Classifications

• • 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
• • 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
  • A61P1/16—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
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/38—Nitrogen atoms
  • C07D215/42—Nitrogen atoms attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/94—Nitrogen atoms
• • 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

Definitions

• Bicyclic heterocycles pharmaceutical compositions containing these compounds, their use and process for their preparation
• the present invention relates to bicyclic heterocycles of the general formula
• R a is a hydrogen atom or a C ⁇ alkyl group
• R b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus is in each case substituted by the radicals R x to R 3 , where
• R x and R 2 which may be the same or different, each have a hydrogen, fluorine, chlorine, bromine or iodine atom, a C 1 . 4 -alkyl-, hydroxy-, C 1 . 4 -alkoxy-, C 3 _ 6 -cycloalkyl-, C 4 . 6- cycloalkoxy, C 2 _ 5 alkenyl or C 2 _ 5 alkynyl group,
• R 3 is a hydrogen, fluorine, chlorine or bromine atom
• X is a methine group or a nitrogen atom substituted by a cyano group
• A is an optionally by a C 1 _ 4 alkyl substituted imino group
• B is a carbonyl or sulfonyl group
• C is a 1, 3-allenylene, 1,1 or 1, 2-vinylene group, each of which can be substituted by one or two methyl groups or by a trifluoromethyl group,
• D is an alkylene, -CO-alkylene or -S0 2 -alkylene group in which the alkylene part in each case contains 1 to 8 carbon atoms and 1 to 4 hydrogen atoms in the alkylene part can also be replaced by fluorine atoms, the linkage of the -CO-alkylene- or -S0 2 -alkylene group with the adjacent group C must take place in each case via the carbonyl or sulfonyl group,
• R 4 represents a hydrogen atom or a C 1-4 alkyl group
• E is an amino, C 1-4 alkylamino or di- (1-4 alkyl) amino group in which the alkyl parts can be the same or different,
• R s is a hydroxy, C 1 . 4 -alkoxy-, amino-, C ⁇ -alkylamino or di- (C x _ 4 -alkyl) -amino group,
• a 6- to 7-membered alkyleneimino group optionally substituted by one or two methyl groups, in each of which a methylene group in position 4 is represented by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or N- (C ⁇ -alkyl) -imino group is replaced,
• 3 -alkylamino group in each of which the nitrogen atom can be substituted by a further C 1-4 alkyl group, an amino or C - ⁇ - alkylamino group, in each of which the nitrogen atom is substituted by a tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, optionally substituted by 1 to 3 C ⁇ alkyl groups, Tetrahydrofuranylmethyl-, 1- (tetrahydrofuran-3-yl) -piperidin-4-yl-, 1- (tetrahydropyran- 3-yl) -piperidin-4-yl-, 1- (tetrahydropyran-4-yl) -piperidin-4 -yl, 3-pyrrolidinyl, 3-piperidinyl, 4-piperid
• a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 C 1-4 alkyl groups, in each of which a methylene group in the 4-position by an oxygen or sulfur atom, by an imino group substituted by the radical R 6 , by a sulfinyl - Or sulfonyl group is replaced, wherein
• R 6 is a hydrogen atom, a C 1 _ 4 alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C 3 . 7- cycloalkyl-, C 3 . 7- Cycloalkyl-C 1 _ 4 -alkyl-, tetrahydrofuran-3-yl-, tetrahydropyran-3-yl-, tetrahydropyran-4-yl-, tetrahydrofuranylmethyl-, formyl-, C ⁇ -alkylcarbonyl-, C Represents ⁇ alkyl sulfonyl, aminocarbonyl, C ⁇ alkyl aminocarbonyl or di (C 1, 4 alkyl) aminocarbonyl group,
• a carbonyl group which is substituted by a 4- to 7-membered alkyleneimino group, and in the above-mentioned 6- to 7-membered alkyleneimino groups each a methylene group in the 4-position by an oxygen or sulfur atom, by one substituted by the radical R 6 Imino group, may be replaced by a sulfinyl or sulfonyl group, where R 6 is as defined above, and
• R c is a C 4 _ 7 cycloalkoxy or C 3 _ 7 cycloalkyl C 1 . 6 -alkoxy group, in which the cycloalkyl part in each case by a C ⁇ alkyl, hydroxy, C ⁇ alkoxy, amino, C 1 . 4 alkylamino, di- (C 1 4 alkyl.) - (.
• a C 2 _ 4 -alkoxy group which is substituted in the ⁇ , ⁇ or ⁇ position relative to the oxygen atom by an azetidin-1-yl, 4-methyl-homopiperazino or 4-ethyl-homopiperazino group,
• E is an amino, C 1 _ 4 alkylamino -amino or di- (C ⁇ alkyl), in which the alkyl portions can be the same or different,
• R s is a hydroxy, C 1 . 4 -alkoxy-, amino-, C 1 . 4 -alkylamino or di- (C 1-4 -alkyl) amino group,
• a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 C 1-2 alkyl groups, in each of which a methylene group in the 4-position by an oxygen or sulfur atom, by an imino substituted by the radical R 6 group, is replaced by a sulfinyl or sulfonyl group, wherein
• R 6 is a hydrogen atom, a C 1-4 alkyl, C 3 _ 7 cycloalkyl, C 3 _ 7 cycloalkyl C 1 .
• 4- alkyl-, formyl-, C 1-4 -alkylcarbonyl-, C ⁇ -alkylsulfonyl-, aminocarbonyl-, C 1 . 4 alkylaminocarbonyl or di- (C 1 _ i alkyl) aminocarbonyl group represents,
• a carbonyl group which is substituted by a 4- to 7-membered alkyleneimino group, and in the above-mentioned 6- to 7-membered alkyleneimino groups each a methylene group in the 4-position by an oxygen or sulfur atom, by one substituted by the radical R 6 Imino group, may be replaced by a sulfinyl or sulfonyl group, where R 6 is as defined above, and R c a C 4 .
• 3-pyrrolidinyloxy, 2-pyrrolidinyl C 1 4- alkyloxy-, 3-pyrrolidinyl-C ⁇ -alkyloxy-, 3-piperidinyloxy-, 4-piperidinyloxy-, 2-piperidinyl-C 1.4 -alkyloxy-, 3-piperidinyl-C 1 .
• each mono-substituted by R 7, R 8 by mono-, di- or tri-substituted or monosubstituted by R7 and additionally mono- or disubstituted by R 8 may be , where the substituents can be the same or different and
• R 7 is a cyano, carboxy, C ⁇ alkoxycarbonyl, aminocarbonyl, C x _ 4 alkylaminocarbonyl, di (C x _ 4 alkyl) aminocarbonyl, C 1.4 alkylsulfenyl, C ⁇ alkylsulfinyl - (. C 1 4 alkyl), C 1 _ 4 alkylsulfonyl, hydroxy, C ⁇ alkylsulfonyloxy, Trifluormethyloxy-, nitro, amino, C 1.4 alkylamino, di- -amino, C 1 _ 4 alkyl carbonylamino, N- (C 1-4 alkyl) -C 1 .
• R 8 is a fluorine, chlorine, bromine or iodine atom, a C ⁇ alkyl, trifluoromethyl or C ⁇ alkoxy group or
• heteroaryl groups mentioned in the definition of the above-mentioned groups there is a 5-membered heteroaromatic group containing an imino group, an oxygen or sulfur atom or an imino group, an oxygen or sulfur atom and one or two nitrogen atoms, or
• the abovementioned 5-membered heteroaromatic groups each having 1 or 2 methyl or ethyl groups and the abovementioned ⁇ -membered heteroaromatic groups each having 1 or 2 methyl or ethyl groups or a fluorine, chlorine, bromine or iodine atom, can be substituted by a trifluoromethyl, hydroxyl, methoxy or ethoxy group.
• Preferred compounds of the above general formula I are those in which R a is a hydrogen atom
• R b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus is in each case substituted by the radicals R x to R 3 , where
• R x and R 2 which may be the same or different, each have a hydrogen, fluorine, chlorine, bromine or iodine atom,
• R 3 is a hydrogen, fluorine, chlorine or bromine atom
• X is a methine group or a nitrogen atom substituted by a cyano group
• B is a carbonyl or sulfonyl group
• C is a 1,3-allenylene, 1,1 or 1,2-vinylene group
• D is an alkylene, -CO-alkylene or -S0 2 -alkylene group in which the alkylene part in each case contains 1 to 4 carbon atoms and an additional 1 to 4 hydrogen atoms in the alkylene part can be replaced by fluorine atoms, the linkage of the -CO-alkylene or -S0 2 -alkylene group to the adjacent group C must take place in each case via the carbonyl or sulfonyl group,
• R 4 represents a hydrogen atom or a C 1-4 alkyl group
• E is a di- (C _ 4 alkyl) amino group in which the alkyl moieties may be the same or different,
• R s is a hydroxy, C 1-4 alkoxy or di- (C 1-4 alkyl) amino group
• a 6- to 7-membered alkyleneimino group optionally substituted by one or two methyl groups, in each of which a methylene group in position 4 is replaced by an oxygen or sulfur atom, by a sulfinyl, sulfonyl or N- (C 1-4 -alkyl) -imino group is represents a di- (C 2 _ 4 -alkyl) amino group in which both C 2 _ 4 -alkyl parts are each substituted in the ⁇ , ⁇ or ⁇ position relative to the nitrogen atom of the amino group by the radical R 5 , the substituents ducks may be the same or different and R 5 is defined as mentioned above,
• a 6 to 7-membered alkyleneimino group which is optionally substituted by 1 or 2 methyl groups, in each of which a methylene group in the 4 position is replaced by an oxygen or sulfur atom, by an imino group substituted by the radical R 6 , by a sulfinyl or sulfonyl group , in which R 6 is a C 1-4 alkyl, 2-methoxy-ethyl, 3-methoxy-propyl, C 3 . 7- cycloalkyl-, C 3 . 7- cycloalkyl-C 1 .
• a carbonyl group which is substituted by a 4- to 7-membered alkyleneimino group, and in the above-mentioned 6- to 7-membered alkyleneimino groups each a methylene group in the 4-position by an oxygen or sulfur atom, by one substituted by the radical R 6 Imino group, may be replaced by a sulfinyl or sulfonyl group, where R 6 is as defined above, and
• R c a C 4 . 7- Cycloalkoxy- or C 3 . 7- Cycloalkyl-C 1 _ 6 alkoxy group, in which the cycloalkyl part in each case by a Hydroxy-, C 1 _ 4 -alkoxy-, di- (C 1. 4 -alkyl) -amino-, pyrrolidino-, pipe- ridino-, morpholino-, N- (C 1-2 -alkyl) -piperazino-, hydroxy- C ⁇ -alkyl-, C 1.4 -alkoxy-C 1 .
• R 7 is a cyano, carboxy, C ⁇ alkoxycarbonyl, aminocarbonyl, C 1 _ i alkylaminocarbonyl -, di- (1 i _ alkyl) aminocarbonyl, C ⁇ -Alkylsulfenyl-, C ⁇ alkylsulfinyl , C 1 . 4 -alkylsulfonyl-, hydroxy-, C ⁇ .4 -alkylsulfonyloxy-, trifluoromethyloxy-, nitro-, amino-, C ⁇ -alkylamino-, di- (C ⁇ -alkyl) -amino-, C 1 .
• R 8 is a fluorine, chlorine, bromine or iodine atom, a C ⁇ alkyl, trifluoromethyl or C x _ 4 alkoxy group or
• bicyclic heterocycles of the general formula I are those in which
• R a is a hydrogen atom
• R b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus is in each case substituted by the radicals R x and R 2 , where
• R- L and R 2 which may be the same or different, each represent a hydrogen, fluorine, chlorine or bromine atom,
• X is a nitrogen atom, A an imino group,
• B is a carbonyl group
• C is a 1,2-vinylene group
• D is a C x _ 4 alkylene group
• E is a di- ⁇ C t _ 4 alkyl amino group) in which the alkyl moieties may be the same or different,
• R 5 is a hydroxy, C 1 _ 3 alkoxy or di (C 1 -C 4 alkyl) amino group
• a 5- to 7-membered alkyleneimino group which is optionally substituted by 1 or 2 methyl groups and which may be substituted either on a ring carbon atom or on one of the methyl groups by the group R 5 , where R 5 is defined as mentioned above, or
• R 6 is a C 1-4 alkyl, 2-methoxy-ethyl, 3-methoxypropyl, C 3 _ 6 cycloalkyl, C 3 . 6- cycloalkyl-C 1 .
• R c is a C 4 _ 7 cycloalkoxy or C 3-7 cycloalkyl C 1 . 4 -alkoxy group, in which the cycloalkyl part can in each case be substituted by a C 1 _ 3 -alkyl or C ⁇ - j -alkoxy group,
• aryl moieties mentioned in the definition of the abovementioned radicals should be understood to mean a phenyl group which may be mono-, di- or tri-substituted by R 8 , where the substituents can be identical or different and
• R 8 represents a fluorine, chlorine, bromine or iodine atom, a C 1-4 alkyl, trifluoromethyl or C x _ 4 alkoxy group,
• R a is a hydrogen atom
• R b is a phenyl, benzyl or 1-phenylethyl group in which the phenyl nucleus is in each case substituted by the radicals R z and R 2 , where
• R ⁇ and R 2 which may be the same or different, each represent a hydrogen, fluorine, chlorine or bromine atom,
• X is a nitrogen atom
• B is a carbonyl group
• C is a 1, 2-vinylene, ethinylene or 1, 3-butadien-1, 4-ylene group,
• D is a C - ⁇ - alkylene group
• E is a di (C 1-4 alkyl) amino group in which the alkyl parts can be the same or different,
• a methylamino or ethylamino group in each of which the nitrogen atom is replaced by a 2-methoxy-ethyl, 1-methoxy-2-propyl, 2-methoxy-propyl, 3-methoxy-propyl, tetrahydrofuran-3-yl -, tetrahydropyran-4-yl-, tetrahydrofuran-2 -ylmethyl-, l-methyl-piperidin-4-yl-, l-ethyl-piperidin-4-yl-, 1- (tetrahydrofuran-3-yl) - piperidin-4-yl, cyclopropyl or cyclopropylmethyl group is substituted,
• a pyrrolidino, piperidino or morpholino group which is optionally substituted by one or two methyl groups, a piperazino group which is substituted in the 4-position by a methyl, ethyl, cyclopropyl, cyclopropylmethyl, 2-methoxy-ethyl, tetrahydrofuran-3 -yl, tetrahydropyran-4-yl or tetrahydrofuran-2 -ylmethyl group ,
• E represents a hydrogen atom, a methyl, phenyl, methoxycarbonyl or ethoxycarbonyl group and
• R c is a cyclopropyl methoxy, cyclobutyl methoxy, cyclopentyl methoxy or cyclohexyl methoxy group
• R a is a hydrogen atom
• R b is a 1-phenylethyl group or a phenyl group in which the phenyl nucleus is substituted by the radicals R x and R 2 , where
• R x and R 2 which may be the same or different, each represent a hydrogen, fluorine, chlorine or bromine atom,
• X is a nitrogen atom
• B is a carbonyl group
• C is a 1, 2-vinylene, ethynylene or 1, 3-butadiene-1, 4 -ylene group,
• E is dimethylamino, diethylamino, bis (2-methoxy-ethyl) amino, N-methyl-N- (2-methoxy-ethyl) -amino, N-ethyl-N- (2-methoxy-ethyl) ) -amino-, N-methyl-N-cyclopropyl-amino-, N-methyl-N-cyclopropylmethyl-amino-, N-methyl-N- (1-methoxy-2-propyl) -amino-, N-methyl- N- (2-methoxypropyl) amino, N-methyl-N- (3-methoxypropyl) amino, N-methyl-N- (tetrahydrofuran-3-yl) amino, N-methyl -N- (tetrahydropyran-4-yl) amino, N-methyl-N- (tetrahydrofuran-2-ylmethyl) amino or N-methyl-N- (1-methyl-piperidin-4-
• E represents a hydrogen atom, a methyl, phenyl or ethoxycarbonyl group
• R c is a cyclopropylmethoxy, cyclobutyloxy or cyclopentyloxy group
• R a to R c , A and X are defined as mentioned above, with a compound of the general formula
• Z 1 represents a leaving group such as a halogen atom, for example a chlorine or bromine atom, or a hydroxyl group.
• the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent, at temperatures between -50 and 150 ° C, preferably at temperatures between -20 and 80 ° C, performed.
• a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane
• __ 1 represents a leaving group
• the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane.
• a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane.
• a tertiary organic base such as triethyl in, pyridine or 2-dimethylaminopyridine
• N-ethyl-diisopropylamine Hünig base
• an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution expediently at temperatures between -50 and 150 ° C, preferably at temperatures between -20 and 80 ° C.
• the reaction is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N, N ' -Dicyclohexylcarbodiimid, N, N '-Dicyclohexylcarbodiimid / N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylamino-pyridine, N, N' -carbonyldiimidazole or triphenylphosphine / tetra-chlorocarbon Solvents such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl
• R a to R c , A to D and X are defined as mentioned in the introduction and
• a leaving group such as a halogen atom, a substituted hydroxy or sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, with a compound of the general formula
• E ' represents one of the radicals mentioned at the outset for E, which is linked to the radical D via a nitrogen atom.
• the reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethyl sulfoxide, methylene chloride, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, optionally in the presence of an inorganic or tertiary organic base, for example sodium carbonate or potassium hydroxide, potassium hydroxide, a tertiary organic base, for example triethylamine, or in the presence of N-ethyl-diisopropylamine (Hünig base), where these organic bases can also serve as solvents, and if appropriate in the presence of a reaction accelerator such as an alkali metal halide at temperatures between -20 and 150 ° C, but preferably at temperatures between -10 and 100 ° C.
• a reaction accelerator such as an alkali metal halide at temperatures
• reaction can also be carried out without a solvent or in an excess of the compound of the general formula V used. If, according to the invention, a compound of the general formula I is obtained which contains an amino, alkylamino or imino group, this can be converted into a corresponding acyl or sulfonyl compound of the general formula I by means of acylation or sulfonylation or
• the subsequent esterification is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane or particularly advantageously in a corresponding alcohol, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent , for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide, N, N' -dicyclohexylcarbodiimine-benzide or N-hydroxysolimide / N-hydroxysolimide and optionally additionally in the presence
• the subsequent ester formation can also be carried out by reacting a compound which contains a carboxy or hydroxyphosphoryl group with an appropriate alkyl halide.
• the subsequent acylation or sulfonylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with a corresponding acyl or sulfonyl derivative, optionally in the presence of a tertiary organic base or in the presence of an inorganic base or in the presence of a dehydrating agent, e.g.
• a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with a corresponding acyl or sulfonyl derivative, optionally in the presence of a tertiary organic base or in the presence of an inorganic base
• the subsequent alkylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, for example with methyl iodide, ethyl bromide, dimethyl sulfate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, conveniently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C.
• a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxan
• the subsequent reductive alkylation is advantageously carried out with a corresponding carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde, acetone or butyraldehyde in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride at a pH of 6-7 and at room temperature or in the presence of a hydrogenation catalyst , for example with hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.
• the methylation can also be carried out in the presence of formic acid as a reducing agent at elevated temperatures, for example at temperatures between 60 and 120 ° C.
• amide formation is optionally carried out by reacting an appropriate reactive carboxylic acid derivative with an appropriate amine, optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, the amine used can simultaneously serve as solvent in the presence of a tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N '-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole
• any reactive groups present such as hydroxyl, carboxy, phosphono, O-alkylphosphono, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups protected, which are split off after the implementation.
• the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group
• protective residues for a phosphono group an alkyl group such as the methyl, ethyl, isopropyl or n-butyl group, the phenyl or benzyl group and
• 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 radical is split off, for example by hydrogenolysis, for example using 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 - see 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.
• cleavage of a tert-butyl or tert. -Butyloxycarbonyl residue is preferably carried out 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.
• an acid such as trifluoroacetic acid or hydrochloric acid
• 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.
• the cleavage of only one alkyl radical from an O, O 'dialkylphosphono group takes place, for example, with sodium iodide in a solvent such as acetone, ethyl methyl ketone, acetonitrile or dimethylformamide at temperatures between 40 and 150 ° C., but preferably at temperatures between 60 and 100 ° C.
• a solvent such as acetone, ethyl methyl ketone, acetonitrile or dimethylformamide
• alkyl radicals from a 0, 0 '-dialkylphosphonophone group is carried out, for example, using iodotrimethylsilane, bromotrimethylsilane or chlorotrimethylsilane / sodium iodide in a solvent such as methyl chloride, chloroform or acetonitrile at temperatures between 0 ° C. and the boiling point of the reaction mixture, but preferably at temperatures between 20 and 60 ° 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 eis 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 physicochemical 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-o-tolyltartaric acid, malic acid. right, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
• suitable optically active alcohols 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.
• suitable acids for this 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 new compounds of the formula I obtained in this way contain a carboxy, hydroxyphosphoryl, sulfo or 5-tetrazolyl group, they can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for pharmaceutical use in their physiologically tolerable salts , convict.
• bases which can be used here are sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
• a starting compound of the general formula II is obtained by reacting a 7-fluoro-6-nitro compound correspondingly substituted in the 4-position with a corresponding alcoholate and subsequently reducing the nitro compound or a starting compound of the general formula IV by reacting a 7-fluoro-6-nitro compound correspondingly substituted in the 4-position with a corresponding alcoholate, then reducing the nitro compound thus obtained and then acylating with a corresponding compound.
• the compounds of the general formula I according to the invention and their physiologically tolerated 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, the 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
• EGF-R mediated signal transmission can e.g. can be detected with cells that express human EGF-R and whose survival and proliferation depends on stimulation by EGF or TGF-alpha.
• An interleukin-3 (IL-3) -dependent cell line of murine origin was used here, which has been genetically modified in such a way that it expresses functional human EGF-R.
• the proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see von Rüden, T. et al. In EMBO J. 7_, 2749-2756 (1988) and Pierce, JH et al. in Science 2i9_, 628-631 (1988)).
• other growth factor-dependent cells can also be used (see, for example, Pierce, JH et al. In Science 239: 628-631 (1988) Shibuya, H. et al. in Cell 7J1, 57-67 (1992) and Alexander, WS et al. in EMBO J. HL, 3683-3691 (1991)).
• Recombinant retroviruses were used to express the human EGF-R cDNA (see Ullrich, A. et al.
• F / L-HERc cells were in RPMI / 1640 medium (BioWhittaker), supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng / ml human EGF (Promega), at 37 ° C and 5% CO2 cultivated.
• FCS fetal bovine serum
• FCS Boehringer Mannheim
• 2 mM glutamine BioWhittaker
• standard antibiotics 20 ng / ml human EGF (Promega)
• 20 ng / ml human EGF Promega
• the relative cell number was determined using the Cell
• the compounds of the general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by hyperfunction of tyrosine kinases.
• pathophysiological processes which are caused by hyperfunction of tyrosine kinases.
• tyrosine kinases e.g. benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
• the compounds of the invention are also useful for the prevention and treatment of respiratory and lung diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases such as e.g. for inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ l-antitrypsin deficiency, or for cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
• tyrosine kinases such as e.g. for inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, ⁇ l-antitrypsin deficiency, or for cough, pulmonary
• the compounds are also suitable for the treatment of diseases of the gastrointestinal tract and bile ducts and - bladder that is associated with a disturbed activity of the tyrosine kinases, such as those found in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as in gastrointestinal disorders -Tracts associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes.
• diseases of the gastrointestinal tract and bile ducts and - bladder that is associated with a disturbed activity of the tyrosine kinases, such as those found in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as in gastrointestinal disorders -Tracts associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes.
• the compounds of general formula I and their physiologically acceptable salts can be used for the treatment of other diseases caused by the aberrant function of tyrosine kinases, such as e.g. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells etc.
• tyrosine kinases e.g. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells etc.
• 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) Mitosis 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.
• Mitosis inhibitors e.g. vinblastine
• nucleic acids e.g. cis-platinum, cyclophosphamide, adriamycin
• hormone antagonists e.g. tamoxifen
• inhibitors of metabolic processes e.g. 5-FU etc.
• these compounds can be used alone or in combination with other respiratory therapeutic agents, such as secretolytic, broncholytic and / or anti-inflammatory substances.
• these compounds can also be given alone or in combination with substances that influence motility or secretion. These combinations can be administered either simultaneously or sequentially.
• These compounds can be used either alone or in combination with other active compounds 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 body weight, preferably 0.1-15 mg / kg.
• these are mixed with one or more conventional inert carriers and / or diluents, e.g.
• R f value 0.54 (silica gel, ethyl acetate)
• R f value 0.54 (silica gel, ethyl acetate)
• the aqueous phase is extracted with methylene chloride and the extract is concentrated.
• the combined raw products are dissolved in ethyl acetate and stirred with a little silica gel and 120 mg of activated carbon.
• the suspension is filtered and the filtrate is concentrated, the desired product remaining as a yellow resin.
• the reaction mixture is poured onto 20 ml of ice water and mixed with 2-3 ml of 2N sodium hydroxide solution, a light precipitate being formed.
• the precipitate is filtered off, washed with cold water and dissolved in dichloromethane.
• the solution is dried over sodium sulfate and concentrated.
• the resinous crude product is purified by chromatography on a silica gel column with methylene chloride / methanol / concentrated ammonia solution (90: 10: 0.5). Yield: 118 mg (35% of theory)
• R f value 0.29 (aluminum oxide, activity III; methylene chloride / -
• R f value 0.26 (aluminum oxide, activity III; methylene chloride / -
• R f value 0.40 (aluminum oxide, activity III; methylene chloride / -
• the acid chloride formed is largely removed from the solvent on a rotary evaporator in vacuo. free of solvents.
• the crude product is then dissolved in 10 ml of methylene chloride and cooled with an ice bath to a mixture of 1.00 g of 6-amino-4- [(3-chloro-4-fluorophenyl) amino] - 7-cyclopropylmethoxy-quinazoline and 1.60 ml of Hunig base in 50 ml of tetrahydrofuran were added dropwise.
• the reaction mixture is stirred for 1.5 hours in an ice bath and for a further 2 hours at room temperature.
• 2.90 ml of diethylamine are added and the mixture is stirred for 2.5 days at room temperature.
• N-methyl-N- (3-tetrahydrofuranyl) amine used was obtained by reacting tetrahydrofuran-3-carboxylic acid with phosphoric acid diphenyl ester azide in benzyl alcohol and subsequent reduction of the 3 - (benzyloxycarbonylamino) tetrahydrofuran formed with lithium aluminum hydride ) Melting point: 157-159 ° C
• N-methyl-N- (1-methoxy-2-propyl) amine used was obtained by reductive amination of methoxyacetone with methylamine- hydrochloride and sodium triacetoxyborohydride obtained in the presence of sodium acetate. The reaction was carried out in tetrahydrofuran. )
• 1 coated tablet contains:
• the active substance is mixed with calcium phosphate, corn starch, polyvinyl pyrrolidone, hydroxypropyl methyl 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 on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.
• stamp 9 mm, arched
• the dragee cores produced in this way are covered with a film which essentially consists of hydroxypropylmethyl cellulose.
• the finished film coated tablets are polished with beeswax.
• Composition 1 tablet contains:
• Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinylpyrrolidone. After screening the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C, sieving is again carried out (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 facet on both sides and partial notch on one side.
• Composition 1 tablet contains:
• the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a mesh size of 1.5 mm.
• the granules dried at 45 ° C are again rubbed through the same sieve and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.
• 1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx. 180.0 mg milk sugar powder 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 shell hard gelatin capsule size 1.
• 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 2 000.0 mg
• Carboxymethylcellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g
• Dest. Water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After adding and dissolving the sugar, the sorbitol solution and the aroma, the suspension is evacuated with stirring for deaeration.
• 5 ml of suspension contain 50 mg of active ingredient.
• 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.
• 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 1N hydrochloric acid.
• the adjusted solution is filtered and filled into containers (cartridges) suitable for the hand-held nebulizer.

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