WO2000045799A2 - Use of substituted isoxazol carboxylic acids and derivatives and novel substances - Google Patents

Abstract

The invention relates to the use of substituted isoxazol carboxylic acids and derivatives of general formula (I) in the treatment and prophylaxis of anaemia disorders. The invention also relates to novel substances of formula (Ia) and novel methods for the production thereof.

Description

Use of substituted isoxazolecarboxylic acids and derivatives and new substances

The present invention relates to the use of substituted isoxazole carboxylic acids and derivatives for the production of medicaments for the prophylaxis and / or treatment of anemias, new isoxazole carboxylic acids and derivatives 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.

Blood EPO levels are normally low, but the O ₂ content of the blood drops

Blood, then there is an increase in EPO synthesis and thus an increase in EPO levels in the blood. As a result, 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 anemia. 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 isoxazoles are known from the publication US 3948937 as plant growth regulators. Substituted isoxazoles are also described in publication WO 97/19039. This is where the isoxazole derivatives are synthesized on the solid phase to build up a substance library. After cleavage, isoxazolphenyl carboxamides are obtained.

The present invention now relates to the use of substituted isoxazole carboxylic acids and derivatives of the general formula (I)

in welcher

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 for a radical of the formula

steht, worin R³ (C₆-C₁₀)-Aryl oder einen 5- bis 6-gliedrigen aromatischen, gegebenenfalls benzokondensierten Heterocyclus mit bis zu 3 Heteroatomen aus der Reihe S, N und/oder O bedeutet, wobei die Ringsysteme ihrerseits gegebenenfalls bis zu 3-fach gleich oder verschieden durch Halogen, durch (C,-C₆)-Alkyl, (C,-C₆)-Alkoxy, Trifluormethyl oder Trifluormethoxy substituiert sind,

stands in what R ^{3 is} (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered aromatic, optionally benzocondensed heterocycle with up to 3 heteroatoms from the series S, N and / or O, the ring systems in turn optionally up to 3- are identical or differently substituted by halogen, by (C, -C ₆ ) -alkyl, (C, -C ₆ ) -alkoxy, trifluoromethyl or trifluoromethoxy,

R ² for carboxyl or for radicals of the formula -CO-NH ₂ , -CH ₂ -NR ⁴ R ⁵ or -CO-

NH-R ⁶ stands.

wherein

R ⁴ and R ^{5 are the} same or different and

Is hydrogen, (C, -C ₆ ) acyl, (C, -C ₆ ) alkyl or a group of the formula -CO-NHR ⁷ ,

wherein

R ^{7 represents} hydrogen or (C, -C ₄ ) -alkyl,

R ⁶ denotes (C ₃ -C ₈ ) cycloalkyl or (C, -C ₆ ) alkyl,

and their isomer mixtures and their respective salts

as medicinal products, which are therefore suitable for the prophylaxis and / or treatment of diseases, for example anemia. 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 and the diastereomers and 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 be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to 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 _r C ₆ ) -alkyl or (C _r C ₄ ) -alkyl stands for a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 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 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.

(C ₃ -C ₈ ) Cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned: cyclopropyl, cyclopentyl and cyclohexyl.

A 5- to 6-membered aromatic heterocycle with 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, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.

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

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

in welcher

in which

A ', D', E 'and G' are the same or different and stand for hydrogen, halogen, trifluoromethyl, hydroxy or for (C _r C ₆ ) -alkyl or for (C, -C ₆ ) -alkoxy, R ¹ for a radical of the formula

O-N N-O

//

-R ^J or ^ R ³ stands.

wherein

R ^{3 is} (C ₆ -C _{] 0} ) aryl or a 5- to 6-membered aromatic, optionally benzocondensed heterocycle with up to 3 heteroatoms from the series S, N and / or O, the ring systems in turn optionally up to 3 -fold the same or different

Halogen, substituted by (C, -C ₆ ) alkyl, (C, -C ₆ ) alkoxy, trifluoromethyl or trifluoromethoxy,

R 'represents carboxyl or radicals of the formula -CH ₂ -NR ⁴ R ⁵ or -CO-NH-R ⁶

wherein

R ⁴ and R ^{5 'are the} same or different and

Is hydrogen, (C, -C ₆ ) acyl, (C, -C ₆ ) alkyl or a group of the formula -CO-NHR ^{7 '} .

wherein

R ^{7 'is} hydrogen or (C, -C ₄ ) alkyl

R ^{6 '} denotes (C ₃ -C ₆ ) cycloalkyl or (C, -C ₆ ) alkyl, with the proviso that R ^{3 'must} not represent unsubstituted phenyl when R ^{2 is} carboxyl,

and their isomer mixtures and respective salts.

Compounds of the general formula (Ia) according to the invention are preferred,

in which

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

R ¹ for a radical of the formula

steht, worin

stands in what

R ³ denotes phenyl, furyl, thienyl, benzothiophene or pyridyl, which are optionally substituted up to twice in the same or different manner by halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy,

R ^{2 'represents} carboxyl or radicals of the formula -CH ₂ -NR R ^5' or -CO-NH-R ^{6 '} ,

wherein

R and R are the same or different and Is hydrogen, (C, -C ₄ ) -acyl, (C, -C ₄ ) -alkyl or a group of the formula -CO-NHR ^{7 '} ,

wherein

R ^{7 'is} hydrogen or (C, -C ₄ ) -alkyl,

R ^{6 '} denotes cyclopropyl, cyclopentyl, cyclohexyl or (C 1 -C ₄ ) alkyl,

with the proviso that R ³ cannot stand for unsubstituted phenyl if R ^{2 stands} for

Carboxyl stands,

and their isomer mixtures and salts.

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

(Ia),

in which

A ', D', E 'and G' represent hydrogen,

R ¹ for a radical of the formula

steht, worin

stands in what

R ³ 'denotes phenyl or benzothiophene, which are optionally substituted by halogen, methyl, methoxy or trifluoromethyl,

with the proviso that R ^{3 must} not represent unsubstituted phenyl when R ^{2 is} carboxyl, and their isomer mixtures and salts.

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

und deren Isomerengemische und jeweiligen Salze.

and their isomer mixtures and respective salts.

In addition, processes for the preparation of the novel compounds of the general formula (Ia) according to the invention were found, which are characterized in that

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

in which

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

and

R ^{8 'represents} a (C, -C ₄ ) alkyl radical,

with hydroxylamine of the formula (III)

H ₂ N-OH (III)

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

in welcher A', D', E', G', R und R die oben angegebene Bedeutung haben,

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

saponified to give compounds of the general formula (Ia) in which R ^{2 represents} carboxyl,

and optionally reacting them with ammonia to give the corresponding primary amides or, optionally via activated intermediates, with amines of the formula -NH ₂ -R ^{6 '} to give compounds with R ^2' = -CO-NHR ^{6 '} and the amides, if appropriate, using known methods, if appropriate after reduction acylated, alkylated or reacted with isocyanates,

or

[B] produces the partially known compounds of the general formula (I) in which R ² = -CO-NH ₂ means by using compounds of the general formula (V)

in welcher

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 (VI)

R ⁹ -OOC-R ³ (VI) in which

R ^{3 has} the meaning given above

and

R ^{9 represents} a (C, -C ₄ ) alkyl radical,

reacted on the solid phase and then reacted with hydroxylamine (H ₂ N-OH), the compounds then split off from the resin and, if appropriate, the isomers separated.

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

IA]

in the

Secession separation

Inert organic solvents which do not change under the reaction conditions are suitable as solvents for [A]. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichlorethylene or trichlorethylene, hydrocarbon such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetonitrile or acetonitrile, such as acetonitrile or acetonitrile , Ethanol, 2-propanol or DMSO. It is also possible to use mixtures of the solvents. Ethanol and DMSO are particularly preferred.

The usual inorganic or organic bases are suitable as bases for [A]. These include, for example, alkali metal hydrides and alkaline earth metal hydrides such as sodium hydride and calcium hydride, 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-butylate sodium hydride or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide or organometallic compounds such as butyl lithium or phenyllithium.

Inert organic solvents which do not change under the reaction conditions are suitable as solvents for [B]. 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 or acetonitrile DMSO and ethers such as diethyl ether or THF or dioxane. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.

The reaction according to [A] and [B] 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 according to [A] and [B] 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 formulas (V) and (VI) are known or can be prepared by customary methods.

The reduction can generally be carried out using complex hydrides such as aluminum hydrides or boranes or borane complexes in inert solvents, if appropriate in the presence of a catalyst. The borane / tetrahydrofuran complex is preferred. The reduction is generally carried out in a temperature range from -50 ° C to the respective boiling point of the solvent, preferably from -20 ° C to + 50 ° C.

All inert organic solvents which do not change under the reaction conditions are suitable as solvents. 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. It is also possible to use mixtures of the solvents mentioned.

Conventional organic solvents which do not change under the reaction conditions are suitable as solvents for the alkylation. 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, tetrachloromethane, dichloroethylene, trichlorethylene or chlorobenzene or chlorobenzene or chlorobenzene

Dimethyl sulfoxide, dimethylformamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dimethyl sulfoxide and dimethylformamide are preferred.

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

The acylation is generally carried out in ethers or halogenated hydrocarbons, preferably tetrahydrofuran or methylene chloride, in a temperature range from

-30 ° C to 50 ° C, preferably from -10 ° C to room temperature.

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, preferably in a temperature range from 20 ° C to 80 ° C and normal pressure . 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 SAMSMA resins (abbreviation for standard amide resin) and RAM resins (abbreviation for Rink amide resin) are particularly preferred. Examples of amino-functionalized resins which can be used according to the invention are Tentagel SAM (S 30022) and Tentagel R RAM (R 28 023), both from Rapp Polymer GmbH.

The compounds of the general formula (II) 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].

The compound of formula (III) is known.

Some of the compounds of the general formula (IV) are new or known and can then 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

Treatment and prophylaxis of diseases suitable.

They can preferably be used in pharmaceuticals for the treatment and prophylaxis of anemia, such as, for example, premature anemia, anemia in the case of chronic renal failure, anemia after chemotherapy and the

Anemia in HIV patients, thus also for the treatment of severe anemia.

Even in the case of 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 the case of 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 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. In addition, the administration of EPO sensitizers in the case of completely intact endogenous EPO production can also be considered for additional stimulation of erythropoiesis, which can be used in particular in 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 anemia which intervenes even before the stage in which the conventional treatment methods are concerned use with EPO. 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 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 renal failure, anemia after chemotherapy or anemia in HIV patients.

Test description (in vitro)

Cell proliferation of human erythroid progenitor cells 20 ml heparin blood were diluted with 20 ml 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 to 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). D34 positive cells (6000-10000 cells / ml) were resuspended in StemCell Technologies Inc. in stem cell media (0.9% methyl cellulose, 30% calf serum, 1% albumin (bovine), 100 µM 2-mercaptoethanol and 2 raM L-glutamine). 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 the erythroid cells, 50 μl of the cell suspension were pipetted into 10 μl of benzidine staining solution (20 μg of benzidine in 500 μl of DMSO, 30 μl of H ₂ O ₂ and 60 μl of concentrated 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 per 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, approx. 70 μl blood are drawn several times by puncturing the retroorbital venous plexus with a hematocrit capillary. The samples are centrifuged and the hematocxit determined by manual reading. The primary 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. Here, the therapeutically active compound should in each case be in a concentration of about 0.5 to

90% by weight of the total mixture is present, 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, 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 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 drug, 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.

Output connections

Example I

1- (4-methoxycarbonylphenyl) -3- (4-trifluoromethylphenyl) propanedione-1,3

10.3 g (53.2 mmol) of dimethyl terephthalate are added to a suspension of 2.13 g (53.2 mmol) of sodium hydride (60%) in 140 ml of THF under an argon atmosphere. It is stirred for 30 minutes and then dropwise with a solution of 10 g

(53.2 mmol) of 4-trifluoromethyl acetophenone in 30 ml of THF, the temperature being kept below 30 ° C. by gentle cooling. The mixture is stirred for 30 minutes, 700 mg of 18-crown-6 are added, and the mixture is then heated to reflux for 2 hours. It is stirred overnight at room temperature, made slightly acidic dropwise with cooling with 10% hydrochloric acid and suctioned off with the addition of a filter aid and washed with THF. It is concentrated, ethanol is added and the mixture is concentrated again. The raw product is further implemented without purification.

Example II and III

Mixture of 3- (4-methoxycarbonylphenyl) -5- (4-trifluoromethylphenyl) isoxazole and 5- (4-methoxycarbonylphenyl) -3- (4-trifluoromethylphenyl) isoxazole

In a suspension of 1.05 g (30 mmol) of the starting compound from Example I in

10 ml of ethanol become 0.42 g (60 mmol) of hydroxylamine hydrochloride and 0.49 g (60 mmol) sodium acetate. The mixture is heated to reflux for 24 hours, cooled and concentrated. It is taken up in ethyl acetate, washed with water, sodium hydrogen carbonate solution and again water, dried and concentrated.

Manufacturing examples

Examples 1 and 2

Mixture of 3- (4-methoxycarbonylphenyl) -5- (4-trifluoromethylphenyl) isoxazole and

5- (4-Hydroxycarbonylphenyl) -3- (4-trifluoromethylphenyl) isoxazole

The starting compounds from Examples II and III are saponified in dioxane with 8 equivalents of 1 N sodium hydroxide solution at room temperature. The free acid is obtained after acidification. HPLC R: Method 1 4.0 minutes.

Examples 3 and 4

Mixture of 3- (4-aminocarbonylphenyl) -5- (4-trifluoromethylphenyl) isoxazole and mixture with 5- (4-aminocarbonylphenyl) -3- (4-trifluoromethylphenyl) isoxazole

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 (o-benzotriazol-l-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate)

(282 mg, 0.88 mmol) and DIEA (diisopropylethylamine) (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 (5 ml each twice).

For the Claisen condensation, the resin (100 mg, 0.21 mmol) is suspended under argon in dimethylacetamide (10 ml), 4-trifluoromethylbenzoic acid methyl ester (710 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

Mix 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 hydroxylamine hydrochloride in dimethylacetamide and 0.3 ml of triethylamine are added. The mixture is stirred at 70 ° C. for 48 hours. The liquid phase is then suctioned off and the resin is washed with dimethylformamide, methanol, methylene chloride and diethyl ether (5 ml each twice).

To split off the intermediate product, 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 5 mg. HPLC: R, 365 minutes method 1

The compounds listed in the following table are prepared in analogy to the instructions of Examples 1-4, the following structures in which one

-N function is present, it always means an -NH function:

Claims

claims 1. Medicament containing substituted isoxazolecarboxylic acids and 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, -C ₆ ) alkyl or for (C, -C ₆ ) alkoxy, R ¹ for a radical of the formula

stands in what R ³ (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered aromatic, optionally benzocondensed heterocycle with up to 3 Heteroatoms from the series S, N and / or O means, the ring systems in turn optionally up to 3 times the same or different by halogen, by (C, -C ₆ ) - alkyl, (C _r C ₆ ) - Alkoxy, trifluoromethyl or trifluoromethoxy are substituted, R ^{2 represents} carboxyl or radicals of the formula -CO-NH ₂ , -CH ₂ -NR ⁴ R ⁵ or - CO-NH-R ⁶ , wherein R ⁴ and R ^{5 are the} same or different and Is hydrogen, (C, -C ₆ ) acyl, (C, -C ₆ ) alkyl or a group of the formula -CO-NHR ⁷ , wherein R ⁷ denotes hydrogen or (C, -C ₄ ) alkyl, R ⁶ denotes (C ₃ -C ₆ ) cycloalkyl or (C, -C ₆ ) alkyl, and their isomer mixtures and respective salts as well as usual auxiliaries and carriers. Use of substituted isoxazolecarboxylic acids and derivatives 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 _r C ₆ ) - Are alkyl or (C, -C ₆ ) -alkoxy, R ¹ for a radical of the formula

stands, woπn R (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered aromatic, optionally benzocondensed heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems in turn optionally up to 3 times are identical or different and are substituted by halogen, by (C, -C ₆ ) -alkyl, (C, -C ₆ ) -alkoxy, trifluoromethyl or trifluoromethoxy, R ² for carboxyl or for radicals of the formula -CO-NH ₂ , -CH ₂ -NR ⁴ R ⁵ or -CO-NH-R ⁶ , wherein R ⁴ and R ^{5 are the} same or different and Is hydrogen, (C, -C ₆ ) acyl, (C, -C ₆ ) alkyl or a group of the formula -CO-NHR ⁷ , wherein R ⁷ denotes hydrogen or (C, -C ₄ ) alkyl, R ⁶ denotes (C ₃ -C ₆ ) cycloalkyl or (C _r C ₆ ) alkyl, and their isomer mixtures and respective salts for the manufacture of medicines for the prophylaxis and / or treatment of anemia. Substituted isoxazole carboxylic acids and 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, -C ₆ ) alkyl or for (C, -C ₆ ) alkoxy, R ¹ for a radical of the formula O-N N-O or ^• R ^J -R ^J stands in what R (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered aromatic, optionally benzocondensed heterocycle with up to 3 Heteroatoms from the series S, N and / or O means, the ring systems in turn optionally up to 3 times the same or different by halogen, by (C, -C ₆ ) alkyl, (C, -C ₆ ) alkoxy, Trifluoromethyl or trifluoromethoxy are substituted, R ^{2 represents} carboxyl or radicals of the formula -CO-NH ₂ , -CH ₂ -NR ⁴ R ⁵ or -CO-NH-R ⁶ , wherein R ⁴ and R ^{5 are the} same or different and are hydrogen, (C, -C ₆ ) acyl, (C _r C ₆ ) alkyl or a group of Formula -CO-NHR ⁷ mean woπn R ⁷ denotes hydrogen or (C, -C ₄ ) alkyl, R ⁶ denotes (C ₃ -Q) cycloalkyl or (C, -C ₆ ) alkyl, and their isomer mixtures and respective salts for the prophylaxis and / or control of diseases. 4. Substituted isoxazolecarboxylic acids and derivatives of the general formula (Ia)

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 for a radical of the formula

stands, wherein R ^{3 '} (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 means, the ring systems in turn optionally up to 3 times the same or different by halogen, by (C, -C ₆ ) alkyl, (C, -C ₆ ) alkoxy, trifluoromethyl or trifluoromethoxy are substituted, R ^{2 'represents} carboxyl or radicals of the formula -CH ₂ -NR ⁴ R ⁵ or -CO-NH-R ^6' , wherein R ⁴ and R ^{5 'are the} same or different and Is hydrogen, (C, -C ₆ ) acyl, (C, -C ₆ ) alkyl or a group of the formula -CO-NHR ^{7 '} , wherein R ^{7 '} denotes hydrogen or (C, -C ₄ ) alkyl, R ^{6 '} denotes (C ₃ -C ₆ ) cycloalkyl or (C, -C ₆ ) alkyl, with the proviso that R ³ cannot stand for unsubstituted phenyl if R ^{2 '} stands for carboxyl, and their isomer mixtures and respective salts. 5. Substituted isoxazolecarboxylic acids and derivatives of the general formula (Ia) according to Claim 4, in which A ', D', E 'and G' are the same or different and for hydrogen. Are fluorine, chlorine, bromine or trifluoromethyl, R ¹ for a radical of the formula

stands in what R ^{3 '} denotes phenyl, furyl, benzothiophene, thienyl or pyridyl, which are optionally up to 2-fold identical or differently substituted by halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy, R ^{2 'represents} carboxyl or radicals of the formula -CH ₂ -NR ⁴ R ^5' or -CO-NH- R ^{6 '} , wherein R and R ^{5 are the} same or different and Is hydrogen, (C, -C ₄ ) -acyl, (C, -C ₄ ) -alkyl or a group of the formula -CO-NHR ^{7 '} , wherein R ^{7 'is} hydrogen or (C, -C ₄ alkyl, R ^{6 '} denotes cyclopropyl, cyclopentyl, cyclohexyl or (C ¹ -C ₄ ) alkyl, with the proviso that R ³ cannot stand for unsubstituted phenyl if R ^{2 '} stands for carboxyl, and their isomer mixtures and respective salts. 6. Substituted isoxazolecarboxylic acids and derivatives of the general formula (Ia) according to Claim 4, in which A \ D ', E' and G 'represent hydrogen, R for a residue of the formula

stands in what R ³ 'is phenyl or benzothiophene, which may be by Halogen, methyl, methoxy or trifluoromethyl are substituted, with the proviso that R ³ cannot stand for unsubstituted phenyl if R ^{2 '} stands for carboxyl, and their isomer mixtures and respective salts. 7. Substituted isoxazolecarboxylic acids and derivatives according to claim 4 with the following structures:

and their isomer mixtures and respective salts. 8. A process for the preparation of substituted isoxazolecarboxylic acids and derivatives according to claims 4 to 7, characterized in that [A] compounds of the general formula (II),

in which A ', D', E ', G' and R ^{3 have} the meaning given above and R ^{8 'represents} a (C, -C ₄ ) alkyl radical, with hydroxylamine of the formula (III) H ₂ N-OH (III) reacted in inert solvents and the esters of general Formula (IV)

in which A ', D', E ', G', R ¹ and R ^{8 have} the meaning given above, saponified to give compounds of the general formula (Ia), and optionally reacting these carboxyl compounds with ammonia to give the corresponding primary amides or, if appropriate, via activated intermediates with amines of the formula -NH ₂ -R ⁶ to give compounds with R ² = -CO-NHR ^{6 ',} and the amides if appropriate by known methods, if appropriate after Reduction acylated, alkylated or reacted with isocyanates, or [B] produces the partially known compounds of the general formula (I) in which R ² = -CO-NH ₂ means by compounding the general formula (V)

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 (VI) R ⁹ -OOC-R ³ (VI) in which R ^{3 has} the meaning given above and R ^{9 represents} a (C, -C ₄ ) alkyl radical, reacted on the solid phase and then reacted with hydroxylamine (H ₂ N-OH), the compounds then split off from the resin and the isomers separated if necessary. 9. Medicament according to claim 1 for the treatment of premature anemia, anemia in chronic renal failure, anemia after chemotherapy and the anemia in HIV patients. 10. Use of erythropoietin sensitizers for the manufacture of medicaments or pharmaceutical compositions for the prophylaxis and / or treatment of anemias. 1 1. Use of erythropoietin sensitizers for the manufacture of medicaments or pharmaceutical compositions for stimulating the erythropoiesis of autologous blood donors. 12. Use according to claim 10 or 11, characterized in that the Erythropoietin sensitizers can be administered orally.