WO2012010578A1 - Substituted methyl-pyrimidin-5-yl carbamates and use thereof - Google Patents

Abstract

The invention relates to novel, substituted methyl-pyrimidin-5-yl carbamates, a method for producing them, their use alone or in combinations for treating and/or preventing diseases and to their use for producing medicaments for treating and/or preventing diseases, in particular for treating and/or preventing cardiovascular diseases.

Description

 Substituted methyl pyrimidin-5-ylcarbamates and their use

The present application relates to novel, substituted methyl-pyrimidin-5-ylcarbamate, 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.

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.

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

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

in which

R ^{1 is} hydrogen or fluorine,

R ^{2 is} trideuteromethyl, (C 1 -C ₄ ) -alkyl, benzyl or amino, where (C 1 -C ₄ ) -alkyl is substituted by 1 to 3 substituents of fluorine, and wherein benzyl may be substituted by 1 to 3 substituents fluorine, 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, 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. 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 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 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. 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. Preferred in the context of the present invention are compounds of the formula (I) in which

R ^{1 is} hydrogen or fluorine,

R ^{2 is} trideuteromethyl, methyl, ethyl, benzyl or amino, wherein methyl and ethyl is substituted with 1 to 3 fluorine substituents, and wherein benzyl is substituted with a fluorine substituent, and their salts, solvates and solvates of the salts.

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

R ^{1 is} hydrogen, trideuteromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or amino, and their salts, solvates and solvates of the salts. Particularly preferred in the context of the present invention are compounds of the formula (I) in which

R ^{1 is} hydrogen,

R ^{2 is} 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or amino, 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} 2,2-difluoroethyl or 2,2,2-trifluoroethyl, and 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 R ^{2 is} trideuteromethyl, 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 ^{2 is} amino, 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} 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.

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 formula (III) R ^{2 χ1} (III) in which R ^{2 has} the meaning indicated above and

X ^{1 is} a suitable leaving group, such as mesylate, tosylate or halogen, in particular bromine or iodine, is reacted, and optionally the resulting compounds of formula (I) with the corresponding (i) solvents and / or (ii) acids or bases converted into their solvates, salts and / or solvates of the salts.

Inert solvents for process step (II) + (III) -> (I) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran (THF ), 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), dimethylsulfoxide (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 (II) + (III) - »(I) 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 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, l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Preference is given to sodium hydride or sodium bis (trimethylsilyl) amide. The reaction (II) + (III) -> (I) 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.

The preparation process described above is exemplified by the following synthesis scheme (Scheme 1):

Scheme 1

[a): NaH, THF]. The compounds of the formula (III) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature.

The compounds of the formula (II) are known from the literature (see, for example, WO 03/095451, Example 5) or can be prepared by reacting a compound of the formula (IV)

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 (V)

in which R ^{1 has} the abovementioned meaning and T ^{2 is} hydrogen or amino, cyclized, these then in an inert solvent with a suitable iodine source ^' compound of formula (VI)

(VI) 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 (VII)

to a compound of formula (VIII)

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 (IX)

to the compound of the formula (X)

then reacting these in an inert solvent with a suitable reducing agent to give a compound of the formula (XI)

in which R ^{1 has} the abovementioned meaning, reduced, and these are subsequently reacted with methyl chloroformate.

Inert solvents for process step (IV) - »(V) 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 (IV) -> (V) 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 (V) - »(VI) 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), NN'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone (ΝΜΡ), pyridine or acetonitrile. Preference is given to DMF.

The reaction (V) -> (VI) 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 (V) is amino, the reaction (V) - »(VI) is carried out 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 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. When T ² in formula (V) is hydrogen, the formation of formula (VI) is carried out 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 (VI) + (VII) -> (VIII) 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 (ΝΜΡ), pyridine, acetonitrile. Preferred is DMF. Suitable bases for process step (VI) + (VII) - »(VIII) 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 l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Cesium carbonate is preferred.

The reaction (VI) + (VII) -> (VIII) is generally carried out in a temperature range from 0 ° C to + 60 ° C, preferably at + 10 ° C to + 25 ° 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 (VIII) + (IX) - »(X) 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 (ΝΜΡ), pyridine , Acetonitrile, sulfolane or even water. It is likewise possible to use mixtures of the solvents mentioned. Dioxane is preferred.

As the palladium catalyst for process step (VIII) + (IX) - »(X) 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 (VIII) + (IX) -> (X) 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 (X) - »(XI) 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 (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, or others 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 (X) - »(XI) are, for example, palladium on activated carbon, platinum on carbon, palladium hydroxide or Raney nickel.

The reduction (X) - »(XI) 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. Inert solvents for process step (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, 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. Preference is given to dichloromethane

Suitable bases for the process step 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 such as sodium or potassium, Sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3 .0] non-5-ene (DBN). Preference is given to pyridine. The reaction (XI) -> (II) 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. The described preparation process can be exemplified by the following synthesis scheme (Scheme 2):

Scheme 2

[a): hydrazine hydrate, 1, 2-ethanediol; b): iodine, THF; c): 2-fluorobenzyl bromide, Cs ₂ C0 _3> DMF; d): Pd (PPh ₃ ) ₄ , hexabutylditin; e) H ₂ , Pd-C; f) ClCOOCH ₃ , pyridine, CH ₂ Cl ₂ ].

The compounds of the formula (IV) are commercially available, known from the literature [cf. eg, 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 3): Scheme 3

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

The compounds according to the invention act as potent stimulators of soluble guanylate cyclase, 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 node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary artery disease Syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, premature ventricular contraction (PVC), for the treatment and / or prophylaxis of thromboembolic Diseases and ischaemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, spasms of the coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or cardiac insufficiency-related edema, peripheral circulatory disorders, Reperfusion damage, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasty (PTCA), heart transplants and bypass operations, as well as micro- and macrovascular damage (vasculitis), increased levels of fibrinogen and low-density LDL as well as elevated levels of plasminogen activator inhibitor 1 (PAI-1), and treatment and / or 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 acutely 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 insufficiency in valvular heart failure, mitral stenosis, Mitral valve 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, Gangren, CREST syndrome, erythematosis, onychomycosis, rheumatic diseases and to promote wound healing can be used.

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

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure. For the purposes of the present invention, the term renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological 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 such as. 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, heart failure, uremia, anemia, electrolyte imbalances (eg, 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 such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorder, difficulty concentrating in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies , Dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment and / or prophylaxis of diseases of the central nervous system such as states of anxiety, tension and depression, central nervous conditional sexual dysfunctions and sleep disorders as well as for the regulation of pathological disorders of food, consumption and addiction 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 according to 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 ocular 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 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 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 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 further provides for the use of the compounds according to the invention for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders 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.

The present invention further relates to the use of the compounds according to the invention for the production 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 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;

Hypotensive 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-altering 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.

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 preferably implitapide, BMS-201038, R-103757 or JTT-130. In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.

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

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

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

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

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

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically 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 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. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For the parenteral application, suitable as application forms i.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. Such adjuvants include, but are not limited to, excipients (e.g., microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g., sodium dodecylsulfate, polyoxysorbitanoleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g. Albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg inorganic pigments such as iron oxides) and flavor and / or odoriferous agents. 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 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.

Starting compounds and intermediates:

Example 1A

 Methyl {4,6-diamino-2- [l- (2-fluorobenzyl) -lH ^

The synthesis of this compound is described in WO 03/095451, Example 5.

EXAMPLES

example 1

Memyl- {4,6-diamino-2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] pyrimidin-5- yl} ⁽² H ₃₎ methylcarbamate

There were 200 mg (0.490 mmol) of the compound of Example 1 A dissolved in 2 ml of THF, at 0 ° C with 43 mg (1.077 mmol) of sodium hydride (60% suspension in oil) and stirred for 90 min at 0 ° C. , 78 mg (0.539 mmol) of iodomethane-d _{3 were} added and the mixture was stirred at RT for 48 h. Water was added and the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (eluent: methanol: water, gradient 30:70 -> 90:10). 49 mg of the target compound were obtained (24% of theory).

LC-MS (Method 1): R, = 0.78 min; MS (EIpos): m / z = 426 [M + H] ⁺ .

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.52 (s, 1.9H), 3.65 (s, 1.1H), 5.80 (s, 2H), 6.34-6.38 (m, 4H) 7.06 -7.14 (m, 2H), 7.20-7.25 (m, 1H), 7.31-7.37 (m, 2H), 8.59 (dd, 1H), 9.06 (dd, 1H). Example 2

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

400 mg (0.979 mmol) of the compound from Example 1A were initially charged in 10 ml of THF and cooled to 0 ° C. Thereafter, 43 mg (1.077 mmol) of sodium hydride (60% in mineral oil) was added and it was stirred at 0 ° C with stirring for 30 min. Subsequently, 230 mg (1.077 mmol) of 2,2-difluoroethyl trifluoromethanesulfonate were added and the mixture was stirred at RT for 1 h. Thereafter, the same amount of sodium hydride and 2,2-difluoroethyl trifluoromethanesulfonate were added again and stirred at RT overnight. Following this, the reaction was stopped with 0.5 ml of water. The reaction mixture was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 198 mg of the target compound were obtained (42% of theory).

LC-MS (Method 1): R, = 0.86 min; MS (EIpos): m / z = 473 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.61 (s, 3H), 3.69-3.75 (m, 2H), 5.81 (s, 2H), 6.15-6.47 (m, 1H) , 6.55 (s br, 4H) 7.07-7.14 (m, 2H), 7.20-7.26 (m, 1H), 7.31-7.40 (m, 2H), 8.61 (dd, 1H), 9.04 (dd, 1H). Example 3

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

100 mg (0.245 mmol) of the compound from Example 1A were initially charged in 4 ml of THF and cooled to 0 ° C. Thereafter, 269 μΐ of an IM solution of bis (trimethylsilyl) sodium amide in THF was added, and it was stirred at 0 ° C for 30 minutes. Subsequently, 92 mg (0.49 mmol) of 4-fluorobenzyl bromide were added and it was stirred overnight at RT. Thereafter, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 3 1 mg of the target compound were obtained (24% of theory).

LC-MS (Method 1): R, = 0.95 min; MS (EIpos): m / z = 517 [M + H] ⁺ . Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.59 (s, 2.4H), 3.75 (s, 0.6H), 4.57 (s, 0.3H), 4.59 (s, 1.7H), 5.77 (s, 2H), 6.12 (s br, 4H) 7.03-7.12 (m, 4H), 7.20-7.26 (m, 1H), 7.29-7.42 (m, 4H), 8.58 (dd, 1H), 9.00 ( dd, 1H).

Example 4

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

100 mg (0.245 mmol) of the compound from Example 1A were initially charged in 4 ml of THF and cooled to 0 ° C. Thereafter, 269 μΐ of an IM solution of bis (trimethylsilyl) sodium amide in THF was added, and it was stirred at 0 ° C for 30 minutes. Subsequently, 92 mg (0.49 mmol) of 3-fluorobenzyl bromide were added and it was stirred overnight at RT. Thereafter, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 3 1 mg of the target compound were obtained (24% of theory).

LC-MS (Method 1): R, = 0.94 min; MS (EIpos): m / z = 517 [M + H] ⁺ . Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.60 (s, 2.4H), 3.75 (s, 0.6H), 4.59 (s, 0.5H), 4.61 (s, 1.5H), 5.72 (s, 0.6H), 5.77 (s, 1.4H), 6.19 (s br, 4H) 7.02-7.35 (m, 9H), 8.58 (dd, 1H), 9.01 (dd, 1H).

Example 5

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

100 mg (0.245 mmol) of Example 1A were initially charged in 4 ml of THF and cooled to 0 ° C. Thereafter, 269 μΐ of an IM solution of bis (trimethylsilyl) sodium amide in THF was added, and it was stirred at 0 ° C for 30 minutes. Subsequently, 92 mg (0.49 mmol) 2-fluorobenzyl bromide were added and it was stirred overnight at RT. Thereafter, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 37 mg of the target compound were obtained (29% of the TL).

LC-MS (Method 1): R, = 0.93 min; MS (EIpos): m / z = 517 [M + H] ⁺ . Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.60 (s, 2.4H), 3.75 (s, 0.6H), 4.69 (s, 0.4H), 4.71 (s, 1.6H), 5.72 (s, 0.7H), 5.78 (s, 1.3H), 6.13 (s br, 4H) 7.05-7.14 (m, 3H), 7.20-7.36 (m, 5H), 7.58 (t, 1H), 8.58 ( dd, 1H), 9.02 (dd, 1H).

Example 6

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

5,000 g (12,243 mmol) of Example 1A were suspended in 50 ml of THF, admixed at 0 ° C with 539 mg (13,467 mmol) of sodium hydride (60% suspension in mineral oil) and stirred at 0 ° C for 90 min had formed a solution. 3,791 g (13,467 mmol) of 2,2,2-trifluoroethyltrichloromethanesulfonate were added and the mixture was stirred at RT for 48 h. Water and IN hydrochloric acid were added and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: methanol / water, gradient 20:80 → 90:10). There were obtained 2,900 g of the target compound (48% of t.l.). LC-MS (Method 1): R, = 0.89 min; MS (EIpos): m / z = 491 [M + H] ⁺ .

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.63 (s, 3H), 4.06-4.15 (m, 2H), 5.80 (s, 2H), 6.40 (s br, 4H) 7.08- 7.14 (m, 2H), 7.20-7.25 (m, 1H), 7.32-7.38 (m, 2H), 8.61 (dd, 1H), 9.07 (dd, 1H).

Example 7

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

500 mg (1.224 mmol) of the compound obtained under Example 1A were initially charged in 12.5 ml of THF at 0 ° C. Then, 1,224 ml of an IM solution of sodium bis (trimethylsilyl) amide in THF was added dropwise, and it was stirred for additional 20 minutes at 0 ° C. Then, 334 mg (1836 mmol) of O- (4-nitrobenzoyl) hydroxylamine was added and stirred at room temperature for 2 h. The mixture was then concentrated to dryness. The residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). The combined product fractions were again purified by chromatography on silica gel (dichloromethane / methanol 100: 1). Finally, it was further purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). There were obtained 79 mg of the target compound (14% of theory).

LC-MS (Method 1): R, = 0.71 min; MS (ESIpos): m / z = 424 (M + H) ⁺

Ή NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.55 (s, 2.3H), 3.68 (s, 0.7H), 5.02 (s br, 2H), 5.80 (s, 2H), 6.37 (s br, 4H) 7.09-7.15 (m, 2H), 7.20-7.25 (m, 2H), 7.32-7.38 (m, 2H), 8.60 (dd, 1H), 9.04 (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]

1 172

2 220

4 107

5 272

6 149 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 TAI 1 PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial. The animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.

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

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

Substances and solutions

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

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

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

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

- Systolic blood pressure (SBP)

- Diastolic blood pressure (DBP) - Arterial mean pressure (MAP)

- heart rate (HR)

- Activity (ACT).

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

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

evaluation After the end of the test, the collected individual data are sorted with the analysis software (DATAQUEST TM ART 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 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 into folders sorted by number in Papierfbrm.

literature

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

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

Claims

claims

 1. Compound of formula (I)

 in which

R ^{1 is} hydrogen or fluorine,

R ^{2 is} trideuteromethyl, (C 1 -C ₄ ) -alkyl, benzyl or amino,

wherein (C 1 -C ₄ ) -alkyl is substituted by 1 to 3 substituents fluorine, and

 wherein benzyl may be substituted by 1 to 3 substituents fluorine, 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

R ^{1 is} hydrogen or fluorine,

R ^{2 is} trideuteromethyl, methyl, ethyl, benzyl or amino,

 wherein methyl and ethyl is substituted by 1 to 3 substituents fluorine, and

wherein benzyl is substituted with a substituent fluorine, and their salts, solvates and solvates of the salts.

A compound of the formula (I) according to claim 1 or 2, in which R ^{1 is} hydrogen,

R ^{2 is} 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or amino, 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 2, in an inert solvent in the presence of a suitable base with the compound of

Formula (III) r ^2-χ1 (III) in which R ^{2 has} the meaning given in claims 1 to 3 and

X ^{1 is} a suitable leaving group such as mesylate, tosylate or halogen, in particular bromine or iodine, is, and if appropriate, the resulting compounds of the formula (I) with the corresponding (i) solvents and / or (ii) acids or bases are converted into their solvates, salts and / or solvates of the salts.

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

6. Use of a compound of 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 diseases and arteriosclerosis.

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 diseases and arteriosclerosis.

8. 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 suitable excipient.

9. A medicament containing a compound of formula (I) as defined in any one of claims 1 to 3, in combination with another active ingredient selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, antithrombotic agents , antihypertensives and lipid metabolising agents.

10. 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

Humans and animals using an effective amount of at least one A compound of the formula (I) as defined in any one of claims 1 to 3 or a pharmaceutical composition as defined in any one of claims 8 to 10.