WO2012010577A1 - Substituted oxazolidinones and oxazinanones and use thereof - Google Patents

Abstract

The invention relates to novel, substituted oxazolidinones and oxazinanones, a method for producing them, and the use thereof alone or in combinations for treating and/or preventing diseases, as well as to their use for producing medicaments for treating and/or preventing diseases, in particular for treating and/or preventing cardiovascular diseases.

Description

 Substituted oxazolidinones and oxazinones and their use

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 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).

WO 00/06569 discloses fused pyrazole derivatives and, in WO 03/095451, carbamate-substituted 3-pyrimidinyl-pyrazolopyridines as stimulators of soluble guanylate cyclase. 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.

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 may be substituted from the group consisting of 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 which are preferred 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, 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 having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, 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.

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 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 that 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), H (tritium), ¹ C , ¹⁴ C, ¹⁵ N, ¹⁷ 0, ¹⁸ 0, ² P, P, S, ⁴ S, ⁵ S, ⁶ S, ¹⁸ F, ⁶ Cl, ⁸² Br, ¹² I, ¹²⁴ I, ¹²⁹ I and ^{1 1} I. Certain isotopic variants of a compound of the invention, such as 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 drug in the body; because of the comparatively easy production and detectability, compounds labeled with H or ¹⁴ C isotopes are particularly suitable for this purpose. In addition, 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 of the invention may according to the Those skilled in the known processes are prepared, for example, by the methods described below and reproduced in the exemplary embodiments provisions by appropriate isotopic modifications of the respective reagents and / or starting compounds are used. 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-l, 2-diyl and propane-l, 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.

In the context of the present invention, preference is also given to 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.

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 abovementioned meaning, in an inert solvent in the presence of a suitable base with the compound of the 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, R, R and X in each case have the abovementioned meanings, and then these in an inert solvent in the presence of a suitable base to give a compound of the formula (I)

in which L, R, R and R are each as defined 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, halohydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 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 (ΝΜΡ) 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 hydrogencarbonate, alkali metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate 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] -ηοη-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 may be carried out at normal, elevated or reduced pressure (e.g., 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 (ΝΜΡ ) 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 hydrogencarbonates 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 butyllithium or phenyllithium, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 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 at 0 ° C to + 20 ° 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): pyridine, CH ₂ Cl ₂ ; c): NaHMDS, 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):

Scheme 2

[a): CH ₂ Cl ₂ , pyridine].

Scheme 3

[a): magnesium bromide, diethyl ether; b): pyridine, THF]. The compounds of the formula (II) are known from the literature (see, for example, WO 03/095451, Example 8A) or can be prepared by reacting a compound of the formula (V)

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

in which R ^{1 has} the abovementioned meaning and represents hydrogen or amino, cyclized, then these in an inert solvent with a suitable iodine source in a compound of formula (VII)

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

(ix) in which R ^{1 has} the abovementioned meaning, then reacting these in an inert solvent in the presence of hexabutyltin and a suitable palladium catalyst with intermediate formation of a tin species with the compound of the 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), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ), pyridine, acetonitrile or also 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 may be carried out at normal, elevated or reduced pressure (e.g., 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 (ΝΜΡ), 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 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 (VI) - »(VII) is carried out with formation of the corresponding diazonium salt by reaction in the presence of a suitable Lewis acid Isopentylnitrit, and the direct subsequent reaction with sodium iodide in a temperature range from -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, carbon tetrachloride, 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), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ), 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 metal bicarbonates such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium , 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 l, 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 from 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 Substances 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 (ΝΜΡ), pyridine, acetonitrile , Sulfolane or water. It is likewise possible to use mixtures of the solvents mentioned. Dioxane is preferred.

As palladium catalyst for process step (IX) + (X) - »(XI) is, for example, palladium on activated carbon, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride and [Ι, - bis (diphenylphosphino) ferrocene] dichloalladium (II) -dichloromethane complex, optionally in combination with additional phosphine ligands such as (2-) biphenyl) di-fert. 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 (xanthphos) [cf. e.g. Hassan J. et al, Chem. Rev. 102, 1359-1469 (2002)].

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 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 reduction (XI) - »(II) takes place in the presence of a suitable catalyst in an inert solvent, in a temperature range from + 20 ° C to + 40 ° C under hydrogen normal 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, tetrahydrofran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ), 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 treated 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. The described preparation process can be exemplified by the following synthesis scheme (Scheme 4):

Scheme 4

[a): hydrazine hydrate, 1,2-ethanediol; b): iodine, THF; c): 2-fluorobenzyl _bromide , Cs ₂ C0 _3j DMF; d): Pd (PPh ₃ ) ₄ , hexabutylditin; e) H ₂ , Pd-C].

The compounds of the formula (IV) are commercially available, known from the literature [cf. e.g. Winn M., J. Med. Chem. 1993, 36, 2676-7688; EP 634 413-A1; CN 1613849-A; EP 1626045-A 1; WO 2009/018415], can be prepared analogously to processes known from the literature or as shown in the synthesis scheme below (Scheme 5):

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 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 are suitable for the treatment and / or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.

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, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, arrhythmia of the atria and the chambers and conduction disorders such for example atrio-ventricular blockades grade I-III (AB-B lock I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, 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, cardiomyopathy), shock such as cardiogenic shock, septic Schoc k and anaphylactic 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, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases , Spasm of the coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or congestive heart failure edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, Cardiac insufficiency, endothelial dysfunction, for 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 LDL low density and elevated levels 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 failure also encompasses more specific or related forms of disease such as acutely decompensated heart failure, right heart failure, left ventricular failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart failure, cardiac valvulopathy, mitral valve stenosis, mitral valve disease. insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, 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, urgency, 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 reduced creatinine and / or water excretion, abnormally elevated blood levels of urinary ff, 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 disorders (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), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis-associated pulmonary hypertension, 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, as they occur especially in situations of disease syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, craniocerebral trauma , Stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized attention deficit disorder, impaired concentration 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 absorption.

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 enteritis (IBD, Crohn s Disease, UC), Pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases and 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 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 Illnesses of the eye, suitable. 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 due to diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).

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 also be used cosmetically on aging and keratinizing skin.

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

Another object of the present invention is the use of the compounds according to the invention fertilize 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 cardiac insufficiency, 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. 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 by way of 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 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 31 12, 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 Antagonists and diuretics understood. 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 of the invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide with potassium sparing diuretics such as amiloride and triamterene, with aldosterone antagonists such as spironolactone, potassium canrenoate and Eplerenone and thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, xipamide, and indapamide administered.

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, 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, by way of example and with preference 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, by way of example and by way of illustration, 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 reab tion inhibitors, such as by way of example and preferably ASBT (= IBAT) inhibitors such. 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., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For 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 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 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

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 1,8μ 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: Micromass Quattro LCZ with HPLC Agilent Series 1 100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 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- [l- (2-fluorobenzyl) -lH-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, with stirring, 612 mg (4.28 1 mmol) of 2-chloroethyl chloroformate were added. The mixture was then warmed to RT and stirred for 12 h at this temperature. 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, = 0.78 min; MS (EIpos): m / z = 457 [M + H] ⁺ . Example 3A 1-chloro-2-methylpropan-2-yl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] pyrimidine 5 -yl} carbamate

175 μΐ (1.713 mmol) of 1-chloro-2-methyl-2-propanol were initially charged in 6 ml of dichloromethane and treated with 169 mg (0.571 mmol) of bis (trichloromethyl) carbonate and cooled to 0 ° C. Thereafter, 110 μΐ (1.37 mmol) of pyridine were added dropwise and it was stirred at 0 ° C for 30 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. Subsequently, 87 μΐ (0.856 mmol) of 1-chloro-2-methyl-2-propanol in 3 ml of dichloromethane were placed in a separate flask and admixed with 85 mg (0.285 mmol) of bis (trichloromethyl) carbonate. After addition of 55 μΐ (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 by addition of 10 ml saturated aqueous sodium bicarbonate solution and quenched 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, = 0.86 min; MS (EIpos): m / z = 485 [M + H] ⁺ . Example 4A 1-Chloropro-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, = 0.82 min; MS (EIpos): m / z = 471 [M + H] ⁺ . Example 5A 3-Bromo-1,1,1-trifluoro-ropan-2-yl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine-3 - yl] pyrimidin-5-yl} carbamate

0.888 ml (8.563 mmol) of 3-bromo-1,1'-trifluoro-2-propanol were initially charged in 22 ml of dichloromethane and admixed 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 for 1 h at 0 ° C. 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 (2% of theory) of the title compound were obtained.

LC-MS (Method 1): R, = 0.92 min; MS (EIpos): m / z = 570 [M + H] ⁺ . Example 6A

(2S) -3-Bromo-1,1,1-trifluoro-ropan-2-yl {4,6-diamino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine 3 -yl] pyrimidin-5-yl} carbamate

Stage a): (2S) -3-bromo-1,1'-l-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 - (+) - l, l, l-trifluoro-2,3-epoxypropane. After addition, it 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).

Stage b): (2S) -3-bromo-1,1,2-trifluoro-ropan-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, = 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, = 1.86 min; MS (EIpos): m / z = 471 [M + H] ⁺ .

EXAMPLES

example 1

3- {4,6-Diamino-2- [1- (2-fluorobenzyl) -1H-pyrazoto

l, 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 an IM 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, = 0.83 min; MS (Eipos): m / z = 449 [M + H] ⁺ .

Ή 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-oxazolidine-2 -οη

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, = 0.73 min; MS (Eipos): m / z = 421 [M + H] ⁺ . Ή 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, IH), 7.32-7.37 (m, 2H), 8.61 (dd, IH), 9.04 (dd, IH).

Example 3

3- {4,6-diamino-2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5-yl} -5-methyl-l, 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, = 0.78 min; MS (Eipos): m / z = 435 [M + H] ⁺ . Ή 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 μΜ 250 * 20 mm) into the enantiomers.

Example 3-1 (Enantiomer 1)

Yield: 101 mg ee> 99% (analytical HPLC: (Laufinittel: (isohexane: ethanol + 0.2% diethylamine 35/65) on chiral phase (Chiralpak AD-H, 5 μΜ 250 * 4.6 mm)

R _t = 6.68 min.

Example 3-2 (Enantiomer 2)

Yield: 84 mg ee> 99% (analytical HPLC: (eluent: (isohexane: ethanol + 0.2% diethylamine 35/65)

Phase (Chiralpak AD-H, 5 μΜ 250 * 4.6 mm)

R, = 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, = 0.90 min; MS (Eipos): m / z = 489 [M + H] ⁺ .

Ή 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 μΜ 250 * 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, = 4.67 min. ee> 99.5% (analytical HPLC: (mobile phase: (methanol / ethanol: isohexane 50/050) on chiral phase (Diacel AD-H, 5 μΜ 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 μΜ 250 * 20 mm) were separated into the enantiomers to give 214 mg of the R enantiomer (Example 5) and 187 mg of the title compound (S enantiomer) ee> 99.5% (analytical HPLC: (eluent: (Methanol / ethanol: isohexane 50/50) on chiral phase (Diacel AD-H, 5 μΜ 250 * 4 mm)

R, = 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-oxazinane-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, = 1.52 min; MS (Eipos): m / z = 435 [M + H] ⁺ . Ή-NMR (500 MHz, DMSO-d ₆ ): δ [ppm] = 2.14-2.21 (m, 2H), 3.29-3.34 (2H under H ₂ 0 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:

Bl. Vessel-relaxing effect in vitro Rabbits are anesthetized by the stroke of the neck and bled to death. 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 μΐ, 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 described in F. Wunder et al., Anal. Biochem. 339. 104-112 (2005). Representative values (MEC = minimum effective concentration) for the compounds according to the invention are given in the table below (Table 2):

Table 2:

B-3. Radiotelemetric blood pressure measurement on awake, spontaneously respirable 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 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 of Okamoto Kyoto School of Medicine, 1963 were crossed out of male Wistar Kyoto rats with high blood pressure and female with slightly elevated blood pressure and in F13 with U.S. Pat. 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 stated, the substances to be tested are each administered orally to one 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.

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, administration of the test substances will take place on the day of the experiment at 9.00. 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 ART TM ANALYSIS). The blank will be here 2 hours before application assuming that the selected record comprises the period from 7:00 on the trial day to 9:00 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 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.

Klaus Witte, Kai Hu, Johanna Swiatek, Claudia Muessig, Georg Ertl and Bjorn Lemmer: Experimental heart failure in rats: effects on cardiovascular 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

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, Item No. 1.04873.1000) and 83.35 g of 1 N 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, Art.

 8.17003.1000) and 70 ml of distilled water are homogenised 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, Art.

 8.17003.1000) and 20 ml of PBS buffer pH 6.5 are homogenized in a 100 ml volumetric flask.

Dimethylsulfoxide (eg 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-mouth 10 mm Screw V-Vial (Glastechnik Gräfenroda GmbH, Item No. 8004-ννΜ-Η / νΐ5μ) 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 μΐ 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): 34.4 μΐ of the stock solution are mixed with 1000 μΐ DMSO and homogenized.

Calibration solution 2 (2.5 μg / ml): 100 μΐ of the calibration solution 1 are mixed with 700 μΐ 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 μΐ of original solution into a microtiter plate and add 1000 μΐ PBS buffer pH 6.5.

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

Sample solution for solubility up to 5 g / liter in PEG / PBS buffer pH 6.5 (80:20): Transfer 10 μΐ of original solution into a microtiter plate and add 1000 μΐ 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. using a temperature-controlled shaker (for example Eppendorf Thermomixer comfort Order No. 5355 000.011 with interchangeable block Art. No. 5362.000.019). Of these solutions, 180 μΐ each are taken off and transferred to Beckman Polyallomer Centrifuge Tubes (Item No. 343621). These solutions are centrifuged for 1 hour at about 223,000 xg (eg Fa. Beckman Optima L-90K Ultracentrifuge with Type 42.2 Ti rotor at 42,000 rpm). From each sample solution, 100 μΐ of the supernatant are removed 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 achieved by 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 (G1315A), quat. Pump (G131 1A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: Phenomenex Gemini C18, 50 mm x 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 min 85% A, 15% B. HPLC method for bases:

Agilent 1100 with DAD (G1315A), quat. Pump (G131 1A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); Column: VDSoptilab Kromasil 100 C 18, 60 mm x 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

Solubility [mg / liter]

 example

 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 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 in a concentration below the 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

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 consisting of 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. 2. 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 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 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 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 represents} a suitable leaving group, such as, for example, meyslate, tosylate or halogen, in particular chlorine or bromine, to give a compound of the formula (IV)

in which L, R ¹ , R ² , R ³ and X ^{1 are} each those specified in claims 1 to 3

Have meanings, and then this 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 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, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.

A compound of formula (I) as defined in any one of claims 1 to 3 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.

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 8 or 9 for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic diseases, fibrotic diseases and arteriosclerosis.

11. Methods 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 the formula (I ) as defined in any one of claims 1 to 3 or a drug as defined in any one of claims 8 to 10.