EP1148879A2

EP1148879A2 - Use of pyrazole carboxamides

Info

Publication number: EP1148879A2
Application number: EP00909096A
Authority: EP
Inventors: Jürgen Stoltefuss; Gabriele Bräunlich; Berthold Hinzen; Thomas Krämer; Josef Pernerstorfer; Thomas STÜDEMANN; Ulrich Nielsch; Martin Bechem; Emanuel Lohrmann; Christoph Gerdes; Michael Sperzel; Klemens Lustig; Lorenz Mayr
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1999-02-04
Filing date: 2000-01-24
Publication date: 2001-10-31
Also published as: CA2361636A1; WO2000045894A3; AR022470A1; WO2000045894A2; DE19904397A1; AU3150300A; GT200000009A; JP2002536348A

Abstract

The present invention relates to novel and known pyrazole carboxamides of general formulae (I and Ia). The invention also relates to the production of pyrazole carboxamides by means of solid phase chemistry or novel pyrazole carboxamides. The pyrazole carboxamides are used as medicaments, especially medicaments for the treatment of anaemias.

Description

Use of pyrazole carboxamides

The present invention relates to the use of pyrazolecarboxamides for the production of medicaments for the prophylaxis and / or treatment of anemias, new pyrazolecarboxamides and processes for their preparation.

Erythropoietin (EPO) is a glycoprotein with a molecular weight of approximately 34,000 Da. Over 90% of EPO synthesis takes place in the kidney, and the EPO produced there is secreted into the blood. The primary physiological function of EPO is the regulation of erythropoiesis in the bone marrow. There EPO stimulates the proliferation and maturation of the erythroid progenitor cells.

The EPO levels in the blood are usually low, but if the O ₂ content in the blood drops, there is an increase in EPO synthesis and therefore an increase in EPO levels in the blood. As a result, the hematopoiesis is stimulated and the hematocrit increases. This leads to an increase in the O ₂ transport capacity in the blood. If the number of erythrocytes is sufficient to transport enough O ₂ , the EPO blood concentration drops again. A lack of oxygen supply (hypoxia) can have a number of causes, such as excessive blood loss, long stays at high altitudes, but also kidney failure or bone marrow suppression.

It is known that recombinant human (rh) EPO stimulates erythropoiesis and has therefore been used in the treatment of severe anemias. Rh EPO is also used to increase the body's own blood cells in order to reduce the need for foreign blood transfusions.

However, strong side effects that occur when rh EPO is administered are known. This includes the emergence and exacerbation of high blood pressure, causation symptoms similar to encephalopathy up to tonic-clonic convulsions and cerebral or myocardial infarction due to thrombosis.

Furthermore, rh EPO is not available orally and must therefore i.p., i.v. or subcutaneously, which limits its use to the treatment of severe anemia.

Substituted pyrazoles are known from publication WO 97/19039. The pyrazole derivatives are synthesized on the solid phase. After cleavage, pyrazole phenyl carboxamides are obtained. The use as a medicine is not described.

The present invention now relates to the use of pyrazolecarboxamides of the general formula (I),

in which

A, D, E and G are the same or different and stand for hydrogen, halogen, trifluoromethyl, hydroxy or for (C, -C ₆ ) -alkyl or for (C, -C ₆ ) -alkoxy,

R ^{1 represents} hydrogen or (C, -C ₆ ) alkyl,

R ^{2 represents} (C ₆ -C _{) 0} ) aryl or a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, the aromatic ring systems listed above optionally up to 3 times the same or different due to halogen, tri- fluoromethyl, trifluoromethoxy, (C, -C ₆ ) alkyl, (C, -C ₆ ) alkoxy or (C, -C ₆ ) alkoxycarbonyl may be substituted,

and their tautomers and the respective salts,

as medicinal products which are suitable for the prophylaxis and / or treatment of diseases, for example anemia.

If R ^{1 is} hydrogen, tautomers of the formulas are obtained

Depending on the substitution pattern, the compounds can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers). The invention relates to both the enantiomers or diastereomers or their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.

Physiologically acceptable salts of the compounds can be salts of the substances according to the 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, fumaric acid, maleic acid or benzoic acid. Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.

(C ₆ -C ₁₀ ) aryl generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

(C, -C ₆ ) alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples include: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 3 carbon atoms is particularly preferred.

(C _r C ₆ ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. A straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy. A straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is particularly preferred.

(C i -C _fi ) - Alkoxycarbonyl stands for a straight-chain or branched alkoxycarbonyl radical with 1 to 6 carbon atoms. A straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. A straight-chain or branched alkoxycarbonyl radical having 1 to 3 carbon atoms is particularly preferred.

A 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the

Row S, O and / or N stands for example for pyridyl, pyrimidyl, pyridazinyl, Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.

A 5- to 6-membered aromatic benzocondensed heterocycle with up to 3 heteroatoms from the series S, O and / or N represents, for example, benzothiophene,

Indole, quinoline or benzofuran, benzothiophene and quinoline are preferred.

Compounds of the general formula are preferably used

in which

A, D, E and G are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,

R ^{1 represents} hydrogen or methyl,

R ^{2 represents} phenyl, furyl, thienyl, benzothiophene or pyridyl, the aromatic ring systems listed above optionally being up to 2 times identical or different by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy,

(C, -C ₄ ) alkyl or (C, -C ₄ ) alkoxy or (C, -C ₄ ) alkoxycarbonyl may be substituted

and their tautomers and the respective salts.

Compounds of the general formula (I) are particularly preferably used, in which

A, D, E and G stand for hydrogen and

R ^{1 represents} hydrogen or methyl and

R ^{2 represents} phenyl, benzothiophene or pyridyl, where the aromatic ring systems listed above may optionally be substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl or methoxy

and their tautomers and their salts.

The compounds listed in the following table are used with very particular preference:

and their salts.

The invention also relates to new substances of the general formula (Ia) in which

A ', D', E ', G' and R ^{1 have} the meaning of A, D, E, G and R ¹ given above,

and

represents CF ₃ or OCF ₃ (ie in other words L = R ² with R ² = para-C ₆ H ₄ -CF or para-C ₆ H ₄ -OCF ₃ ).

and their tautomers and respective salts.

The compound of the following structure is very particularly preferred:

and their salts.

In addition, processes for the preparation of the compounds of the general formula (I) and the new substances of the general formula (Ia) were found, which are characterized in that

[A] compounds of the general formula (II) in which

A, D, E and G have the meaning given above,

couples to an amino-functionalized resin and then with compounds of the general formula (III)

R OOC-R ² (III),

in which

R has the meaning given above

and

R ^{3 represents} a (C, -C ₄ ) alkyl radical,

reacted on the solid phase and then with compounds of the general formula (IV)

^H *% ' ^R1 (IV),

H in which

R ^{1 has} the meaning given above, reacted, the compounds then split off from the resin and optionally (ie for R ¹ ≠ H) separated into the isomers,

or

[B] pyrazole carboxylic acids of the general formula (V)

in which

R. 1, r R> 2, A, D, E and G have the meaning given above,

optionally in the presence of a dehydrating agent or via an activated carboxylic acid derivative (e.g. carboxylic acid halide, anhydride or imidazolide) with ammonia.

The methods can be illustrated using the following formula schemes:

Procedure [A]:

Procedure [B]:

Inert organic solvents which do not change under the reaction conditions are suitable as solvents for the processes described above.

These include halogenated hydrocarbons such as dichloromethane, trichloromethane,

Tetrachloromethane, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloro- ethylene or trichlorethylene, hydrocarbon such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethylacetamide, acetonitrile or DMSO as well as ethers such as diethyl ether, dioxane or tetrahydrofuran. It is also possible to use mixtures of the solvents. Dimethylformamide and dichloromethane are particularly preferred.

The reactions described above generally take place in a temperature range from -78 ° C. to the reflux temperature, preferably from 0 ° C. to the boiling point of the solvent used.

The reactions described above can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.

Suitable dehydrating reagents for process [B] are carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1, 2-oxazolyl compounds such as 2-ethazolium compounds such as 2-ethazolium compounds 5-phenyl-l, 2-oxazolium-3-sulfonate or propanephosphoric anhydride or isobutylchloroformate or benzotriazolyloxy-tris- (dimethylamino) phosphonium hexyfluorophosphate or phosphonic acid diphenyl ester amide or methanesulfonyl chloride, optionally in the presence of base or methylamine aminoline triethene such as triethylamine or ethyl amine niethyl triethylamine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide. Carbonyldiimidazole (CDI) is preferred.

The usual amino-functionalized polystyrenes are used as the solid phase. Amino-functionalized polystyrene-polyethylene copolymers which are modified with a polyethylene glycol chain are preferred. So-called SAM resins (abbreviation for standard amide resin) and RAM resins (abbreviation for Rink amide resin) are particularly preferred. Examples of amino functional, usable according to the invention ,

- 13 -

Resized resins are Tentagel SAM (S 30022) and Tentagel R RAM (R 28 023), both from Rapp Polymer GmbH.

The compounds of the general formulas (II), (III) and (IV) are known per se.

The compounds of formula (V) are new and can be prepared, for example, by

[C] compounds of the general formula (VI),

in which

A, D, E, G, and R have the meaning given above

and

R ^{3 represents} a (C, -C ₄ ) alkyl radical,

with compounds of the general formula (VII)

H ₂ N _{Vιι ι} --R ¹

N ^'

(VII),

in which

R ^{1 has} the meaning given above, reacted in inert solvents and the esters of the general formula (VIII) obtained

in which

A, D, E, G, R, R and R have the meaning given above,

in the event that R ^{1 is} a (C, -C ₆ ) -alkyl radical, separates into the isomers and saponifies to give carboxylic acids of the general formula (V),

and in the event that R ^{1 is} H, firstly by N-alkylation isomeric mixtures with R ¹ ≠ H are prepared, which are separated by suitable separation methods in compounds of the formula (V) with R ¹ for (C, -C ₆ ) -alkyl which are then saponified,

or

[D] in the case that R ^{1 is} methyl, aldehydes of the formula (IX)

in which

R ^{2 has} the meaning given above,

with acetophenones of the general formula (X) in which

R ^{4 represents} a (C, -C ₄ ) alkyl chain,

if appropriate in the presence of a catalyst,

and the resulting compounds of formula (XI)

in which

R ² and R ^{4 have} the meaning given above,

with methylhydrazine to give compounds of the formula (XII)

in which

R and R have the meaning given above,

implements

from which the compounds of formula (V) with R ¹ = methyl are obtained by hydrolysis as described above. Inert organic solvents which do not change under the reaction conditions are suitable as solvents for processes [C] and [D]. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetylene methanol, tetrahydrofuran, tetrahydrofuran Ethanol, 2-propanol or DMSO. It is also possible to use mixtures of the solvents. Ethanol and DMSO are particularly preferred.

For the reaction of the aldehyde with the acetophenones described under [A], the usual acidic and basic catalysts, preferably acid (e.g. para-toluenesulfonic acid chloride), are suitable as catalysts.

The saponification of the carboxylic acid esters is carried out by customary methods by treating the esters in inert solvents with customary bases or acids, the salts initially formed in the case of basic saponification being treated with

Acid can be converted into the free carboxylic acids.

The usual inorganic bases are suitable as bases for the saponification. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or Alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or lithium hydroxide are particularly preferably used.

Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol,

Ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned. Water / tetrahydrofuran or water / ethanol is preferred.

The saponification is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from 0 ° C. to + 80 ° C.

The saponification is generally carried out at normal pressure. But it is also possible to work under negative pressure or overpressure (e.g. from 0.5 to 5 bar).

When carrying out the hydrolysis, the base or the acid is generally used in an amount of 1 to 3 mol, preferably 1 to 2.5 mol, based on 1 mol of the ester. Molar amounts of the reactants are particularly preferably used.

The compounds of the general formulas (VI) and (XI) are known per se or can be prepared by customary methods [cf. Erne, D. et al., Helv. Chim. Acta 62: 994-1006 (1979); Hasegawa, E. et al. J. Org. Chem. 56 (1991), 1631-1635; Watanabe, Kenichi et al., Bull. Chem. Soc. Jpn. 55 (1988) 3208-3211].

The compounds of the general formula (VII), (VIII), (IX), (X) and (XII) are partly new or known and can be prepared as described above. The compounds of the general formula (I) used according to the invention and the new substances of the general formula (Ia) have an unforeseeable, valuable pharmacological activity spectrum and are therefore suitable for the treatment and prophylaxis of diseases.

They can preferably be used in pharmaceuticals for the treatment and prophylaxis of anemia, such as, for example, premature anemia, anemia in chronic renal failure, anemia after chemotherapy and anemia in HIV patients, and thus also for the treatment of severe anemia.

Even with completely intact endogenous EPO production, additional stimulation of erythropoiesis can be induced by the administration of the compounds according to the invention, which can be used in particular in autologous blood donors.

For the application of the compounds according to the invention and used according to the invention, all customary forms of application come into consideration. The application is preferably oral, transdermal or parenteral. Oral application is very particularly preferred, which is a further advantage over the therapy of anemias with rh-EPO known from the prior art.

The compounds according to the invention act in particular as erythropoietin sensitizers.

Erythropoietin sensitizers are compounds that are able to influence the effect of the EPO present in the body so efficiently that the

Erythropoiesis is increased, in particular that the oxygen supply is improved. Surprisingly, they are orally active, which significantly improves and at the same time simplifies the therapeutic use with the exclusion or reduction of the known side effects. The present invention thus also relates to the use of EPO sensitizers for stimulating erythropoiesis, in particular for the prophylaxis and / or treatment of anemia, preferably severe anemia such as premature anemia, anemia in the case of chronic renal failure, anemia after chemotherapy or anemia in HIV -Patients. Besides that comes the

Administration of EPO sensitizers in the case of completely intact endogenous EPO production for additional stimulation of erythropoiesis, which can be used in particular with autologous blood donors.

Oral application of these so-called EPO sensitizers for the aforementioned purposes is particularly preferred.

The compounds according to the invention thus enable efficient stimulation of erythropoiesis and consequently prophylaxis or therapy of anemias which intervenes before the stage in which the conventional treatment methods with EPO are used. This is because the compounds according to the invention allow an effective influence on the body's own EPO, whereby the direct administration of EPO with the associated disadvantages can be avoided.

The present invention therefore furthermore relates to medicaments and pharmaceutical compositions which contain at least one compound of the general formula (I) together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for stimulating erythropoiesis, in particular for the purposes of prophylaxis and / or or treatment of anemia, such as premature anemia, anemia with chronic kidney failure, anemia after chemotherapy or anemia in HIV patients. Test description (in vitro)

Cell proliferation of human erythroid Norrun cells

20 ml of heparin blood was diluted with 20 ml of PBS and centrifuged for 20 min (220xg). The supernatant was discarded, the cells were resuspended in 30 ml PBS and pipetted onto 17 ml Ficoll Paque (d = 1,077 g / ml, Pharmacia) in a 50 ml tube. The samples were centrifuged at 800xg for 20 min. The mononuclear cells at the boundary layer were transferred into a new centrifuge tube, diluted with the 3-fold volume with PBS and centrifuged for 5 min at 300xg.

The CD34 positive cells from this cell fraction were isolated by means of a commercial purification method (CD34 multisort kit from Miyltenyi).

CD34-positive cells (6000-10000 cells / ml) were in stem cell medium (0.9%

Methyl cellulose, 30% calf serum, 1% albumin (bovine), 100 μm 2-mercaptoethanol and 2 mM L-glutamine) from StemCell Technologies Inc. 10 mU / ml human erythropoietin, 10 ng / ml human IL-3 and 0-1 OμM test substance were added. 500 μl well (24-well plates) were cultivated for 14 days at 37 ° C in 5% CO2, 95% air.

Cultures were diluted with 20 ml 0.9% w / v ΝaCl solution, centrifuged for 15 min at 600xg and resuspended in 200 μl 0.9% w / v ΝaCl. To determine the number of erythroid cells, 50 μl of the cell suspension were pipetted into 10 μl benzidine staining solution (20 μg benzidine in 500 μl DMSO, 30 μl H2O2 and 60 μl conc. Acetic acid). The number of blue cells was counted microscopically. Test description hematocrit mouse

Normal mice are treated with test substances over several days. The application takes place intraperitoneally, subcutaneously or by os. Preferred solvents are Solutol / DMSO / sucrose / NaCl solution or glycofurol.

From day 0 (before the first application) up to approx. 3 days after the last application, approximately 70 μl of blood are withdrawn several times by puncturing the retroorbital venous plexus with a hematocrit capillary. The samples are centrifuged and the hematocrit determined by manual reading. The primary parameter is the increase in hematocrit compared to the baseline value of the treated animals compared to the change in the hematocrit in the placebo control (double standardized value).

The new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.

The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents, if appropriate

Auxiliary solvents can be used.

The application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. In general, it has proven to be advantageous to administer amounts of approximately 0.01 to 10 mg / kg, preferably approximately 0.1 to 10 mg / kg, of body weight in the case of intravenous administration in order to achieve effective results.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place . In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

O 00/45894 _ 23 _ PCT / EPOO / 00519

Manufacturing examples

example 1

3- (4-aminocarbonylphenyl) -5- (4-bromophenyl) -1-methylpyrazole

Tentagel SAM resin (100 mg, loading 0.22 mmol / g) is suspended in dimethylformamide (10 ml), with acetophenone-4-carboxylic acid (144 mg, 0.88 mmol), TBTU (TBTU = o- (benztriazol-l-yl) - N, N, N ', N'-tetramethyluronium tetrafluoroborate) (282 mg, 0.88 mmol) and DIEA (DIEA = diisopropylethylamide) (16 mg, 0.12 mmol) were added and shaken overnight at room temperature. The liquid phase is then suctioned off and the resin is washed with dimethylformamide, methanol, methylene chloride and diethyl ether (5 ml each twice).

For the Claisen condensation, the resin (100 mg, 0.21 mmol) is dissolved in argon

Dimethylacetamide (10 ml) suspended, 4-bromo-benzoic acid methyl ester (812 mg, 3.78 mmol) added and shaken at room temperature for 10 min. Then NaH (disp. In mineral oil, 60%, 96.6 mg, 2.52 mmol) is added and the mixture is shaken at 90 ° C. for 1 h. The liquid phase is then suctioned off and the resin is washed with dimethylformamide, methanol, methylene chloride and diethyl ether (5 ml each twice).

For the condensation, the resin (100 mg, 0.2 mmol) is suspended in dimethylacetamide and 2 ml of a 1.5 M solution of methylhydrazine in dimethylacetamide are added. The mixture is stirred at 70 ° C. for 48 hours. Then the liquid

Aspirated phase and the resin washed with dimethylformamide, methanol, methylene chloride and diethyl ether (5 ml twice). To split off, the resin (100 mg) is mixed with 2 ml of a 1: 1 (v: v) mixture of methylene chloride and trifluoroacetic acid and shaken for 1 h at room temperature. The liquid phase is separated off, the solid phase is washed with methylene chloride and the combined liquid phases are evaporated. The product falls as a regioisomer mixture in a yield of 4 mg, and the desired isomer is separated off by means of preparative HPLC.

HPLC: 3.33 and 3.39 min, eluent: aq. 0.05% TFA (A), 0.05% TFA in acetonitrile (B); LiChrosper 100 RP-18; Temp. 40 ° C; Flow = 2.5 ml / min; Gradient: t = 0 min:

90% A, 10% B; t = 5 min: 10% A, 90% B; t = 7 min: 10% A, 90% B; t = 7.05 min: 90% A, 10% B; t = 8 min: 90% A, 10% B. MS ES +: 356 found

The examples listed in the following table are prepared in analogy to the specification given in Example 1:

Method [AI: HPLC: eluent: aq. 0.05% TFA (A), 0.05% TFA in acetonitrile (B); Symmetry C18; Temp. 40 ° C; Gradient: t = 0 min: 10% A, 90% B, flow: 0.5 ml / min; t = 4 min: 90% A, 10% B, flow: 0.5 ml; t = 6 min / min: 90% A, 10% B, flow: 0.5 ml / min; t = 6.1 min: 10% A, 90% B, flow: 1.0 ml / min; t = 7.5 min: 10% A, 90% B, flow: 0.5 ml / min

Method [B]: HPLC: eluent: aq. 0.05% TFA (A), 0.05% TFA in acetonitrile (B); LiChrosper 100 RP-18; Temp. 40 ° C; Flow = 2.5 ml / min; Gradient: t = 0 min: 90% A, 10% B; t = 5 min: 10% A, 90% B; t = 7 min: 10% A, 90% B; t = 7.05 min: 90% A, 10% B; t = 8 min: 90% A, 10% B.

Method \ \: HPLC: eluent: aq. 0.05% TFA (A), 0.05% TFA in acetonitrile (B); LiChrosper 100 RP-18; Temp. 40 ° C; Flow = 1.5 ml / min; Gradient: t = 0 min: 100% A, 0% B; t = 8 min: 0% A, 100% B; t = 9 min: 0% A, 100% B; t = 9.10 min: 100% A, 0% B; t = 10 min: 100% A, 0% B.

Method \ D. HPLC: eluent: aq. 0.05% TFA (A), 0.05% TFA in acetonitrile (B); Vydac TPB 10 C18; Temp. 40 ° C; Flow = 4 ml / min; Gradient: 1 = 0.5 min: 90% A, 10% B; t = 6.2 min: 10% A, 90% B; t = 7 min: 10% A, 90% B; t = 7.05 min: 90% A, 10% B; t = 7.5 min: 900% A, 10% B.

Claims

1. Use of pyrazolecarboxamides of the general formula (I),

in which

A, D, E and G are the same or different and stand for hydrogen, halogen, trifluoromethyl, hydroxy or for (C, -C ₆ ) alkyl or for (C, -C ₆ ) alkoxy,

R ^{1 represents} hydrogen or (C, -C ₆ ) alkyl,

R ^{2 represents} (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, the aromatic ring systems listed above optionally up to 3 times the same or different can be substituted by halogen, trifluoromethyl, trifluoromethoxy, (C, -C ₆ ) alkyl, (C, -C ₆ ) alkoxy or (C, -C ₆ ) alkoxycarbonyl,

and their tautomers and the respective salts

for the manufacture of medicaments for the prophylaxis and / or treatment of diseases, in particular anemia.

2. Use according to claim 1, wherein in the general formula (I) A, D, E and G are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,

R ^! represents hydrogen or methyl,

R ^{2 represents} phenyl, furyl, thienyl, benzothiophene or pyridyl, the aromatic ring systems listed above optionally being up to 2 times identical or different by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, (C, -C ₄ ) -alkyl or (C, -C ₄ ) alkoxy or (C, -C ₄ ) alkoxycarbonyl may be substituted.

3. Use according to claim 1, wherein in the general formula (I)

A, D, E and G stand for hydrogen,

R ^{1 represents} hydrogen or methyl

and

R ^{2 represents} phenyl, thienyl, benzothiophene or pyridyl, where the aromatic ring systems listed above may optionally be substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl or methoxy.

4. Use of pyrazolecarboxamides according to claim 1, wherein the

Compounds of the general formula (I) have the following structures:

5. pyrazole carboxamides of the general formula (Ia)

in which

and

L stands for CF, or OCF.

6. pyrazolecarboxamide of the general formula (Ia) according to claim 5 with the following structure:

7. A process for the preparation of pyrazolecarboxamides of the general formula (I) according to Claims 5 to 6, characterized in that

[A] compounds of the general formula (II)

in which

A, D, E and G have the meaning given above,

R ³ OOC-R ² (III), in which

R ^{2 has} the meaning given above

and R ^{3 represents} a (C, -C ₄ ) alkyl radical,

reacted on the solid phase and then with compounds of the general formula (IV)

^H _ ^N ^ _N - ^R _(IV ),

H in which

R ^{1 has} the meaning given above,

reacted, the compounds then split off from the resin and optionally (namely for R ¹ ≠ H) separated into the isomers,

or

[B] pyrazole carboxylic acids of the general formula (V)

in which

R, R, A; D; E and G have the meaning given above,

optionally reacted with ammonia in the presence of a dehydrating agent or via an activated carboxylic acid derivative.

8. Medicament containing at least one pyrazolecarboxamide according to claims 1 to 6 and pharmacologically acceptable formulation agents.

9. Medicament according to claims 1 to 6 for the prophylaxis and / or treatment of anemia.

10. Medicament according to claims 1 to 6 for the treatment of premature anemia, anemia in chronic renal failure, anemia after chemotherapy and the anemia in HIV patients.

11. Medicament according to claim 8 for stimulating the erythropoiesis of autologous blood donors.

12. pyrazolecarboxamides according to claims 5 and 6 for treatment and

Prophylaxis of diseases

13. Use of erythropoietin sensitizers for the manufacture of medicaments or pharmaceutical compositions for the prophylaxis and / or treatment of anemias.

14. Use according to claim 13 for the manufacture of medicaments or pharmaceutical compositions for the prophylaxis and / or treatment of premature anemia, anemia with chronic renal failure, anemia after chemotherapy and anemia in HIV patients.

15. Use of erythropoietin sensitizers for the production of medicaments or pharmaceutical compositions for stimulating the erythropoiesis of autologous blood donors.

6. Use according to one of claims 13 to 15, characterized in that the erythropoietin sensitizers are administered orally.