DE19904396A1 - Substituted pyrazolbenzylamine derivatives - Google Patents

Abstract

The invention relates to methods for the production of substituted pyrazole benzyl amine derivatives of general formula (I). The key steps are the reduction of the amides followed by acylation or alkylation. The pyrazole benzyl amine derivatives are used in the production of medicaments. They are used more particularly as medicaments in the production and prophylaxis of anaemias.

Description

The present invention relates to substituted pyrazolbenzylamine derivatives, Processes for their production and their use as pharmaceuticals, in particular to combat and prevent anemia.

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 produced EPO 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 erythrocyte count is sufficient to transport enough O ₂ , the EPO blood concentration drops again. A lack of oxygen (hypoxia) can have a number of causes, including: B. severe blood loss, long stays at high altitudes, but also renal failure or bone marrow suppression.

Recombinant human (rh) EPO is known to stimulate erythropoiesis and has been used in the treatment of severe anemia. Farther rh EPO is used to increase the body's own blood cells in order to control the To reduce the need for foreign blood transfusions.

In addition, strong side effects that occur when rh EPO is administered are known. This includes the emergence and exacerbation of high blood pressure, Causing 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 be administered i.p., i.v. or subcutaneously can be applied, making the application to the therapy of severe anemia is limited.

Substituted pyrazoles are described in publication WO 97/19039.

The present invention now relates to substituted pyrazolbenzylamine derivatives 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 ₁ -C ₆ ) alkyl or for (C ₁ -C ₆ ) alkoxy,
R ^{1 represents} hydrogen or (C ₁ -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 being one to three times the same or different by halogen, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, hydroxy, carboxy or by a group of the formula -CH ₂ - NH-R ^{5 are} substituted,
wherein
R ^{5 represents} hydrogen or (C ₁ -C ₄ ) acyl,
R ³ and R ^{4 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl or a group of the formula -CO-NHR ⁶ ,
wherein
R ^{6 represents} hydrogen or (C ₁ -C ₄ ) alkyl,
and their salts and their tautomers.

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

The compounds of the invention can, depending on the Substitution patterns in stereoisomeric forms that are either like picture and Mirror image (enantiomers), or which are not like image and mirror image (Diastereomers) behave, exist. The invention relates to both the enantiomers or diastereomers or their respective mixtures. The racemic forms can be as well as the diastereomers in a known manner in the stereoisomerically uniform Separate components.

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 sulfone be acids. Z are particularly preferred. B. salts with hydrochloric acid, bromine  hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfone 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, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, Dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methyl 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 ₁ -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.

In the context of the invention, (C ₁ -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.

In the context of the invention, (C ₁ -C ₆ ) -acyl represents a straight-chain or branched acyl radical having 1 to 6 carbon atoms. Examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. A straight-chain or branched acyl radical having 1 to 4 carbon atoms is preferred. Acetyl and ethylcarbonyl are particularly preferred.

A 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the Row S, O and / or N in the context of the invention is, for example, pyridyl, Pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl are preferred; Pyrimidyl, pyridazinyl, furyl and thiazolyl.

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

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, the ring systems listed above being optionally one to three times the same or different by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkyl, (C ₁ - C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, hydroxy or carboxy are substituted,
R ³ and R ^{4 are the} same or different and
represent hydrogen, (C ₁ -C ₄ ) -acyl, (C ₁ -C ₄ ) -alkyl or a group of the formula -CO-NHR ⁶ ,
wherein
R ^{6 represents} hydrogen or (C ₁ -C ₄ ) alkyl,
and their salts and their tautomers.

Compounds of the general formula (I) according to the invention are particularly preferred
in which
A, D, E and G stand for hydrogen,
R ^{1 represents} hydrogen or methyl,
R ^{2 represents} phenyl, thienyl or pyridyl, where the aromatic ring systems listed above are optionally substituted one to three times identically or differently by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or carboxy,
R ³ and R ^{4 are} identical or different and represent hydrogen, (C ₁ -C ₃ ) acyl or (C ₁ -C ₃ ) alkyl,
and their salts and their tautomers.

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

We have also found a process for preparing the compounds of the general formula (I) according to the invention, characterized in that compounds of the general formula (II)

in which
A, D, E, G, R ¹ and R ^{2 have} the meaning given above,
with known reducing agents, for example with the borane / tetrahydrofuran complex, to give compounds of the formula (I),
in which
A, D, E, G, R ¹ and R ^{2 have} the meaning given above
and
R ³ and R ^{4 represent} hydrogen
reacted in inert solvents and then optionally carried out an alkylation, acylation or a reaction with isocyanates by customary methods.

The process according to the invention can be illustrated by the following formula scheme:

Inert organic solvents, which are among the Do not change reaction conditions. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloromethane, Trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene,  Hydrocarbon such as benzene, xylene, toluene, hexane or cyclohexane, Dimethylformamide, acetonitrile or THF. It is also possible to mix the Use solvents. Dichloromethane or THF is particularly preferred.

The usual inorganic or organic bases are suitable as bases. For this preferably include alkali metal hydroxides such as sodium or Potassium hydroxide, or alkali carbonates such as sodium or potassium carbonate, or Sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butylate, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, Lithium diisopropylamide, or organometallic compounds such as butyllithium or Phenyllithium. Lithium diisopropylamide and lithium bis- (trimethylsilyl) amide.

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

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

Conventional organic solvents which are suitable as solvents for the alkylation are do not change under the reaction conditions. These preferably include ethers such as Diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions or Halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Dichlorethylene, trichlorethylene or chlorobenzene or ethyl acetate or triethylamine, Pyridine, dimethyl sulfoxide, dimethylformamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Prefers are dichloromethane, dimethyl sulfoxide and dimethylformamide.  

The alkylation is carried out in the solvents listed above at temperatures of 0 ° C to + 150 ° C, preferably at room temperature to + 100 ° C, at normal pressure carried out.

The acylation is generally carried out in ethers or halogenated hydrocarbons, preferably tetrahydrofuran or methylene chloride, in a temperature range of -30 ° C to 50 ° C, preferably from -10 ° C to room temperature.

The acylation is generally carried out in ethers or halogenated hydrocarbons, preferably tetrahydrofuran or methylene chloride, in a temperature range of -30 ° C to 50 ° C, preferably from -10 ° C to room temperature.

The reduction can generally be done by hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, with catalysts such as Raney nickel, palladium, palladium Animal charcoal or platinum, or with hydrides or boranes or borane complexes inert solvents, optionally carried out in the presence of a catalyst become. The borane / tetrahydrofuran complex is preferred.

The reduction generally takes place in a temperature range from -50 ° C to respective boiling point of the solvent, preferably from -20 ° C to + 90 ° C.

Suitable solvents are all inert organic solvents, which are under do not change the reaction conditions. These preferably include alcohols such as Methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, Tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether or amides such as hexamethylphosphoric triamide or dimethylformamide, or acetic acid. It is also possible to use mixtures of the solvents mentioned.

The reaction with isocyanates is generally carried out in ethers, hydrocarbons or halogenated hydrocarbons, preferably tetrahydrofuran, toluene, ethyl acetate or methylene chloride, in a temperature range from -30 ° C to 120 ° C, preferred in a temperature range from 20 ° C to 80 ° C and normal pressure.  

The compounds of the general formulas (II) are known or new from publication WO 97/19039 and can then be prepared by:
[A] compounds of the general formula (III)

in which
A, D, E and G have the meaning given above,
couples to a resin and then with compounds of general formula (IV)

R ⁷ OOC-R ² (IV)

in which
R ^{2 has} the meaning given above
and
R ^{7 represents} a (C ₁ -C ₄ ) alkyl radical,
reacted on the solid phase and then with compounds of the general formula (V)

in which
R ^{1 has} the meaning given above,
reacted, the compounds then split off from the resin and separated into the isomers,
or
[B] pyrazole carboxylic acids of the general formula (VI)

in which
R ¹ , R ² , 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.

Inert organic solvents, which are among the Do not change reaction conditions. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloromethane, Trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, Hydrocarbon such as benzene, xylene, toluene, hexane or cyclohexane, Dimethylformamide, acetonitrile or DMSO. It is also possible to mix the Use 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 reaction can be carried out under normal, elevated or reduced pressure be carried out (e.g. from 0.5 to 5 bar). Generally one works at Normal pressure.

Carbodiimides such as diiso are suitable as dehydration reagents propylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'- ethyl carbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfonate or propane phosphoric anhydride or isobutyl chloroformate or benzotriazolyl oxy-tris (dimethylamino) phosphonium hexyfluorophosphate or phosphonic acid di phenylesteramide or methanesulfonic acid chloride, optionally in the presence of Bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or Di cyclohexylcarbodiimide and N-hydroxysuccinimide. Is preferred Carbonyldiimidazole (CDI).

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

The compounds of formula (VI) are new and can be prepared, for example, by
[C] compounds of the general formula (VII),

in which
A, D, E, G, and R ^{2 have} the meaning given above
and
R ^{8 represents} a (C ₁ -C ₄ ) alkyl radical
with compounds of the general formula (VIII)

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

in which
A, D, E, G, R ¹ , R ² and R ^{8 have} the meaning given above,
in the event that R ^{1 is} a (C ₁ -C ₆ ) -alkyl radical, separates into the isomers and saponifies to give carboxylic acids of the general formula (VI),
and in the event that R ^{1 is} H, isomeric mixtures with R ¹ ≠ H are prepared by N-alkylation and are separated by suitable separation methods in compounds of the formula (VI) with R ¹ for (C ₁ -C ₆ ) -alkyl ,
or [D] if R ^{1 is} methyl, aldehydes of the formula (X)

in which
R ^{2 has} the meaning given above,
with acetophenones of the general formula (XI)

in which
R ^{9 represents} a (C ₁ -C ₄ ) alkyl chain,
implements
and the resulting compounds of formula (XII)

in which
R ² and R ^{9 have} the meaning given above,
with methylhydrazine to give compounds of the formula (XIII)

in which
R ² and R ^{9 have} the meaning given above,
implements
from which the compounds of formula (VI) with R ¹ = methyl are obtained by hydrolysis as described above.

Inert organic solvents are suitable as solvents for processes [C] and [D] Solvents that do not change under the reaction conditions. For this include halogenated hydrocarbons such as dichloromethane, trichloromethane, Tetrachloromethane, 1,2-dichloromethane, trichloroethane, tetrachloroethane, 1,2- Dichloroethane or trichlorethylene, hydrocarbon such as benzene, xylene, toluene, Hexane or cyclohexane, dimethylformamide, acetonitrile or alcohols such as Methanol, ethanol, 2-propanol or DMSO. It is also possible to mix the Use solvents. Ethanol and DMSO are particularly preferred.

The usual inorganic or organic bases are suitable as bases. For this preferably include alkali metal hydroxides such as sodium or Potassium hydroxide, or alkali carbonates such as sodium or potassium carbonate, or Sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butylate, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, Lithium diisopropylamide or organometallic compounds such as butyllithium or Phenyllithium. Lithium diisopropylamide and lithium bis- (trimethylsilyl) amide.

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

The saponification of the carboxylic acid esters is carried out by customary methods, by the esters are treated with customary bases in inert solvents, the first being resulting salts are converted into the free carboxylic acids by treatment with acid can be.

The usual inorganic bases are suitable as bases for the saponification. For this 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 saponification are water or those for saponification usual organic solvents. These preferably include alcohols such as methanol, Ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or Dioxane, or dimethylformamide or dimethyl sulfoxide. Particularly preferred alcohols such as methanol, ethanol, propanol or isopropanol are used. It is also possible to use mixtures of the solvents mentioned. Prefers is water / tetrahydrofuran or water / ethanol.

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

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

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

The usual polystyrenes are used as the solid phase. Are preferred Polystyrene-polyethylene copolymers modified with a polyethylene glycol chain are. SMA resins are particularly preferred.

The compounds of the general formulas (VII) and (XII) are known per se or can be produced 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, Ken-ichi et al., Bull. Chem. Soc. Jpn. 55 (1988) 3208-3211].

The compounds of general formula (VIII), (IX), (X), (XI) and (XIII) are some are new or known and can be made as described above.

The compounds of the general formula (I) according to the invention do not show one predictable, valuable pharmacological spectrum of action and are therefore for Treatment and prophylaxis of diseases suitable.

They can preferably be used in medicinal products for treatment and Prophylaxis of anemia, such as premature anemia, anemia in chronic renal failure, anemia after chemotherapy and Anemia in HIV patients, thus also for the treatment of severe anemia. The Compounds according to the invention act in particular as erythropoietin sensitizers.

Erythropoietin sensitizers are compounds that are able to to influence the effect of the EPO present in the body so efficiently that the Erythropoiesis is increased, especially that the oxygen supply improves becomes. They are surprisingly orally active, making them therapeutic Use with exclusion or reduction of known side effects is significantly improved and simplified at the same time.

Test description (in vitro) Cell proliferation of human erythroid progenitor cells

20 ml heparin blood was diluted with 20 ml PBS and for 20 min (220xg) centrifuged. The supernatant was discarded, the cells were placed in 30 ml PBS resuspended and to 17 ml Ficoll Paque (d = 1,077 g / ml, Pharmacia) in a 50 ml Pipetted tubes. The samples were centrifuged at 800xg for 20 min. The mononuclear cells at the interface were placed in a new centrifuge tube transferred, diluted with 3 times the volume with PBS and for 5 min at 300xg centrifuged.

The CD34 positive cells from this cell fraction were isolated using 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 0-10 µM test substance were added. 500 ul / well (24-well plates) were cultivated for 14 days at 37 ° C in 5% CO ₂ , 95% air.

Cultures were diluted with 20 ml 0.9% w / v NaCl solution, centrifuged for 15 min at 600xg and resuspended in 200 µl 0.9% w / v NaCl. To determine the number of erythroid cells, 50 µl of the cell suspension was pipetted into 10 µl benzidine staining solution (20 µg benzidine in 500 µl DMSO, 30 µl H ₂ O ₂ 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 is intraperitoneal, subcutaneous 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 Approx. 70 µl blood are applied several times by puncturing the retroorbital Venous plexus taken with a hematocrit capillary. The samples will be centrifuged and the hematocrit determined by manual reading. Primary The parameter is the hematocrit increase compared to the initial value of the treated Animals compared to the change in hematocrit in the placebo control (double standardized value).  

The new active ingredients can be introduced into the usual formulations in a known manner are transferred, such as tablets, dragees, pills, granules, aerosols, syrups, emuls ions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. Here, the therapeutically active compound in a concentration of about 0.5 to 90% by weight of the total mixture is present, d. H. in amounts that are sufficient are in order to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the active ingredients substances with solvents and / or carriers, optionally using of emulsifiers and / or dispersants, z. B. in the case of use of water as a diluent, optionally organic solvents Auxiliary solvents can be used.

The application takes place in the usual way, preferably orally, transdermally or parenterally, especially perlingually or intravenously.

In general, it has proven to be advantageous for intravenous administration Amounts from about 0.01 to 10 mg / kg, preferably about 0.1 to 10 mg / kg body weight to give effective results.

Nevertheless, it may be necessary to deviate from the quantities mentioned give way, depending on the body weight or the type of Application route, from individual behavior towards the drug, the Kind of its formulation and the time or interval at which the Administration takes place. So in some cases it may be sufficient with less than the aforementioned minimum quantity, while in other cases the mentioned upper limit must be exceeded. Larger in the case of application Quantities it may be advisable to take these in several single doses throughout the day to distribute.

Manufacturing examples

example 1

3- (4-aminomethylphenyl) -5- (4-methoxyphenyl) -1-methyl-pyrazole

3- (Aminocarbonylphenyl) -5- (4-methoxyphenyl) -1-methyl-pyrazole is made under argon dissolved in THF and mixed with borane-THF complex dissolved in THF (7.5 ml). The Mixture is stirred at 60 ° C. for 4 h and then at RT overnight. Then will acidified with aq. HCl and concentrated. The residue is washed with 2 M NaOH made alkaline, the org. Phase separated and dried. The product is about prep. HPLC isolated.

HPLC: Method A: 3.6 min. 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 / min; 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.
MS ES +: 293 found.

Example 2

3- (4-acetamidomethylphenyl) -5- (4-methoxyphenyl) -1-methyl-pyrazole

For the acylation, the amine is dissolved in THF and mixed with acetyl chloride and triethylamine (3 eq.). The mixture is stirred at RT for 4 h, then evaporated completely and using prep. HPLC cleaned.
HPLC: method A: 4.03 min, eluent: aq. 0.05% TFA (A), 0.05% TFA in acetonitrile (B); Symmetry C 18; 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 / min; t = 6 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.
MS Es +: 335 found.

The compounds listed in the following table are prepared in analogy to the instructions in Examples 1 and 2:
Explanations to the table:
MS each for HPLC pure substances; ES +
HPLC method [A]:
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 mi / min.
HPLC method [B]:
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.

Claims (11)

1. Substituted pyrazolbenzylamine derivatives 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 ₁ -C ₆ ) alkyl or for (C ₁ -C ₆ ) alkoxy,
R ^{1 represents} hydrogen or (C ₁ -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 being one to three times the same or different by halogen, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, hydroxy, carboxy or by a group of the formula -CH ₂ -NH-R ^{5 are} substituted,
wherein
R ^{5 represents} hydrogen or (C ₁ -C ₄ ) acyl,
R ³ and R ^{4 are} identical or different and represent hydrogen, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkyl or a group of the formula -CO-NHR ⁶ ,
wherein
R ^{6 represents} hydrogen or (C ₁ -C ₄ ) alkyl,
and their salts and their tautomers. 2. Substituted pyrazolbenzylamine derivatives 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, the ring systems listed above optionally being one to three times the same or different by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkyl, (C ₁ - C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, hydroxy or carboxy are substituted,
R ³ and R ^{4 are the} same or different and represent hydrogen, (C ₁ -C ₄ ) acyl, (C ₁ -C ₄ ) alkyl or a group of the formula -CO-NHR ⁶ ,
wherein
R ^{6 represents} hydrogen or (C ₁ -C ₄ ) alkyl,
and their salts and their tautomers. 3. Substituted pyrazolbenzylamine derivatives of the general formula (I) according to claim 1,
in which
A, D, E and G stand for hydrogen,
R ^{1 represents} hydrogen or methyl,
R ^{2 represents} phenyl, thienyl or pyridyl, where the aromatic ring systems listed above are optionally substituted one to three times identically or differently by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or carboxy,
R ³ and R ^{4 are the} same or different and
represent hydrogen, (C ₁ -C ₃ ) -acyl or (C ₁ -C ₃ ) -alkyl,
and their salts and their tautomers. 4. Substituted pyrazolbenzylamine derivatives of the general formula (I) according to Claims 1 to 3 with the following structures:
5. Substituted pyrazolbenzylamine derivatives of the general formula (I) according to claims 1 to 4 for the treatment of diseases. 6. A process for the preparation of substituted pyrazolbenzylamine derivatives according to Claims 1 to 4, characterized in that compounds of the general formula (II),
in which
A, D, E, G, R ¹ and R ^{2 have} the meaning given above,
with known reducing agents, for example with the borane / tetrahydrofuran complex, to give compounds of the formula (I),
in which
A, D, E, G, R ¹ and R ^{2 have} the meaning given above
and
R ³ and R ^{4 represent} hydrogen
reacted in inert solvents and then optionally carried out an alkylation, acylation or a reaction with isocyanates by customary methods. 7. Medicament containing at least one substituted Pyrazolbenzylamine derivative according to claims 1 to 4 and pharmacologically acceptable formulation agents.   8. Medicament according to claim 7 for the treatment and prophylaxis of Anemia. 9. Medicament according to claim 8 for the treatment of premature babies. Anemia, anemia with chronic renal failure, anemia after chemotherapy and anemia in HIV patients. 10. Use of substituted pyrazolbenzylamine derivatives according to Claims 1 to 4 for the manufacture of medicaments for treatment and prophylaxis of anemia.