WO2017121693A1

WO2017121693A1 - Substituted thiazole and thiadiazole amides, and use thereof

Info

Publication number: WO2017121693A1
Application number: PCT/EP2017/050311
Authority: WO
Inventors: Markus Follmann; Johannes-Peter Stasch; Niels Lindner; Gorden Redlich; Nils Griebenow; Frank Wunder; Volkhart Min-Jian Li
Original assignee: Bayer Pharma Aktiengesellschaft
Priority date: 2016-01-15
Filing date: 2017-01-09
Publication date: 2017-07-20

Abstract

The invention relates to novel substituted thiazole and thiadiazole amides, to a method for producing same, and to the use of same alone or in combinations for treating and/or preventing diseases, as well as to their use for producing medication for treating and/or preventing diseases, particularly for treating and/or preventing cardiovascular diseases.

Description

Substituted thiazole and thiadiazolamides and their use

The present application relates to novel substituted thiazole and thiadiazolamides, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular Treatment and / or prophylaxis of cardiovascular diseases.

One of the most important cellular transmission systems in mammalian cells is cyclic guanosine monophosphate (cGMP). Together with nitric oxide (NO), which is released from the endothelium and transmits hormonal and mechanical signals, it forms the NO / cGMP system. The guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). The previously known members of this family can be divided into two groups according to both structural features and the nature of the ligands: the particulate guanylate cyclases stimulable by natriuretic peptides and the soluble guanylate cyclases stimulable by NO. The soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer that is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Also, carbon monoxide (CO) is able to bind to the central iron atom of the heme, with stimulation by CO being significantly less than by NO. Through the formation of cGMP and the resulting regulation of phosphodiesterases, ion channels and protein kinases, guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations. Under pathophysiological conditions, the NO / cGMP system may be suppressed, which may, for example, lead to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.

A NO-independent treatment option for such diseases, which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.

For therapeutic stimulation of soluble guanylate cyclase, only compounds such as organic nitrates have been used, whose action is based on NO. This is converts and activates the soluble guanylate cyclase by attack on the iron central atom of the heme. In addition to the side effects, tolerance development is one of the decisive disadvantages of this treatment.

In recent years, some substances have been described which directly release the soluble guanylate cyclase, i. without stimulating NO, such as 3- (5'-hydroxymethyl-2'-furyl) -l-benzylindazole [YC-1; Wu et al., Blood 84 (1994), 4226; Mülsch et al., Brit. J. Pharmacol. 120 (1997), 681], fatty acids [Goldberg et al., J. Biol. Chem. 252 (1977), 1279], diphenyliodonium hexafluorophosphate [Pettibone et al., Eur. J. Pharmacol. 116 (1985), 307], iso-liquiritigenin [Yu et al., Brit. J. Pharmacol. 114 (1995), 1587] and various substituted pyrazole derivatives (WO 98/16223). In addition, WO 00/06568 and WO 00/06569 disclose fused pyrazole derivatives and WO 03/095451 discloses carbamate-substituted 3-pyrimidinyl-pyrazolopyridines. 3-Pyrimidinyl-pyrazolopyridines with phenylamide substituents are described in E.M. Becker et al, BMC Pharmacology, 2001, 1 (13). WO 2004/009590 describes pyrazolopyridines with substituted 4-aminopyrimidines for the treatment of CNS diseases. WO 2010/065275 and WO 2011/149921 disclose substituted pyrrolo and dihydropyridopyrimidines as sGC activators. The sGC stimulators described in WO 2012/004259 are fused aminopyrimidines and in WO 2012/004258, WO 2012/143510 and WO 2012/152629 fused pyrimidines and triazines. WO 2012/28647 discloses pyrazolopyridines with various azaheterocycles for the treatment of cardiovascular diseases. WO 2008/052898 describes indazoles with thiazolamide substituents for the treatment of diabetes and related diseases. WO 2006/015263 discloses N-benzyl-indazoles having various amide substituents for the treatment of cancer and benign prostatic hyperplasia.

The object of the present invention was to provide novel substances which act as stimulators of soluble guanylate cyclase.

The present invention relates to compounds of the general formula (I)

in which

U stands for O or S,

V is CR ³ or N, where

R is hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₁ -C ₄ ) -alkoxycarbonyl, phenyl, pyridyl, -NR ⁵ R ⁶ , -S (O) _n R ⁷ , -S0 ₂ NR ⁸ R ⁹ or -OR ¹⁰ , wherein (Ci-C6) alkyl having 1 to 3 substituents independently selected from the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy, (Ci-C i) - Alkoxy, hydroxycarbonyl, (C 1 -C 4) -alkoxycarbonyl, (C 1 -C 4) -alkoxycarbonylamino, mono (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamino, phenyl, phenoxy, 4 to 7 be substituted heterocyclyl and 5- or 6-membered heteroaryl may be substituted, wherein phenyl may be substituted with 1 or 2 substituents independently selected from the group consisting of halogen, (Ci-C4) alkyl and (Ci-C4) alkoxy, wherein 4 - to 7-membered heterocyclyl in turn may be substituted with 1 or 2 substituents independently selected from the group fluorine, (Ci-C4) alkyl, hydroxy, oxo and (Ci-C4) alkoxy, and wherein phenoxy and 5- or 6-membered heteroaryl of hers ts having 1 or 2 substituents independently of one another can be substituted from the group halogen, (C 1 -C 4) -alkyl and (C 1 -C 4) -alkoxy, in which phenyl and pyridyl having 1 to 3 substituents independently of one another can be substituted from the group halogen, (Ci-C i) -alkyl and (Ci-C4) -alkoxy, and wherein n is a number 0, 1 or 2,

R ^{5 is} hydrogen or (Ci-C ₆ ) alkyl, wherein (Ci-C6) alkyl in turn with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy and (Ci-C4) alkoxy may be substituted

R ^{6 is} hydrogen, (Ci-C ₆ ) alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl or 4- to 7-membered heterocyclyl, wherein phenyl in turn having 1 or 2 substituents independently selected from the group halogen , (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy and (C 1 -C 4) -alkylcarbonylamino, or

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle in which 4- to 7-membered heterocycle may be substituted by (C 1 -C 4) -alkyl, in which C4) -alkyl may be substituted by hydroxy,

R ^{7 is} (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, R ^{8 is} hydrogen or (C ₁ -C ₆ ) -alkyl, R ^{9 is} hydrogen, (C ₁ -C ₆ ) -Alkyl or (C ₃ -C ₇ ) -cycloalkyl, R ^{10 is} (Ci-C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, is CR ⁴ or N, wherein R ^{4 is} hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or 3 to 7-membered heterocyclyl, wherein (C ₁ -C ₄ ) -alkyl having 1 to 3 substituents selected independently of one another the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy, (Ci-C4) alkoxy, hydroxycarbonyl, (Ci-C4) alkoxycarbonyl, amino, mono (Ci-C4) alkylamino and

Di- (C 1 -C 4) -alkylamino, in which mono- (C 1 -C 4) -alkylamino and di- (C 1 -C 4) -alkylamino in turn have 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl and phenyl in which 4- to 7-membered heterocyclyl may in turn be substituted by 1 or 2 substituents independently of one another selected from the group of fluoro, (C 1 -C 4) -alkyl, hydroxyl, oxo and (C 1 -C 4) -alkoxy, in which (C 1 -C 4) -alkyl in turn contains 1 or 2 substituents independently of one another selected from the group of fluorine, trifluoromethyl, hydroxy,

Trifluoromethoxy and (Ci-C4) alkoxy may be substituted, or

R ³ and R ⁴ together with V and W to which they are attached form a 4- to 7-membered heterocyclyl ring wherein the 4- to 7-membered heterocyclyl ring is substituted with (C 1 -C 4) -alkyl can

R ^{1 is} hydrogen or fluorine, R ^{2 is} (C ₁ -C ₆ ) -alkyl or benzyl, where (C ₁ -C ₆ ) -alkyl is substituted by a substituent trifluoromethyl, where (C 1 -C 6) -alkyl having 1 to 3 Substituents fluorine may be substituted, and wherein benzyl is substituted by 1 to 3 substituents fluorine, with the proviso that when V is N, W is CR, with the proviso that when W is N, V is CR ³ , and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the following compounds are not already salts, solvates and solvates of the salts.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, for example and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of Solvates where coordination with water occurs. As solvates, hydrates are preferred in the context of the present invention.

The compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or distribution of the drug in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. iso- Topical variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the instructions given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

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

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

In the context of the invention, alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms. By way of example and preferably mention may be made of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl.

Cycloalkyl in the context of the invention is a monocyclic, saturated carbocycle having 3 to 7 ring carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert. Butoxy.

Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group. Examples which may be mentioned by way of example include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert. Butoxycarbonyl.

Heterocyclyl in the context of the invention is a saturated heterocycle having a total of 4 to 7 ring atoms, which contains one or two ring heteroatoms from the series N, O and / or S and is linked via a ring carbon atom or optionally a ring nitrogen atom. Examples which may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl. Preferred are azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.

Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine.

An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred.

Preferred in the context of the present invention are compounds of the formula (I) in which

U stands for O or S,

V is CR ³ or N, where

R ³ is hydrogen, trifluoromethyl, (Ci-C ₆₎ -alkyl, (C ₃ -C ₆₎ cycloalkyl, _(Ci-C4) - alkoxycarbonyl, phenyl, pyridyl, -NR ⁵ R ^6, -S (0) _{n is} R ⁷ or -SO ₂ NR ⁸ R ⁹ , wherein (Ci-C6) alkyl having 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, trifluoromethoxy, (Ci-C i) alkoxy, methylamino, ethylamino , Dimethylamino, diethylamino, phenoxy, azetidinyl, pyrrolodinyl, piperidinyl, morpholinyl, piperazinyl and pyrazolyl may be substituted, wherein pyrazolyl in turn may be substituted with 1 or 2 substituents independently selected from the group of fluoro, methyl and ethyl, wherein phenyl and pyridyl substituted with 1 or 2 substituents independently selected from the group fluorine, chlorine, methyl, ethyl, methoxy and ethoxy and where n is a number 1 or 2,

R ^{5 is} hydrogen or (C 1 -C ₄ ) -alkyl, in which (C 1 -C ₄ ) -alkyl in turn may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, hydroxyl, trifluoromethoxy, methoxy and ethoxy,

R ^{6 is} (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dioxotetrahydrothiolanyl, piperidinyl, tetrahydropyranyl, in which phenyl is in turn independently selected with 1 or 2 substituents from the group of fluorine, chlorine, methyl, ethyl, methoxy, ethoxy and methylcarbonylamino, or R ⁵ and R ⁶ together with the nitrogen atom to which they are bonded form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl or dioxothiomorpholinyl ring, wherein the piperazinyl ring on the nitrogen may be substituted with ethyl wherein ethyl is substituted with hydroxy,

R ^{7 is} (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl, is hydrogen, methyl or ethyl, R ^{9 is} hydrogen, methyl or ethyl; W is CR ⁴ or N, wherein

R ^{4 is} hydrogen, (C 1 -C ⁴ ) -alkyl, cyclopropyl, cyclobutyl or cyclopentyl, in which (C 1 -C 4) -alkyl with trifluoromethyl, hydroxy, hydroxycarbonyl,

Methoxycarbonyl, ethoxycarbonyl, methylamino, ethylamino, dimethylamino or diethylamino may be substituted, wherein methylamino, ethylamino, dimethylamino and diethylamino may be substituted by phenyl, R ^{1 is} hydrogen,

R ^{2 is} 2-fluorobenzyl, provided that when V is N, W is CR ⁴ , with the proviso that when W is N, V is CR ³ , and their salts, solvates and solvates salts. Particularly preferred in the context of the present invention are compounds of the formula (I) in which

U is S, V is CR ³ or N, where R ^{3 is} hydrogen, trifluoromethyl, (C 1 -C 6) -alkyl, cyclopropyl, cyclohexyl, methoxycarbonyl, phenyl, pyridyl, -NR ⁵ R ⁶ , -S (0) _{n is} R ⁷ or -SO ₂ NR ⁸ R ⁹ , in which (C 1 -C 6) -alkyl may be substituted by trifluoromethyl, (C 1 -C 4) -alkoxy, methylamino, ethylamino, dimethylamino, diethylamino, phenoxy, pyrrolodinyl or pyrazolyl, wherein pyrazolyl in turn may be substituted with 1 or 2 substituents independently selected from the group consisting of methyl and ethyl, wherein phenyl and pyridyl may be substituted with 1 or 2 substituents independently selected from the group fluorine, chlorine, methyl, methoxy and ethoxy, and where n is a number 1 or 2,

R ^{5 is} hydrogen or (C 1 -C ₄ ) -alkyl, in which (C 1 -C ₄ ) -alkyl may in turn be substituted by hydroxyl,

R ^{6 is} (C 1 -C 4) -alkyl, cyclohexyl, phenyl or dioxotetrahydrothiolanyl, in which phenyl in turn may be substituted by methoxy, ethoxy or methylcarbonylamino, or

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperazinyl or morpholinyl ring in which the piperazinyl ring on the nitrogen is substituted by ethyl, in which ethyl is substituted by hydroxy,

R ^{7 is} (C 1 -C ₄ ) -alkyl or cyclohexyl,

R ^{8 is} hydrogen, methyl or ethyl,

R ^{9 is} hydrogen, methyl or ethyl, CR ⁴ or N, wherein

R ^{4 is} hydrogen, (C 1 -C ⁴ ) -alkyl or cyclopropyl, in which (C 1 -C 4) -alkyl or methylamino may be substituted, wherein methylamino may be substituted with phenyl,

R is hydrogen,

R 2 is 2-fluorobenzyl, provided that when V is N, W is CR, with the proviso that when W is N, V is CR ³ , and their salts, solvates and solvates of the salts ,

Particularly preferred in the context of the present invention are also compounds of the formula (I) in which

R ^{1 is} hydrogen, and their salts, solvates and solvates of the salts.

R ^{2 is} 2-fluorobenzyl, and their salts, solvates and solvates of the salts. Particularly preferred in the context of the present invention are also compounds of the formula (I) in which

U is S, and their salts, solvates and solvates of the salts.

V is N, and their salts, solvates and solvates of the salts.

Particularly preferred in the context of the present invention are also compounds of the formula (I) in which stands for CR ³ , where

R ^{3 is} hydrogen, trifluoromethyl, (C 1 -C 6) -alkyl, cyclopropyl, cyclohexyl, methoxycarbonyl, phenyl, pyridyl, -NR ⁵ R ⁶ , -S (O) _n R ⁷ or -SO ₂ NR ⁸ R ⁹ in which (C 1 -C 6) -alkyl with trifluoromethyl, (C 1 -C 4) -alkoxy, methylamino, ethylamino,

Dimethylamino, diethylamino, phenoxy, pyrrolodinyl or pyrazolyl, in which pyrazolyl may in turn be substituted with 1 or 2 substituents independently selected from the group consisting of methyl and ethyl, wherein phenyl and pyridyl having 1 or 2 substituents independently selected from the group fluorine , Chloro, methyl, methoxy and ethoxy, and wherein n is a number 1 or 2,

R ^{7 is} (C 1 -C ₄ ) -alkyl or cyclohexyl, R ^{8 is} hydrogen, methyl or ethyl, R ^{9 is} hydrogen, methyl or ethyl, and their salts, solvates and solvates of the salts.

W is N, and their salts, solvates and solvates of the salts.

Also particularly preferred in the context of the present invention are compounds of the formula (I) in which W is CR ⁴ , where

R ^{4 is} hydrogen, (C 1 -C ⁴ ) -alkyl or cyclopropyl, in which (C 1 -C 4) -alkyl or methylamino may be substituted, in which methylamino may be substituted by phenyl, and their salts, solvates and solvates of the salts.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Particularly preferred are combinations of two or more of the preferred ranges mentioned above.

The invention further provides a process for the preparation of the compounds of the formula (I) according to the invention which comprises reacting a compound of the formula (II)

in which R ¹ and R ² each have the meanings given above, in an inert solvent in the presence of a suitable base and a suitable coupling reagent with a compound of the formula (III)

in which R has the meanings given above, and, if appropriate, converting the resulting compounds of the formula (I) with the appropriate (i) solvents and / or (ii) acids or bases into their solvates, salts and / or solvates of the salts.

The reaction (II) + (III) -> (I) takes place in a solvent which is inert under the reaction conditions. Inert solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1, 2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrogen halides such as dichloromethane, trichloromethane, Tetrachloromethane, trichlorethylene, chlorobenzene or 1, 2-dichlorobenzene, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU ), N-methylpyrrolidone (NMP), sulfolane or pyridine. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane, DMF or DMSO. In process step (II) + (III) -> ■ (I) are suitable as coupling reagents, for example carbodiimides such as NN'-diethyl, NN'-dipropyl, NN'-diisopropyl, NN'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiirnide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3 -sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or isobutyl chloroformate, propanephosphonic anhydride, diethyl cyanophosphonate, bis (2-oxo-3 -oxazolidinyl) -phosphoryl chloride, benzotriazole-1-ynyloxy-tris (dimethylamino) phosphonium hexafluorophosphate, benzotriazole-1-ylxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), 0- (benzotriazol-1-yl) -N, N , N ', N'-tetramethyluronium tetrafluoroborate (TBTU), 2- (1H-benzotriazol-1-yl) -1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2- (2-oxo) l- (2H) -pyrido dyl) -l, l, 3,3-tetramethyluronium tetrafluoroborate (TPTU), 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) or 0 - (lH-6-chlorobenzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with other excipients such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu). Preference is given to N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) in combination with N, N-diisopropylethylamine or O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate ( TBTU) in combination with 4-methylmorpholine.

The reaction (II) + (III) -> (I) is generally carried out in a temperature range from 0 ° C to + 140 ° C, preferably carried out in a temperature range from + 20 ° C to + 60 ° C. The reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.

The described preparation process can be exemplified by the following synthesis scheme (Scheme 1): Scheme 1

[a): EDC, diisopropylethylamine, DMF / CH ₂ Cl ₂ (1: 1), RT]. The compounds of the formula (III) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.

The compounds of the formula (II) are known from the literature (cf., for example, WO 2007/124854), and can be prepared in analogy to processes known from the literature. Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular those listed under R ³ and R ⁴ , starting from the compounds of the formula (I) obtained by the above methods. These transformations are carried out as described in the present experimental part, according to customary methods known to the person skilled in the art, and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, eliminations, alkylation, amination, esterification, ester cleavage, Etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protecting groups.

The compounds of the invention act as stimulators of soluble guanylate cyclase and possess valuable pharmacological, and are therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.

The compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular cGMP increase. In addition, the compounds according to the invention enhance the action of substances which increase cGMP levels, such as, for example, EDRF (endothelium-derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

The compounds according to the invention can therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, acute and chronic heart failure, heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, arrhythmias of the atria and the chambers and Transient disorders such as atrio-ventricular blockades grade I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles, AV junctional Extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, Cardiomyopathies), cardiogenic shock, aneurysms, premature ventricular contraction (PVC), for the treatment and / or prophylaxis of thromboembolic disorders and ischaemias such as myocardial ischemia, myocardial infarction, stroke, shock, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular Diseases, spasms of the coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or heart failure-related edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations, as well as microvascular and macrovascular lesions (vasculitis), increased levels of fibrinogen and low-density LDL and elevated levels of plasminogen activator inhibitor 1 (PAI-1), and for the treatment and / or prophylaxis of erectile dysfunction and female sexual dysfunction. For the purposes of the present invention, the term cardiac insufficiency also encompasses more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart failure, cardiac valvulopathy, mitral valve stenosis, mitral valve insufficiency, Aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid regurgitation, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure. In addition, the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and combined hyperlipidemias and the metabolic syndrome. In addition, the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrenous, CREST syndrome, Erythematosis, onychomycosis, rheumatic diseases and to promote wound healing.

Furthermore, the compounds according to the invention are suitable for the treatment of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure. For the purposes of the present invention, the term renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological renal diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome which are diagnostic for example, abnormally decreased creatinine and / or water excretion, abnormally elevated blood levels of urine toff, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, e.g. Glutamyl synthetase, altered urinary or urinary output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.

Furthermore, the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and others Forms of pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg cigarette smoke-induced pulmonary emphysema) and cystic fibrosis (CF). The compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system. In particular, they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorder, difficulty concentrating in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies , Dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous conditional sexual dysfunctions and sleep disorders as well as for the regulation of pathological disorders of food, consumption and addiction.

Furthermore, the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds of the invention can be used to combat pain and tinnitus.

In addition, the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases as well as inflammatory eye diseases. Furthermore, the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, as well as dermatological fibroses and fibrotic disorders of the eye. For the purposes of the present invention, the term fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical procedures), nevi, diabetic retinopathy and proliferative vitroretinopathy.

Furthermore, the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.

The compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.

In addition, the compounds according to the invention are suitable for the treatment and / or prophylaxis of diabetes, hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disease, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis. The present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.

Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases. Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis.

Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases. Examples of suitable combination active ingredients are: organic nitrates and NO donors, such as, for example, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP), such as inhibitors of phosphodiesterases (PDE) 1, 2 and / or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil; antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances; antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin all-antagonists, ACE inhibitors, endothelin antagonists, renin Inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics; and / or lipid metabolism-altering agents, by way of example and with preference from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, by way of example and preferably, HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin. Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - understood antagonists and diuretics. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol Absoφtionhemmer, polymeric Bensäureadsorber, bile acid Reabsoφtionshemmer, lipase inhibitors and the lipoprotein (a) understood antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214). In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are used in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.

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

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

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

For the oral administration are according to the prior art functioning, the compounds according to the invention quickly and / or modified donating application forms, the Compounds according to the invention in crystalline and / or amorphised and / or dissolved form, such as tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention) in the oral cavity quickly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragées, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to 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 other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral administration. 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 adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitol oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers ( For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight. Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples. The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

A. Examples

Abbreviations and acronyms: aq. Aqueous solution

Calculated

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide

d. Th. Of theory (at yield)

eq. Equivalent (s)

ESI electrospray ionization (in MS)

Et ethyl

gef. Found

h hour (s)

HPLC high pressure, high performance liquid chromatography

HRMS high-resolution mass spectrometry

conc. concentrated

LC / MS liquid chromatography-coupled mass spectrometry

LiHMDS lithium hexamethyldisilazide

Me methyl

min minute (s)

MS mass spectrometry

NMR nuclear magnetic resonance spectrometry

Pd2dba3 tris (dibenzylideneacetone) dipalladium

Ph phenyl

RT room temperature

R _t retention time (by HPLC)

THF tetrahydrofuran

UV ultraviolet spectrometry

v / v volume to volume ratio (of a solution)

XPHOS dicyclohexyl- (2 ', 4', 6'-triisopropylbiphenyl-2-yl) -phosphine LC / MS methods:

Method 1 (LC-MS):

Instrament: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1,8μ 50 x 1mm; Eluent A: 1 l of water + 0.25 ml of 99% formic acid, eluent B: 1 l of acetonitrile + 0.25 ml of 99% formic acid; Gradient: 0.0 min 90% A -> 1.2 min 5% A -> 2.0 min 5% A; Oven: 50 ° C; Flow: 0.40 ml / min; UV detection: 210 - 400 nm.

Method 2 (LC-MS):

Instrument MS: Waters, Instrument HPLC: Waters (column Phenomenex Luna 5μ C18 (2) 100A, AXIA Tech 50 x 21.2 mm, eluent A: water + 0.05% formic acid, eluent B: acetonitrile (ULC) + 0.05% formic acid, gradient : 0.0 min 95% A - 0.15 min 95% A - 8.0 min 5% A - 9.0 min 5% A, flow: 40 ml / min, UV detection: DAD, 210 - 400 nm).

Method 3 (LC-MS):

Method 4 (LC-MS): LC-MS Analytical Method SCDK SQD SB AQ:

Instrument MS: Waters SQD; Instrument HPLC: Waters UPLC; Column: Zorbax SB-Aq (Agilent), 50 mm x 2.1 mm, 1.8 μιη; Eluent A: water + 0.025%> formic acid, eluent B: acetonitrile (ULC) + 0.025% formic acid; Gradient: 0.0 min 98% A - 0.9 min 25% A - 1.0 min 5% A - 1.4 min 5% A - 1.41 min 98% A - 1.5 min 98% A; Oven: 40 ° C; Flow: 0.600 ml / min; UV detection: DAD; 210 nm.

Starting compounds and intermediates:

Example 1A

1 - (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carboxylic acid

The synthesis of this compound is described in WO 2007/124854 Example 29A step a).

Exemplary embodiments: Example 1

N- (5-Cyclopropyl-1,3,3,4-thiadiazol-2-yl) -1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carboxamide

500 mg (1.843 mmol) of Example 1A were initially charged in 5 ml of dichloromethane and 5 ml of dimethylformamide and then with 312 mg (2.212 mmol) of 2-amino-5-cyclopropyl-l, 3,4-thiadiazole, 530 mg (2.765 mmol) - (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.963 ml (5.530 mmol) of Ν, Ν-diisopropylethylamine. Thereafter, it was stirred for 1.5 hours at room temperature. It was then diluted with water and dichloromethane and the phases separated. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were concentrated. Further purification was carried out by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 146 mg of the target compound were obtained (19% of theory).

LC-MS (Method 1): R _t = 1.08 min; MS (ESIpos): m / z = 395 (M + H) ⁺ .

'H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.00-1.04 (m, 2H), 1.13-1.21 (m, 2H), 2.40-2.47 (m, 1H), 5.88 (s, 2H ), 7.16 (t, 1H), 7.24 (t, 1H), 7.34-7.40 (m, 2H), 7.49 (dd, 1H), 8.59 (dd, 1H), 8.72 (dd, 1H), 12.91 (s br , 1H).

Example 2

N- [5- (2-Ethoxyethyl) -1,3,4-thiadiazol-2-yl] -1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carboxamide

H ₃ C

17 mg (0.1 mmol) of 5- (2-ethoxyethyl) -1,3,4-thiadiazol-2-amine were placed in a well of a 96-well multititer plate and treated with 0.2 ml of DMSO. To this solution was added 27.1 mg (0.1 mmol) of 1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3-carboxylic acid and O- (benzotriazol-1-yl) -N, N, N '. , N'-tetramethyluronium tetrafluoroborate (TBTU), each dissolved in 0.2 ml of DMSO, and 20 mg (0.2 mmol) of 4-methylmorpholine. The multi-well plate was covered and shaken at room temperature for 18 h. It was then filtered off and the filtrate purified directly via preparative LC-MS method 2 or 3. The product-containing fractions were concentrated by means of a centrifugal dryer in vacuo. The residue of the individual fractions was dissolved in 0.6 ml of DMSO and combined. Subsequently, the solvent was completely evaporated in a centrifugal dryer. There were obtained 4.2 mg (10% of theory) of the title compound.

LC-MS (Method 4): R _t = 1.19 min; MS (ESIpos): m / z = 427 (M + H) ⁺ ,

In analogy to Example 2, the examples listed in Table 1 were prepared by reaction of.

Table 1

In these reactions, DMF was used in the reaction instead of DMSO as the solvent and HATU (N-

[(Dimethylamino) (3H- [1,2,3-jtriazolo [4,5-b] pyridine-3-yloxy) methylidene] -N-methylmethanaminium hexafluorophosphate) was used instead of TBTU as coupling reagent.

Example 14

N- [5- (Dimethylsulfamoyl) -4-methyl-1,3-thiazol-2-yl] -1- (2-fluorobenzyl) -1 H -pyrazolo [3,4-b] pyridine-3-carboxamide

22 mg (0.1 mmol) of 2-amino-N, N, 4-trimethyl-l, 3-thiazole-5-sulfonamide were placed in a well of a 96-well multititer plate. 27.1 mg (0.1 mmol) of N - [(dimethylamino) (3H- [1,2,3-jtriazolo [4,5-b] pyridine-3-oxy) methylidene] -N-methylmethanaminium hexafluorophosphate HATU) and (2-fluorobenzyl) -LH-pyrazolo [3,4-b] pyridine-3-carboxylic acid, each dissolved in 0.3 ml of DMF, and 32 mg (0.4 mmol) of pyridine was added. The multi-well plate was covered and shaken at room temperature for 18 h. It was then filtered off and the filtrate was purified directly via preparative LC-MS according to Method 2 or 3. The product-containing fractions were concentrated by means of a centrifugal dryer in vacuo. The residue of the individual fractions was dissolved in 0.6 ml of DMSO and combined. Subsequently, the solvent was completely evaporated in a centrifugal dryer. 5.80 mg (12% of theory) of the title compound were obtained.

LC / MS (Method 4): R _t = 1.24 min

MS (ESIpos): m / z = 475

In analogy to Example 14, the compounds listed in Table 2 were prepared.

Table 2:

N- (5-ethyl-l, 3,4-oxadiazol-2-yl) -l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridine-3-carboxamide

150 mg (0.553 mmol) of the compound from Example 1A were initially charged in 5 ml of dimethylformamide and then with 284 mg (0.664 mmol) of N - [({[(LZ) -l-cyano-2-ethoxy-2-oxoethylidene] amino} oxy) (molybin-4-yl) methylene] -N-methylmethanaminium hexafluorophosphate (COMU) and 187 mg (1.327 mmol) of 2,2,6,6-tetramethylpiperidine. Thereafter, it was stirred for 5 min. At room temperature and 75 mg (0.664 mmol) of 5-ethyl-l, 3,4-oxadiazol-2-yl-amine (described in WO 00/63166, Example 48b) added. The mixture was stirred for 3 d at room temperature, treated with 10 ml of 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: water / acetonitrile / water + 1% trifluoroacetic acid, gradient 55: 40: 5 ^{→ 0.95} : 5). 20 mg (10% of theory) of the title compound were obtained.

LC-MS (Method 1): R _t = 0.93 min; MS (ESIpos): m / z = 367 (M + H)

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be demonstrated in the following assays:

B-l. Vascular Relaxation In Vitro Rabbits are stunned and bled by a stroke of the neck. The aorta is harvested, detached from adherent tissue, divided into 1.5 mm wide rings and placed individually under bias in 5 ml organ baths with 37 ° C warm, carbogen-fumed Krebs-Henseleit solution of the following composition (in each case mM): Sodium chloride: 119; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1.2; Sodium hydrogencarbonate: 25; Glucose: 10. The force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on a chart recorder. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration. After several control cycles, the substance to be examined is added in each subsequent course 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% (IC50 value). The standard application volume is 5 μΐ, the DMSO content in the bath solution corresponds to 0.1%.

Representative IC50 values for the compounds according to the invention are given in the table below (Table 1):

Table 1 :

Example No. IC50 [nM]

1 767

2 363

4 1000

7 602

9,805 Example No. IC ₅₀ [nM]

10,345

11 454

13 1990

B-2. Effect on recombinant guanylate cyclase reporter cell line

The cellular activity of the compounds of the invention is measured on a recombinant guanylate cyclase reporter cell line as described in F. Wunder et al., Anal. Biochem.339, 104-112 (2005).

Representative values (EC 50 values) for the compounds according to the invention are given in the table below (Table 2):

Table 2

Example No. MECso [μΜ] Example No. MECso [μΜ]

1 0.3 16 3.0

2 0.3 17 3.0

3 1.0 18 1.0

4 1.0 19 1.0

5 1.0 20 1.0

6 1.0 21 1.0

7 0.3 22 1.0

8 0.3 23 1.0

9 1.0 24 1.0

10 0.3 25 1.0

11 0.3 26 1.0

12 0.3 27 1.0

13 1.0 28 1.0

14 3.0 29 1.0

15 3.0 30 1.0 Example No. MECso [μΜ] Example No. MECso [μΜ]

31 1 .0 43 1 .0

32 1 .0 44 1 .0

33 1 .0 45 1 .0

34 1 .0 46 1 .0

35 1 .0 47 1 .0

36 1 .0 48 1 .0

37 1 .0 49 1 .0

38 1 .0 50 1 .0

39 1 .0 51 1 .0

40 1 .0 52 1 .0

41 1 .0 53 3.0

42 1 .0

B-3. Radiotelemetric blood pressure measurement on awake, spontaneously hypertensive rats

A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.

The system consists of 3 main components:

Implantable transmitters (Physiotel® telemetry transmitters)

Receivers (Physiotel® receivers) connected to a data acquisition computer through a multiplexer (DSI Data Exchange Matrix).

The telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat.

Animal material Investigations are carried out on adult female spontaneously hypertensive rats (SHR Okamoto) weighing> 200 g. SHR / NCrl from Okamoto Kyoto School of Medicine, 1963 were crossed male Wistar Kyoto rats with high blood pressure and female with slightly elevated blood pressure and delivered in the Fl 3 to the US National Institutes of Health.

The experimental animals are kept individually in macroion cages type 3 after transmitter implantation. You have free access to standard food and water.

The day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.

transmitter implantation

The TAH PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial. The animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.

For implantation, the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side. After opening the abdominal cavity along the alba line, the system's fluid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD ™, 3M). The transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.

Postoperatively, an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)

Substances and solutions

Unless otherwise described, the substances to be tested are each administered orally to a group of animals (n = 6) by gavage. According to an application volume of 5 ml / kg body weight, the test substances are dissolved in suitable solvent mixtures or suspended in 0.5% Tylose.

A solvent-treated group of animals is used as a control.

experimental procedure

The existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day). The instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).

The implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run. The emitted signals can be recorded online by a data acquisition system (Dataquest ™ A.R.T. for Windows, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.

The standard procedure measures duration of 10 seconds each: Systolic blood pressure (SBP) Diastolic blood pressure (DBP) Arterial mean pressure (MAP) Heart rate (HR) Activity (ACT).

The measured value acquisition is repeated computer-controlled in 5-minute intervals. The absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).

Unless otherwise stated, the administration of the test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.

evaluation

After the end of the test, the collected individual data are sorted with the analysis software (DATAQUEST TM A.RT. TM ANALYSIS). The blank value is assumed here 2 hours before application, so that the selected data record covers the period from 7:00 am on the day of the experiment to 9:00 am on the following day.

The data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk. The so presorted and compressed measured values are transferred to Excel templates and displayed in tabular form. The filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper. literature

Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and Björn Lemmer: Experimental heart failure in rats: effects on cardiac vascular circadian rhythms and on myocardial beta-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000; Kozo Okamoto: Spontaneous hypertension in rats. Int Rev. Exp Pathol 7: 227-270, 1969; Maarten van den Buuse: Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured with Radio Telemetry. Physiology & Behavior 55 (4): 783-787, 1994

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet: composition:

100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm. production:

The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

production:

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

Composition:

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

production:

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

The compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and / or 30% PEG 400 solution). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

Claims

claims

1. Compound of formula (I)

in which

U stands for O or S,

V represents CR ³ or N, wherein for hydrogen, trifluoromethyl, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₁ -C ₄ ) -alkoxycarbonyl, phenyl, pyridyl, -NR ⁵ R ⁶ , -S (O) _n R ⁷ , -SO ₂ NR ⁸ R ⁹ or - OR ¹⁰ , wherein (Ci-C6) alkyl having 1 to 3 substituents independently selected from the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy , (C 1 -C 4) -alkoxy, hydroxycarbonyl, (C 1 -C 4) -alkoxycarbonyl, (C 1 -C 4) -alkoxycarbonylamino, mono (C 1 -C 4) -alkylamino, di- (C 1 -C 4) -alkylamino, phenyl, Phenoxy, 4- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl may be substituted, wherein phenyl having 1 or 2 substituents independently selected from the group halogen, (Ci-C4) alkyl and (C1-C4) - Alkoxy can be substituted, wherein 4- to 7-membered heterocyclyl in turn with 1 or 2 substituents independently selected from the group fluorine, (Ci-C ₄ ) alkyl, hydroxy, oxo and (Ci-C ₄ ) alkoxy substituted can and wherein phenoxy and 5- or 6-membered heteroaryl may in turn be substituted with 1 or 2 substituents independently selected from the group consisting of halogen, (Ci-C i) -alkyl and (Ci-C4) -alkoxy, wherein phenyl and pyridyl with 1 to 3 substituents independently of one another can be substituted from the group halogen, (C 1 -C 4) -alkyl and (C 1 -C 4) -alkoxy, and in which n is a number 0, 1 or 2,

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle in which 4- to 7-membered heterocycle may be substituted by (C 1 -C 4) -alkyl, in which C4) -alkyl may be substituted by hydroxy, R ^{7 is} (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, R ^{8 is} hydrogen or (C ₁ -C ₆ ) -alkyl, R ^{9 is} hydrogen, (C ₁ -C ₆ ) -Alkyl or (C ₃ -C ₇ ) -cycloalkyl, R ^{10 is} (Ci-C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or phenyl, is CR ⁴ or N, wherein

R ^{4 is} hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or 3 to 7-membered heterocyclyl, wherein (C ₁ -C ₄ ) -alkyl having 1 to 3 substituents selected independently of one another the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy, (Ci-C i) alkoxy, hydroxycarbonyl, (C 1 -C 4) - alkoxycarbonyl, amino, mono- (C 1 -C 4) -alkylamino and di- (C 1 -C 4) -alkylamino in which mono- (C 1 -C 4) -alkylamino and di- (C 1 -C 4) -alkylamino may themselves be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl and phenyl, and in which 4 to 7-membered heterocyclyl may in turn be substituted by 1 or 2 substituents independently of one another selected from the group fluorine, (C 1 -C 4) -alkyl, hydroxy, oxo and (C 1 -C 4) -alkoxy, in which (C 1 -C 4) -alkyl in turn with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, hydroxy, trifluoromethoxy and (Ci-C4) alkoxy substituted can be, or

R ³ and R ⁴ together with V and W to which they are attached form a 4- to 7-membered heterocyclyl ring, wherein the 4- to 7-membered heterocyclyl ring may be substituted by (Ci-C i) -alkyl,

R ^{1 is} hydrogen or fluorine, R ^{2 is} (C ₁ -C ₆ ) -alkyl or benzyl, where (C ₁ -C ₆ ) -alkyl is substituted by a substituent trifluoromethyl, where (C 1 -C 6) -alkyl having 1 to 3 Substituents fluorine may be substituted, and wherein benzyl is substituted with 1 to 3 substituents fluorine, provided that when V is N, W is CR ⁴ , with the proviso that when W is N, V is CR ³ and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.

2. A compound of formula (I) according to claim 1, in which

U stands for O or S,

V is CR ³ or Ν, where

R ³ is hydrogen, trifluoromethyl, (Ci-C ₆₎ -alkyl, (C ₃ -C ₆₎ cycloalkyl, (Ci C ₄₎ -alkoxycarbonyl, phenyl, pyridyl, -NR ⁵ R ^6, -S (0) _{n is} R ⁷ or -SO ₂ NR ⁸ R ⁹ , in which (C 1 -C 6) -alkyl having 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluoromethoxy,

C i) alkoxy, methylamino, ethylamino, dimethylamino, diethylamino, phenoxy, azetidinyl, pyrrolodinyl, piperidinyl, morpholinyl, piperazinyl and pyrazolyl may be substituted, wherein pyrazolyl in turn having 1 or 2 substituents independently selected from the group fluorine, methyl and ethyl may be substituted wherein phenyl and pyridyl may be substituted with 1 or 2 substituents independently selected from the group of fluorine, chlorine, methyl, ethyl, methoxy and ethoxy, and wherein n is a number 1 or 2,

R ^{6 is} (C ₁ -C ₄ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, phenyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dioxotetrahydrothiolanyl, piperidinyl, tetrahydropyranyl, in which phenyl is in turn independently selected from the group consisting of 1 or 2 substituents Group fluorine, chlorine, methyl, ethyl, methoxy, ethoxy and methylcarbonylamino may be substituted, or

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or dioxothiomoφholinyl ring in which the piperazinyl ring on the nitrogen may be substituted with ethyl, wherein ethyl is substituted with hydroxy,

R ^{7 is} (C ₁ -C ₄ ) -alkyl or (C ₃ -C ₆ ) -cycloalkyl,

R ^{8 is} hydrogen, methyl or ethyl,

R ^{9 is} hydrogen, methyl or ethyl, W is CR ⁴ or N, where

R ^{4 is} hydrogen, (C 1 -C ⁴ ) -alkyl, cyclopropyl, cyclobutyl or cyclopentyl, in which (C 1 -C 4) -alkyl may be substituted by trifluoromethyl, hydroxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, methylamino, ethylamino, dimethylamino or diethylamino, wherein methylamino, ethylamino, dimethylamino and diethylamino may be substituted by phenyl,

R ^{1 is} hydrogen,

R ^{2 is} 2-fluorobenzyl, provided that when V is N, W is CR ⁴ , with the proviso that when W is N, V is CR ³ , and their salts, solvates and solvates salts. A compound of the formula (I) according to claim 1 or 2, in which U is S, V is CR ³ or N, where

R ^{3 is} hydrogen, trifluoromethyl, (C 1 -C 6) alkyl, cyclopropyl, cyclohexyl, methoxycarbonyl, phenyl, pyridyl, -NR ⁵ R ⁶ , -S (O) _n R ⁷ or -SO ₂ NR ⁸ R ⁹ , in which (C 1 -C 6) -alkyl may be substituted by trifluoromethyl, (C 1 -C 4) -alkoxy, methylamino, ethylamino, dimethylamino, diethylamino, phenoxy, pyrrolodinyl or pyrazolyl, wherein pyrazolyl in turn may be substituted with 1 or 2 substituents independently selected from the group of methyl and ethyl, wherein phenyl and pyridyl having 1 or 2 substituents independently selected from the group fluorine, chlorine, methyl, methoxy and

Ethoxy can be substituted, and wherein n is a number 1 or 2,

R ^{6 is} (C 1 -C ₄ ) -alkyl, cyclohexyl, phenyl or dioxotetrahydrothiolanyl, in which phenyl in turn may be substituted by methoxy, ethoxy or methylcarbonylamino, or

R ^{7 is} (C 1 -C ₄ ) -alkyl or cyclohexyl,

R ^{8 is} hydrogen, methyl or ethyl,

R ^{9 is} hydrogen, methyl or ethyl; W is CR ⁴ or N, wherein R ^{4 is} hydrogen, (C 1 -C ⁴ ) -alkyl or cyclopropyl, in which (C 1 -C 4) -alkyl or methylamino may be substituted, in which methylamino may be substituted by phenyl, R ^{1 is} hydrogen,

R 2 is 2-fluorobenzyl, provided that when V is N, W is CR, with the proviso that when W is N, V is CR, and their salts, solvates and solvates of the salts.

4. A process for the preparation of compounds of the formula (I) as defined in claims 1 to 3, which comprises reacting a compound of the formula (II)

in which R ¹ and R ² each have the meanings given in claims 1 to 3, in an inert solvent in the presence of a suitable base and a suitable coupling reagent with a compound of the formula (III)

H

in which R has the meanings given in claims 1 to 4, and, if appropriate, the resulting compounds of the formula (I) with the corresponding (i) solvents and / or (ii) acids or bases are converted into their solvates, salts and / or solvates of the salts.

5. A compound of formula (I) as defined in any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases.

6. Use of a compound of the formula (I) as defined in any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic

Diseases and arteriosclerosis.

7. A pharmaceutical composition comprising a compound of the formula (I) as defined in any one of claims 1 to 3, in combination with an inert, non-toxic, pharmaceutically suitable excipient. 8. A medicament containing a compound of formula (I) as defined in any one of claims 1 to 3, in combination with another active ingredient selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents , antihypertensives and lipid metabolising agents. 9. Medicament according to claim 7 or 8 for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic diseases, fibrotic diseases and arteriosclerosis.

10. A method for the treatment and / or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and arteriosclerosis in humans and animals using an effective amount of at least one compound of formula (I) as defined in claims 1 to 3, or a pharmaceutical composition as defined in any one of claims 7 to 9.