EP1740577A2 - Antagonistes du cgrp selectionnes, procedes de production de ces antagonistes et leur utilisation comme medicaments - Google Patents

Antagonistes du cgrp selectionnes, procedes de production de ces antagonistes et leur utilisation comme medicaments

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Publication number
EP1740577A2
EP1740577A2 EP05735460A EP05735460A EP1740577A2 EP 1740577 A2 EP1740577 A2 EP 1740577A2 EP 05735460 A EP05735460 A EP 05735460A EP 05735460 A EP05735460 A EP 05735460A EP 1740577 A2 EP1740577 A2 EP 1740577A2
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European Patent Office
Prior art keywords
alkyl
amino
group
oxo
atom
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.)
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Application number
EP05735460A
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German (de)
English (en)
Inventor
Stephan Georg Mueller
Klaus Rudolf
Philipp Lustenberger
Dirk Stenkamp
Marco Santagostino
Fabio Paleari
Gerhard Schaenzle
Kirsten Arndt
Henri Doods
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1740577A2 publication Critical patent/EP1740577A2/fr
Withdrawn legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
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    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to the CGRP antagonists of the general formula
  • A, Q, X, R 1 , R 2 and R 3 are as defined in claim 1, their tautomers, their isomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, as well as those compounds of the general formula I in which one or more hydrogen atoms are replaced by deuterium, medicaments containing these compounds, their use and processes for their preparation.
  • A is an oxygen or sulfur atom
  • X is an oxygen or sulfur atom
  • Q is a heterocycle bonded via a carbon or nitrogen atom and consisting of two or three, each of 4- to 8-membered, independently saturated, partially unsaturated or fully unsaturated, condensed rings, where the heterocycle has one to five heteroatoms selected independently of one another from the group O, N and S may contain one or two carbonyl groups as ring members and each saturated nitrogen atom as a ring member of the heterocycle may be substituted by the group R a and one or two carbon atoms as ring members of the heterocycle may be substituted by the group R b ,
  • R 1 is a saturated, mono- or diunsaturated 5- to 7-membered aza-, diaza-, triaza-, oxaza-, thiaza-, thiadiaza- or S, S-dioxo-thiadiaza heterocycle, where the heterocycles mentioned above are linked via a carbon or nitrogen atom to the piperidine ring in formula I or spirocyclically linked to the piperidine ring in formula I via two carbon atoms, via a carbon atom and a nitrogen atom, via a carbon and an oxygen atom or via a carbon and a sulfur atom are one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen atom contained on one of the nitrogen atoms by a C- ⁇ - 6 alkyl, C 3 - 6 alkenyl or C.
  • 3 6 alkenyl group may be substituted at one or two carbon atoms by a C ⁇ _ 6 alkyl, C 2 - 6 alkenyl or C2- 6 alkynyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl -, diazinyl, furyl, thienyl, pyrrolyl, 1, 3-oxazolyl, 1, 3-thiazolyl, isoxazolyl, pyrazolyl, 1- (C 3 -alkyl) -pyrazolyl, imidazolyl or 1- (C 1-3 alkyl) -imidazolyl may be substituted, wherein the substituents may be identical or different, and an olefinic double bond of one of the aforementioned unsaturated heterocycles with a phenyl, naphthyl, pyridine, diazine, 1, 3-oxazole, thienyl, furan, thiazo
  • R 2 is the hydrogen atom
  • a phenyl or pyridinyl group wherein the phenyl, pyridinyl and diazinyl groups mentioned in the groups defined above for R 2 or contained as substituents additionally in the carbon skeleton by halogen, by C- ⁇ - 3 alkyl, C 2 - 3 alkenyl -, C 2 - 3 -alkynyl, -C. 3 alkoxy, hydroxy, amino, C 3 -alkylamino, di (C ⁇ _ 3 -alkyl) amino, amino, C ⁇ . 3 -alkyl, C ⁇ . 3- alkyl-amino-C. 3- alkyl-, di- (-C 3 -alkyI) amino-C ⁇ .
  • R 3 is the hydrogen atom or a substituted by a phenyl or pyridinyl C ⁇ . 3- alkyl group, wherein the C ⁇ - 3 alkyl group having an alkyl group contained in R 2 or a phenyl or pyridyl ring contained in R 2 , including the nitrogen atom to which R 2 and R 3 are bonded, to form a 4- may be linked to the membered ring
  • R 2 and R 3 together with the enclosed nitrogen atom is a radical of the general formula
  • Y 1 represents the carbon atom or, if R 5 represents a lone pair of electrons, also the nitrogen atom, q and r, if Y 1 represents the carbon atom, the numbers 0, 1 or 2, or q and r when Y 1 represents the nitrogen atom, the numbers 1 or 2,
  • R 4 is the hydrogen atom, an amino, alkylamino, C ⁇ - 6 alkyl, an optionally substituted by a hydroxycarbonyl, C ⁇ _ 6 alkoxycarbonyl, hydroxycarbonyl -C. alkyl or C 6 -alkoxycarbonyl
  • heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to 10-membered oxaza-, thiaza-, S, S-dioxothiaza- and
  • Diazacycloalkyl group and a 6- to 10-membered azabicycloalkyl group are provided.
  • a methine group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms and a methylene group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms,
  • Y 1 represents the carbon atom, the hydroxycarbonyl, aminomethyl, C 1 . 4 alkyl-aminornet.hyl- or di- (C ⁇ - 4 alkyl) -aminomethyl distr,
  • R is a hydrogen atom or a hydroxy group
  • a C ⁇ - 4 alkyl group wherein an unbranched alkyl radical in ⁇ -position by a phenyl, pyridinyl, diazinyl, amino, C- ⁇ - 4 alkylamino, di- (C ⁇ - 4 alkyl) amino , 4-C ⁇ - 4- alkyl-1-piperazinyl or 4-morpholinyl group may be substituted,
  • Y 1 represents 6 alkoxycarbonyl, cyano or aminocarbonyl group or a nitrogen atom, a free electron pair
  • Y 1 represents the carbon atom, also the fluorine atom, or
  • R 4 together with R 5 and Y 1 is a 4- to 7-membered cycloaliphatic ring in which a methylene group by a group -NH-, -N (C ⁇ ⁇ alkyl) - (. 3 C 4 alkenyl), -N -, -N (C 3 - 4 alkynyl) -, -N (cyclo-C 3 7 alkyl.) -, -N (C 3 - C cycloalkyl- ⁇ - 3 alkyl) -, -N ( hydroxycarbonyl-3 C ⁇ _ -alkyl) - or -N (C ⁇ - 6 alkoxycarbonyl
  • C ⁇ - 3 alkyl) - may be replaced, with one to a nitrogen atom in one of the above for R 4 defined Groups bonded hydrogen atom may be replaced by a protective group,
  • R 6 and R 7 which may be the same or different, each represents a hydrogen atom, a or also, when Y 1 represents a carbon atom, the fluorine atom, an amino, -C ⁇ alkylamino or di (C ⁇ _ 4 alkyl) - amino group, wherein the two CM-alkyl groups may be connected together to form a ring, and R 8 and R 9 , which may be identical or different, each represent a hydrogen atom or a C 1-3 -alkyl group,
  • R a represents a hydrogen atom, a linear or branched C 1 -C 6 -alkyl, C 3 . 6 alkenyl, C 3 - 6 alkynyl or cyclo C 3 -, provided that it is not -alkyIuite 7 in which each hydrogen atom in ⁇ -position to a nitrogen atom may be replaced by fluorine, means
  • R b is a halogen atom, a linear or branched C ⁇ - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, cyclo C. 3 7 -alkyl, cyano, hydroxy, hydroxy-C 6 -alkyl, Ci- ⁇ -alkoxy, C ⁇ .
  • alkyl, alkenyl and alkynyl groups mentioned or included in the above defined radicals may be straight chain or branched, any methine group having one fluorine atom contained in the above-defined radicals, any methylene group having up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms and two alkyl and alkenyl groups bonded to a nitrogen atom may be linked together to form a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
  • alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso propoxycarbonyl, t7-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxy-carbonyl or fet-t-butyloxycarbonyl group,
  • halogen atom under a halogen atom, a fluorine, chlorine, bromine or iodine atom and
  • a second embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • A is an oxygen or sulfur atom
  • X is an oxygen or sulfur atom
  • Q is a heterocycle bonded via a carbon or nitrogen atom and consisting of two or three, each of 4- to 8-membered, independently saturated, partially unsaturated or fully unsaturated, condensed rings, where the heterocycle comprises one to five heteroatoms selected independently of one another the group O, N and S may contain one or two carbonyl groups as ring members and each saturated nitrogen atom as a ring member of the heterocycle may be substituted by the group R a and one or two carbon atoms as ring members of the heterocycle may be substituted by the group R b ,
  • R 1 is a saturated, mono- or diunsaturated 5- to 7-membered aza-, diaza-, triaza-, oxaza-, thiaza-, thiadiaza- or S, S-dioxo-thiadiaza heterocycle, where the heterocycles mentioned above via a carbon or nitrogen atom are linked to the piperidine ring in formula I or via two carbon atoms, via a carbon and a nitrogen atom, via a carbon and an oxygen atom or via a carbon and a sulfur atom with the piperidine ring in formula I.
  • C ⁇ - 6 alkyl are spirocyclically linked, one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen atom contained in one of the nitrogen atoms by a C ⁇ - 6 alkyl
  • C 3 - 6 alkenyl or C 3 - 6 alkenyl group may be substituted, at one or two carbon atoms by a C ⁇ _ 6 alkyl, C 2 - 6 alkenyl or C 2 - 6 alkynyl, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl -, thienyl, pyr rolyl, 1, 3-oxazolyl, 1, 3-thiazolyl, isoxazolyl, pyrazolyl, 1- (C ⁇ - 3 alkyl) pyrazolyl, imidazolyl or 1- (C ⁇ - 3 alkyl) imidazolyl may be substituted, wherein the substitu
  • 3- alkyl-pyrrole or quinoline ring with a on the nitrogen atom optionally substituted by a C ⁇ _ 6 alkyl, C 3 - 6 -AlkenyI- or C 3 - 6 alkynyl-substituted 1 H-quinolin-2-one ring or with a Imidazole or ⁇ / -C ⁇ .
  • two olefinic double bonds of one of the abovementioned unsaturated heterocycles may each be condensed with a phenyl or pyridine ring, the phenyl, pyridinyl, diazinyl, furyl, thienyl, radicals contained in R 1 being condensed Pyrrolyl-, 1, 3-oxazolyl, 1, 3-thiazolyl, isoxazolyl, pyrazolyl, 1-C ⁇ _ 3 -AlkyI- pyrazolyl, imidazolyl or 1-C.
  • 6- alkyl-sulfinyl C 2 - 6 alkenyl-sulfinyl, C 2 - 6 alkynyl-sulfinyl, Ci- ⁇ -alkyl-sulfonylamino, C 2 - 6 alkenyl-sulfonylamino, C 2 - 6 Alkynylsulfonylamino, Ct_ 6 alkylsulfonyl C ⁇ . 6 -alkylamino, C ⁇ .6-alkyl-sulfonyl-C 3 . 6 -alkenylamino, -C.
  • R is the hydrogen atom
  • a phenyl or pyridinyl group wherein the phenyl, pyridinyl and diazinyl groups mentioned in the groups defined above for R 2 or contained as substituents additionally in the carbon skeleton by halogen, by C. 3 alkyl, C 2 - 3 alkenyl, C 2 - 3 alkynyl, C ⁇ - 3 alkoxy, hydroxy, amino, C ⁇ - 3 alkylamino, di- (3 C ⁇ - alkyl) -amino, amino- C ⁇ - 3 -alkyl-, C ⁇ - 3- alkyl-amino-C ⁇ . 3 -alkyl-, di- (C ⁇ - 3 -alkyI) amino-C ⁇ .
  • R 3 represents the hydrogen atom or a C 1-3 alkyl group substituted by a phenyl or pyridinyl group, the C 1-3 -alkyl group having an alkyl group contained in R 2 or a phenyl or pyridyl ring contained in R 2 , including the nitrogen atom to which R 2 and R 3 are bonded to form a 4-7 membered ring,
  • R 2 and R together with the enclosed nitrogen atom is a radical of the general formula
  • Y represents the carbon atom or, when R represents a lone pair of electrons, also the nitrogen atom, q and r, when Y 1 represents the carbon atom, the numbers 0, 1 or 2, or q and r, when Y 1 represents the nitrogen atom, the numbers 1 or 2,
  • R 4 is the hydrogen atom, an amino, -C. Alkyl-amino, di- (. C ⁇ 4 alkyl) - alkylamino, C ⁇ . 6- alkyl, cyclo-C 3 .
  • a heterocycle selected from a 4- to 10-membered azacycloalkyl group, a 6- to 10-membered oxaza-, thiaza- and diazacycloalkyl group and a 6- to 10-membered azabicycloalkyl group,
  • a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group wherein the abovementioned mono- and bicyclic heterocycles are bonded to Y 1 in formula (II) via a nitrogen or a carbon atom, in the abovementioned mono- and bicyclic heterocycles, a methine group not directly linked to a nitrogen, oxygen or sulfur atom by a fluorine atom and a methylene group not directly linked to a nitrogen, oxygen or sulfur atom by one or two fluorine atoms can
  • Y 1 represents the carbon atom, the hydroxycarbonyl, aminomethyl, C 1-6 -alkylaminomethyl- or di- (C 1-6 -alkyl) -aminomethyl group,
  • R 5 is a hydrogen atom
  • a C ⁇ - 4 alkyl group wherein an unbranched alkyl radical in ⁇ -position by a phenyl, pyridinyl, diazinyl, amino, C ⁇ _ 4 alkylamino, di- (C ⁇ - 4 -alkyl) -amino, 4- C ⁇ - 4 alkyl-piperazinyl-1 or 4-morpholinyl group may be substituted,
  • Y 1 represents a nitrogen atom, a lone pair of electrons
  • Y 1 represents the carbon atom, also the fluorine atom, or
  • R 4 together with R 5 and Y 1 is a 4- to 7-membered cycloaliphatic ring in which a methylene group by a group -NH-, -N (C ⁇ - 4 alkyl) -, -N (. C 3 -alkenyl) may be substituted, wherein - -, -N (. 3 C 4 alkynyl) -, -N (Cycio-C 3 - 7 alkyl) - or -N (C 3 - 7 cycloalkyl C ⁇ - 3 alkyl) a hydrogen atom bonded to a nitrogen atom in one of the groups defined above for R 4 may be replaced by a protective group,
  • R 6 and R 7 which may be identical or different, each represent a hydrogen atom, a C- M- alkyl group or, if Y 1 represents a carbon atom, the fluorine atom, a Cu-alkylamino or di (C ⁇ - 4- alkyl ) -amino group, wherein the two C- M- alkyl groups may be connected together to form a ring, and
  • R 8 and R 9 which may be the same or different, each represents a hydrogen atom or a C 1-3 alkyl group, in which
  • R a is a hydrogen atom, a linear or branched C. 6 alkyl, C 3 . 6 alkenyl, C 3 . 6- alkynyl or cyclo-C 3 . 7 -alkyl group in which each hydrogen atom, unless it is in ⁇ -position to a nitrogen atom, may be replaced by fluorine means
  • R b is a halogen atom, a linear or branched C- ⁇ . 6 alkyl, C 2 - 6 alkenyl, C2-6-alkynyl, cyclo-C3-7-alkyl, cyano, hydroxy, hydroxy-C ⁇ _ 6 alkyl, C ⁇ _ 6 alkoxy, C ⁇ 6 -alkoxy-C ⁇ _ 6 alkyl, amino, C ⁇ _ 6 alkyl-amino or di-C ⁇ - 6 alkyl-amino group in which each hydrogen atom, unless it is in ⁇ -position to a nitrogen atom may be replaced by fluorine and the two alkyl groups of the di-C ⁇ - 6 alkyl-amino substituents may be linked together to form a 4- to 8-membered ring,
  • a third embodiment of the present invention consists in the compounds of the above general formula (I) in which A, X, Q, R 2 and R 3 are defined as mentioned above under the first or second embodiment, and
  • R 1 represents a mono- or diunsaturated 5- to 7-membered aza, diaza, triaza or thiaza heterocycle, wherein the aforementioned heterocycles are linked via a carbon or nitrogen atom or via a carbon atom and a nitrogen atom a carbon and an oxygen atom, or spirocyclically linked via a carbon and a sulfur atom, containing one or two carbonyl groups adjacent to a nitrogen atom, on a carbon atom through a phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1, 3-thiazolyl, isoxazolyl, pyrazolyl or 1- (C ⁇ - 4 alkyl) pyrazolyl group may be substituted and wherein an olefinic double bond of one of the aforementioned unsaturated heterocycles with a phenyl, naphthyl, pyridine, diazine , Thienyl or quinoline ring or may be fused
  • alkyl, alkenyl and alkynyl groups mentioned or contained in the radicals defined above under R 1 may be straight-chain or branched, any methine group having one fluorine atom, each methylene group contained in the above defined radicals up to 2 fluorine atoms and each methyl group can be substituted with up to 3 fluorine atoms and two bonded to a nitrogen atom alkyl and alkenyl groups to form a 4- to 7-membered, saturated or unsaturated heterocyclic ring may be joined together, and
  • R 1 all of the aromatic and heteroaromatic radicals mentioned or contained in the radicals defined above under R 1 may additionally be mono-, di- or trisubstituted by halogen, by cyano or hydroxyl groups and the substituents may be identical or different,
  • a fourth embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • A, X, Q, R 2 and R 3 are defined as mentioned above under the first or second embodiment, and
  • R 1 represents a monounsaturated 5- to 7-membered diaza or triaza heterocycle, wherein the above-mentioned heterocycles are linked via a nitrogen atom or are spirocyclically linked via a carbon and a nitrogen atom or via a carbon and an oxygen atom, contain a carbonyl group adjacent to a nitrogen atom, may additionally be substituted on a carbon atom by a phenyl group, and wherein an olefinic double bond of one of the aforementioned unsaturated heterocycles having a Phenyl, thienyl or quinoline ring may be condensed, wherein the phenyl groups contained in R 1 and benzo-fused heterocycles in the carbon skeleton additionally by halogen, by methyl, methoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, -C- -AlkyIamino-, di (C ⁇ _ 4 alkyl) amino, acetylamino, ace
  • alkyl groups mentioned or included in the radicals defined above under R 1 may be straight-chain or branched, any methine group having one fluorine atom contained in the above-defined radicals, any methylene group having up to 2 fluorine atoms and any methyl group be substituted by up to 3 fluorine atoms,
  • a fifth embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • A, X, Q, R 2 and R 3 are defined as mentioned above under the first or second embodiment, and
  • R 1 is 1, 3,4,5-tetrahydro-1,3-benzdiazepin-2-one-3-yl, 3,4-dihydro-1H-quinazolin-2-on-3-yl, 5-phenyl -2,4-dihydro-1,2,4-triazol-3-on-2-yl, 1,3-dihydroimidazo [4,5-c] quinolin-2-one-3-yl , 1, 3-Dihydro-naphth [1,2-c] imidazol-2-on-3-yl, 1, 3-dihydro-benzimidazol-2-one-3-yl, 4-phenyl-1 , 3-dihydro-imidazol-2-one-1-yl, 3,4-dihydro-1H-thieno [3,2-c] pyrimidin-2-one-3-yl or 3,4-dihydro -1 H-thieno [3,4] pyrimidin-2-on-3-yl-group-pe or together with the piperidine
  • R 1 all the aromatic and heteroaromatic radicals mentioned or contained in the radicals defined above under R 1 may additionally be mono-, di- or trisubstituted by halogen atoms, by cyano or hydroxyl groups and the substituents may be identical or different,
  • a sixth embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • A, X, R 1 , R 2 and R 3 are defined as mentioned above under the first, second, third, fourth or fifth embodiment, and Q is a heterocycle bonded via a carbon or a nitrogen atom and consisting of a ring A and a ring B which is fused via two adjacent carbon atoms or via a carbon atom and an adjacent nitrogen atom to the ring A, the rings A and B being selected independently of one another are from a 4-membered, saturated or monounsaturated carbocycle in which a ring member may be replaced by a> NR a group, an oxygen or sulfur atom or, in the case of an unsaturated ring member, by a nitrogen atom, a 5-membered, saturated, mono- or diunsaturated carbocycle in which one, two or three ring members can be replaced independently of one another by a> NR a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by a nitrogen atom, in each case two or three oxygen or
  • a methylene group as a ring member in the 4-membered rings A and B may each be independently replaced by a carbonyl group
  • one or two methylene groups as ring members in the 5- to 8-membered rings A and B may each be independently replaced by carbonyl groups,
  • one or two carbon atoms may be substituted as ring members of rings A and B by R b , where the substituents may be the same or different,
  • a hydrogen atom bound to a carbon or nitrogen atom as the ring member of ring A and another hydrogen atom bonded to a carbon or nitrogen atom as ring member of ring B, said ring members being separated from each other by two bonds by a C 2 - 5 -n- Alkylene bridge can be replaced and thus form a tricycle, wherein in the aforementioned C 3 - 6 -n-alkylene bridges and C 2 - 5 -n-alkylene bridges, a methylene group may be replaced by a carbonyl group and / or one or two methylene groups independently of the Given that two oxygen and two sulfur atoms are not directly linked to one another, in each case by a> NR a group, an oxygen or sulfur atom may be replaced or / and a carbon atom may be substituted by R b ,
  • R a is a hydrogen atom, a linear or branched Ci- ⁇ -alkyl, C 3 . 6 alkenyl, C 3 - 6 alkynyl or cyclo-C 3 -7-alkyl group in which each hydrogen atom, unless it is in ⁇ -position to a nitrogen atom, may be replaced by fluorine,
  • R b is a halogen atom, a linear or branched C- ⁇ - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, cyclo C. 3 7 -alkyl, cyano, hydroxy, hydroxy -C.
  • the group Q contains a total of no more than five heteroatoms as ring members
  • the group Q contains a total of not more than two carbonyl groups as ring members
  • a group R b bound to a saturated carbon atom in the ⁇ position relative to a saturated nitrogen atom substituted by the group R a , an oxygen or sulfur atom as ring member of a bi- or tricyclic heterocycle of the group Q does not have the meanings of a hydroxyl group.
  • a seventh embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • A, X, R 1 , R 2 and R 3 are defined as mentioned above under the first, second, third, fourth or fifth embodiment, and
  • Q is a heterocycle bonded via a carbon or a nitrogen atom and consisting of a ring A and a ring B which is fused via two adjacent carbon atoms or via a carbon atom and an adjacent nitrogen atom to the ring A, the rings A and B being selected independently of one another are composed of a 5-membered, saturated, mono- or diunsaturated carbocycle in which one, two or three ring members are independently of each other represented by a> NR a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, by a nitrogen atom may be replaced, wherein a maximum of two ring members oxygen or sulfur atoms and these may not be directly linked, or a 6-membered, saturated, mono-, di- or triunsaturated carbocycle, in which one, two or three ring members independently in each case by a> NR a group, an oxygen or sulfur atom or, im Case of unsaturated ring members, may be replaced by a nitrogen atom, where
  • one or two methylene groups as ring members in the 5- to 7-membered rings A and B may each be independently replaced by carbonyl groups,
  • one or two carbon atoms may be substituted as ring members of rings A and B by R b , where the substituents may be the same or different,
  • R a represents a hydrogen atom, a linear or branched C 1-3 -alkyl, C 3 -alkenyl, C 3 -alkynyl or cyclo-C 3-6 -alkyl group in which each hydrogen atom, if it is not in the ⁇ -position to a nitrogen atom, may be replaced by fluorine,
  • R b is a halogen atom, a linear or branched -C. 3- alkyl, C 2 - 3 alkenyl, C 2 - 3 alkynyl, cyclo-C 3 . 6 -alkyl, cyano, hydroxy, hydroxy-C- ⁇ . 3 -alkyl, C ⁇ . 3 -alkoxy, C ⁇ . 3 -alkoxy-C ⁇ - 3 -alkyl-, amino, -C.
  • the group Q contains in total not more than three heteroatoms as ring members
  • the group Q contains a total of not more than two carbonyl groups as ring members
  • A, X, R 1 , R 2 and R 3 are defined as mentioned above under the first, second, third, fourth or fifth embodiment, and
  • Q is a heterocycle bonded via a carbon or a nitrogen atom and consisting of a ring A and a ring B which is fused via two adjacent carbon atoms or via a carbon atom and an adjacent nitrogen atom with the ring A, wherein the rings A and B with the proviso in that A is a 5- or 6-membered ring and B is a 6- or 7-membered ring selected from a 5-membered, saturated, mono- or diunsaturated carbocycle in which one, two or three ring members are independently in each case by a> NR a group, an oxygen or sulfur atom or, in the case of unsaturated ring members, may be replaced by a nitrogen atom, wherein a maximum of two ring members oxygen atom, which may not be directly linked together, represent and a maximum of one ring member is a sulfur atom , or a 6-membered, saturated, mono-, di- or triunsaturated carbocycle in which one, two or three Ringglie each
  • one or two methylene groups as ring members in the 5- to 7-membered rings A and B may each be independently replaced by carbonyl groups,
  • one or two carbon atoms may be substituted as ring members of rings A and B by R b , where the substituents may be the same or different,
  • a hydrogen atom bonded to a carbon or nitrogen atom as ring member of ring A and another hydrogen atom bonded to a carbon or nitrogen atom as ring member of ring B, said ring members being separated by two bonds, by a C 2 - 3 -n- Alkylene bridge can be replaced, thus forming a tricycle, wherein in the aforementioned C 3 . 4 -n-alkylene bridges and C 2 - 3 -n-alkylene bridges one or two methylene groups may be substituted independently of one another by R b ,
  • R a represents a hydrogen atom or a linear or branched C 1-3 -alkyl group in which each hydrogen atom, if it is not in the ⁇ -position to a nitrogen atom, may be replaced by fluorine,
  • R b is a halogen atom or a linear or branched C ⁇ _ 3 alkyl group in which each hydrogen atom, unless it is in ⁇ position to a nitrogen atom, may be replaced by fluorine, with the stipulations that
  • the group Q contains in total not more than three heteroatoms as ring members
  • the group Q contains a total of not more than two carbonyl groups as ring members
  • a ninth embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • A, X, Q and R 1 are defined as mentioned above under the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment, and
  • R 2 is the hydrogen atom
  • R 3 represents the hydrogen atom or a C ⁇ _ 3 alkyl group or
  • R 2 and R 3 together with the enclosed nitrogen atom is a radical of the general formula
  • Y 1 is the carbon atom or, when R 5 is a lone pair, also the nitrogen atom, q and r, when Y 1 represents the carbon atom, the numbers 0 or 1, or q and r, when Y 1 represents the nitrogen atom, the numbers 1 or 2, R 4 is the hydrogen atom, an amino, -C.
  • alkyl group a phenyl, pyridinyl or diazinyl group, each represented by a halogen, by a -C-3-alkyl, C ⁇ _ 3 alkoxy, hydroxy, amino, Cu-alkyl-amino, di (C
  • 3- alkyl group a heterocycle selected from a 4- to 7-membered azacycloalkyl group, a 6- to 7-membered oxazal, S, S-dioxothiaza- or diazacycloalkyl group and a 7- to 9-membered azabicycloalkyl group, wherein the above-mentioned mono- and bicyclic heterocycles are bonded to Y 1 in formula (II) via a nitrogen or a carbon atom, in the above-mentioned mono- and bicyclic heterocycles a methylene group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms and the abovementioned mono- and bicyclic heterocycles one or two times by hydroxy, C ⁇ 3 -AlkyI- or hydroxy-C- ⁇ - 3 -alkyl groups or simply by a benzyl, cyclo C 3 - 6 alkyl, Hydroxycyclo-
  • 3- alkyl-, hydroxyaminocarbonyl-C 3 -alkyl-, C 1-3 -alkoxyaminocarbonyl-C 1-3 -alkyl or hydroxy- (C 1-3 -alkyl) -aminocarbonyl-C 1-3 -alkyl groups may be substituted,
  • R 5 is a hydrogen atom, a d- 3 alkyl group or, if Y 1 represents a nitrogen atom, also a free Eiektronenjo,
  • R 6 and R 7 which may be identical or different, each represent a hydrogen atom, a C 1-3 -alkyl group or also, when Y 1 represents a carbon atom, an amino, C 3-3 -alkylamino or di- (-C-3 -Alkyl) -amino group, it being possible for the two C 1-3 -alkyl groups to be linked together to form a ring, and
  • R 8 and R 9 which may be identical or different, each represent a hydrogen atom or a C 1-3 -alkyl group
  • alkyl, alkenyl and alkynyl groups mentioned or included in the above-defined radicals may be straight or branched, any methine group having one fluorine atom contained in the above-defined radicals, any methylene group having up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms and two alkyl and alkenyl groups bonded to a nitrogen atom may be linked together to form a 4- to 7-membered, saturated or unsaturated heterocyclic ring,
  • aromatic and heteroaromatic radicals mentioned or contained in the radicals defined above may additionally be mono-, di- or trisubstituted by halogen, by cyano or hydroxyl groups and the substituents may be identical or different,
  • a tenth embodiment of the present invention is the compounds of the above general formula (I) in which
  • A, X, Q and R 1 are defined as mentioned above under the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment, and
  • R 2 is the hydrogen atom
  • R 3 represent kyl distrin or the hydrogen atom or a C- ⁇ - 3 -A!
  • R 2 and R 3 together with the enclosed nitrogen atom is a radical of the general formula in the
  • Y 1 is the carbon atom or, when R 5 is a lone pair, also the nitrogen atom, q and r, when Y 1 represents the carbon atom, the numbers 0 or 1, or q and r, when Y 1 represents the nitrogen atom, the numbers 1 or 2,
  • R 4 is the hydrogen atom, an amino, -C. 4- alkyl-amino, di (-C.-alkyl) - alkylamino, -C. 6- alkyl, cyclo-C 3 . 7 -alkyl-, cyclo-C. 7 alkenyl, amino-C 2 - 7 alkyl, C ⁇ - 4 alkyl-amino-C 2 - 7 -alkyl, di- (C ⁇ -4 alkyl amino.) -C 2 - 7 -alkyl , C ⁇ . Alkyl- aminocarbonyl, di- (C ⁇ . 4 alkyl) aminocarbonyl, aminocarbonyl-C ⁇ . 3 -alkyl, C ⁇ .
  • R 5 is a hydrogen atom, a Ct- 3 -AlkyIrest or, if Y 1 represents a nitrogen atom, and a lone electron pair
  • R 6 and R 7 which may be the same or different, each represents a hydrogen atom, a -C 3 alkyl group or when Y 1 represents a carbon atom, a C ⁇ _ 3 -Alkylamino- or di- (C ⁇ - 3 alkyl) -amino group, wherein the two C ⁇ . 3 alkyl groups may be connected to form a ring with each other and
  • R 8 and R 9 which may be identical or different, each represent a hydrogen atom or a C 1-3 alkyl group
  • alkyl, alkenyl and alkynyl groups mentioned or included in the above-defined radicals may be straight-chain or branched, each contained in the above-defined radicals Methine group having one fluorine atom, each methylene group having up to 2 fluorine atoms, and each methyl group may be substituted with up to 3 fluorine, and two alkyl and alkenyl groups bonded to a nitrogen atom to form a 4- to 7-membered, saturated or unsaturated heterocyclic ring could be,
  • aromatic and heteroaromatic radicals mentioned or contained in the radicals defined above may additionally be mono-, di- or trisubstituted by halogen, by cyano or hydroxyl groups and the substituents may be identical or different,
  • A, X, Q and R 1 are defined as mentioned above under the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment, and
  • R 2 is the hydrogen atom
  • a phenylmethyl group or a C 2 - 7 alkyl group in ⁇ -position by a phenyl, amino, C ⁇ . 6- Alkylamino-, di- (C ⁇ - 6 alkyl) -amino group may be substituted, wherein the above-mentioned phenyl and phenylmethyl group in addition to an aromatic carbon atom by halogen, by C ⁇ . 3- alkyl, C ⁇ _ 3 alkoxy, amino Cvs-alkyl, C ⁇ . 3- Alkylamino-C ⁇ . 3- alkyl- or di- (C 1, 3 -alkyl) -amino-C.
  • R 3 represents the hydrogen atom or a C 1-3 alkyl group or
  • R 2 and R 3 together with the enclosed nitrogen atom is a radical of the general formula
  • Y 1 is the carbon atom or, when R 5 is a lone pair, also the nitrogen atom, q and r, when Y 1 represents the carbon atom, the numbers 0 or 1, or q and r, when Y 1 represents the nitrogen atom, the numbers 1 or 2,
  • R is the hydrogen atom, an amino, C ⁇ _ 4 alkyl-amino, di (-C. 4 -AlkyI) - alkylamino, C- ⁇ _ 6 alkyl, optionally substituted by a hydroxycarbonyl, C ⁇ - 6 alkoxycarbonyl , Hydroxycarbonyl-C ⁇ _ 3 -alkyl- or -C. 6 -alkoxycarbonyl-C 3 -alkyl-substituted cyclo-C 3 . 7 -alkyl- or cyclo-C 3 .
  • 4- alkyl-amino, di (-C.-alkyl) -amino group may be substituted, a heterocycle selected from a 6- to 7-membered azacycloalkyl group, a 6- to 7-membered S, S, dioxothiaza- and diazacycloalkyl group and a 7- to 9-membered azabicycloalkyl group, wherein the above-mentioned mono- and bicyclic heterocycles via a nitrogen - or a carbon atom to Y 1 are bound in formula (II), in the abovementioned mono- and bicyclic heterocycles a methylene group not directly linked to a nitrogen, oxygen or sulfur atom may be substituted by one or two fluorine atoms and those mentioned above mono- mono- and bicyclic heterocycles or disubstituted by a hydroxy, C ⁇ - alkyl 3 alkyl or hydroxy-C ⁇ - 3, by a benzyl, CycIo-
  • R 5 is a hydrogen atom or, if Y 1 represents a nitrogen atom, also a lone pair of electrons,
  • R 6 and R 7 which may be identical or different, each represent a hydrogen atom, a C ⁇ _ 3 alkyl group or, if Y 1 represents a carbon atom, a C ⁇ - 3- alkylamino or di- (C ⁇ - 3 alkyl) - amino group, wherein the both C ⁇ .3-alkyl groups can be connected together to form a ring and
  • R 8 and R 9 which may be identical or different, each represent a hydrogen atom or a C 1-3 alkyl group
  • a twelfth embodiment of the present invention is the compounds of the above general formula (I) in which
  • A, X, Q and R 1 are defined as mentioned above under the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment, and
  • R 2 is a phenylmethyl group or a C ⁇ -alkyl group which may be substituted in ⁇ -position by a phenyl, amino, C ⁇ - 6 alkylamino, di (C ⁇ - 6 alkyl) amino group, wherein the above-mentioned phenyl and phenylmethyl group on an aromatic carbon atom by an amino-C 1-3 -alkyl, C 1-3 -alkylamino C 1-3 -alkyl or di- (C 1-3 -alkyl) -amino-C 1-3 . alkyl group may be substituted,
  • R> 3 is the hydrogen atom or a C 1-3 alkyl group or
  • R 2 and R 3 together with the enclosed nitrogen atom is a radical of the general formula
  • R 6 and R 7 are each a hydrogen atom or a dimethylamino group
  • R 8 and R 9 are each the hydrogen atom and (a) Y 1 is the carbon atom, q and r are the numbers 0 or 1,
  • R 4 represents the hydrogen atom, a phenyl, pyridinyl or pyrimidinyl group which may be substituted by a halogen, by an amino, methylamino, dimethylamino, methyl or methoxy group, a hydroxy, 2-diethylaminoethyl, amino , Methylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, 4-amino-piperidin-1-yl, 4-methylamino-piperidin-1-yl, 4-dimethylamino piperidin-1-yl, 4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 4-methoxy-piperidin-1-yl, 4-hydroxy-4-methyl-piperidine 1-yl, 4-hydroxy-4-trifluoromethyl-piperidin-1-yl, 4-ethyl-4-hydroxy-piperidin-1-yl, 4,4-di
  • R 5 is a hydrogen atom
  • Y 1 is a nitrogen atom
  • q and r are the numbers 1 or 2
  • R 4 represents the hydrogen atom, a phenyl, pyridinyl or pyrimidinyl group, each of which may be substituted by a halogen, by an amino, methylamino, dimethylamino, methyl or methoxy group, a methyl, ethyl, isopropyl, cyclopropyl , Cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, 2-diethylamino-propyl, 1-quinuclidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1 Ethylpiperidin-4-yl, 1- (2-hydroxyethyl) -piperidin-4-yl, 1-cyclopropylpiperidin-4-yl, 1-cyclopropylmethyl-piperidin-4-yl, 1-hydroxycarbon
  • R -5 represent a lone pair of electrons
  • a thirteenth embodiment of the present invention is the compounds of the above general formula (I) in which
  • A, X, Q and R 1 are defined as mentioned above under the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment, and R 2 is a phenylmethyl group or a C 2 - 7 alkyl group in ⁇ -position by a phenyl, amino, C ⁇ . 6- Alkylamino-, di- (C ⁇ - 6 alkyl) -amino group may be substituted, wherein the above-mentioned phenyl and phenylmethyl group on an aromatic carbon atom by an amino-C ⁇ _ 3 -alkyl, -C. 3- Alkylamino- C ⁇ _ 3 -alkyl- or di- (C 3 -alkyl) -amino-C. 3- alkyl group may be substituted,
  • R 3 is the hydrogen atom or a -C. 3- alkyl group or
  • R 2 and R 3 together with the enclosed nitrogen atom is a radical of the general formula
  • R 6 and R 7 each represent a hydrogen atom or a dimethylamino group
  • R 8 and R 9 each represent the hydrogen atom
  • R 4 is the hydrogen atom, a phenyl, pyridinyl or pyrimidinyl group, each represented by a halogen, by an amino, methylamino, dimethylamino, methyl or methoxy group may be substituted, a hydroxy, 2-diethylamino-ethyl, amino, methylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, 4-amino-piperidine-1 -yl, 4-methylamino-piperidin-1-yl, 4-dimethylaminopiperidin-1-yl, 3-amino-piperidin-1-yl, 3-methylamino-piperidin-1-yl, 3 Dimethylamino-piperidine-1-yl, perhydro-azepine-1-yl, perhydro-1, 4-diazepin-1-yl, 4-methyl-perhydro-1,4-diazepin-1-
  • R 5 is a hydrogen atom
  • Y 1 is a nitrogen atom
  • q and r are the numbers 1 or 2
  • R 4 is the hydrogen atom, a phenyl, pyridinyl or pyrimidinyl group, each of which may be substituted by a halogen, by an amino, methylamino, dimethylamino, methyl or methoxy group, a methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethyl, 2-diethylamino-propyl, 1-quinuclidin-3-yl, 1-piperidin-4-yl, 1-methylpiperidin-4-yl , 1-ethyl-piperidin-4-yl, 1-cyclopropyl-piperidin-4-yl, 1-cyclopropylmethyl-piperidin-4-yl, 1-hydroxycarbonylmethyl-piperidin-4-yl or 1 Ethoxycarbonylmethyl-piperidin-4-yl group and
  • R 5 represent a lone pair of electrons
  • R 1 , R 2 and R 3 are defined as mentioned above under the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment, and
  • a and X each represent an oxygen atom
  • a fourteenth embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • R 1 is 1, 3,4,5-tetrahydro-1,3-benzodiazepin-2-one-3-yl, 3,4-dihydro-1 / - / - quinazolin-2-one-3-yl, 5-phenyl-2,4-dihydro-1,2,4-triazol-3-on-2-yl, 1,3-dihydroimidazo [4,5-c] quinolin-2-one-3 yl, 1,3-dihydro-naphth [1,2- ⁇ f] imidazol-2-on-3-yl, 1,3-dihydro-benzimidazol-2-on-3-yl, 4-phenyl -1, 3-dihydro-imidazol-2-one-1-yl, 3,4-dihydro-1 / -thieno [3,2-c / pyrimidin-2-one-3-yl or 3 , 4-dihydro-1H-thieno [3,4-c] pyrimi
  • R 2 and R 3 are defined as mentioned above under the first or second embodiment, wherein the heterocycles mentioned above under R 1 may be additionally monosubstituted in the carbon skeleton by a methoxy group,
  • R 1 aromatic and heteroaromatic radicals and moieties mentioned or contained in the radicals defined under R 1 may additionally be mono-, di- or tri-substituted by halogen atoms, by cyano or hydroxyl groups and the substituents may be identical or different,
  • a fifteenth embodiment of the present invention consists in the compounds of the above general formula (I) in which
  • a and X each represent an oxygen atom
  • R 1 is as defined above under the fifth embodiment
  • R 2 and R 3 are as defined above in the ninth or tenth embodiment is of outstanding importance
  • a sixteenth embodiment of the present invention is the compounds of the above general formula (I) in which A and X each represent an oxygen atom,
  • R 1 is defined as mentioned under the fifth embodiment
  • R 2 and R 3 are defined as mentioned under the twelfth embodiment
  • the bi- and tricyclic heterocycles listed in Table I are suitable, these being able to be substituted on a saturated nitrogen atom by the group R a ' and, independently of this, in the carbon skeleton by the group R b and R a' being the methyl , Ethyl or 2,2,2-trifluoroethylene group and
  • R b is the chlorine or bromine atom, the methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, amino, methylamino or Dimethylamino group means.
  • Q may in all the above-mentioned embodiments assume the meanings of the radicals shown in Table I, either unsubstituted as explicitly shown or, as mentioned above, optionally substituted by the radicals R a ' or / and R b .
  • (31) 4- (2-Oxo-1,2,4,5,5-tetrahydro-1,3-benzadiazepin-3-yl) piperidine-1-carboxylic acid (R) -2- (4-amino-4-) methyl-1, 4'-bipiperidinyl-1'-yl) -1- (3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester, (32) 4- (2-Oxo-1,2,4,5,5-tetrahydro-1,3-benzadiazepin-3-yl) piperidine-1-carboxylic acid (R) -1- (3,4-dimethyl) 2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2- (1'-ethoxycarbonylmethyl-4,4'-bipiperidinyl-1-yl) -2-oxo-ethyl ester,
  • the compounds of general formula (I) are prepared by methods known in principle. The following processes have proven particularly suitable for the preparation of the compounds of general formula (I) according to the invention:
  • the coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), where, for example, carbodiimides, such as, for example, Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethyl-amino-propyl) -carbodiimide, O- (1H-benzotriazol-1-yl) - / V, / V- ⁇ / -metramethyl-uronium hexa-fluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP).
  • DCC Dicyclohexylcarbodiimide
  • DI diisopropylcarbodiimi
  • the couplings are usually with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / -methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 and + 30 ° C, preferably -20 and + 25 ° C performed. If necessary, preference is given as an additional auxiliary base / V-ethyldiisopropylamine (Hünig base).
  • solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / -methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 and + 30 ° C, preferably -20 and + 25 ° C performed.
  • solvents such as dichloromethane, te
  • the mixed anhydride is obtained from the carboxylic acid of the general formula (III) to be coupled and the carbonic acid monoisobutyl ester.
  • the preparation of this mixed anhydride and the coupling with the amines of general formula HNR 2 R 3 is carried out in a one-pot process, using the abovementioned solvents and at temperatures between -20 ° C and + 25 ° C, preferably between 0 ° C and + 25 ° C.
  • Nu is a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms in the alkyl moiety, optionally by chlorine or bromine atoms, by methyl or Nitro groups mono-, di- or trisubstituted phenylsulfonyloxy or naphthylsulfonyloxy group, where the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl optionally substituted by one or two methyl groups in the carbon skeleton , a 1H-1, 2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a Vinyl, propargyl, p-nitrophenyl, 2,4-dinitroph
  • auxiliary bases at temperatures between -50 ° C and + 120 ° C, preferably -10 ° C and + 30 ° C, and optionally reacted in the presence of solvents.
  • Preferred auxiliary bases are alkali metal and alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, eg. Sodium carbonate, potassium carbonate or cesium carbonate, alkali acetates, e.g.
  • Sodium or potassium acetate, and tertiary amines for example pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, ⁇ / ethyldiisopropylamine, ⁇ / -Ethyldicyclohexylamin, 1, 4-di-azabicyclo [2,2,2] octane or 1, 8-diazabicyclo [5,4,0] undec-7-ene, as solvent, for example, dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, / V-methylpyrrolidone or mixtures thereof into consideration; If alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as auxiliary bases, water may also be added to the reaction mixture as cosolvent.
  • novel compounds of the general formula (I) according to the invention contain one or more chiral centers. For example, if there are two chiral centers, then the compounds can be in the form of two diastereomeric antipode pairs.
  • the invention includes the individual isomers as well as their mixtures.
  • the separation of the respective diastereomers is possible due to their different physicochemical properties, e.g. by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
  • racemates which fall under the general formula (I) is achieved, for example, by HPLC on suitable chiral stationary phases (eg chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be resolved via the diastereomeric, optically active salts which, when reacted with an optically active acid, for example (+) - or (-) - tartaric acid, (+) - or (-) ) -Diacetyltartaric acid, (+) - or (-) - monomethyl tartrate or (+) - or (-) - camphorsulfonic acid, or an optically active base, for example with (R) - (+) - 1-phenylethylamine, (S) - (-) - 1-phenylethylamine or (S) -brucine arise.
  • an optically active acid for example (+) - or (-) - tartaric acid, (+) - or (-) ) -Diacetyltartaric acid,
  • the racemate of a compound of the general formula (I) is reacted with one of the above-mentioned optically active acids or bases in an equimolar amount in a solvent and the resulting crystalline, diastereomeric, optically active salts utilizing their different Lösliehkeit separated.
  • This reaction can be carried out in any kind of solvents as long as they have a sufficient difference in the solubility of the salts.
  • methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, are used.
  • each of the optically active salts is dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, for example, with dilute hydrochloric acid or aqueous methanesulfonic acid, thereby giving the corresponding free compound in the (+) - or ( -) - Form received.
  • a base such as sodium carbonate or potassium carbonate
  • a suitable acid for example, with dilute hydrochloric acid or aqueous methanesulfonic acid
  • Yi and Y 2 denote nucleofuge groups which may be identical or different, preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group, if A represents the oxygen atom, or the chlorine atom, if A represents the sulfur atom,
  • Zi represents a protective group for a carboxy group, for example a C ⁇ . 6 alkyl or benzyl group, wherein the alkyl groups may be linear or branched and the benzyl group may be substituted by one or two methoxy groups.
  • Zi is the methyl, ethyl, ferf-butyl or benzyl group.
  • any carboxylic acid functions, primary or secondary amino functions or hydroxyl functions which may be present in the radical R 1 of a compound of the formula (V) and / or in a compound of the formula (VII) may be protected by customary protective radicals and any protective radicals used may be used after the reaction has taken place The methods familiar to the person skilled in the art are split off again.
  • a first step the compounds of general formula (V) in a solvent, for example in dichloromethane, THF, pyridine or mixtures thereof, at a temperature between -20 to 50 ° C in the presence of a base, for example triethylamine, pyridine or ethyldiisopropylamine, with the carbonic acid derivatives of general formula (VI) reacted.
  • a base for example triethylamine, pyridine or ethyldiisopropylamine
  • reaction of these intermediates with compounds of general formula (VII) is also carried out in one of the abovementioned solvents, and at the abovementioned temperatures, in the presence of a base such as triethylamine or pyridine, with or without the addition of an activating reagent such as 4-dimethylaminopyridine ,
  • a base such as triethylamine or pyridine
  • an activating reagent such as 4-dimethylaminopyridine
  • the compounds of general formula (VII) can also be deprotonated by means of a metal hydride, such as NaH or KH, in which case the presence of the base or of the activating reagent can be dispensed with.
  • the starting compounds of the formula (V) and (VI) are either commercially available, known from the literature or can be prepared by methods known from the literature.
  • the azlactones formed primarily are hydrolyzed without isolation to give the compounds of general formula (XI).
  • aqueous mineral acids such as sulfur, phosphoric or hydrochloric acid, but preferably of hydrochloric acid
  • compounds of general formula (XII) are obtained. These are then converted with suitable reducing agents into the compounds of general formula (VIII).
  • alkali borohydrides such as sodium or potassium borohydride can be used.
  • Further reducing agents are chlorodialkylboranes, such as chlorodicyclohexylborane. If chiral chlorodialkylboranes, such as, for example, B-chlorodiisopinocampheylborane, are used, the compounds of general formula (VIII) can be isolated in enantiomerically pure form.
  • shark is a chlorine, bromine or iodine atom, and Q are defined as mentioned above, in analogy to literature methods (Michael T. Crimmins, Kyle
  • Ethanol in the presence of a suitable acid such as hydrochloric acid.
  • a suitable acid such as hydrochloric acid.
  • the reaction can be carried out by reaction in alcoholic solvents, preferably methanol, with thionyl chloride.
  • All compounds of the general formula (I) which contain primary or secondary amino, hydroxy or hydroxycarbonyl functions are preferably obtained from protective groups with precursors.
  • Suitable protective groups for amino functions are, for example, a benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxy carbonyl, 4-biphenylyl- ⁇ , ⁇ -dimethylbenzyloxycarbonyl or 3,5-dimethoxy- ⁇ , ⁇ -dimethylbenzyloxycarbonyl group, an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety, for example the methoxycarbonyl, ethoxy - carbonyl, n-propoxycarbonyl, isopropoxycarbonyl, / 7-butoxycarbonyl, 1-methyl
  • a protective group for hydroxy functions is, for example, a trimethylsilyl, triethylsilyl, triisopropyl, terf-butyldimethylsilyl or fetf-Butyldiphenylsilyl distr, a tert-butyl, benzyl, 4-methoxybenzyl or 3,4-Dimethoxybenzyl distr in Question.
  • a protective group for hydroxycarbonyl functions for example, is an alkyl group having a total of 1 to 5 carbon atoms, for example, the methyl, ethyl, / 7-propyl, isopropyl, / 7-butyl, tert-butyl, allyl, 2,2,2 Trichloroethyl, benzyl or 4-methoxybenzyl group in question.
  • the compounds of the general formula (I) obtained may, provided they contain suitable basic functions, be converted, in particular for pharmaceutical applications, into their physiologically acceptable salts with inorganic or organic acids.
  • suitable acids are hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, acetic, fumaric, succinic, lactic, mandelic, malic, citric, tartaric and maleic acids.
  • novel compounds of the formula (I), if they contain carboxylic acid function, can be converted into their addition salts with inorganic or organic bases, in particular for the pharmaceutical application, into their physiologically tolerable addition salts.
  • Suitable bases for this example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine into consideration.
  • the present invention relates to racemates, provided that the compounds of the general formula (I) have only one chiral element.
  • the application also includes the individual pairs of diastereomeric antipodes or mixtures thereof which are present when more than one chiral element is present in the compounds of general formula (I) and the individual optically active enantiomers constituting the racemates mentioned.
  • the compounds of the invention including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
  • the novel compounds of the general formula (I) and their physiologically tolerable salts have valuable pharmacological properties which are based on their selective CGRP antagonistic properties.
  • Another object of the invention are these compounds containing drugs, their use and their preparation.
  • the above new compounds and their physiologically acceptable salts have CGRP antagonistic properties and show good affinities in CGRP receptor binding studies.
  • the compounds have CGRP antagonist properties in the pharmacological test systems described below.
  • SK-N-MC cells are cultured in "Dulbecco's modified Eagle Medium”. The medium of confluent cultures is removed. The cells are washed twice with PBS buffer (Gibco 041-04190 M), removed by addition of PBS buffer, mixed with 0.02% EDTA, and isolated by centrifugation. After resuspension in 20 ml of Balanced Salts Solution [BSS (in mM): NaCl 120, KCl 5.4, NaHCO 3 16.2, MgSO 0.8, NaHPO 4 1.0, CaCl 2 1.8, D-glucose 5.5, HEPES 30, pH 7.40] Centrifuge the cells twice at 100xg and resuspend in BSS.
  • BSS Balanced Salts Solution
  • the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000 xg. The supernatant is discarded and the pellet recentrifuged and resuspended in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) supplemented with 1% bovine serum albumin and 0.1% bacitracin (1 ml / 1000000 cells). The homogenate is frozen at -80 ° C. The membrane preparations are in these conditions for more than 6 weeks stable.
  • the homogenate is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) and homogenized for 30 seconds with an Ultra-Turrax. 230 ⁇ l of the homogenate are incubated for 180 minutes at room temperature with 50 pM 125 l-iodotyrosyl-calcitonin gene-related peptides (Amersham) and increasing concentrations of the test substances in a total volume of 250 ⁇ l. Incubation is terminated by rapid filtration through polyethyleneimine (0.1%) treated GF / B glass fiber filters using a cell harvester. The protein bound radioactivity is determined using a gamma counter. Non-specific binding is defined as the bound radioactivity after the presence of 1 ⁇ M human CGRP-alpha during the incubation.
  • assay buffer 50 mM Tris, 150 mM NaCl, 5 mM MgCl 2
  • concentration-binding curves The analysis of the concentration-binding curves is carried out by means of a computer-aided non-linear curve fitting.
  • SK-N-MC cells (1 million cells) are washed twice with 250 ⁇ l of incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and at 37 ° C for 15 minutes pre-incubated. After addition of CGRP (10 ⁇ l) as agonist in increasing concentrations (10 -11 to 10 -6 M) or additionally of substance in 3 to 4 different concentrations, the mixture is incubated again for 15 minutes.
  • incubation buffer Horte, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4
  • Intracellular cAMP is then extracted by addition of 20 ⁇ l of 1 M HCl and centrifugation (2000 x g, 4 ° C for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at -20 ° C.
  • the cAMP contents of the samples are determined by radioimmunoassay (Amersham) determined and the pA 2 values of antagonistically acting substances determined graphically.
  • the compounds of the invention show in the process described in w ⁇ ro test model CGRP-antagonistic properties in a dosage range between 10 ⁇ -12 and 10 -5 M.
  • the compounds according to the invention and their salts with physiologically tolerated acids are thus suitable for the acute and prophylactic treatment of headaches, in particular migraine or cluster headache.
  • the compounds according to the invention also have a positive influence on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM”), complex regional pain syndrome (CRPS1), cardiovascular diseases, morphine tolerance, diarrheal diseases caused by clostritium toxins, disorders of the skin, in particular thermal and radiation-induced skin damage Sunburn, inflammatory diseases, eg inflammatory joint diseases (arthritis), neurogenic inflammations of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases associated with excessive vasodilation and consequent reduced tissue perfusion, e.g.
  • the compounds according to the invention have a soothing effect on pain conditions in general.
  • the symptoms of menopausal, caused by vasodilation and increased blood flow hot flushes of estrogen-deficient women and hormone-treated prostate cancer patients is influenced by the CGRP antagonists of the present application preventively and acutely therapeutically, with this therapeutic approach is characterized by hormone substitution by side effect poverty.
  • the dosage required to achieve a corresponding effect is expediently by intravenous or subcutaneous administration 0.0001 to 3 mg / kg body weight, preferably 0.01 to 1 mg / kg body weight, and by oral, nasal or inhalative administration 0.01 to 10 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight, 1 to 3 times daily.
  • the compounds according to the invention can be administered either alone or optionally in combination with other active substances for the treatment of migraine intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, in particular aerosol formulations being suitable for inhalation.
  • the combinations may be administered either simultaneously or sequentially.
  • Possible drug classes as combination partners are e.g. Antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, angiotensin receptor blockers (angiotensin II antagonists), iNOS inhibitors, AMPA antagonists, anticonvulsants, histamine H1 receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, Ergot alkaloids, weak analgesics, non-steroidal anti-inflammatory drugs, corticosteroids, calcium antagonists, 5-HTIB / ID agonists or other antimigraine agents, together with one or more inert conventional carriers and / or diluents, eg with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerine, water / sorbitol, water
  • the non-steroidal anti-inflammatory drugs aceclofenac, acemetacin, acetyl- salicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulfasalazine, tenoxicam, zomepirac or their pharmaceutically acceptable salts, and meloxicam and other selective COX 2 - inhibitors such as rofecoxib and celecoxib.
  • the dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage, so for example 20 to 100 mg sumatriptan.
  • Another object of the invention is the use of the compounds of the invention as valuable tools for generating and purifying (affinity chromatography) of antibodies and, after appropriate radioactive labeling, for example by tritiation of suitable precursors, for example by catalytic hydrogenation with trithium or replacement of halogen atoms by tritium, in RIA and ELISA assays and as diagnostic and analytical tools in neurotransmitter research.
  • R f values are obtained using DC finished films Polygram SIL G / UV 254 (coated with 0.2 mm silica gel) from Macherey-Nagel (Düren, article number 805 021)
  • the R f values determined under the name Polygram-Alox are determined using DC Finished films Polygram Alox N / UV 254 (coated with 0.2 mm aluminum oxide) from Macherey-Nagel (Düren, Article No. 802 021)
  • the ratios given for the flow agents are based on volume the respective solvents.
  • the indicated volume units at NH 3 refer to a concentrated solution of NH 3 in water.
  • Method B Analytical column: Zorbax column (Agilent Technologies), SB (stable bond) C18; 3.5 ⁇ m; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 1.6 mL / min; Injection volume: 5 ⁇ L; Detection at 254 nm
  • Preparative HPLC purifications generally use the same gradients used in the collection of analytical HPLC data.
  • the collection of products is mass-controlled, the product-containing fractions are combined and freeze-dried. If further information on the configuration is missing, it remains unclear whether they are pure enantiomers or whether partial or even complete racemization has occurred.
  • the reaction mixture was cooled to about 60 ° C and added dropwise with 40 mL of water, stirred for 10 min at this temperature and then heated to 95 ° C for 1 h.
  • the reaction solution was poured onto 500 ml of water, extracted three times with 300 ml of EtOAc each time, the combined organic phases were extracted twice with 200 ml of 7% K 2 CO 3 solution each time, the combined aqueous phases were treated with conc. HCI and extracted again three times with 200 mL EtOAc.
  • the combined organic phases were filtered through charcoal and i.vac. concentrated.
  • reaction solution was poured into 400 ml of water, extracted five times with 200 ml of EtOAc each time, the combined organic phases were washed twice with 300 ml of water each time, dried over Na 2 SO 4 and concentrated by evaporation i.vac. evaporated.
  • reaction mixture was stirred for 30 minutes at this temperature and allowed to warm to RT, concentrated i.vac to about 50 mL and filtered through silica gel, washed with 200 mL DCM / EtOAc (1: 1) and concentrated The filtrate was again concentrated i.vac .. The residue was stirred with diisopropyl ether, filtered off with suction and dried i.vac.
  • the reaction mixture was stirred for 24 h at 90 ° C bath temperature, i.vac.
  • the residue is combined with 200 ml of water and 200 ml of EtOAc, and the precipitate is filtered off.
  • the crystals were dissolved in 500 mL MeOH at reflux, filtered hot and the filtrate i.vac. concentrated to dryness.
  • the reaction solution was admixed with 4.9 g (20.0 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepine-2-one and stirred at 100 ° C. for 2 h.
  • 150 mL EtOAc were added, washed three times with 70 mL 1 M KHSO 4 solution and 12 times with 50 mL 15% K 2 CO 3 solution each time, and the organic phase was dried over MgSO 4.
  • the residue was dissolved in 60 ml of THF, combined with 250 mg of LiOH in 10 ml of water and the reaction mixture was stirred at RT for 3 h. One removed i.vac.
  • the reaction mixture was purified via HPLC, the fractions containing the product were combined and lyophilized.
  • the coupling product was taken up in 4 mL DCM, mixed with 0.5 mL TFA and the reaction was shaken at RT for 5 h and without closure overnight, with the DCM evaporating.
  • the residue was admixed with 2 ml of 15% K 2 C0 3 solution and extracted twice with 2 ml of DCM each time.
  • the solvent of the combined organic phases was allowed to evaporate overnight, the residue was taken up in 1 mL of DMF and the crude product was purified by HPLC.
  • the fractions containing the product were combined and lyophilized. Yield: 42 mg (36% of theory)
  • the reaction mixture was concentrated i.vac., admixed with 150 mL EtOAc and the organic phase was washed three times with 40 mL 1 M KHSO 4 solution and washed 12 times with 30 mL 15% K CO 3 solution each time and dried over MgSO 4 cken- and solvent, the residue was dissolved in 60 mL of THF, treated with 250 mg of LiOH in 10 mL of water and the reaction mixture was stirred for 3 h at RT. One removed i.vac. the THF, the aqueous phase was diluted with 60 mL EtOAc, filtered from insoluble components, and the organic phase separated.
  • the aqueous phase was acidified with 15 mL 1 M HCl, extracted three times with 50 mL EtOAc each time, and the combined organic phases were dried over MgSO 4 . After removal of the drying agent and solvent, the residue was dissolved at 80 ° C in 30 ml of isopropanol. The solution was allowed to cool slowly overnight, the precipitate was filtered off with suction, washed with isopropanol and dried at 60 ° C in a vacuum oven.
  • the reaction mixture was purified via HPLC, the fractions containing the product were combined and lyophilized.
  • the residue obtained was dissolved in 4 mL DCM, combined with 0.5 mL TFA and the reaction solution was stirred at RT for 5 h.
  • the DCM was allowed to evaporate overnight, the residue added with 2 mL 15% K 2 CO 3 solution and extracted twice with 2 mL DCM each. After removal of the solvent, the residue was taken up in 1 ml of DMF and purified by HPLC.
  • the fractions containing the product were combined and lyophilized. Yield: 40 mg (35% of theory)
  • Composition 1 capsule for powder inhalation contains: Active ingredient 1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 m ⁇ 71.0 mg
  • the active ingredient is ground to the particle size required for inhalation.
  • the ground active substance is mixed homogeneously with the milk sugar.
  • the mixture is filled into hard gelatin capsules.
  • Composition 1 stroke contains:
  • the active substance and benzalkonium chloride are dissolved in water and dissolved in Respimat ® -
  • 1 vial contains:
  • 1 hub contains:
  • micronized drug is homogeneously suspended in the mixture of lecithin and propellant.
  • the suspension is filled into a pressure vessel with metering valve.
  • the active ingredient and the excipients are dissolved in water and filled into a corresponding container.
  • Injection solution with 5 mg active substance per 5 ml Composition: Active substance: 5 mg glucose 250 mg human serum albumin 10 mg glykofurol 250 mg water for injections ad 5 ml
  • Preparation Dissolve glycofurol and glucose in water for injection (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl on application volumes; Fill into ampoules under nitrogen fumigation.
  • Dissolve polysorbate 80 sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (Wfl); Add human serum albumin; Dissolve active ingredient with heating; fill with Wfl to batch volume; fill in ampoules.

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Abstract

L'invention concerne les antagonistes du CGRP représentés par la formule générale (I), dans laquelle A, X, Q et R<1> à R<3> sont tels que définis dans la revendication n DEG 1, ainsi que leurs tautomères, isomères, diastéréoisomères, énantiomères, hydrates, mélanges et sels et les hydrates de ces sels, notamment leurs sels physiologiquement tolérables contenant des acides inorganiques ou organiques. L'invention concerne également des médicaments contenant ces composés, leur utilisation et des procédés de production desdits composés.
EP05735460A 2004-04-22 2005-04-18 Antagonistes du cgrp selectionnes, procedes de production de ces antagonistes et leur utilisation comme medicaments Withdrawn EP1740577A2 (fr)

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PCT/EP2005/004104 WO2005103037A2 (fr) 2004-04-22 2005-04-18 Antagonistes du cgrp selectionnes, procedes de production de ces antagonistes et leur utilisation comme medicaments

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Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7220862B2 (en) 2002-06-05 2007-05-22 Bristol-Myers Squibb Company Calcitonin gene related peptide receptor antagonists
US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
DE10250082A1 (de) 2002-10-25 2004-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US7595312B2 (en) 2002-10-25 2009-09-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions
TW200524601A (en) 2003-12-05 2005-08-01 Bristol Myers Squibb Co Heterocyclic anti-migraine agents
TW200533398A (en) 2004-03-29 2005-10-16 Bristol Myers Squibb Co Novel therapeutic agents for the treatment of migraine
DE102004015723A1 (de) 2004-03-29 2005-10-20 Boehringer Ingelheim Pharma Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7449586B2 (en) 2004-12-03 2008-11-11 Bristol-Myers Squibb Company Processes for the preparation of CGRP-receptor antagonists and intermediates thereof
DE102004063753A1 (de) * 2004-12-29 2006-07-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung ausgewählter CGRP-Antagonisten in Kombination mit anderen Arzneistoffen gegen Migräne für die Behandlung von Migräne
DE102004063752A1 (de) * 2004-12-29 2006-07-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verwendung ausgewählter CGRP-Antagonisten zur Bekämpfung menopausaler Hitzewallungen
EP1770091A1 (fr) * 2005-09-29 2007-04-04 Boehringer Ingelheim Pharma GmbH & Co. KG Antagonistes CGRP, leur procédé de préparation ansi que leur utilisation comme médicaments
DE102005038831A1 (de) * 2005-08-17 2007-02-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US7834007B2 (en) 2005-08-25 2010-11-16 Bristol-Myers Squibb Company CGRP antagonists
DE102005050892A1 (de) * 2005-10-21 2007-04-26 Boehringer Ingelheim Pharma Gmbh & Co. Kg Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US8168592B2 (en) 2005-10-21 2012-05-01 Amgen Inc. CGRP peptide antagonists and conjugates
CN101500653A (zh) * 2006-06-08 2009-08-05 贝林格尔.英格海姆国际有限公司 使用cgrp拮抗剂对胃肠道病症的治疗
US9108948B2 (en) * 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
JP2010508358A (ja) 2006-11-01 2010-03-18 ブリストル−マイヤーズ スクイブ カンパニー グルココルチコイド受容体、ＡＰ−１、および／またはＮＦ−κＢ活性の調節剤、並びにその使用
EP2065381A1 (fr) 2007-10-18 2009-06-03 Boehringer Ingelheim Pharma GmbH & Co. KG Antagonistes du CGRP
AU2008313733A1 (en) 2007-10-18 2009-04-23 Boehringer Ingelheim International Gmbh CGRP antagonists
CA2705405A1 (fr) 2007-11-22 2009-05-28 Boehringer Ingelheim International Gmbh Nouveaux composes
US9062046B2 (en) * 2010-07-16 2015-06-23 Piramal Enterprises Limited Substituted imidazoquinoline derivatives as kinase inhibitors
MX2016004250A (es) 2013-10-07 2016-07-12 Bayer Pharma AG Tienouracilcarboxamidas ciclicas y usos de las mismas.
GB201519196D0 (en) 2015-10-30 2015-12-16 Heptares Therapeutics Ltd CGRP Receptor Antagonists
GB201519195D0 (en) 2015-10-30 2015-12-16 Heptares Therapeutics Ltd CGRP Receptor Antagonists
GB201519194D0 (en) 2015-10-30 2015-12-16 Heptares Therapeutics Ltd CGRP receptor antagonists
JP6695441B2 (ja) 2016-03-03 2020-05-20 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４−シアノ−ベンジルカルバミミドイルカルバメート誘導体およびａｏｃ３阻害剤としてのそれらの使用
WO2017148519A1 (fr) 2016-03-03 2017-09-08 Boehringer Ingelheim International Gmbh Dérivés pyridinylméthyl carbamimidoylcarbamate et leur utilisation comme inhibiteurs d'aoc3

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092880A1 (fr) * 2004-03-29 2005-10-06 Boehringer Ingelheim International Gmbh Antagonistes cgrp selectionnes, procedes de production associes et leur utilisation en tant que medicaments

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2314305T3 (es) * 1996-09-10 2009-03-16 BOEHRINGER INGELHEIM PHARMA GMBH &amp; CO.KG Aminoacidos modificados, medicamentos que contienen estos compuestos y procedimiento para su obtencion.
EP1117662A1 (fr) * 1998-09-30 2001-07-25 Merck Sharp &amp; Dohme Limited Piperidines de benzimidazolinyle en tant que ligands de cgrp
DE19937304C2 (de) * 1999-08-10 2003-08-21 Boehringer Ingelheim Pharma Verwendung von CGRP-Antagonisten zur Bekämpfung menopausaler Hitzewallungen
DE10300973A1 (de) * 2003-01-14 2004-07-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Carbonsäuren und deren Ester, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
TW200533398A (en) * 2004-03-29 2005-10-16 Bristol Myers Squibb Co Novel therapeutic agents for the treatment of migraine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092880A1 (fr) * 2004-03-29 2005-10-06 Boehringer Ingelheim International Gmbh Antagonistes cgrp selectionnes, procedes de production associes et leur utilisation en tant que medicaments

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TW200606151A (en) 2006-02-16
CA2565219A1 (fr) 2005-11-03
DE102004019492A1 (de) 2005-11-10
WO2005103037A2 (fr) 2005-11-03
UY28859A1 (es) 2005-11-30
PE20060186A1 (es) 2006-04-18
AR049422A1 (es) 2006-08-02
WO2005103037A3 (fr) 2006-01-12
JP2007533689A (ja) 2007-11-22

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