DE10010429A1 - New 6-(4-sulfonamido-phenyl)-5-methyl-dihydropyridazinones, having erythropoietin sensitizing and erythropoiesis stimulating activity, useful for treating anemia - Google Patents

Abstract

6-(4-Sulfonamido-phenyl)-5-methyl-dihydropyridazinone derivatives (I) are new. Pyridazinone derivatives of formula (I) (including their tautomers and salts) are new. A, D, E, G = H, alkyl, OH, CF3, halo or alkoxy; R1, R2 = H or alkyl; R3 = 1-8C alkyl; aryl or Het (both optionally substituted by 1-3 of halo, CF3, NO2, OH, COOH, alkyl, alkoxy, alkoxycarbonyl, 1-6C acyl, Het, OR4 or -(CH2)a-NR5COR6); or 1,2,3,4-tetrahydro-6-naphthyl or a heterocyclic group of formula (i)-(iii); Het = 5-6 membered aromatic heterocycle, containing 1-3 O, S and/or N as heteroatom(s); R4 = aryl (optionally substituted by 1-3 of halo, NO2, CF3 or alkyl); a = 0-2; R5 = H or 1-4C alkyl; R6 = alkyl or aryl (optionally substituted by 1-3 of halo or alkyl); R7, R8 = halo (preferably Cl); unless specified otherwise alkyl moieties have 1-6C and aryl moieties 6-10C. An Independent claim is included for the preparation of (I).

Description

The present invention relates to the field of erythropoiesis. In particular concerns the present invention new 6- [4-sulfonamidophenyl] dihydropyridazinones, Process for their preparation and their use as medicaments, preferably for the prophylaxis and / or control 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 Mutschler, 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 new substances zen, 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.  

The present invention thus relates to new 6- [4-sulfonamidophenyl] dihydropyridazinones of the general formula (I)

in which
A, D, E and G are the same or different and
represent hydrogen, halogen, trifluoromethyl, hydroxy or (C ₁ -C ₆ ) -alkyl or (C ₁ -C ₆ ) -alkoxy,
R ^{1 represents} hydrogen or (C ₁ -C ₆ ) alkyl,
R ^{2 represents} hydrogen or (C ₁ -C ₆ ) alkyl, in particular hydrogen,
R ^{3 represents} (C ₁ -C ₈ ) alkyl or
represents (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered aromatic heterocycle with up to 3 ring heteroatoms from the series S, N and / or O, the ring systems listed here optionally up to 4 times, the same or different, by substituents selected from the group consisting of: halogen, trifluoromethyl, nitro, hydroxy, carboxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ - C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) acyl, a 5- to 6-membered aromatic heterocycle with up to 3 ring heteroatoms from the series S, N and / or O, groups of the formulas -OR ⁴ and - ( CH ₂ ) _a -NR ⁵ -CO-R ⁶ can be substituted,
wherein
R ⁴ denotes (C ₆ -C ₁₀ ) aryl which is optionally substituted up to 3 times, identically or differently, by halogen, nitro, trifluoromethyl or (C ₁ -C ₆ ) alkyl,
a represents a number 0, 1 or 2,
R ⁵ denotes hydrogen or (C ₁ -C ₄ ) alkyl,
R ^{6 is} (C ₁ -C ₆ ) alkyl or
(C ₆ -C ₁₀ ) aryl which is optionally substituted up to 3 times, identically or differently, by halogen or (C ₁ -C ₆ ) alkyl,
and in the case of the 5-membered, nitrogen-containing, aromatic heterocycles one of the above-mentioned substituents can also be bonded via a nitrogen atom,
or
R ³ for residues of the formulas

stands,
wherein
R ⁷ and R ^{8 are} identical or different and are halogen, in particular chlorine,
and their tautomers and their respective salts.

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 as well as their respective mixtures. Let the racemic shapes as well as the diastereomers in a known manner in the stereoisomer separate uniform components. The compounds of the invention can optionally also in the form of their tautomers.

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 with customary bases can also be mentioned, 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.

(C ₁ -C ₈ ) -alkyl represents a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. 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. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 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, n-butoxycarbonyl, isobutoxycarbonyl 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 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 5, O and / or N represents, for example, pyridyl, pyrimidyl, pyridazinyl, Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl or imidazolyl. Prefers are pyridyl, furyl, thienyl, oxazolyl and isoxazolyl.

From the publication EP 711 002 the compound N- [2-amino-4- (1,4,5,6- tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl] benzenesulfonamide as an intermediate Product known for the preparation of Benzotriazolylpyridazinone, the latter with have an inhibitory effect on platelet aggregation.

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 or bromine,
R ^{1 represents} hydrogen or (C ₁ -C ₄ ) alkyl,
R ^{2 represents} hydrogen or (C ₁ -C ₄ ) alkyl, in particular hydrogen,
R ^{3 represents} (C ₁ -C ₆ ) alkyl or
represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrazolyl, pyrryl, oxazolyl or isoxazolyl, the ring systems listed here optionally being up to 4-fold, identical or different, by substituents selected from the group consisting of: fluorine, Chlorine, bromine, trifluoromethyl, nitro, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, acetyl, pyridyl, thienyl, oxazolyl, isoazolyl and groups of Formulas -OR ⁴ and - (CH ₂ ) _a -NR ⁵ -CO-R ⁶ can be substituted,
wherein
R ^{4 is} phenyl which is optionally substituted up to 2 times, identically or differently, by fluorine, chlorine, bromine, nitro, trifluoromethyl or (C ₁ -C ₄ ) -alkyl,
a represents a number 0 or 1,
R ⁵ denotes hydrogen or (C ₁ -C ₃ ) alkyl,
R ⁶ denotes (C ₁ -C ₄ ) -alkyl or phenyl which is optionally substituted up to 3 times, identically or differently, by fluorine, chlorine, bromine or (C ₁ -C ₃ ) -alkyl,
or
R ³ for residues of the formulas

stands,
wherein
R ⁷ and R ^{8 are} chlorine,
and their tautomers and their respective salts.

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} hydrogen,
R ^{3 represents} (C ₁ -C ₄ ) alkyl or
stands for naphthyl, phenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl or isoxazolyl, the ring systems listed here optionally being up to 4-fold, identical or different, by substituents selected from the group consisting of: fluorine. Chlorine, trifluoromethyl, nitro, methyl, ethyl, methoxy, acetyl, pyridyl, thienyl, oxazolyl, isoxazolyl and groups of the formulas -OR ⁴ and - (CH ₂ ) _a -NR ⁵ -CO-R ⁶ can be substituted,
wherein
R ^{4 is} phenyl which is optionally substituted up to twice, identically or differently, by chlorine, bromine, nitro or methyl,
a represents a number 0 or 1,
R ^{5 represents} hydrogen or methyl,
R ^{6 is} methyl or
Phenyl which is optionally substituted up to 3 times, identically or differently, by fluorine, chlorine, bromine or methyl,
or
R ³ for residues of the formulas

stands,
wherein
R ⁷ and R ^{8 are} chlorine,
and their tautomers and their respective salts.

The present invention also relates to a process for the preparation of the compounds of the general formula (I) according to the invention, wherein
[A] compounds of the general formula (II)

in which
A, D, E, G and R ^{1 have} the meaning given above,
with compounds of the general formula (III)

R ³ -SO ₂ -L (III),

in which
R ^{3 has} the meaning given above
and
L represents halogen, preferably chlorine,
are reacted in inert solvents, if appropriate in the presence of a base,
or
[B] in the event that R ^{1 is} not hydrogen, first compounds of the general formula (IV)

in which
A, D, E and G have the meaning given above,
with an alkylating agent of the general formula (V)

R ¹ -X (V),

in which
R ^{1 has} the meaning given above
and
X represents halogen, preferably iodine,
in inert solvents and in the presence of a base in the compounds of the general formula (VI)

in which
A, D, E, G and R ^{1 have} the meaning given above,
be transferred, then reduced to the compounds of the general formula (II) using customary methods known to those skilled in the art and finally reacted with compounds of the general formula (III) as described under [A].

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

Suitable solvents are organic solvents, which are among the Reaction conditions are inert. These include halogenated hydrocarbons such as Dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, Tetrachloroethane, 1,2-dichlorethylene or trichlorethylene, hydrocarbons such as Benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetonitrile or Hexamethylphosphoric triamide. It is also possible to use mixtures of solvents to use.

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-butoxide or amides such as sodium amide, lithium bis (trimethylsilyl) amide or Lithium diisopropylamide or organometallic compounds such as butyllithium or Phenyllithium.  

Lithium diisopropylamide or organometallic compounds such as butyllithium or Phenyllithium.

The base can be present in an amount of 1 to 5 moles, preferably 1 to 2 moles, based on 1 mole of the compounds of general formula (II) can be 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. in a range from 0.5 to 5 bar). In general 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.

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.

Some of the compounds of the general formula (II) are known or new and can then be prepared, for example, by, as described in process [B] described, proceeded.  

The compounds of the general formulas (III), (IV) and (V) are known to the person skilled in the art known per se or can be produced by customary methods.

Some of the compounds of the general formula (VI) are known, some are new and can be prepared as described under method [B].

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

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 inventions compounds according to the invention an additional stimulation of erythropoiesis indu be adorned, which can be used in particular with autologous blood donors.

For the application of the compounds according to the invention, all customary ones come Application forms 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 according to the invention act in particular as erythropoietin Sensitizer. "Erythropoietin Sensitizer" refers to compounds that are found in are able to influence the effects of the EPO in the body so efficiently flow that increased erythropoiesis, especially the oxygen supply ver is improved. Surprisingly, they are also orally active, which means that  therapeutic use excluding or reducing the known names effects are significantly improved and at the same time simplified.

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 according to the invention thus enable efficient stimulation of erythropoiesis and consequently a prophylaxis or therapy of anemia, which still intervenes before the stage in which the conventional treatment methods use with EPO. Because the compounds of the invention allow one Effectively influencing the body's own EPO, which means 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 of PBS and poured onto 17 ml of Ficoll Paque® (d = 1,077 g / ml, Pharmacia) pipetted into 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, a significant increase in the cell proliferation of erythroid progenitor cells is observed in each case.

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, 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 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

2-bromo-N [4- (4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl) phenyl] benzenesulfonamide

A suspension of 50 mg (0.25 mmol) 6- (4-aminophenyl) -5-methyl-4,5-dihydro-2H-pyridazin-3-one, 46 mg (0.59 mmol) pyridine and 75 mg (0.30 mmol) of 2-bromo-benzenesulfonic acid chloride in 2 ml of CH ₂ Cl ₂ is stirred at 20 ° C. overnight. After adding 5 ml of diethyl ether, the mixture is left to stand at 20 ° C. for 1 h. The resulting precipitate is filtered off, washed with 0.5 M HCl solution and water and dried in a high vacuum.
Yield: 75 mg (72%)
R _f = 0.56 (EtOAc / Cyclohexane / HOAc 5: 5: 1).

The examples listed in Table 1 are prepared in analogy to the above-mentioned regulation. In the structures of the following table, the one or more residues

is always one

meant.

The abbreviation (Z) when specifying the melting point means decomposition.  

Table 1

Claims (13)

1. 6- [4-sulfonamidophenyl] dihydropyridazinones of the general formula (I)
in which
A, D, E and G are the same or different and
represent hydrogen, halogen, trifluoromethyl, hydroxy or (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy,
R ^{1 represents} hydrogen or (C ₁ -C ₆ ) alkyl,
R ^{2 represents} hydrogen or (C ₁ -C ₆ ) alkyl, in particular hydrogen,
R ^{3 represents} (C ₁ -C ₈ ) alkyl or
represents (C ₆ -C ₁₀ ) aryl or a 5- to 6-membered aromatic heterocycle with up to 3 ring heteroatoms from the series S, N and / or O, the ring systems listed here optionally up to 4 times, the same or different, by substituents selected from the group consisting of: halogen, trifluoromethyl, nitro, hydroxy, carboxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ - C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) acyl, a 5- to 6-membered aromatic heterocycle with up to 3 ring heteroatoms from the series S, N and / or O and groups of the formulas -OR ⁴ and - ( CH ₂ ) _a -NR ⁵ -CO-R ⁶ can be substituted,
wherein
R ⁴ denotes (C ₆ -C ₁₀ ) aryl which is optionally substituted up to 3 times, identically or differently, by halogen, nitro, trifluoromethyl or (C ₁ -C ₆ ) alkyl,
a represents a number 0, 1 or 2,
R ⁵ denotes hydrogen or (C ₁ -C ₄ ) alkyl,
R ^{6 is} (C ₁ -C ₆ ) alkyl or
(C ₆ -C ₁₀ ) aryl which is optionally substituted up to 3 times, identically or differently, by halogen or (C ₁ -C ₆ ) alkyl,
and in the case of the 5-membered, nitrogen-containing, aromatic heterocycles one of the above-mentioned substituents can also be bonded via a nitrogen atom,
or
R ³ for residues of the formulas
stands,
wherein
R ⁷ and R ^{8 are} identical or different and are halogen, in particular chlorine,
and their tautomers and their respective salts. 2. Compounds 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 or bromine,
R ^{1 represents} hydrogen or (C ₁ -C ₄ ) alkyl,
R ^{2 represents} hydrogen or (C ₁ -C ₄ ) alkyl, in particular hydrogen,
R ^{3 represents} (C ₁ -C ₆ ) alkyl or
represents naphthyl, phenyl, pyridyl, thienyl, imidazolyl, pyrazolyl, pyrryl, oxazolyl or isoxazolyl, the ring systems listed here optionally being up to 4-fold, identical or different, by substituents selected from the group consisting of: fluorine, Chlorine, bromine, trifluoromethyl, nitro, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, acetyl, pyridyl, thienyl, oxazolyl, isoazolyl and groups of Formulas -OR ⁴ and - (CH ₂ ) _a -NR ⁵ -CO-R ⁶ can be substituted,
wherein
R ^{4 is} phenyl which is optionally substituted up to 2 times, identically or differently, by fluorine, chlorine, bromine, nitro, trifluoromethyl or (C ₁ -C ₄ ) -alkyl,
a represents a number 0 or 1,
R ⁵ denotes hydrogen or (C ₁ -C ₃ ) alkyl,
R ^{6 represents} (C ₁ -C ₄ ) alkyl or
Phenyl which is optionally substituted up to 3 times, identically or differently, by fluorine, chlorine, bromine or (C ₁ -C ₃ ) -alkyl,
or
R ³ for residues of the formulas
stands,
wherein
R ⁷ and R ^{8 are} chlorine,
and their tautomers and their respective salts. 3. Compounds of the general formula (I) according to claim 1 or 2,
in which
A, D, E and G stand for hydrogen,
R ^{1 represents} hydrogen or methyl,
R ^{2 represents} hydrogen,
R ^{3 represents} (C ₁ -C ₄ ) alkyl or
represents naphthyl, phenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl or isoxazolyl, the ring systems listed here optionally being up to 4-fold, identical or different, by substituents selected from the group consisting of: fluorine, chlorine, Trifluoromethyl, nitro, methyl, ethyl, methoxy, acetyl, pyridyl, thienyl, oxazolyl, isoxazolyl and groups of the formulas -OR ⁴ and - (CH ₂ ) _a -NR ⁵ -CO-R ⁶ can be substituted,
wherein
R ^{4 is} phenyl which is optionally substituted up to twice, identically or differently, by chlorine, bromine, nitro or methyl,
a represents a number 0 or 1,
R ^{5 represents} hydrogen or methyl,
R ^{6 is} methyl or
Phenyl which is optionally substituted up to 3 times, identically or differently, by fluorine, chlorine, bromine or methyl,
or
R ³ for residues of the formulas
stands in what
R ⁷ and R ^{8 are} chlorine,
and their tautomers and their respective salts. 4. A process for the preparation of compounds according to claims 1 to 3, characterized in that
[A] compounds of the general formula (II)
in which
A, D, E, G and R ^{1 have} the meaning given above,
with compounds of the general formula (III)
R ³ -SO ₂ -L (III),
in which
R ^{3 has} the meaning given above
and
L represents halogen, preferably chlorine,
in inert solvents, optionally in the presence of a base,
or
[B] in the event that R ^{1 is} not hydrogen, first compounds of the general formula (IV)
in which
A, D, E and G have the meaning given above,
with an alkylating agent of the general formula (V)
R ¹ -X (V),
in which
R ^{1 has} the meaning given above
and
X represents halogen, preferably iodine,
in inert solvents and in the presence of a base in the compounds of the general formula (VI)
in which
A, D, E, G and R ^{1 have} the meaning given above,
transferred, then reduced to the compounds of the general formula (II) using customary methods known to those skilled in the art and finally reacted with compounds of the general formula (III) as described under [A]. 5. Medicament or pharmaceutical composition containing at least one compound of the general formula (I) and pharmacologically acceptable auxiliaries and carriers. 6. Medicament or pharmaceutical composition according to Claim 5 for the prophylaxis and / or treatment of anemia. 7. Medicament according to claim 5 or 6 for prophylaxis and / or Treatment of premature anemia, chronic anemia Renal failure, anemia after chemotherapy and anemia in HIV patients. 8. Medicament or pharmaceutical composition according to Claim 5 for stimulating erythropoiesis in autologous blood donors. 9. Use of the compounds according to one of claims 1 to 3 for the manufacture of pharmaceuticals or pharmaceuticals Prophylaxis and / or treatment compositions for Diseases. 10. Use according to claim 9 for prophylaxis and / or treatment of anemia. 11. Use according to claim 9 or 10 for the production of Medicines or pharmaceutical compositions for Prophylaxis and / or treatment of premature anemia,  Anemia with chronic renal failure, anemia after Chemotherapy and anemia in HIV patients. 12. Use according to claim 9 or 10 for the production of Medicines or pharmaceutical compositions for Stimulation of the erythropoiesis of autologous blood donors. 13. Use according to one of claims 9 to 12, characterized characterized in that the drugs or compositions be administered orally.