, 2H) , 4.4 (m, 1H), 7.15 (m, 4H), 12.34 (s, 1H).

Example 6 4- [4- (2-Hydroxyethyl) -1-piperidinyl] -2- (2-methylbenzyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

0.1 g (0.37 mmol) of 2- (2-methylbenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile are dissolved under argon with 0.14 g (1.1 mmol) of 2- (4-piperidinyl) ethan-1-ol in 3 ml of acetonitrile heated to 90 ° C for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 13 mg (10% of theory) of the title compound are obtained as a colorless solid.
LC-MS (Method 5): R _t = 1.74 min., MS (ESIpos): m / z = 353 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.06 (m, 2H), 1.34 (m, 2H), 1.68 (m, 3H), 2.30 (s, 3H), 3.00 (t, 2H) , 3.42 (t, 2H), 3.80 (s, 2H), 4.51 (d, 2H), 7.16 (m, 4H), 12.33 (s, 1H).

Example 7 2- (2-Fluorobenzyl) -4- [4- (2-hydroxyethyl) -1-piperidinyl] -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

0.1 g (0.37 mmol) of 2- (2-fluorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile are dissolved, under argon, with 0.14 g (1.1 mmol) of 2- (4-piperidinyl) ethan-1-ol in 3 ml of acetonitrile for six days at 90 ° C hitzt. After cooling to room temperature, the crude product is purified by preparative HPLC. There are obtained 31 mg (24% of theory) of the title compound as a colorless solid.
LC-MS (Method 2): R _t = 2.94 min., MS (ESIpos): m / z = 357 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.01 (m, 2H), 1.33 (m, 2H), 1.67 (m, 3H), 2.97 (t, 2H), 3.41 (dd, 2H) , 3.87 (s, 2H), 4.32 (t, 1H), 4.47 (d, 2H), 7.16 (m, 2H), 7.36 (m, 2H), 12.38 (s, 1H).

Example 8 2- (2-Ethoxybenzyl) -4- [4- (2-hydroxyethyl) -1-piperidinyl] -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile

0.1 g (0.37 mmol) of 2- (2-ethoxybenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile are dissolved under argon with 0.13 g (0.99 mmol) of 2- (4-piperidinyl). ethan-1-ol in 3 ml of acetonitrile heated to 90 ° C for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 45 mg (43% of theory) of the title compound are obtained as a colorless solid.
LC-MS (method 6): R _t = 2:01 min, MS (ESIpos):. M / z = 383 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.04 (m, 2H), 1.23 (t, 3H), 1.34 (m, 2H), 1.67 (m, 3H), 2.94 (t, 2H) , 3.41 (t, 2H), 3.87 (s, 2H), 3.96 (q, 2H), 4.48 (d, 2H), 6.92 (m, 2H), 7.17 (m, 2H), 12.26 (s, 1H).

Example 9 2- (3-Chlorobenzyl) -6-oxo-4- (propylamino) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 203 mg (3.43 mmol) of n-propylamine to 12 mg (12% of theory) of the title compound.
HPLC (Method 12): R _t = 4.4 min.
MS (ESIpos): m / z = 303 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 0.75 (t, 3H), 1.40 (m, 2H), 3.23 (m, 2H), 3.83 (s, 2H), 7.23-7.38 (m, 4H), 7.42 (s, 1H), 12.34 (s, 1H).

Example 10 2- (3-Chlorobenzyl) -4- (cyclopentylamino) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 292 mg (3.43 mmol) of cyclopentylamine become 10 mg (9% of theory) of the title compound.
HPLC (Method 12): R _t = 4.6 min.
MS (ESIpos): m / z = 329 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.38-1.85 (m, 8H), 3.82 (s, 2H), 4.20-4.37 (m, 1H), 7.23-7.46 (m, 4H), 7.66-7.80 (s, 1H), 12.25-12.44 (s, 1H).

Example 11 2- (3-Chlorobenzyl) -6-oxo-4- (1-pyrrolidinyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 244 mg (3.43 mmol) of pyrrolidine become 29 mg (27% of theory) of the title compound.
HPLC (Method 12): R _t = 4.4 min.
MS (ESIpos): m / z = 315 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.80-1.95 (m, 4H), 3.58-3.71 (m, 4H), 3.79 (s, 2H), 7.25-7.45 (m, 4H), 12.28-12.39 (s, 1H).

Example 12 4- (4,4-Dimethylpiperidin-1-yl) -2- (3-chlorobenzyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 150 mg (0.51 mmol) of 2- (3-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 582 mg (5.14 mmol) of 4.4 Dimethylpiperidine to 96 mg (52% of theory) of the title compound.
HPLC (Method 12): R _t = 4.8 min.
MS (ESIpos): m / z = 357 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 0.96 (s, 6H), 1.30-1.41 (m, 4H), 3.75-3.87 (m, 6H, s at 3.81), 7.24-7.45 (m , 4H), 12.39 (s, 1H).

Example 13 2- (3-Chlorobenzyl) -4 - [(2-methoxyethyl) amino] -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 257 mg (3.43 mmol) of 2-methoxyethylamine to 61 mg (56% of theory) of the title compound.
HPLC (Method 12): R _t = 4.0 min.
MS (ESIpos): m / z = 319 [M + H] ^+
1 H-NMR _(CDCl3, 300 MHz): δ = 3:38 (s, 3H), 3:53 (t, 2H), 3.75 (q, 2H), 3.88 (s, 2H) 6.00 (t, 1H), 7.25 -7.31 (m, 3H), 7.38 (s, 1H), 12.56 (s, 1H).

Example 14 2- (3-Chlorobenzyl) -4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 150 mg (0.51 mmol) of 2- (3-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 448 mg (5.14 mmol) morpholine to 109 mg (63% of theory) of the title compound.
HPLC (Method 12): R _t = 4.0 min.
MS (ESIpos): m / z = 331 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 3.59-3.69 (t, 4H), 3.79-3.90 (m, 6H, s at 3.82), 7.25-7.44 (m, 4H), 12.53 (s , 1H).

Example 15 2- (3-Chlorobenzyl) -4- (4-methylpiperazin-1-yl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 343 mg (3.43 mmol) of N-methylpiperazine to 101 mg (84% of theory) of the title compound.
HPLC (Method 12): R _t = 3.5 min.
MS (ESIpos): m / z = 344 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 2.18 (s, 3H), 2.35 (t, 4H), 3.79-3.88 (m, 6H, s at 3.82), 7.25-7.44 (m, 4H ) 12.48 (s, 1H).

Example 16 2- (3-Chlorobenzyl) -4 - [(2-methoxybenzyl) amino] -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (3-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 470 mg (3.43 mmol) of 2-methoxybenzylamine to 37 mg (28% of theory) of the title compound.
HPLC (Method 12): R _t = 4.6 min.
MS (ESIpos): m / z = 381 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 3.77 (s, 2H), 3.79 (s, 3H), 4.52 (d, 2H), 6.84 (t, 1H), 6.92-6.99 (m, 2H), 7.12 (d, 1H), 7.19-7.33 (m, 4H), 8.14 (t, 1H), 12.39 (s, 1H).

Example 17 2- (4-Chlorobenzyl) -4- (cyclobutylamino) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (4-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 244 mg (3.43 mmol) of cyclobutylamine become 15 mg (14% of theory) of the title compound.
HPLC (Method 12): R _t = 4.5 min.
MS (ESIpos): m / z = 315 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.50-1.67 (m, 2H), 2.03-2.15 (m, 4H), 3.79 (s, 2H), 4.37-4.51 (m, 1H), 7.31-7.43 (m, 4H), 8.00 (s, 1H), 12.33 (s, 1H).

Example 18 2- (4-Chlorobenzyl) -6-oxo-4- (1-pyrrolidinyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.34 mmol) of 2- (4-chlorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 244 mg (3.43 mmol) of pyrrolidine become 45 mg (42% of theory) of the title compound.
HPLC (Method 12): R _t = 4.4 min.
MS (ESIpos): m / z = 315 [M + H] ^+
1 H-NMR (CD ₃ OD, 300 MHz): δ = 1.88-2.03 (m, 4H), 3.69-3.86 (m, 6H, s at 3.82), 7.25-7.35 (m, 4H).

Example 19 4- (Cyclopentylamino) -2- (3-fluorobenzyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.36 mmol) of 2- (3-fluorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 309 mg (3.63 mmol) of cyclopentylamine to 12 mg (11% of theory) of the title compound.
HPLC (Method 12): R _t = 4.4 min.
MS (ESIpos): m / z = 313 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.29-1.71 (m, 8H), 3.89 (s, 2H), 3.98-4.14 (m, 1H), 7.11-7.42 (m, 4H), 7.63-7.75 (s, 1H), 12.34-12.43 (s, 1H).

Example 20 2- (3-Fluorobenzyl) -6-oxo-4- (1-piperidinyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.36 mmol) of 2- (3-fluorobenzyl) -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 309 mg (3.63 mmol) of piperidine become 40 mg (35% of theory) of the title compound.
HPLC (Method 12): R _t = 4.3 min.
MS (ESIpos): m / z = 313 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.40-1.66 (m, 6H), 3.66-3.76 (m, 4H), 3.76 (s, 2H), 7.12-7.42 (m, 4H), 12.27-12.41 (s, 1H).

Example 121 6-Oxo-4- (1-piperidinyl) -2- [3- (trifluoromethyl) benzyl] -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.31 mmol) of 4- (methylsulfanyl) -6-oxo-2- [3- (trifluoromethyl) benzyl] -1,6-dihydropyrimidine-5-carbonitrile with 262 mg (3.07 mmol) Piperidine to give 26 mg (22% of theory) of the title compound.
HPLC (Method 12): R _t = 4.7 min.
MS (ESIpos): m / z = 363 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.43-1.70 (m, 6H), 3.71-3.83 (m, 4H), 3.93 (s, 2H), 7.51-7.78 (m, 4H), 12.42 (s, 1H).

Example 22 6-Oxo-4- (propylamino) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 224 mg (3.80 mmol) of n-propylamine to 14 mg (13% of theory) of the title compound.
HPLC (Method 12): R _t = 4.1 min.
MS (ESIpos): m / z = 275.2 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 0.79 (t, 3H), 1.46 (m, 2H), 3.29 (m, 2H), 3.81 (s, 2H), 7.06 (d, 1H) , 7.33 (s, 1H), 7.49 (m, 1H), 7.87 (s, 1H), 12.27 (s, 1H).

Example 23 4- (Cyclopropylamino) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 217 mg (3.80 mmol) of cyclopropylamine become 44 mg (43% of theory) of the title compound.
HPLC (Method 12): R _t = 3.8 min.
MS (ESIpos): m / z = 273 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 0.60-0.78 (m, 4H), 2.84-2.98 (m, 1H), 3.80 (s, 2H), 7.08 (d, 1H), 7.35 ( s 1H), 7.49 (m, 1H), 7.85-8.05 (s, 1H), 12.32 (s, 1H).

Example 24 4- (Cyclopentylamino) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 150 mg (0.57 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 485 mg (5.70 mmol) of cyclopentylamine become 46 mg (26% of theory) of the title compound.
HPLC (Method 12): R _t = 4.4 min.
MS (ESIpos): m / z = 301.2 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.40-1.91 (m, 8H), 3.81 (s, 2H), 4.36 (m, 1H), 7.07 (d, 1H), 7.34 (s, 1H), 7.50 (m, 1H), 7.65 (s, 1H), 12.28 (s, 1H).

Example 25 6-Oxo-4- (1-pyrrolidinyl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 270 mg (3.80 mmol) of pyrrolidine to 64 mg (59% of theory) of the title compound.
HPLC (Method 12): R _t = 4.1 min.
MS (ESIpos): m / z = 287 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.80-1.96 (m, 4H), 3.60-3.76 (m, 4H), 3.78 (s, 2H), 7.08 (d, 1H), 7.35 ( s, 1H), 7.48 (m, 1H), 12.27 (s, 1H).

Example 26 4- (4-Methylpiperidin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thie nylmethyl) -1,6-dihydropyrimidine-5-carbonitrile were reacted with 377 mg (3.80 mmol) of 4-methylpiperidine to give 65 mg (54% of theory) of the title compound.
HPLC (Method 12): R _t = 4.5 min.
MS (ESIpos): m / z = 315 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 0.91 (d, 3H), 1.05-1.18 (t, 2H), 1.62-1.77 (m, 3H), 3.06 (t, 2H), 3.80 ( s, 2H), 4.61 (d, 2H), 7.07 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.32 (s, 1H).

Example 27 4- (4,4-Dimethylpiperidin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 430 mg (3.80 mmol) of 4.4 Dimethylpiperidine to 42 mg (34% of theory) of the title compound.
HPLC (Method 12): R _t = 4.6 min.
MS (ESIpos): m / z = 329 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 0.97 (s, 6H), 1.37 (t, 4H), 3.77-3.87 (m, 6H, s at 3.80), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.31 (s, 1H).

Example 28 4- [4- (tert-Butyl) piperidin-1-yl] -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 536 mg (3.80 mmol) of 4-tert Butylpiperidine to 57 mg (42% of theory) of the title compound.
HPLC (Method 12): R _t = 4.9 min.
MS (ESIpos): m / z = 357 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 0.82 (s, 9H), 1.02-1.42 (m, 3H), 1.74 (d, 2H), 2.96 (t, 2H), 3.78 (s, 2H), 4.72 (d, 2H), 7.06 (d, 1H), 7.33 (s, 1H), 7.49 (m, 1H), 12.35 (s, 1H).

Example 29 4- (4-Hydroxypiperidin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 384 mg (3.80 mmol) of piperidine-4 -ol to 47 mg (39% of theory) of the title compound.
HPLC (Method 12): R _t = 3.50 min.
MS (ESIpos): m / z = 317 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.29-1.50 (m, 2H), 1.72-1.90 (m, 2H), 3.42-3.60 (m, 2H), 3.68-3.86 (m, 3H , s at 3.79), 4.10-4.26 (m, 2H), 4.83 (d, 1H, OH), 7.07 (d, 1H), 7.35 (s, 1H), 7.50 (m, 1H), 11.79-12.29 (s , 1H, NH).

Example 30 4- [4- (2-Hydroxyethyl) piperidin-1-yl] -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 491 mg (3.80 mmol) of 2- (methylene) 4-piperidinyl) ethan-1-ol to 64 mg (49% of theory) of the title compound.
HPLC (Method 12): R _t = 3.70 min.
MS (ESIpos): m / z = 345 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.02-1.20 (m, 2H), 1.32-1.42 (q, 2H), 1.68-1.81 (m, 3H), 3.05 (t, 2H), 3.44 (q, 2H), 3.80 (s, 2H), 4.34 (t, 1H, OH), 4.62 (d, 2H), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H) , 12.31 (s, 1H, NH).

Example 31 4 - [(2-Methoxyethyl) amino] -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 285 mg (3.80 mmol) of 2-methoxyethylamine to 76 mg (69% d. Th.) Implemented the title compound.
HPLC (Method 12): R _t = 3.7 min.
MS (ESIpos): m / z = 291 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 3.20 (s, 3H), 3.35-3.42 (m, 2H), 3.47-3.56 (m, 2H), 3.82 (s, 2H), 7.07 ( d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 7.79 (s, 1H), 12.33 (s, 1H).

Example 32 4- (1,4-Dioxa-8-azaspiro [4.5] dec-8-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 544 mg (3.80 mmol) of 1,4 Dioxa-8-azaspiro [4.5] decane to give 65 mg (48% of theory) of the title compound.
HPLC (Method 12): R _t = 4.0 min.
MS (ESIpos): m / z = 359 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.70 (t, 4H), 3.81 (s, 2H), 3.86-3.95 (m, 8H, s at 3.92), 7.07 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.41 (s, 1H).

Example 33 4- (7,11-dioxa-3-azaspiro [5.5] undec-3-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 597 mg (3.80 mmol) of 1.5 Dioxa-9-azaspiro [5.5] undecane to 86 mg (61% of theory) of the title compound.
HPLC (Method 12): R _t = 4.0 min.
MS (ESIpos): m / z = 373 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 1.56 (m, 2H), 1.82-1.94 (m, 4H), 3.75-3.92 (m, 10H, s at 3.80), 7.07 (d, 1H ), 7.35 (s, 1H), 7.50 (m, 1H), 12.43 (br s, 1H).

Example 34 4- (4-Methylpiperazin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 380 mg (3.80 mmol) of N-methylpiperazine to 36 mg (30% of theory) of the title compound.
HPLC (Method 12): R _t = 3.2 min.
MS (ESIpos): m / z = 316 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 2.19 (s, 3H), 2.37 (t, 4H), 3.77-3.91 (m, 6H, s at 3.80), 7.07 (d, 1H), 7.35 (s, 1H), 7.50 (m, 1H), 12.43 (s, 1H).

Example 35 6-Oxo-4- (piperazin-1-yl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 80 mg (0.30 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 326 mg (3.80 mmol) of piperazine become 45 mg (49% of theory) of the title compound.
HPLC (Method 12): R _t = 3.15 min.
MS (ESIpos): m / z = 302 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 2.75 (t, 4H), 3.76-3.82 (m, 6H, s at 3.80), 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H).

Example 36 4- (Benzylamino) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 407 mg (3.80 mmol) of benzylamine to 43 mg (35% of theory) of Title compound implemented.
HPLC (Method 12): R _t = 4.3 min.
MS (ESIpos): m / z = 323 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 3.80 (s, 2H), 4.52 (d, 2H), 6.95 (d, 1H), 7.16-7.32 (m, 6H), 7.45 (m, 1H), 8.49 (t, 1H), 12.40 (s, 1H).

Example 37 4 - [(2-Methoxybenzyl) amino] -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

Analogously to the preparation of Example 1, 100 mg (0.38 mmol) of 4- (methylsulfanyl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile with 521 mg (3.80 mmol) of 2-methoxybenzylamine to 62 mg (46% of theory) of the title compound.
HPLC (Method 12): R _t = 4.4 min.
MS (ESIpos): m / z = 353 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 3.75 (s, 2H), 3.80 (s, 3H), 4.56 (d, 2H), 6.84-6.90 (m, 2H), 6.96-7.04 ( m, 2H), 7.16 (s, 1H), 7.23 (t, 1H), 7.39 (m, 1H), 8.15 (t, 1H), 12.34 (s, 1H).

Example 38 4- [4- (2-Hydroxyethyl) piperidin-1-yl] -2- [2- (6-methoxypyridin-3-yl) benzyl] -6-oxo-1,6-dihydropyrimidine-5-carbonitrile

Analogous to prepare Example 1, 80 mg (0.22 mmol) of 2- [2- (6-methoxypyridin-3-yl) benzyl] -4- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carbonitrile with 85 mg (0.65 mmol) 2- (4-piperidinyl) ethan-1-ol to 62 mg (63% of theory) of the title compound.

• a) 1. Toluol, Bortrifluorid-Etherat, RT, 30 min.; 2. Amin-Komponente R¹R²NH, 150°C, 16 h; oder: Schmelze der Ausgangsverbindungen bei 150°C, 1-16 h; b) DMF, Triethylamin, 100°C, 16 h oder DMF, Kaliumcarbonat, 90°C 16 h.

The following compound is prepared by the general synthetic route shown in Scheme II: Scheme II:

• a) 1. Toluene, boron trifluoride etherate, RT, 30 min .; 2. Amine Component R ¹ R ² NH, 150 ° C, 16 h; or: Melting of the starting compounds at 150 ° C, 1-16 h; b) DMF, triethylamine, 100 ° C, 16 h or DMF, potassium carbonate, 90 ° C for 16 h.

Example 39 4- (Cyclohexylamino) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

69.5 mg (0.39 mmol) of 2- (3-thienyl) ethanamidine hydrochloride are treated with 100 mg (0.39 mmol) of methyl (2E / Z) -2-cyano-3- (cyclohexylamino) -3-methylthio-prop-2-enoate and 159 mg (1.57 mmol) of triethylamine dissolved in 0.5 ml of DMF and stirred overnight at 100 ° C. The cooled mixture is taken up in a little water and extracted with dichloromethane. The dichloromethane phase is dried over sodium sulfate, concentrated and the residue is flash chromatographed on silica gel (eluent: dichloromethane, then dichloromethane / methanol 200: 1, 100: 1). This gives 23 mg (19% of theory) of the product.
HPLC (Method 12): R _t = 4.55 min.
MS (DCI, NH _3): m / z = 315 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 400 MHz): δ = 0.98-1.43 (m, 5H), 1.53-1.74 (m, 5H), 3.78-3.94 (m, 3H, s at 3.82), 7.06 (i.e. , 1H), 7.33 (s, 1H), 7.50 (m, 1H), 7.54 (m, 1H), 12.28 (s, 1H).

Example 40 4- (4-Formylpiperazin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

11.3 mg (0.17 mmol) of imidazole with 33.6 mg (0.33 mmol) of triethylamine and 7.64 mg (0.17 mmol) of formic acid in 5 ml of dichloromethane are placed under an argon atmosphere and cooled to 0 ° C. Then a solution of 21.1 mg (0.17 mmol) of oxalyl chloride in dichloromethane is added dropwise and the mixture is subsequently stirred for 15 minutes. 50 mg (0.17 mmol) of 6-oxo-4- (piperazin-1-yl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile are added and the mixture is stirred at RT overnight. Then it is washed with 1 N potassium hydrogen sulfate solution, the dichloromethane phase dried over sodium sulfate, concentrated and the residue flash-chromatographed on silica gel (eluent: dichloromethane / methanol 100: 1, 80: 1, 60: 1). 16 mg (29% of theory) of the title compound are obtained.
HPLC (Method 12): R _t = 3.4 min.
MS (ESIpos): m / z = 330 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 200 MHz): δ = 3.42-3.54 (m, 4H), 3.79-3.94 (m, 6H, s at 3.82), 7.09 (d, 1H), 7.36 (s, 1H ), 7.51 (m, 1H), 8.06 (s, 1H), 12.55 (s, 1H).

Example 41 4- (4-Acetylpiperazin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

50 mg (0.17 mmol) of 6-oxo-4- (piperazin-1-yl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile are dissolved in DMF with 34 mg (0.33 mmol) of triethylamine and with 14.3 mg (0.18 mmol) of acetyl chloride overnight at RT. The mixture is then diluted with dichloromethane and washed with water. The organic phase is separated, dried over sodium sulfate and the residue flash-chromatographed on silica gel (eluent: dichloromethane / methanol 100: 1, 80: 1, 60: 1). 42 mg (74% of theory) of the title compound are obtained.
HPLC (Method 12): R _t = 3.5 min.
MS (ESIpos): m / z = 344 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 2.02 (s, 3H), 3.50-3.61 (m, 4H), 3.80-3.95 (m, 6H, s at 3.82), 7.08 (d, 1H ), 7.36 (s, 1H), 7.50 (m, 1H), 12.47 (s, 1H).

Example 42 4- (4-Ethylpiperazin-1-yl) -6-oxo-2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile

50 mg (0.17 mmol) of 6-oxo-4- (piperazin-1-yl) -2- (3-thienylmethyl) -1,6-dihydropyrimidine-5-carbonitrile are dissolved in DMF with 34 mg (0.33 mmol) of triethylamine, with 19.9 mg (0.18 mmol) of bromoethane and stirred overnight at RT. Then the reaction is diluted with dichloromethane and washed with water. The organic phase is separated, dried over sodium sulfate and the residue flash-chromatographed on silica gel (eluent: dichloromethane / methanol 100: 1, 80: 1, 60: 1, 40: 1). 38 mg (70% of theory) of the title compound are obtained.
HPLC (Method 12): R _t = 3.3 min.
MS (ESIpos): m / z = 330 [M + H] ^+
1 H-NMR (DMSO-d ₆ , 300 MHz): δ = 1.00 (t, 3H), 2.34 (q, 2H), 2.42 (t, 4H), 3.80 (s, 2H), 3.86 (t, 4H) , 7.06 (d, 1H), 7.34 (s, 1H), 7.49 (m, 1H), 12.39 (s, 1H).

The exemplary embodiments listed in the following table are prepared in analogy to the examples described above:

The in vitro action of the compounds of the formula according to the invention (I) and (II) can be shown with 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, 129; 239-247), PDESA (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.SA 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 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 expressed in Sf9 cells using the pFASTBAC baculovirus expression system (GibcoBRL). PDES 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 MgCl2)). 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; 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 PDE 9A 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 PDES, the protocol is additionally adapted as follows: In the case of PDE1, additionally 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 PDES [8- ³ H] guanosine 3 ', 5'-cyclic phosphate (1 μCi / μL; Amersham Pharmacia Biotech., Piscataway, NJ).

vasorelaxant 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 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 of 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 3-5kg 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 U. 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 of pharmacokinetic Characteristics 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 the 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 8 Cultivated for days. The cell culture medium is changed daily.

To 48 hours in culture, the hepatocytes over 5 days in duplicate 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 mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic Systems (such as patches), milk, pastes, foams, Implants or stents.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersants. or wetting agents (e.g., sodium dodecylsulfate, polyoxysorbitanoleate), 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 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 the In general, it has proved to be advantageous in parenteral Application per day amounts of about 0.001 to 10 mg / kg body weight to achieve effective results. For oral administration is the amount per day about 0.005 to 3 mg / kg 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:

• Tablettengewicht 212 mg, Durchmesser 8 mm, Wölbungsradius 12 mm.

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 according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400.

one Single dose of 100 mg of the compound of the invention correspond 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.

i.v.Lösung:

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 according to 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 AC is C ₁ -C ₈ -alkyl, C ₃ -C ₈ -cycloalkyl, tetrahydrofuryl or tetrahydropyranyl, 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, trifluoromethyl, trifluoromethoxy, amino, hydroxy, C ₁ -C ₆ -alkylamino, halogen, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ - C ₆ alkylsulfonyl and C ₁ -C ₆ alkylthio are substituted, wherein C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylaminocarbonyl, C ₁ C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylsulfonyl and C ₁ -C ₆ alkylthio optionally with one or more radicals selected from the group hydroxy, cyano, halogen, hydroxycarbonyl and a group of Formula -NR ³ R ⁴ , wherein R ³ and R ^{4 are} independently hydrogen or C ₁ -C ₆ alkyl, or R ³ and R ⁴ together with the nitrogen atom to which they are attached, 5- to 8-membered heterocyclyl l are substituted, B is phenyl or heteroaryl optionally with up to 3 radicals 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 ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio where C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkylsulfonyl and C ₁ -C ₆ -alkylthio optionally with a radical selected from the group consisting of hydroxy, cyano, halogen, hydroxycarbonyl and a group of the formula -NR ³ R ⁴ , where R ³ and R ⁴ are those indicated above Have meanings, are substituted, 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

in which D is phenyl, heteroaryl or a group of the formula

where phenyl and heteroaryl are optionally substituted by up to 2 radicals independently of one another selected from the group consisting of heteroaryl, halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy and benzyl, where C ₁ - C ₆ alkyl optionally with a group of the formula -NR ⁵ R ⁶ , in which R ^{5 is} C ₁ -C ₆ alkyl and R ^{6 is} hydrogen or C ₁ -C ₆ alkoxy (C ₁ -C ₆ ) alkyl, and Heteroaryl is optionally substituted by C ₁ -C ₆ -alkoxy, R ^{1 is} C ₃ -C ₈ -cycloalkyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy (C ₁ -C ₆ ) -alkyl, benzyl or a

where C ₃ -C ₈ -cycloalkyl is optionally substituted by hydroxy, C ₁ -C ₆ -alkyl or trifluoromethyl, C ₁ -C ₆ -alkyl optionally with heteroaryl, C ₃ -C ₈ -cycloalkyl or hydroxy, and benzyl optionally with C ₁ - C ₆ alkoxy or halogen, R ^{2 is} hydrogen, or R ¹ and R ² together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclyl, optionally selected with up to 2 substituents independently from the group C ₁ -C ₆ -alkyl, hydroxy, cyano, oxo, heteroaryl, benzyl, formyl, C ₁ -C ₆ -alkylcarbonyl and one of the following groups

which are bonded via the two oxygen atoms to one of the carbon atoms in the heterocycle, substitu wherein C ₁ -C ₆ alkyl is optionally substituted by hydroxy or heteroaryl, 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-II) according to claims 1 and 2 for the preparation of medicaments for the treatment of hypertension. Use of compounds of the general formula (I-II) according to claims 1 and 2 for the preparation of medicaments for the treatment of stable and unstable angina pectoris. Use of compounds of the general formula (I-II) according to claims 1 and 2 for the preparation of medicaments for the treatment of renal insufficiency. Use of compounds of the general formula (I-II) according to claims 1 and 2 for the preparation of medicaments for the treatment of acute renal failure. Use of compounds of the general formula (I-II) according to claims 1 and 2 for the preparation of medicaments for the treatment of ischemic Kidney disease. Use of compounds of the general formula (I-II) according to claims 1 and 2 for the preparation of medicaments for the treatment of ischemia. Use of compounds of the general formula (I-II) according to claims 1 and 2 for the preparation of medicaments for the treatment of heart failure. Use of compounds of the general formula (I-II) according to claims 1 and 2 for the preparation of medicaments for the treatment of venous diseases.