Pyrazole derivates, their preparation and their use in drugs

ES 2 345 249 T3

DESCRIPTION

Derivatives of pyrazole, their preparation and their use in medicines.

The present invention relates to pyrazole derivatives of Formula I,

<img file="ES2345249T3_D0001.tif" />

where X, R¹, R^1st, R², R³, R⁴ and n have the meanings indicated below, that they are valuable drug active substances for the therapy and prophylaxis of diseases, for example of cardiocirculatory diseases such as high blood pressure, angina pectoris, heart failure, thrombosis or atherosclerosis. The compounds of Formula I have the ability to modulate the body's own production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of disease states, which are associated with a disturbed balance of cGMP. The invention also concerns processes for the preparation of compounds of Formula I, their use for the therapy and prophylaxis of the indicated disease states and for the preparation of medicaments for these, as well as pharmaceutical preparations containing compounds of Formula I.

CGMP is an important intracellular messenger substance that, through modulation of cGMP-dependent protein kinases, phosphodiesterases and ion channels, causes a large number of different effects. Examples are smooth muscle relaxation, inhibition of thrombocyte activation, and inhibition of smooth muscle cell proliferation and leukocyte adhesion. CGMP is produced by guanylate cyclase (GC) in particulate and soluble form, in response to a series of extra- and intra-cellular stimuli. In the case of particulate guanylate cyclases, stimulation is effected primarily by signal peptide substances, such as atrial natriuretic peptide or brain natriuretic peptide. Soluble guanylate cyclases (sGC), which are cytosolic, heterodimeric heme proteins, are regulated, on the contrary, essentially by a family of low molecular weight factors, formed enzymatically. The most important stimulant is nitrogen monoxide (NO) or a closely related species. The importance of other factors such as carbon monoxide or the hydroxyl radical is still largely unclear. As a mechanism of activation by NO, the fixation of NO to heme mediating the formation of a pentacoordinated heme-nitrosyl complex is discussed. The associated release of iron-bound insulin in the basal state transforms the enzyme to the activated conformation.

Active soluble guanylate cyclases are composed of both α and β subunits. Of the subunits, several subtypes were described, which differ among themselves in terms of sequence, specific distribution in tissues, and expression at different stages of development. The α1 and β1 subtypes are expressed mainly in the brain and lungs, while β2 is found mainly in the liver and kidneys. The α subtype could be detected in a human fetal brain₂. The subunits designated as α₃ and β₃ were isolated from a human brain and are homologous with respect to α₁ and β₁. More recent works allude to a subunit a_2i, which contains an insert in the catalytic domain. All the subunits show high homologies in the region of the catalytic domains. The enzymes presumably contain one heme for each heterodimer, which is bound through β1Cys-78 and / or β₁ -His-105 and is part of the regulatory center.

Under pathological conditions, the formation of factors that activate guanylate cyclases can be reduced or, through the increased appearance of free radicals, an increased degradation of these can be effected. The resulting decreased activation of sGCs leads through the weakening of the respective cGMP-mediated cellular response, for example to increased blood pressure, to platelet activation or to cell proliferation and adhesion. cell phone increased. As a consequence of this, the genesis of endothelial dysfunction, atherosclerosis, blood hypertension, stable and unstable angina pectoris, thrombosis, myocardial infarction, strokes or erectile dysfunction occurs. Pharmacological stimulation of sGCs offers a possibility for the normalization of cGMP production and thereby enables the treatment or prevention of such diseases.

Compounds, the effect of which is based on an intermediate release of NO, for example organic nitrates, have so far been used almost exclusively for the pharmacological stimulation of sGC. The downside of this mode of

ES 2 345 249 T3 treatment lies in the development of tolerance and the weakening of the effects and the higher dosage that becomes necessary with it.

Different stimulators of sGC that did not act through a release of NO were described by Veseley in a large number of works. The compounds, which mostly consist of hormones, plant hormones, vitamins or, for example, natural substances such as reptile (lizard) poisons, however, generally have only weak effects on the formation of cGMP in lysed materials. cell phones (DL Veseley, Eur. J. Clin. Invest. fifteen (1985) 258; DL Veseley, Biochem. Biophys. Res. Comm. 88 (1979) 1244). A heme-free guanylate cyclase stimulation by protoporphyrin IX was found by Ignarro et al. (Adv. Pharmacol. 26 (1994) 35). Pettibone et al. (Eur. J. Pharmacol. 116 (1985) 307) describe a blood hypotensive effect for diphenyl iodonium hexafluorophosphate and attributed this to a stimulation of sGCs. Isoliquirritiginin, which shows a relaxing effect in isolated rat aortas, is active according to Yu et al. (Brit. J. Pharmacol. 114 (1995) 1587) also to sGCs. Ko et al. (Blood 84 (1994) 4226), Yu et al. (Biochem. J. 306 (1995) 787) and Teng et al. (Brit. J. Pharmacol. 116 (1995) 1973) detected a stimulatory activity of sGC of 1-benzyl-3- (5-hydroxymethyl-2-furyl) -indazole and demonstrated an antiproliferative and thrombocyte inhibitory effect. Different indazoles are described in European patent document EP-A-667 345 as inhibitors of thrombocyte aggregation.

Surprisingly, it was finally discovered that the pyrazole derivatives of the Formula I produce guanylate cyclase activation and are therefore suitable for therapy and prophylaxis of diseases, which are associated with a low level of cGMP.

The present invention therefore concerns compounds of Formula I,

<img file="ES2345249T3_D0002.tif" />

in which

X represents O;

R¹ represents an unsaturated alkyl radical with up to 10 carbon atoms, containing one or two double bonds or one or two triple bonds, or one double bond and one triple bond, and which is substituted with hydroxy;

R^1st represents hydrogen;

R² and R³, together with the carbon atoms that carry them, form a benzene ring, which is unsubstituted or is substituted with one or more R substituents⁵ the same or different, where R⁵ represents halogen, alkyl (C₁-C₃), CF₃or (Ci-C3) alkyl -O-;

R⁴ represents 5 or 6-membered phenyl or heteroaryl, which in each case is unsubstituted or is substituted with one or more substituents, taken from the series consisting of halogen, alkyl (C₁-C₃) and CF₃;

n represents 0, 1 or 2;

in all its stereoisomeric forms and mixtures of these in all ratios, as well as their physiologically compatible salts.

Alkyl radicals can be straight chain or branched. This also applies when they are contained in other groups, for example alkoxy groups. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3-dimethylbutyl, n- heptyl , noctyl, n-nonyl and n-decyl. In the case of the alkyl group, which represents R¹ or is contained in R¹The term "alkyl" means unsaturated alkyl radicals, which contain one or two double bonds or one or two triple bonds, or one double bond and one triple bond. Examples of such radicals are the vinyl radical, the 2-propeni radical

ES 2 345 249 T3 lo (allyl radical), 2-butenyl radical, 3-methyl-2-butenyl radical, ethynyl radical, 2-propynyl radical (propargyl radical) or 3-butynyl radical.

The phenyl radicals can be unsubstituted or substituted one or more times, for example two or three times, the substituents can be found in arbitrary positions. Monosubstituted phenyl radicals can be substituted at position 2, position 3 or position 4, disubstituted phenyl radicals can be substituted at position 2,3, position 2,4, position 2,5, position 2,6 , position 3,4 or position 3,5. In trisubstituted phenyl radicals, the substituents can be, for example, at the 2,3,4 position, the 2,3,5 position, the 2,3,6 position or the 3,4,5 position.

Examples of heterocyclic 5-membered and 6-membered ring systems, from which the 5- or 6-membered heteroaryl group can be derived, which may be unsubstituted or substituted, are pyrrole, furan, thiophene, imidazole, pyrazine, 1, 2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, all in each case in the most unsaturated form (the aromatic form). The heterocyclic radical can be attached through any carbon atom, for example in the case of radicals, which are derived from the furan system, from the thiophene system or from the pyrrole system, it can be attached in the 2-position or the 3-position, in the case of radicals, which are derived from the imidazole system or derived from the 1,3-thiazole system, can be attached at the 2-position, the 4-position or the 5-position, or in the case of radicals , which are derived from the pyridine system, It can be attached at the 2-position, at the 3-position or at the 4-position. Nitrogen heterocycles, which on a ring nitrogen atom may carry a substituent, can also be attached through a ring nitrogen atom, when the corresponding heterocyclic radical is attached to a carbon atom. Heterocycles can be substituted once or multiple times, for example twice, three times or four times, and in any positions. The substituents present on a heterocycle can also form a ring, ie fused heterocycles may be present, for example cyclopenta-fused, cyclohexa-fused or benzo-fused heterocycles. Suitable substituents on a nitrogen atom of a heterocycle are, for example, alkyl radicals (C₁ -C₃). Nitrogen heterocycles can also occur as N-oxides.

Halogen means, as long as nothing else is indicated, fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

When the benzene ring formed by R² and R³, in common with the carbon atoms that carry them, is substituted with one or more radicals R⁵, it is preferably substituted with one, two, three or four radicals R⁵the same or different, especially preferably with one or two radicals. Radicals R⁵ they can be in any position.

The substituent Rⁱ it can be found in any positions of the heterocycle, therefore in positions 3, 4 and 5 of the furan ring. In compounds of the formula IR² and R³, in common with the carbon atoms bearing them, form a benzene ring, namely benzopyrazoles (Formula Ia), which are also referred to as indazoles (the compounds according to the invention are 1H-indazoles). In the compounds of Formula Ia X, R¹, R^1st, R⁴, R⁵ and n have the meanings indicated above, and y, corresponding to the above data, represents 0 or an integer, preferably 0, 1, 2, 3 or 4, especially preferably 0, 1 or 2. The radicals R⁵, which can be the same or different, can be found at any positions on the carbocycle.

<img file="ES2345249T3_D0003.tif" />

If n, in Formula I, represents the number 0, the radical R⁴ it is attached directly to the nitrogen atom of the pyrazole.

Compounds of Formula I, in the case of a corresponding substitution, can occur in stereoisomeric forms. If the compounds of Formula I contain one or more centers of asymmetry, these, independently of one another, can have the S configuration or the R configuration. The invention includes all possible stereoisomers, for example enantiomers and diastereoisomers, and mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and / or diastereoisomers, in all ratios. The enantiomers are therefore the subject of the invention in pure enantiomeric form, both in the form of left-handed antipodes and also in the form of dextrorotatory antipodes, in the form of racemates and as mixtures of both enantiomers in all ratios. In the case of presenting a cis / trans isomerism, both the cis form and also the trans form and mixtures of these forms are the object of the invention. The preparation of individual stereoisomers can be carried out if desired by separating a mixture according to customary methods, for example by chromatography or crystallization.

ES 2 345 249 T3ization, by using stereochemically uniform starting substances during the synthesis, or by stereoselective synthesis. The separation of a mixture of stereoisomers can be carried out in the stage of the compounds of Formula I or in the course of the synthesis.

In the case of the presence of mobile hydrogen atoms, the present invention also encompasses all tautomeric forms of the compounds of Formula I, for example the lactam / lactime tautomers.

If the compounds of Formula I contain one or more acidic or basic groups, the corresponding physiologically or toxicologically compatible forms are also the subject of the invention, especially the pharmaceutically usable salts. Thus, the compounds of Formula I, which contain one or more acid groups, for example COOH groups, can occur together with these groups, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts, and are can be used according to the invention. Examples of such salts are sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, such as for example ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the formula I, which contain one or more basic groups, that is to say protonable, can be present in the form of their acid addition salts with inorganic or organic acids and can be used according to the invention, for example as salts with hydrochloric acid. , hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid , citric acid, adipic acid, etc. If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule, together with the salt forms that have been described, also internal salts, the so-called betaines, belong to the invention. The salts can be obtained from the compounds of Formula I according to customary procedures, known to a person skilled in the art, for example by combining with an organic or inorganic acid or base in a solvent agent. or dispersant, or also by anion exchange or cation exchange from other salts. The present invention also encompasses all salts of the compounds of the formula I, which due to their low physiological compatibility are not directly suitable for use in medicaments, but come into consideration, for example, as intermediates for chemical reactions or for the preparation physiologically compatible salts.

The present invention further encompasses all solvates of compounds of Formula I, for example hydrates or adducts with alcohols, as well as derivatives of compounds of Formula I, for example esters, prodrugs and metabolites, which act the same as the compounds of the Formula I.

R¹ preferably represents CH (OH) -alk, where alk represents an unsaturated alkyl radical, containing up to 5 carbon atoms and having the characteristics indicated above for an alkyl radical representing R¹ or contained in R¹. In a particularly preferred manner, the radical R¹ it is at position 5 of the heterocycle.

n preferably represents 0 or 1.

Radicals R⁵ that occur in radicals R² and R³, preferably represent CF₃.

A 5- or 6-membered heteroaryl radical preferably means the radical of an aromatic heterocycle having one, two, three or four heteroatoms from the series consisting of nitrogen, oxygen and sulfur, especially preferably with one or two heteroatoms, or it means the tetrazolyl radical. Very particularly preferably, a 5- or 6-membered heteroaryl means the radical of one of the aromatic heterocycles furan, thiophene, 1,3-thiazole, 1,3-oxazole, 1,2-oxazole, tetrazole, pyridine and pyrimidine, and even more preferably 1,3-thiazole or tetrazole. These radicals are attached through a carbon atom and can be unsubstituted or substituted as indicated above.

Preferred compounds of Formula I are those in which one or more of the radicals contained therein have preferred meanings, all combinations of preferred definitions of substituents being encompassed. Also of all the preferred compounds of Formula I, the present invention encompasses all their stereoisomeric forms and mixtures thereof in all ratios, as well as their physiologically compatible salts.

The compounds of Formula I can be prepared according to different procedures, which are described hereinafter and which are also the subject of the present invention.

The compounds of Formula I according to the invention, in which the radicals R² and R³ they form, in common with the carbon atoms that carry them, a benzene ring, that is to say compounds of the Formula Ia, they can be prepared by reacting compounds of the Formula VII with hydrazines of the Formula III or their salts. In Formulas VII and VIII the radicals X, R¹', R^1st', R⁴', R⁵'and the number n have the above meanings of X, R¹, R^1st, R⁴, R⁵and n. However, functional groups can also occur in these radicals in protected form or in the form of precursors. and has in the formulas Ia ', VII and VIII the meanings indicated above, and represents in this case, therefore, 0, 1, 2, 3 or 4. Z¹ in formulas VII and VIII it represents a leaving group, for example halogen or other suitable groups, such as the trifluoromethanesulfonyl radical. Preferably Z¹ represents fluorine. From the compounds of the formula Ia 'then, optionally, compounds of the formula Ia can be obtained according to

ES 2 345 249 T3 the invention, transforming in a subsequent reaction step the groups present in protected form or in the form of precursors into the desired functional groups mentioned in the previous definitions of R¹, R⁴ and R⁵.

<img file="ES2345249T3_D0004.tif" />

In the reactions of compounds of formulas VII and III, a hydrazone can be formed, that is to say a compound of formula VIII which can be isolated, depending on the reactivity of the starting substances used and the reaction conditions. . Depending on the particular case, it may be favorable to carry out the reaction of the compounds of the formulas III and VII by choosing the reaction conditions, such as solvents, temperature and catalyst, in such a way that first it only leads to the hydrazone of the Formula VIII and this, then in a separate step, is cyclized to form the indazole of the formula Ia ', but it may also be favorable to carry out the reaction so that the indazole results directly first. Again, in other cases, depending on the reactivities of the starting compounds, it may be suitable to carry out the reaction in two stages, and in the second stage, the cyclization of the hydrazone of formula VIII to give the indazole of formula Ia ', vary the reaction conditions. Thus, for example, when group Z¹ since the compound of the formula VII or of the formula VIII is not activated by substituents on the benzene ring, it is generally suitable to first condense the compounds of the formulas VII and III to form the hydrazone of the formula VIII, in the presence of an acid catalyst, and then carry out the cyclization in a second stage, working in the presence of a base, by which the nucleophilicity of the nitrogen atom β in the hydrazone group is increased. If the reaction is carried out in two stages, then for the cyclization of the hydrazone of formula VIII, the latter can be isolated, or the reaction mixture of the hydrazone preparation can be used in the cyclization, without isolation of the hydrazone. .

The reactions of compounds of the Formula VII with the hydrazines of the Formula III or their salts are preferably carried out in a dissolving or dispersing agent. Suitable solvents are, for example, water, alcohols, ethers, monoethers and dieters of ethylene glycol and di- and tri-ethylene glycol, esters, amides, nitriles, acids, sulfoxides and sulfones, hydrocarbons and chlorinated hydrocarbons. Examples of these solvents are methanol, ethanol, n-propanol, isopropanol or butanols, diethyl ether, dipropyl ether, dibutyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane, ethylene glycol monomethyl ether, ethylene glycol- monoethyl ether, ethylene glycol dimethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether or diethylene glycol dimethyl ether, acetic acid ethyl ester or acetic acid butyl ester, dimethyl formamide, dimethyl acetamide, N-methyl-pyrrolidone or hexamethyl-triamide of phosphoric acid, acetonitrile, acetic acid, dimethyl sulfoxide or sulfolane, fractions of benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, methylene chloride or chloroform. Mixtures of two or more solvents can also be used. Preferred solvents are alcohols such as methanol and ethanol. The reaction is generally carried out at temperatures from 0 ° C to 150 ° C, preferably at temperatures from 20 ° C to 130 ° C. It is especially preferred to carry it out under reflux at the boiling point of the solvent, for example at the boiling point of methanol or ethanol.

The duration of the reaction is oriented to the individual case and depends, for example, on the reactivity of the reaction partners and the reaction conditions. Treatment of the reaction mixture can be carried out

ES 2 345 249 T3 according to standard procedures and the product can be purified if desired according to customary purification methods, for example by recrystallization or chromatography.

If free hydrazines of the Formula III are used, in many cases it is especially advantageous to carry out the reaction with the dicarbonyl compounds of the Formula VII under acid catalysis. Suitable catalysts are, for example, carboxylic acids and organic sulfonic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid, inorganic acids such as hydrogen chloride, sulfuric acid or phosphoric acid, acid salts such as salts of ammonium or hydrogen phosphates, or acid ion exchangers. It may also be favorable to adjust a certain pH value or to work in the presence of a buffer system. The type and amount of an added acid catalyst are oriented to each individual case and depend, for example, on the reactivity of the reaction partners, the solvent or the expected temperature. If, for example, an acid such as acetic acid is used, this, depending on the amount used, can act both as a solvent as well as as a catalyst. For example, if an acid is used, such as acetic acid, it can act, depending on the amount used, both as a solvent and as a catalyst. It is preferred to carry out the reaction of compounds of the formula VII with free hydrazines of the formula III in the presence of acetic acid. If instead of a free hydrazine an acid addition salt of a hydrazine is used, for example a hydrazinium chloride or hydrazinium sulfate substituted with R⁴ - (CH₂)_n, as a result, an acid compound is already incorporated into the reaction mixture, which can act catalytically, and it is advantageous in many cases, in order to adjust a favorable pH value, to capture a part of the acid incorporated by adding a certain amount of a base, for example by adding sodium acetate.

The quantitative ratio, in which the compounds of Formulas II and III are advantageously used in the reaction, depends on each individual case. This ratio can be about 1: 1, but a reaction partner in a minor excess or a major excess can also be employed. When, for example, one partner in the reaction is prepared in a complex way in a multistage synthesis and the other partner in the reaction is easily accessible, for the broader use of the former it may be advantageous to use the latter in excess, for example in a molar amount of 1.1 to 5 times higher.

As already mentioned, the reaction of the compounds of the Formulas VII and III can be interrupted in the hydrazone step of the Formula VIII. The cyclization of the hydrazone, which is then carried out in a second stage, to form the indazole of Formula Ia ', which constitutes a nucleophilic substitution of the group Z¹ on the aromatic radical via the nitrogen atom β of the hydrazone group, depending on the reactivities which occur in each individual case, it can be effected, for example, by heating in a solvent or dispersing agent. In many cases it is advantageous to add a base at the same time. When in the case of the preparation of compounds of Formula Ia 'the cyclization is carried out in a separate stage, it is preferred to work in this stage in the presence of a base. Suitable bases are, for example, hydroxides, carbonates, hydrogen carbonates, hydrides, amides, alcoholates or organic metal compounds of alkali metals such as lithium, sodium, potassium or cesium, or of alkaline earth metals such as magnesium or calcium. Preferred bases are alkali metal alcoholates derived from alkanols (C₁-C₄), such as sodium and potassium methylates, sodium and potassium ethylates, and sodium and potassium tert-butylates. Mixtures of two or more bases can also be used. The base is preferably used in an equimolar amount or in excess, usually in an amount of 1 to 3 times the equimolar amount.

As dissolving or dispersing agents for a cyclization, carried out in a separate step, of a hydrazone of the Formula VIII to form indazole, for example, water, alcohols, ethers, monoethers and dieters of ethylene glycol and of di- and tri-ethylene glycols, esters, amides, nitriles, sulfoxides, sulfones, hydrocarbons and chlorinated hydrocarbons. Examples of these solvents have been mentioned above. Mixtures of two or more solvents can also be used. Preferred solvents for cyclization in the presence of a base are aprotic solvents, especially dipolar aprotic solvents such as dimethylformamide, dimethylacetamide, phosphoric acid hexamethyl triamide, N-methylpyrrolidone or dimethyl sulfoxide.

A cyclization of the hydrazone of the Formula VII, which is carried out in a separate step, is generally carried out at temperatures from 0 ° C to 150 ° C, preferably at temperatures from 20 ° C to 130 ° C. It is especially preferred, again, to carry them out under reflux at the boiling temperature of the solvent, or of the solvent mixture, that is used. The treatment can be carried out according to classical methods.

Another process for the preparation of compounds of Formula I or Ia ', together with the reaction of compounds of Formula VII with R-substituted hydrazines⁴'- (CH2) n of Formula III, is the reaction of compounds of Formula VII with acylhydrazines of Formula IX. In Formula IX, R may represent, for example, an alkyl radical, for example a (C1-C4) alkyl radical such as the methyl radical or the tert-butyl radical, or represent an aryl radical, for example a phenyl radical. , which may be unsubstituted or substituted. An example of a suitable compound of Formula IX is benzoic acid hydrazide. The reaction of the compounds of the Formulas VII and IX can be carried out under the same conditions as indicated above for the reaction of the compounds of the Formulas VII and III. All the above explanations are valid here accordingly. The reaction of the compounds of the Formulas VII and IX, which in turn can be carried out in a single stage or in two stages, leads firstly to the acyl-hydrazones or the acyl-indazoles corresponding to the Formulas VIII or Ia 'respectively, containing the R-CO group instead of the R group⁴'- (CH2)_n. After having removed the acyl group, the indazoles of Formula X are obtained from these compounds, in which X, R¹', R^1st, R⁵'and and have the meanings indicated above for Formulas Ia', VII and VIII.

ES 2 345 249 T3

<img file="ES2345249T3_D0005.tif" />

For the removal of the acyl group, the acyl compounds can first be isolated, but the removal can also be carried out in situ without their isolation. The removal of the acyl group can be carried out, for example, in the usual way by hydrolysis under acidic or basic conditions, for example by hydrochloric acid, sulfuric acid, phosphoric acid, lithium hydroxide, sodium hydroxide, sodium carbonate or hydroxide. potassium. This can be carried out in water or in an organic dissolving or dispersing agent containing water. The reaction temperature and the duration of this reaction are oriented to each individual case, generally working at temperatures from room temperature to 100 ° C. The indazoles of the Formula X unsubstituted in the 1-position can be isolated according to the usual methods or they can also be used directly in a consecutive reaction. The indazoles of Formula X can then be transformed by reaction with alkylating agents of Formula XI into the 1-substituted indazoles of Formula Ia '. In Formula XI, R⁴'and n have the meanings indicated above, Z²represents a leaving group, for example chlorine, bromine, iodine or a sulfonyloxy radical such as methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy. In general, the alkylating agent of Formula XI is used in equimolar amount or in excess, for example in an amount of 1 to 3 times the equimolar.

The alkylation of the compounds of Formula X can be carried out under the usual alkylation conditions. Preferably, it is carried out within a dissolving or dispersing agent, for example in water, an alcohol, an ether, a monoether or a diether of ethylene glycol and of di- and tri-ethylene glycols, of a ketone such as acetone or methyl ethyl ketone, an ester, an amide, a nitrile, a sulfoxide or a sulfone, a hydrocarbon or a chlorinated hydrocarbon. The above-mentioned examples of these solvents also apply in this case. It is also possible to use mixtures of two or more solvents, for example mixtures of an organic solvent with water. Preferably, the alkylation is carried out in water or in a dipolar aprotic solvent, for example dimethylformamide. The alkylation is generally carried out at temperatures from 0 ° C to 150 ° C, preferably at temperatures from 20 ° C to 130 ° C. It is especially preferred to carry it out at the boiling temperature of the solvent used.

The alkylation of the compounds of the Formula X with the compounds of the Formula XI is preferably carried out with the addition of a base. Suitable bases are, for example, the hydroxides, carbonates, acetates, hydrides or alcoholates of alkali metals such as lithium, sodium or potassium or of alkaline earth metals such as magnesium or calcium. Mixtures of bases can also be used. In general, the base is used in an equimolar amount or in excess, for example in an amount of 1 to 3 times the equimolar amount. Especially preferred are alkylation using potassium tert-butylate or sodium hydride within dimethylformamide, and the use of sodium hydroxide in water. Work-up of the reaction mixture can be carried out according to standard procedures and the product can be purified if desired by customary purification methods, for example by recrystallization or chromatography.

In the compounds of Formula Ia ', as already mentioned above, the radicals R¹', R⁴'and R⁵'as well as and have the meanings indicated in the definitions of R¹, R⁴ and R⁵, in such a way that the reaction products of Formula Ia ', obtained according to the synthesis procedures explained, already constitute compounds according to the invention of Formula Ia. However, in the compounds of Formula Ia ', obtained according to the synthetic procedures explained, structural modifications can still be carried out in a multiple and varied way. As already mentioned, the release of functional groups, which were present in protected form during the synthesis, can be treated in the case of these modifications. However, additional functional groups can also be introduced into compounds of the Formula Ia 'according to the invention according to customary chemical methods, or structural elements or functional groups present in compounds according to the invention can be modified according to customary methods. These methods are known to a person skilled in the art and are described in detail in classical works, for example in Houben-Weyl, Methoden der Organischen Chemie, editorial

ES 2 345 249 T3

Thieme, Stuttgart, or Organic Reactions, John Wiley &amp; Sons, New York. An optionally necessary adaptation of the reaction conditions to the reactivity of the compounds of the Formula Ia 'does not pose any problem to a person skilled in the art. By way of example, the following types of reaction will be mentioned:

Hydrolysis of carboxylic acid esters to form carboxylic acids or alcohols.

Transformation of carboxylic acids into carboxylic acid esters by esterification with alcohols in the presence of an acid, transformation of carboxylic acids into carboxylic acid esters by in situ activation of carboxylic acids and reaction with alcohols or transformation of carboxylic acids into reactive derivatives, for example in carboxylic acid chlorides by reacting the acids or their salts with chlorinating agents such as thionyl chloride, oxalyl chloride or phosphorous halides, and reaction of the reactive derivatives with alcohols to form carboxylic acid esters.

Reduction of carboxylic acid derivatives to form aldehydes or alcohols and reduction of aldehydes and ketones to form alcohols as well as reaction by addition of metallic organic compounds such as Grignard compounds or organic lithium compounds with carboxylic acid groups or groups of aldehydes or ketones mediating formation of ketones or alcohols.

Oxidation of alcohols to form aldehydes or ketones.

Etherification, halogenation and esterification of alcohols.

Nucleophilic substitutions on aliphatic carbon atoms.

Electrophilic aromatic substitution by replacement of a hydrogen atom in a carbocyclic or heterocyclic aromatic ring by a functional group, for example halogenation.

The starting materials of the Formula VII are known or can be prepared analogously to known compounds according to well-known classical procedures, described in the literature. The aromatic compounds of the Formula VII can be obtained, for example, by Friedel-Crafts acylations of furans with benzoic acid derivatives such as, for example, acid chlorides. More details about these reactions are found in the classics such as Houben-Weyl or Organic Reactions (see above). Also the hydrazines of the Formulas III and IX as well as the alkylating agents of the Formula XI are known or can be prepared according to well-known procedures, about which more detailed data can be found in these classical works.

The compounds of the Formula I according to the invention cause, through the activation of soluble guanylate cyclases (sGC), an increase in the concentration of cGMP and are therefore valuable agents for the therapy and prophylaxis of diseases. which are associated with or caused by a low or decreased level of cGMP, or for whose therapy or prophylaxis an increase in the existing level of cGMP is intended. The activation of sGC by the compounds of the Formula I can be investigated for example by means of the activity analysis described below, and their effect on the organs can be investigated for example by the determination of the relaxation of the aorta of a rat .

Diseases and pathological states, which are associated with a low level of cGMP, or in which an increase in the level of cGMP is intended and for whose therapy and prophylaxis compounds of the Formula I can be used, are for example cardio-circulatory diseases such such as endothelial dysfunction, diastolic dysfunction, atherosclerosis, high blood pressure, stable and unstable angina pectoris, thrombosis, restenosis, myocardial infarction, strokes, heart failure and pulmonary hypertonia or, for example, erectile dysfunction, bronchial asthma, chronic kidney failure and diabetes. The compounds of the Formula I can furthermore be used in the therapy of cirrhosis of the liver as well as, because of their partly synergistic effect with the NO retrograde messenger substance, to improve a limited learning capacity or a limited performance of the memory.

The compounds of the Formula I and their physiologically compatible salts can therefore be used in an animal, preferably in a mammal, and especially in a human being, as medicaments on their own, in mixtures with one another or in the form of pharmaceutical preparations. . Therefore, the object of the present invention are also the compounds of the Formula I and their physiologically compatible salts for use as medicaments, their use for the normalization of a disturbed balance of cGMP and especially their use in the therapy and prophylaxis of the aforementioned morbid pictures, as well as their use for the preparation of drugs for them. Furthermore, the object of the present invention is pharmaceutical preparations, which as an active component contain an effective dose of at least one compound of Formula I and / or of a physiologically compatible salt thereof, together with suitable pharmaceutically correct carrier materials and additive substances.

Medications can be administered orally, for example in the form of pills, tablets, film tablets, lozenges, granules, hard gelatin and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or by rectally, for example in the form of suppositories. However, administration can also take place parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or solutions for infusion. Other forms of application that come into consideration

ES 2 345 249 T3 doses are for example percutaneous or topical application, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or the application by inhalation in the form of nasal sprays or aerosol mixtures, or for example microcapsules, implants or rods (rods). The preferred form of application depends, for example, on the disease to be treated and its severity.

Pharmaceutical preparations normally contain from 0.5 to 90 percent by weight of the compounds of Formula I and / or their physiologically compatible salts. The pharmaceutical preparations can be produced in a manner known per se. For this, one or more of the compounds of Formula I and / or their physiologically compatible salts, together with one or more carrier materials and / or solid or liquid galenic adjuvant materials and, when desired, in combination with other active medicinal substances that have therapeutic or prophylactic effect are brought into an appropriate form of administration or dosage form, which can then be used as a medicine in human medicine or in veterinary medicine.

For the preparation, for example, of pills, tablets, dragees and hard gelatin capsules, lactose, starch, for example cornstarch, or derivatives of starches, talc, stearic acid or its salts, etc. can be used. Carrier materials for hard gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. Suitable carrier materials for the preparation of solutions, for example solutions for injection, or of emulsions or syrups, are suitable for example water, a physiological sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugars, glucose , handyman, vegetable oils, etc. The compounds of Formula I and their physiologically compatible salts can also be lyophilized, and the lyophilized materials obtained can be used, for example, for the production of preparations for injection or infusion. Suitable carrier materials for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

The pharmaceutical preparations can contain, together with the active substances and the carrier materials, in addition customary additive materials, for example fillers and fillers, disintegrating agents, binders, slip agents, humectants, stabilizers, emulsifiers, dispersants, preservatives, sweeteners. , colorants, flavorings or flavorings, thickeners and diluents, buffering substances and also solvents or solubilizers, or agents to achieve a delayed release (depot) effect, salts to modify the osmotic pressure, coating agents or antioxidants.

The dosage of the active substance of the Formula I to be administered and / or of one of the physiologically compatible salts thereof depends on each individual case and has to be adapted, as usual, to obtain an optimal effect to the particularities. individual. Thus, this dosage depends on the type and severity of the disease to be treated, as well as on the sex, age, weight and individual responsiveness of the person or animal to be treated, on the intensity of effect and duration of this effect of the compounds used, whether the therapy is carried out in an acute or chronic regimen or whether prophylaxis is carried out, or whether other active substances are administered together with the compounds of Formula I. In general, a daily dose of about 0.01 to 100 mg / kg, preferably 0.1 to 10 mg / kg, especially 0.3 to 5 mg / kg (in each case mg per kg of body weight) in the case of administration to an adult weighing about 75 kg, it is desirable to achieve effective results. The daily dose can be administered in a single dose or, especially in the case of the application of large amounts, in several, for example two, three or four individual doses. Eventually, depending on individual behavior, it may be necessary to deviate towards higher values ​​or lower values ​​with respect to the indicated daily dose. Pharmaceutical preparations normally contain 0.2 to 500 mg, preferably 1 to 200 mg of the active substance of the Formula I and / or its physiologically compatible salts for each dose.

Compounds of Formula I activate soluble guanylate cyclases. As a consequence of this property, they can be used, apart from as active medicinal substances in human medicine and veterinary medicine, also as a scientific tool or as adjuvant agents for biochemical research, in which such type of influence on guanylate is intended. -cyclases, as well as for diagnostic purposes, for example in the in vitro diagnosis of cellular or tissue samples. Furthermore, the compounds of the Formula I and their salts, as already mentioned above, can serve as intermediates for the preparation of other active medicinal substances.

The following Examples explain the invention, but do not limit it.

In the descriptions of the experiments they mean:

RT room temperature

THF tetrahydrofuran

DMF dimethylformamide.

ES 2 345 249 T3

Example 1

Potassium salt of 1-Benzyl-3- (5-carboxy-2-furyl) -indazole (starting material) la) 5- (2-Fluoro-benzoyl) -furan-2-carboxylic acid

132.6 g (0.53 mol) of 5- (2-fluoro-benzoyl) -furan-2-carboxylic acid methyl ester were incorporated into a solution of 31.47 g (0.56 mol) of potassium hydroxide in 350 ml of water and heated to 70 ° C. After 1 hr, the solution was filtered and acidified with concentrated hydrochloric acid. The precipitate was filtered off with suction and recrystallized from ethanol. 106.3 g (85%) of the title compound were obtained. Melting point: 195-196 ° C.

lb) 1-Benzyl-3- (5-carboxy-2-furyl) -indazole potassium salt

70.26 g (0.3 mol) of 5- (2-fluoro-benzoyl) -furan-2-carboxylic acid were previously placed in 350 ml of methanol, 109.95 g (0.9 mol) of benzyl were added -hydrazine and, after adding 8 ml of glacial acetic acid, it was heated under reflux for 6 h. For work-up, it was concentrated by rotary evaporation, the residue was taken up in 2N sodium hydroxide solution and extracted with ethyl acetate. The aqueous phase was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The residue, which remained after being dried and concentrated by rotary evaporation, was recrystallized from a mixture of ethyl acetate and n-hexane. The 68.3 g (0.20 mol) of benzyl-hydrazone of 5- (2-fluoro-benzoyl) -furan-2-carboxylic acid (melting point: 147 ° C (with decomposition)), obtained in this way, are dissolved in 400 ml of DMF, 45.38 g (0.40 mol) of potassium tert-butylate were added and the mixture was heated under reflux for 30 min. The deposited precipitate was filtered off with suction, washed with dichloromethane and recrystallized from a mixture of ethanol and water (95: 5). 57.7 g (54%) of the title compound were obtained. Corresponding cyclization of the parent compound, still contained in the mother liquor, provided 25.9 g of a product. Melting point:&gt; 300 ° C.

¹H-NMR (D₆-DMSO): δ = 5.73 (s, 2H, CH2), 6.68 (d, 1H, H-3 '), 6.92 (d, 1H, H-4'), 7.18-7 , 38 (m, 6H, phenyl-H, H5), 7.45 (t, 1H, H-6), 7.75 (d, 1H, H-7), 8.18 (d, 1H, H- 4).

Example 2

1-Benzyl-3- (5-ethoxycarbonyl-2-furyl) -indazole (starting material)

52.4 g (0.15 mol) of the potassium salt of 1-benzyl-3- (5-carboxy-2-furyl) -indazole were previously placed in 1250 ml of toluene and, after adding 200 ml of absolute ethanol and 50 ml of concentrated sulfuric acid, stirred under reflux in a water separator. After 3 h, it was concentrated by rotary evaporation, the remaining oil was taken up in a mixture of water and ethyl acetate, and the aqueous phase was separated. The organic phase was washed with water and a 7.5% NaHCO3 solution, dried over sodium sulfate and concentrated. The residue was recrystallized from isopropanol. 37.8 g (73%) of the title compound were obtained.

Melting point: 98-99 ° C.

Example 3

1-benzyl-3- (5-hydroxymethyl-2-furyl) -indazole (starting material)

2.06 g (54.6 mmol) of lithium aluminum hydride were previously introduced and a solution of 18.8 g (54.6 mmol) of 1-benzyl-3- (5-ethoxycarbonyl- 2-furyl) -indazole in 250 ml of THF. After 45 min, 25% potassium carbonate solution was added, stirring was continued for 30 min at RT, filtered off with suction and the precipitate was washed with THF. The combined organic phases were concentrated by rotary evaporation and the residue was recrystallized from isopropanol. 11.0 g (67%) of the title compound were obtained.

Melting point: 113-114 ° C.

Correspondingly, the following were prepared:

Example 4 (Starting material) 3- (5-carboxy-2-furyl) -1- (3,5-bis (trifluoromethyl) -phenyl) -indazole

Melting point: 256-257 ° C.

ES 2 345 249 T3

Example 5 (Starting material) 3- (5-ethoxycarbonyl-2-furyl) -1- (3,5-bis (trifluoromethyl) -phenyl) -indazole

Melting point: 128-129 ° C.

Example 6 (Starting material) 3- (5-hydroxymethyl-2-furyl) -1- (3,5-bis (trifluoromethyl) -phenyl) -indazole

Melting point: 136-138 ° C.

Example 8 (Starting materail) 1-benzyl-3- (5-methoxycarbonyl-2-furyl) -5-nitro-indazole

8a) 5- (2-Fluoro-5-nitro-benzoyl) -furan-2-carboxylic acid methyl ester

To a suspension of 2 g of iron (III) chloride and 29.0 g (0.14 mol) of 2-fluoro-5-nitro-benzoyl chloride in 100 ml of dry carbon tetrachloride was added dropwise a solution of 24.7 g (0.2 mol) of furan-2-carboxylic acid methyl ester in 50 ml of dry carbon tetrachloride, and heated for 14 h at reflux (80 ° C).

Then 50 ml of methanol were added, the mixture was stirred at RT for 30 min and concentrated by rotary evaporation. The remaining residue was taken up in ethyl acetate, washed with water and with a NaHCO solution.₃, dried over sodium sulfate, concentrated by rotary evaporation and recrystallized from isopropanol. 3.5 g (9%) of the title compound were obtained.

Melting point: 134-135 ° C.

8b) 1-benzyl-3- (5-methoxycarbonyl-2-furyl) -5-nitro-indazole

2.6 g (9 mmol) of 5- (2-fluoro-5-nitro-benzoyl) -furan-2-carboxylic acid methyl ester and 3.31 g (27 mmol) of benzyl-hydrazine were previously placed in approximately 60 ml of methanol and heated under reflux for 15 min after adding 0.2 ml of glacial acetic acid. The deposited precipitate was filtered off with suction, washed with a little methanol and dried at RT in a drying oven under vacuum. The crude product was purified by chromatography on silica gel with dichloromethane. 2.9 g (85%) of the title compound were obtained.

Melting point: 171-173 ° C.

Example 9 (Starting material) 5-aminO-1-benzyl-3- (5-methoxycarbonyl-2-furyl) -indazole

0.9 g (2.4 mmol) of 1-benzyl-3- (5-methoxycarbonyl-2-furyl) -5-nitro-indazole was dissolved by slight heating in 100 ml of a mixture of methanol and THF (1: 1), a solution of 2.5 g (14.4 mmol) of sodium dithionite in 50 ml of water was added and the mixture was stirred for 16 h at RT. For work-up, it was concentrated and the residue was chromatographed on silica gel with a mixture of dichloromethane and methanol (98.5: 1.5). 140 mg (17%) of the title compound were obtained.

Melting point: 195-196 ° C.

Example 10 (Starting material) 5-amino-1-benzyl-3- (5-hydroxymethyl-2-furyl) -indazole

To 0.01 g (0.3 mmol) of lithium aluminum hydride in 5 ml of THF was added dropwise a solution of 80 mg (0.23 mmol) of 5-amino-1-benzyl-3- ( 5-methoxycarbonyl-2-furyl) -indazole in 5 ml of THF and stirred at RT. After 3 h, 10 ml of K solution was added₂CO₃ 25% and stirring was continued for 30 min. The filtrate was filtered off with suction, boiled with THF, the combined organic phases were dried, concentrated and the residue was chromatographed on silica gel with dichloromethane / methanol (95: 5). 21 mg (29%) of the title compound were obtained.

Melting point: 156 ° C.

ES 2 345 249 T3

Example 11 (Starting material) 1-benzyl-3- (5-carboxy-2-furyl) -6-nitro-indazole) 5- (2-fluoro-4-nitro-benzoyl) -furan- 2-carboxylic

8.4 g of iron (III) chloride, 44.8 g (0.22 mol) of 2-fluoro-4-nitro-benzoyl chloride and 33.4 g (0.26 mol) were heated under reflux for 2 days of furan-2-carboxylic acid methyl ester in 80 ml of carbon tetrachloride. For the treatment, 100 ml of methanol were added, it was stirred for 10 min, it was concentrated, the residue was taken up in a mixture of ethyl acetate and water, and the organic phase was extracted multiple times by stirring with a Na2CO3 solution. The residue, which remained after the ethyl acetate phase had been dried and concentrated, was extracted with methanol and the insoluble portion was chromatographed on silica gel with dichloromethane. 19.0 g (29%) of the title compound were obtained.

Melting point: 136-138 ° C.

llb) 5- (2-Fluoro-4-nitro-benzoyl) -furan-2-carboxylic acid

14.5 g (49 mmol) of 5- (2-fluoro-4-nitro-benzoyl) -furan-2-carboxylic acid methyl ester were added to 200 ml of 0.1N sodium hydroxide solution and stirred for 3 days at TA. It was then adjusted to pH 4 with 1N hydrochloric acid, cooled for 30 min in an ice bath and filtered with suction. 8.6 g (62%) of the title compound were obtained. Melting point: 170 ° C (with decomposition).

¹H-NMR (D₆-DMSO): δ = 7.39 (d, 1H, H-4 '), 7.50 (d, 1H, H-3'), 8.00 (dd, 1H, H-6), 8.25 (dd, 1H, H-5), 8.34 (dd, 1H, H-3).

llc) 1-Benzyl-3- (5-carboxy-2-furyl) -6-nitro-indazole

8.5 g (30 mmol) of 5- (2-fluoro-4-nitro-benzoyl) -furan-2-carboxylic acid were dissolved in 100 ml of methanol, mixed with 11.2 g (91 mmol) of benzyl-hydrazine and heated under reflux for 7 h. It was then poured into water, adjusted to pH 4 with concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried and concentrated. The crude intermediate was dissolved in 50 ml of DMF to perform cyclization, 6.8 g (61 mmol) of potassium tert-butylate was added, and heated under reflux for 3 h. For the treatment, it was concentrated, adjusted to pH 4 with 1N hydrochloric acid, extracted with ethyl acetate, the organic phase was concentrated and the residue was chromatographed on silica gel with a mixture of ethyl acetate and glacial acetic acid. (60: 1). 8 g (about 73%) of the title compound were obtained as an oil.

¹H-NMR (D₆-DMSO): δ = 5.96 (s, 2H, CH₂), 7.22-7.41 (m, 7H, phenyl-H, H-3 ', H-4'), 8.13 (dd, 1H, H-5), 8.38 (d, 1H, H-4), 8.93 (d, 1H, H-7).

Example 12 (Starting material) 3- (5-carboxy-2-furyl) -1- (2-phenyl-ethyl) -indazole g (21 mmol) of 5- (2-fluoro-benzoyl) -furan-2 acid -carboxylic acid, 12 g (51 mmol) of (2-phenyl-ethyl) hydrazinium sulfate and 8.4 g (102 mmol) of sodium acetate were refluxed for 12 h in 50 ml of ethanol. It was then concentrated, mixed with stirring with a mixture of water and ethyl acetate, the ethyl acetate phase was separated, dried and concentrated. The crude intermediate product (hydrazone) was chromatographed, for purification, on silica gel with a mixture of dichloromethane and methanol (9: 1). 4 g (11.3 mmol) of the hydrazone were dissolved in 20 ml of DMF and heated under reflux for 3 h together with 2.5 g (23 mmol) of potassium tert-butylate. The precipitated potassium salt of the title acid was filtered off with suction. The concentrated filtrate was chromatographed on silica gel with a mixture of dichloromethane and methanol (7: 3). In total 1.9 g (27%, calculated for acid) of the title compound were obtained. As a by-product, 3- (5-carboxy-2-furyl) -indazole was formed.

Melting point: with decomposition&gt; 190 ° C.

¹H-NMR (D₆-DMSO): δ = 3.20 (t, 2H, CH₂-phenyl), 4.65 (t, 2H, CH₂-N), 7.00 (m, 2H, H-3 ', H-4'), 7.13-7.23 (m, 6H, phenyl-H, H-5), 7.38 (t, 1H, H-6), 7.60 (d, 1H, H-7), 8.14 (d, 1H, H-4).

Example 13 (Starting material) 3- (5-ethoxycarbonyl-2-furyl) -1- (2-phenyl-ethyl) -indazole

0.8 g (2.4 mmol) of 3- (5-carboxy-2-furyl) -1- (2-phenyl-ethyl) -indazole were mixed with 25 ml of ethanol, 150 ml of toluene and 2 ml of concentrated sulfuric acid, and heated for 3 h in a water separator apparatus. The

ES 2 345 249 T3 Chromatography of the residue, obtained after having been concentrated by rotary evaporation, carried out on silica gel with a mixture of dichloromethane and hexane (2: 1) yielded 400 mg (46%) of the title compound.

¹H-NMR (D₆-DMSO): δ = 1.40 (t, 3H, CH₃), 3.34 (t, 2H, CH2-phenyl), 4.35 (q, 2H, OCH2), 4.73 (t, 2H, CH2-N), 7.08-7.37 (m, 6H , phenyl-H, H-3 '), 7.38 (t, 1H, H-5), 7.45 (t, 1H, H-6), 7.48 (d, 1H, H-4') , 7.65 (d, 1H, H-7), 8.10 (d, 1H, H-4).

Example 14 (Starting material) 3- (5-hydroxymethyl-2-furyl) -1- (2-phenyl-ethyl) -indazole

To 31.5 mg (0.83 mmol) of lithium aluminum hydride in 10 ml of THF was added a solution of 3- (5-ethoxycarbonyl-2-furyl) -1- (2-phenyl-ethyl) -indazole in 10 ml of THF. After 1 h, 25% potassium carbonate solution was added, the precipitate was separated and washed with THF. The combined THF filtrates were dried and concentrated. The crude product was purified by chromatography on silica gel with dichloromethane / methanol (95: 5). 220 mg (75%) of the title compound were obtained.

¹H-NMR (D6-DMSO): δ = 3.20 (t, 2H, CH2-phenyl), 4.53 (s broad, 2H, CH2O), 4.66 (t, 2H, CH2-N), 6 , 50 (d, 1H, H-3 '), 6.98 (d, 1H, H-4'), 7.15-7.27 (m, 6H, phenyl-H, H-5), 7, 38 (t, 1H, H-6), 7.58 (t, 1H, H-7), 8.08 (d, 1H, H-4).

Example 15 (Starting material) 3- (5-carboxy-2-furyl) -indazole

2.5 g (11 mmol) of 5- (2-fluoro-benzoyl) -furan-2-carboxylic acid, 3.28 g (24 mmol) of benzoic acid hydrazide and 2 drops of glacial acetic acid in 50 ml of ethanol. It was then concentrated by rotary evaporation, the residue was taken up with water, made alkaline with a NaHCO solution₃ 2N and extracted with ethyl acetate. The aqueous phase was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried and concentrated by rotary evaporation. The residue was dissolved in 25 ml of DMF, 2.74 g (24.2 mmol) of potassium tert-butylate was added, and it was stirred at reflux for 1.5 h. After cooling, it was concentrated by rotary evaporation, the residue was taken up in 1N sodium hydroxide solution and extracted with ethyl acetate. The precipitate deposited on acidifying the aqueous phase was filtered with suction, washed with water and dried in a vacuum drying oven at 40 ° C. 1.88 g (75%) of the title compound were obtained. Melting point: 205 ° C (with decomposition).

¹H-NMR (D6-DMSO): δ = 7.15 (d, 1H, H-3 '), 7.28 (t, 1H, H-5), 7.40 (d, 1H, H-4' ), 7.48 (t, 1H, H-6), 7.63 (d, 1H, H-7), 8.15 (d, 1H, H-4), 13.1 (s broad, 1H, COOH), 13.54 (s broad, 1H, H-1).

Example 16 (Starting material) 3- (5-ethoxycarbonyl-2-furyl) -indazole

1.75 g (7.7 mmol) of 3- (5-carboxy-2-furyl) -indazole, together with 2.5 ml of concentrated sulfuric acid in 60 ml of toluene and 20 ml of ethanol, were heated in a water separating apparatus. The usual work-up gave 1.2 g (60%) of the title compound.

¹H-NMR (D₆-DMSO): δ = 1.36 (t, 3H, CH₃), 4.35 (q, 2H, CH₂), 7.10 (d, 1H, H-3 '), 7.30 (t, 1H, H-5), 7.44 (t, 1H, H-6), 7.46 (d, 1H, H-4 '), 7.64 (d, 1H, H-7), 8.13 (d, 1H, H-4), 13.60 (s broad, 1H, H-1).

Example 17 (Starting material) 1 - ((5-chloro-2-thienyl) -methyl) -3- (5-ethoxycarbonyl-2-furyl) -indazole

600 mg (2.3 mmol) of 3- (5-ethoxycarbonyl-2-furyl) -indazole, together with 265 mg (2.4 mmol) of potassium tert-butylate, were previously placed in 10 ml of DMF, 430 mg (2.6 mmol) of 2-chloro5- (chloromethyl) -thiophene in 1 ml of DMF were added dropwise and the mixture was stirred for 2 h at RT. Usual work-up gave 350 mg (41%) of the title compound.

Melting point: 124-126 ° C.

ES 2 345 249 T3

Example 18 (Starting material) 1 - ((5-chloro-2-thienyl) -methyl) -3- (5-hydroxymethyl-2-furyl) -indazole

The compound was prepared analogously to Example 14, from 1 - ((5-chloro-2-thienyl) -methyl) -3- (5-ethoxycarbonyl-2-furyl) -indazole, by reduction with lithium aluminum hydride.

¹H-NMR (D6-DMSO): δ = 4.50 (d, 2H, CH2O), 5.35 (t, 1H, OH), 5.88 (s, 2H, N-CH2), 6.48 ( d, 1H, thiophen-H-3), 6.98 (m, 2H, H-3 ', thiophen-H-4), 7.26 (t, 1H, H-5), 7.41 (t, 1H, H-6), 7.81 (d, 1H, H-7), 8.10 (d, 1H, H-4).

Example 41 (Starting material) 1- (benzyl-3- (5-formyl-2-furyl) -indazole

7.7 g (25.3 mmol) of 1- (benzyl-3- (5-formyl-2-furyl) -indazole and 11 g (126.5 mmol of activated manganese (IV) oxide were stirred under reflux for 4.5 h in 200 ml of carbon tetrachloride. For work-up, it was filtered with suction, the filtrate was washed with water, dried and concentrated by rotary evaporation. The crude product was recrystallized from isopropanol. 4.8 g were obtained. (63%) of the title compound.

Melting point: 108 ° C.

Example 42 (Reference example)

1- (benzyl-3- (5- (1-hydroxypropyl) -2-furyl) -indazole

To 300 mg (0.99 mmol) of 1- (benzyl-3- (5-formyl-2-furyl) -indazole in 20 ml of diethyl ether, 1.1 ml (1 , 1 mmol) of a 1 M solution of ethylmagnesium bromide in THF After 1 h at 10 ° C, it was poured into ice-water, extracted with ethyl acetate, dried and concentrated.The crude product was purified by means of Chromatography on silica gel with dichloromethane / methanol (95: 5), 200 mg (61%) of the title compound were obtained.

¹H-NMR (D₆-DMSO): δ = 0.95 (t, 3H, CH3), 1.80 (m, 2H, CH2-CO), 4.55 (m, 1H, CH-O), 5.36 (s broad, 1H, OH), 5.78 (s, 2H, CH₂-phenyl), 6.43 (d, 1H, H-3 '), 6.94 (d, 1H, H-4'), 7.20-7.38 (m, 6H, phenyl-H, H- 5), 7.45 (t, 1H, H6), 7.75 (d, 1H, H-7), 8.12 (d, 1H, H-4).

Analogously to Example 42, the following was obtained:

Example 44

1- (benzyl-5- (5- (1-hydroxypropyl-2-in-1-yl) -2-furyl) -indazole

Melting point: 151 ° C.

Example 50 (Starting material) 3- (5-carboxy-2-furyl) -1- (4-trifluoromethyl-pyrimidin-2-yl) -indazole hydrochloride

1.3 g (5.7 mmol) of 3- (5-carboxy-2-furyl) -indazole were dissolved together with 1.3 g (11.4 mmol) of potassium tert-butylate in 5 ml of dry DMF and they were mixed with 2-chloro-4-trifluoromethyl-pyrimidine, dissolved in 5 ml of DMF. After stirring at 60 ° C for 3 h, it was concentrated, taken up in 500 ml of water, extracted with ethyl acetate and the hydrochloride was separated from the aqueous phase by adding 1N hydrochloric acid. 420 were obtained. mg (25%) of the title compound.

Melting point: 258-261 ° C.

Pharmacological Investigations

1) Activation of soluble guanylate cyclase

The activation of soluble guanylate cyclase (sGC), which catalyzes the transformation of guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP) and pyrophosphate, by the compounds according to the invention, was quantified with the aid of an enzymatic analysis. EIA of the entity Amersham. For this, the substances subjected

ES 2 345 249 T3 tested were first incubated with sGC in microtiter plates and then the amount of the resulting cGMP was determined.

The sGC used had been isolated from a bovine lung (see Methods in Enzymology, Volume 195, page 377). The solutions tested (100 µ per well) contained 50 mM triethanolamine (TEA) buffer (pH 7.5), MgCl₂ 3 mM, 3 mM reduced glutathione (GSH), 0.1 mM GtP, 1 mM 3-isobutyl-1-methyl-xanthine (IBMX), an appropriately diluted enzyme solution as well as the test substance or solvent, in the case of control experiments. The test substances were dissolved in dimethyl sulfoxide (DMSO) and the solution was diluted in a mixture of DMSO and water, whereby the final concentration of the test substance in the test solution was 50 pM. The DMSO concentration in the tested solution was 5% (v / v). The reaction was started by adding the sGC. The reaction mixture was incubated for 15 to 20 minutes at 37 ° C and then stopped by ice cooling and addition of the stop reagent (50 mM EDTA, pH 8.0). A 50 µl aliquot was removed and used for cGMP content determination with the acetylation protocol of the Amersham cGMP-EIA assay kit. The absorption of the samples was measured at 450 nm (reference wavelength 620 nm) on a microtiter plate reading apparatus. The cGMP concentration was determined through the calibration curve, which had been obtained under the same experimental conditions. Activation of sGC by a test substance is indicated as stimulation at a multiple in n of the basal enzyme activity, which was found in the control experiments (with solvent, rather than the test substance) (calculated according to the Formula

Multiple stimulation at n = [cGMP]_theirt_old test / [cGMP]_teafollow)

The following values ​​were determined:

Compound Concentration Multiple stimulation in n

Example 44 100 pM multiple of 3.2

2) Relaxation of the rat aorta

For this test, normotensive male Wistar-Kyoto rats were killed by a blow to the neck. The ventral space and rib cage were opened using a central sternotomy. The descending aorta was then removed, freed from connective tissue, and subdivided into 8 rings with a length of approximately 4 mm. In the lumen of 4 of the 8 rings, the tip of a pin was incorporated. By careful rolling movements of the rings on the tip of the pin, the endothelium was removed. All 8 aortic rings (4 with endothelium and 4 without endothelium) were then hung inside an organ bath (Schuler organ bath; Hugo Sachs Elektronik) with constant temperature of 37 ° C for isometric measurement of contractile tone. . The rings were calibrated for 30 minutes with a resting tension of 1 g in a carbonated solution of Krebs-Henseleit (95% O₂; 5% CO₂) (composition: Na⁺144.0 mM; K⁺ 5.9 mM; Cl^- 126.9 mM; AC²⁺ 1.6 mM; Mg²⁺ 1.2 mM; H2PO4^- 1.2 mM; SO4^2- 1.2 mM; HCO3^- 25.0 mM; 11.1 mM D-glucose) with a pH value of 7.4. In addition, 1 pmol / l indomethazine was added to the Krebs-Henseleit solution for inhibition of prostaglandin biosynthesis. The rings were then pre-contracted by addition of phenylephrine (concentration in solution: 1 pM) and endothelium-dependent relaxation or functional loss of endothelium was tested by addition of acetylcholine (concentration in solution: 1 juM). Following a 30 minute wash period, the rings were then pre-contracted again by the addition of phenylephrine (1 pM) and by administration of cumulative doses of the tested Formula I substances their relaxing effect was determined. The evaluation of the data is carried out according to classical procedures. The IC50 concentration is indicated, by which the contraction is inhibited by 50% (50% relaxation).