Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
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  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
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  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
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  • 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
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D267/02—Seven-membered rings
  • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
  • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
  • C07D267/20—[b, f]-condensed

Definitions

• the present invention relates to compounds, processes for their preparation, pharmaceutical compositions comprising them and their use in the treatment and / or prophylaxis of diseases in humans or animals, in particular cardiovascular diseases, e.g. B. of atherosclerosis.
• cardiovascular diseases e.g. B. of atherosclerosis.
• Dibenzoxazepines are described in WO 00/48603 as ⁇ vß 3 , ⁇ vßs and / or ⁇ ß 6 integrin receptor antagonists, inter alia for the treatment of atherosclerosis.
• WO 99/11626 describes dibenzoxazepines as fibrinogen and / or vitronectin receptor antagonists, inter alia for the treatment of atherosclerosis.
• EP-A 419 861 describes the use of dibenzoxazepines for the treatment and / or prophylaxis of AID S.
• the inflammatory component in the pathophysiology of atherosclerosis is widely recognized today. These inflammatory vascular changes are characterized, among other things, by the immigration of monocytes and the increased release of pro-inflammatory cytokines. In particular, the formation of foam cells from the immigrated monocytes and the changed metabolism of these foam cells play a central role with regard to plaque development and stability. It could be shown that macrophages change their gene expression under lipid loading. The increased expression of aminopeptidase N is particularly prominent. Aminopeptidase-N is a transmembrane ectoenzyme (EC 3.4.11.12) that is identical to the CD13 antigen.
• Aminopeptidase-N catalyzes the N-terminal cleavage of amino acids, with neutral amino acid residues being preferred. In synaptic membranes, aminopeptidase N inactivates neuropeptide hormones such as endorphins and enkephalins. Other substrates include kinins, chemotactic peptides (MCP-1) and components of the extracellular matrix. Many publications indicate that aminopeptidase-N is involved in the vascularization and spread of tumors. Membrane proteases can have their biological effect not only through the cleavage of proteins, but also via
• aminopeptidase N Similar to foam cell formation, and the involvement of aminopeptidase N in inflammatory processes of lymphocytes and monocytes indicate that the inhibition of aminopeptidase N leads to protective effects on the vessel wall, as well as positively influences plaque development and plaque stability.
• the present invention therefore relates to compounds of the formula
• Y is a Ci-Cö-alkylene chain which optionally contains one or more double or triple bonds, in which one or several oxo carbon atoms are substituted and in which one or more carbon atoms are optionally replaced independently of one another by a nitrogen, oxygen or sulfur atom, where there must be at least 1 carbon atom between the heteroatom in Y and R 3 and where there are between two heteroatoms in Y must have at least 1 carbon atom,
• R 1 is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl,
• alkoxycarbonyl and alkylaminocarbonyl can be substituted with 0, 1 or 2 substituents, the substituents being selected independently of one another from the group consisting of alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl and trimethylsilyl,
• n a number 0, 1, 2 or 3
• radicals R 1 may be the same or different
• R 2 represents alkyl
• alkyl can be substituted with 0, 1 or 2 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxy, oxo, alkoxy, carboxyl, alkoxycarbonyl,
• aryl, heteroaryl, cycloalkyl and heterocyclyl can be substituted with 0, 1, 2 or 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, trifluoro methyl, trifluoromethoxy, cyano, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl,
• R 3 denotes hydroxy or amino
• R 4 denotes halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl,
• n a number 0, 1 or 2
• radicals R 4 can be the same or different
• Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, and also the compounds encompassed by formula (I), hereinafter referred to as exemplary embodiment (s), and their salts, solvates and solvates of the salts, insofar as it is possible the compounds mentioned below by formula (I) are not already salts, solvates and solvates of the salts.
• the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
• the invention therefore relates to the enantiomers or diastereomers and their respective mixtures.
• the stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and or diastereomers.
• the invention also relates to
• preferred salts are physiologically acceptable salts of the compounds according to the invention.
• Physiologically acceptable salts of compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of 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, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• salts of 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, malic acid, citric acid
• Physiologically acceptable salts of the compounds (I) also include salts of conventional bases, for example and preferably alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 Carbon atoms, such as, for example and preferably, ylarnin, dimethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine; Dibenzylamine, N-methylmo holin, dihydroabietyl-a in, arginine, lysine, ethylenediamine and methylpiperidine.
• alkali metal salts for example sodium and potassium salts
• alkaline earth metal salts for example calcium and magnesium salts
• solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.
• Alkyl per se and "alk” and “alkyl” in alkoxy, alkylamino, alkylarynocarbonyl and alkoxycarbonyl represent a linear or branched alkyl radical having 1 to 8 carbon atoms, usually 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 Carbon atoms, for example and preferably for methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
• Alkylene stands for a straight-chain or branched alkylene radical, which optionally contains one or more double or triple bonds, in which one or more carbon atoms are optionally substituted oxo and in which one or more carbon atoms optionally independently of one another by a nitrogen, oxygen or Sulfur atom are replaced.
• Examples include methylene, ethylene, propylene, propane-1,2-diyl, propane-2,2-diyl, butane-1,3-diyl, butane-2,4-diyl and pentane-2,4-diyl , 2-methylpentane-2,4-diyl,
• Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
• Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents, for example and preferably for methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, NN-dime ylamino, NN -Diethylamino, N-ethyl-N-me ylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, Nt-butyl-N-memylamino, N-emyl-Nn-pentylamino and Nn-hexyl-N- memylamino.
• Alkylaminocarbonyl represents an alkylaminocarbonyl radical with one or two
• alkyl substituents by way of example and preferably for methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylarninocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, NN-dimethylaminocarbonyl, NN-diethylaminocarbonyl, - methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propyl- aminocarbonyl, Nt-butyl-N-memylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-me ylaminocarbonyl.
• Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
• Cycloalkyl stands for a cycloalkyl group with generally 3 to 8, preferably 5 to 7 carbon atoms, examples and preferably for cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• Aryl stands for a mono- to tricyclic aromatic radical with usually 6 to 14 carbon atoms; exemplary and preferably for aryl are phenyl, ⁇ aphthyl and phenanthrenyl.
• Heteroaryl stands for an aromatic, mono- or bicyclic radical with generally 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and ⁇ , by way of example and preferably for thienyl, furyl , Pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, irnidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, rndolyl, indazolyl, benzofuranyl, benzothiophenyl,
• Heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, heterocyclic radical with generally 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series ⁇ , O, S, SO, SO 2 .
• the heterocyclyl residues can be saturated or partially unsaturated.
• Heterocyclylcarbonyl stands for a heterocyclyl radical which is bonded via a cabonyl group, such as, for example and preferably, tetrahydrofuran-2-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl, pyrrolinylcarbonyl, piperidinylcarbonyl, mopholinylcarbonylyl, perhydrorophenylcarbonyl.
• a cabonyl group such as, for example and preferably, tetrahydrofuran-2-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrrolidin-3-ylcarbonyl, pyrrolinylcarbonyl, piperidinylcarbonyl, mopholinylcarbonylyl, perhydrorophenylcarbonyl.
• Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
• radicals in the compounds according to the invention are substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.
• the invention relates to compounds of the formula (I)
• Y represents a C 1 -C 6 alkylene chain which optionally contains one or more double or triple bonds in which one or more carbon atoms are optionally substituted oxo and in which one or more carbon atoms are optionally replaced independently of one another by a nitrogen, oxygen or sulfur atom where at least 1 carbon atom must be between the heteroatom in Y and R 3 and where there must be at least 1 carbon atom between two heteroatoms in Y,
• R 1 denotes halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl, n represents a number 0, 1, 2 or 3,
• radicals R 1 may be the same or different
• R 2 represents alkyl
• alkyl can be substituted with 0, 1 or 2 substituents, the substituents being selected independently of one another from the group consisting of halogen, hydroxy, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aryl, heteroaryl, cycloalkyl and
• aryl, heteroaryl, cycloalkyl and heterocyclyl can be substituted with 0, 1, 2 or 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkylamino , Hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl and alkylaminocarbonyl,
• R 3 denotes hydroxy or amino
• R 4 is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl,
• n a number 0, 1 or 2
• the radicals R 4 may be the same or different.
• the invention relates to compounds of the formula (I),
• R 1 halogen, trifluoromethyl, cyano, amino, hydroxy, alkoxy, carboxyl,
• alkoxycarbonyl can be substituted with 0 or 1 substituents, the substituent being selected from the group consisting of alkoxy, aryl, cycloalkyl and trimethylsilyl,
• n a number 1 or 2
• radicals R 1 may be the same or different
• alkyl can be substituted with 0 or 1 substituents, the substituent being selected from the group consisting of hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aryl and heteroaryl,
• aryl and heteroaryl can be substituted with 0, 1, 2 or 3 substituents, the substituents being selected independently of one another from the group consisting of halogen, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl and
• alkylaminocarbonyl R »3 means hydroxy
• n a number 0.
• the invention relates to compounds of the formula
• R 1 denotes halogen, amino, hydroxy, alkoxy, carboxyl, alkoxycarbonyl, aminocarbonyl or alkylaminocarbonyl,
• n a number 0, 1 or 2
• radicals R 1 may be the same or different
• R 2 represents alkyl
• alkyl can be substituted with 0 or 1 substituents, the substituent being selected from the group consisting of hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aryl and heteroaryl,
• aryl and heteroaryl can be substituted with 0, 1, 2 or 3
• Substituents are selected from the group consisting of halogen, amino, alkylamino, hydroxy, alkyl, alkoxy, carboxyl, alkoxycarbonyl, arninocarbonyl and alkylaminocarbonyl,
• R 3 means hydroxy
• n a number 0.
• the invention relates to compounds of the formula (I)
• R 1 is fluorine, chlorine, bromine, trifluoromethyl, cyano, carboxyl, methoxycarbonyl or ethoxycarbonyl,
• methoxycarbonyl and ethoxycarbonyl can be substituted with 0 or 1 substituents, the substituent being selected from the group consisting of methoxy, phenyl, cyclopentyl and trimethylsilyl,
• n a number 1
• R 2 represents alkyl, where alkyl is substituted by 1 substituent, the substituent being selected from the group consisting of hydroxy, tert-butyloxy, tert-butyloxycarbonyl and 2,2-dimethylprop-l-yloxycarbonyl,
• R 3 means hydroxy
• n a number 0.
• R 1 is alkoxycarbonyl and R 2 to R 4 , Y, m and n are as defined above.
• R 1 is trifluoromethyl, cyano, carboxyl or methoxycarbonyl
• R 2 to R 4 , Y, m and n are as defined above.
• R 1 represents trifluoromethyl or cyano
• R 2 to R 4 , Y, m and n are as defined above.
• n denotes a number 1 and R 1 to R 4 , Y and m are as defined above.
• R 2 means alkyl, where alkyl can be substituted with 1 substituent, the substituent being selected from the group consisting of carboxyl and alkoxycarbonyl, and R 1 , R 3 , R 4 , Y, m and n are as defined above.
• R 2 is tert-butyloxycarbonylmethyl, and R 1 , R 3 , R 4 , Y, m and n are as defined above.
• R 2 has the meaning given above
• X 1 is halogen, preferably chlorine or bromine
• X 2 is halogen, preferably chlorine or bromine
• A is the C 1 -C 8 alkylene chain of Y shortened by one heavy atom, which optionally contains one or more double or triple bonds in which one or more carbon atoms are optionally substituted oxo and in which one or more carbon atoms optionally independently of one another by a nitrogen , Oxygen or sulfur atom are replaced, where at least 1 carbon atom must be between the heteroatom in A and R and where there must be at least 1 carbon atom between two heteroatoms in A,
• R 1 to R 4 , A, m and n have the meaning given above,
• the compounds of the formula (Ia) are compounds of the formula (I) in which Y is -OA-.
• the reaction according to process [A] and process [B] is generally carried out in inert solvents in the presence of a base, optionally in the presence of potassium iodide, preferably in a temperature range from room temperature to 50 ° C. at atmospheric pressure.
• Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, optionally in aqueous solution, preferably potassium carbonate.
• Inert solvents are, for example, ethers such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or dimethylformamide, or mixtures of solvents dimethylformamide or dioxane is preferred.
• ethers such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
• alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or dimethylformamide, or mixtures of solvents dimethylformamide or dioxane is preferred.
• the radicals R 1 , R 2 and R 3 of the compounds of the formula (I) can, if appropriate, contain protective groups which are eliminated by a deprotection reaction after the reaction. This is done according to standard methods of protecting group chemistry.
• R 1 , R 3 , R 4 , Y, m and n have the meaning given above, and R 5 is alkyl, preferably methyl or ethyl, are reacted with acidic organic catalysts.
• the reaction is generally carried out in inert solvents, preferably in a temperature range from 50 ° C. to the reflux of the solvents at normal pressure.
• Acidic organic catalysts are, for example, para-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid or champhorsulfonic acid; p-toluenesulfonic acid is preferred.
• Inert solvents are, for example, ethers such as dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene or petroleum fractions; xylene or toluene is preferred.
• ethers such as dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether
• hydrocarbons such as benzene, xylene, toluene or petroleum fractions
• xylene or toluene is preferred.
• the compounds of formula (VI) are known or can be prepared by compounds of the formula
• R 1 , R 3 , R 4 , R 5 , Y, m and n have the meaning given above, are reacted with a reducing agent.
• the reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure up to 3 bar.
• Reducing agents are, for example, palladium on carbon in a hydrogen atmosphere, palladium on carbon in the presence of ammonium formate, iron in concentrated acetic acid, iron / iron (HI) chloride, tin (II) chloride or tin in hydrochloric acid, tin (II) chloride is preferred ,
• Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethyl glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixtures of alcohols with water, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or pyridine.
• ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofur
• ethanol In the case of palladium on carbon, ethanol, methanol, isopropanol, tetrahydrofuran or a mixture of ethyl acetate and ethanol are preferred in the case of iron / iron (i ⁇ ) chloride a mixture of water and ethanol and in the case of tin (II) chloride dimethylformamide, dioxane or methanol.
• the compounds of the formula (VII) are known or can be synthesized from the corresponding starting materials by known processes.
• X is halogen, preferably chlorine or bromine, are reacted with one equivalent of the compounds of the formula (IX).
• the reaction is carried out according to the reaction conditions described for processes [A] and [B].
• the compounds of the formula (IX) are known or can be synthesized from the corresponding starting materials by known processes.
• the compounds of the formula (VE!) are known or can be prepared by using compounds of the formula
• the reaction is carried out according to the reaction conditions described for compounds of the formula (U).
• R 1 , R 4 , m and n have the meaning given above, are reacted with a reducing agent.
• R 1 , R 2 , R 4 , m and n have the meaning given above, are reacted with reducing agents, the reaction with palladium on carbon in a hydrogen atmosphere in ethanol, methanol, isopropanol or tetrahydrofuran in a temperature range from room temperature is preferred until the solvents reflux at normal pressure up to 3 bar.
• R 1 , R 4 , m and n have the meaning given above, and
• R 6 is alkyl, preferably methyl or ethyl, according to the reaction conditions described for compounds of the formula (LT).
• the present invention further relates to compounds of the formula (I) for combating diseases, in particular cardiovascular diseases, for example atherosclerosis, and also medicaments containing compounds of the formula (I) and auxiliaries and also the use of compounds of the formula (I) for the preparation - Provision of a drug for the treatment of cardiovascular diseases, especially atherosclerosis.
• cardiovascular diseases such as atherosclerosis, reperfusion tissue damage after
• Stroke heart attack or peripheral vascular occlusions
• inflammatory diseases and autoimmune diseases such as arthritis, rheumatoid arthritis, osteoporosis, Crohn's disease, chronic inflammatory lung diseases such as Adult Respiratory Distress Syndrome (ARDS), transplant rejection, chronic inflammatory fibrotic organ changes such as Liver fibrosis, or the generalized autoimmune disease systemic lupus erythematosus or other forms of lupus erythematosus or dermal inflammatory diseases such as psoriasis) or cancer (such as lung cancer and prostate cancer) or chronic pain.
• ARDS Adult Respiratory Distress Syndrome
• the active substance can act systemically and / or locally.
• it can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sub-lingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as an implant.
• the active ingredient can be administered in suitable administration forms for these administration routes.
• Tablets or film-coated tablets capsules, dragees, granules, pellets, powders, emulsions, suspensions and solutions.
• Parenteral administration can be done by bypassing a resorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
• Application forms suitable for parenteral administration include injection and fusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.
• Oral application is preferred.
• Inhaled drug forms including powder inhalers, nebulizers
• nasal drops / solutions, sprays e.g., nasal drops / solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.
• the active compounds can be converted into the application forms mentioned in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable excipients.
• Carriers e.g. microcrystalline cellulose
• solvents e.g. liquid polyethylene glycols
• emulsifiers e.g. sodium dodecyl sulfate
• dispersants e.g. polyvinylpyrrolidone
• synthetic and natural biopolymers e.g. albumin
• stabilizers e.g. antioxidants such as ascorbic acid
• dyes e.g. inorganic pigments
• iron oxides e.g. inorganic pigments
• Method 3 Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Column: Grom-SIL120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 11 water + 1 ml 50% formic acid, eluent B: 11 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0min 100% A -> 0.2min 100% A -> 2.9min 30% A -> 3.1min 10% A -> 4.5min 10% A; Oven: 55 ° C; Flow: 0.8ml / min; UV detection: 208-
• Method 4 Instrument: Micromass Quattro LCZ, with HPLC Agilent Series 1100; Column: Grom-SLL120 ODS-4 HE, 50 mm x 2.0 mm, 3 ⁇ m; Eluent A: 11 water + 1 ml 50% formic acid, eluent B: 11 acetonitrile + 1 ml 50% formic acid; Gradient: 0.0min 100% A - »0.2min 100% A -» 2.9min 30% A -> 3.1min 10% A - »4.5min 10% A; Oven: 55 ° C; Flow: 0.8ml / min; UV detection: 208-
• Method 5 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Grom-Sil 120 ODS-4 HE 50x2 mm, 3.0 ⁇ m; Eluent A: water + 500 ⁇ l 50% formic acid / 1; Eluent B: acetonitrile + 500 ⁇ l 50%
• Method 8 Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60mm x 2mm, 3.5 ⁇ m; Eluent A: 5 ml HC1O 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Temp .: 30 ° C; UN detection: 210 nm.
• Method 9 Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60mm x 2mm, 3.5 ⁇ m; Eluent A: 5 ml HClO 4 / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9 min 90% B; Flow: 0.75 ml / min; Temp .: 30 ° C, UV detection: 210 nm.
• Method 10 Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Merck Chromolith SpeedROD RP-18e 50x4.6mm; Eluent A: water + 500 ⁇ l 50% formic acid / 1; Eluent B: acetonitrile + 500 ⁇ l 50% formic acid / 1; Gradient: 0.0min 10% B- 3.0min 95% B-> 4.0min 95% B; Oven: 35 ° C; Flow: 0.0min 1.0ml min- 3.0min 3.0ml / min-> 4.0min 3.0ml / min; UV-
• Hybrid is poured onto 20 ml of water and 20 ml of ethyl acetate.
• the organic phase is extracted with 20 ml of water and saturated sodium chloride solution.
• the organic phases are dried over magnesium sulfate. After removal of the solvent at reduced pressure, a residue is obtained which is purified on a silica gel column (dichloromethane) to give 213 mg (51% of theory) of product.
• Example 4A The preparation is carried out analogously to Example 4A from 400 mg (1.4 mmol) of the compound from Example 3A and 293 mg (1.4 mmol) of tert-butyl bromopropionate.
• the purification is carried out on a silica gel column (ethyl acetate-cyclohexane 5: 1) to give 37 mg (7% of theory) of product.
• Example 7A The preparation is carried out analogously to Example 7A from 2 g (5.0 mmol) of the compound from Example 4A and 1.15 g (5.0 mmol) of benzyl bromoacetate.
• chromatographed on a silica gel column (dichloromethane: methanol 1: 0 to 3: 1) and gives 2.47 g (90% of theory) of the product.
• a solution of 50 mg (0.1 mmol) of the compound from Example 9A, 10.6 mg (0.12 mmol) of N-methyl-N-tert-butylamine and 77 mg (0.2 mmol) of HATU in 2 ml of DMF is mixed with 0.04 ml (0.2 mmol ) N, N-diisopropylethylamine added.
• the mixture is stirred at RT for 16 h, diluted with ethyl acetate and washed successively with 0.1 M hydrochloric acid and sat. aqueous sodium bicarbonate solution. It is dried over magnesium sulfate and the volatile constituents are removed in vacuo. The product is obtained, which is further implemented without purification.
• Example 4A The preparation is carried out analogously to Example 4A from 500 mg (1.75 mmol) of the compound from Example 3A and 338 mg (1.75 mmol) of l-bromo-4,4-dimethyl-2-pentanone.
• the purification is carried out on a silica gel column (ethyl acetate: cyclohexane 5: 1) to 290 mg (41% of theory) of the product.
• Example 7A The preparation is carried out analogously to Example 7A from 230 mg (0.58 mmol) of the compound from Example 12A and 133 mg (0.58 mmol) of benzyl bromoacetate.
• the mixture is chromatographed on a silica gel column (dichloromethane: methanol 1: 0 to 3: 1) and 302 mg (91% of theory) of the product are obtained.
• Example 14A The preparation is carried out analogously to Example 14A from 15 g (89.2 mmol) methyl 2,6-dihydroxybenzoate, 12.3 g (80.3 mmol) methyl bromoacetate, 12.3 g (89.2 mmol) potassium carbonate in 120 ml acetone. The resulting mixture is separated on a silica gel column (ethyl acetate cyclohexane 1: 5). 3.38 g (16% of theory) of the desired product are obtained.
• Example 14A The preparation is carried out analogously to Example 14A from 11 g (58.6 mmol) of 2,6-dihydroxy-4-methylbenzoic acid methyl ester and 9.02 g (52.7 mmol) of benzyl bromide. The resulting mixture is separated on a silica gel column (ethyl acetate: cyclohexane 1: 5). 4.4 g (28% of theory) of the desired product are obtained.
• Example 17A The preparation is carried out analogously to Example 17A from 2.20 g (8.1 mmol) of the compound from Example 16A and 1.92 g (8.9 mmol) of 4-chloro-3-nitrobenzoic acid methyl ester.
• the crude product is chromatographed on silica gel (ethyl acetate: cyclohexane 1: 5). 1.0 g (27% of theory) of the desired product are obtained.
• Example 28 A The preparation is carried out analogously to Example 28 A from 1.20 g (3.11 mmol) of the compound from Example 18A in 50 ml of methanol and 3.50 g (15.5 mmol)
• Tin (II) chloride dihydrate 1.02 g (92% of theory) of the desired product are obtained.
• Example 28 A The preparation is carried out analogously to Example 28 A from 1.00 g (2.22 mmol) of the compound from Example 19A.
• the crude product is chromatographed on silica gel (ethyl acetate: cyclohexane 1: 3). 700 mg (75% of theory) of the desired product are obtained.
• the filtrate is concentrated and suspended in 5: 1 methylene chloride / ethyl acetate.
• the precipitate is filtered off with suction and, after drying, 1.46 g (32% of theory) of the product, which is not further purified.
• Example 38A The preparation is carried out analogously to Example 38A from 700 mg (1.66 mmol) of the compound from Example 30A.
• the crude product is chromatographed on silica gel (CyclohexamExhylacetat 3: 1). 448 mg (67% of theory) of the desired compound are obtained.
• the mixture is stirred for 4 hours at RT.
• the mixture is diluted with water, mixed with 1 ⁇ hydrochloric acid and extracted with ethyl acetate.
• the organic phase is washed with saturated sodium carbonate solution and with sodium chloride solution, dried over sodium sulfate and concentrated.
• the crude product is purified on silica gel (mobile phase: ethyl acetate). 100 mg (30% of theory) of the product are obtained.
• the reaction mixture is diluted with plenty of water and extracted three times with ethyl acetate.
• the organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.
• the residue is chromatographed on silica gel (eluent: 1: dichloromethane / ethyl acetate '10). 123 mg (71% of theory) of the product are obtained.
• the mixture is diluted with plenty of water and extracted three times with ethyl acetate.
• the organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.
• the residue is chromatographed on silica gel (mobile phase: dichloromethane / ethyl acetate 10: 1). 248 mg (61% of theory) of the product are obtained.
• the reaction solution is diluted with water and extracted with ethyl acetate.
• the organic phase is washed once with sodium carbonate solution and sodium chloride solution.
• the organic phase is dried over magnesium sulfate and concentrated in vacuo.
• the residue is suctioned off through a silica gel frit (mobile phase: ethyl acetate) and concentrated in vacuo. 74 mg (85% of theory) of the product are obtained.
• a solution of 300 mg (0.8 mmol) of the compound from Example 38A in 0.6 ml DMF / 12 ml 1,4-dioxane is sequentially treated with 255 mg (1.2 mmol) 2-tert-butoxyethyl bromide, 276 mg (2.0 mmol) Potassium carbonate and 26.5 mg (0.16 mmol) potassium iodide added.
• the mixture is stirred for 1 h at 60 ° C. oil bath temperature and then for 30 h at the reflux temperature. After cooling to RT, the mixture is diluted with 100 ml of dichloromethane and washed with water. The organic phase is dried over magnesium sulfate and condensed in vacuo. 411 mg (95% of theory) of the desired product are obtained.
• Example 64A The preparation is carried out analogously to Example 64A from 125 mg (0.39 mmol) of the compound from Example 39A and 123 mg (0.58 mmol) of tert-butoxyethyl bromide.
• the crude product is chromatographed on silica gel (cyclohexamethyl acetate 3: 1). 68 mg (41% of theory) of the desired product are obtained.
• Example 64A The preparation is carried out analogously to Example 64A from 428 mg (1.10 mmol) of the compound from Example 40A and 398 mg (1.65 mmol) of tert-butoxyethyl bromide. 295 mg (55% of theory) of the desired product are obtained.
• Example 64A The preparation is carried out analogously to Example 64A from 186 mg (0.57 mmol) of the compound from Example 39A and 120 mg (0.69 mmol) of 5-tert-butyl-3- (chloromethyl) - 1,2,4-oxadiazole.
• the crude product is separated by means of preparative HPLC (method 11). 28 mg (10% of theory) of the desired product are obtained.
• Example 64A The preparation is carried out analogously to Example 64A from 224 mg (0.69 mmol) of the compound from Example 39A and 171 mg (0.83 mmol) of l-bromo-4,4-dimethyl-2-pentanone.
• the crude product is chromatographed on silica gel (cyclohexamethyl acetate 5: 1). 111 mg (37% of theory) of the desired product are obtained.
• Example 71A (m, 2H), 6.75 (d, IH), 6.82 (d, IH), 7.35 (dd, IH), 7.46 (d, IH), 7.80 (d, IH), 8.51 (s, IH), 10.3 ( s, br, IH).
• Example 71A
• Washed ethanol After the volatile constituents have been condensed, they are taken up in ethyl acetate and washed several times with water. The organic phase is dried over magnesium sulfate and condensed in vacuo. 222 mg (99% of theory) of the desired product are obtained.
• Example 7A The preparation is carried out analogously to Example 7A from 211 mg (0.55 mmol) of the compound from Example 70A and 125 mg (0.55 mmol) of benzyl bromoacetate. For purification, chromatographed on silica gel (dichloromethane methanol 1: 0 to 3: 1) and 279 mg (85% of theory) of the product are obtained.
• Example 7A The preparation is carried out analogously to Example 7A from 93 mg (0.48 mmol) of the compound from Example 71A and 140 mg (0.58 mmol) of benzyl bromoacetate.
• the residue is chromatographed on a silica gel column (dichloromethane: methanol 1: 0 to 3: 1) and 241 mg (92% of theory) of the product are obtained.
• reaction solution is diluted with 1 ml of water and purified by means of preparative HPLC (method 11). 66 mg (27% of theory) of the product are obtained.
• a solid which is crystallized from dichloromethane / diethyl ether is obtained from 75 mg (0.13 mmol) of the compound from Example 10A by the process described for Example 5. 28 mg (45% of theory) of the product are obtained.
• a solid which is crystallized from diethyl ether is obtained from 60 mg (0.11 mmol) of the compound from Example HA by the process described for Example 5. 30 mg (60% of theory) of the product are obtained.
• Example 8 ⁇ [10- (4,4-Dimethyl-2-oxopentyl) -8- (methoxycarbonyl) - 11 -oxo-10,11 -dihydro-dibenzo [b, fj [1,4] oxazepin-1-yl] oxy ⁇ acetic acid
• Example 8 The preparation is carried out analogously to Example 8 from 72 mg (0.13 mmol) of the compound from Example 72A. 59 mg (99% of theory) of the desired product are obtained.
• the preparation is carried out analogously to the instructions from Example 2 from 28 mg (0.06 mmol) of the compound from Example 21 and 0.09 ml (0.18 mmol) of 2 M lithium hydroxide solution. 23 mg (84% of theory) of the desired product are obtained.
• a solution of 49 mg (0.12 mmol) of the compound from Example 65A in 1 ml of THF -.Methanol 1: 1 is mixed with 0.06 ml (0.12 mmol) of a 2 M LitMumhydroxid solution in water. The mixture is stirred for 30 min at an oil bath temperature of 60 ° C., diluted with 10 ml of ethyl acetate and the organic phase is washed with dilute hydrochloric acid and water. It is dried over magnesium sulfate and the volatile constituents are condensed off in vacuo. 46 mg (98% of theory) of the desired product are obtained.
• Example 8 The preparation is carried out analogously to Example 8 from 270 mg (0.13 mmol) of the compound from Example 73A. 220 mg (95% of theory) of the desired product are obtained.
• Example 9 The preparation is carried out analogously to Example 9 from 74 mg (0.18 mmol) of the compound from Example 26.
• the crude product is purified by means of preparative HPLC (Method 11). 5 mg (7% of theory) of the desired product are obtained.
• Example 25 The preparation is carried out analogously to Example 25 from 40 mg (0.09 mmol) of the compound from Example 69 A.
• the crude product is chromatographed on silica gel (cyclohexane: ethyl acetate 1: 1). 35 mg (88% of theory) of the product are obtained.
• the catalyst is filtered off through Celite and washed with ethanol.
• the solvent is removed in vacuo, the residue is taken up in 5 ml of trichloromethane and 1 ml of 1N hydrochloric acid is added. You suck over a sodium sulfate cartridge and concentrated in vacuo. 34 mg (99% of theory) of the product are obtained.
• Human blood plasma (Sigma, St. Louis, USA) is fractionated using ammonium sulfate precipitation. More than 80% of the total aminopeptidase N activity is found in the 50-70% saturation fraction. After centrifugation at 10,000g, it will
• buffer T (20mM Tris-HCl, pH 7.5, 2mM magnesium sulfate, 0.1M ethylene diamine tetraacetate and 200mM sodium chloride).
• the resulting protein solution is centrifuged again at 10,000 g and desalted on a Sephadex G-25 (Pharmacia Biotech, Uppsala, Sweden). The column is equilibrated with buffer T.
• the desalted fraction is loaded onto an affinity chromatography column.
• This is prepared by coupling monoclonal anti-CD 13 mouse antibodies (Acris SM1070P, Bad Nauheim, Germany) to an N-hydroxysuccinimide-activated HiTrap column (Pharmacia Biotech, Uppsala, Sweden). The column is equilibrated with buffer T.
• Ala-7-amido-4-methylcoumarin (Bachern, Heidelberg, Germany) is selected as the fluorogenic substrate for the aminopeptidase N.
• the enzymatic activity is measured in a buffer of 20mM MOPS pH 7.0, 100mM sodium chloride, 5mM calcium chloride, 0.1% BSA, 25 ⁇ M substrate and 1-5 ng / ml aminopeptidase N.
• the reaction is incubated for 1-3 h at a temperature of 37 ° C in 384 or 1536 microtiter plate format. Fluorescence is measured in the fluorescence reader Spectra Fluor (Tecan, Crailsheim, Germany).
• Table A shows selected compounds with IC50 values.
• hCAVSMC Human coronary arterial vascular smooth muscle cells (hCAVSMC, 1.5x10 cell well) (TEBU, Offenbach, Germany) are sown in a 6-well plate and added for 48 h in M 231 medium (growth medium) (TEBU, Offenbach, Germany) 37 ° C / 5% carbon dioxide cultivated.
• the plates are coated beforehand with Vitronectin (50 ng / cm 2 ) (Gibco / Invitrogen, Düsseldorf, Germany). After the incubation period, half of the confluent cell monolayer is removed. About 50% of the vitronectin coating remains in the cell-free area of the well.
• the growth medium is replaced by the test medium MCDB-131 / 0.2% BSA (molecular cellular developmental biology (MCDB); basal medium (BSA)) (Gibco / Invitrogen, Düsseldorf, Germany) and the cells are treated with 0.1 U aminopeptidase N (pig oderhuman) (Sigma, Taufkirchen, Germany).
• BSA molecular cellular developmental biology
• BSA basal medium
• U aminopeptidase N pig oderhuman
• test substances are then added in the specified concentrations. After incubation for 24 and 48 hours, the migration distance of the cells into the free well area is determined microscopically.
• Each measuring point represents an average of four different regions that were selected at the time 0 h.
• PDGF platelet derived growth factor
• LOnM positive control
• test substance is dissolved in a mixture of 5% Transcutol®, 10% Cremophor and 85% physiological saline.
• Female mice (strain: OF1) (Iffa Credo, L'Arbresle Cedex, France) are treated orally or intravenously with test substance solution. Control mice receive only the solvent. 30 or 45 minutes after the intravenous or oral treatment, all animals are given 2 mg / kg i.p. Lipopolysaccarid (strain: Salmonella Minnesota, manufacturer: Sigma, Steinheim, Germany) injected. A blood sample is taken 90 minutes after the i.p. injection. The tumor necrosis factor (TNF) alpha concentration in the serum is determined using a commercially available ELISA assay (manufacturer: R&D, Wiesbaden-
• the substances according to the invention can be converted into pharmaceutical preparations as follows:
• Example 1 100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg corn starch, 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Germany) and 2 mg magnesium stearate.
• the mixture of the compound of Example 1, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
• the granulate is after
• composition composition:
• a single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.
• Rhodigel is suspended in ethanol, the compound of Example 1 is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stirred for about 6 hours.
• Example 1 The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring.
• the solution is sterile filtered (pore diameter 0.22 ⁇ m) and filled into heat-sterilized hydration bottles under aseptic conditions. These are closed with infusion stoppers and crimp caps.

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