Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to the field of erythropoiesis.
• the present invention relates to new 6-carboxyphenyldihydropyridazinone derivatives, processes for their preparation and their use as medicaments, preferably for
• Anemia also known as anemia, is characterized by a decrease in the number of erythrocytes, hemoglobin concentration and / or hematocrit below the age-appropriate and gender-specific reference values.
• the anemia is characterized by the reduced oxygen transport capacity of the blood, inter alia by the disturbance of oxygen-dependent metabolic and organ functions; with acute development (e.g. due to blood loss), symptoms of shock may appear, and with chronic development there is often a slowly progressive course with decreased performance, fatigue, dyspnoea and tachycardia.
• anemia can be classified or classified according to the morphology and hemoglobin content of the erythrocytes or according to the etiology (eg post-hemorrhagic anemia, gestational anemia, tumor anemia, infectious anemia or deficiency anemia). Furthermore, it is possible to classify the various forms of anemia according to their pathogenesis, taking into account the possible causes, for example in anemia caused by excessive blood loss (e.g.
• erythropoiesis eg iron deficiency anemia, nephrogenic anemia or myelopathic anemia
• hemolytic anemia e.g iron deficiency anemia, nephrogenic anemia or myelopathic anemia
• iron preparations are generally used, which are administered either orally or parenterally.
• oral administration gastrointestinal disorders are observed as a side effect.
• Simultaneous administration of antacids to treat gastrointestinal disorders affects iron absorption.
• the absorption of iron from the intestinal tract is anyway only very limited due to the ability of the mucosa to make it difficult for iron to pass through.
• the dose administered orally must not be chosen too high, since otherwise signs of intoxication can occur, in the worst case even hemorrhagic gastroenteritis with shock symptoms and death.
• RhEPO recombinant human EPO stimulates erythropoiesis humorally, so that it has found use as an antianemic agent in the therapy of severe anemias, in particular in the case of renal or nephrogenic anemias.
• Rh EPO is also used to increase the body's own blood cells in order to reduce the need for foreign blood transfusions.
• EPO Erythropoietin
• rh EPO is not available orally and must therefore be administered intraperitoneally (ip), intravenously (iv) or subcutaneously (sc), which limits its use to the therapy of severe anemia (Kai-Uwe Eckardt, “Erythropoietin: career one Hormons ", Academics ⁇ Arlingtonblatt 95, Issue 6 of February 6, 1998 (41), pages A-285 to A-290; Red List 1998, Editio Cantor Verlag fürtechnik, see” Epoetin alfa "and” Epoetin beta " ).
• the object of the present invention is now to provide new substances which are particularly suitable for the more efficient treatment of anemias and thereby avoid the disadvantages of the therapeutic methods for anemia known from the prior art.
• the present invention thus relates to 6-carboxyphenyldihydropyridazinone derivatives of the general formula (I)
• 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 and R 2 are identical or different and represent hydrogen or (C, -C 6 ) -alkyl
• R 3 represents radicals of the formulas -OR 4 or -NR 5 R 6 ,
• R 4 denotes cycloalkyl having 3 to 8 carbon atoms or denotes (C, -C 3 ) -alkyl, which may be replaced by hydroxy, (C, -C 6 ) -
• Alkoxy, cycloalkyl with 3 to 8 carbon atoms or aryl with 6 to 10 carbon atoms is substituted, which in turn is monosubstituted or disubstituted, identical or different, by substituents selected from the group: halogen, (C, -C 6 ) alkoxy, hydroxy or trifluoromethyl, may be substituted, or Is (C, -C 8 ) alkyl, which is optionally substituted by a group of the formula -NR 7 R 8 ,
• R 7 and R 8 are identical or different and are hydrogen, (C, -C 6 ) -alkyl or benzyl,
• R 4 means vinyl or allyl
• R 4 is aryl having 6 to 10 carbon atoms, optionally one to two times, identical or different, by substituents selected from the group consisting of: halogen, (C, -C 6 ) alkyl, (C r C 6 ) Alkoxy or hydroxy, is substituted,
• R 5 denotes hydrogen or (C, -C 4 ) -alkyl
• R 6 denotes cycloalkyl having 3 to 8 carbon atoms or a radical of the formula
• Aryl with 6 to 10 carbon atoms or a 5- to 7-membered aromatic heterocycle with up to 3 heteroatoms from the series S, N and / or O means, the ring systems listed here, if appropriate, one or more times, identically or differently, by substituents , selected from the group: halogen, trifluoromethyl, Hydroxy, (C, -C 6 ) - alkoxy, carboxyl, (C, -C 6 ) - alkoxy carbonyl, (C r C 6 ) alkyl and residues of the formulas -SO 2 -NR 9 R 10 and - (CO) a -NR "R 12 can be substituted,
• R 9 , R 10 , R “and R 12 are identical or different and are hydrogen or (C, -C 6 ) alkyl
• a represents a number 0 or 1
• R 6 denotes (C, -C 8 ) -alkyl, which may be mono- or discrete, identical or different, by substituents selected from the group: halogen, trifluoromethyl, hydroxy, (C, -C 6 ) -alkoxy, carboxyl, (C r C 6 ) -alkoxycarbonyl, aryl with 6 to 10 carbon atoms and 5- to 7-membered aromatic heterocycles with up to 3 heteroatoms from the series S, N and / or O, in which the ring systems are optionally substituted - to triple, identical or different, by (C, -C 6 ) alkyl, halogen, (C, -C 6 ) alkoxy, (C, -C 6 ) alkoxycarbonyl, trifluoromethyl or by the radical -CO-NH 2 can be substituted
• the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
• the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
• 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. Particularly preferred are, for example, 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 also 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.
• alkali metal salts for example sodium or potassium salts
• alkaline earth metal salts for example calcium or magnesium salts
• ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine , N-methylmorpholine, dihydroabietylamine, 1-ephenamine or
• (CC 8 ) -cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. The following may preferably be mentioned: cyclopropyl, cyclopentyl and cyclohexyl.
• (C 6 -C, 0 ) aryl represents an aromatic radical having 6 to 10 carbon atoms.
• Preferred aryl radicals are phenyl and naphthyl.
• -C fi ) alkyl represents a straight-chain or branched alkyl radical having 1 to 6 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, -C ⁇ ) - Alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy,
• a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred.
• a straight-chain or branched alkoxy radical with 1 to 3 is particularly preferred
• Carbon atoms. (C i -C 6 ) - Alkoxy carbonyl stands for a straight-chain or branched alkoxy carbonyl radical with 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.
• a 5- to 6-membered aromatic heterocycle with up to 3 heteroatoms from the series S, O and / or N represents, for example, pyridyl, pyrimidyl, pyridazinyl,
• A, D, E and G are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,
• R 1 and R 2 are the same or different and represent hydrogen or methyl
• R 3 represents radicals of the formulas -OR 4 or -NR 5 R 6 ,
• R 4 represents cyclopropyl, cyclopentyl or cyclohexyl or
• (C, -C 6 ) alkyl means, which is optionally substituted by hydroxy, (C, -C 4 ) alkoxy, cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which in turn is one or two times, identical or different. may be substituted by substituents selected from the group: fluorine, chlorine, bromine, (C, -C 4 ) - alkoxy, hydroxy or trifluoromethyl, or
• R 7 and R 8 are the same or different and are hydrogen or (C, -C 4 ) alkyl
• R 4 means allyl
• R 5 denotes hydrogen or (C, -C 3 ) alkyl
• R 6 denotes cyclopropyl, cyclopentyl or cyclohexyl or
• Phenyl, thienyl, thiazolyl, furyl or pyridyl means, the aromatic ring systems listed optionally being one to two times, identical or different, by substituents selected from the group: fluorine, chlorine, bromine, trifluoromethyl, hydroxy, (C, -C 3 ) - Alkoxy, (C, -C 3 ) - alkoxy carbonyl, (C, -C 4 ) alkyl and radicals of the formulas -SO 2 NR 9 R 10 and - (CO) a -NR "R , 2 , substituted can,
• R 9 , R 10 , R "and R ' 2 are identical or different and are hydrogen or (C, -C 4 ) alkyl
• R (C, -C 6 ) alkyl means that optionally one or two times, identical or different, by substituents selected from the group:
• A, D, E and G stand for hydrogen
• R 1 and R 2 are the same or different and represent hydrogen or methyl
• R 3 represents radicals of the formulas -OR 4 or -NR 5 R 6 ,
• R 4 represents cyclopropyl, cyclopentyl or cyclohexyl or
• Means (C, -C 5 ) alkyl which is optionally substituted by (C, -C 4 ) alkoxy, cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which in turn is selected one or two times, identically or differently, by substituents the group: fluorine, chlorine, (C, -C 4 ) - alkoxy, hydroxy or trifluoromethyl, may be substituted, or (C, -C 4 ) alkyl, which is optionally substituted by a group of the formula -NR 7 R 8 is
• R 7 and R 8 are identical or different and are hydrogen, benzyl or methyl
• R 4 means allyl
• R 5 is hydrogen or (C.-CO-alkyl
• R 6 denotes cyclopropyl, cyclopentyl or cyclohexyl or
• Phenyl, naphthyl, thienyl, thiazolyl, furyl or pyridyl means, the ring systems listed optionally being one to two, identical or different, by substituents selected from the group: fluorine, chlorine, bromine, trifluoromethyl, (C, -C 3 ) Alkoxy, (C, -C 3 ) - alkoxycarbonyl, (C, -C 3 ) alkyl and radicals of the formulas -SO 2 -NR 9 R 10 and - (CO) a -NR "R 12 , are substituted,
• R 9 , R 10 , R 11 and R 12 are identical or different and are hydrogen or (C, -C 4 ) alkyl
• a number means 0 or 1
• R 6 is (C, -C 6 ) - alkyl, which is optionally substituted by substituents selected from the group: fluorine, chlorine, trifluoromethyl, (C, -C 3 ) -
• Thienyl or thiazolyl is substituted, the ring systems optionally being one to two times, identical or different, by
• A, D, E and G stand for hydrogen
• the present invention also relates to processes for the preparation of the compounds of the general formula (I) according to the invention, wherein
• A, D, R 1 and R 2 have the meaning given above
• L represents an activating radical, preferably chlorine or imidazolyl
• R 4 has the meaning given above
• L represents an activating radical, preferably chlorine or imidazolyl
• R 5 and R 6 have the meaning given above
• Suitable carboxylic acid-activating reagents for the purposes of the present invention are, in particular, carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethyl laminopropy 1) -N'-ethyl carbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds Ethyl 5-phenyl-l, 2-oxazolium-3-sulfonate or
• carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethyl laminopropy 1) -N'-ethyl carbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds Ethyl 5-phenyl-l, 2-oxazolium-3
• bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or di-cyclo-midoxinidodisuboxysin.
• Thionyl chloride is also suitable.
• Preferred carboxylic acid activating reagents are carbonyldiimidazole (CDI) and thionyl chloride.
• Organic solvents which are inert under the reaction conditions are suitable as solvents. 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, ethers such as diethyl ether, dioxane, THF and dimethylformamide, acetonitrile, acetone or hexamethylphosphoric triamide. Dichloromethane, DMF and dioxane are particularly preferred. It is also possible to use solvent mixtures.
• halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichlor
• bases are suitable as bases. These preferably include 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 ethoxide 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 and organic bases such as triethylamine, pyridine, dimethylaminopyridine, l-8-diazobicyclo [5.4.0] undec-7-ene (DBU), 1,5-diaza-bicyclo [4.3.0] non-5-ene (DBU) or N-methylmorpholine. Pyridine and triethylamine are preferred.
• the base can be used in an amount of 1 to 5 mol, preferably 1 to 2 mol, based on 1 mol of the compounds of the general formula (II).
• the reaction generally takes place in a temperature range from -78 ° C to
• Reflux temperature preferably in the range of -78 ° C to + 20 ° C.
• the reaction can be carried out at normal, elevated or reduced pressure (e.g. in the range from 0.5 to 5 bar). Generally one works at normal pressure.
• the compounds of the general formula (IV) are partly new and can be prepared, for example, as described above.
• the compounds of the general formula (I) according to the invention have an unforeseeable, valuable spectrum of pharmacological activity and are therefore particularly suitable for the prophylaxis and / or treatment of diseases.
• anemia such as premature anemia, nephrogenic or renal anemia such as anemia in chronic kidney disease.
• efficiency in the case of anemia after chemotherapy and in the anemia of HIV patients, ie in particular for the treatment of severe anemia.
• the application is preferably oral, transdermal or perenteral. Oral application is very particularly preferred, in which there is a further advantage over the therapy of anemias with rhEPO known from the prior art.
• the compounds according to the invention act in particular as erythropoietin sensitizers.
• “Erythropoietin sensitizers” are compounds which are capable of influencing the action of the EPO present in the body so efficiently that erythropoiesis is increased, in particular the oxygen supply is improved. Surprisingly, they are also orally active, which makes therapeutic use with the exclusion or reduction of the known side effects significantly improved and simplified at the same time.
• the present invention thus also relates to the use of EPO sensitizers for stimulating erythropoiesis, in particular for the prophylaxis and / or treatment of anemias, preferably severe anemias such as premature anemia, anemia in the case of chronic renal failure, anemia after
• the compounds according to the invention thus enable efficient stimulation of erythropoiesis and consequently prophylaxis or therapy of anemias that intervenes before the stage in which conventional treatments with EPO begin. This is because the compounds according to the invention allow an effective influencing of the body's own EPO, whereby the direct administration of EPO with the associated disadvantages can be avoided.
• the present invention further relates to pharmaceuticals and pharmaceutical compositions which contain at least one compound of the general formula (I) according to the invention 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
• anemia such as Premature anemia, anemia with chronic renal failure, anemia after chemotherapy or anemia in HIV patients.
• the CD34 positive cells from this cell fraction were isolated using a commercial purification method (Miyltenyi CD34 Multisort Kit).
• 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 ⁇ M 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 0-1 O ⁇ M test substance were added. 500 ⁇ l / / 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 600xg and resuspended in 200 ⁇ l 0.9% w / v NaCl. To determine the
• Number of erythroid cells were pipetted 50 ⁇ l of the cell suspension into 10 ⁇ l benzidine staining solution (20 ⁇ g benzidine in 500 ⁇ l DMSO, 30 ⁇ l H 2 O 2 and 60 ⁇ l concentrated acetic acid). The number of blue cells was counted microscopically.
• test substances according to the present invention When the test substances according to the present invention are added, a significant increase in the cell proliferation of erythroid precursor cells is observed in each case.
• mice Normal mice are treated with test substances over several days. The application takes place intraperitoneally, subcutaneously or by os. Preferred solvents are Solutol / DMSO / sucrose / NaCl solution or glycofurol. From day 0 (before the first application) up to approx. 3 days after the last application, approx. 70 ⁇ l of blood are made several times by puncturing the retroorbital
• Venous plexus taken with a hematocrit capillary The samples are centrifuged and the hematocrit 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 test substances administered according to the present invention lead to a significant increase in the hematocrit.
• the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
• the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, 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, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
• the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously.

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