DE102010031665A1 - Substituted oxazolidinones and oxazinones and their use - Google Patents

Abstract

The present application relates to new, substituted oxazolidinones and oxazinanones, 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 for the treatment and / or prophylaxis of cardiovascular diseases.

Description

The present application relates to novel, substituted oxazolidinones and oxazinanones, 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 for the treatment and / or prophylaxis of cardiovascular disease.

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 formed by bioconversion and activates the soluble guanylate cyclase by attack on the central iron 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 stimulate soluble guanylate cyclase directly, ie without prior release of NO, such as 3- (5'-hydroxymethyl-2'-furyl) -1-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 ], Isoliquiritigenin [ Yu et al., Brit. J. Pharmacol. 114 (1995), 1587 ] as well as various substituted pyrazole derivatives ( WO 98/16223 ).

As stimulators of soluble guanylate cyclase be in WO 00/06569 fused pyrazole derivatives and in WO 03/095451 Carbamate-substituted 3-pyrimidinyl-pyrazolopyridines disclosed. WO 02/042299 describes lactam-substituted pyrazolopyridines for the treatment of cardiovascular diseases.

The object of the present invention was to provide novel substances which act as potent stimulators of soluble guanylate cyclase, have improved solubility in aqueous media and have the same or improved therapeutic profile over the compounds known from the prior art.

in welcher
L für (C₁-C₃)-Alkandiyl steht,
wobei (C₁-C₃)-Alkandiyl mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe Trifluormethyl und (C₁-C₄)-Alkyl substituiert sein kann,
R¹ für Wasserstoff oder Fluor steht,
R² für Wasserstoff, Fluor, (C₁-C₄)-Alkyl, Difluormethyl oder Trifluormethyl steht,
R³ für Wasserstoff oder (C₁-C₄)-Alkyl steht,
sowie ihre N-Oxide, Salze, Solvate, Salze der N-Oxide und Solvate der N-Oxide und Salze.The present invention relates to compounds of the general formula (I)

in which
L is (C ₁ -C ₃ ) -alkanediyl,
where (C ₁ -C ₃ ) -alkanediyl having 1 to 3 substituents independently of one another can be substituted from the group trifluoromethyl and (C ₁ -C ₄ ) -alkyl,
R ^{1 is} hydrogen or fluorine,
R ^{2 is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl, difluoromethyl or trifluoromethyl,
R ^{3 is} hydrogen or (C ₁ -C ₄ ) -alkyl,
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 compounds mentioned below 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, eg. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

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 with 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

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

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

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

The present invention also includes all suitable isotopic variants of the compounds of the invention. An isotopic variant of a compound according to the invention is 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, ¹⁸ O, ¹⁸ O, 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 drug distribution 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. Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

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. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl.

Alkanediyl in the context of the invention is a linear divalent alkyl radical having 1 to 3 carbon atoms. Examples include: methylene, ethane-1,2-diyl and propane-1,3-diyl.

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

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.

In the context of the present invention, preference is given to compounds of the formula (I) in which
L is methylene or ethane-1,2-diyl,
R ^{1 is} hydrogen or fluorine,
R ^{2 is} hydrogen, fluorine, methyl, ethyl, difluoromethyl or trifluoromethyl,
R ^{3 is} hydrogen, methyl or ethyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, particular preference is given to compounds of the formula (I) in which
L is methylene,
R ^{1 is} hydrogen,
R ^{2 is} hydrogen, methyl or trifluoromethyl,
R ^{3 is} hydrogen or methyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which L is methylene, and also to their salts, solvates and solvates of the salts.

Also preferred in the context of the present invention are compounds of the formula (I) in which L is methylene or ethane-1,2-diyl, and also their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{1 is} hydrogen, and also to their salts, solvates and solvates of the salts.

In the context of the present invention, preference is also given to compounds of the formula (I) in which R ^{1 is} fluorine, and also to their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
R ^{2 is} hydrogen or methyl,
R ^{3 is} hydrogen or methyl,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
R ^{2 is} hydrogen,
R ^{3 is} hydrogen,
and their salts, solvates and solvates of the salts.

In the context of the present invention, compounds of the formula (I) in which
R ^{2 is} methyl,
R ^{3 is} methyl,
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.

in welcher R¹ die oben angegebene Bedeutung hat,
in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base mit der Verbindung der Formel (III)

in welcher L, R² und R³ jeweils die oben angegebenen Bedeutungen haben und
X¹ für eine geeignete Abgangsgruppe, wie beispielsweise Meyslat, Tosylat oder Halogen, insbesondere Chlor oder Brom, steht
zu einer Verbindung der Formel (IV)

in welcher L, R¹, R², R³ und X¹ jeweils die oben angegebenen Bedeutungen haben,
umsetzt, und diese anschliessend in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base zu einer Verbindung der Formel (I)

in welcher L, R¹, R² und R³ jeweils die oben angegebenen Bedeutungen haben,
cyclisiert,
und gegebenenfalls die resultierenden Verbindungen der Formel (I) mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Säuren oder Basen in ihre Solvate, Salze und/oder Solvate der Salze überführt.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 has} the meaning given above,
in an inert solvent in the presence of a suitable base with the compound of formula (III)

in which L, R ² and R ³ each have the meanings given above, and
X ^{1 is} a suitable leaving group such as meyslate, tosylate or halogen, in particular chlorine or bromine
to a compound of the formula (IV)

in which L, R ¹ , R ² , R ³ and X ¹ each have the meanings given above,
reacted, and this then in an inert solvent in the presence of a suitable base to give a compound of formula (I)

in which L, R ¹ , R ² and R ³ each have the meanings given above,
cyclized
and optionally the resulting compounds of formula (I) with the corresponding (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.

Inert solvents for process step (II) + (III) → (IV) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether , Halogenated hydrocarbons such as dichloromethane, Trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane Suitable bases for process step (II) + (III) → (IV) are alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal bicarbonates such as Sodium or potassium bicarbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene ( DBU) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to pyridine.

The reaction (II) + (III) → (IV) is generally carried out in a temperature range of -10 ° C to + 30 ° C, preferably at 0 ° C to + 20 ° C. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for process step (IV) → (I) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane , Trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferred is THF.

Suitable bases for process step (IV) → (I) are alkali metal hydrides such as potassium hydride or sodium hydride, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium, sodium or potassium or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyllithium or phenyllithium, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8- Diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). Preferred is sodium bis (trimethylsilyl) amide.

The reaction (IV) → (I) is generally carried out in a temperature range of -10 ° C to + 30 ° C; preferably carried out at 0 ° C to + 20 ° C. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

• [a): Pyridin, CH₂Cl₂; c): NaHMDS, THF].

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

• [a): pyridine, CH ₂ Cl ₂ ; c): NaHMDS, THF].

• [a): CH₂Cl₂, Pyridin].

Schema 3

• [a): Magnesiumbromid, Diethylether; b): Pyridin, THF].

The compounds of the formula (III) are commercially available, known from the literature, can be prepared in analogy to processes known from the literature or as shown by way of example in the following synthesis schemes (Schemes 2 and 3):

• [a): CH ₂ Cl ₂ , pyridine].

Scheme 3

• [a): magnesium bromide, diethyl ether; b): pyridine, THF].

in welcher R¹ die oben angegebene Bedeutung hat und
T¹ für Formyl oder Cyano steht,
in einem inerten Lösungsmittel mit Hydrazinhydrat zu einer Verbindung der Formel (VI)

in welcher R¹ die oben angegebene Bedeutung hat und
T² für Wasserstoff oder Amino steht,
zyklisiert, diese anschliessend in einem inerten Lösungsmittel mit einer geeigneten Iod-Quelle in eine Verbindung der Formel (VII)

in welcher R¹ die oben angegebene Bedeutung hat,
überführt, diese im Folgenden in einem inerten Lösungsmittel in Gegenwart einer geeigneten Base mit der Verbindung der Formel (VIII)

zu einer Verbindung der Formel (IX)

in welcher R¹ die oben angegebene Bedeutung hat,
umsetzt, diese dann in einem inerten Lösungsmittel in Gegenwart von Hexabutylzinn und einem geeigneten Palladiumkatalysator unter intermediärer Bildung einer Zinnspecies mit der Verbindung der Formel (X)

zur Verbindung der Formel (XI)

umsetzt, diese dann in einem inerten Lösungsmittel mit einem geeigneten Reduktionsmittel reduziert.The compounds of the formula (II) are known from the literature (see, for example, US Pat. WO 03/095451 , Example 8A) or can be prepared by reacting a compound of formula (V)

in which R ^{1 has} the meaning given above and
T ^{1 is} formyl or cyano,
in an inert solvent with hydrazine hydrate to give a compound of formula (VI)

in which R ^{1 has} the meaning given above and
T ^{2 is} hydrogen or amino,
cyclized, this then in an inert solvent with a suitable iodine source in a compound of formula (VII)

in which R ^{1 has} the meaning given above,
these are subsequently converted in an inert solvent in the presence of a suitable base with the compound of the formula (VIII)

to a compound of the formula (IX)

in which R ^{1 has} the meaning given above,
then reacting these in an inert solvent in the presence of hexabutyltin and a suitable palladium catalyst to intermediately form a tin species with the compound of formula (X)

to the compound of the formula (XI)

then reduced in an inert solvent with a suitable reducing agent.

Inert solvents for process step (V) → (VI) 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, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to 1,2-ethanediol.

The reaction (V) → (VI) is generally carried out in a temperature range of + 60 ° C to + 200 ° C, preferably at + 120 ° C to + 180 ° C. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for the reaction (VI) → (VII) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO ), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. Preference is given to DMF.

The reaction (VI) → (VII) is carried out in The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

When T ² in formula (VI) is amino, the reaction takes place (VI) → (VII) to form the corresponding diazonium salt by reaction in the presence of a suitable Lewis acid with isopentyl nitrite, and the subsequent reaction with sodium iodide in a temperature range of -78 ° C to + 40 ° C, preferably at 0 ° C to + 20 ° C. Suitable Lewis acids are boron trifluoride-diethyl ether complex, cerium (IV) ammonium nitrate (CAN), stannous chloride, lithium perchlorate, zinc (II) chloride, indium (III) chloride or indium (III) bromide. Boron trifluoride diethyl ether complex is preferred.

If T ² in formula (VI) is hydrogen, the formation of formula (VII) by reaction with iodine in the presence of a suitable base in a temperature range from 0 ° C to + 80 ° C, preferably from + 40 ° C to + 60 ° C. Suitable bases are alkali metal hydroxides such as potassium, lithium or sodium hydroxide, alkali metal such as sodium or potassium, sodium or potassium or potassium tert-butoxide. Preference is given to sodium hydroxide in a mixture of water and dioxane.

Inert solvents for the reaction (VII) + (VIII) → (IX) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents, such as dimethylformamide (DMF). , Dimethylsulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile. Preferred is DMF.

Suitable bases for process step (VII) + (VIII) → (IX) are alkali metal hydrides, such as potassium hydride or sodium hydride, alkali metal carbonates, such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates, such as sodium or potassium bicarbonate, alkali metal alcoholates, such as sodium or potassium methoxide. Sodium or potassium ethoxide or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). Cesium carbonate is preferred.

The reaction (VII) + (VIII) → (IX) is generally carried out in a temperature range of 0 ° C to + 60 ° C, preferably at + 10 ° C to + 25 ° C. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

Inert solvents for process step (IX) + (X) → (XI) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether , Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone (NMP), pyridine, Acetonitrile, sulfolane or even water. It is likewise possible to use mixtures of the solvents mentioned. Dioxane is preferred.

As a palladium catalyst for process step (IX) + (X) → (XI), for example, palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium ( II) chloride, bis (acetonitrile) palladium (II) chloride and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex, optionally in combination with additional phosphine ligands such as (2-) Biphenyl) di-tert-butylphosphine, dicyclohexyl [2 ', 4', 6'-tris (1-methylethyl) biphenyl-2-yl] phosphine (XPHOS), bis (2-phenylphosphinophenyl) ether (DPEphos) or 4, 5-bis (diphenylphosphino) -9,9-dimethylxanthene (xantphos) [cf. z. B. Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002) ] suitable.

The reaction (IX) + (X) → (XI) is generally carried out in a temperature range from + 20 ° C to + 180 ° C, preferably at + 50 ° C to + 120 ° C, optionally in a microwave. The reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.

The reduction (XI) → (II) is carried out in the presence of a suitable catalyst in an inert solvent, in a temperature range from + 20 ° C to + 40 ° C under normal hydrogen pressure.

Inert solvents for the reduction (XI) → (II) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Preferred are DMF and pyridine.

Suitable catalysts for the reaction (XI) → (II) are, for example, palladium on activated carbon, platinum on carbon, palladium hydroxide or Raney nickel.

The reduction (XI) → (II) may alternatively be carried out with a metal or metal salt such as iron, zinc or stannous chloride in a suitable acid such as hydrochloric acid / hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid in a temperature range of + 20 ° C to + 140 ° C take place.

• [a): Hydrazinhydrat, 1,2-Ethandiol; b): Iod, THF; c): 2-Fluorbenzylbromid, Cs₂CO₃, DMF; d): Pd(PPh₃)₄, Hexabutyldizinn; e) H₂, Pd-C].

The described preparation process can be exemplified by the following synthetic scheme (Scheme 4): Scheme 4

• [a): hydrazine hydrate, 1,2-ethanediol; b): iodine, THF; c): 2-fluorobenzyl bromide, Cs ₂ CO ₃ , DMF; d): Pd (PPh ₃ ) ₄ , hexabutylditin; e) H ₂ , Pd-C].

• [a): Schwefelsäure; b): Zink, Methanol, Eisessig; c): Trifluoressigsäureanhydrid, Dichlormethan].

The compounds of the formula (IV) are commercially available, known from the literature [cf. z. B. Winn M., J. Med. Chem. 1993, 36, 2676-7688 ; EP 634 413-A1 ; CN 1613849-A ; EP 1626045-A1 ; WO 2009/018415 ], can be prepared analogously to processes known from the literature or as shown in the synthesis scheme below (Scheme 5):

• [a): sulfuric acid; b): zinc, methanol, glacial acetic acid; c): trifluoroacetic anhydride, dichloromethane].

The compounds of the invention act as potent stimulators of soluble guanylate cyclase and show improved solubility in aqueous media. They have valuable pharmacological properties, 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 via direct stimulation of soluble guanylate cyclase and intracellular cGMP increase. In addition, the compounds of the invention potentiate the action of cGMP level enhancing substances such as endothelium-derived relaxing factor (EDRF), 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 node reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), cardiogenic shock, aneurysms, Boxer cardiomyopathy (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, coronary artery spasm and peripheral arteries Edema formation such as pulmonary edema, cerebral edema, renal edema or cardiac insufficiency-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 angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery, as well as microvascular and macrovascular damage (vasculitis), increased levels of fibrinogen and low density LDL, and increased levels nations of plasminogen activator inhibitor 1 (PAI-1), as well as 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 prostatic hyperplasia (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feline'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 kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome abnormally decreased creatinine and / or water excretion, abnormally elevated blood levels of urea f, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such. Glutamyl synthetase, altered urinary or urine abundance, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilatation, 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 other 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 central nervous system diseases 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 the 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 for controlling postoperative scarring, z. Due to 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.

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, thromboembolic disorders and arteriosclerosis.

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 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.

• • organische Nitrate und NO-Donatoren, wie beispielsweise Natriumnitroprussid, Nitroglycerin, Isosorbidmononitrat, Isosorbiddinitrat, Molsidomin oder SIN-1, sowie inhalatives NO;
• • Verbindungen, die den Abbau von cyclischem Guanosinmonophosphat (cGMP) inhibieren, wie beispielsweise Inhibitoren der Phosphodiesterasen (PDE) 1, 2 und/oder 5, insbesondere PDE 5-Inhibitoren wie Sildenafil, Vardenafil und Tadalafil;
• • antithrombotisch wirkende Mittel, beispielhaft und vorzugsweise aus der Gruppe der Thrombozytenaggregationshemmer, der Antikoagulantien oder der profibrinolytischen Substanzen;
• • den Blutdruck senkende Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Calcium-Antagonisten, Angiotensin AII-Antagonisten, ACE-Hemmer, Endothelin-Antagonisten, Renin-Inhibitoren, alpha-Rezeptoren-Blocker, beta-Rezeptoren-Blocker, Mineralocorticoid-Rezeptor-Antagonisten sowie der Diuretika; und/oder
• • den Fettstoffwechsel verändernde Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Thyroidrezeptor-Agonisten, Cholesterinsynthese-Inhibitoren wie beispielhaft und vorzugsweise HMG-CoA-Reduktase- oder Squalensynthese-Inhibitoren, der ACAT-Inhibitoren, CETP-Inhibitoren, MTP-Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta-Agonisten, Cholesterin-Absorptionshemmer, Lipase-Inhibitoren, polymeren Gallensäureadsorber, Gallensäure-Reabsorptionshemmer und Lipoprotein(a)-Antagonisten.

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. As suitable combination active ingredients may be mentioned by way of example and preferably:

• • organic nitrates and NO donors, such as 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 AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor Antagonists and diuretics; and or
• Lipid metabolism-modifying agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, for example and preferably, HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors 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 of 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-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 blockers, beta-receptor blockers, mineralocorticoid receptor 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 absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of 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 ECHT 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 according to 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. 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 can be applied in a suitable manner, such as. As oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or implant or stent.

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

For oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. As 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 Hart - or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out bypassing a resorption step (eg intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or using absorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). For parenteral administration are suitable as application forms u. a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are z. As inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), 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 excipients include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitanoleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (U.S. albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides), and flavor and / or odoriferous agents.

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 manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The 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

  calc.

  Calculated

  DCI

  direct chemical ionization (in MS)

  DMF

  dimethylformamide

  DMSO

  dimethyl sulfoxide

  d. Th.

  the theory (at yield)

  eq.

  Equivalent (s)

  IT I

  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

  me

  methyl

  min

  Minute (s)

  MS

  Mass spectrometry

  NMR

  nuclear magnetic resonance spectrometry

  Pd ₂ dba ₃

  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):

• Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8 μ 50 × 1 mm; 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: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2 μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.

Starting compounds and intermediates:

Example 1A

2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidine-4,5,6-triamine

The synthesis of this compound is described in WO 03/095451 Example 8A.

Example 2A

{2-chloroethyl 4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate

1.50 g (4.281 mmol) of the compound from Example 1A were dissolved in 15 ml of dichloromethane and 15 ml of pyridine and cooled to 0 ° C. Thereafter, 612 mg (4.281 mmol) of 2-chloroethyl chloroformate were added with stirring. The mixture was then warmed to RT and stirred at this temperature for 12 h. The reaction was then poured onto ice-water and extracted twice with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. This gave 1031 g (52% of theory) of the title compound, which was reacted further without further purification.
LC-MS (Method 1): R _t = 0.78 min; MS (EIpos): m / z = 457 [M + H] ⁺ .

Example 3A

1-chloro-2-methyl propan-2-yl- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5- yl} carbamate

175 μl (1.713 mmol) of 1-chloro-2-methyl-2-propanol were introduced into 6 ml of dichloromethane and treated with 169 mg (0.571 mmol) of bis (trichloromethyl) carbonate and cooled to 0 ° C. Thereafter, 110 μl (1.37 mmol) of pyridine were added dropwise and it became 30 Stirred at 0 ° C min. Subsequently, 400 mg (1.142 mmol) of the compound from Example 1A were added and then 2.93 ml (36.26 mmol) of pyridine. It was stirred for a further 30 min at 0 ° C. Then 87 μl (0.856 mmol) of 1-chloro-2-methyl-2-propanol in 3 ml of dichloromethane were introduced into a separate flask and 85 mg (0.285 mmol) of bis (trichloromethyl) carbonate were added. After addition of 55 .mu.l (0.685 mmol) of pyridine was stirred for 30 min at 0 ° C and the solution thus prepared added to the approach described above. After a further 30 min stirring at 0 ° C, the approach was stopped by the addition of 10 ml of saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. 500 mg (84% of theory) of the title compound were obtained, which were used without further purification.
LC-MS (Method 1): R _t = 0.86 min; MS (EIpos): m / z = 485 [M + H] ⁺ .

Example 4A

1-chloropropane-2-yl- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate

The compound was prepared in analogy to Example 3A. Starting from 400 mg (1.142 mmol) of Example 1A, 469 mg (87% of theory) of the title compound were obtained, which was reacted further without further purification.
LC-MS (method 1): R _t = 0.82 min; MS (EIpos): m / z = 471 [M + H] ⁺ .

Example 5A

3-bromo-1,1,1-trifluoropropan-2-yl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate

0.888 ml (8.563 mmol) of 3-bromo-1,1,1-trifluoro-2-propanol were initially charged in 22 ml of dichloromethane and combined with 952 mg (3,211 mmol) of bis (trichloromethyl) carbonate and cooled to 0 ° C. Thereafter, 0.519 ml (6.422 mmol) of pyridine were added dropwise and it was stirred at 0 ° C for 1 h. Subsequently, 1.5 g (4.281 mmol) of the compound from Example 1A dissolved in pyridine (11 ml) were added and the mixture was stirred at 0 ° C. for a further 30 min. After a further 12 h at RT, the batch was quenched by the addition of 30 ml of saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane: methanol gradient). 532 mg (21% of theory) of the title compound were obtained.
LC-MS (Method 1): R _t = 0.92 min; MS (EIpos): m / z = 570 [M + H] ⁺ .

Example 6A

(2S) -3-bromo-1,1,1-trifluoropropan-2-yl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine 3-yl] pyrimidin-5-yl} carbamate Step a): (2S) -3-bromo-1,1,1-trifluoropropan-2-ol

1.00 g (5.431 mmol) of magnesium bromide were initially charged in diethyl ether (30 ml) and then slowly treated with 608 mg (5.431 mmol) of R - (+) - 1,1,1-trifluoro-2,3-epoxypropane. After addition, the mixture was heated to reflux for 1 h, cooled, poured onto ice-water and acidified with dilute sulfuric acid. The phases were separated and the aqueous phase was extracted three more times with diethyl ether. The combined organic phases dried over sodium sulfate, filtered and concentrated under vacuum (up to 500 mbar). This gave 1.11 g of the intermediate, which was further reacted directly in step b).

Step b): (2S) -3-bromo-1,1,1-trifluoropropan-2-yl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} carbamate

The compound was prepared in analogy to Example 5A. Starting with 400 mg (1142 mmol) of Example 1A, 201 mg (31% of theory) of the title compound were obtained, which was reacted further without further purification.
LC-MS (Method 1): R _t = 0.91 min; MS (EIpos): m / z = 570 [M + H] ⁺ .

Example 7A

3-chloropropyl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate

300 mg (0.856 mmol) of the compound from Example 1A were initially charged in 9 ml of pyridine and admixed with 175 mg (1,113 mmol) of 3-chloropropyl chloroformate. The mixture was stirred for 3 h at RT. Thereafter, the solvent was removed in vacuo. The residue was added with a little methanol. The product crystallized, was filtered off and dried in vacuo. 383 mg (93% of theory) of the title compound were obtained.
LC-MS (Method 2): R _t = 1.86 min; MS (EIpos): m / z = 471 [M + H] ⁺ .

EXAMPLES

example 1

3- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} -5,5-dimethyl-1 , 3-oxazolidin-2-one

500 mg (1033 mmol) of the compound prepared in Example 3A were dissolved in THF (10 ml) and treated at 0 ° C with 1033 ml of a 1M solution of sodium bis (trimethylsilyl) amide in THF. After 5-10 min stirring at 0 ° C, the approach was stopped by the addition of saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). There were obtained 329 mg of the title compound (71% of theory).
LC-MS (Method 1): R _t = 0.83 min; MS (Eipos): m / z = 449 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.55 (s, 6H), 3.43 (s, 2H), 5.81 (s, 2H), 6.44 (s br, 4H) 7.10-7.14 (m, 2H), 7.20-7.25 (m, 1H), 7.32-7.37 (m, 2H), 8.61 (dd, 1H), 9.08 (dd, 1H).

Example 2

3- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -1,3-oxazolidin-2 -one

The compound was prepared from 1,109 mg (2.427 mmol) of Example 2A in analogy to Example 1. There were obtained 362 mg of the title compound (35% of theory).
LC-MS (Method 1): R _t = 0.73 min; MS (Eipos): m / z = 421 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.63-3.67 (m, 2H), 4.40-4.44 (m, 2H), 5.80 (s, 2H), 6.60 (s br, 4H ) 7.12-7.14 (m, 2H), 7.21-7.25 (m, 1H), 7.32-7.37 (m, 2H), 8.61 (dd, 1H), 9.04 (dd, 1H).

Example 3

3- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -5-methyl-1,3 oxazolidin-2-one (racemate)

The compound was prepared starting from 467 mg (0.992 mmol) of Example 4A in analogy to Example 1. There were obtained 209 mg of the title compound (48% of theory).
LC-MS (Method 1): R _t = 0.78 min; MS (Eipos): m / z = 435 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.46 (d, 3H), 3.65 (t, 1H), 4.85-4.94 (m, 1H), 5.80 (s, 2H), 6.53 (br s, 2H), 6.63 (br s, 2H), 7.10-7.15 (m, 2H), 7.22 (t, 1H), 7.32-7.38 (m, 2H), 8.60 (dd, 1H), 9.05 (dd , 1H).

Separation into enantiomers:

186 mg of the resulting racemate were purified by preparative HPLC (mobile phase: (isohexane: ethanol + 0.2% diethylamine 50/50, flow 15 ml / min, temperature 45 ° C., wavelength: 220 nM) on a chiral phase (Daicel Chiralpak AD-H, 5 μM 250 x 20 mm) into the enantiomers.

Example 3-1 (Enantiomer 1)

• Yield: 101 mg
• ee> 99% (analytical HPLC: (mobile phase: (isohexane: ethanol + 0.2% diethylamine 35/65) on a chiral phase (Chiralpak AD-H, 5 μM 250 × 4.6 mm)
• R _t = min.

Example 3-2 (Enantiomer 2)

• Yield: 84 mg
• ee> 99% (analytical HPLC: (mobile phase: (isohexane: ethanol + 0.2% diethylamine 35/65) on a chiral phase (Chiralpak AD-H, 5 μM 250 × 4.6 mm)
• R _t = 8.58 min.

Example 4

3- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -5- (trifluoromethyl) -1 , 3-oxazolidin-2-one

The compound was prepared starting from 123 mg (0.216 mmol) of Example 5A in analogy to Example 1. 45 mg of the title compound were obtained (42% of theory).
LC-MS (Method 1): R _t = 0.90 min; MS (Eipos): m / z = 489 [M + H] ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.74 (dd, 1H), 4.00 (t, 1H), 5.42 (m, 1H), 5.81 (s, 2H), 6.19 (s br, 2H), 6.86 (s br, 2H), 7.12-7.16 (m, 2H), 7.22 (t, 1H), 7.32-7.38 (m, 2H), 8.61 (dd, 1H), 9.05 (dd, 1H ).

Example 5

(5R) -3- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -5- ( trifluoromethyl) -1,3-oxazolidin-2-one

Representation starting from Example 6A:

The compound was prepared starting from 200 mg (0.351 mmol) of Example 6A in analogy to Example 1. There were obtained 85 mg of the title compound (49% of theory).

Representation by enantiomer separation starting from Example 4:

624 mg of Example 4 (racemate) were purified by preparative HPLC (mobile phase: (ethanol: methanol: isohexane 20/20/60, flow: 20 ml / min, wavelength: 320 nM, temperature 20 ° C.) on a chiral phase (Daicel Chiralpak AD-H, 5 μM 250 x 20 mm) into the enantiomers.

There were obtained 214 mg of the title compound (R-enantiomer) and 187 mg of the S-enantiomer (Example 6)
R _t = 4.67 min.
ee> 99.5% (analytical HPLC: (mobile phase: (methanol / ethanol: isohexane 50/050) on a chiral phase (Diacel AD-H, 5 μM 250 × 4 mm)

The assignment was made by comparing the synthetically uniquely produced batch by means of chiral HPLC.

Example 6

(5S) -3- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -5- ( trifluoromethyl) -1,3-oxazolidin-2-one

624 mg of the racemate obtained in Example 4 were purified by preparative HPLC (mobile phase: (ethanol: methanol: isohexane 20/20/60, flow: 20 ml / min, wavelength: 320 nM, temperature 20 ° C.) on a chiral phase (Daicel Chiralpak AD-H, 5 μM 250 x 20 mm) into the enantiomers.

There were obtained 214 mg of the R-enantiomer (Example 5) and 187 mg of the title compound (S-enantiomer)
ee> 99.5% (analytical HPLC: (mobile phase: (methanol / ethanol: isohexane 50/50) on a chiral phase (Diacel AD-H, 5 μM 250 × 4 mm)
R _t = 5.84 min.

Example 7

3- {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl) -1,3-oxazinan-2 -one

670 mg (1.422 mmol) of Example 7A were suspended in 12 ml of methanol and admixed with 1.32 ml (7.11 mmol) of a 5.4 N solution of sodium methoxide in methanol. It was heated for 15 min to reflux. Thereafter, the reaction mixture was concentrated and dissolved in water / ethyl acetate. The organic phase was separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (acetonitrile: water (+ 0.2% trifluoroacetic acid) - 70:30). There were obtained 77 mg of the title compound (12% of theory).
LC-MS (Method 2): R _t = 1.52 min; MS (Eipos): m / z = 435 [M + H] ⁺ .
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 2.14-2.21 (m, 2H), 3.29-3.34 (2H under H ₂ O signal), 4.40 (t, 2H), 5.80 ( s, 2H), 6.44 (br s, 4H), 7.08-7.15 (m, 2H), 7.23 (dd, 1H), 7.32-7.38 (m, 1H), 7.34 (dd, 1H), 8.60 (dd, 1H ), 9.06 (dd, 1H).

B. Evaluation of Pharmacological Activity

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

B-1. Vessel-relaxing effect 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-gassed 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 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 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% (IC ₅₀ value). The standard application volume is 5 μl, the DMSO content in the bath solution corresponds to 0.1%.

Representative IC ₅₀ values for the compounds according to the invention are given in the table below (Table 1): Table 1: Example no. IC ₅₀ [nM] 3-1 81 4 86 5 129 6 70

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 in F. Wunder et al., Anal. Biochem. 339 104-112 (2005) described, determined.

Representative values (MEC = minimum effective concentration) for the compounds of the invention are given in the table below (Table 2): TABLE 2 Example no. MEC [μM] 3-1 3.0 4 12:01 5 0.1 6 12:03

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.

• – Implantierbare Sender (Physiotel^® Telemetrietransmitter)
• – Empfänger (Physiotel^® Receiver), die über einen Multiplexer (DSI Data Exchange Matrix) mit einem
• – Datenakquisitionscomputer

verbunden sind.The system consists of 3 main components:

• - Implantable Transmitters (Physiotel ^® Telemetry Transmitter)
• - Receiver (Physiotel ^® Receiver), which is connected via a multiplexer (DSI Data Exchange Matrix) with a
• - Data acquisition computer

are connected.

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

animal material

The investigations are carried out on adult female spontaneously hypertensive rats (SHR Okamoto) with a body weight of> 200 g. SHR / NCrl from Okamoto Kyoto School of Medicine, 1963 were crossed from male Wistar Kyoto rats with markedly elevated blood pressure and female with slightly elevated blood pressure and delivered in the F13 to the US National Institutes of Health.

The experimental animals are kept individually in Makrolon 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 TA11 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 liquid-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 prophylaxis (Tardomyocel COMP Bayer 1 ml / 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.

• – Systolischer Blutdruck (SBP)
• – Diastolischer Blutdruck (DBP)
• – Arterieller Mitteldruck (MAP)
• – Herzfrequenz (HR)
• – Aktivität (ACT).

In the standard procedure, duration is measured over 10 seconds:

• - Systolic blood pressure (SBP)
• - Diastolic blood pressure (DBP)
• - Mean Arterial 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.R.T. 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 cardiovascular circadian rhythms and on myocardial β-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

B-eighth Determination of solubility

Required reagents:

• PBS buffer pH 6.5: 90.00 g NaCl pa (for example from Merck, Item No. 1.06404.1000), 13.61 g KH ₂ PO ₄ pa (for example from Merck, Art 1.04873.1000) and 83.35 g of 1N sodium hydroxide solution (eg from Bernd Kraft GmbH, Item No. 01030.4000) are weighed into a 1 liter volumetric flask, made up to 1 liter with distilled water and stirred for 1 hour , Thereafter, the pH is adjusted to 6.5 with 1 N hydrochloric acid (for example from Merck, Item No. 1.09057.1000).
• • PEG / water solution (30:70 v / v): 30 ml of polyethylene glycol 400 (for example from Merck, article No. 8.17003.1000) and 70 ml of distilled water are homogenized in a 100 ml volumetric flask ,
• PEG / PBS buffer pH 6.5 (80:20 v / v): 80 ml of polyethylene glycol 400 (for example from Merck, Item No. 8.17003.1000) and 20 ml of PBS buffer pH 6.5 are added in one Homogenized 100 ml volumetric flask.
• Dimethylsulfoxide (for example Baker, Art No. 7157.2500)
• • distilled water.

Preparation of the starting solution (original solution):

At least 4 mg of the test substance are accurately weighed into a wide-necked 10 mm Screw V-Vial (Fa. Glastechnik Gräfenroda GmbH, Item No. 8004-WM-H / V15μ) with matching screw cap and septum in a pipetting robot with DMSO until added to a concentration of 50 mg / ml and shaken for 10 minutes.

Preparation of the calibration solutions:

Preparation of the starting solution for calibration solutions (stock solution): Transfer 10 μl of the original solution into a microtiter plate using a pipetting robot and make up to a concentration of 600 μg / ml with DMSO. The sample is shaken until completely dissolved.

Calibration solution 1 (20 μg / ml): Mix 34.4 μl of the stock solution with 1000 μl of DMSO and homogenize.

Calibration solution 2 (2.5 μg / ml): 100 μl of the calibration solution 1 are mixed with 700 μl of DMSO and homogenized.

Preparation of the sample solutions:

Sample solution for solubility up to 5 g / liter in PBS buffer pH 6.5: Transfer 10 μl of the original solution into a microtiter plate and add 1000 μl of PBS buffer pH 6.5.

Sample solution for solubility up to 5 g / liter in PEG / water (30:70): Transfer 10 μl of the original solution into a microtiter plate and add 1000 μl of PEG / water (30:70).

Sample solution for solubility up to 5 g / liter in PEG / PBS buffer pH 6.5 (80:20): Transfer 10 μl of original solution into a microtiter plate and add 1000 μl of PEG / PBS buffer pH 6.5 (80:20).

Execution:

The sample solutions prepared in this way are shaken at 1400 rpm for 24 hours at 20 ° C. by means of a temperature-controlled shaker (eg Eppendorf Thermomixer comfort Article No. 5355 000.011 with interchangeable block Article No. 5362.000.019). 180 μl of each of these solutions are taken off and transferred to Beckman Polyallomer Centrifuge Tubes (Item No. 343621). These solutions are centrifuged for 1 hour at about 223,000 × g (eg, Beckman Optima L-90K Ultracentrifuge with Type 42.2 Ti rotor at 42,000 rpm). From each sample solution, 100 μl of the supernatant are taken and diluted to 1: 5 and 1: 100 with DMSO. Each dilution is bottled in a suitable vessel for HPLC analysis.

analytics:

The samples are analyzed by RP-HPLC. Quantification is via a two-point calibration curve of the test compound in DMSO. The solubility is expressed in mg / liter. Analysis sequence: 1) Calibration solution 2.5 mg / ml; 2) Calibration solution 20 μg / ml; 3) Sample solution 1: 5; 4) Sample solution 1: 100.

HPLC method for acids:

• Agilent 1100 with DAD (G13 15A), quat. Pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: Phenomenex Gemini C18, 50 mm × 2 mm, 5 μ; Temperature: 40 ° C; Eluent A: water / phosphoric acid pH 2; Eluent B: acetonitrile; Flow rate: 0.7 ml / min; Gradient: 0-0.5 min 85% A, 15% B; Ramp: 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; Ramp: 3.5-4 min 85% A, 15% B; 4-5 minutes 85% A, 15% B.

HPLC method for bases:

• Agilent 1100 with DAD (G1315A), quat. Pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: VDSoptilab Kromasil 100 C18, 60 mm × 2.1 mm, 3.5 μ; Temperature: 30 ° C; Eluent A: water + 5 ml perchloric acid / liter; Eluent B: acetonitrile; Flow rate: 0.75 ml / min; Gradient: 0-0.5 min 98% A, 2% B; Ramp: 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; Ramp: 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.

Table C lists the solubility values for representative embodiments.

Table C

example Solubility [mg / liter] PBS buffer pH = 6.5 2 140

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 dried after drying with the magnesium stearate 5 Mixed 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 according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (for example isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 98/16223 [0006]
• WO 00/06569 [0007]
• WO 03/095451 [0007, 0042, 0127]
• WO 02/042299 [0007]
• EP 634413 A1 [0060]
• CN 1613849 A [0060]
• EP 1626045-A1 [0060]
• WO 2009/018415 [0060]

Cited non-patent literature

• Wu et al., Blood 84 (1994), 4226 [0006]
• Mülsch et al., Brit. J. Pharmacol. 120 (1997), 681 [0006]
• Goldberg et al., J. Biol. Chem. 252 (1977), 1279 [0006]
• Pettibone et al., Eur. J. Pharmacol. 116 (1985), 307 [0006]
• Yu et al., Brit. J. Pharmacol. 114 (1995), 1587 [0006]
• Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002) [0053]
• Winn M., J. Med. Chem. 1993, 36, 2676-7688 [0060]
• F. Wunder et al., Anal. Biochem. 339 104-112 (2005) [0164]
• Okamoto Kyoto School of Medicine, 1963 [0169]
• Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Müssig, Georg Ertl and Björn Lemmer: Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial β-adrenergic signaling. Cardiovasc Res 47 (2): 203-405, 2000 [0185]
• Kozo Okamoto: Spontaneous hypertension in rats. Int Rev Exp Pathol 7: 227-270, 1969 [0185]
• 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 [0185]

Claims (9)

Compound of the formula (I)

in which L is (C ₁ -C ₃ ) -alkanediyl, where (C ₁ -C ₃ ) -alkanediyl having 1 to 3 substituents independently of one another may be substituted from the group trifluoromethyl and (C ₁ -C ₄ ) -alkyl , R ^{1 is} hydrogen or fluorine, R ^{2 is} hydrogen, fluorine, (C ₁ -C ₄ ) -alkyl, difluoromethyl or trifluoromethyl, R ^{3 is} hydrogen or (C ₁ -C ₄ ) -alkyl, and their N Oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts. A compound of the formula (I) according to claim 1, in which L is methylene or ethane-1,2-diyl, R ^{1 is} hydrogen or fluorine, R ^{2 is} hydrogen, fluorine, methyl, ethyl, difluoromethyl or trifluoromethyl, R ^{3 is} hydrogen, methyl or ethyl, and their salts, solvates and solvates of the salts. A compound of the formula (I) according to claim 1 or 2, in which L is methylene, R ^{1 is} hydrogen, R ^{2 is} hydrogen, methyl or trifluoromethyl, R ^{3 is} hydrogen or methyl, and their salts, solvates and solvates salts. Process for the preparation of compounds of the formula (I) as defined in claims 1 to 3, characterized in that a compound of the formula (II)

in which R has the meaning given in claims 1 to 3, in an inert solvent in the presence of a suitable base with the compound of formula (III)

in which L, R ² and R ³ each have the meanings given in claims 1 to 3 and X ^{1 is} a suitable leaving group, such as, for example, meyslate, tosylate or halogen, in particular chlorine or bromine, is a compound of formula (IV)

in which L, R ¹ , R ² , R ³ and X ^{1 in} each case have the meanings given in claims 1 to 3, and these are subsequently reacted in an inert solvent in the presence of a suitable base to give a compound of the formula (I)

in which L, R ¹ , R ² and R ³ each have the meanings given in claims 1 to 3, cyclized, and optionally the resulting compounds of 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. A compound of the formula (I) as defined in any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases. Use of a compound of 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 disorders, thromboembolic disorders and arteriosclerosis. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 3, in combination with an inert, non-toxic, pharmaceutically-acceptable excipient. A pharmaceutical composition comprising a compound of the 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, the Antihypertensive agents and lipid metabolizing agents. Medicament according to claim 7 or 8 for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, thromboembolic disorders and arteriosclerosis.