HK1023119B - Novel substituted pyrazole derivatives for the treatment of cardiocirculatory diseases - Google Patents

Description

Novel substituted pyrazole derivatives for the treatment of cardiovascular diseases

The present invention relates to novel substituted pyrazole derivatives, to processes for their preparation and to their use as medicaments, in particular for the treatment of cardiovascular diseases.

The effect of 1-benzyl-3- (substituted heteroaryl) -fused pyrazole derivatives in inhibiting platelet aggregation has been disclosed (see EP667345a 1).

The present invention relates to novel substituted pyrazole derivatives represented by the general formula (I) and isomers and salts thereof,

wherein

R¹Represents a saturated OR aromatic 5-OR 6-membered heterocycle, where the heterocycle contains up to 3 heteroatoms from the group S, N and/OR O, the heterocycle may be bonded via a nitrogen atom and may optionally be substituted up to 3 times by identical OR different amino, azido, formyl, mercapto, carboxyl, hydroxyl, OR straight-chain OR branched acyl, alkoxy, sulfanyl, OR alkoxycarbonyl containing up to 6 carbon atoms, OR by nitro, cyano, halogen, phenyl OR straight-chain OR branched alkyl containing up to 6 carbon atoms, where said straight-chain OR branched alkyl may be substituted by hydroxyl, amino, azido, carboxyl, OR straight-chain OR branched acyl, alkoxy, alkoxycarbonyl, OR amido containing up to 5 carbon atoms OR by the formula-OR⁴The group represented by (a) is substituted,

wherein

R⁴Represents a straight-chain or branched acyl radical having up to 5 carbon atoms or a radical of the formula-SiR⁵R⁶R⁷A group represented by (A) a group,

wherein R is⁵、R⁶And R⁷Are identical or different radicals and represent aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or heterocyclic ring systemsor-S (O) c-NR⁹R¹⁰The group represented by (a) is substituted,

wherein a, b and b' are identical or different numbers and represent 0, 1, 2 or 3,

R⁸represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

c represents a number of 1 or 2,

R⁹and R¹⁰Are identical or different radicals and represent hydrogen or a linear or branched alkyl radical having up to 10 carbon atoms, where the alkyl radical may optionally be substituted by cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms, the cycloalkyl and aryl radicals may be substituted by halogen, or R⁹And R¹⁰Represents aryl having 6 to 10 carbon atoms which is optionally substituted by halogen, or represents cycloalkyl having 3 to 7 carbon atoms, or

R⁹And R¹⁰Together with the nitrogen atom, form a 5-or 7-membered saturated heterocyclic ring optionally containing an oxygen atom or-NR¹¹A group represented by (A) a group,

wherein R is¹¹Represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, orRepresents a group or represents benzyl or phenyl, wherein the ring system may optionally be substituted by halogen,

R²and R³Together, including the double bond between them, form a 6-membered saturated or aromatic heterocycle containing up to 3 heteroatoms selected from S, N and/or O, which may optionally be substituted up to 3 times by identical or different formyl, carboxyl, hydroxyl, mercapto, or straight or branched acyl, sulfanyl or alkoxycarbonyl containing up to 6 carbon atoms, or nitro, cyano, halogen, or straight or branched alkyl or alkoxy containing up to 6 carbon atoms, which may optionally be substituted by hydroxyl, amino, carboxyl, or straight or branched acyl, alkoxy or alkoxycarbonyl containing up to 5 carbon atoms, and/or the heterocycle may optionally be substituted by-NR¹²R¹³or-S (O) c' NR^9’R^10’The group represented by (a) is substituted,

wherein R is¹²And R¹³Are identical or different radicals and representHydrogen or a linear or branched alkyl group containing up to 6 carbon atoms, or

R¹²Represents hydrogen and R¹³Represents a formyl group,

c’、R^9’and R^10’The definition of (1) and c, R above⁹And R¹⁰And are identical to c, R⁹And R¹⁰Are identical or different radicals, and/or the heterocycles may optionally be substituted by phenyl, where the phenyl radicals may be substituted identically or differently by halogen or straight-chain or branched alkyl or alkoxy having up to 6 carbon atoms, up to 2 times, and/or the heterocycles may optionally be substituted by radicals of the formula-N ═ CH-NR¹⁴R¹⁵The group represented by (a) is substituted,

wherein R is¹⁴And R¹⁵Are identical or different radicals and represent hydrogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,

a represents a 5-or 6-membered aromatic or saturated heterocycle containing up to 3 heteroatoms from the group S, N and/or O or a phenyl group, each heterocycle or phenyl group being optionally substituted up to 3 times by the same or different amino, mercapto, hydroxyl, formyl, carboxyl, or straight-chain or branched acyl, sulfanyl, alkyloxyacyl, alkoxy or alkoxycarbonyl containing up to 6 carbon atoms, or nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl containing up to 6 carbon atoms, where said straight-chain or branched alkyl may be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl containing up to 5 carbon atoms, and/or the heterocycle may be substituted by a group of the formula- (CO)_d-NR¹⁶R¹⁷The group represented by (a) is substituted,

wherein

d represents the number 0 or 1 and,

R¹⁶and R¹⁷Are identical or different radicals and represent hydrogen, phenyl, benzyl or a straight-chain or branched alkyl or acyl radical having up to 5 carbon atoms.

The compounds of the general formula (I) according to the invention can also be present in the form of their salts. The present invention relates generally to salts of compounds of formula (I) with organic or inorganic bases or acids.

In the present invention, physiologically acceptable salts are preferred. The physiologically acceptable salts of the compounds according to the invention may be salts of the compounds according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citraconic acid, fumaric acid, maleic acid or benzoic acid.

In the context of the present invention, physiologically acceptable salts can also be metal or ammonium salts of compounds containing free carboxyl groups. Particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or organic amines, such as ethylamine, diethylamine or triethylamine, diethanolamine or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention may exist in the form of stereoisomers which may or may not be as images and mirror images of each other (enantiomers). The present invention relates to enantiomers, as well as to diastereomers, and to the respective mixtures thereof. Like diastereomers, racemic compounds can also be resolved into the individual components of the stereoisomers by known techniques.

The heterocycles described in the invention, depending on the substituents mentioned above, generally represent saturated or aromatic 5-or 6-membered heterocycles containing up to 3 heteroatoms selected from S, N and/or O and being able to be bonded via the N atom, examples of heterocycles being: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, 1, 2, 3-triazolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl or piperidinyl. Thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl are preferred.

Preferred compounds of the formula (I) are

Wherein

R¹Represents pyrimidinyl, pyridazinyl, pyridinyl, pyrazinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, 1, 2, 3-triazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, pyranyl or morpholinyl, wherein each heterocycle may be optionally substituted up to 3 times by the same or different amino, formyl, mercapto, carboxyl, hydroxyl, or straight or branched acyl, alkoxy, sulfanyl or alkoxycarbonyl containing up to 5 carbon atoms, or nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight or branched alkyl containing up to 5 carbon atoms, wherein said straight or branched alkyl may be substituted up to 3 times by hydroxyl, amino, azido, carboxyl or straight or branched acyl containing up to 5 carbon atoms, Alkoxy, alkoxycarbonyl, OR amido substituted OR substituted by a group of formula-OR⁴The group represented by (a) is substituted,

wherein

R⁴Represents straight-chain or branched acyl and/or heterocyclic ring containing up to 4 carbon atomsor-S (O) c-NR⁹R¹⁰The group represented by (a) is substituted,

wherein a, b and b' are identical or different numbers and represent 0, 1, 2 or 3,

R⁸represents hydrogen or a linear or branched alkyl group containing up to 3 carbon atoms,

c represents a number of 1 or 2,

and R is⁹And R¹⁰Are identical or different radicals and represent hydrogen or a straight-chain or branched chain having up to 9 carbon atomsAlkyl, wherein alkyl may optionally be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or naphthyl or phenyl, said substituents may be substituted by fluorine or chlorine, or R⁹And R¹⁰Represents phenyl or naphthyl, which are optionally substituted by fluorine or chlorine, or R⁹And R¹⁰Represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or R⁹And R¹⁰Together with the nitrogen atom forming a morpholine ring or formulaOrA group represented by (A) a group,

wherein R is¹¹Represents hydrogen, methyl orA group represented by or representing benzyl or phenyl, wherein said ring system may optionally be substituted by fluorine or chlorine,

R²and R³Together, including the double bond between them, form a pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl ring, wherein each heterocyclic ring may be optionally substituted up to 3 times by the same or different formyl, carboxyl, hydroxyl, mercapto, or straight or branched acyl, alkylthio, or alkoxycarbonyl groups containing up to 5 carbon atoms, or nitro, cyano, azido, fluorine, chlorine, bromine, or straight or branched alkyl or alkoxy groups containing up to 5 carbon atoms, wherein said straight or branched alkyl or alkoxy groups may be substituted by hydroxyl, amino, carboxyl, or straight or branched acyl, alkoxy, or alkoxycarbonyl groups containing up to 4 carbon atoms, and/or the above-mentioned heterocyclic rings may optionally be substituted by groups of the formula-NR¹²R¹³or-S (O) c.NR^9’R^10’The group represented by (a) is substituted,

wherein R is¹²And R¹³Are identical or different radicals and represent hydrogen or a linear or branched alkyl radical having up to 4 carbon atoms, or

R¹²Represents hydrogen and R¹³Represents a formyl group,

c’、R^9’and R^10’The definition of (1) and c, R above⁹And R¹⁰And are identical to c, R⁹And R¹⁰Are identical or different radicals, and/or the abovementioned heterocycles are optionally substituted by phenyl which may be substituted by fluorine, chlorine, bromine or by straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, and/or the abovementioned heterocycles are optionally substituted by radicals of the formula-N ═ CH-NR¹⁴R¹⁵The group represented by (a) is substituted,

wherein R is¹⁴And R¹⁵Represents hydrogen or a linear or branched alkyl group containing up to 4 carbon atoms,

a represents thienyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridazinyl or pyridinyl, each heterocycle or phenyl being optionally substituted up to 2 times by the same or different hydroxy, formyl, carboxy, or a straight or branched acyl, sulfanyl, alkyloxyacyl, alkoxy or alkoxycarbonyl group containing up to 4 carbon atoms, or by fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, or a straight or branched alkyl group containing up to 4 carbon atoms, wherein the straight or branched alkyl group may be substituted by hydroxy, carboxy, a straight or branched acyl, alkoxy or alkoxycarbonyl group containing up to 4 carbon atoms, and/or the heterocycle may be substituted by a group of the formula- (CO)_d-NR¹⁶R¹⁷The group represented by (a) is substituted,

wherein

d represents the number 0 or 1 and,

R¹⁶and R¹⁷Are identical or different radicals and represent hydrogen, phenyl, benzyl or a linear or branched alkyl or acyl radical having up to 4 carbon atoms, and isomers and salts thereof.

Particularly preferred compounds of the formula (I) according to the invention are

Wherein

R¹Represents imidazolyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, isoxazolyl, oxazolyl or thiazolyl, wherein each heterocycle may optionally be substituted up to 3 times by the same or different formyl, fluorine, chlorine, amino, mercapto, cyano, or straight-chain or branched acyl, sulfanyl, alkoxy or alkoxycarbonyl having up to 4 carbon atoms or by straight-chain or branched alkyl having up to 4 carbon atoms, wherein the straight-chain or branched alkyl may be substituted by hydroxyl, carboxyl, amino, azido, or straight-chain or branched acyl, alkoxy, alkoxycarbonyl or amido having up to 3 carbon atoms, and/or the heterocycle is substituted by the formulaor-S (O) c-NR⁹R¹⁰The group represented by (a) is substituted,

wherein

a. b and b' are identical or different numbers and represent 0, 1 or 2,

R⁸represents hydrogen or a methyl group,

c represents a number of 1 or 2,

and R is⁹And R¹⁰Are identical or different radicals and represent hydrogen or a linear or branched alkyl radical having up to 9 carbon atoms, where the alkyl radical may optionally be substituted by naphthyl or phenyl, or R⁹And R¹⁰Represents phenyl or naphthyl, which are optionally substituted by fluorine or chlorine, or R⁹And R¹⁰Represents cyclopropyl or cycloheptyl, or R⁹And R¹⁰Together with the nitrogen atom forming a morpholine ring or formulaOrA group represented by (A) a group,

wherein R is¹¹Represents hydrogen, methyl orA group represented by or representsBenzyl or phenyl, wherein said ring system may optionally be substituted by chlorine,

R²and R³Together form a pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl ring, including the double bond between the two, wherein each heterocycle may optionally be substituted up to 3 times by the same or different formyl, mercapto, carboxyl, hydroxyl, or straight or branched acyl, alkoxy, sulfanyl or alkoxycarbonyl containing up to 4 carbon atoms, or nitro, cyano, fluorine, chlorine, or straight or branched alkyl or alkoxy containing up to 3 carbon atoms, wherein said linear or branched alkyl or alkoxy groups may be substituted by hydroxy, amino, carboxy, or linear or branched acyl, alkoxy or alkoxycarbonyl groups containing up to 3 carbon atoms, and/or the heterocyclic ring may optionally be substituted by amino, N-dimethyl-amino or a compound of formula-NH-CHO or-N ═ CH-N (CH).₃)₂And/or phenyl, wherein the phenyl group may be substituted by a group of formula-O (CH)₂)₂-CH₃The group represented by (a) is substituted,

a represents tetrahydropyranyl, phenyl, pyrimidinyl, thienyl or pyridyl, wherein each heterocycle or phenyl group may optionally be substituted up to 2 times by the same or different formyl, carboxy, or straight or branched chain acyl, sulfanyl, alkyloxyacyl, alkoxy or alkoxycarbonyl groups containing up to 3 carbon atoms, or by fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, or straight or branched chain alkyl groups containing up to 3 carbon atoms, wherein said straight or branched chain alkyl groups may be substituted by hydroxy, carboxy, straight or branched chain acyl, alkoxy or alkoxycarbonyl groups containing up to 3 carbon atoms, and isomers and salts thereof.

More particularly preferred compounds of the general formula (I) according to the invention are those in which a represents phenyl, pyrimidinyl or fluoro-substituted phenyl or fluoro-substituted pyrimidinyl and isomers and salts thereof.

Furthermore, a process for the preparation of the compounds of the general formula (I) according to the invention, characterized in that it depends on what has been described aboveR²And R³Definition of the different heterocycles formed, [ A ]]A compound of the general formula (II)

R¹-D(II)

Wherein

R¹The definition of (a) is as described above,

and D represents formulaOrA group represented by (A) a group,

wherein R is¹⁸Represents C₁-C₄-an alkyl group,

a compound of the general formula (III)

A-CH₂-NH-NH₂(III)

Wherein A is as defined above, and wherein,

reacting a compound of the formula (II) with a compound of the formula (III) in an inert solvent, if desired with the addition of a base, to give a compound of the formula (IV) or (IVa)And

wherein

A and R¹The definition of (a) is as described above,

and, when a compound of the general formula (IVa) is produced, cyclizing it with a carboxylic acid, nitrile, formamide or guanidine salt, when a compound of the general formula (IV) is produced, cyclizing the compound with a1, 3-dicarbonyl derivative, a salt thereof, a tautomer, an enol ether or an enamine in the presence of an acid and, if necessary, under microwave conditions, or [ B]When R is²And R³When they form a pyrazine ring, the compound of formula (IV) is nitrosatedTo a compound of the general formula (V)

Wherein

A and R¹The definition of (a) is as described above,

then in a second reaction step, the compound of the general formula (VI) is prepared by reduction and finally the compound of the general formula (VI) is cyclized with an aqueous 1, 3-dicarbonyl derivative, preferably glyoxal,

wherein

A and R¹Is as defined above, or [ C]A compound of the formula (VII)

Wherein

A¹、R²And R³The definition of (a) is as described above,

and L represents the formula-SnR¹⁹R²⁰R²¹、ZnR²²Iodine, bromine or trifluoromethanesulfonate,

wherein

R¹⁹、R²⁰And R²¹Are identical or different radicals and represent straight-chain or branched alkyl radicals having up to 4 carbon atoms,

and R is²²Represents a halogen atom or a halogen atom,

general formula (VIII)

R¹-T(VIII)

Wherein R is¹The definition of (a) is as described above,

and when L ═ SnR¹⁹R²⁰R²¹Or ZnR²²When the temperature of the water is higher than the set temperature,

t represents trifluoromethanesulfonate or halogen, preferably bromine,

when L ═ iodine, bromine or triflate,

t represents SnR^19’R^20’R^21’、ZnR^22’Or BR^23’R^24’，

Wherein

R^19’、R^20’、R²¹And R^22’Having a radical of formula (I) with R¹⁹、R²⁰、R²¹And R²²The same definition, and are the same or different groups from them,

R^23’and R^24’Are identical or different radicals and represent hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having up to 5 carbon atoms, or R^23’And R^24’Together form a 5-or 6-membered carbocyclic ring,

the compound of the formula (VII) is reacted with a compound of the formula (VIII) in an inert solvent, if desired with the addition of a base, [ D ]]If R is¹＝

Wherein R is²⁵Represents (C) optionally halogen-substituted₁-C₆) -an alkyl group,

a compound of the formula (IX)

Wherein

A、R²And R³The definition of (a) is as described above,

a compound of the formula (X)

Wherein R is²⁵The definition of (a) is as described above,

a compound of the formula (Ia)

Wherein R is²、R³And A and R²⁵The definition of (a) is as described above,

the compound of the formula (IX) is reacted with a compound of the formula (X) in NaOCO-CH₃Reaction in the N-methylpyrrolidine system directly to give the compounds of the general formula (Ia) and subsequent removal of the acetyl groups in methanol by addition of potassium hydroxide, or

The compound of the formula (XI) is prepared by first reacting a compound of the formula (IX) with a compound of the formula (X)

Wherein R is²、R³A and R²⁵The definition of (a) is as described above,

then potassium hydroxide is added in the next step to prepare a methylol compound,

when preparing a catalyst having the formula-S (O) cNR⁹R¹⁰and-S (O) c' NR^9’R^10’Compounds of the general formula (I) having substituents which are not substituted by these two substituents are, in a first step, first reacted with thionyl chloride and, in a second step, with a suitable amine,

and, if appropriate, the above-mentioned R may be changed or introduced according to a conventional method¹、R²、R³And/or substituents on a, preferably by chlorination, catalytic hydrogenation, reduction, oxidation, removal of protecting groups and/or nucleophilic substituents.

The above-mentioned compounds of the general formula (II) with suitable substitution can also be introduced by reacting them according to other known heterocyclic synthesis methods²And R³The heterocyclic ring formed.

The preparation according to the invention is illustrated by the following specific reaction schemeThe method comprises the following steps:[A][A]and derivatization reaction

Suitable solvents for the reactions of the various steps of the present invention are inert organic solvents which do not change under the reaction conditions.

These solvents include ethers such as diethyl ether or tetrahydrofuran, DME, dioxane, alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride, chloroform, tetrachloromethane, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoramide (hexamethylphosphorated). Mixtures of these solvents may also be used. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The base used in the preparation process of the present invention is usually an inorganic or organic base. Preferred bases include alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium tert-butoxide, or organic amines (trialkyls (C)₁-C₆) Amines), e.g. triethylamine, or heterocycles, e.g. 1, 4-diazabicyclo [2.2.2]Octane (DABCO), 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidineOr morpholine. Alkali metals like bases, such as sodium, and alkali metal hydrides, such as sodium hydride, can also be used. Preference is given to sodium and potassium carbonate, triethylamine and sodium hydride.

The base is used in an amount of 1mol to 5mol, preferably 1mol to 3mol, relative to 1mol of the compound of the formula (II).

The reaction is generally carried out at from 0 ℃ to 150 ℃, preferably from +20 ℃ to +110 ℃.

The reaction can be carried out under normal pressure, under increased pressure or under reduced pressure (for example, 0.5 to 5 bar). Usually under atmospheric conditions.

Suitable acids for the cyclization reaction are generally protic acids. Preferred acids include inorganic acids, such as hydrochloric acid or sulfuric acid, or organic carboxylic acids having 1 to 6 carbon atoms, optionally substituted by fluorine, chlorine and/or bromine, such as acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or containing C₁-C₄Alkyl or aryl sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

The catalytic hydrogenation is usually carried out in water or an inert organic solvent such as an alcohol, ether or halogenated hydrocarbon, or a mixture thereof, using hydrogen and a catalyst such as Raney nickel, palladium or platinum adsorbed on animal charcoal, or in an inert solvent with a hydride or borane, if desired with the addition of a catalyst.

The chlorination reaction is usually carried out with a conventional chlorinating agent such as PCl₃、PCl₅、POCl₃Or elemental form of chlorine. In the present invention, POCl₃Is preferred.

If the compounds of the formula (I) to be prepared contain compounds of the formula-S (O) cNR⁹R¹⁰and-S (O) c.NR^9’R^10’The substituents are initially reacted with thionyl chloride using compounds which are not substituted by these two groups. In a next step, the product is then reacted with an amine in one of the above-mentioned ethers, preferably dioxane. When c is 2, the oxidation reaction is carried out according to a conventional method. The reaction is carried out at 0-70 ℃ and under normal pressure.

The nucleophilic substitution reaction and the Vilsmeier reaction are carried out according to conventional, published methods.

The reduction is generally carried out with a reducing agent, preferably with a reducing agent suitable for reducing carbonyl compounds to hydroxyl compounds. Reduction reactions using metal hydrides or metal hydride complexes in inert solvents are particularly suitable, if desired trihydrocarbylboranes can be added. The reduction is preferably carried out using a metal hydride complex such as lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, lithium trihydrocarbon borohydride, diisobutylaluminum hydride or lithium aluminum hydride. The reduction reaction with diisobutylaluminum hydride and sodium borohydride is particularly preferred.

The reducing agent is generally used in an amount of 1mol to 6mol, preferably 1mol to 4mol, relative to 1mol of the compound to be reduced.

The reduction is generally carried out at from-78 ℃ to +50 ℃ and, when DIBAH is used, preferably from-78 ℃ to +50 ℃ when NaBH is used₄Preferably from 0 ℃ to room temperature.

The reduction reaction is usually carried out under normal pressure, but may be carried out under increased pressure or reduced pressure. The compounds of the formulae (II) and (III) are known per se or can be prepared by customary methods (cf. J.Hromatha et al, Monatsh. chem.1976.107.233).

Some of the compounds of the formulae (IV), (IVa), (V) and (VI) are known and can be prepared by the processes described above.

Suitable solvents for use in step [ C ] are inert organic solvents which do not change under the reaction conditions. These solvents include ethers such as diethyl ether or tetrahydrofuran, DME, dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, tetrachloromethane, 1, 2-dinitroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene or trichloroethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoramide. Mixtures of these solvents may also be used. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is generally carried out at from 0 ℃ to 150 ℃, preferably from +20 ℃ to +110 ℃.

The reaction can be carried out under normal pressure, under increased pressure or under reduced pressure (for example, 0.5 to 5 bar). Usually at atmospheric pressure.

Palladium compounds suitable for use in the present invention are typically PdCl₂(P(C₆H₅)₃)₂Bis-dibenzylideneacetone palladium (Pd (dba)₂) Chlorinated [1, 1' -bis- (diphenylphosphino) ferrocene]Palladium (II) (Pd (dppf) Cl₂) Or Pd (P (C)₆H₅)₃)₄. Pd (P (C) is preferred₆H₅)₃)₄。

The compounds of the general formula (VIII) are known per se or can be prepared by customary methods.

Some of the compounds of the formula (VII) are known or, when stannyl is present, they are novel and can be prepared, for example, by palladium-catalyzed reaction of compounds of the formula (XII) with compounds of the formula (XIII) in a manner described above

Wherein

R²、R³And A is as defined above,

L¹represents trifluoromethanesulfonate or halogen, preferably iodine,

compounds of the general formula (XIII)

(SnR¹⁹R²⁰R²¹)₂ (XIII)

Wherein

R¹⁹、R²⁰、R²¹The definition of (A) is as described above.

The compounds of the formulae (XII) and (XIII) are known per se or can be prepared by customary methods.

The step [ D ] reaction of the present invention is carried out using one of the above-mentioned bases, preferably in N-methylpyrrolidone, at a temperature of from 100 ℃ to 200 ℃, preferably at 150 ℃.

The compounds of the formulae (IX) and (X) are known or can be prepared by customary methods.

The general formulae (Ia) and (XI) are novel and can be prepared by the processes described above.

When typical protecting groups are introduced in the derivatization reaction, their removal is usually carried out in one of the above-mentioned alcohols and/or THF or acetone, preferably methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulfonic acid, at temperatures of from 0 ℃ to 70 ℃, preferably at room temperature, and under normal pressure.

The compounds of general formula (I) according to the invention exhibit an unexpected and valuable spectrum of pharmacological effects.

The compounds of formula (I) are capable of vasodilation/inhibition of platelet aggregation and lowering blood pressure and increasing coronary blood flow. These effects are achieved by direct stimulation of soluble guanylate cyclase and increased intracellular cGMP. Furthermore, the compounds according to the invention increase the activity of substances which increase the cGMP level, such as EDRF (endothelial derived relaxation factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

The compounds of the invention can therefore be used in medicaments for the treatment of cardiovascular diseases, such as for example the treatment of hypertension and myocardial insufficiency, stable or unstable angina pectoris, peripheral or cardiovascular diseases, arrhythmias, treatment of thromboembolic disorders and ischaemia, such as myocardial infarction, stroke, transient ischaemic attacks, peripheral circulatory disorders, prevention of restenosis, for example thrombolytic therapy, percutaneous transluminal angioplasty (PAT), percutaneous transluminal coronary angioplasty (PACT), and restenosis following shunts, and also for the treatment of arteriosclerosis and genitourinary disorders, such as prostate hypertrophy, erectile dysfunction and incontinence.

Furthermore, the invention also includes the combination of the compounds of the general formula (I) according to the invention with an organic nitrate (or ester) and an NO donor.

The organic nitrate and NO donor of the present invention are typically substances that exert their therapeutic activity by releasing NO or NO species. Preferred are sodium nitroprusside, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1.

In addition, the invention also comprises a combination of the compound of the general formula (I) and a compound capable of inhibiting the degradation of cyclic guanylic acid (cGMP). These compounds are, in particular, inhibitors of phosphodiesterase 1, 2 and 5; according to Beavo and Reifsnyder (1990) TiPS 11P 150-155 nomenclature. The activity of the compounds according to the invention is potentiated and these inhibitors enhance the desired pharmacological effect.

The invention also comprises a process for the production of a medicament, characterized in that at least one compound of the general formula (I) is converted into a suitable administration form, if desired using customary auxiliaries and additives.

To determine the cardiovascular activity of a compound, the following tests were performed: in vitro experiments with vascular cells, the influx of cGMP formed, which is dependent on guanylate cyclase, was determined with and without a NO donor. The compounds exhibit properties against collagen-stimulated human platelet aggregation. Vasodilatory activity was measured in the aortic annulus of rabbits pre-contracted with phenylephrine. Hypotensive activity was measured in anesthetized rats.Stimulation of soluble guanylate cyclase in primary endothelial cells

Primary endothelial cells isolated from rabbit aorta were treated with collagenase solution. Then at 37 deg.C/5% CO₂Culturing the cells in a medium under conditions until cell confluence occurs, subculturing the cells, plating into 24-well cell culture dishes, and culturing again until cell confluence occursThen (about 2X 10)⁵Cells/well). To stimulate guanylate cyclase in endothelial cells, the medium was withdrawn and the cells washed once with Ringer solution. After removal of Ringer solution, cells were incubated at 37 deg.C/5% CO₂Incubate for 10 min in stimulation buffer with or without NO donor (sodium nitroprusside, SNP, 1. mu.M). The test compound was then added to the cells with a pipette and incubated for an additional 10 minutes. After the incubation time was reached, the buffer was pumped out and a cold stop buffer at 4 ℃ was added to the cells. The cells were then lysed at-20 ℃ for 16 hours. The supernatant containing intracellular cGMP was removed and the concentration of cGMP was determined using the cGMP-SPA system (Amersham Buchler, Brunswick).TABLE A

Example No. 2	Percentage increase in cGMP (%)
		14	＞1000
15	504
		16	652
17	＞1000
		32	135

In vitro vasodilating Activity

Anesthetizing and bleeding the rabbit by hitting the rabbit's neck, and removingAorta, the tissue attached to it was removed, cut into 1.5mM wide rings, and each aortic ring was preshrinked by placing it in a 5ml organ bath containing a warm Krebs-Henseleit solution filled with carbopol gold at 37 ℃ containing the following components (mM): NaCl: 119; KCl: 4.8; CaCl₂×2H₂O：1；MgSO₄×7H₂O：1.4；KH₂PO₄：1.2；NaHCO₃: 25; glucose: 10.

the contractility was measured using Statham UC2 cells, amplified and digitized with an A/D converter (DAS-1802HC, Keithley Instruments Munich), and recorded side-by-side on a linear recorder. To produce the contractile effect, phenylephrine is added cumulatively to the organ bath at increasing concentrations.

After several control cycles, the activity of the substance to be tested is determined in each test sample at each step of the dose increase, and the height of the contraction is compared with the height of the contraction determined in the initial step. To reduce the 50% control value (IC)₅₀) The concentration needs to be calculated. The standard dosing volume was 5 μ l and the ratio of DMSO in the organ bath solution corresponded to 0.1%.TABLE B

Example No. 2	Aorta (IC)50)μM
		14	1.8
15	13.0
		16	1.7

Blood pressure determination in anesthetized rats

Male Wistar rats weighing 300-350g were anesthetized with thiopental (100mg/kgi. p.). After tracheotomy, a catheter was inserted into the femoral artery to measure blood pressure. Test compounds were administered orally at various doses through a gastric tube, where the test compounds were administered as a suspension in a solution of tylose sodium acetate.Watch C

Example No. 2	Dosage (mg/kg)	Maximum value of blood pressure decrease (mm Hg)	Time (minutes)
				13	1030	-13-23	6060
14	1030	-18-21	4050
				16	1030	-9-16	5050

Inhibiting platelet aggregation in vitro

To determine the platelet aggregation inhibiting activity of the compounds, blood extracted from healthy subjects of both sexes was used. As an anticoagulant, 9 parts of blood were mixed with 1 part of 38% strength aqueous sodium citrate solution. Platelet-rich citrate serum (PRP) was obtained from Blood by centrifugation (Jurgens/Beller, Klinische method of Blurgerinningsanalyse [ Clinical Methods of Blood Coagulation Analysis ]; Thieme Verlag, Struttgart, 1959).

For these tests, 445. mu.l of PRP and 5. mu.l of active compound solution were preincubated in a water bath at 37 ℃. Turbidimetry (Born, g.v.r, JPhysiol. (London) was used at 37 c,168178-195, 1963) in an aggregation meter (aggregometer). For this test, the pre-incubated specimen was treated with 50. mu.l of collagen, which is an aggregation inducer, and the change in optical density was determined. For quantitative evaluation, the maximal aggregation response was determined and used to calculate the percent inhibition relative to the control. The compounds of the invention also have utility in the treatment of central nervous system disorders characterized by a disturbance of the NO/cGMP system. In particular, the compounds of the invention are suitable for eliminating cognitive deficits, for improving learning and memory functions and for treating alzheimer's disease. The compounds of the invention are also suitable for the treatment of central nervous system disorders such as anxiety, stress and depression states, sexual dysfunction and sleep disorders associated with the central nervous system, and also for the control of pathological disorders of food, tea, coffee, alcohol, tobacco and addictive drug intake.

Furthermore, the active compounds of the present invention are also suitable for modulating cerebral blood flow circulation and are therefore effective therapeutic agents for controlling migraine.

The compounds of the invention are also suitable for the prophylaxis and treatment of cerebral infarctions (cerebral stroke) such as stroke, cerebral ischemia and craniocerebral trauma. The compounds according to the invention can also be used to control pain states.

The invention encompasses pharmaceutical preparations which, in addition to nontoxic, inert, pharmaceutically acceptable excipients, contain one or more active compounds according to the invention or consist of one or more active compounds according to the invention, and processes for the preparation of these preparations.

The active compound can optionally be present in one or more of the above-mentioned excipients and can also be prepared in the form of microcapsules.

In the above pharmaceutical formulations, the concentration of the therapeutically active compound should be about 0.1-99.5%, preferably about 0.5-95%, wherein the percentages are percentages by weight based on the total mixture.

In addition to the compounds according to the invention, the abovementioned pharmaceutical preparations may also contain other active compounds.

In general, it has proven advantageous in human and veterinary medicine to administer these active compounds in an amount of from about 0.5 to about 500mg/kg of body weight, preferably from 5 to 100mg/kg of body weight, per 24 hours. The compounds are administered, if appropriate, in the form of several individual doses to achieve the desired effect. Each individual dose preferably contains about 1 to 80mg/kg of body weight, particularly preferably 3 to 30mg/kg of body weight, of active compound.AcronymsMeOH, ethanol, EA, ethyl acetate, T, toluene, Ph, phenyl

In the following table, at R_fBelow the columns, the numbers following the solvent represented by the abbreviations represent parts by weight.

Starting compounds

Example 1A

5-amino-1-benzyl-3- (5-hydroxymethyl-2-furyl) -pyrazoles

44.1g (817mmol) of sodium methoxide are added with stirring to 79.5g (40 mmol)8mmol) of benzylhydrazine dihydrochloride in 1.31 ethanol. After 15 minutes 67.4g (408mmol) of 2-cyanomethylcarbonyl-5-hydroxymethylfuran were added and the mixture was refluxed for 3 hours with stirring. After cooling, 1l of water was added, the ethanol was evaporated in vacuo and the precipitated crystals were filtered off with suction. After washing with water, further with diethyl ether and then with P₂O₅The precipitate was dried to yield 91g of product (83% yield) having a melting point of 163 ℃.

The compounds in table 1A were prepared in a similar manner: TABLE 1A

Example No. 2	R1	Melting Point [. degree.C. ]]	Rf	Yield (%)
					2A	2-furyl radical	124	0.63(T1E1)	49
3A	2-pyrimidinyl radicals	178	0.49(MeOH1E4 )	665
					4A	2-pyridyl group	130	0.08(T1E1)	30

Example 5A

5-amino-1- (2-fluorobenzyl) -3- (5-hydroxymethyl-2-furyl) -4-nitroso-pyrazole

10g (34.8mmol) of 5-amino-1- (2-fluorobenzyl) -3- (5-hydroxymethyl-2-furyl) -pyrazole were initially introduced into a mixture of 66ml of ethanol and 26.7ml of 5% aqueous hydrochloric acid, treated with 26.4ml of 15% aqueous ethyl nitrite solution in ethanol for 5 minutes and stirred at room temperature for 1 hour. The dark purple reaction solution was added to an aqueous potassium carbonate solution, and extracted with ethyl acetate. After evaporation of the organic phase in vacuo, 8g of residue are obtained, which can be reacted further immediately. (R)_f＝0.17，T1E1，SiO₂)。Example 6A

4, 5-diamino-1- (2-fluorobenzyl) -3- (5-hydroxymethyl-2-furyl) -pyrazole

The compound obtained in example 5A (8g) was dissolved in ethanol. Treated with 0.5g of 5% strength palladium adsorbed on carbon and hydrogenated for 15 minutes with hydrogen at a pressure of 2bar in a Parr's apparatus. The solution was filtered off with suction over kieselguhr and used in the next preparation in batches (R)_f＝0.21，T1E1，SiO₂)。Example 7A

3-amino-2- (2-fluorobenzyl) -pyrazole was prepared analogously to French patent 1403372 (chemical abstracts, 1965, 63, 14871 a).Example 8A

1- (2-fluorobenzyl) pyrazolo [3, 4-b]Pyrimidines

32g of 3-amino-2- (2-fluorobenzyl) -pyrazole are dissolved in 1.5l dioxane and treated with 31.45g of dimethylaminopropenal. The mixture was heated to 50 ℃ and then 16.65g of trifluoroacetic acid was added. The mixture was boiled for 60 hours, then the solvent was evaporated in vacuo and the resulting residue was treated with water and extracted with ethyl acetate. Subjecting the organic phase to Na₂SO₄Dried and evaporated in vacuo and the residue chromatographed on silica gel. After elution with toluene to 9: 1 toluene/ethyl acetate, 17.3g (46.3% yield) of R were obtained_fIs 0.69 (SiO)₂T1E1) to the title compound of this example.Example 9A

3-bromo-1- (2-fluorobenzyl) pyrazolo [3, 4-b]Pyrimidines

8g (35.2mmol) of 1- (2-fluorobenzyl) pyrazolo [3, 4-b]The pyrimidine was dissolved in 284ml chloroform and slowly treated with 14g (87.3mmol) of bromine at room temperature. The mixture was stirred overnight and then 1.2ml of bromine was further added dropwise. After 2 hours, the reaction was quenched and the solvent was evaporated in vacuo. The residue was treated with 20ml of ethyl acetate and crystallization was induced. After washing the crystals with diethyl ether, 7.5g (yield 70%) of R were obtained_fIs 0.2 (SiO)₂Toluene) of the title compound of this example.Example 10A

1- (2-fluorobenzyl) -3-trimethylstannylpyrazolo [3, 4-b]Pyrimidines

1.22g (4mmol) of 3-bromo-1- (2-chlorobenzyl) pyrazolo [3, 4-b in the presence of argon]The pyrimidine was dissolved in 200ml dioxane and treated with 45g (13.74mmol) hexamethyltin dihydroxide and 1.2g and 12g tetrakis (triphenylphosphine palladium). The mixture was stirred at 100 ℃ overnight, water was added and extracted with ethyl acetateAnd (6) taking. Subjecting the organic phase to Na₂SO₄Dried and evaporated in vacuo and chromatographed on silica gel. After elution with toluene, 1.4g (89.7% yield) of R were obtained_fIs 0.074 (SiO)₂Toluene) of the title compound of this example.Example 11A

500mg of 1- (2-fluorobenzyl) pyrazolo [3, 4-b ] pyridine-3-carboxylic acid (1.84mmol) are partly dissolved in 10ml of dichloromethane. 400mg of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (2.3mmol) were added. The mixture was stirred at room temperature for 10 minutes (complete dissolution) and then 5ml of a solution of 260mg of 1, 1-dichloro-3-amino-but-1-ene (1.84mmol) in dichloromethane were added dropwise.

After about 3 hours, the mixture was concentrated and purified on silica gel (solvent: cyclohexane/EA 1: 1). 340mg (yield 47%) of 1- (2-fluorobenzyl) -3- (1, 1-chlorobutan-1-en-3-yl-amido) pyrazolo [3, 4-b are obtained]Pyridine, R_fIt was 0.35 (cyclohexane/EA 2: 1). Ms (esipositive): 417(27, [ M + Na ]]⁺)；415(42，[M+Na]⁺)；395(60，[M+H]⁺)；393(100，[M+H]⁺)。Preparation examples Example 1

1- (2-fluorobenzyl) -3- (2-hydroxymethyl-2-furyl) pyrazolo [3, 4-b]Pyrazine esters

The crude product from example 6A was treated with 4.61g of 40% strength aqueous glyoxal solution and stirred at room temperature for 10 hours. The mixture was evaporated in vacuo and chromatographed on silica gel with a toluene/ethyl acetate mixture. After crystallization from diethyl ether, 0.57g (7.6% yield) of the title compound of this example having a melting point of 194 ℃ are obtained.Example 2

1- (2-fluorobenzyl) -3- (2-furyl) -6-hydroxypyrazolo [3, 4-b]Pyridine compound

7g (27.2mmol) of 5-amino-1- (2-fluorobenzyl) -3- (2-furyl) -6-hydroxypyrazolo [3, 4-b]Pyridine, 3.49g (273mmol) of ethyl 3-ethoxyacrylate and 1.96ml (27.3mmol) of trifluoroacetic acid were mixed well and reacted in a microwave oven for 2 minutes. The mixture was added to 500ml of a solution containing 10gK₂HPO₄The aqueous solution of (1) was extracted with 500ml of ethyl acetate. The organic phase is extracted with MgSO₄After drying, 30g of silica gel were added and the mixture was evaporated in vacuo. The residue was chromatographed on a silica gel column using a toluene-ethyl acetate gradient eluent. The first portion was crystallized from diethyl ether to yield 1.8g (21.4% yield) of the title compound of this example having a melting point of 250 ℃.

The compounds listed in table 1 were prepared in analogy to example 2:TABLE 1

Example No. 2	R1	R19	Yield (%)	RfMelting Point C
					3*	2-furyl radical	-CH3	24	226
4	2-pyridyl group	H		0.8(EA)

^*With ethyl acetoacetateExample 5

4-amino-1- (2-fluorobenzyl) -3- (2-furyl) pyrazolo [3, 4-b]Pyrimidines

2g (7.1mmol) of 5-amino-4-cyano-1- (2-fluorobenzyl) -3- (2-furyl) pyrazole and 30ml of formamide are initially stirred at 100 ℃ and then at 195 ℃ for 3 hours. The material which crystallized on cooling was filtered off with suction and washed with formamide, the residue was taken up in ethyl acetate and the solution was washed with water. After drying and evaporation of the organic phase, 2.13g (97% yield) of the title compound of the example having a melting point of 190 ℃ are obtained. R_f＝0.07(T1E1) 。

The compounds listed in Table 2 are prepared in a similar manner, for example using 2-propoxybenzonitrile, benzonitrile or guanidinium bicarbonate:TABLE 2

Example No. 2	R27	R28	Melting Point (. degree.C.)	Rf	Yield (%)
						6	F	2-propoxyphenyl group	187	0.6(T1E1)	42.7
7	F	Ph	205	0.69(T1E1)	100
						8	F	NH2	205	0.22(EA)	71
9	H	H	174	0.15(T1E1)	90

Example 10

1-benzyl-3- (2-furyl) -4-hydroxyPyrazolo [3, 4-b]Pyrimidines

6.14g (23.2mmol) of 5-amino-1-benzyl-4-cyano-3- (2-furyl) pyrazole (R)_f0.6) was boiled in 100ml formic acid for 3.75 hours. The mixture was then evaporated in vacuo. The residue was treated with water and the mixture was extracted with ethyl acetate by shaking. The insoluble portion was filtered off with suction to obtain 5.1g of the title compound of this example (melting point 242 ℃ C., R)_f＝0.3，SiO₂Toluene/ethyl acetate 1: 1). The title compound can be further isolated by evaporation of the organic phase.Example 11

1-benzyl-4-chloro-3- (2-furyl) pyrazolo [3, 4-b]Pyrimidines

6.6g of 1-benzyl-3- (2-furyl) -4-hydroxypyrazolo [3, 4-b]Pyrimidine in 100ml POCl₃Boiled for 12 hours. The mixture was evaporated in vacuo and the residue was taken up with K₂HPO₄The aqueous solution was stirred together and the mixture was extracted with ethyl acetate. With Na₂SO₄After drying and concentration on a rotary evaporator, 7.47g of solid product (R) are obtained which can be reacted directly in the next step_f＝0.8，SiO₂Toluene/ethyl acetate 1: 1).Example 12

1-benzyl-3- (2-furyl) pyrazolo [3, 4-b]Pyrimidines

5.81g of 1-benzyl-4-chloro-3- (2-furyl) pyrazolo [3, 4-b]Pyrimidine was dissolved in 450ml dioxane, 2.61ml triethylamine was added, and 4g 20% Pd (OH) adsorbed on charcoal was used₂The mixture was hydrogenated in a Party apparatus at a pressure of 3 bar. After filtration through celite, the mixture is evaporated and chromatographed to give 2.26g of pale yellow crystals (m.p.: 106 ℃, R)_f＝0.8，SiO₂Toluene/ethyl acetate 1: 1).Example 13

1-benzyl-3- (5-hydroxymethyl-2-furyl) -1-H-pyrazolo [3, 4-b]Pyridine compound

2.69g (10mmol) of 5-amino-1-benzyl-3- (5-hydroxymethyl-2-furyl) pyrazole and 1.4g of sodium propionaldehyde are stirred in 100ml of dioxane at 100 ℃ for 30 minutes and treated slowly with 1.9ml of trifluoroacetic acid for 5.5 hours. The mixture was evaporated in vacuo and the residue was taken up in ethyl acetate. Mixing the mixture with K₂HPO₄The solution was extracted by shaking and the organic phase was extracted with Na₂SO₄Dried and concentrated under reduced pressure in a rotary evaporator. The residue is chromatographed on silica gel. 200mg (yield 6.6%) of crystals having a melting point of 104 ℃ were obtained. The compounds listed in table 3 were prepared using a method similar to that described above:TABLE 3 Example 20

3- (4, 5-dimethylpyrimidin-2-yl) -1- (2-fluorobenzyl) pyrazolo [3, 4-b]Pyrimidines

1.4g (3.59mmol) of 1- (2-fluorobenzyl) -3-trimethylstannylpyrazolo [3, 4-b]The pyrimidine was boiled with 0.51g (3.58mmol) of 2-chloro-4, 5-dimethylpyrimidine and 0.2g (0.28mmol) of bis (triphenylphosphine) palladium dichloride in toluene in the presence of argon overnight. 3g of silica gel were added and the solvent was evaporated in vacuo. The residue is chromatographed on silica gel, eluting with a toluene/ethyl acetate mixture. 0.34mg (yield 28.4% melting point 167 ℃ C., R) was obtained_fIs 0.08 (SiO)₂T4E).

The compounds in table 4 were prepared in a similar manner.TABLE 4 Example No. 2 R¹21 Example 22

1-benzyl-3- (5-formyl-2-furyl) pyrazolo [3, 4-b]Pyrimidines

0.74ml of POCl was added at 0 deg.C₃Added to 0.64ml DMF. The solidified mixture was allowed to reach room temperature and 14ml of 1, 2-dichloroethane were added. To this solution was added dropwise 14ml of a solution containing 2g of 1-benzyl 3-3- (2-furyl) pyrazolo [3, 4-b ] dissolved at 15 DEG]Pyrimidines (R)_f＝0.45，SiO₂Toluene/ethyl acetate 1: 1) in 1, 2-dichloroethane and then heated to 80 ℃. After 4 hours, the batch was added dropwise to another Vilsmeier reagent using 1.5ml POCl and stirred at 80 ℃ for 24 hours₃And 1.3ml DMF. The mixture was then added to 50% K₂HPO₄In (1), rapidly heated to 75 ℃ with stirring. After extraction with ethyl acetate, the organic phase is dried, concentrated in a rotary evaporator and washed with SiO₂Chromatography gave 0.6g (27% yield) of the product as an oil (R)_f＝0.3，SiO₂Toluene/ethyl acetate 1: 1).

The compounds of the examples in table 5 were prepared in analogy to the procedure described above:TABLE 5 TABLE 5 TABLE 5 TABLE 5 Example 33

1-benzyl-3- (5-hydroxymethyl-2-furyl) pyrazolesAnd [3, 4-b ]]Pyrimidines

0.6g (1.97mmol) of 1-benzyl-3- (5-formyl-2-furyl) pyrazolo [3, 4-b) was reacted at room temperature]Pyrimidines (R)_f＝0.65，SiO₂Ethyl acetate) with 60mgNaBH₄Stirred well in 20ml of 1-propanol. After 15 minutes, 50ml of water and 2.5ml of glacial acetic acid were added. The mixture was partially concentrated in a rotary evaporator, extracted with ethyl acetate, and after addition of toluene, the extracts were dried and concentrated in a rotary evaporator. By SiO₂After chromatography, 74.8mg (yield 12.4%) of product are obtained (melting point 165 ℃ C., R)_f＝0.43，SiO₂Ethyl acetate).

The compounds in table 6 were prepared in a similar manner to example 33.TABLE 6 TABLE 6 TABLE 6 TABLE 6 TABLE 6 Example 46

Preparation of 1- (2-fluorobenzyl) -3- [5- (piperidin-1-sulfinyl) furan-2-yl]-1H-pyrazolo [3, 4-b]Pyridine compound

a) Preparation of 1- (2-fluorobenzyl) -3- [ 5-chlorosulfinyl furan-2-yl]Pyrazolo [3, 4-b]Pyridine compound

0.85g (2.86mmol) of 1- (2-fluorobenzyl) -3- (2-furyl) pyrazolo [3, 4-b ] pyridine is stirred with 20ml of thionyl chloride at 70 ℃ for 25 minutes. The solution was evaporated in vacuo and the next reaction was carried out as crude product.

b) The product prepared above was dissolved in 30ml dioxane, treated with 0.6ml (about 6mmol) piperidine, shaken vigorously and then left overnight. The solution was heated to water and the mixture was extracted with ethyl acetate by shaking. The organic phase is treated with Na₂SO₄After drying, the solvent is evaporated and the residue is chromatographed on silica gel using a toluene/ethyl acetate gradient eluent. 0.49g (yield 12.4%) of a brown, clear and viscous paste-like product (R) is obtained_f(SiO₂；T1E1)＝0.36)。

The compounds in table 7 were prepared in a similar manner to the above-described method and the method in example 46.

Example 67 was prepared in a similar manner to example 20. TABLE 7TABLE 7 TABLE 7 TABLE 7 TABLE 7 TABLE 7 TABLE 7 TABLE 7 TABLE 7 Example 68

1- (2-fluorobenzyl) -3- (4-methyl-3-hydroxymethyl oxazol-2-yl) pyrazolo [3, 4-b]Pyridine compound

330mg of 1- (2-)Fluorobenzyl) -3- (1, 1-dichlorobut-1-en-3-yl-amido) pyrazolo [3, 4-b]Pyridine (0.84mmol), 1.7ml NaOH 1N (1.68mmol) and 3.3ml 1-methyl-2-pyrrolidone were stirred at 50 ℃ overnight and then cooled. The mixture was treated with water and ethyl acetate. Separating the organic phase with Na₂SO₄Dried and concentrated. The mixture was dried under high vacuum. The solid was treated with cyclohexane/EA 2: 1, resulting in the formation of crystals. The crystals were filtered off with suction and stirred with diethyl ether at room temperature. Insoluble impurities are removed. The ether solution was concentrated and purified by chromatography. 52.1mg (18%) of 1- (2-fluorobenzyl) -3- (4-methyl-3-hydroxymethyloxazol-2-yl) pyrazolo [3, 4-b ] are obtained]Pyridine. Melting point 145 ℃ R_f: 0.074 (cyclohexane: EA 2: 1). MS (ESI-POSITIVE): 339(100, [ M + H ]]^-)。Example 69

1- (2-fluorobenzyl) -3- (4-ethyl-3-hydroxymethyl oxazol-2-yl) pyrazolo [3, 4-b]Pyridine compound

This compound was prepared in analogy to example 68. Yield (52%), R_fIt was 0.33 (hexane: EA 1: 1).

Claims (8)

1. Substituted pyrazole derivatives of the general formula (I) or isomers or salts thereof,

wherein

R¹Represents pyridyl, pyrimidyl or oxazolyl, in which each heterocycle may be optionally substituted identically or differently by formyl, fluoro, chloro, amino, mercapto, cyano, or by straight-chain or branched acyl, thioalkyl, alkoxy or alkoxycarbonyl having up to 4 carbon atoms or by straight-chain or branched alkyl having up to 4 carbon atomsUp to 3 times, wherein the linear or branched alkyl group can be substituted by hydroxyl, carboxyl, amino, azido, or linear or branched acyl, alkoxy, alkoxycarbonyl or acylamino groups containing up to 3 carbon atoms,

R²and R³Together form a pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl ring, including the double bond between the two, wherein each heterocycle may optionally be substituted up to 3 times by the same or different formyl, mercapto, carboxyl, hydroxyl, or straight or branched acyl, alkoxy, sulfanyl or alkoxycarbonyl containing up to 4 carbon atoms, or nitro, cyano, fluorine, chlorine, or straight or branched alkyl or alkoxy containing up to 3 carbon atoms, wherein said linear or branched alkyl or alkoxy groups may be substituted by hydroxy, amino, carboxy, or linear or branched acyl, alkoxy or alkoxycarbonyl groups containing up to 3 carbon atoms, and/or the heterocyclic ring may optionally be substituted by amino, N-dimethyl-amino or a compound of formula-NH-CHO or-N ═ CH-N (CH).₃)₂And/or phenyl, wherein the phenyl group may be substituted by a group of formula-O (CH)₂)₂-CH₃Substituted by the radicals represented, A represents phenyl which may optionally be substituted up to 2 times by identical or different fluorine, chlorine or bromine.

2. Process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that it depends on R as defined in claim 1²And R³Different definitions of the heterocyclic ring formed, [ A ]]A compound of the general formula (II)

R¹-D(II)

Wherein

R¹Is as defined in claim 1, wherein,

and D represents formulaOrA group represented by (A) a group,

wherein R is¹⁸Represents C₁-C₄-an alkyl group,

a compound of the general formula (III)

A-CH₂-NH-NH₂(III) wherein A is as defined in claim 1,

reacting a compound of the formula (II) with a compound of the formula (III) in an inert solvent, if desired with the addition of a base, to give a compound of the formula (IV) or (IVa)And

wherein

A and R¹Is as defined in claim 1, wherein,

and, when the compound of the general formula (IVa) is produced, cyclizing it with a carboxylic acid, nitrile, formamide or guanidine salt,

when a compound of the general formula (IV) is formed, the compound is cyclized with a1, 3-dicarbonyl derivative, a salt thereof, a tautomer, an enol ether or an enamine in the presence of an acid and, if necessary, under microwave conditions, or [ B]When R is²And R³Together form a pyrazine ring, the compounds of the formula (IV) are first converted into compounds of the formula (V) by nitrosation

Wherein

A and R¹Is as defined in claim 1, wherein,

then in a second reaction step, the compound of the general formula (VI) is prepared by reduction and finally, the compound of the general formula (VI) is cyclized using a1, 2-dicarbonyl derivative,

wherein

A and R¹Is as defined in claim 1, or [ C]A compound of the formula (VII)

Wherein

A¹、R²And R³Definition of (1)As described in the above-mentioned claim 1,

and is

L represents-SnR¹⁹R²⁰R²¹、ZnR²²Iodine, bromine or trifluoromethanesulfonate,

wherein

R¹⁹、R²⁰And R²¹Are identical or different radicals and represent straight-chain or branched alkyl radicals having up to 4 carbon atoms,

and R is²²Represents a halogen atom or a halogen atom,

general formula (VIII)

R¹-T(VIII)

Wherein R is¹Is as defined in claim 1, wherein,

and when L ═ SnR¹⁹R²⁰R²¹Or ZnR²²When the temperature of the water is higher than the set temperature,

t represents a triflate or a halogen,

when L ═ iodine, bromine or triflate,

t represents SnR^19’R^20’R²¹、ZnR^22’Or BR^23’R^24’，

Wherein

R¹⁹、R^20’、R^21’And R^22’Having a radical of formula (I) with R¹⁹、R²⁰、R²¹And R²²The same definition, and are the same or different groups from them,

R^23’and R^24’Are identical or different radicals and represent hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having up to 5 carbon atoms, or R^23’And R^24’Together form a 5-or 6-membered carbocyclic ring,

the compound of the formula (VII) is reacted with a compound of the formula (VIII) in an inert solvent, if desired with the addition of a base, [ D ]]If it is not

Wherein R is²⁵Represent canOptionally substituted by halogen (C)₁-C₆) -an alkyl group,

a compound of the formula (IX)

Wherein

A、R²And R³Is as defined in claim 1, wherein,

a compound of the formula (X)

Wherein R is²⁵The definition of (a) is as described above,

a compound of the formula (Ia)

Wherein R is²、R³And A is as defined in claim 1, R²⁵Is as defined above, the compound of formula (IX) is reacted with the compound of formula (X) in NaOCO-CH₃Reaction in the N-methylpyrrolidine system directly to give the compounds of the general formula (Ia) and subsequent removal of the acetyl groups in methanol by addition of potassium hydroxide, or

The compound of the formula (XI) is prepared by first reacting a compound of the formula (IX) with a compound of the formula (X)

Wherein R is²、R³A is as defined in claim 1, R²⁵The definition of (a) is as described above,

then potassium hydroxide is added in the next step to prepare a methylol compound,

if necessary, the methylol compound is converted into the corresponding alkoxy compound by alkylation according to a conventional method,

when preparing a catalyst having the formula-S (O) cNR⁹R¹⁰and-S (O) c, NR^9’R^10’Compounds of the general formula (I) having substituents which are not substituted by these two substituents are, in a first step, first reacted with thionyl chloride and, in a second step, with a suitable amine,

and, if appropriate, according to the usualBy modifying or introducing R as mentioned above¹、R²、R³And/or substituents on A.

3. Pharmaceutical compositions containing at least one compound of general formula (I) according to claim 1.

4. Process for the production of a medicament, characterized in that at least one compound of the general formula (I) according to claim 1 is converted into a suitable administration form, if desired with the use of customary auxiliaries and additives.

5. A pharmaceutical composition according to claim 3, further comprising an organic nitrate or ester or a NO donor.

6. A pharmaceutical composition according to claim 3, further comprising a compound capable of inhibiting the degradation of cyclic guanylic acid.

7. Use of a compound of general formula (I) according to claim 1 for the manufacture of a medicament for the treatment of cardiovascular diseases.

8. Use according to claim 7, wherein the cardiovascular disease is thromboembolism and ischemia.