EP1315716A1 - Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire - Google Patents

Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire

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Publication number
EP1315716A1
EP1315716A1 EP01969610A EP01969610A EP1315716A1 EP 1315716 A1 EP1315716 A1 EP 1315716A1 EP 01969610 A EP01969610 A EP 01969610A EP 01969610 A EP01969610 A EP 01969610A EP 1315716 A1 EP1315716 A1 EP 1315716A1
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
substituted
alkylene
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01969610A
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German (de)
English (en)
Inventor
Frank Himmelsbach
Elke Langkopf
Birgit Jung
Stefan Blech
Flavio Solca
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
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Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1315716A1 publication Critical patent/EP1315716A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

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 methyl 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,
  • R 3 is a hydrogen, fluorine, chlorine or bromine atom
  • R c is a hydrogen atom or a methyl group
  • X is a methine group or a nitrogen atom substituted by a cyano group
  • A is a 1,1- or 1,2-vinylene group, which can in each case be substituted by one or two methyl groups or by a trifluoromethyl group,
  • B is a hydrogen atom or a C 1 _ 4 -alkyl group, a methyl group substituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to 5 fluorine atoms, a C 1 _ 4 -alkylcarbonyl, carboxy, C - ⁇ - alkoxycarbonyl- , aminocarbonyl, C 1-4 kylaminocarbonyl- -Al-, di- (C 1. 4, alkyl) aminocarbonyl, pyrrolidino carbonyl, piperidinocarbonyl, morpholinocarbonyl or 4- (C ⁇ alkyl) -Piperazinocarbonyl distr , or
  • R 4 is a C 1 . 4 alkoxy group, one by 2 C 1 . 4 alkyl-substituted amino group in which the alkyl groups may be the same or different and each alkyl moiety from position 2 by a C 1-4 alkoxy or di- (C 1 _ 4 alkyl) amino group or by a 4- to 7 -linked alkyleneimino group can be substituted, 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 a sulfinyl, sulfonyl or N- ( C 1, 4- alkyl) -imino group can be replaced,
  • a 6 to 7-membered alkyleneimino group optionally substituted by 1 or 2 methyl groups, in each of which a methylene group in the 4-position by an oxygen or sulfur atom, by a sulfinyl, sulfonyl or N- (C ⁇ -alkyl) -imino group is replaced, or
  • C is a C 1 _ 6 alkylene group, a wherein the alkylene part is linked to the radical D, or an oxygen atom, which cannot be linked to a nitrogen atom of the radical D, and
  • D is a pyrrolidino group in which the two hydrogen atoms in the 2-position are replaced by a group E in which
  • E is -CH 2 -0-CO-CH 2 -, -CH 2 CH 2 -0-CO-, -CH 2 -0-C0-CH 2 CH 2 - optionally substituted by one or two C 1 _ 2 alkyl groups Represents -CH 2 CH 2 -0-CO-CH 2 - or -CH 2 CH 2 CH 2 -0-CO- bridge,
  • R 5 is a hydrogen atom or a C 1 . 4 -alkyl group means
  • a pyrrolidino or piperidino group in which two vicinal hydrogen atoms are substituted by one -0-CO-CH 2 -, -CH 2 -0-CO-, -0-CO-CH 2 which is optionally substituted by one or two C 1-4 alkyl groups CH 2 -, -CH 2 -0-CO-CH 2 -, -CH 2 CH 2 -0-CO-, -0-C0-CH 2 -NR 5 - or -0-CO-CH 2 -0-bridge are replaced, where R 5 is defined as mentioned above and the heteroatoms of the abovementioned bridges are not bonded to the 2- or 5-position of the pyrrolidino ring and not to the 2- or 6-position of the piperidine ring,
  • a piperazino or 4- (C 1.4 alkyl) piperazino group in which a hydrogen atom in the 2 position together with a water atom in the 3-position of the Piperazinoringes by an optionally by one or two C 1 "2 alkyl substituted -CH 2 -0-C0-CH 2 - CO-bridge are replaced -0 or -CH 2 CH 2,
  • R 6 is a 2-0xo-tetrahydrofuranyl-, 2-oxo-tetra-hydropyranyl-, 2-oxo-l, 4-dioxanyl- or 2-0xo-4- (optionally substituted by one or two C - ⁇ - alkyl groups Represents C 1-4 alkyl) morpholinyl group,
  • a pyrrolidino group substituted in the 3-position by a 2-oxomorpholino group it being possible for the 2-oxomorpholino group to be substituted by one or two C 1-4 alkyl groups,
  • R s substituted 4- (C 1 4 alkyl.) -piperazino- or 4- (C - ⁇ - alkyl) -homopiperazino- group in which R 6 is defined as mentioned above,
  • R 7 is a 2-oxo-tetrahydrofuran-3-yl-, 2-0xo-te- which is optionally substituted by one or two C ⁇ -alkyl groups trahydrofuran-4-yl, 2-oxo-tetrahydropyran-3-yl, 2-oxo-tetrahydropyran-4-yl or 2-oxo-tetrahydropyran-5-yl group,
  • R 5 NR 7 (R 5 NR 7 ) -CO group substituted pyrrolidino, piperidino or hexahydroazepino group in which R s to R 7 are defined as mentioned above,
  • R 6 -CO-NR 4 -, R 6 -C 1 4- alkylene-CONR 4 -, (R 5 NR 7 ) -C ⁇ -alkylene-CONR,; -, R. j OC ⁇ -alkylene-CONR,; -, R 7 SC 1 _ 4 -alkylene-CONR 5 -, R 7 SO-C 1 . 4 -alkylene-CONR 5 -, R 7 S0 2 -C 1 _ 4 -alkylene-CONR 5 -, 2-0xo-morpholino-C 1 . 4 -alkylene-C0NR s -, R s -C 1 .
  • R 5 to R 7 are as defined above and
  • Y represents an oxygen or sulfur atom, an imino, N- (C - ⁇ - alkyl) imino, sulfinyl or sulfonyl group,
  • R s -CO-NR 5 - one in the 3 or 4 position by an R s -CO-NR 5 -, R g -C ⁇ -alkylene-CONR s -, (R S NR 7 ) -C 1 .
  • the 2-oxomorpholino part may be substituted by one or two C 1-4 alkyl groups can and the C 2 . 4 -alkyl part of the C 2 . 4 -Alkyl-Y group in each case from position 2 by a • (R 5 NR 7 ) -, R 7 0-, R 7 S, R 7 SO or R 7 S0 2 group, where R s to R 7 are defined as mentioned above,
  • R S NR 7 one on a ring carbon atom by a (R S NR 7 ) -C 1 . 4 -alkyl-, R 7 0-C 1-4 -alkyl-, R 7 SC 1 . 4- alkyl-, R 7 SO-C 1 . 4 -alkyl-, R 7 S0 2 -C 1 _ 4 -alkyl or R 5 NR 7 -CO group substituted 4- (C 1. 4 -alkyl) -piperazino- or 4- (C 1. 4 Alkyl) homopiperazino group in which R 5 to R 7 are defined as mentioned above,
  • R s -CO- one in 4 position by one , R s -CO-, R s -C 1 . 4 -alkylene-CO-, (R 5 NR 7 ) -C ⁇ -alkylene-CO-, R 7 0-C 1 . 4 -alkylene-CO-, R 7 SC 1 . 4 -alkylene-CO-, R 7 SO-C 1 . 4 -alkylene-CO- or R 7 S0 2 -C 1 _ 4 -alkylene- CO group substituted piperazino or homopiperazino group in which R 5 to R 7 are as defined above ,.
  • 4- Alkyl-Y group substituted piperidino or hexahydroazepino group in which Y is as defined above and the C 2 . 4 alkyl part of the C 2 .
  • 4- alkyl-Y group is substituted in each case from position 2 by a 2-0xo-morpholino group which is optionally substituted by one or two C 1-4 alkyl groups,
  • R 7 one in the 1 position by the radical R 7 , by a , Rg-CO-, R 6 -C 1 _ 4 -alkylene-CO-, (R 5 NR 7 ) -C ⁇ -alkylene-CO-, ⁇ -C ⁇ -alkylene-CO-, R 7 SC 1 _ 4 -alkylene-CO-, R 7 SO-C 1 . 4 -alkylene-CO-, R 7 S0 2 -C 1 . 4- alkylene-CO- or 2-0xo-morpholino-C 1 .
  • R 7 one at the ring nitrogen atom through the radical R 7 , through one , R 6 -C0-, , (R 5 NR 7 ) -C 1 _ 4 -alkylene-CO-, R 7 0-C 1 . 4 -alkylene-CO-, R 7 SC 1 . 4 -alkylene-CO-, R ⁇ OC ⁇ -alkylene-CO-, R 7 S0 2 -C 1 .
  • a C 2 _ 4 alkyl-NR 4 group in which the C 2 " 4 -alkyl part in each case from position 2 by a (R 5 NR 7 ) -, R 7 0-, R 7 S-, R 7 SO- , R 7 S0 2 - or 2-0xo-morpholino group is substituted, where R 5 and R 7 are defined as mentioned above and the 2-oxo-morpholino part can be substituted by one or two C 1-4 alkyl groups,
  • a 2-oxomorpholin-4-yl group substituted by the radical R 8 or by the radical R 8 and a C- ⁇ ' -alkyl group, where R 8 is a C 3 . 4 alkyl, hydroxy-C ⁇ alkyl, C - ⁇ - alkoxy-C ⁇ alkyl-, di- (. 1 C 4 alkyl) amino-C 1 _ 4 alkyl, pyrrolidino C 1 .
  • a 2-oxomorpholin-4-yl group in which the two hydrogen atoms of a methylene group are substituted by - (CH 2 ) m -, -CH 2 -Y-CH 2 -, optionally substituted by one or two C ⁇ alkyl groups, -CH 2 -Y-CH 2 -CH 2 -, -CH 2 CH 2 -Y-CH 2 CH 2 - or -CH 2 CH 2 -Y-CH 2 CH 2 CH 2 - bridge are replaced, whereby
  • n represents the number 2, 3, 4, 5 or 6 and Y represents an oxygen or sulfur atom, a sulfinyl, sulfonyl or C - ⁇ - alkylimino group,
  • a 2-oxomorpholin-4-yl group in which a hydrogen atom in the 5-position together with a hydrogen atom in the 6-position is replaced by a - (CH 2 ) n -, -CH 2 -Y-CH 2 -, - CH 2 -Y-CH 2 CH 2 - or -CH 2 -CH 2 -Y-CH 2 - bridge is replaced, wherein
  • Y is defined as mentioned above and n represents the number 2, 3 or 4,
  • R 9 represents a fluorine, chlorine, bromine or iodine atom, a C ⁇ alkyl, trifluoromethyl or C ⁇ alkoxy group, or
  • R a is a hydrogen atom
  • R b is a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl or 3-chloro-4-fluorophenyl group,
  • R c is a hydrogen atom
  • X is a nitrogen atom
  • A is a 1,2-vinylene or ethynylene group
  • B is a hydrogen atom
  • C is a -0-CH 2 CH 2 -, -0-CH 2 CH 2 CH 2 - or -0-CH 2 CH 2 CH 2 CH 2 - group, the alkylene part in each case being linked to the radical D, and
  • D is a piperidino group in which the two hydrogen atoms are in the 4-position by a -CH 2 -0-CO-CH 2 -, -CH 2 CH 2 -0-C0-, -CH 2 CH 2 -0-CO-CH 2 -, -0-CO-CH 2 -NCH 3 -CH 2 - or -0-CO-CH 2 -0-CH 2 bridge are replaced, a piperazino group in which a hydrogen atom in the 3-position together with the hydrogen atom in the 4-position are replaced by a -C0-0-CH 2 -CH 2 - or -CH 2 -0-CO-CH 2 bridge, in each case the left end of the protruding bridges is bound to the 3-position of the piperazin ring,
  • R s represents a 2-oxotetrahydrofuran-3-yl or 2-oxotetrahydrofuran-4-yl group
  • a 2 -oxo-morpholin-4-yl group in which the two hydrogen atoms of a methylene group are replaced by a -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 -0-CH 2 CH 2 - or -CH 2 CH 2 -0-CH 2 CH 2 bridge are replaced,
  • R a is a hydrogen atom
  • R b is a 1-phenylethyl or 3-chloro-4-fluorophenyl group
  • R c is a hydrogen atom
  • X is a nitrogen atom
  • A is a 1,2-vinylene group
  • B is a hydrogen atom
  • C is a -0-CH 2 CH 2 -, -0-CH 2 CH 2 CH 2 - or -0-CH 2 CH 2 CH 2 CH 2 - group, the alkylene part in each case being linked to the radical D, and
  • D is a piperazino group which is substituted in the 4-position by a 2-oxo-tetrahydrofuran-4-yl or 2-oxo-tetrahydrofuran-5-ylcarbonyl group,
  • the compounds of the general formula I can be prepared, for example, by the following process:
  • R a to R c , C, D and and X are as defined in the introduction, with a compound of the general formula
  • a and B are 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, or a hydroxyl group.
  • the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride / tetrahydrofuran or dioxane, optionally in the presence of an inorganic or organic base and, if appropriate, in the presence of a dehydrating agent, at temperatures between -80 and 150 ° C, preferably at temperatures between -60 and 80 ° C.
  • the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride / tetrahydrofuran or dioxane in the presence of a tertiary organic Base such as triethylamine, pyridine, 2-dimethylaminopyridine or N-ethyl-diisopropylamine (Hünig base), which organic bases can also serve as solvents at the same time, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide solution advantageously at temperatures between -80 and 150 ° C, preferably at temperatures between -60 and 80 ° C, performed.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chlor
  • reaction is preferably In
  • a dehydrating agent for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimine-benzide or hydroxysolimide-n-hydroxysolimide and optionally additionally in the presence of 4-dimethylamino-pyridine, N, N'-carbonyldiimidazole or triphenylphosphine / tetrahloro carbon, expediently in a solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, ethylene glycol diethyl ether or sulfolane and optionally in the presence of a s
  • reaction is carried out particularly advantageously with acrylic acid and acrylic acid chloride in the presence of triethylamine.
  • any reactive groups present such as hydroxyl, carboxy or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group
  • the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-ethoxybenzyl group are considered.
  • the subsequent subsequent splitting off of a protective radical used is carried out, 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 how.
  • 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.
  • 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 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 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. ,
  • 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 on the basis of their physicochemical differences according to methods known per se, for example by Separate 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 separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms 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, e.g. due to 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.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • 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 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. 1, 2749-2756 (1988) and Pierce, JH et al. in Science 23_9_, 628-631 (1988)).
  • the FDC-Pi cell line the production of which by Dexter, TM et al. in J. Exp. Med. 152, 1036-1047 (1980).
  • other growth factor-dependent cells can also be used (see, for example, Pierce, JH et al. In Science 2.3_9_, 628-631 (1988), Shibuya, H. et al. in Cell 2__, 51-67 (1992) and Alexander, WS et al. in EMBO J. IQ, 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% CO 2 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 compounds according to the invention were dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated at 37 ° C for 48 hours.
  • DMSO dimethyl sulfoxide
  • 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 was shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by overfunction of tyrosine kinases.
  • pathophysiological processes which are caused by overfunction of tyrosine kinases.
  • tyrosine kinases are, for example, 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 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 chronically inflammatory changes, such as cholecystitis, M. Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or how they are associated with diseases of the gastrointestinal tract that increase Secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes,
  • nasal polyps as well as of polyps of the gastrointestinal tract of different genesis such as e.g. villous or adenomatous polyps of the large intestine, but also of polyps for familial polyposis coli, for intestinal polyps as part of Gardner syndrome, for polyps in the entire gastrointestinal tract for Koz-Jeghers syndrome, for inflammatory pseudopolypes, for juvenile polyps , with colitis cystica profunda and with Pneumatosis cystoides intestinales.
  • different genesis such as e.g. villous or adenomatous polyps of the large intestine, but also of polyps for familial polyposis coli, for intestinal polyps as part of Gardner syndrome, for polyps in the entire gastrointestinal tract for Koz-Jeghers syndrome, for inflammatory pseudopolypes, for juvenile polyps , with colitis cystica profunda and with Pneumatosis cystoides intestinales.
  • kidney diseases in particular in the case of cystic changes such as in cystic kidneys
  • kidney cysts which may be of idiopathic origin or occur in the context of syndromes such as e.g. in tuberous sclerosis, in von Hippel-Lindau syndrome, in nephronophthisis and marrow marrow as well as other diseases which are caused by aberrant function of tyrosine kinases, such as e.g. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells etc.
  • psoriasis epidermal hyperproliferation
  • 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 therapies, such as secretolytic, broncholytic and / or anti-inflammatory substances.
  • these compounds can also be given alone or in combination with motility or secretion-influencing or anti-inflammatory substances. These combinations can be administered either simultaneously or sequentially.
  • Combination with other active substances can take place intravenously, subcutaneously, intramuscularly, intrarectally, 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.
  • the reaction mixture is refluxed for about two hours.
  • the inorganic salts are filtered off and washed with ethyl acetate and methylene chloride / methanol.
  • the filtrate is concentrated and the evaporation residue is taken up in methylene chloride / methanol.
  • the solution is washed with water, dried over magnesium sulfate and concentrated.
  • the yellow, resinous residue is chromatographed on a silica gel column using methylene chloride / methanol / concentrated, aqueous ammonia solution (95: 4: 1).
  • the title compound is obtained as a yellow solid. Yield: 625 mg (49% of theory),
  • 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.
  • a tableting machine compacts with a diameter; 13 mm, which 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 tabletting machine into tablets with 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.
  • 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.
  • Diameter 10 mm, biplane with facet on both sides and partial notch on one side.
  • Composition 1 tablet contains:
  • colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg
  • 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 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 shell hard gelatin capsule size 1.
  • 1 suppository contains: active ingredient 150.0 mg
  • Polyethylene glycol 1500 550.0 mg
  • Hprst-.sllnn ⁇ After the suppository mass has melted, the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.
  • 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.
  • Active ingredient 50.0 mg 0.01N hydrochloric acid s.q.
  • 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:
  • 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 nebuliser. Filling mass of the container: 4.5 g

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des hétérocycles bicycliques de formule générale (I) dans laquelle Ra à Rc, A à E et X ont la signification mentionnée dans la revendication 1, leurs tautomères, leurs stéréoisomères et leurs sels, notamment leurs sels physiologiquement tolérables avec des acides ou des bases inorganiques ou organiques, qui présentent des propriétés pharmacologiques intéressantes, en particulier un effet inhibiteur sur la transduction de signaux induite par tyrosine-kynases. L'invention concerne en outre l'utilisation desdits hétérocycles bicycliques pour traiter des affections, en particulier des affections tumorales, des affections des poumons et des voies respiratoires, ainsi que leur mode de production.
EP01969610A 2000-08-26 2001-08-18 Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire Withdrawn EP1315716A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10042061A DE10042061A1 (de) 2000-08-26 2000-08-26 Bicyclische Heterocyclen,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042061 2000-08-26
PCT/EP2001/009535 WO2002018370A1 (fr) 2000-08-26 2001-08-18 Heterocycles bicycliques, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire

Publications (1)

Publication Number Publication Date
EP1315716A1 true EP1315716A1 (fr) 2003-06-04

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Country Status (7)

Country Link
EP (1) EP1315716A1 (fr)
JP (1) JP2004507533A (fr)
AU (1) AU2001289814A1 (fr)
CA (1) CA2417042A1 (fr)
DE (1) DE10042061A1 (fr)
MX (1) MXPA03001510A (fr)
WO (1) WO2002018370A1 (fr)

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TWI324597B (en) 2002-03-28 2010-05-11 Astrazeneca Ab Quinazoline derivatives
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20040044014A1 (en) 2002-04-19 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof
DE10217689A1 (de) * 2002-04-19 2003-11-13 Boehringer Ingelheim Pharma Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
GB0317665D0 (en) 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
CN1882569B (zh) 2003-09-19 2010-09-29 阿斯利康(瑞典)有限公司 喹唑啉衍生物
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
CA2592900A1 (fr) 2005-01-03 2006-07-13 Myriad Genetics Inc. Composes et utilisation therapeutique associee
AR055564A1 (es) 2005-02-26 2007-08-22 Astrazeneca Ab Derivados de quinazolina
EP1921070A1 (fr) 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG heterocycles bicycliques, medicaments á base de ces composes, leur usage et procédé pour leur preparation
KR20090116782A (ko) 2007-02-06 2009-11-11 베링거 인겔하임 인터내셔날 게엠베하 바이사이클릭 헤테로사이클, 당해 화합물을 함유하는 약물, 이의 용도 및 이의 제조방법
KR20100111291A (ko) 2008-02-07 2010-10-14 베링거 인겔하임 인터내셔날 게엠베하 스피로사이클릭 헤테로사이클, 상기 화합물을 함유하는 약제, 이의 용도 및 이의 제조 방법
US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
US8507502B2 (en) 2008-11-10 2013-08-13 National Health Research Institutes Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors
ES2639407T3 (es) * 2010-06-09 2017-10-26 Tianjin Hemay Oncology Pharmaceutical Co., Ltd. Derivados de cianoquinolina
CN102382106A (zh) 2010-08-30 2012-03-21 黄振华 苯胺取代的喹唑啉衍生物
KR101317809B1 (ko) 2011-06-07 2013-10-16 한미약품 주식회사 암세포의 성장을 억제하는 아마이드 유도체 및 비금속염 활택제를 포함하는 약학 조성물
KR20140096571A (ko) 2013-01-28 2014-08-06 한미약품 주식회사 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법
SG11202102981SA (en) 2018-09-25 2021-04-29 Black Diamond Therapeutics Inc Quinazoline derivatives as tyrosine kinase inhibitor, compositions, methods of making them and their use

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Also Published As

Publication number Publication date
CA2417042A1 (fr) 2002-03-07
JP2004507533A (ja) 2004-03-11
AU2001289814A1 (en) 2002-03-13
WO2002018370A1 (fr) 2002-03-07
DE10042061A1 (de) 2002-03-07
MXPA03001510A (es) 2003-06-09

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