SK67699A3 - Novel substituted pyrazole derivatives for the treatment of cardiocirculatory diseases - Google Patents

Abstract

The present invention relates to novel substituted pyrazole derivatives, a method for the production and the use thereof as a medicament, specially as a medicament to treat cardiocirculatory diseases.

Description

The invention relates to novel substituted pyrazole derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use as medicaments for the treatment of diseases of the cardiovascular system.

BACKGROUND OF THE INVENTION

It is already known that 1-benzyl-3- (substituted heteroaryl) -condensed pyrazole derivatives inhibit stimulated platelet aggregation / n v / tro (see EP 667 345 A1).

SUMMARY OF THE INVENTION

The invention relates to novel substituted pyrazole derivatives of the general formula I

R ^: /

(D

CH .--- And in which

R ¹ represents a five or six membered saturated aromatic heterocycle with up to three heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, which may be bonded via a nitrogen atom and which may optionally be up to three times the same or differently substituted by amino, azide, formyl, carboxyl, mercaptyl

31215 / H, hydroxy, straight or branched acyl, alkylthio, alkoxy or alkoxycarbonyl of up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight or branched alkyl of f, * t 'to 6 carbon atoms, which may itself be substituted by 1'-hydroxy, amino, carboxyl, straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino, each having up to 5 carbon atoms or a radical of the formula -OR ⁴ , wherein

R ⁴ represents a straight or branched acyl group of up to 5 carbon atoms or a group of the formula -SiR ⁵ R ⁶ R ⁷ , wherein:

R ⁵ , R ⁶ and R ⁷ are the same or different and represent an aryl group of 6 to 10 carbon atoms or an alkyl group of up to 6 carbon atoms, and / or are substituted with the remainder of the formula

O --- CH.

- (I _it

CCH, (C · -.) ₃

or -S (O) _C NR ⁹ R ¹⁰ wherein a and bab 'are the same or different and are 0,1, 2 or 3,

R ⁸ represents a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, c represents the number 1 or 2, and

R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 10 carbon atoms, which is optionally substituted with a cycloalkyl group of 3 to 8 carbon atoms or an aryl group of 6 to 10 carbon atoms

31215 / H atoms, which may itself be substituted by a halogen atom, or an aryl group of 6 to 10 carbon atoms, which is optionally substituted by a halogen atom, or a cycloalkyl group of 3 to 7 carbon atoms, or

R ⁹ and R ¹⁰ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle, which may optionally contain an additional oxygen atom or a NR ¹¹ radical, wherein:

R ¹¹ represents hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, a residue of formula

a benzyl or phenyl group, wherein the ring systems are optionally substituted with halogen,

R ² and R ³ form a six-membered saturated or aromatic heterocycle with up to three heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, which is optionally up to three times the same or differently substituted by a formyl, carboxy, hydroxy, mercaptyl, or a branched acyl, alkylthio or alkoxycarbonyl group of up to 6 carbon atoms, nitro, cyano, halogen or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each of which may be substituted by hydroxy, amino, carboxy or branched, acyl, alkoxy or alkoxycarboxy having up to 5 carbon atoms in each case, and / or the heterocycle optionally substituted by a radical of formula -NR ¹² R ¹³ or -S (O) _c -NR ⁹ R ¹⁰ ', wherein:

31215 / H

R ¹² and R ¹³ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms or

R ¹² represents a hydrogen atom and

R ¹³ represents a formyl group a

I '1c', R ⁹ and R ¹⁰ are as defined above for c, R ⁹ and R ¹⁰ and are the same or different therewith and / or the heterocycle is optionally substituted by a phenyl group which may itself be up to twice the same or optionally substituted by a halogen atom or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each, and / or the heterocycle optionally substituted by a group of the formula -N = CH-NR ¹⁴ R ¹⁵ , wherein:

R ¹⁴ and R ¹⁵ are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group of up to 6 carbon atoms;

A is a 5- or 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen or phenyl, optionally substituted up to three times equally or differently with amino, mercaptyl, hydroxy, formyl, carboxy, straight or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl of up to 6 carbon atoms, nitro, cyano, frifluoromethyl, azido, halogen, phenyl or straight or branched alkyl of up to 6 carbon atoms be substituted with hydroxy, carboxy, straight or branched acyl, alkoxy or alkoxycarbonyl of up to 5 carbon atoms, and / or is substituted with - (CO) _d -NR ¹⁶ R ¹⁷ , wherein:

31215 / H d is 0 or 1 a

R ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl or acyl group of up to 5 carbon atoms each, and their isomeric forms and salts.

The compounds of the formula I according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids can be mentioned here.

Physiologically acceptable salts are preferred within the scope of the present invention. Physiologically acceptable salts of the pyrazole derivatives may be salts of the compounds of the present invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts 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, citric acid, citric acid. , maleic acid or benzoic acid.

Physiologically acceptable salts may also be metal or ammonium salts of the compounds of the present invention having a free carboxyl group. Particularly suitable are, for example, sodium, potassium, magnesium or calcium salts as well as ammonium salts derived from ammonia or organic amines, such as, for example, ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds of the present invention may exist in stereoisomeric forms that exist either as an image and a mirror image (enantiomers) or not as an image and a mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers as well as to their enantiomers or diastereomers

31215 / H of the corresponding mixtures. Like the diastereomers, the racemate forms can be resolved into stereoisomerically uniform moieties by known methods.

Heterocycle in the context of the invention, depending on the abovementioned substituents, is generally a saturated or aromatic five- or six-membered heterocycle which may contain up to three heteroatoms from the group consisting of sulfur, nitrogen and / or oxygen and in the case of a nitrogen atom may also be bound thereto. Examples include oxadiazolyl, thiadiazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, thienyl, tetrahydropyranyl, furyl, morpholinyl, pyrrolyl, thiazolyl, oxazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, or a tetrahydrofuranyl group, with thiazolyl, furyl, oxazolyl, pyrazyl, triazolyl, pyridyl, pyrimidyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl groups being preferred.

Preferred are compounds of the present invention of the general formula I in which:

R ¹ represents pyrimidinyl, pyridazinyl, pyridyl, pyrazinyl, tetrahydropyranyl, tetrahydrofuranyl, furyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, pyrazolyl, isadiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, optionally substituted up to three times equally or differently with amino, formyl, mercaptyl, carboxy, hydroxy, straight or branched acyl, alkoxy, alkylthio or alkoxycarbonyl of up to 5 carbon atoms, nitro, cyano, azide, fluorine, chlorine or bromine, phenyl or a straight or branched alkyl group of up to 5 carbon atoms, which itself may be substituted by hydroxy, amino, carboxy, straight or branched acyl, alkoxy, alkoxycarbonyl

31215 / H

Ί or an acylamino group of up to 4 carbon atoms or the radical of the formula -OR ⁴ , whereby

R ⁴ represents a straight or branched acyl group having up to 4 carbon atoms,

J, and / or are substituted with the remainder of the formula

or

-S (O) _c -NR ⁹ R ¹⁰ , wherein a and bab 'are the same or different and are 0,1, 2 or 3,

R ⁸ represents a hydrogen atom or a straight or branched alkyl group having up to 3 carbon atoms, c represents the number 1 or 2, and

R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 9 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl or naphthyl or phenyl groups which may themselves be substituted fluorine or chlorine, or a phenyl or naphthyl group optionally substituted by fluorine or chlorine, or a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, or

R ⁹ and R ¹⁰ together with the nitrogen atom form a morpholine ring or a radical of formula

31215 / H

or -n nr ¹¹ wherein

R ¹¹ represents hydrogen, methyl or a radical of the formula or represents benzyl or phenyl, where the ring systems are optionally substituted by fluorine or chlorine,

R ² and R ³ , with the double bond included, form a pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, which may optionally be up to three times the same or differently substituted by a formyl, carboxy, hydroxy, mercaptyl, straight or branched acyl, alkylthio or alkoxycarbonyl group. up to 5 carbon atoms, nitro, cyano, azide, fluorine, chlorine or bromine or straight or branched alkyl or alkoxy of up to 5 carbon atoms, which may themselves be substituted by hydroxy, amino, carboxy or straight or branched, acyl, alkoxycarbonyl having up to 4 carbon atoms in each case, and / or the above heterocyclic rings being optionally substituted by a group of the formula -NR ¹² R ¹³ or -S (O) _C NR ⁹ R ¹⁰ ', wherein:

R ¹² and R ¹³ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, or

R ¹² represents a hydrogen atom and

R ¹³ represents a formyl group a

31215 / H c ', R ⁹ and R ¹⁰ are as defined above for c, R ⁹ and R ¹⁰ and are the same or different therewith and / or the above heterocyclic rings are optionally substituted with a phenyl group which may itself be substituted with a fluorine atom , chlorine or bromine or a straight or branched alkyl or alkoxy group of up to 4 carbon atoms in each case, and / or the above heterocyclic rings are optionally substituted by a group of formula -N = CH-NR ¹⁴ R ¹⁵ , wherein:

R ¹⁴ and R ¹⁵ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms and

A is tetrahydropyranyl, thienyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl, optionally substituted up to two times the same or differently with hydroxy, formyl, carboxy, straight or branched acyl. alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl of up to 4 carbon atoms, fluorine, chlorine or bromine, nitro, cyano, trifluoromethyl or a straight or branched alkyl of up to 4 carbon atoms, which in itself may be hydroxy, carboxy-substituted a straight or branched acyl, alkoxy or alkoxycarbonyl group of up to 4 carbon atoms in each case and / or substituted by a group of the formula - (CO) j-NR ¹⁶ R ¹⁷ , where d is 0 or 1 and

R ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl or acyl group of up to 4 carbon atoms each, and their isomeric forms and salts.

31215 / H

Particularly preferred are the compounds of the present invention of the general formula I in which

R ¹ represents an imidazolyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, isoxazolyl, oxazolyl or thiazolyl group, which are optionally substituted up to three times with the same or different formyl, mercaptyl, amino, fluoro or chloro, cyano, cyano, cyano, cyano, cyano, cyano , alkoxy, alkylthio or alkoxycarbonyl of up to 4 carbon atoms or straight or branched alkyl of up to 4 carbon atoms, which may itself be substituted by hydroxy, amino, carboxy, straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino to 3 carbon atoms, and / or are substituted with the remainder of the formula

O --- CH.

or

-S (O) _c -NR ⁹ R ¹⁰ , wherein a and bab 'are the same or different and are 0,1 or 2,

R ⁸ represents a hydrogen atom or a methyl group, c 'represents the number 1 or 2 and

R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 9 carbon atoms optionally substituted by a naphthyl or phenyl group, or a phenyl or naphthyl group optionally substituted by fluorine or chlorine, or is cyclopropyl or cycloheptyl or

31215 / H

R ⁹ and R ¹⁰ together with the nitrogen atom form a morpholine ring or a radical of formula

or

while

R ¹¹ represents hydrogen, methyl or a radical of formula

or represents a benzyl or phenyl group, the ring systems being optionally substituted by chlorine,

R ² and R ³ , with the double bond included, form a pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, which may optionally be three or more times the same or differently substituted by a formyl, carboxy, hydroxy, mercaptyl, straight or branched acyl, alkylthio or alkoxycarbonyl group. up to 4 carbon atoms, nitro, cyano, fluorine or chlorine, or a straight or branched alkyl or alkoxy group of up to 3 carbon atoms, which may themselves be substituted by hydroxy, amino, carboxy or straight or branched acyl, alkoxy or alkoxycarbonyl groups 3 carbon atoms, and / or the above heterocyclic rings are optionally substituted with amino, Ν, Ν-dimethylamino or a radical of the formula -NH-CHO or -N = CH-N (CH 3) 2 and / or a phenyl group which may itself be substituted radical of the formula -O (CH 2) 2 CH 3 and

31215 / H

A represents tetrahydropyranyl, thienyl, phenyl, pyrimidyl or pyridyl, optionally substituted up to two times the same or differently with hydroxy, formyl, carboxy, straight or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl, in each case up to 3 carbon atoms fluorine, chlorine or bromine, nitro, cyano, trifluoromethyl or straight or branched alkyl of up to 3 carbon atoms, which may itself be substituted by hydroxy, carboxy, straight or branched acyl, alkoxy or alkoxycarbonyl, in each case up to 3 and isomeric forms and salts thereof.

Particularly particularly preferred are the compounds of the present invention of formula (I) wherein:

And. represents a phenyl group, a pyrimidyl group or a fluorine-substituted phenyl or pyrimidyl group, and isomeric forms and salts thereof.

The present invention further provides a process for the preparation of substituted pyrazole derivatives of the general formula (I), characterized in that, depending on the different meanings of the heterocycles mentioned under R ² and R ³ ,

A) Compounds of formula II

R ¹ -D (II), wherein R ^{1 is} as defined above and a

D stands for formula remnants

CN

31215 / H in which

R ¹⁸ is alkyl of 1 to 4 carbon atoms, are converted by reaction with compounds of formula III

A-CH ₂ -NH-NH ₂ (III), wherein A is as defined above, in inert solvents, optionally in the presence of a base, to compounds of formula IV or IVa

(IV)

(IVa) in which A and R ^{1 are} as defined above, and in the case of compounds of formula IVa are then cyclized with carboxylic acids, nitriles, formamides or guanidine salts, and in the case of compounds of formula IV, cyclized with 1,3-dicarbonyl derivatives, their salts, tautomers, enol ethers or enamines, in the presence of acids and optionally using microwave radiation, or

B) when R ² and R ³ together form a pyrazine ring, first convert the compounds of formula IV by nitrosation to compounds of formula V

A

O (V).

in which A and R ^{1 are} as defined above,

31215 / H in the second step are produced by reducing a compound of formula VI (VI), in which A and R ^{1 are} as defined above, and finally cyclized using 1,2-dicarbonyl compounds, preferably an aqueous glyoxal solution, or

C) compounds of formula VII

N.-A

Λ

(VII) wherein A ¹ , R ² and R ^{3 are} as defined above and

L represents a radical of the formula -SnR ¹⁹ R ²⁰ R ²¹ , -Zn R ²² , an iodine atom, a bromine atom or a triflate group, wherein:

R ¹⁹ , R ²⁰ and R ²¹ are the same or different and represent a straight or branched alkyl group having up to 4 carbon atoms and

R is halogen, reacted with compounds of formula VIII

R ¹ -T (VIII), wherein R ^{1 is} as defined above, and when L = -SnR ¹⁹ R ²⁰ R ²¹ or -ZnR ²² ,

T represents a triflate group or a halogen atom, preferably bromine, and when L = iodine, bromine or a triflate group,

31215 / H

T represents a residue of the formula SnR ¹⁹ R ²⁰ R ²¹ , ZnR ²² or BR ²³ R ²⁴ , wherein

R ¹⁹ , R ²⁰ , R ²¹ and R ²² have the meanings given above for R ¹⁹ , R ²⁰ , R ²¹ and R ²² and are the same or different thereto and

R ²³ and R ²⁴ are the same or different and represent hydroxy, aryloxy of 6 to 10 carbon atoms or a straight or branched alkyl or alkoxy group of up to 5 carbon atoms or together form a 5- or 6-membered carbocyclic ring, in a palladium catalyzed reaction in inert solvents, optionally in the presence of a base;

D) in case R ¹ = where

R ²⁵ . represents an alkyl group having 1 to 6 carbon atoms, which is optionally substituted by a halogen atom, convert IX either directly by reaction with a compound of formula X

(X) in the NaOCO-CH3 / N-methylpyrrolidine system to compounds of formula Ia

31215 / H in which R ² , R ³ , A and R ^{25 are} as defined above and then the acetyl group is cleaved off by treatment with potassium hydroxide in methyl alcohol, or

I '.

first by reacting compounds of formula IX with compounds of formula X to produce compounds of formula XI

wherein R ² , R ³ , A and R ^{25 are} as defined above, and in the next step, potassium hydroxide is prepared by treatment with potassium hydroxide, and in the case of the -S (O) _C NR ⁹ R ¹⁰ and -S (O) _C NR ⁹ R groups. ¹⁰ , starting from unsubstituted compounds of formula I, are first reacted with thionyl chloride and in the second step with the corresponding amines, and optionally the substituents mentioned for R ¹ , R ² , R ³ and / or A are varied or introduced by conventional methods , preferably by chlorination, catalytic hydrogenation, reduction, oxidation, cleavage of the protecting groups and / or nucleophilic substitution.

The heterocycles mentioned under R ² and R ³ can also be introduced by reaction of appropriately substituted compounds of formula II by other known heterocyclic syntheses.

The process of the present invention may be illustrated by way of example by the following reaction scheme:

31215 / H

31215 / Η [A]

CF.COOH

malodialdehyde derivative prip. salts of tautomers

31215 / H [A] Derivatization

C, H _S O

COXjHc

31215 / H [E] [E]

1.) HNO,

Pd-C / H ₂

3.) Glyoxal

[C]

Pd _(PPh3), C !,

Suitable solvents for the individual process steps are inert organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, tetrahydrofuran, dimethyl ether and dioxane, alcohols such as methanol and ethyl alcohol, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane or 1,2-dichloroethylene trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

Generally, inorganic or organic bases can be used as bases for the process of the present invention. These preferably include alkali metal hydroxides such as sodium hydroxide or hydroxide

31215 / H potassium, 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, alkali metal or alkaline earth metal alcoholates such as sodium methoxide or potassium, sodium or potassium ethanolate and potassium or tert-butylate or organic. amines (trialkyl- (C 1 -C 6) -amines) such as triethylamine or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) ), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to use alkali metals such as sodium or their hydrides such as sodium hydride as bases. Sodium and potassium carbonate, triethylamine and sodium hydride are preferred.

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

The reaction is generally carried out at a temperature in the range of 0 ° C to 150 ° C, preferably 20 ° C to 110 ° C.

The reaction may be carried out at normal, elevated or reduced pressure, for example in the range 0.05 to 0.5 MPa. In general, working at normal pressure.

Protonic acids are generally suitable as cyclic acids. These preferably 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 sulfonic acids having alkyl radicals of 1 to 4 carbon atoms or aryl radicals such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

The catalytic hydrogenation can generally be carried out with hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, using catalysts such as Raney nickel, palladium, palladium on charcoal or platinum, or

31215 / H hydrides or borates in inert solvents, optionally in the presence of a catalyst.

Chlorination is generally carried out using conventional chlorinating agents such as PCh, PCl 3, POCl 3 or elemental chlorine. POCl 3 is preferred in the present invention.

When residues of the formulas -S (O) _C NR ⁹ R ¹⁰ and S (O) c NR ⁹ R ¹⁰ are present, the corresponding unsubstituted compounds are reacted first with thionyl chloride. The next step is to react with the amines in any of the above-mentioned ethers, preferably dioxane. When c = 2, the oxidation is then carried out by conventional methods. The reactions are carried out at a temperature between 0 ° C and 70 ° C and under normal pressure.

Nucleophilic substitution and Vilsmeier reaction are performed using conventional published methods.

The reduction is generally carried out with reducing agents, preferably those suitable for reducing the carbonyl compounds to the hydroxy compounds. Particularly suitable here is a reduction using metal hydrides or complex metal hydrides in inert solvents, optionally in the presence of a trialkylborate. In particular, the reduction is carried out using complex metal hydrides such as lithium borate, sodium borate, potassium borate, zinc borate, lithium trialkyl hydride borane, diisobutylaluminium hydride or lithium aluminum hydride. Quite particularly preferably, the reduction is carried out with diisobutylaluminium hydride and sodium borohydride.

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

The reduction is generally carried out at a temperature in the range of -78 ° C to 50 ° C, preferably -78 ° C to 0 ° C, in the case of DIBAH at 0 ° C to room temperature for NaBH 4.

The reduction can generally be carried out at normal pressure, but it is also possible to work at elevated or reduced pressure.

31215 / H

The compounds of formulas II and III are known or can be prepared by conventional methods (see, for example, J. Hromath et al., Monatsh. Chem. 1976, 107, 233).

The compounds of the formulas IV, IVa, V and VI are known in part and can be prepared as described above.

Suitable solvents for process (C) are inert organic solvents which do not change under the reaction conditions. These include ethers such as diethyl ether, tetrahydrofuran, dimethyl ether and dioxane, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. Mixtures of solvents may also be used. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

, I

The reaction is generally carried out at a temperature in the range of 0 ° C to 150 ° C, preferably 20 ° C to 110 ° C.

The reaction may be carried out at normal, elevated or reduced pressure, for example in the range 0.05 to 0.5 MPa. In general, working at normal pressure.

PdCl ₂ (P (C 6 H 5) ₃ ) ₂ , palladium bis-dibenzylideneacetone (Pd (dba) ₂ ), [1,1'-bis- (diphenylphosphino) -ferocene] -palladium are generally suitable as palladium compounds within the scope of the present invention. (II) chloride (Pd (dppf) Cl ₂ ) or Pd (P (C ₆ H ₅ ) 3) 4. Preferred are Pd (P (C ₆ H _{5) 3)} 4th

The compounds of formula (VIII) are known or can be prepared by conventional methods.

Compounds of formula (VII) are known in part or novel in the case of tanyl and can then be prepared, for example, by reacting compounds of formula (XII)

31215 / H

N

II (XH)

wherein R ² , R ³ and A are as defined above and

L ¹ represents a triflate group or a halogen atom, preferably iodine, with compounds of the general formula XIII (SnR ¹⁹ R ²⁰ R ²¹ ) ₂ (XIII) in which R ¹⁹ , R ²⁰ and R ^{21 have} the meanings given above as catalysed above palladium.

Compounds of formulas XII and XIII are known or can be prepared by conventional methods.

Process D) according to the invention is carried out with one of the abovementioned bases, preferably in N-methylpyrrolidone, at a temperature in the range 100 ° C to 200 ° C, preferably 150 ° C.

Compounds of formula (IX) and (X) are known or obtainable by conventional methods.

The compounds of formulas Ia and XI are novel and can be prepared as described above.

If typical protecting groups are used in the derivatization reactions, they are generally cleaved in one of the abovementioned alcohols and / or tetrahydrofuran or acetone, preferably in a methanol / tetrahydrofuran system, in the presence of hydrochloric acid, trifluoroacetic acid or toluenesulfonic acid. at a temperature in the range of 0 ° C to 70 ° C, preferably at room temperature and at normal pressure.

The compounds of the formula I according to the invention exhibit an unexpected valuable spectrum of pharmacological action.

31215 / H

The compounds of the present invention of formula I cause vascular relaxation, inhibition of platelet aggregation and lowering of blood pressure as well as an increase in coronary blood flow. These effects are mediated through direct stimulation of soluble guanylate cyclase and an increase in intracellular cGMP. In addition, the compounds of the present invention potentiate the effect of agents that increase cGMP levels, such as Endothelium derived relaxing factor (EDRF), NO-donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

Thus, they can be used in medicaments for the treatment of cardiovascular diseases, such as for the treatment of high blood pressure and cardiac insufficiency, stable and instable angina pectoris, peripheral and cardiovascular diseases, arrhythmias, thromboembolic diseases and ischemia such as myocardial infarction stroke, transient and ischemic attacks, peripheral vascular disorders, suppression of restenosis such as thrombolysis therapies, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronarrangioplasty (PTCA) and bypase, as well as treatment of the urinary artery disease erectile dysfunction and incontinence.

In addition, the invention encompasses the combination of the compounds of the present invention of formula I with organic nitrates and NO-donors.

The organic nitrates and NO-donors within the scope of the present invention are generally substances which exert their therapeutic effect through the release of NO or of the NO type. Preferred are sodium nitropruzide (SNP), nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 and the like.

In addition, the present invention encompasses a combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). These are in particular inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beava and Reifsynder (1990) TIPS 11, p. 150-155. These inhibitors potentiate the effect of the compounds of the present invention and increase the desired pharmacological effect.

31215 / H

The following tests were performed to determine cardiovascular effects: In vitro assays on cells of vascular origin were tested for guanylate cyclase-dependent effects of cGMP formation with and without NO-donor. Anti-aggregation properties are shown on collagen-stimulated human platelets. The vascular-relaxing effect is determined on phenylephrine precontracted rings of rabbit aorta. The blood pressure lowering effect was tested in anesthetized rats.

Stimulation of soluble guanylate cyclase in primary endothelial cells

Primary endothelial cells are isolated from pig aorta by treatment with collagenase solution. The cells are then cultured in culture medium at 37 ° C / 5% CO ₂ until confluency is reached. For assays, cells are passaged, plated in 24-well cell culture plates and subcultured (~ 2 x 10 ⁵ cells / well) until confluency is reached. To stimulate endothelial guanylate cyclase, the culture medium is aspirated, cells are washed once with Ringer's solution and incubated in stimulation buffer with or without NO-donor (sodium nitropruzide, SNP, 1 µm) for 10 minutes at 37 ° C / 5% CO ₂ ). Test substances (final concentration 1 µM) are then pipetted into the cells. At the end of the 10 minute incubation period, the buffer solution is aspirated and added to the 4 ° C stoppufor cells. The cells are then lysed for 16 hours at -20 ° C. Finally, the intracellular cGMP containing liquid is collected and the cGMP concentration is determined using the cGMP-SPA system (Amersham Buchler, Braunschweig). The results are shown in Table A.

31215 / H

Table A

Example cGMP increase (%) 14 > 1,000 15 504 16 652 17 > 1,000 32 135

Blood vessels relaxing effect in vitro

The rabbits are sacrificed in the tulle and bled. The aorta is removed and free of adhering tissues. The isolated 1.5 mm wide rings of the isolated rabbit aorta are individually preloaded into a 5 ml organ bath with Krebs-Heseleite solution (mM): NaCl: 119, KCI: 4.8, CaCl ₂ x 2 H ₂ O : 1, MgSO ₄ x 7 H ₂ O: 1.4, KH ₂ PO ₄ : 1.2, NaHCO ₃ : 25, glucose: 10, 37 ° C.

The contraction force is determined with Staham UC2-Zellen, amplified and A / D-Wandler (DAS-1802 HC, Keithley Instruments Munchen) is digitized and parallel-registered on a line recorder. To achieve contraction, phenylephrine is added cumulatively to the bath at increasing concentrations.

After several control cycles, the test substance is added at increasing dose at each additional run, and the contraction achieved is compared to the contraction achieved in the last embodiment. From this, the concentration required to reduce the control value by 50% (IC ₅₀ ) is calculated. The standard application volume is 5 μΙ, the proportion of DMSO in the bath solution is 0.1%. The results are shown in Table B below.

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Table B

Example Aorta (IC50) μΜ 14 1.8 15 13.0 16 1.7

Measurement of blood pressure in narcotized rats

Male Wistar rats weighing 300-350 g are anesthetized with thiopental (100 mg / kg i.p.). Following tracheotomy, a blood pressure catheter is inserted into the femoral artery. The test substances are administered orally by means of the esophagus probe at various doses as a suspension in the tylose solution. The results are shown in Table C below.

Table C

Example Dose (mg / kg) Max. blood pressure drop (mmHg) Time (min) 13 10 -13 60 30 -23 60 14 10 -18 40 30 -21 50 16 10 -9 50 30 -16 50

Inhibition of platelet aggregation in vitro

Blood of healthy individuals of both sexes is used to determine the inhibitory effect of platelet aggregation. As an anticoagulant, 9 parts of blood are mixed into one part of a 3.8% aqueous sodium citrate solution. By centrifugation, platelet-enriched citrate plasma (PRP) is obtained from this blood (Jürgens / Beller, Klinische Methoden der Blutgerinnungsanalyse, Thieme Verlag, Stuttgart, 1959).

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For these tests, 445 μΙ of PRP and 5 μΙ of the active substance solution are preincubated at 37 ° C in a water bath. Platelet aggregation is then determined by a turbidometric method (Bom, G.V.R., J. Physiol. (London), 168, 178-195, 1963) in a segregometer at 37 ° C. To this end, a preincubated sample is mixed with 50 μΙ of collagen, an aggregation-inducing agent, and the change in optical density is determined. For quantitative evaluation, the maximal aggregation response is determined and percent inhibition compared to control is calculated.

The compounds described according to the invention are also active substances for the treatment of diseases in the central nervous system characterized by disorders of the NO / cGMP system. They are particularly suitable for the elimination of cognitive deficits, for improving learning and memory performance and for the treatment of Alzheimer's disease. They are also suitable for the treatment of central nervous system diseases such as states of fear, tension and depression, central nervous system-induced sexual dysfunctions and sleep disorders, as well as for the control of eating and eating disorders. '

Furthermore, they are also suitable for regulating blood flow to the brain and are therefore an effective means of treating migraines.

They are also suitable for the prophylaxis and treatment of the consequences of cerebral infarction (Apoplexia cerebri), such as cases of stroke, cerebral ischemia and trauma following brain damage. Likewise, the compounds of the present invention can be used to treat pain conditions.

The present invention includes pharmaceutical compositions which, in addition to non-toxic, inert, pharmaceutically acceptable carriers, comprise one or more of the compounds of the present invention or consist of one or more of the compounds of the present invention as well as a process for making such compositions.

The active ingredient (s) may also be present in one or more of the above-mentioned carriers, also in microencapsulated form.

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The therapeutically active compounds should be present in the above pharmaceutical compositions in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, based on the total composition.

I

In addition to the compounds of the present invention, the above pharmaceutical compositions may also contain other pharmaceutical active ingredients.

In general, it has proven advantageous in both human and veterinary medicine to administer the active ingredient (s) in a total amount of about 0.5 to 500 mg / kg body weight per 24 hours, preferably 5 to 100 mg / kg, to achieve the desired results. body weight, optionally in the form of multiple individual doses. A single dose comprises the active compound (s) of the present invention in an amount of about 1 to 80 mg / kg body weight, in particular 3 to 30 mg / kg.

DETAILED DESCRIPTION OF THE INVENTION

The following abbreviations are used in the following examples:

MeOH = methanol

E = diethyl ether

EE = ethyl acetate

T = toluene

Ph = phenyl

The numbers following the abbreviations of the solvents in the following tables in column Rf are parts by weight.

Starting compounds

Example 1A

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

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To a solution of 79.5 g (408 mmol) of benzyl hydrazine dihydrochloride in 1.3 L of ethanol was added with stirring 44.1 g (817 mmol) of sodium ethanolate. After 15 minutes, 67.4 g (408 mmol) of 2-cyanomethylcarbonyl-5-hydroxymethylfuran are added and the reaction mixture is stirred under reflux for 3 hours. After cooling, 1 L of water was added, the ethanol portion was evaporated in vacuo and the precipitated crystals were filtered off with suction. After washing with water and then diethyl ether, it is dried over phosphorus pentoxide. 91 g (83% of theory) of the product with a melting point of 163 DEG C. are obtained.

The compounds listed in Table 1A are obtained analogously.

Table 1A

Example R ¹ Tt ( ^e ) Rf Yield (%) 2A 2-furyl 124 0.63 (T1E1) 49 3A 2-pyrimidinyl 178 0.48 (MeOH1E4) 66.5 4A 2-pyridyl 130 0.08 (T1E1) 30

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Example 5A

5-Amino-1- (2-fluorobenzyl) -3- (5-hydroxymethyl-2-furyl) -4-nitrosopyrazolo

g (34.8 mmol) of 5-amino-1- (2-fluorobenzyl) -3- (5-hydroxymethyl-2-furyl) pyrazole is introduced into a mixture of 66 ml of ethyl alcohol and 26.7 ml of 5% aqueous hydrochloric acid, 26.4 ml of a 15% ethanolic ethylnitrite solution are added over 5 minutes and the reaction mixture is stirred for 1 hour at room temperature. The dark violet reaction solution was added to an aqueous potassium carbonate solution and extracted with ethyl acetate. Evaporation of the organic phase in vacuo to give 8 g of a residue which can be directly further reacted (Rf: 0.17, T1E1, _SiO2).

Example 6A

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

g of the compound of Example 5A is dissolved in ethyl alcohol, treated with 0.5 g of 5% palladium on carbon and hydrogenated in a Paar apparatus under a hydrogen pressure of 20 bar for 15 minutes. The solution is then aspirated through diatomaceous earth and used for the next reaction (Rf = 0.21, T1E1, S1O2).

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Example 7A

3-amino-2- (2-fluorobenzyl) pyrazole

Said compound is obtained analogously to FR 1 403 372 (Chem. Abstr. 1965, 63,14871a).

Example 8A

1- (2-fluorobenzyl) pyrazolo [3,4-a] pyrimidine

3 g of 3-amino-2- (2-fluorobenzyl) pyrazole is dissolved in 1.5 l of dioxane and stirred with 31.45 g of dimethylaminoacrolein. The mixture was then heated to 50 ° C and trifluoroacetic acid (16.65 g) was added. The reaction mixture is boiled for 60 hours, then the solvent is evaporated in vacuo, the residue is mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, evaporated in vacuo and the residue is chromatographed on silica gel. After elution using toluene -> toluene / ethyl acetate 9: 1 gave 17.3 g (46.3%) of the title compound having Rf = 0.69 _(SiO2, T1E1).

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Example 9A

3-bromo-1- (2-fluorobenzyl) pyrazolo [3 4 _I-a] pyrimidine

g (35.2 mmol) of 1- (2-fluorobenzyl) -pyrazolo [3,4-b] pyrimidine was dissolved in 284 ml of chloroform and slowly treated with 14 g (87.3 mmol) of bromine at room temperature. The reaction mixture was stirred overnight and then added dropwise

1.2 ml bromine. After two hours, the reaction is complete and the reaction solution is evaporated in vacuo. The residue is mixed with 20 ml of ethyl acetate and crystallized. After washing the crystals with diethyl ether, 7.5 g (70% of theory) of the title compound of Rf 0.2.2 (SiO2, toluene) are obtained.

Example 10A

1- (2-fluorobenzyl) -3-trimetylstanylpyrazolo [3,4-a] pyrimidine

1.22 g (4 mmol) of 3-bromo-1- (2-fluorobenzyl) -pyrazolo [3,4-b] pyrimidine was dissolved in 200 ml of dioxane under argon and mixed with 4.5 g (13.74 g). mmol) hexamethyldistanane and 1.2 g tetrakis (triphenylphosphine) palladium. The reaction mixture was stirred overnight at 100 ° C, then added to water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, evaporated in vacuo and chromatographed on

31215 / H silica gel. Elution with toluene gave 1.4 g (89.7%) of the title compound with Rf 0.074 (SiO _2, toluene).

Example 11A

500 mg (1.84 mmol) of 1- (2-fluorobenzyl) -pyrazolo [3,4-b] pyridine-3-carboxylic acid are dissolved in 10 ml of methylene chloride and 400 mg (2.3 mmol) of N - (-) hydrochloride are added. (3-dimethylaminopropyl) - / V'-ethylcarbodiimide hydrochloride. The reaction mixture was stirred for 10 minutes at room temperature (complete dissolution), and a solution of 260 mg (1.84 mmol) of 1,1-dichloro-3-aminobut-1-ene in 5 ml of methylene chloride was added dropwise. After about 3 hours, the mixture is concentrated and the residue is purified on silica gel (eluent: cyclohexane / EE 1: 1). 340 mg (47% of theory) of 1- (2-fluorobenzyl) -3- (1,1-dichlorobut-1-en-3-yl-amido) -pyrazolo [3,4] pyridine are obtained with an Rf value of 0, 35 (cyclohexane / EA 2: 1).

MS (ESI-POSITIVE): 417 (27, [M + Na] ⁺ ), 415 (42, (M + Na) ⁺ ), 395 (60 [M + H] ⁺ ), 393 (100, [M + H] ⁺ ) ).

Production examples

Example 1

1- (2-fluorobenzyl) -3- (2-hydroxymethyl-2-furyl) pyrazolo (3,4-b] pyrazine

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The crude substance (8 g in 200 mL of ethyl alcohol) from Example 6A was mixed with 4.61 g of a 40% aqueous glyoxal solution and stirred for 10 hours at room temperature. The reaction mixture is then evaporated in vacuo and the residue is chromatographed on SiO2 using toluene / ethyl acetate. After crystallization with diethyl ether, 0.57 g (7.6% of theory) of the title compound of melting point 194 DEG C. is obtained.

Example 2

1- (2-fluorobenzyl) -3- (2-furyl) -6-hydroxy-pyrazolo [3,4-b] pyridine

g (27.2 mmol) of 5-amino-1- (2-fluorobenzyl) -3- (2-furyl) -pyrazole, 3.94 g (27.3 mmol) of 3-ethoxyacrylic acid ethyl ester and 1.96 ml ( The trifluoroacetic acid (27.3 mmol) was stirred vigorously and reacted in the microwave for 2 minutes. The mixture is then added to a solution of 10 g of potassium hydrogen phosphate in 500 ml of water and extracted with 500 ml of ethyl acetate. After drying the organic phase over anhydrous magnesium sulfate, 30 g of silica gel are added and the mixture is evaporated in vacuo. The residue is chromatographed on a silica gel column using a toluene / ethyl acetate gradient. The first fraction was crystallized with diethyl ether to give 1.8 g (21.4% of theory) of the title compound, mp 250 ° C.

Analogously to Example 2, the compounds listed in the following Table 1 were prepared.

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Table 1

Example R ¹ ------ ^TS Yield (%) Rf / F ’C 3 * 2-furyl -ch ₃ 24 226 4 2-pyridyl H 0.8 (EE)

* from ethyl acetate

Example 5

4-Amino-1- (2-fluorobenzyl) -3- (2-furyl) -pyrazolo [3,4-a] pyrimidine

g (7.1 mmol) of 5-amino-4-cyano-1- (2-fluorobenzyl) -3- (2-furyl) pyrazole and 30 ml of formamide are stirred first at 100 ° C and then for 3 hours at 195 ° C. The mass crystallizing on cooling is filtered off with suction, washed with cold formamide, the residue is taken up in ethyl acetate and washed with water. Drying and evaporation of the organic phase, 2.13 g (97%) of the title compound, mp 190 ^e C and Rf 0.07 (T1E1).

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In a similar manner, for example, the compounds listed in the following Table 2 are obtained from 2-propyloxyphenylnitrile, benzonitrile or guanidinium bicarbonate.

Table 2

Example R ² ' Ŕ ²⁸ MP: (° C) Rf Yield (%) 6 F 2-propyloxyphenyl 187 0.6 (T1E1) 42.7 7 F ph 205 0.69 (T1E1) 100 8 F NH ₂ 205 0.22 (EE) 71 9 H H 174 0.15 (T1E1) 90

Example 10

1-Benzyl-3- (2-furyl) -4-hydroxy-pyrazolo [3,4-d] pyrimidine

6.14 g (23.2 mmol) of 5-amino-1-benzyl-4-cyano-3- (2-furyl) pyrazole (Rf = 0.6) is boiled in 100 ml of formic acid for 3.75 hours. The batch is evaporated in vacuo, the residue is mixed with water and shaken with ethyl acetate. The insoluble material was filtered off with suction to give 5.1 g of the title compound (mp = 242 ° C, R f = 0.3, SiO 2, toluene / ethyl acetate = 1: 1). By evaporation of the organic phase, another fraction can be isolated.

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Example 11

1-benzyl-4-chloro-3- (2-furyl) pyrazolo [3,4-d] pyrimidine

6.6 g of 1-benzyl-3- (2-furyl-4-hydroxypyrazolo [3,4-d] pyrimidine) is boiled for 12 hours in 100 ml of POCl3, then evaporated in vacuo, stirred with aqueous potassium hydrogen phosphate solution. The extract was dried over anhydrous sodium sulfate and evaporated on a rotary evaporator to give 7.47 g of a solid which could be reacted directly in the next step (Rf = 0.8, SiO2, toluene / ethyl acetate). = 1: 1).

Example 12

1-Benzyl-3- (2-furyl) pyrazolo [3,4-d] pyrimidine

5.81 g of 1-benzyl-4-chloro-3- (2-furyl) -pyrazolo [3,4-d] pyrimidine are dissolved in 450 ml of dioxane and 4 g of 20% palladium hydroxide on carbon are added after addition of 2 g. , 61 ml

The 31215 / H triethylamine is hydrogenated for 5 hours at 0.3 MPa hydrogen pressure in a Paar apparatus. After filtration through diatomaceous earth, evaporation and chromatography of the residue, 2.26 g of a yellowish crystalline solid is obtained (m.p. = 106 DEG C., Rf = 0.2, toluene / ethyl acetate = 4: 1).

Example 13

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

2.69 g (10 mmol) of 5-amino-1-benzyl-3- (5-hydroxymethyl-2-furyl) pyrazole and 1.4 g of sodium malondialdehydhydrátu was stirred in 100 mL of dioxane at 100 C for 30 ^e minutes and 5.5 ml of trifluoroacetic acid are slowly added over 5.5 hours. The reaction mixture is then evaporated in vacuo, the residue is taken up in ethyl acetate, shaken with sodium hydrogen phosphate solution, the organic phase is separated, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on silica gel to give 200 mg (6.6% of theory) of crystalline substance, m.p. 104 ° C.

>

The compounds listed in the following Table 3 were prepared analogously to the above.

Table 3

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Pr. R ²⁹ R ¹ R ³⁰ R ³ ' R ³² 1.1. CC] Rf yield ^ 14 F Z ° X = CH.OH. about H H H 115 0.6 EE 1.1 15 F H H H 45 0.69 (TIEl) 68 16 F -ABOUT H H H 163 0.33 (TIE!) 11 17 F -ABOUT H H H 7i 0,65 σΐΞΐ) 41 1S The Me Me Me 115 0.84 (TIE i) 71 19 -about Me 1 H Me 78 0.77 (Tiel) 7!

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Example 20

3- (4 _l 5-dimethyl-pyrimidin-2-yl) -1- (2-fluorobenzyl) pyrazolo [3 _liter 4-a] pyrimidine

1- (2-Fluorobenzyl) -3-trimethylstanylyrazolo [3,4-b] pyrimidine (1.4 g, 3.59 mmol) was boiled overnight in toluene under argon with 0.51 g (3.58 mmol) of 2-chloro-4. Of 5-dimethylpyrimidine and 0.2 g (0.28 mmol) of bis (triphenylphosphine) dichloropalladium. 3 g of silica gel are then added and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel using toluene / ethyl acetate. 0.34 g (28% of theory) of the title compound of m.p. 167 ° C and an Rf value of 0.08 (SiO2, T4E1).

The compound shown in Table 4 was prepared in an analogous manner.

Table 4

Example

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Example 22

1-benzyl-3- (5-formyl-2-furyl) pyrazolo [3,4-d] pyrimidine

At 0 ° C, 0.74 ml of POCl ₃ is added to 0.64 ml of dimethylformamide. The solidified mixture was allowed to come to room temperature and 14 mL of 1,2-dichloroethane was added. To this solution was added dropwise a solution of 2 g of 1-benzyl-3- (2-furyl) -pyrazolo [3,4-d] pyrimidine (Rf = 0.45, SiO2, toluene / ethyl acetate = 1: 1) at 15 ° C in 14 ml of 1,2-dichloroethane and the reaction mixture is heated to 80 ° C. After four hours, the entire batch was added dropwise to another Vilsmeier reagent made from 1.5 ml POCl 3 and 1.3 ml dimethylformamide and stirred for 24 hours at 80 ° C. The mixture was then added to a 50% aqueous potassium hydrogen phosphate solution and heated briefly to 75 ° C with stirring. Extraction with ethyl acetate, drying the organic phase, concentration and chromatography on _SiO2 gave 0.6 g (27%) of oil _(Rf = 0.3, ₂₁ SiO toluene / ethyl acetate = 1: 1).

Analogously to the above, the compounds shown in Table 5 are prepared.

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Table 5

Pr. 1 structure 1.1. (° C) yield ^ Rf 23 ⁰ n'V h ₃ c ^ J * ³ NI ch ₃ 203 56.1 0.17 (EE)

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Table 5 (continued)

Pr. structure t -------- t. t. (° C) výťažokW Rf 24 H, CH ² - X 1 CH _a 220 80.6 0.23 (EE) 25 H, C \ A? - LV 1 ch ₃ 205 100 0.61 (EE) 26 oj-fÁ ° ^from Uf ^- H _{in I} Ak / ^ch - NN ^ NN H ^{1 h} h ₃ c 225 22.1 0.74 (T / E = 2: 1)

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Table 5 (continued)

Pr. 1 / _z Structure mp (° C) Yield < J Rf 27 F | 220 75 0.34 Ί k) - (T1E1) u \ N ^{1 H} 3 ^C XN X 1 H, C 28 V> ^F 9¾ ΤΛ 157 .79 0.44 (TIElj _N 'h ₃ c · h x . 70 with ABOUT LA ) = / 0 ό ^ ° 118 13.09 0.49 (T4: E1) Q - ^CH 3 h ₃ c ch ₃ •

Table 5 (continued)

Pr. in / structure t. t. (° C) 79 rr 30 Q ^N at / ^CH = H, C 125 27.56 0.46 (T4: E1) 31 Q 123 93 0.63 (Τ1.ΈΙ) I 1 32 0 ° v * ° yj HO 265 97 0.49 (Tl: E1)

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Example 33

-benzyl-3- (5-hydroxymethyl-2-fluoro) -pyrazolo [3,4-d] pyrimidine

0.6 g (1.97 mmol) of 1-benzyl-3- (5-formyl-2-furyl) -pyrazolo [3,4-d] pyrimidine (R f = 0.65, SiO 2, ethyl acetate) was mixed in 20 mL ml of 1-propanol at room temperature with good stirring with 60 mg of sodium borohydride. After 15 minutes, 50 mL of water and 2.5 mL of glacial acetic acid were added. After partial concentration, the mixture is extracted with ethyl acetate, dried and concentrated by adding toluene. Chromatography on SiO ₂ gave 74.8 mg (12.4% of theory) of the product (mp 165 ° C, R f = 0.43, SiO ₂ , ethyl acetate).

The compounds listed in Table 6 were prepared analogously to Example 33.

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Table 6

Pr. structure 1 1.1. [° C] yield [% J Rf 34 -O ŕ V · II, N \ J OH 165 43.5 0.37 (EE) 35 ^H 'o _N - / Y YY η, ν ^ ν 213 60 0.15 (EE) 36 ^H 'O _o NN - ^' W ^at λ? h ₂ n ⁿ 207 63 0.21 (EE)

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Table 6 (continued)

Pr. in _z Structure t. t. [° C] Yield /% 1 Rf 37 ^H o V // V ^ V 1 h ₃ c 94 30 0.45 (EE) ' 38 ' ^K ' O 'NHsT'O ^ ° Uk \\ // ^N H λλ, Η ^η ν ^ ν N ¹ 14 H ^H 205 » 27.6 0.11 (EE) 39 F ^H C N- / V) \\ 225 23.5 0.29 (T1E1)

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Table 6 (continued)

Pr. structure ’1, mp [° C] Yield 1 ^R r 40 IX> ^γς γ ^ΝΗ H 0 1 H » 189 1 23 0.43 (T1E1) 41 and, CHX vH ° \ y — n h about •

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Table 6 (continued)

Pr. structure mp [° C] yield / ^ * r 42 0 ^F L of ° x $ 0 CH, 106 15.46 0.25 (T1E1) 43 0 ^N p = ^CH = ^H H _S C 155 81.73 0.48 (T1E1)

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Table 6 (continued)

Pr. structure mp [° C] Yield Rf 44 180 72.08 0.53 (T1E1) y / ~ ^{CH3 H} H, ch ₃ 45 ZA .0.21 (T1E1) ^H0 ^ ^N x, U- Y \ J - 0 1 H

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Example 46

1- (2-fluorobenzyl) -3- [5- (piperidin-1-sulfinyl) furan-2-yl] -1 H -pyrazolo [3,4-b] pyridine

a) Preparation of 1- (2-fluorobenzyl) -3- [5-chlorosulfinylfuran-2-yl] -pyrazolo [3,4-b] pyridine

0.85 g (2.86 mmol) of 1- (2-fluorobenzyl) -3- (2-furyl) -pyrazolo [3,4-b] pyridine is stirred for 25 minutes at 70 ° C with 20 ml of thionyl chloride, then the mixture is evaporated in vacuo and the crude product is allowed to react further.

b) The product obtained above is taken up in 30 ml of dioxane, mixed with 0.6 ml (about 6 mmol) of piperidine, shaken vigorously and allowed to stand overnight, then taken up in water and shaken with ethyl acetate. After drying the organic phase over anhydrous sodium sulfate, it is evaporated and the residue is chromatographed on silica gel using a toluene / ethyl acetate gradient. 0.49 g (40% of theory) of a brown clear viscous syrup is obtained (Rf = 0.36, SiO2, T1E1).

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Analogously to the above, the compounds listed in Table 7 were prepared. The compound of Example 67 was prepared according to the procedure of Example 20.

Table 7

Pr. structure t .t. (° C) yield /% / I · R 47 / / CV ^H yj H — 0 29,34 · 0.37 EE 48 \ = / _o / \ 8.23 0.12 (T1E1) 49 WITH W oil 10 0.37 (T1E1)

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Table 7 (continued)

Pr. structure mp (° C) yield /% / Rf 50 fy _F '- \ 9 ~ ζ ^x K ^CHa ' -Zy-Aj ^CH · O 107 37 0.28 (T1E1) 51 Q-V from ^N in ') ^H O 126 27 0.43 (T1E1) 52 W o- / V_ / ¹ l _Z N / \\ b 279 77 0.16 (ΕΕΈίΟΗ = 1: 1) 53 <y _F % .k b \ x — CH 69 56 0.49 (T1E1)

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Table 7 (continued)

Pr. structure mp (° C) yield /% / rr and 54 (Y · % / - \ S-N o 0- / \ - / -AiZ 122 34. 1 0.31 (T1: E1) ABOUT 55 oil 4.2 0.37 (T1E1) p ,. \ / HN \ S. XT > .-A

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Table 7 (continued)

Pr. structure t. t. CC) výťažokM Rf 5'6 H, ) ~ CH> 136 76 0.33 (T1E1) à HN • I I \ x * F Y \ JPi ⁰ Sn y ABOUT 57 · I Λ 13S 50 0.31 (T1E1) ΓΊ HN \ WITH WITH P I « / ° i ⁰ Sn in * · \ -l IN - about

31215 / H

Table 7 (continued)

Pr. structure t. t. (° C) yield / W 58 H ₃ Cl 2 ^CH 3 109 59 0.38 (TIEl) I from HN \ T z ^S <> 0— (0 -v L ' N 'IN' 59 · and H ₂ C 11.4 53 0.45 (.TIEl) A I o A> ur "Y -IN < 1

31215 / H

Table 7 (continued)

Pr. structure mp (° C) Yield /% / « Rf 60 about 161 40 0.46 (T1EI) ⁶¹ H, C C ^H i ^{F F F} Fuuu 109 58 0.58 (T1E1)

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Table 7 (continued)

Pr. structure 1.1. (° C) yield /% / Rf 62 F ^ 0 x> y-0 oil 65 0.17 (T1E1) • n 0 \ S. o-Z% xy Å 3 1 63 w 153 66 0.47 (T1E1) I * I HN l w N °

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Table 7 (continued)

Pr. structure t. t. (° C) yield / ³ // Rf 64 A yo l 132 60 0.41 (T1E1) ' ^F LN The _C 0- / ^x o λ y - 65 T Q 107 71 0.4 (TIE1) V.Š Sk ° “knows ⁰ ABOUT

31215 / H

Table 7 (continued)

1 '

Pr. ! structure 1.1. (° C) Yield /% / * r 66 ^c 'v ^ 110 62 0.57 (TlÉľ) ABOUT - HN 1 ^F 7 ° T ° k / y ABOUT 1 » 67 about 106 6 0.23 (Hexane: EE < ⁿ x Λ ΎΫ N / ^CK 3 X ^Z J CT 3: 1) Al, 0 ₃ U

31215 / H

Example 68

- (2-Fluorobenzyl) -3- (4-methyl-3-hydroxymethyl-oxazol-2-yl) -pyrazolo [3,4-b] pyridine

330 mg (0.84 mmol) of 1- (2-fluorobenzyl) -3- (1,1-dichlorobut-1-en-3-yl-amido) pyrazolo [3,4-b] pyridine, 1.7 ml of sodium hydroxide 1 N (1.68 mmol) and 3.3 mL of 1-methyl-2-pyrrolidone were stirred overnight at 50 ° C and then cooled. The reaction mixture is mixed with water and ethyl acetate, the organic phase is separated, dried over sodium sulphate, concentrated and the residue is dried under high vacuum. The solid is then mixed with cyclohexane / EE 2: 1 to give crystals. The crystals are then aspirated and stirred at room temperature with diethyl ether. The insoluble impurities are separated, the ether solution is concentrated and the residue is purified by chromatography. 52.1 mg (18%) of 1- (2-fluorobenzyl) -3- (4-methyl-3-hydroxymethyl-oxazol-2-yl) -pyrazolo [3,4-b] pyridine is obtained. Mp = 145 ° C, R f = 0.074 (cyclohexane / EE 2: 1), MS (ESI-POSITIV): 339 (100 [M + H] ⁺ ).

Example 69

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

31215 / H

The title compound was prepared analogously to Example 68 in a yield of 52% of theory. _Rf = 0.33 (hexane / ethyl acetate 1: 1).

31215 / H

Claims (10)

PATENT CLAIMS Substituted pyrazole derivatives of the general formula I (D) wherein: R ¹ represents a five- or six-membered saturated aromatic heterocycle with up to three heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen, which may be bonded via a nitrogen atom and which is optionally up to three times the same or differently substituted by amino, azide, formyl, carboxyl, mercaptyl, hydroxy, straight or branched acyl, alkylthio, alkoxy or alkoxycarbonyl of up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight or branched alkyl of up to 6 carbon atoms it may be substituted by hydroxy, amino, carboxyl, straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino of up to 5 carbon atoms or the radical of the formula -OR ⁴ , wherein: R ⁴ represents a straight or branched acyl group of up to 5 carbon atoms or a group of the formula -SiR ⁵ R ⁶ R ⁷ , wherein: R ⁵ , R ⁶ and R ⁷ are the same or different and represent an aryl group of 6 to 10 carbon atoms or an alkyl group of up to 6 carbon atoms, and / or are substituted with the remainder of the formula 31215 / H or -S (O) _C NR ⁹ R ¹⁰ wherein a and bab 'are the same or different and are 0,1, 2 or 3, R ⁸ represents a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, c represents the number 1 or 2, and R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 10 carbon atoms optionally substituted by a cycloalkyl group of 3 to 8 carbon atoms or an aryl group of 6 to 10 carbon atoms which may itself be substituted with a halogen atom, or an aryl group of 6 to 10 carbon atoms, which is optionally substituted with a halogen atom, or a cycloalkyl group of 3 to 7 carbon atoms, or R ⁹ and R ¹⁰ together with the nitrogen atom form a 5- to 7-membered saturated heterocycle, which may optionally contain an additional oxygen atom or a NR ¹¹ radical, wherein: R11 represents a hydrogen atom, a straight or branched alkyl group having from 1 to ³ carbon atoms; 4 carbon atoms, the radical of the formula benzyl or phenyl, the ring systems being optionally substituted by halogen, 31215 / H R ² and R ³ , including the double bond, form a six-membered saturated or aromatic heterocycle with up to three heteroatoms from the group consisting of sulfur, nitrogen and / or oxygen, optionally up to three times the same or differently substituted with formyl, carboxy, hydroxy, mercaptyl, or a branched acyl, alkylthio or alkoxycarbonyl radical of up to 6 carbon atoms, nitro, cyano, halogen or a straight or branched alkyl or alkoxy radical of up to 6 carbon atoms each of which may be substituted by hydroxy, amino, carboxy or straight or branched chain , an alkoxy or alkoxycarboxyl group of up to 5 carbon atoms in each case, and / or the heterocycle is optionally substituted by a radical of the formula -NR ¹² R ¹³ or -S (O) c NR ⁹ R ¹⁰ ', wherein R ¹² and R ¹³ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms or R ¹² represents a hydrogen atom and R ¹³ represents a formyl group and c ', R ⁹ and R ¹⁰ are as defined above for c, R ⁹ and R ¹⁰ and are the same or different therewith and / or the heterocycle is optionally substituted by a phenyl group, which may itself be up to twice the same or optionally substituted by a halogen atom or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms in each case, and / or the heterocycle optionally substituted by a group of the formula -N = CH-NR ¹⁴ R ¹⁵ , wherein: R ¹⁴ and R ¹⁵ are the same or different and represent a hydrogen atom, a phenyl group or a straight or branched alkyl group having up to 6 carbon atoms, and 31215 / H A is a 5- or 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and / or oxygen or phenyl, optionally substituted up to three times equally or differently with amino, mercaptyl, hydroxy, formyl, carboxy, straight or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl of up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or a straight or branched alkyl of up to 6 carbon atoms which may itself be substituted hydroxy, carboxy, straight or branched chain acyl, alkoxy or alkoxycarbonyl of up to 5 carbon atoms, and / or substituted by - (CO) d-NR ¹⁶ R ¹⁷ , where d is 0 or 1a R ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl or acyl group of up to 5 carbon atoms each, and their isomeric forms and salts. Substituted pyrazole derivatives according to claim 1, in which R ¹ represents pyrimidinyl, pyridazinyl, pyridyl, pyrazinyl, tetrahydropyranyl, tetrahydrofuranyl, furyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, pyrazolyl, isadiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl, which are optionally substituted up to three times equally or differently with amino, formyl, mercaptyl, carboxy, hydroxy, straight or branched acyl, alkoxy, alkylthio or 31215 / H alkoxycarbonyl of up to 5 carbon atoms, nitro, cyano, azide, fluorine, chlorine or bromine, phenyl or straight or branched alkyl of up to 5 carbon atoms, which may itself be substituted by hydroxy, amino, carboxy , a straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino group each having up to 4 carbon atoms or the radical of the formula -OR ⁴ , wherein: R ⁴ represents a straight or branched acyl group of up to 4 carbon atoms, and / or is substituted with a radical of formula O ---- CH. OCH. - (CH3) _and n *. = or OR " -S (O) c-NR ⁹ R ¹⁰ , wherein a and bab 'are the same or different and are 0, 1, 2 or 3, R ⁸ represents a hydrogen atom or a straight or branched alkyl group having up to 3 carbon atoms, c represents the number 1 or 2, and R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 9 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl or naphthyl or phenyl groups which may themselves be substituted fluorine or chlorine, or represents a phenyl or naphthyl group optionally substituted by fluorine or chlorine, 31215 / H or is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, or R ⁹ and R ¹⁰ together with the nitrogen atom form a morpholine ring or a radical of formula Alebo · d or where R ¹¹ represents hydrogen, methyl or a radical of the formula or represents benzyl or phenyl, where the ring systems are optionally substituted by fluorine or chlorine, R ² and R ³ form a double bond and including the pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl which are optionally substituted up to three times in an identical or different manner by formyl, carboxyl, hydroxyl, mercapto group, a linear or branched acyl, alkylthio or alkoxycarbonyl having, in each case up to 5 carbon atoms, nitro, cyano, azide, fluorine, chlorine or bromine or straight or branched alkyl or alkoxy of up to 5 carbon atoms, which may themselves be substituted by hydroxy, amino, carboxy or straight or branched acyl or alkoxycarbonyl having up to 4 carbon atoms in each case, 31215 / H and / or the abovementioned heterocyclic rings are optionally substituted by a group of the formula -NR ¹³ R ^1Z, or -S (O) NR ⁹ _C ¹⁰ R ', wherein R ¹² and R ¹³ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, or R ¹² represents a hydrogen atom and R ¹³ is a formyl group and c ', R ⁹ and R ¹⁰ are as defined above for c, R ⁹ and R ¹⁰ and are the same or different with them and / or the above heterocyclic rings are optionally substituted with a phenyl group which may itself be substituted by a fluorine, chlorine or bromine atom or a straight or branched alkyl or alkoxy group of up to 4 carbon atoms each, and / or the aforementioned heterocyclic rings optionally substituted by a group of formula -N = CH-NR ¹⁴ R ¹⁵ , wherein R ¹⁴ and R ¹⁵ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms and A represents tetrahydropyranyl, thienyl, tetrahydrofuranyl, phenyl, morpholinyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl group, which may optionally be up to two times the same or differently substituted by hydroxy, formyl, carboxy, straight or branched alkoxy, alkyloxy, alkoxy, alkoxy, alkyloxy up to 4 carbon atoms, fluorine, chlorine or bromine, nitro, cyano, trifluoromethyl or straight or branched alkyl of up to 4 carbon atoms, which may itself be substituted by hydroxy, carboxy, straight or branched alkoxy, alkoxy or alkoxy each having up to 4 carbon atoms, and / or substituted by a group of the formula - (CO) _d -NR ¹⁶ R ¹⁷ , wherein 31215 / H DΑ d stands for 0 or 1 a R ¹⁶ and R ¹⁷ are the same or different and represent a hydrogen atom, a phenyl group, a benzyl group or a straight or branched alkyl or acyl group of up to 4 carbon atoms each, and their isomeric forms and salts. The substituted pyrazole derivatives according to claim 1, in which R ¹ represents an imidazolyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, isoxazolyl, oxazolyl or thiazolyl group, which are optionally substituted up to three times with the same or different formyl, mercaptyl, amino, fluoro or chloro, cyano, cyano, cyano, cyano, cyano, cyano , alkoxy, alkylthio or alkoxycarbonyl having up to 4 carbon atoms or straight or branched alkyl having up to 4 carbon atoms, which itself may be substituted by hydroxy, amino, carboxy, straight or branched acyl, alkoxy, alkoxycarbonyl or acylamino in each case up to 3 carbon atoms, and / or substituted by the radical of the formula OCH ₂ - (CH ₂ ) _a ΟίΟΗ, ζ-CH " O (CH 2) _b '—CH ₃ or -S (O) _c -NR ⁹ R ¹⁰ , wherein a and bab 'are the same or different and are 0,1 or 2, R ⁸ represents a hydrogen atom or a methyl group, c represents the number 1 or 2 and 31215 / H R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a straight or branched alkyl group of up to 9 carbon atoms optionally substituted by a naphthyl or phenyl group, or a phenyl or naphthyl group optionally substituted by fluorine or chlorine, or is cyclopropyl or cycloheptyl or R ⁹ and R ¹⁰ together with the nitrogen atom form a morpholine ring or a radical of formula or wherein R ¹¹ represents a hydrogen atom, a methyl group or a radical of formula or represents a benzyl or phenyl group, the ring systems being optionally substituted with chlorine, R ² and R ³ , with the double bond included, form a pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, which may optionally be up to three times the same or differently substituted by a formyl, carboxy, hydroxy, mercaptyl, straight or branched acyl, alkylthio or alkoxycarbonyl group. up to 4 carbon atoms, nitro, cyano, fluorine or chlorine, or a straight or branched alkyl or alkoxy group of up to 3 carbon atoms, which may themselves be substituted by hydroxy, amino, carboxy or straight or branched acyl, 31215 / H alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, and / or the above heterocyclic rings are optionally substituted with amino, Ν, Ν-dimethylamino or the radical of the formula -NH-CHO or -N = CH-N (CH ₃ ) ₂ and / or a phenyl group, which may itself be substituted by the radical of the formula -O (CH ₂ ) ₂ -CH 3 and A represents a tetrahydropyranyl, thienyl, phenyl, pyrimidyl or pyridyl group optionally substituted up to two times the same or differently with hydroxy, formyl, carboxy, straight or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl, in each case up to 3 carbon atoms, fluorine, chlorine or bromine, nitro, cyano, trifluoromethyl or straight or branched alkyl of up to 3 carbon atoms, which may itself be substituted by hydroxy, carboxy, straight or branched acyl, alkoxy or alkoxycarbonyl, in each case up to 3 and isomeric forms and salts thereof. A process for the preparation of substituted pyrazole derivatives of the general formula I according to claim 1, characterized in that, depending on the different meanings of the heterocycles mentioned, A) Compounds of formula II R ^{@ 1} --D (H). wherein R ^{1 is} as defined above and D stands for formula remnants CN cn. 31215 / H in which R ¹⁸ is C 1 -C 4 alkyl, reacted with compounds of formula III A-CH2-NH-NH 2 in which A has the abovementioned meaning, in inert solvents, if appropriate formula IV or IVa in the presence of a base, the compound (IVa) in which A and R ¹ as defined above, then cyclized sav for compounds of the formula IVa with carboxylic acids, nitriles, formamides or guanidine salts, and in the case of the compounds of the formula IV cyclized with 1,3-dicarbonyl derivatives, their salts, tautomers, enol ethers or enamines, in the presence of acids and optionally using microwave radiation, or the B) when R ² and R ³ together form a pyrazine ring, first convert the compounds of formula IV by nitrosation to compounds of formula V A L _N ' ⁿ H _: N (V). 31215 / H in which A and R ^{1 are} as defined above, in a second step, is produced by reducing the compound of the general formula VI h ₂ n A n ₂ (VI). in which A and R ^{1 are} as defined above, and are finally cyclized with 1,2-dicarbonyl compounds, preferably an aqueous solution of glyoxal, or C) compounds of formula VII (VII) wherein A ¹ , R ² and R ^{3 are} as defined above and a L represents a radical of the formula -SnR ¹⁹ R ²⁰ R ²¹ , -Zn R ²² , an iodine atom, a bromine atom or a triflate group, wherein: R ¹⁹ , R ²⁰ and R ²¹ are the same or different and represent a straight or branched alkyl group having up to 4 carbon atoms and R ²² is halogen, reacted with compounds of formula VIII R ¹ - H (VIII) wherein R ¹ has the abovementioned meaning, and, if L = -SnR ¹⁹ R ²⁰ R ²¹ or -ZnR ^22, T represents a triflate group or a halogen atom, preferably bromine, 31215 / H and when L = iodine, bromine or triflate, T represents a residue of the formula SnR ¹⁹ R ²⁰ R ²¹ , ZnR ²² or BR ²³ R ²⁴ , wherein R ¹⁹ , R ²⁰ , R ²¹ and R ²² have the meanings given above for R ¹⁹ , R ²⁰ , R ²¹ and R ²² and are the same or different thereto and R ²³ and R ²⁴ are the same or different and represent hydroxy, aryloxy of 6 to 10 carbon atoms or a straight or branched alkyl or alkoxy group of up to 5 carbon atoms or together form a 5- or 6-membered carbocyclic ring, in a palladium catalyzed reaction in inert solvents, optionally in the presence of a base; D) in case R ¹ = where R ²⁵ represents an alkyl group having 1 to 6 carbon atoms, which is optionally substituted with a halogen atom, will convert compounds of formula IX CO-CI (IX) in which A, R and R ^{3 are} as defined above, either directly by reaction with a compound of formula X 31215 / H in which R ^{25 is} as defined above, in the NaOCO-CH 3 / N-methylpyrrolidine system to compounds of formula Ia * in which R ² , R ³ , A and R ^{25 are} as defined above and then treated with potassium hydroxide in methyl alcohol, the acetyl group is cleaved, or compounds of formula XI (Xi) are first prepared by reacting compounds of formula IX with compounds of formula X. wherein R ² , R ³ , A and R ^{25 are} as defined above, and in the next step, potassium hydroxide is prepared by treatment with potassium hydroxide and optionally converted to the corresponding alkoxy compounds by alkylation and, for the -S (O) _C NR ⁹ R ¹⁰ and -S ( O) _C NR ⁹ R ¹⁰ , starting from unsubstituted compounds of formula I, are first reacted with thionyl chloride and in the second step with the corresponding amines and optionally with the substituents mentioned for R ¹ , R ² , R ³ and / or A, or introduced by conventional methods, preferably by chlorination, catalytic 31215 / H by hydrogenation, reduction, oxidation, cleavage of protecting groups and / or nucleophilic substitution. Medicament, characterized in that it contains at least one pyrazole derivative of the general formula I according to claim 1. A process for the manufacture of medicaments, characterized in that at least one compound of the formula I according to claim 1 is converted, if appropriate, with customary auxiliaries and additives into a suitable dosage form. Medicaments comprising at least one compound of the formula I according to claim 1 in combination with an organic nitrate or NO-donor. Medicaments comprising at least one compound of the formula I according to claim 1 in combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment of cardiovascular diseases. Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the prophylaxis and treatment of thromboembolic diseases and ischemia.