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
  • C07D401/12—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
• • 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
• • 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
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
  • C07D401/14—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 three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • 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
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to bicyclic heterocycles of the general formula
• R a is a hydrogen atom or ad. alkyl group
• R b is a 1-phenylethyl group in which the phenyl nucleus is in each case substituted by the radicals R 1 to R 3 , where
• R 1 and R 2 which may be the same or different, each have a hydrogen, fluorine, chlorine, bromine or iodine atom, a C 1 -C alkyl, hydroxy, C 4 -4 alkoxy, C 2-3 Alkenyl or C 2 -3-alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group, a methyl or methoxy group substituted by 1 to 3 fluorine atoms or a cyano, nitro or amino group, and
• R 3 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl or trifluoromethyl group
• R ° is a cyclobutyl, cyclopentyl or cyclohexyl group, each of which is substituted by a group R 4 -NR 5 , where
• R 4 is a hydrogen atom or a C -3 alkyl group
• R 5 is a hydrogen atom or a C -3 alkyl group, an aminocarbony I C 3 alkyl 3 , C 3 alkylaminocarbonyl C 3 alkyl, di (Ci-s-alky aminocarbonyl-Ci- s-alkyl-, pyrrolidin-1 -ylcarbonyl-C ⁇ -3 -alkyl-, piperidin- 1 -ylcarbonyl-C ⁇ - 3 -alkyl-, homopiperidin-1 -ylcarbonyl-C ⁇ -3 -alkyl-, morpholin-4-yl- carbonyl-C- 3- alkyl-, homomorpholin-4-ylcarbonyl-C-3-alkyl-, piperazin-1 -ylcarbonyl-C ⁇ - 3 -alkyl-, 4-C ⁇ -3 -alkyl-piperazin-1 -ylcarbonyl-d- 3 -alkyl-, homopiperazin-1-yl- carbonyl-
• R 6 is 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 -C ⁇ . 3 -alkyl-imidazolidin-1 -yl-, 2-oxo-hexahydro-pyrimidin-1-yl or a 2-oxo-3-C ⁇ -3 -alkyl-hexahydropyrimidin-1-yl group,
• R d is a hydrogen atom or a fluorine, chlorine or bromine atom
• R 6 is defined as mentioned above and
• R 7 is a hydroxy, C 3 -3 alkyloxy, C 3 - 6 cycloalkyloxy, amino, C 3 -3 alkylamino, di (C 3 -3 alkyl) amino, bis (2- methoxyethyl) amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yI, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl-, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl-, 8-oxa-3-aza-bicyclo [3.2.1] oct- 3-yl, piperazin-1-yl, 4-C ⁇ -3- alkyl-piperazin-1-yl, homopiperazin-1-yl or C ⁇ -3-alkyl-homopiperazin-l-yl group, or a formylamino , C ⁇ - 4
• X represents a methine group or a nitrogen atom substituted by a cyano group
• aryl groups mentioned in the definition of the abovementioned radicals are each to be understood as a phenyl group which is mono- or disubstituted by R 9 , where the substituents can be identical or different and
• R 9 represents a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a d- 3 alkyl, hydroxy, C 3 -3 alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group .
• heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, the heteroaryl groups mentioned above in each case being mono- or disubstituted by the radical R 9 , the substituents being identical or different can and R 9 is defined as mentioned above, and
• pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups can each be substituted by one or two C -3 alkyl groups, and
• alkyl groups mentioned above can be straight-chain or branched.
• R a is a hydrogen atom
• R b is a 1-phenylethyl group
• R c is a cyclopentyl group which is substituted in the 3-position by a group R 4 -NR 5 , where
• R 4 represents a hydrogen atom or ad -3 alkyl group
• R 5 is a hydrogen atom or a d- 3 alkyl group, an aminocarbonyl-C 1-3 alkyl, C ⁇ . 3 -Alkylaminocarbonyl-C ⁇ - 3 -alkyl-, di- (d-3-al- kyl) aminocarbonyl-C ⁇ -3 -alkyl-, pyrrolidin-1 -ylcarbonyl-C ⁇ -3 -alkyl-, piperidin-1 -yl- carbonyl-C ⁇ - 3 -alkyl-, piperazin-1 -ylcarbonyl-C ⁇ -3 -alkyl-, 4-d -3 -alkyl-piperazin-1 -yl- carbonyl-d- 3 -alkyl- or morpholin-4-ylcarbonyl -C ⁇ -3 -alkyl group, a hydroxy-C 2-4 -alkyl-, C ⁇ - 3 -alkyloxy-C 2 - 4 -alkyl-,
• R 6 is 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 represents methyl imidazolidin-1-yl, 2-oxo-hexahydro-pyrimidin-1-yl or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,
• R d is a hydrogen atom
• R 7 is a hydroxy, C 3 alkyloxy, amino, C 3 alkylamino, di (C 3 alkyl) amino, bis (2-methoxyethyl) amino, pyrrolidine-1- yl-, piperidin-1-yl-, morpholin-4-yI-, homomorpholin-4-yl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl-, 3-oxa-8 -aza-bicyclo- [3.2.1] oct-8-yl-, 8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl-, piperazin-1-yl- or a 4-C ⁇ - 3 -Alkyl-piperazin-1 -yl distr, or a formylamino, C ⁇ -4 -alkylcarbonylamino-, ds-alkyloxy-ds-alkyl carbonylamino-, C- ⁇ .
• X represents a nitrogen atom
• alkyl groups mentioned above can be straight-chain or branched
• R a is a hydrogen atom
• R b is a 1-phenylethyl group
• R c is a cyclohexyl group which is substituted in the 3-position or in the 4-position by a group R 4 -NR 5 , where
• R 4 is a hydrogen atom, a methyl or ethyl group
• R 5 is a hydrogen atom, a methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, pyrrolidine-1 -ylcarbonylmethyl-, piperidine-1 -ylcarbonylmethyl-, piperazin-1 -ylcarbonylmethyl-, 4-methylpiperazin- 1 -ylcarbonylmethyl-, Morpholin-4-ylcarbonylmethyl, 2- (morpholin-4-ylcarbonyl) ethyl or 3- (morpholin-4-ylcarbonyl) propyl group, an ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl , 2-methoxyethyl, 3-methoxypropyl, 2- (butyloxycarbonylamino) ethyl, 2-aminoethyl, 3-aminopropyl, 2- (acetylamino) ethyl, 3- (acetylamino) propyl, 2-
• a formyl acetyl, ethylcarbonyl, propylcarbonyl, methoxyacetyl, (2-methoxyethyl) carbonyl, (3-methoxypropyl) carbonyl, tetrahydrofuran-2-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, aminoacetyl, methylaminoacetyl -, dimethylaminoacetyl, morpholin-4-ylacetyl, [2- (morpholin-4-yl) ethyl] carbonyl, [3- (morpholin-4-yl) propyl] carbonyI or a methylsulfonylacetyl group,
• R 6 is 2-oxopyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxomorpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3 represents methyl imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,
• R d is a hydrogen atom
• R 7 is a hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis (2-methoxyethyl) amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4- yl-, homomorpholin-4-yl-, 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl-, 3-oxa-8-aza-bicyclo [3.2.1] oct-8-yl -, 8-Oxa-3-aza-bicyclo [3.2.1] oct-3-yl, piperazin-1-yl, 4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl group, or an acetylamino, ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino, ethylamin
• X represents a nitrogen atom
• alkyl groups mentioned above can be straight-chain or branched
• R a is a hydrogen atom
• R b is a 1-phenylethyl group
• R c is a cyclohexyl group which is in the 4-position by an amino, methylamino, dimethylamino, acetylamino, N- (acetyl) methylamino, methoxyacetylamino, N- (methoxyacetyl) methylamino, tetrahydropyran-4-ylcarbonylamino -, N-
• a pyrrolidin-3-yl group which is substituted in the 1-position by a tert-butyloxycarbonyl or methylsulfonyl group,
• Methylsulfonyl, Dimethylaminosulfonyl- or Morpholin-4-ylsulfonyl distr is substituted, or
• R d is a methoxy, ethyloxy or a 2- (methoxy) ethyloxy group
• R a is a hydrogen atom
• R b is a 1-phenylethyl group
• R c is a piperidin-4-yl group
• a piperidin-4-yl group which is substituted in the 1-position by a methyl, cyano, acetyl, morpholin-4-ylcarbonyl, tert-butyloxycarbonyl or methylsulfonyl group,
• R d is a methoxy group
• X represents a nitrogen atom
• the compounds of the general formula I can be prepared, for example, by the following processes:
• R a , R b , R d and X are defined as mentioned at the outset, with a compound of the general formula
• R c is defined as mentioned at the beginning and Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group or a hydroxyl group.
• Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group or a hydroxyl group.
• the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as, for example, triphenylphosphine / diethyl azodicarboxylate, advantageously in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, Dioxane, toluene or ethylene glycol diethyl ether at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C.
• a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as, for example, triphenylphosphine / diethyl azodicarboxylate
• a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, Dioxane, toluene or ethylene glycol diethyl
• R a , R b , R ° and X are defined as mentioned at the beginning, are with a compound of the general formula
• R 6 and R 7 are defined as mentioned at the outset, a C -4 alkyl group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the radical R 8 , or ad -4 alkyl group which is substituted by a substituted in the 4-position by the radical R 8 morpholinyl group, where R 8 . is defined in each case as mentioned at the outset, and
• Z 2 represents a leaving group such as a halogen atom, an alkylsulfonyloxy, arylsulfonyloxy or a hydroxy group.
• the reaction is preferably carried out in the presence of an organic or inorganic base such as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine performed.
• an organic or inorganic base such as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine performed.
• the reaction is carried out in the presence of a dehydrating agent, preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / diethyl azodicarboxylate.
• a dehydrating agent preferably in the presence of a phosphine and an azodicarboxylic acid derivative such as triphenylphosphine / diethyl azodicarboxylate.
• R a , R b , R c and X are defined as mentioned at the outset and Z 3 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom or a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group
• Ammonia a corresponding, optionally substituted alkylamine, dialkylamine or an imino compound or their suitable salts or derivatives, such as, for example, morpholine.
• R a , R b , R c and X are defined as mentioned at the outset and R d "represents a group which can be converted into a hydroxyl group, for example an optionally substituted benzyloxy group, a trimethylsilyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy , tert-butoxy or trityloxy group.
• the protective residue is split off, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or Potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
• an aqueous solvent for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or Pot
• a benzyl or methoxybenzyl radical is cleaved off, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
• a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
• a tert-butyl or benzyl radical is split off, for example, by treatment with an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
• an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid
• iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
• R a , R b , R d and X are defined as mentioned at the beginning and R ° ' with the proviso has the meanings mentioned at the beginning for R c that R ° contains a protected nitrogen atom.
• Typical protective residues for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, for which Amino group, the phthalyl group also comes into consideration.
• the protective residue is split off, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
• an aqueous solvent e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such
• a benzyl, methoxybenzyl or benzyloxycarbonyl residue is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
• a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
• a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
• a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
• a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
• Z 3 represents a leaving group, for example a halogen atom such as a chlorine or bromine atom, or a sulfonyloxy group such as a methanesulfonyloxy or p-toluenesulfonyloxy group, and R c " with the proviso that a hydrogen atom bound to an aliphatic carbon atom is replaced by the group Z 3 , which has the meanings mentioned for R c at the outset,
• a compound of general formula I which contains an amino, alkylamino or imino group, this can be converted into a corresponding acyl, cyano or sulfonyl compound of general formula I by means of acylation, cyanation or sulfonylation, the acylating agent used for example isocyanates, carbamoyl chlorides,
• Carboxylic acid halides, carboxylic acid anhydrides and carboxylic acids with activating agents such as N, N'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide or O- (benzotriazol-1 -yl) -N, N, N'N'-tetramethyluronium tetrafluoroborate, as sulfonyl halide, as sulfonyl halide and chlorine or bromine cyanide are suitable as cyanating agents, and / or
• a compound of the general formula I which contains a tert-butyloxycarbonylamino, N-alkyl-N- (tert-butyloxycarbonyl) amino or an N-tert-butyloxycarbonylimino group
• this can be treated by treatment with an acid such as hydrochloric acid or Trifluoroacetic acid can be converted into a corresponding amino, alkylamino or imino compound of the general formula I.
• any reactive groups present such as hydroxyl, amino, Al.kylamino or imino groups, can be protected during the reaction by conventional protective groups, which are split off again after the reaction.
• the trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group can be used as a protective radical for a hydroxyl group.
• Protective residues for an amino, alkylamino or imino group are, for example, the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group.
• the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
• an aqueous solvent e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
• an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
• an alkali base
• a benzyl, methoxybenzyl or benzyloxycarbonyl residue is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
• a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
• a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
• a trifluoroacetyl radical is preferably cleaved off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with Sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran or methanol at temperatures between 0 and 50 ° C.
• the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
• cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
• the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in " Topics in Stereochemistry ", Vol. 6, Wiley Interscience, 1971)) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
• the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
• an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols
• optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-op-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
• suitable optically active alcohol are (+) - or (-) - menthol and optically active acyl radicals in amides are, for example, (+) - or (-) - menthyloxycarbonyl.
• the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
• acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
• the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), this being achieved, for example, by inhibiting the Ligand binding, receptor dimerization or the tyrosine kinase itself can be effected. It is also possible that the signal transmission on further downstream components may be blocked.
• EGF-R epidermal growth factor receptor
• the inhibition of human EGF receptor kinase was determined with the aid of the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418).
• the protein was expressed in Sf9 insect cells as a GST fusion protein using the baculovirus expression system.
• the enzyme activity was measured in the presence or absence of the test compounds in serial dilutions.
• the polymer pEY (4: 1) from SIGMA was used as the substrate.
• Biotinylated pEY (bio-pEY) was added as a tracer substrate.
• Each 100 l reaction solution contained 10 ⁇ l of the inhibitor in 50% DMSO, 20 ⁇ l of the substrate solution (200 mM HEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg / ml poly (EY), 5 // g / ml bio-pEY ) and 20 ⁇ ⁇ enzyme preparation.
• the enzyme reaction was started by adding 50 I of a 100 ⁇ M ATP solution in 10 mM magnesium chloride.
• the dilution of the enzyme preparation was adjusted so that the phosphate incorporation into the bio-pEY was linear with regard to time and the amount of enzyme.
• the enzyme preparation was diluted in 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% Triton X-100, 1 mM DTT and 10% glycerin.
• the enzyme assays were carried out at room temperature over a period of 30 minutes and ended by adding 50 ⁇ l of a stop solution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 ⁇ ⁇ were placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. The plate was then washed with 200 ⁇ l of a washing solution (50 mM Tris, 0.05% Tween 20). After addition of 100 ⁇ ⁇ of an HRPO-labeled anti-PY antibody (PY20H anti-PTy ⁇ HRP from Transduction Laboratories, 250 ng / ml), the mixture was incubated for 60 minutes.
• a stop solution 250 mM EDTA in 20 mM HEPES pH 7.4
• 100 ⁇ ⁇ were placed on a streptavidin-coated microtiter plate and incubated for 60 minutes at room temperature. The plate was then washed with 200 ⁇ l of a washing solution (50
• the microtiter plate was then washed three times with 200 ⁇ l wash solution.
• the compounds of the general formula I according to the invention inhibit signal transduction by tyrosine kinases, for example the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by overactive tyrosine kinases.
• tyrosine kinases for example the human EGF receptor
• pathophysiological processes which are caused by overactive tyrosine kinases.
• tyrosine kinases for example the human EGF receptor
• the compounds of the invention are also useful for the prevention and treatment of respiratory and lung diseases associated with an increased or altered mucus production caused by stimulation of tyrosine kinases, such as in inflammatory respiratory diseases such as acute bronchitis, chronic bronchitis, chronic obstructive bronchitis (COPD), cough, emphysema, allergic or non-allergic rhinitis or sinusitis, chronic sinusitis or rhinitis, asthma, allergic bronchitis, alveolitis, Farmer 's disease, hyperreactive airways, bronchitis or pneumonitis caused by infections such as bacteria or Viruses, helminths, fungi or protozoa, pediatric asthma, bronchiectasis, acute respiratory distress syndrome (ARDS), pulmonary edema, bronchitis or pneumonitis or interstitial pneumonia or pulmonary fibrosis from various causes, such as through aspiration, inhalation of toxic gases or vapors, through
• the compounds are also suitable for the treatment of diseases of the gastrointestinal tract and of the bile ducts and bladder, which are associated with an impaired activity of the tyrosine kinases, such as are found, for example, in the case of chronic inflammatory changes, such as villous or adenomatous polyps of the stomach Colon tracts, polyps in familial polyposis coli, intestinal polyps in Gardner 's syndrome, polyps in Koz-Jehers syndrome, inflammatory pseudopolyps, juvenile polyps, polyps in colitis cystica profunda and in pneumatosis cystoides intestinales, acute or chronic cholecystitis, M. Crohn's disease , Ulcerative colitis, ulcers or polyps of the gastrointestinal tract, diseases of the gastrointestinal tract associated with increased secretion, such as M. Menetrier, secreting adenomas or protein loss syndrome.
• chronic inflammatory changes such as villous or adenomatous polyps of the stomach Colon
• the compounds of general formula I and their physiologically tolerable salts can be used for the treatment of inflammatory diseases of the skin and joints which are caused by the aberrant function of tyrosine kinases such as epidermal hyperproliferation (psoriasis) and arthritis, and for the treatment of benign prostatic hyperplasia (BPH), diseases of the immune system and hyperproliferation of hematopoietic cells.
• tyrosine kinases such as epidermal hyperproliferation (psoriasis) and arthritis
• BPH benign prostatic hyperplasia
• the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (for example etoposide), mitotic inhibitors (e.g. vinblastine), compounds interacting with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies etc.
• topoisomerase inhibitors for example etoposide
• mitotic inhibitors e.g. vinblastine
• compounds interacting with nucleic acids e.g. cis-platinum, cyclophosphamide, adriamycin
• hormone antagonists e.g. tamoxifen
• respiratory diseases can use these compounds alone or in combination with other respiratory therapies, such as secretolytic (e.g. ambroxol, N-acetylcysteine), broncholytic (e.g. tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and / or anti-inflammatory (e.g. theophylline or glucocorticoids) substances.
• secretolytic e.g. ambroxol, N-acetylcysteine
• broncholytic e.g. tiotropium or ipratropium or fenoterol, salmeterol, salbutamol
• anti-inflammatory e.g. theophylline or glucocorticoids
• These compounds can be used either alone or in combination with other active substances, intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation or transdermally or orally, aerosol formulations in particular being suitable for inhalation.
• the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg of body weight, preferably at 0.1-15 mg / kg.
• these are mixed with one or more customary inert carriers and / or diluents, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, Water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat or their suitable mixtures are incorporated into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.
• the reaction is carried out with (morpholin-4-yl) carbonyl chloride.
• the reaction is carried out using cyanogen bromide in methylene chloride.
• 1 coated tablet contains: active substance 75.0 mg calcium phosphate 93.0 mg maize starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Production: The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed through a sieve with a 1.5 mm mesh size on a suitable machine and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.
• the dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose.
• the finished film coated tablets are polished with beeswax.
• Composition 1 tablet contains: Active ingredient 100.0 mg milk sugar 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg
• Active ingredient, milk sugar and starch are mixed and mixed with an aqueous solution of the
• Polyvinylpyrrolidons evenly moistened After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C is sieved again (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets.
• Tablet weight 220 mg, diameter: 10 mm, biplane with double-sided facet and one-sided partial notch.
• Composition 1 tablet contains: Active ingredient 150.0 mg powdered milk sugar. 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg
• the active substance mixed with milk sugar, corn starch and silica is mixed with a
• the granules dried at 45 ° C are rubbed through the same sieve again and mixed with the specified amount of magnesium stearate. The mixture becomes
• Tablet weight 300 mg stamp: 10 mm, flat
• Composition 1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx. 180.0 mg powdered milk sugar approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg
• the active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.
• the final mix is filled into size 1 hard gelatin capsules. Capsule filling: approx. 320 mg
• Capsule shell hard gelatin capsule size 1.
• Composition 1 suppository contains: Active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg
• Example 10 After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.
• Example 10 After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.
• 100 ml suspension contain: Active ingredient 1.00 g carboxymethyl cellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g cane sugar 10.00 g glycerin 5.00 g sorbitol solution 70% 20.00 g aroma 0.30 g water dist.ad 100.00 ml
• 5 ml of suspension contain 50 mg of active ingredient.
• composition active ingredient 10.0 mg 0.01 n hydrochloric acid sq aqua bidest ad 2.0 ml production:
• the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
• composition active ingredient 50.0 mg 0.01 n hydrochloric acid s.q. Aqua bidest to 10.0 ml
• the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.
• 1 capsule contains:
• the active substance is mixed with lactose for inhalation purposes.
• the mixture is filled into capsules on a capsule machine (weight of the empty capsule approx. 50 mg).
• 1 hub includes:
• the active substance and benzalkonium chloride are dissolved in ethanol / water (50/50).
• the pH of the solution is adjusted with 1 N hydrochloric acid.
• the adjusted solution is filtered and filled into containers (cartridges) suitable for the hand nebuliser.

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• 2003
  • 2003-09-30 DE DE10345875A patent/DE10345875A1/de not_active Withdrawn
• 2004
  • 2004-09-24 JP JP2006530024A patent/JP2007507445A/ja active Pending
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