WO2000046207A1

WO2000046207A1 - Pyrazole alkylamides

Info

Publication number: WO2000046207A1
Application number: PCT/EP2000/000504
Authority: WO
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 Aktiengesellschaft
Priority date: 1999-02-04
Filing date: 2000-01-24
Publication date: 2000-08-10
Also published as: DE19904391A1; AU3421100A; GT200000008A

Abstract

The invention relates to novel pyrazole alkylamides of general formula (I). The invention also relates to methods for the production of pyrazole alkylamides. The key step in the production thereof is either alkylation of primary amides or amidation of carboxylic acids with alkylamides. The pyrazolamids are used as medicaments, especially as medicaments in the treatment and prophylaxis of anaemias.

Description

Pyrazole alkyl amides

The present invention relates to substituted pyrazole-alkylamides, processes for their preparation and their use as medicaments, in particular for the prophylaxis and / or control of anemias.

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 there

"EPO produced 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 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, e.g. severe blood loss, longer stays at high altitudes, but also

Renal 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

To reduce the need for foreign blood transfusions.

However, strong side effects that occur when rh EPO is administered are known. These include the development and exacerbation of high blood pressure, causing symptoms similar to encephalopathy to tonic-clonic symptoms

Convulsions and cerebral or myocardial infarction due to thrombosis. Furthermore, rh EPO is not available orally and must therefore be administered ip, iv or subcutaneously, which limits its use to the therapy of severe anemia.

The present invention now relates to pyrazole alkylamides 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 benzocondensed heterocycle having up to 3 heteroatoms from the series S, N and / or O which, in the case of phenyl, preferably in para position for ring attachment - can be substituted by halogen, (C, -C ₆ ) -alkyl, (C _r C ₆ ) -alkoxy, trifluoromethyl or trifluoromethoxy,

R ^{3 represents} (C ₃ -C ₈ ) cycloalkyl or (C, -C ₆ ) alkyl,

and their tautomers and the respective salts.

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

A, D, E, G, R ² and R ^{3 have} the meaning given above.

The following structure is particularly preferred:

in which

A, D, E, G, R ² and R ^{3 have} the meaning given above.

Depending on the substitution pattern, the compounds according to the invention 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 according to the invention can

Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid are particularly preferred. 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 conventional bases, for example

Alkali metal salts (e.g. sodium or potassium salts), alkaline earth salts (e.g. calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, or 1-ephenylamine - piperidine.

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

In the context of the invention, (C _r C _fi ) alkyl represents a straight-chain or branched

Alkyl radical with 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.

In the context of the invention, (C _] -C ₆ ) -alkoxy stands for 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.

In the context of the invention, (C ₃ -C ₈ ) cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. May be mentioned:

Cyclopropyl, cyclopentyl and cyclohexyl. In the context of the invention, a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, O and / or N is, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl are preferred; Pyrimidyl, pyridazinyl, furyl and thienyl.

A 5- to 6-membered aromatic benzocondensed heterocycle with up to 3 heteroatoms from the S, O and / or N series is, for example, benzothiophene, quinoline, indole or benzofuran in the context of the invention. Benzothiophene and quinoline are preferred.

Preferred compounds of the general formula (I) according to the invention are

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 or pyridyl optionally substituted by halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy, in the case of phenyl the phenyl ring may preferably be substituted in the para position to the ring attachment,

R ^{3 represents} cyclopropyl, cyclopentyl, cyclohexyl or (C, -C ₄ ) -alkyl,

and their tautomers and the respective salts.

Compounds of the general formula according to the invention are particularly preferred

(I), in which

A, D, E and G stand for hydrogen,

R ^{1 represents} methyl,

R ^{2 represents} phenyl, thienyl or pyridyl which is optionally substituted by halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy, where in the case of phenyl the phenyl ring can preferably be substituted in the para position,

and

R ^{3 represents} methyl or cyclopropyl,

and their salts.

The compounds listed in the following table are very particularly preferred:

and their salts.

In addition, a process for the preparation of the compounds of the general formula (I) according to the invention was found, which is characterized in that

[A] compounds of the general formula (II),

in which

A, D, E, G, R ¹ and R have the meaning given above,

with compounds of the general formula (III)

R ³ -X (III)

in which R ^{3 has} the meaning given above

and

X represents chlorine, bromine or iodine,

bound to a resin or as a free compound in inert solvents, optionally in the presence of a base,

or

[B] by using compounds of the general formula (IV)

in which

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

optionally in the presence of a dehydrating agent or via an activated one

Carboxylic acid derivative (e.g. carboxylic acid halide, anhydride or imidazolide) with compounds of the formula (V)

R ³ -NH, (V),

in which R ^{3 has} the meaning given above,

implements.

The processes according to the invention can be illustrated by the following formula schemes:

[A]

[B]

Inert organic solvents which do not change under the reaction conditions are suitable as solvents for [A] and [B]. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichlorethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetonitrile, acetonitrile. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred. The usual inorganic or organic bases are suitable as bases. These include, for example, alkali metal hydrides and alkaline earth metal hydrides such as sodium hydride and calcium hydride or alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, sodium hydride or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyl lithium or phenyllithium. NaHMDS, lithium diisopropylamide and lithium bis (trimethylsilyl) amide are preferred.

The base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compounds of the general formula (II).

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

Some of the compounds of the general formula (II) are known or new and can then be prepared by

[C] compounds of the general formula (VI)

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 (VII)

R OOC-R ² (VII)

in which

R ^{2 has} the meaning given above

and

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

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

H ₂ N., R ¹

N '(VIII) H

in which

R ^{1 has} the meaning given above,

reacted, the compounds then split off from the resin and in the event that R ¹ ≠ H, separates into the isomers. Inert organic solvents which do not change under the reaction conditions are suitable as solvents for process [C]. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, carbon tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane or

Cyclohexane, dimethylformamide, acetonitrile, tetrahydrofuran or DMSO. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.

The reaction generally takes place in a temperature range from -78 ° C to

Reflux temperature, preferably from 0 ° C to the boiling point of the solvent used.

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

[D] compounds of the general formula (IX)

in which

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

and R ^{5 represents} a (C, -C ₄ ) alkyl radical,

with compounds of the general formula (VIII)

H ₂ N., R ¹

N ^' (VIII) H

in which

R ^{1 has} the meaning given above,

reacted in inert solvents and the esters of the general formula (X) obtained

in which

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

in the case where R ^{1 is} a (C, -C ₆ ) alkyl radical, separate into the isomers and to

Saponified carboxylic acids of the general formula (IV),

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 (IV) with R ¹ for (C, -C ₆ ) -alkyl which are then saponified, or

[E] if R ^{1 is} methyl, aldehydes of the formula (XI)

H

R ^

<O (XI)

in which

R ^{2 has} the meaning given above,

with acetophenones of the general formula (XII)

in which

R ^{6 represents} a (C _r C ₄ ) alkyl chain,

if appropriate in the presence of a catalyst

and the resulting compounds of formula (XIII)

in which

R and R have the meaning given above, reacted with methylhydrazine to give the corresponding pyrazole derivatives,

from which the compounds of formula (IV) with R ^! = Methyl can be obtained.

Inert organic solvents which do not change under the reaction conditions are suitable as solvents for processes [D] and [E]. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acoleitrile methanol, acetonitrile, acetonitrile Ethanol, 2-propanol or DMSO. It is also possible to use mixtures of the solvents mentioned. Ethanol and DMSO 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.

For the reaction of the aldehyde with the acetophenones described under [E], the customary acidic and basic catalysts are used as catalysts

Consider, preferably acidic catalysts (e.g. para-toluenesulfonic acid).

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 are particularly preferred

SAM resins (abbreviation for standard amide resins) and RAM resins (abbreviation for Rink amide resins). Examples of resins which can be used according to the invention are Tentagel SAM (S 30022) and Tentagel R RAM (R 28 023) from Rapp Polymer GmbH.

The compounds of the general formulas (III), (V), (VII), (VIII), (XII) and (XIII) are known.

The compounds of the general formulas (VI), (IX), (XI) and (XI) are partly new or known and can be prepared, for example, as described above.

The compounds of the general formula (I) according to the invention 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, in which there 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 comprise at least one compound of the general Formula (I) together with one or more pharmacologically acceptable auxiliaries or carriers, and their use for stimulating erythropoiesis, in particular for the purposes of prophylaxis and / or treatment of anemias, such as prematurity anemia, anemia with chronic renal insufficiency, anemia after chemotherapy or anemia in HIV patients.

Test description (in vitro)

Cell proliferation of human erythroid progenitor 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 resuspended 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 ul deep well (24-well plates) were in 14% at 37 ° C in 5%

CO2, 95% air cultivated.

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, 50μl of the cell suspension was made into 10μl benzidine stain. solution (20μg benzidine in 500 μl DMSO, 30μl H2O2 and 60 μl conc. acetic acid). The number of blue cells was counted microscopically.

The following connection was tested using this method:

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 Glycofürol.

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. Primary

The parameter is the hematocrit increase 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 compounds 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. 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, ie in amounts which are sufficient to achieve the dosage range indicated. The formulations are prepared, for example, by stretching the active compounds with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, it being possible, for example if organic solvents to be used as diluents, to use organic solvents as auxiliary solvents.

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 for intravenous administration

To administer amounts of about 0.01 to 10 mg / kg, preferably about 0.1 to 10 mg / kg body weight for effective results.

Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of

The route of application, the individual's behavior towards the medication, the type of 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. Larger in the case of application

It may be advisable to distribute quantities in several individual doses throughout the day.

Manufacturing examples

example 1

l-methyl-3- (4-methylaminocarbonylphenyl) -5- (4-trifluoromethylphenyl) pyrazole

Tentagel SAM resin (100 mg, loading 0.22 mmol / g) is suspended in dimethylformamide (10 ml) and with acetophenone-4-carboxylic acid (144 mg, 0.88 mmol),

TBTU (282 mg, 0.88 mmol) and DIEA (16 mg, 0.12 mmol) were added and shaken at room temperature overnight. The liquid phase is then suctioned off and the resin is washed with dimethylformamide, methanol, methylene chloride and diethyl ether (2 times 5 ml each).

For the Claisen condensation, the resin (100 mg, 0.21 mmol) is suspended under argon in dimethylacetamide (10 ml), 4-trifluoromethyl-benzoic acid methyl ester (771 mg, 3.78 mmol) is added and the mixture is shaken for 10 min at room temperature. 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 (2 times 5 ml each).

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 h. Then the aspirated liquid phase and the resin washed with dimethylformamide, methanol, methylene chloride and diethyl ether (2 times 5 ml).

For N-alkylation, the resin (100 mg “0.2 mmol) is suspended in 1.1 ml of tetrahydrofuran, and NaHMDS (1 M solution in tetrahydrofuran, 5.5 ml, 5.5 mmol) is added. The mixture is stirred at room temperature for 30 min, in which case methyl iodide (1.05 g, 7.38 mmol, dissolved in 4 ml of tetrahydrofuran) is then added. The mixture is stirred at 50 ° C. for 6 h, then the liquid phase is separated off and the resin is washed with dimethylformamide, methanol, methylene chloride and ether (5 ml each 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 is obtained as a mixture of regioisomers in a yield of 4 mg. HPLC: 3.42 min.

Method 2: 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 f31: 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.

The examples listed in Table 1 are prepared in analogy to the instructions given in Example 1:

Claims

1. pyrazole-alkylamides of the general formula (I)

in which

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

Are alkyl or (C, -C ₆ ) -alkoxy,

R ^! 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, which - in the case of phenyl - is preferred in para position to the ring attachment - can be substituted by halogen, (C, -C ₆ ) -alkyl, (C, -C ₆ ) -alkoxy, trifluoromethyl or trifluoromethoxy,

R ^{3 represents} (C ₃ -C ₆ ) cycloalkyl or (C, -C ₆ ) alkyl,

and their tautomers and their respective salts.

2. pyrazole-alkylamides of the general formula (I) according to claim 1,

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 or pyridyl, where the rings - in the case of phenyl preferably in the para position to the ring attachment - can be substituted by halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy,

R ^{3 represents} cyclopropyl, cyclopentyl, cyclohexyl or (C, -C ₄ ) -alkyl,

and their tautomers and the respective salts.

3. pyrazole-alkylamides of the general formula (I) according to claim 1,

in which

A, D, E and G stand for hydrogen,

R ^{1 represents} methyl,

R ^{2 represents} phenyl, thienyl or pyridyl, the rings - in the case of

Phenyl the phenyl ring preferably in the para position - can be substituted by halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy, and

R ^{3 represents} methyl or cyclopropyl, and their salts.

4. Substituted pyrazole carboxylic acids of the general formula (I) according to Claims 1 to 3 with the following structures:

and their salts.

5. pyrazole-alkylamides of the general formula (I) according to Claims 1 to 4

Prophylaxis and / or treatment of diseases, especially anemia.

Process for the preparation of pyrazole-alkylamides according to Claims 1 to 4, characterized in that

[A] compounds of the general formula (II),

in which

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

with compounds of the general formula (III)

R ³ -X (III)

in which

R ^{3 has} the meaning given above

and

X represents chlorine, bromine or iodine,

either bound to a resin or as a free compound in inert solvents, optionally in the presence of a base,

or

[B] by using compounds of the general formula (IV)

in which

R ¹ , 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 with compounds of the formula (V)

R ³ -NH ₂ (V),

in which

R ^{3 has} the meaning given above,

implements.

7. Medicament containing at least one pyrazole alkylamide according to claims 1 to 4 and pharmacologically acceptable auxiliaries and carriers.

8. Medicament according to claim 7 for the treatment and prophylaxis of anemia.

9. Medicament according to claim 8 for the treatment of premature anemia, anemia in chronic renal failure, anemia after a

Chemotherapy and anemia in HIV patients.

10. Medicament according to claim 7 for stimulating the erythropoiesis of autologous blood donors.

11. Use of pyrazole-alkylamides according to claims 1 to 4 for the manufacture of medicaments for the treatment and prophylaxis of anemia.

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

13. Use according to claim 12 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.

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

15. Use according to one of claims 12 to 14, characterized in that the erythropoietin sensitizers are administered orally.