DE10010426A1 - Medicaments, especially for treating anemia, containing 6-(4-(acylamino)-phenyl)-dihydropyridazinones having erythropoietin sensitizing and erythropoiesis stimulating activity - Google Patents

Abstract

The use of 6-(4-(acylamino)-phenyl)-dihydropyridazinone derivatives (I) as medicaments, especially for the treatment of anemia, is new. Pyridazinone derivatives of formula (I) (including their tautomers and salts) are claimed for the prophylaxis and/or treatment of diseases. [Image] A, D, E, G : H, benzyloxy, alkyl, OH, NO2, halo or alkoxy; R1H or 1-4C alkyl; R25,5-dimethyl-2-oxo-tetrahydrofuranyl, 2,5-dihydrothienyl, 2-oxo-tetrahydrofuran-5-yl, 2-oxo-pyrrolidin-5-yl, CCl3, 4-methyl-2-oxo-pyrrolidin-5-yl or -CHPh2, cycloalkyl (optionally substituted (os) by 1-3 of alkyl, alkoxy, alkoxycarbonyl, OH, COOH or aryl (itself os by 1-3 halo)), or aryl, aryloxy, arylthio, dihydropyridinone or Het (all os by 1-3 of CF3, NO2, OH, CN, cycloalkyl, halo, alkyl, naphthyl, phenoxy, alkyl, alkoxycarbonyl, COOH or NR3R4, or by aryl or Het (themselves os by 1-3 of halo, OH or alkoxy)), 1-10C alkyl (os by 1-3 of halo, alkoxycarbonyl, COOH, NR5R6, S(C(S)NR7R8 or OR9), alkoxycarbonyl, NR13R14, or alkenyl (os by aryl); Het : 5- or 6-membered aromatic heterocycle, containing 1-3 of O, S and/or N as heteroatom(s); R9H, alkyl or alkenyl (os by aryl); or 1-10C alkyl (os by 3-8C cycloalkyl, aryl or Het' (where the ring systems are os by 1-3 of OH, CN, cycloalkyl, halo, alkyl, aryl, OPh, 1-8C alkoxy, alkoxycarbonyl, COOH or NR11R12; or aryl (itself os by halo))); R3 - R8, R11, R12H, alkyl or 1-6C acyl; Het' : optionally benzo-fused, aromatic or saturated, 5- or 6-membered heterocycle containing 1-3 of O, S, N and/or NR10 as heteroatom(s); R10H, Ph or alkyl; R13, R14H, alkyl or 1-6C acyl; 3-8C cycloalkyl, aryl or 5- or 6-membered heterocycle containing 1-3 of O, S and/or N as heteroatom(s) (all os by 1 or 2 of OH, alkyl, alkoxycarbonyl, alkoxy, halo, CONR15R16 or SO2NR17R18); or alkyl (os by phenyl, itself os by 1-3 halo); or NR13R145- or 6-membered saturated heterocycle, optionally containing another O, S or NR19 heteroatom; R15-R18H, aryl or alkyl; R19H, 1-4C alkyl, (1-4C) alkoxycarbonyl or COOCF3; Unless specified otherwise alkyl moieties have 1-6C, cycloalkyl moieties 3-6C, alkenyl moieties 2-6C and aryl moieties 6-10C. Independent claims are included for: (1) the use of (I) in the production of medicaments or pharmaceutical compositions for the prophylaxis and/or treatment of anemia; and (2) medicaments or pharmaceutical compositions containing (I), together with auxiliaries and carriers. - ACTIVITY : Antianemic; nephrotropic; anti-HIV. - MECHANISM OF ACTION : Erythropoiesis stimulant; erythropoietin (EPO) sensitizer. (I) stimulate the action of EPO present in the body and thus stimulate erythropoiesis (especially by improving oxygen utilization). (I) significantly stimulate the proliferation of human erythroid precursor cells in vitro and increase the hematocrit value in mice (no quantitative results given and no specific active compounds mentioned).

Description

The present invention relates to the field of erythropoiesis. In particular concerns the present invention the use of substituted 6- [4'-aminophenyl] - dihydropyridazinones for the manufacture of medicaments, preferably for Prophylaxis and / or treatment of anemia.

Anemia, also known as anemia, is reduced of erythrocyte count, hemoglobin concentration and / or hematocrit below that age-appropriate and gender-specific reference values. However, reducing one of these parameters is only a sign of one Anemia, when blood volume is normal, but not in acute, stronger ones Blood loss, desiccation (pseudopolyglobulia) or hydremia (pseudoanemia). (Pschyrembel, Clinical Dictionary, 257th edition, 1994, Walter de Gruyter Verlag, page 59 ff., Keyword "anemia"; Römpp Lexicon Chemie, Version 1.5, 1998, Georg Thieme Verlag Stuttgart, keyword "anemia").

Clinical anemia is due to the reduced oxygen transport capacity of the Blood, among other things, by disturbance of oxygen-dependent metabolism and organ functions marked; in case of acute development (e.g. due to blood loss) symptoms of shock may appear, and chronic development occurs often a slowly progressive course with decreased performance, fatigue, dyspnea and Tachycardia.

A classification or classification of different forms of anemia can either according to the morphology and hemoglobin content of the erythrocytes or according to the etio logic (e.g. in posthemorrhagic anemia, pregnancy anemia, tumor anemia, Infectious anemia or deficiency anemia). Furthermore, there is a division of different forms of anemia according to their pathogenesis taking into account the possible possible causes, for example in anemia excessive blood loss (e.g. acute or chronic bleeding anemia), anemia in  follow reduced or ineffective erythropoiesis (e.g. iron deficiency anemia, nephrogenic anemia or myelopathic anemia) or anemia resulting from over moderate erythrocyte breakdown (so-called hemolytic anemia) (pschyrembel, Clinical Dictionary, 257th edition, 1994, Walter de Gruyter Verlag, page 59 ff., Keyword "anemia"; Roche Medical Lexicon, 4th edition, 1999, Urban & Schwarzenberg, keyword "anemia").

The treatment methods for anemia known from the prior art prove to be very difficult and inefficient in practice. Mostly kick number rich, often serious side effects for the patient.

So in the treatment of iron deficiency anemia in general iron preparations used either orally or parenterally. With the oral appli cation are mainly observed as a side effect of gastrointestinal disorders. Simultaneous administration of antacids for the treatment of gastrointestinal disorders affects iron absorption. In addition, the absorption of iron from the int stinal tract due to the ability of the mucosa to make it difficult for iron to pass through, only very limited anyway. On the other hand, the oral dose must not be chosen too high because otherwise signs of poisoning can occur, in the worst case even hemorrhagic gastroenteritis with shock symptoms and consequence of death. In parenteral iron therapy, which is due to the only low iron binding capacity of the plasma can also prove difficult it is especially in case of overdose to nausea, vomiting, heart and head pain, sensation of heat and severe drop in blood pressure with collapse, further to Abla iron in the reticuloendothelium (hemosiderosis); the vessel walls are damaged by the intravenous injection, must also with a thrombo phlebitis and thrombosis. A dosage turns out to be extremely difficult because all the iron that is not physiological when administered parenterally can be bound, has a toxic effect (Gustav Kuschinsky, Heinz Lüllmann and Thies Peters, Short textbook on pharmacology and toxicology, 9th edition, 1981, Georg Thieme Verlag Stuttgart, pages 139 ff .; Ernst Mutschier, pharmaceuticals  effects, textbook of pharmacology and toxicology, scientific Verlagsgesellschaft mbH Stuttgart, 1986, page 383 ff.).

For more than 10 years it has stood for therapeutic use for treatment severe anemias genetically engineered, recombinant erythropoietin (rhEPO) are available. Namely, it is known that recombinant human (rh) EPO stimulates humoral erythropoiesis, making it an anti-anemic in Thera severe anemia, especially with renal or nephrogenic anemia, Has found application. Furthermore rh EPO is used to increase the body's own blood cells to increase the need for foreign blood transfusions Reduce.

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 that there per reduced 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 Pro liferation and maturation of erythroid progenitor cells.

However, strong side effects occur when rh EPO is administered. This includes the emergence and exacerbation of high blood pressure as well as the cause of one Encephalopathy-like symptoms up to tonic-clonic cramps and cerebral or myocardial infarction due to thrombosis. Rh is also EPO not available orally and must therefore be intraperitoneal (i.p.), intravenous (i.v.) or sub cutan (s. c.) can be applied, making the application more difficult on therapy Anemia is limited (Kai-Uwe Eckardt, "Erythropoietin: career of a hormone", Deutsches Ärzteblatt 95, No. 6 of February 6, 1998 (41), pages A-285 to A-290; Red List 1998, Editio Cantor Verlag für Medizin und Naturwissenschaften GmbH, see "Epoetin alfa" and "Epoetin beta").

The object of the present invention is now to provide substances which are particularly suitable for the more efficient treatment of anemia and here the disadvantages of the therapy methods known from the prior art avoid for anemia.  

Surprisingly, it has now been found that the compounds of the general formula (I)

in which
A, D, E and G are the same or different and represent hydrogen, benzyloxy, (C ₁ -C ₆ ) alkyl, hydroxy, nitro, halogen or (C ₁ -C ₆ ) alkoxy,
R ^{1 represents} hydrogen or (C ₁ -C ₄ ) alkyl,
R ² for residues of the formulas

stands,
or but
R ^{2 stands} for (C ₃ -C ₈ ) cycloalkyl, which is optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, hydroxyl, carboxyl and (C ₆ -C ₁₀ ) aryl, aryl optionally being substituted one to three times, identically or differently, by halogen,
or but
R ² for (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryloxy, (C ₆ -C ₁₀ ) arylthio, dihydropyridinone or for a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the Row S, N and / or O stands, where the ring systems listed are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: trifluoromethyl, nitro, hydroxy, cyano, (C ₃ -C ₆ ) -cycloalkyl, halogen, (C ₁ -C ₆ ) -alkyl, naphthyl, phenoxy, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkoxycarbonyl, carboxyl and a radical of the formula -NR ³ R ⁴ ,
wherein
R ³ and R ^{4 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl,
and / or the ring systems listed above are optionally substituted by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which in turn are mono- to triple, identical or different, by Halogen, hydroxy or (C ₁ -C ₆ ) alkoxy may be substituted,
or but
R ^{2 represents} (C ₁ -C ₁₀ ) alkyl which is optionally mono- to trisubstituted, identically or differently, by substituents which are selected from the group consisting of: halogen, (C ₁ -C ₆ ) alkoxycarbonyl, Carboxyl and radicals of the formulas -NR ⁵ R ⁶ , -SC (= S) -NR ⁷ R ⁸ or -OR ⁹ ,
wherein
R ⁵ , R ⁶ , R ⁷ and R ⁸ , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
R ⁹ denotes hydrogen, (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl, which is optionally substituted by (C ₆ -C ₁₀ ) aryl,
or
(C ₁ -C ₁₀ ) alkyl optionally by (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or by a 5- to 6-membered, aromatic or saturated, optionally also benzo-condensed heterocycle with up to 3 Heteroatoms from the series S, N and / or O or a radical -NR ¹⁰ is substituted as a ring member,
wherein
R ¹⁰ denotes hydrogen, phenyl or (C ₁ -C ₆ ) alkyl,
wherein the ring systems listed are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: hydroxy, cyano, (C ₃ -C ₆ ) cycloalkyl, halogen, (C ₁ -C ₆ ) Alkyl, (C ₆ -C ₁₀ ) aryl, phenoxy, (C ₁ -C ₈ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, carboxyl and a radical of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ¹² , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
and / or the ring systems are optionally substituted by (C ₆ -C ₁₀ ) aryl, which in turn can be substituted by halogen,
or but
R ^{2 represents} (C ₁ -C ₆ ) alkoxycarbonyl or a radical of the formula -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl,
or (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered heterocycle with up to 3 heter atoms from the series S, N and / or O, the ring systems listed optionally being up to substituted twice, identical or different, by substituents selected from the group of: hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) - Alkoxy, halogen and radicals of the formula -CO-NR ¹⁵ R ¹⁶ or -SO ₂ -NR ¹⁷ R ¹⁸ ,
wherein
R ¹⁵ , R ¹⁶ , R ¹⁷ and R ^{18 are} identical or different and are hydrogen, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkyl,
or
R ¹³ and R ^{14 are} identical or different and denote (C ₁ -C ₆ ) -alkyl which is optionally substituted by phenyl, which in turn can be substituted one to three times, by identical or different means, by halogen,
or
R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle which optionally carries an additional oxygen or sulfur atom or a radical of the formula -NR ¹⁹ as a ring member,
wherein
R ¹⁹ denotes hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxycarbonyl or a radical of the formula -CO ₂ CF ₃ ,
or but
R ^{2 represents} (C ₂ -C ₆ ) alkenyl which is optionally substituted by (C ₆ -C ₁₀ ) aryl,
and their tautomers and their respective salts are suitable for the prophylaxis and / or treatment of anemias.

The compounds used according to 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. The compounds used according to the invention can optionally also in the form of their tautomers.

Physiologically acceptable salts of the compounds used according to the invention salts of the substances used according to the invention with mineral acids, Be carboxylic acids or sulfonic acids. Z are particularly preferred. B. 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 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 ₃ -C ₈ ) Cycloalkyl stands for a cycloalkyl group with 3 to 8 carbon atoms such as. B. cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned: cyclopropyl, cyclopentyl and cyclohexyl.

Halogen includes fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.  

(C ₆ -C ₁₀ ) aryl, also as a constituent of other substituents, generally represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

(C ₁ -C ₁₀ ) -alkyl, (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₄ ) -alkyl stand for a straight-chain or branched alkyl radical with 1 to 10, 1 to 6 and 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 8, 1 to 4 and 1 to 3 carbon atoms is preferred. A straight-chain or branched alkyl radical having 1 to 6 carbon atoms is particularly preferred.

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

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

(C ₂ -C ₆ ) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Examples include: vinyl, allyl, isopropenyl and n-but-2-en-1-yl. A straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred.

(C ₁ -C ₆ ) -acyl stands for a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a double-bonded oxygen atom in the 1-position and is linked via the 1-position. Examples include: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl.

A 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the Series S, O and / or N or a radical of the formula -NH stands for, for example Pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or Imidazolyl. Pyridyl are preferred; Pyrimidyl, pyridazinyl, furyl and thiazolyl.

The compounds of the general formula (I) are preferably used for the prophylaxis and / or treatment of anemias,
in which
A, D, E and G are identical or different and represent hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, benzyloxy, hydroxyl, fluorine, chlorine or bromine,
R ^{1 represents} hydrogen or (C ₁ -C ₃ ) alkyl,
R ² for residues of the formulas

or

stands,
or but
R ^{2 represents} cyclopropyl, cyclopentyl or cyclohexyl, which are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) Alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, hydroxyl, carboxyl, phenyl and naphthyl, where phenyl and naphthyl are optionally substituted one to three times, identically or differently, by fluorine, chlorine or bromine,
or but
R ^{2 represents} phenyl, naphthyl, phenoxy, phenylthio, furyl, pyridyl, thienyl, isoxazolyl or oxazolyl, the ring systems listed optionally being substituted one to three times, identically or differently, by substituents which are selected from the group of: trifluoromethyl , Nitro, hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ₁ -C ₄ ) alkyl, naphthyl, phenoxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) Alkoxycarbonyl and a radical of the formula -NR ³ R ⁴ ,
wherein
R ³ and R ^{4 are} identical or different and are hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -acyl,
and / or the ring systems listed above are optionally substituted by phenyl, pyridyl or thienyl, which in turn can be substituted once or twice, identically or differently, by chlorine, hydroxy or (C ₁ -C ₃ ) alkoxy,
or but
R ^{2 stands} for (C ₁ -C ₈ ) -alkyl, which is optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: fluorine, chlorine, bromine, (C ₁ -C ₄ ) -Alkoxycarbonyl, carboxyl and radicals of the formulas -NR ⁵ R ⁶ , -SC (= S) -NR ⁷ R ⁸ or -OR ⁹ ,
wherein
R ⁵ , R ⁶ , R ⁷ and R ⁸ , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
R ⁹ denotes hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₂ -C ₄ ) -alkenyl, which is optionally substituted by phenyl or naphthyl,
or
(C ₁ -C ₈ ) alkyl is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, pyridyl, isoxazolyl or furyl,
wherein the ring systems listed are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ₁ -C ₄ ) Alkyl, phenyl, naphthyl, phenoxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, carboxyl and a radical of the formula -NR ¹¹ R ¹²
wherein
R ¹¹ and R ¹² , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
and / or the ring systems are optionally substituted by phenyl or naphthyl, which in turn can be substituted by fluorine, chlorine or bromine,
or but
R ^{2 represents} (C ₁ -C ₆ ) alkoxycarbonyl or a radical of the formula -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -acyl,
or cyclopentyl, cyclohexyl, phenyl or pyridyl, the ring systems listed optionally being substituted up to twice, identically or differently, by substituents which are selected from the group of: hydroxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, fluorine, chlorine, bromine and radicals of the formula -CO-NR ¹⁵ R ¹⁶ or -SO ₂ -NR ¹⁷ R ¹⁸ ,
wherein
R ¹⁵ , R ¹⁶ , R ¹⁷ and R ^{18 are} identical or different and are hydrogen, phenyl, naphthyl or (C ₁ -C ₄ ) -alkyl,
or
R ¹³ and R ^{14 are the} same or different and are (C ₁ -C ₄ ) -alkyl, which is optionally substituted by phenyl, which in turn can be substituted once or twice, identical or different, by fluorine or chlorine,
or
R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached, a morpholine or a piperidine ring or a radical of the formula

form,
wherein
R ¹⁹ denotes hydrogen, methyl, (C ₁ -C ₃ ) alkoxycarbonyl or a radical of the formula -CO ₂ CF ₃ ,
or but
R ^{2 represents} (C ₂ -C ₆ ) alkenyl which is optionally substituted by phenyl,
and their tautomers and their respective salts.

The compounds of the general formula (I) are particularly preferably used for the prophylaxis and / or treatment of anemias,
in which
A, D, E and G are the same or different and represent hydrogen, methyl, hydroxy, methoxy or benzyloxy,
R ^{1 represents} hydrogen or (C ₁ -C ₃ ) alkyl,
R ² for residues of the formulas

stands,
or but
R ^{2 represents} cyclopropyl, cyclopentyl or cyclohexyl, which are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) Alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, hydroxyl, carboxyl, phenyl and naphthyl, where phenyl and naphthyl are optionally substituted one to three times, identically or differently, by fluorine, chlorine or bromine,
or but
R ^{2 represents} phenyl, naphthyl, phenoxy, phenylthio, furyl, pyridyl, thienyl, isoxazolyl or oxazolyl, the ring systems listed optionally being substituted one to three times, identically or differently, by substituents which are selected from the group of: trifluoromethyl , Nitro, hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ₁ -C ₄ ) alkyl, naphthyl, phenoxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) Alkoxycarbonyl and a radical of the formula -NR ³ R ⁴ ,
wherein
R ³ and R ^{4 are} identical or different and are hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -acyl,
and / or the ring systems listed above are optionally substituted by phenyl or pyridyl, which in turn can be substituted one to two times, identically or differently, by chlorine, hydroxy or methoxy,
or but
R ^{2 stands} for (C ₁ -C ₈ ) -alkyl, which is optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: fluorine, chlorine, bromine, (C ₁ -C ₄ ) -Alkoxycarbonyl, carboxyl and radicals of the formulas -NR ⁵ R ⁶ , -SC (= S) -NR ⁷ R ⁸ or -OR ⁹ ,
wherein
R ⁵ , R ⁶ , R ⁷ and R ⁸ , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
R ⁹ denotes hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₂ -C ₄ ) -alkenyl, which is optionally substituted by phenyl or naphthyl,
or
(C ₁ -C ₈ ) alkyl is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, pyridyl, furyl or isoxazolyl,
wherein the ring systems listed are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ₁ -C ₄ ) Alkyl, phenyl, naphthyl, phenoxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, carboxyl and a radical of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ¹² , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
and / or the ring systems are optionally substituted by phenyl or naphthyl, which in turn can be substituted by fluorine, chlorine or bromine,
or but
R ^{2 represents} (C ₁ -C ₆ ) alkoxycarbonyl or a radical of the formula -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -acyl,
or cyclopentyl, cyclohexyl, phenyl or pyridyl, the ring systems listed optionally being substituted up to twice, identically or differently, by substituents which are selected from the group of: hydroxy, (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, fluorine, chlorine, bromine and radicals of the formula -CO-NR ¹⁵ R ¹⁶ or -SO ₂ -NR ¹⁷ R ¹⁸ ,
wherein
R ¹⁵ , R ¹⁶ , R ¹⁷ and R ^{18 are} identical or different and are hydrogen, phenyl, naphthyl or (C ₁ -C ₄ ) -alkyl,
or
R ¹³ and R ^{14 are the} same or different and are (C ₁ -C ₄ ) -alkyl, which is optionally substituted by phenyl, which in turn can be substituted once or twice, identical or different, by fluorine or chlorine,
or
R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a radical of the formula

form,
wherein
R ¹⁹ denotes hydrogen, methyl or a radical of the formula -CO ₂ CF ₃ ,
or but
R ^{2 represents} (C ₂ -C ₆ ) alkenyl, which is optionally substituted by phenyl, and their tautomers and their respective salts.

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

and their tautomers and their respective salts.  

The compounds of general formula (I) can be prepared by:
[A] compounds of the general formula (II)

in which
A, D, E and G have the meaning given above,
with compounds of the general formula (III)

R ² -CO-T (III),

in which
R ^{2 has} the meaning given above
and
T is hydroxy or halogen, preferably chlorine,
in inert solvents, if appropriate in the presence of a base, in the case of the carboxylic acid (T = OH) in the presence of a reagent reactivating carboxylic acid,
or
[B] in the case that R ^{2 represents} the radical of the formula -NR ¹³ R ¹⁴ ,
Compounds of the general formula (II) with compounds of the general formula (IV)

R ² -N = C = O (IV),

in which
R ^{2 has} the meaning given above,
implemented directly in inert solvents
or first the compounds of the general formula (II) with diphosgene to give the compounds of the general formula (V)

in which
A, D, E and G have the meaning given above,
reacted in inert solvents and in a second step with amines of the general formula (VI)

NH ₂ -R ² (VI),

in which
R ^{2 has} the meaning given above,
reacted in inert solvents.

The methods described above can be illustrated using the following formula schemes:

Inert organic solvents are suitable as solvents for processes [A] and [B] 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 Hexamethylphosphoric triamide. It is also possible to mix the solvents  to use. Dimethylformamide and. Are particularly preferred for process [A] for the process [B] dichloromethane.

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 or dimethylaminopyridine or triethylamine. Are preferred for that Method [A] Dimethylaminopyridine and Triethylamine.

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.

As carboxylic acid activating reagents in the sense of the present invention carbodiimides such as diisopropylcarbodiimide are particularly suitable, Dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide- 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 benzotriazolyloxy tris (dimethylamino) phosphonium hexyfluorophosphate or phosphonic acid diphe nyl ester amide 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 also suitable Thionyl chloride. Preferred carboxylic acid activating reagents are carbonyldi imidazole (CDI) and thionyl chloride. As carboxylic acid activating reagents Also suitable are compounds which convert the carboxylic acid function into the corresponding carboxylic acid halide can convert, such. B. Thionyl chloride.  

The carboxylic acid reactivating reagent is in an amount of 1 to 5, preferably from 1 to 2 moles, based on 1 mole of the compounds of the general Formula (III) used.

The reaction generally takes place in a temperature range from -78 ° C to Reflux temperature, preferably in a range from -78 ° C to + 20 ° C.

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 compounds of the general formulas (II), (III), (IV), (V) and (VI) are per se known or can be produced by customary methods.

The compounds of the general formula (I) used according to the invention show an unpredictable, valuable pharmacological spectrum of action and are therefore especially for the prophylaxis and / or treatment of diseases suitable.

They can preferably be used in medicines for prophylaxis and / or Treatment of anemia, such as premature anemia nephrogenic or renal anemia such as anemia with chronic kidney disease efficiency, with anemia after chemotherapy and with the anemia of HIV patients ducks, d. H. in particular for the treatment of severe anemia.

Even with completely intact endogenous EPO production, the administration of Compounds used according to the invention an additional stimulation of Erythropoiesis are induced, which is used particularly in autologous blood donors can be.  

All come for the application of the compounds used according to the invention usual forms of application into consideration. Application is preferably oral, transdermally or perenterally. Oral application is very particularly preferred, wherein another advantage over that known from the prior art Therapy of anemia with rhEPO lies.

The compounds used according to the invention act in particular as Erythropoietin sensitizer. Connections are called "erythropoietin sensitizers" referred to, which are able to influence the effect of the EPO present in the body to influence efficiently that increased erythropoiesis, especially the Oxygenation is improved. Surprisingly, they are also oral effective, thereby excluding or reducing therapeutic use the known side effects significantly improved and simplified at the same time becomes.

The present invention thus also relates to the use of EPO Sensitizers for stimulating erythropoiesis, in particular for prophylaxis and / or Treatment of anemia, preferably severe anemia such as Premature anemia, anemia with chronic renal failure, anemia after Chemotherapy or anemia in HIV patients. The is particularly preferred oral application of these so-called EPO sensitizers for the aforementioned Purposes.

The compounds used according to the invention thus enable efficient Stimulation of erythropoiesis and consequently prophylaxis or therapy of Anemia that intervenes before the stage in which the conventional Use treatment methods with EPO. Because the used according to the invention Compounds allow an effective influence on the body's EPO, whereby the direct administration of EPO with the associated disadvantages can be avoided.  

Another object of the present invention are pharmaceuticals and pharma Zeutische compositions containing at least one compound of the invention the general formula (I) together with one or more pharmacologically contain safe auxiliaries or carriers, and their use for Stimulation of erythropoiesis, in particular for the purposes of prophylaxis and / or Treatment of anemia, such as B. premature anemia, chronic anemia Renal insufficiency, anemia after chemotherapy or anemia in HIV- Patient.

The present invention is illustrated by the following examples which illustrate the However, in no way limit the invention.  

A Assessment of physiological effectiveness 1. General test methods a) Test description (in vitro) Cell proliferation of human erythroid progenitor cells

20 ml of heparin blood were diluted with 20 ml of PBS (phosphate-buffered saline) and centrifuged for 20 min (220 xg). 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 800 xg for 20 min. The mononuclear cells at the interface were transferred to a new centrifuge tube, diluted with 3 times the volume of PBS and centrifuged for 5 min at 300 xg. The CD34 positive cells from this cell fraction were isolated by means of a commercial purification method (CD34 multisort kit from Miyltenyi). The 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 (interleukin-3) and 0-10 µM test substance were added. 500 µl / well (microtiter plate with 24 wells each) were cultivated for 14 days at 37 ° C in 5% CO ₂ /95% air.

The cultures were diluted with 20 ml 0.9% w / v NaCl solution, centrifuged for 15 min at 600 xg and resuspended in 200 µl 0.9% w / v NaCl. To determine the number of 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.

When the test substances according to the present invention are added, one is added significant increase in cell proliferation of erythroid progenitor cells was observed.  

b) Test description of 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 administered test substances according to the present invention lead to a significant increase in hematocrit.

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, i.e. 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 body weight or the type of Application route, from individual behavior towards the drug, from the type of 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.  

B Manufacturing examples example 1

6- [4- (2,2'-difluorobenzoylamino) -2-methoxyphenyl] dihydropyridazinone

109 mg (0.5 mmol) of 5- [4-aminophenyl] -6-methyl-3,6-dihydrothiadiazon are dissolved in 1 ml of THF. With stirring, 88 mg (0.2 mmol) of 2,2'-difluorobenzoyl chloride are added dropwise at 0.degree. The mixture is allowed to come to room temperature, stirred for a further 10 minutes and 2 ml of water are added with repeated cooling. The resulting precipitate is filtered, washed with water and ether and dried.
Yield: 14%
R _f = 0.3 (methylene chloride / methanol = 100/5)

The compounds listed in the following tables are prepared in analogy to the procedure of Example 1. With the structures that the or the remnants

is always one

meant.

Claims (13)

1. Substituted 6- [4'-aminophenyl] dihydropyridazinones of the general formula (I)
in which
A, D, E and G are the same or different and represent hydrogen, benzyloxy, (C ₁ -C ₆ ) alkyl, hydroxy, nitro, halogen or (C ₁ -C ₆ ) alkoxy,
R ^{1 represents} hydrogen or (C ₁ -C ₄ ) alkyl,
R ² for residues of the formulas
or
stands,
or but
R ^{2 stands} for (C ₃ -C ₈ ) cycloalkyl, which is optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, hydroxyl, carboxyl and (C ₆ -C ₁₀ ) aryl, aryl optionally being substituted one to three times, identically or differently, by halogen,
or but
R ² for (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryloxy, (C ₆ -C ₁₀ ) arylthio, dihydropyridinone or for a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the Row S, N and / or O stands, where the ring systems listed are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: trifluoromethyl, nitro, hydroxy, cyano, (C ₃ -C ₆ ) -cycloalkyl, halogen, (C ₁ -C ₆ ) -alkyl, naphthyl, phenoxy, (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkoxycarbonyl, carboxyl and a radical of the formula -NR ³ R ⁴ ,
wherein
R ³ and R ^{4 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl,
and / or the ring systems listed above are optionally substituted by phenyl or by a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O, which in turn are mono- to triple, identical or different, by Halogen, hydroxy or (C ₁ -C ₆ ) alkoxy may be substituted,
or but
R ^{2 represents} (C ₁ -C ₁₀ ) alkyl which is optionally mono- to trisubstituted, identically or differently, by substituents which are selected from the group consisting of: halogen, (C ₁ -C ₆ ) alkoxycarbonyl, Carboxyl and radicals of the formulas -NR ⁵ R ⁶ , -SC (= S) -NR ⁷ R ⁸ or -OR ⁹ ,
wherein
R ⁵ , R ⁶ , R ⁷ and R ⁸ , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
R ⁹ denotes hydrogen, (C ₁ -C ₆ ) alkyl or (C ₂ -C ₆ ) alkenyl, which is optionally substituted by (C ₆ -C ₁₀ ) aryl,
or
(C ₁ -C ₁₀ ) alkyl optionally by (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or by a 5- to 6-membered, aromatic or saturated, optionally also benzo-condensed heterocycle with up to 3 Heteroatoms from the series S, N and / or O or a radical -NR ¹⁰ is substituted as a ring member,
wherein
R ¹⁰ denotes hydrogen, phenyl or (C ₁ -C ₆ ) alkyl,
wherein the ring systems listed are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: hydroxy, cyano, (C ₃ -C ₆ ) cycloalkyl, halogen, (C ₁ -C ₆ ) Alkyl, (C ₆ -C ₁₀ ) aryl, phenoxy, (C ₁ -C ₈ ) alkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, carboxyl and a radical of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ¹² , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
and / or the ring systems are optionally substituted by (C ₆ -C ₁₀ ) aryl, which in turn can be substituted by halogen,
or but
R ^{2 represents} (C ₁ -C ₆ ) alkoxycarbonyl or a radical of the formula -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -acyl,
or (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered heterocycle with up to 3 heter atoms from the series S, N and / or O, the ring systems listed optionally being up to substituted twice, identical or different, by substituents selected from the group of: hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) - Alkoxy, halogen and radicals of the formula -CO-NR ¹⁵ R ¹⁶ or -SO ₂ -NR ¹⁷ R ¹⁸ ,
wherein
R ¹⁵ , R ¹⁶ , R ¹⁷ and R ^{18 are} identical or different and are hydrogen, (C ₆ -C ₁₀ ) aryl or (C ₁ -C ₆ ) alkyl,
or
R ¹³ and R ^{14 are} identical or different and denote (C ₁ -C ₆ ) -alkyl which is optionally substituted by phenyl, which in turn can be substituted one to three times, by identical or different means, by halogen,
or
R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle which optionally carries an additional oxygen or sulfur atom or a radical of the formula -NR ¹⁹ as a ring member,
wherein
R ¹⁹ denotes hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxycarbonyl or a radical of the formula -CO ₂ CF ₃ ,
or but
R ^{2 represents} (C ₂ -C ₆ ) alkenyl which is optionally substituted by (C ₆ -C ₁₀ ) aryl,
and their tautomers and their respective salts for the prophylaxis and / or treatment of diseases. 2. Compounds according to claim 1, wherein in the above general formula (I)
A, D, E and G are identical or different and represent hydrogen, (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, benzyloxy, hydroxyl, fluorine, chlorine or bromine,
R ^{1 represents} hydrogen or (C ₁ -C ₃ ) alkyl,
R ² for residues of the formulas
stands,
or but
R ^{2 represents} cyclopropyl, cyclopentyl or cyclohexyl, which are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) Alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, hydroxyl, carboxyl, phenyl and naphthyl, where phenyl and naphthyl are optionally substituted one to three times, identically or differently, by fluorine, chlorine or bromine,
or but
R ^{2 represents} phenyl, naphthyl, phenoxy, phenylthio, furyl, pyridyl, thienyl, isoxazolyl or oxazolyl, the ring systems listed optionally being substituted one to three times, identically or differently, by substituents which are selected from the group of: trifluoromethyl , Nitro, hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ₁ -C ₄ ) alkyl, naphthyl, phenoxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) Alkoxycarbonyl and a radical of the formula -NR ³ R ⁴ ,
wherein
R ³ and R ^{4 are} identical or different and are hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -acyl,
and / or the ring systems listed above are optionally substituted by phenyl, pyridyl or thienyl, which in turn can be substituted once or twice, identically or differently, by chlorine, hydroxy or (C ₁ -C ₃ ) alkoxy,
or but
R ^{2 stands} for (C ₁ -C ₈ ) -alkyl, which is optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: fluorine, chlorine, bromine, (C ₁ -C ₄ ) -Alkoxycarbonyl, carboxyl and radicals of the formulas -NR ⁵ R ⁶ , -SC (= S) -NR ⁷ R ⁸ or -OR ⁹ ,
wherein
R ⁵ , R ⁶ , R ⁷ and R ⁸ , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
R ⁹ denotes hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₂ -C ₄ ) -alkenyl, which is optionally substituted by phenyl or naphthyl,
or
(C ₁ -C ₈ ) alkyl is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, pyridyl, isoxazolyl or furyl,
wherein the ring systems listed are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ₁ -C ₄ ) Alkyl, phenyl, naphthyl, phenoxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, carboxyl and a radical of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ¹² , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
and / or the ring systems are optionally substituted by phenyl or naphthyl, which in turn can be substituted by fluorine, chlorine or bromine,
or but
R ^{2 represents} (C ₁ -C ₆ ) alkoxycarbonyl or a radical of the formula -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -acyl,
or cyclopentyl, cyclohexyl, phenyl or pyridyl, the ring systems listed optionally being substituted up to twice, identically or differently, by substituents which are selected from the group of: hydroxy, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, fluorine, chlorine, bromine and radicals of the formula -CO-NR ¹⁵ R ¹⁶ or -SO ₂ -NR ¹⁷ R ¹⁸ ,
wherein
R ¹⁵ , R ¹⁶ , R ¹⁷ and R ^{18 are} identical or different and are hydrogen, phenyl, naphthyl or (C ₁ -C ₄ ) -alkyl,
or
R ¹³ and R ^{14 are the} same or different and are (C ₁ -C ₄ ) -alkyl, which is optionally substituted by phenyl, which in turn can be substituted once or twice, identical or different, by fluorine or chlorine,
or
R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached, a morpholine or a piperidine ring or a radical of the formula
form,
wherein
R ¹⁹ denotes hydrogen, methyl, (C ₁ -C ₃ ) alkoxycarbonyl or a radical of the formula -CO ₂ CF ₃ ,
or but
R ^{2 represents} (C ₂ -C ₆ ) alkenyl, which is optionally substituted by phenyl. 3. Compounds according to claim 1 or 2, wherein in the above general formula (I)
A, D, E and G are the same or different and represent hydrogen, methyl, hydroxy, methoxy or benzyloxy,
R ^{1 represents} hydrogen or (C ₁ -C ₃ ) alkyl,
R ² for residues of the formulas
stands,
or but
R ^{2 represents} cyclopropyl, cyclopentyl or cyclohexyl, which are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) Alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, hydroxyl, carboxyl, phenyl and naphthyl, where phenyl and naphthyl are optionally substituted one to three times, identically or differently, by fluorine, chlorine or bromine,
or but
R ^{2 represents} phenyl, naphthyl, phenoxy, phenylthio, furyl, pyridyl, thienyl, isoxazolyl or oxazolyl, the ring systems listed optionally being substituted one to three times, identically or differently, by substituents which are selected from the group of: trifluoromethyl , Nitro, hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ₁ -C ₄ ) alkyl, naphthyl, phenoxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) Alkoxycarbonyl and a radical of the formula -NR ³ R ⁴ ,
wherein
R ³ and R ^{4 are} identical or different and are hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -acyl,
and / or the ring systems listed above are optionally substituted by phenyl or pyridyl, which in turn can be substituted one to two times, identically or differently, by chlorine, hydroxy or methoxy,
or but
R ^{2 stands} for (C ₁ -C ₈ ) -alkyl, which is optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: fluorine, chlorine, bromine, (C ₁ -C ₄ ) -Alkoxycarbonyl, carboxyl and radicals of the formulas -NR ⁵ R ⁶ , -SC (= S) -NR ⁷ R ⁸ or -OR ⁹ ,
wherein
R ⁵ , R ⁶ , R ⁷ and R ⁸ , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
R ⁹ denotes hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₂ -C ₄ ) -alkenyl, which is optionally substituted by phenyl or naphthyl,
or
(C ₁ -C ₈ ) alkyl is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, thienyl, pyridyl, furyl or isoxazolyl,
wherein the ring systems listed are optionally substituted one to three times, identically or differently, by substituents which are selected from the group of: hydroxy, cyano, cyclopropyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, (C ₁ -C ₄ ) Alkyl, phenyl, naphthyl, phenoxy, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, carboxyl and a radical of the formula -NR ¹¹ R ¹² ,
wherein
R ¹¹ and R ¹² , identical or different, have the meaning of R ³ and R ⁴ given above and are identical or different with these,
and / or the ring systems are optionally substituted by phenyl or naphthyl, which in turn can be substituted by fluorine, chlorine or bromine,
or but
R ^{2 represents} (C ₁ -C ₆ ) alkoxycarbonyl or a radical of the formula -NR ¹³ R ¹⁴ ,
wherein
R ¹³ and R ^{14 are} identical or different and are hydrogen, (C ₁ -C ₄ ) -alkyl or (C ₁ -C ₄ ) -acyl,
or cyclopentyl, cyclohexyl, phenyl or pyridyl, the ring systems listed optionally being substituted up to twice, identically or differently, by substituents which are selected from the group of: hydroxy, (C ₁ -C ₃ ) -alkyl, (C ₁ -C ₃ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, fluorine, chlorine, bromine and radicals of the formula -CO-NR ¹⁵ R ¹⁶ or -SO ₂ -NR ¹⁷ R ¹⁸ ,
wherein
R ¹⁵ , R ¹⁶ , R ¹⁷ and R ^{18 are} identical or different and are hydrogen, phenyl, naphthyl or (C ₁ -C ₄ ) -alkyl,
or
R ¹³ and R ^{14 are the} same or different and are (C ₁ -C ₄ ) -alkyl, which is optionally substituted by phenyl, which in turn can be substituted once or twice, identical or different, by fluorine or chlorine,
or
R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a radical of the formula
form,
wherein
R ¹⁹ denotes hydrogen, methyl or a radical of the formula -CO ₂ CF ₃ ,
or but
R ^{2 represents} (C ₂ -C ₆ ) alkenyl, which is optionally substituted by phenyl. 4. Compounds of the general formula (I) with the following structure:
5. Use of compounds of general formula (I), as in the Claims 1 to 4 defined for the manufacture of drugs or pharmaceutical compositions for prophylaxis and / or treatment of anemia. 6. Use according to claim 5 for the manufacture of medicaments or pharmaceutical compositions for prophylaxis and / or treatment premature anemia, anemia with chronic renal failure, Anemia after chemotherapy and anemia in HIV patients. 7. Use according to one of claims 5 or 6 for the production of Medicines or pharmaceutical compositions for stimulation the erythropoiesis of autologous blood donors.   8. Use according to one of claims 5 to 7, characterized in that the drugs or compositions are administered orally. 9. Medicament or pharmaceutical composition containing at least a 6- [4'-aminophenyl] dihydropyridazinone of the general formula (I), such as previously defined, as well as pharmacologically acceptable auxiliary and Carriers. 10. Medicament or pharmaceutical composition according to claim 9 for Prophylaxis and / or treatment of anemia. 11. Medicament or pharmaceutical composition according to claim 9 or 11 for the prophylaxis and / or treatment of premature anemia, Anemia with chronic renal failure, anemia after Chemotherapy and anemia in HIV patients. 12. Medicament or pharmaceutical composition according to claim 9 for Stimulation of erythropoiesis in autologous blood donors. 13. Medicament or pharmaceutical composition according to one of the Claims 9 to 12, characterized in that the medicament or the Compositions can be applied orally.