EP1411948A1 - Tetrahydrochinoxaline als bradykininantagonisten - Google Patents

Tetrahydrochinoxaline als bradykininantagonisten

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Publication number
EP1411948A1
EP1411948A1 EP02762319A EP02762319A EP1411948A1 EP 1411948 A1 EP1411948 A1 EP 1411948A1 EP 02762319 A EP02762319 A EP 02762319A EP 02762319 A EP02762319 A EP 02762319A EP 1411948 A1 EP1411948 A1 EP 1411948A1
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EP
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Prior art keywords
alkyl
halogen
phenyl
diyl
mono
Prior art date
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German (de)
English (en)
French (fr)
Inventor
Bettina Beyreuther
Michael Hahn
Christopher Kallus
Joachim Krüger
Heinrich Meier
Elke Reissmüller
Leila Telan
Reilinde Nopper
Mathias Kroll
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Bayer AG
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Bayer AG
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Publication of EP1411948A1 publication Critical patent/EP1411948A1/de
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P11/06—Antiasthmatics
    • 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
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    • 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
    • A61P27/00—Drugs for disorders of the senses
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    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to new tetrahydroquinoxalines and processes for their preparation, their use for the treatment and / or prophylaxis of diseases, in particular for the treatment and / or prophylaxis of pain conditions.
  • Kinins are peptides that are formed in plasma (bradykinin) and peripheral tissues (kallidin) due to injuries, inflammation, asthma and anaphylactic and endotoxic shock. In addition to the important role that kinins play in cardiovascular homeostasis or smooth muscle contraction and relaxation (Bhoola al. Pharmacol. Rev. 1992, 44, 1-80), they primarily lead to pain, inflammation and hyperalgesia. By promoting the production of other pain mediators such as prostaglandins, tachykinins and interleukins, the pain response is further potentiated.
  • kinins act via 7 Gm / 11-protein-linked 7 transmembrane receptor subtypes: while the bradykinin 2 receptor (B2-R) is activated by bradykinin and kallidin, their main fragments of-Arg9-bradykinin and des-ArglO-kallidin are the preferred agonists for the bradykinin 1 receptor (Bl-R).
  • Receptor activation leads on the one hand to stimulation of phospholipase C and thus to the release of intracellular calcium ions and on the other hand to activation of phospholipase A2, which opens ion channels via protein kinase C and thus causes the depolarization and excitation of the cell (Textbook of Pain, 4th ed. ; Wall and Melzack, eds .; Edinburgh, 1999, pp.61-62).
  • the Bl-R In contrast to the B2-R, the Bl-R is down-regulated under physiological conditions and is stimulated by disease-related mediators, e.g. Interleukins, expressed in cells and up-regulated. It therefore primarily contributes to the chronic phase of the inflammatory response and to the maintenance of persistent hyperalgesia.
  • the Bl-R is also at the central sensitization
  • BL-R antagonists are therefore useful for the treatment of patients with inflammatory pain, neuropathic pain and lower back pain, pain associated with osteoarthritis and pain associated with another etiology.
  • Bl-R antagonists are also suitable for the treatment of asthma, diabetic nasculopathy, rhinitis, septic shock, atherosclerosis, multiples
  • EP-A-0 509 398 and WO 00/00478 tetrahydroquinoxalines are described as HIN reverse transcriptase inhibitors for the treatment of viral diseases.
  • DE-A-43 41 663 discloses tetrahydroquinoxaline as an endothelin receptor
  • Antagonists for the treatment of Migraine Antagonists for the treatment of Migraine.
  • the present invention relates to compounds of the general formulas (I) and (Ia), in which
  • A represents (-CC 6 ) alkanediyl
  • E represents a bond or (CrC 6 ) alkanediyl
  • Y represents CO or SO 2
  • R 1 , R 2 , R 3 and R 4 are the same or different and are hydrogen, halogen,
  • R 5 represents (C 6 -C 10 ) aryl or 5- to 10-membered heteroaryl, aryl and heteroaryl optionally being the same or different by radicals selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, cyano, amino, (-C ⁇ alkyl, (C 1 -C 6 ) alkoxy, phenoxy, (C 1 -C 6 ) alkylthio, Mono- or di- (dC 6 ) -alkylamino, (dC 6 ) -acyl, (dC 6 ) -acyloxy, (dC 6 ) - acylamino, (C ⁇ -C6) -alkoxycarbonyl, mono- or di- (dC 6 ) -Alkylamino-carbonyl, carbamoyl, carboxy, phenyl, 5- to 6-membered heteroaryl, propane-1,3-diyl, butane-1,
  • R and R are identical or different and represent hydrogen, (C 6 -C 10 ) aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, or
  • aryl, heteroaryl, heterocyclyl and carbocyclyl identically or differently, through radicals selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, cyano, amino, (dC 6 ) alkyl, (C 3 - C 8 ) cycloalkyl, 5 - Up to 7-membered heterocyclyl, (dC 6 ) alkoxy, phenoxy, (C ⁇ -C 6 ) alkylthio, mono- or di- (dC 6 ) alkylamino, (C 1 -C 6 ) acyl, (dC 6 ) - acyloxy, (C 1 -C 6 ) acylamino, (dC 6 ) alkoxycarbonyl, mono- or di- (d-
  • C 6 C 6 ) -alkylaminocarbonyl, carbamoyl, carboxy, phenyl, 5- to 6-membered heteroaryl, propane-l, 3-diyl, butane-1,4-diyl, l, 3-dioxa-propane-l, 3-diyl or 1,4-dioxa-butane-1,4-diyl are substituted,
  • R 6 and R 7 together with the nitrogen atom form a 4- to 12-membered heterocyclyl radical which is bonded via nitrogen and which, if appropriate, is identical or different and is selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, cyano and amino, (dC 6 ) alkyl, (dC 6 ) alkoxy, mono- or di- (Ci-C 6 ) alkylamino, (dC 6 ) acyloxy, (dC 6 ) acyl,
  • alkyl, cycloalkyl and phenyl in turn, the same or different, are substituted by one to three radicals selected from the group halogen, phenyl, (dC 6 ) - alkyl, (-C-C 6 ) - alkoxy and (dC 6 ) -alkylthio, in which Phenyl, for its part, is optionally identical or differently substituted by radicals selected from the group halogen or methyl,
  • R represents hydrogen or (C 1 -C 3 ) -alkyl optionally substituted by fluorine
  • R 9 represents hydrogen or (C 1 -C 6 ) alkyl
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both the enantiomers or diastereomers or their respective mixtures. These mixtures of the enantiomers and diastereomers can be separated into the stereoisomerically uniform constituents in a known manner.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention.
  • Acid addition salts of the compounds with mineral acids, carboxylic acids or sulfonic acids for example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or
  • salts with conventional bases can also be mentioned as salts, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, Procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiper
  • Hydrates of the compounds according to the invention are stoichiometric compositions of the compounds or their salts with water.
  • Solvates of the compounds according to the invention are stoichiometric compositions of the compounds or their salts with solvents.
  • (-C 6 ) -acyl represents a straight-chain or branched acyl radical having 1 to 6, preferably 1 to 4, carbon atoms. Examples and preferably mentioned are: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. Acetyl and ethylcarbonyl are particularly preferred.
  • C CfiVAcyloxy stands in the context of the invention for a straight-chain or branched acyl radical having 1 to 6, preferably 1 to 4 carbon atoms which is bonded via an oxygen atom.
  • (CrCfiVAcylamino in the context of the invention represents a straight-chain or branched acyl radical having 1 to 6, preferably 1 to 4, carbon atoms which is bonded via a nitrogen atom.
  • Examples and preferably mentioned are: acetylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, Isobutylcarbonylamino, pentylcarbonylamino and hexylcarbonylamino, particularly preferred are acetylamino and ethylcarbonylamino.
  • (C 1 -C 6 -alkanediyl in the context of the invention represents a straight-chain or branched alkanediyl radical having 1 to 6, preferably 1 to 4, carbon atoms.
  • alkanediyl radical having 1 to 6, preferably 1 to 4, carbon atoms.
  • methylene, ethylene, ethane-l, l-diyl, propylene, propane 1,2-diyl, propane-2,2-diyl, methylene is preferred.
  • D-C ⁇ VAlkoxy stands for a straight-chain or branched alkoxy radical with 1 to 6, preferably 1 to 4 carbon atoms. Examples and preferably mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • Alkoxycarbonyl stands for a straight-chain or branched alkoxycarbonyl radical with 1 to 6, preferably 1 to 4 carbon atoms. Examples and preferably mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • (d-dn -, (dC 6 - and (C 1 -C 3 ) -alkyl represent a straight-chain or branched alkyl radical having 1 to 10, 1 to 6 or 1 to 3 carbon atoms.
  • (dC 10 ) - alkyl is a straight-chain or branched alkyl radical with 1 to 6 carbon atoms
  • Substance atoms in the case of (dC 6 ) alkyl a straight-chain or branched alkyl radical with 1 to 4 carbon atoms, in the case of (dC 3 ) alkyl methyl.
  • methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl For example and preferably, the following may be mentioned: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • a straight-chain or branched alkyl radical having 1 to 3 carbon atoms is particularly preferred.
  • (Ci-CfiVAlkylthio in the context of the invention represents a straight-chain or branched alkylthio radical having 1 to 6, preferably 1 to 4 carbon atoms. Examples and preferably mentioned are: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n- Pentylthio and n-hexylthio A straight-chain or branched alkylthio radical having 1 to 3 carbon atoms is particularly preferred.
  • mono- Cj-C ⁇ -alkylamino represents an amino group with a straight-chain or branched alkyl substituent which has 1 to 6, preferably 1 to 4, carbon atoms.
  • alkyl substituent which has 1 to 6, preferably 1 to 4, carbon atoms.
  • di- (-C 6 ) -alkylamino represents an amino group with two identical or different straight-chain or branched alkyl substituents, each having 1 to 6, preferably 1 to 4, carbon atoms.
  • Mono-Cd-C ⁇ VAlkylaminocarbonyl stands in the context of the invention for an amino group with a straight-chain or branched alkyl substituent which has 1 to 6, preferably 1 to 4 carbon atoms and which is bonded via a carbonyl group. Examples and preferably mentioned are: methylaminocarbonyl,
  • di-fd-C ⁇ Valkylaminocarbonyl stands for an amino group with two identical or different straight-chain or branched alkyl substituents, each having 1 to 6, preferably 1 to 4, carbon atoms and which is bonded via a carbonyl group.
  • NN-dimethylaminocarbonyl NN-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-memyl-Nn-propylaminocarbonyl, N-methyl-N-cyclopropylaminocarbonyl, N-isopropyl-Nn-propyl-aminocarbonyl, Nt-butyl-N-methylamino-carbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl.
  • (O 3 -Cs) cycloalkyl represents a cycloalkyl group having 3 to 8, preferably 5 to 7, carbon atoms. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • aryl radicals in the context of the invention represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and ⁇ aphthyl.
  • Halogen generally represents fluorine, chlorine, bromine and
  • Iodine Fluorine, chlorine and bromine are preferred. Fluorine and chlorine are particularly preferred.
  • 3- to 12-membered carbocyclyl generally represents a mono- or polycyclic, carbocyclic radical having 3 to 12 ring atoms.
  • Up to 10-membered, in particular 3- to 8-membered carbocyclyl are preferred.
  • Mono- or bicyclic carbocyclyl is preferred.
  • Monocyclic carbocyclyl is particularly preferred.
  • the carbocyclyl residues can be saturated or partially unsaturated. Saturated carbocyclyl residues are preferred.
  • Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, Cyclohexyl, Cycloheptyl, Norborn-1-yl, Norborn-2-yl, Norborn-7-yl, Norborn-2-en- 7-yl, Cyclooctyl, Cubyl, Cyclononyl, Cyclodecyl, Decalinyl, Adamant-1-yl, Adamant- 2-yl.
  • 5- to 10-membered heteroaryl generally represents an aromatic, mono- or bicyclic radical having 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N.
  • 5- to 6 are preferred -linked heteroaryls with up to 4 heteroatoms.
  • the heteroaryl residue can be attached via a carbon or heteroatom. Examples and preferably mentioned are: thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl,
  • 4- to 12-membered and 5- to 7-membered heterocyclyl generally represent a mono- or polycyclic, heterocyclic
  • 5- to 7-membered heterocyclyl is preferred.
  • Mono- or bicyclic heterocyclyl is preferred.
  • Monocyclic heterocyclyl is particularly preferred.
  • O, N and S are preferred as heteroatoms.
  • the heterocyclyl residues can be saturated or partially unsaturated. Saturated heterocyclyl residues are preferred.
  • the heterocyclyl radicals can be bonded via a carbon atom or a hetero atom.
  • 5- to 7-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the O, N and S series are particularly preferred. Examples and, preferably, are: tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3 -yl, pyrrolinyl, piperidinyl,
  • radicals in the compounds according to the invention are optionally substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred. Compounds of the general formulas (I) and (Ia) are preferred
  • A, E, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 have the meaning given above,
  • A represents methylene
  • R 5 represents phenyl which is optionally identical or different and is substituted by one to three radicals selected from the group consisting of methyl, chlorine, trifluoromethyl and trifluoromethoxy,
  • A, Y, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 have the meaning given above,
  • E represents a bond or (dC 6 ) alkanediyl
  • R 1 , R 2 , R 3 and R 4 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, cyano, amino, (dC 6 ) alkyl, (C ⁇ -C 6 ) alkoxy, ( C 1 -C 6 ) -alkylthio, mono- or di- (C 1 -C 6 ) -alkylamino, (d- C 6 ) -acyl, (-C-C 6 ) -acyloxy, (dC 6 ) -acylamino, ( C 1 -C 6 ) alkoxycarbonyl,
  • R 5 represents (C 6 -C 8 ö ) aryl or 5- to 10-membered heteroaryl, aryl and heteroaryl optionally being the same or different by radicals selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro,
  • R 6 and R 7 are identical or different and are hydrogen, (C 6 -C 10 ) aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, or for optionally with halogen or a radical selected from the group (dC 6 ) alkoxy, (C 6 -C 10 ) aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to 12-membered Heterocyclyl-substituted (d-do) alkyl,
  • aryl, heteroaryl, heterocyclyl and carbocyclyl identically or differently, through radicals selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, cyano, amino, (dC 6 ) alkyl, (C 3 - Cg) cycloalkyl, 5- to 7-membered heterocyclyl, (-C-C 6 ) alkoxy, phenoxy, (dC 6 ) alkylthio, mono- or di- (C 1 -C 6 ) alkylamino, (dC 6 ) acyl, (C r C 6 ) -
  • R 6 and R 7 together with the nitrogen atom form a 4- to 12-membered heterocyclyl radical which is bonded via nitrogen and which, if appropriate, is identical or different and is selected from the group consisting of halogen, trifluoromethyl,
  • alkyl, cycloalkyl and phenyl in turn, the same or different, are substituted by one to three radicals selected from the group consisting of halogen, phenyl, (dC 6 ) alkyl, (dC 6 ) alkoxy and (C 1 -C 6 ) alkylthio, in which Phenyl, for its part, is optionally identical or differently substituted by radicals selected from the group halogen or methyl, R 8 represents hydrogen,
  • R 9 represents hydrogen
  • A represents methylene or ethylene
  • E represents a bond, methylene or ethylene
  • R 1 , R 2 , R 3 and R 4 are identical or different and represent hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, carbamoyl or carboxy,
  • R 5 represents (C 6 -C 10 ) aryl or 5- to 10-membered heteroaryl, where appropriate aryl and heteroaryl, identically or differently, selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, ethyl, iso- propyl, methoxy, ethoxy, phenoxy, dimethylamino, (C 1 -C 6 ) alkoxycarbonyl, carbamoyl, carboxy, phenyl, 5- to 6-membered heteroaryl and butane-1,4-diyl are substituted, where phenoxy, phenyl and 5- to 6-membered heteroaryl are optionally substituted with trifluoromethyl, (dC 6 ) - alkyl, (dC 6 alkoxy or halogen,
  • R 6 and R 7 are the same or different and and for hydrogen, phenyl, 3- to 12-membered carbocyclyl, 4- to 12-membered
  • a radical selected from the group consisting of halogen, (Ci-C 6 ) alkoxy, (C 6 -C 10 ) aryl, 5- to 10-membered heteroaryl, 3- to 12-membered carbocyclyl and 4- to 12 -linked heterocyclyl substituted (-C-C 10 ) -
  • aryl, heteroaryl, heterocyclyl and carbocyclyl identically or differently, through radicals selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, 5- to 7-membered heterocyclyl , (dC 6 ) - alkoxy, phenoxy, (-C-C 6 ) alkoxycarbonyl, carbamoyl, carboxy, phenyl, 5- to 6-membered heteroaryl and butane-1,4-diyl are substituted,
  • R 6 and R 7 together with the nitrogen atom form a 4- to 12-membered heterocyclyl radical which is bonded via nitrogen and which, if appropriate, is the same or different and is selected by one to three radicals selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, (dC 6 ) - alkyl, (C ⁇ -C 6 ) - alkoxy, (dC 6 ) -
  • alkyl, cycloalkyl and phenyl in turn, may be the same or different and may be selected from the group consisting of halogen, phenyl, (C 1 -C 6 ) -
  • R 8 represents hydrogen or (dC 3 ) -alkyl optionally substituted by fluorine
  • R 9 represents hydrogen or (dC 6 ) alkyl
  • A represents methylene or ethylene
  • E represents a bond, methylene or ethylene
  • R 1 , R 2 , R 3 and R 4 are identical or different and represent hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, carbamoyl or carboxy,
  • R 5 represents (C 6 -C 10 ) aryl or 5- to 10-membered heteroaryl, aryl and heteroaryl optionally being the same or different and selected by radicals selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl, Methoxy, ethoxy, phenoxy, dimethylamino, (dC ⁇ -alkoxycarbonyl, carbamoyl, carboxy, phenyl, 5- to 6-membered heteroaryl and butane-1,4-diyl are substituted, where phenoxy, phenyl and 5- to 6-membered heteroaryl are optionally substituted with trifluoromethyl, (dC 6 ) - alkyl, (dC 6 ) - alkoxy or halogen,
  • R 6 and R 7 are the same or different and represent hydrogen, phenyl, 3- to 12-membered carbocyclyl, 4- to 12-membered heterocyclyl, where R 6 and R 7 are not simultaneously hydrogen, or
  • aryl, heteroaryl, heterocyclyl and carbocyclyl identically or differently, through radicals selected from the group halogen, trifluoromethyl, trifluoromethoxy, (dC 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl, 5- to 7-membered heterocyclyl, ( dC 6 ) - alkoxy, phenoxy, (C 1 -C 6 ) alkoxycarbonyl, carbamoyl, carboxy, phenyl, 5- to 6-membered heteroaryl and butane-1,4-diyl are substituted,
  • R 6 and R 7 together with the nitrogen atom form a 4- to 12-membered heterocyclyl radical which is bonded via nitrogen and which, if appropriate, is the same or different and is selected by one to three radicals selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, (dC 6 ) - Alkyl, (dC 6 ) - alkoxy, (-C-C 6 ) - alkoxycarbonyl, carbamoyl, carboxy, (C 3 -C8) cycloalkyl and phenyl is substituted, where alkyl, cycloalkyl and phenyl are in turn optionally substituted, identically or differently, by radicals selected from the group consisting of halogen, phenyl, (C 1 -C 6 ) alkyl and (dC 6 ) alkoxy,
  • R 8 represents hydrogen
  • R 9 represents hydrogen
  • A represents methylene
  • R 1 , R 2 , R 3 and R 4 are the same or different and each represents hydrogen
  • R 5 represents phenyl, which is optionally identical or different and is substituted by one to three radicals selected from the group consisting of methyl, isopropyl, methoxy, ethoxy, halogen, p-chlorophenoxy, trifluoromethyl and trifluoromethoxy, R and R are identical or different and represent hydrogen, phenyl or 5- to 8-membered carbocyclyl, where R and R 7 are not simultaneously hydrogen,
  • phenyl, heterocyclyl and carbocyclyl identically or differently, with one to three radicals selected from the group halogen, trifluoromethyl, trifluoromethoxy, (dC 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, 5- to 7-membered heterocyclyl, (dC 6 ) - alkoxy, (dC ⁇ -alkoxycarbonyl and butane
  • R 8 represents hydrogen
  • R 9 represents hydrogen
  • R 1 , R 2 , R 3 and R 4 are the same or different and represent hydrogen or halogen
  • R 5 represents phenyl, which may be the same or different with one to three
  • Radicals selected from the group consisting of methyl, isopropyl, halogen, trifluoromethyl and trifluoromethoxy is substituted
  • R 6 and R 7 are the same or different and
  • R> 8 8 represents hydrogen
  • R 9 represents hydrogen
  • the invention further relates to processes for the preparation of the compounds of the formulas (I) and (Ia).
  • A, E, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 have the meaning given above, and
  • X 1 represents halogen, preferably bromine or chlorine, or hydroxy
  • NR 6 (III) H or their salts for example hydrochloride or hydrobromide salts
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, carbon tetrachloride, 1,2-
  • Dichloroethane or trichlorethylene ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, dimethyl acetamide, acetone , 1,2-dimethoxyethane, 2-butanone, dimethyl sulfoxide, acetonitrile, pyridine or hexamethylphosphoric acid triamide, tetrahydrofuran or methylene chloride are preferred.
  • ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol di
  • Bases are, for example, alkali hydroxides such as sodium or potassium hydroxide, or alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or amides such as lithium diisopropylamide, or other bases such as DBU, triethylamine or diisopropylethylamine, preferably triethylamine.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol
  • halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene
  • ethers such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol
  • Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran, dimethylformamide or methylene chloride are preferred.
  • Typical condensing agents are, for example, carbodiimides such as N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'- ethyl carbodiimide hydrochloride (EDC), N-cyclohexyl-carbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2- oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium-perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-
  • Bases are, for example, alkali carbonates, such as, for example, sodium or potassium carbonate, or bicarbonate, or organic bases, such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates such as, for example, sodium or potassium carbonate, or bicarbonate
  • organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt) and the combination of N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) are particularly preferred.
  • HATU uronium hexafluorophosphate
  • the compounds of the general formula (III) are known or can be synthesized from the corresponding starting materials by known processes.
  • R, 1 ⁇ 0 ⁇ stands for (dC 6 ) alkyl
  • X represents halogen, preferably bromine or iodine
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as acetone, dimethylformamide, dimethylacetamide, 2-butanone or acetonitrile, preferably tetrahydrofuran and
  • Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, or other bases such as sodium hydride, potassium hexadimethyl disilazide, lithium hexadimethyl disilazide or DBU, preferably potassium hexadimethyldisilazide or sodium hydride.
  • alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide
  • other bases such as sodium hydride, potassium hexadimethyl disilazide, lithium hexadimethyl disilazide or DBU, preferably potassium hexadimethyldisilazide or sodium hydride.
  • X 3 represents halogen, preferably bromine or chlorine
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane, ethers such as diethyl ether, dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, or other solvents such as acetone, dimethylformamide, 2-butanone, Acetonitrile or pyridine, pyridine, acetonitrile, methylene chloride or tetrahydrofuran are preferred.
  • halogenated hydrocarbons such as methylene chloride, trichloromethane or 1,2-dichloroethane
  • ethers such as diethyl ether, dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene or toluene
  • Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, or other bases such as sodium hydride, DBU, triethylamine, diisopropylethylamine or pyridine, alkali carbonates are preferred such as cesium carbonate, sodium or potassium carbonate or pyridine.
  • the compounds of the general formula (VT) are known or can be synthesized from the corresponding starting materials by known processes.
  • the compounds of the general formula (V) can be prepared from the corresponding starting materials in analogy to the synthesis method given below for the compounds of the general formula (X).
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 8 have the meaning given above,
  • R 1 , R 2 , R 3 and R 4 have the meaning given above,
  • inert solvents preferably in a temperature range from room temperature to the reflux of the solvents at normal pressure.
  • Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixtures of the solvents mentioned, if appropriate with water, a mixture of ethanol and water being preferred.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixtures of the solvents mentioned, if appropriate with water, a mixture of ethanol and water being preferred.
  • A, E, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 have the meaning given above, and
  • R 1 ' represents (C r C 6 ) -alkyl, preferably methyl and ethyl,
  • inert solvents preferably in a temperature range from room temperature to 60 ° C at normal pressure.
  • Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, preferably sodium hydroxide or lithium hydroxide.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, trichloroethane, carbon tetrachloride, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixtures of the solvents mentioned, optionally with water, preferably tetrahydrofuran and / or Methanol or a mixture of water and ethanol or a mixture of water and dioxane.
  • halogenated hydrocarbons such as methylene chloride, carbon tetrachloride
  • A, E, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 11 have the meaning given above,
  • R 1 , R 2 , R 3 , R 4 , R 8 and R 11 have the meaning given above,
  • R 1 , R 2 , R 3 , R 4 , R 8 and R 11 have the meaning given above, and
  • R 12 represents (dC 6 ) alkyl, preferably methyl and ethyl,
  • Reducing agents are, for example, palladium on activated carbon and hydrogen, tin dichloride or titanium trichloride; palladium on activated carbon and hydrogen or tin dichloride is preferred.
  • Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile or pyridine, preferred solvents are methanol, ethanol, isopropanol or, in the case of tin dichloride, in ethanol, methanol or dimethylformamide.
  • ethers such as diethyl ether, methyl
  • R 1 , R 2 , R 3 and R 4 have the meaning given above,
  • R 8 , R 11 and R 12 have the meaning given above,
  • hydrochloride or hydrobromide salts for example hydrochloride or hydrobromide salts, in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure.
  • Inert solvents are, for example, ethers such as 1,2-dimethoxyethane, dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine, and dimethyl sulfoxide is preferred as the solvent.
  • ethers such as 1,2-dimethoxyethane, dioxane, glycol dimethyl ether or diethylene glycol dimethyl ether
  • hydrocarbons such as benzene, xylene, toluene or petroleum fractions
  • other solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine, and dimethyl sulfoxide is preferred as the solvent.
  • Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine.
  • alkali carbonates such as cesium carbonate, sodium or potassium carbonate
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine.
  • X represents halogen, preferably chlorine
  • potassium nitrate and sulfuryl chloride in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvents at normal pressure.
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethanol, methanol, alcohol, methanol dimethanol, alcohol, alcohol dimethanol, alcohol, methanol dimethanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile or
  • the compounds of the general formula (I) according to the invention are suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
  • the compounds of the invention have an antagonistic effect on the B1 receptor.
  • the compounds according to the invention can be used alone or in combination with other medicaments for the prophylaxis and treatment of acute and / or chronic pain (for a classification see "Classification of Chronic Pain, Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms" , 2nd ed., Meskey and Begduk, eds .; IASP-Press, Seattle, 1994), especially for treatment development of cancer-induced pain and chronic neuropathic pain, such as, for example, in diabetic neuropathy, post-herpetic neuralgia, peripheral nerve damage, central pain (for example as a result of cerebral ischemia) and trigeminal neuralgia, and other chronic pain, such as, for example, lumbago, back pain (low back pain), inflammatory or rheumatic pain.
  • these substances are also suitable for the therapy of primary acute pain of any genesis and the secondary pain states resulting therefrom, as well as for the treatment of chronic, formerly acute pain states.
  • Bradykinin 1 antagonists are also suitable for the treatment of asthma, diabetic vasculopathy, rhinitis, septic shock, atherosclerosis, multiple sclerosis or rheumatic arthritis.
  • vz ' tro activity of the compounds according to the invention can be shown with the following biological assays:
  • Agonists such as des-Arg9-BK and des-ArglO-kallidin activate the Bl receptor and stimulate phospholipase C to release calcium ions from intracellular stores. Antagonists block the activation of the receptor by the agonist and thus also the agonist-dependent stimulation of phospholipase C and the intracellular calcium release triggered thereby.
  • a functional in vz ' tro assay can be carried out with stable cell lines, for example CHO or HEK 293, which recombinantly express the human Bl receptor.
  • the activation of the receptor by the agonist is measured indirectly via the intracellular calcium release triggered thereby (in microtiter plates with 96, 384 and 1536 wells / plate).
  • the effect of the tested substances can be given as an Ido value.
  • Examples 170 and 177 have IC 50 values of 25nM and 17nM, respectively.
  • a suspension of carrageenin (0.35 mg per paw in 0.10 ml of physiological saline) is injected into the right hind paw of rats. Two hours later the rats are successively thermally stimulated on the non-inflamed as well as on the inflamed hind paw.
  • the thermal stimulation device (Ugo Basile, Ref .: 7371) consists of 6 individual plexiglass boxes placed on a raised glass plate
  • a rat is placed in the box for 30 minutes for habituation. Then a movable infrared source (setting 20) is focused under the non-inflamed and the inflamed rear paw and the latency times until the paw is removed are recorded automatically. Pulling the paw away interrupts the reflected radiation and automatically switches off the counter and light source.
  • test is ended after 45 s, even if no paw pull reaction is registered.
  • At least 12 rats are examined per group: male Wistar (Han) rats, 180-220 g. The test is carried out blindly
  • the data analysis is carried out by comparing the treated groups with the corresponding controls using the unpaired Student's test.
  • the new active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, for example when used of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. It can also be inhaled over
  • Mouth or nose for example using a spray, or topically on the skin.
  • TIPS Triisopropylsilyl titr. titrated
  • the LC-MS data were determined using the following methods:
  • HPLC HP 1100 UV detector DAD: 208-400 nm column: Symmetry C 18; 50 mm x 2.1 mm; 3.5 ⁇ m ionization: ESI positive / negative oven temperature: 40 ° C
  • Solvent A CH3CN + 0.1% formic acid
  • Solvent B H 2 O + 0.1% formic acid
  • Solvent B 0.3 g HCl (30%) / l 1 water Gradient: A / B 2/98 to 95/5 within 2.5 min flow: 0.9 ml / min to 1.2 ml / min within 2 min
  • This compound is obtained analogously to the procedure of Example I from 1.00 g (9.25 mmol) of 1,2-phenylenediamine and 1.88 g (9.25 mmol) of N- (2-methoxyphenyl) maleinimide after refluxing for 3.5 hours and triturating the precipitate obtained with isopropanol.
  • a solution of 53.6 g (380 mmol) of l-fluoro-2-nitrobenzene, 25.0 g (127 mmol) of DL-aspartic acid dimethyl ester and 49.1 g (380 mmol) of N, N-diisopropylethylamine in 150 ml of DMSO is in an argon atmosphere overnight at 60 ° C stirred. It is cooled to room temperature and 300 ml of water and ethyl acetate are added to the mixture. The aqueous phase is extracted three times with 300 ml of ethyl acetate and the combined organic phases are washed twice with 100 ml of water.
  • the organic phase is dried over sodium sulfate and the solvent is distilled off on a rotary evaporator.
  • the crude product is purified on a flash column (eluent: toluene). 21.8 g (61%) of the target connection are obtained.
  • the aqueous phase is extracted six times with 100 ml of ethyl acetate.
  • the combined organic phases are dried over sodium sulfate and the solvent is distilled off on a rotary evaporator. 3.05 g (70%) of the title compound are obtained.
  • Hexamethyldisilazane in 100 ml of toluene was added dropwise. The solution is then heated to 100 ° C. and stirred overnight. After the reaction solution has cooled, the solution is added to 200 ml of 0.5N HCl and the organic phase is separated off. The aqueous phase is extracted three more times with 200 ml of ethyl acetate, the combined organic phases are dried over gastric sulfate and the solvent is distilled off on a rotary evaporator. The crude product is purified on a flash column (mobile phase: cyclohexane / ethyl acetate). 18.78 g (94%) of the title compound are obtained as a white solid.
  • a suspension of 6.72 g (62.1 mmol) of 1,2-phenylenediamine and 12 g (62.1 mmol) of l-cycloheptyl-lH-pyrrole-2,5-dione are heated to boiling in 200 ml of ethanol / water 1: 1. After 12 hours at reflux, the mixture is allowed to cool and the precipitate formed is separated off. The filter cake is washed with ethanol / water 1: 1 and dried in vacuo.
  • the organic phase is washed twice with saturated sodium chloride solution, dried over sodium sulfate and the solvent is distilled off on a rotary evaporator.
  • the crude product is purified on a flash column (mobile phase: dichloromethane / methanol 100: 2). 550 mg (44%>) of the title compound are obtained.
  • Examples 2-106 listed in Tables 1 and 2 are obtained in accordance with this specification.
  • the optically active compounds in Table 2 are prepared starting from dimethyl L-aspartate:
  • Wavelength 254 nM solvent: ethyl acetate packing material: 6784 (600 * 30); LNW 2951; N-MA-L-leu-2,4-dimethylpentyl amide
  • concentration c specified in connection with the specific rotation value is defined as the amount of substance (in g) per 100 ml of solution. Layer thickness: 100 mm).

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EP02762319A 2001-07-17 2002-07-04 Tetrahydrochinoxaline als bradykininantagonisten Withdrawn EP1411948A1 (de)

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AU2003228825A1 (en) * 2002-05-03 2003-11-17 Elan Pharmaceuticals, Inc. Sulfonylquinoxalone acetamide derivatives and related compounds as bradykinin antagonists
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US6908921B2 (en) 2002-12-13 2005-06-21 Merck & Co., Inc. Quinoxalinone derivatives as bradykinin B1 antagonists
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