WO2010097373A1 - Composés servant d'antagonistes de bradykinine b1 - Google Patents

Composés servant d'antagonistes de bradykinine b1 Download PDF

Info

Publication number
WO2010097373A1
WO2010097373A1 PCT/EP2010/052235 EP2010052235W WO2010097373A1 WO 2010097373 A1 WO2010097373 A1 WO 2010097373A1 EP 2010052235 W EP2010052235 W EP 2010052235W WO 2010097373 A1 WO2010097373 A1 WO 2010097373A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
substituted
fluorine atoms
optionally substituted
Prior art date
Application number
PCT/EP2010/052235
Other languages
German (de)
English (en)
Inventor
Ingo Konetzki
Angelo Ceci
Henri Doods
Norbert Hauel
Jürgen Mack
Henning Priepke
Annette Schuler-Metz
Rainer Walter
Original Assignee
Boehringer Ingelheim International Gmbh
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International Gmbh filed Critical Boehringer Ingelheim International Gmbh
Publication of WO2010097373A1 publication Critical patent/WO2010097373A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the compounds of general formula I.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 and X 3 are defined as described below, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts with organic or inorganic acids or bases which have valuable properties, their preparation, the medicaments containing the pharmacologically active compounds, their preparation and their use.
  • R 1 is (a) optionally substituted with a radical R 1-1 substituted Ci -6 alkyl group,
  • each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,
  • R 1 is 2-substituted C3 -6 cycloalkyl group, can be a -CH 2 moiety replaced by a -C (O) group (c),
  • R 1 is 4-substituted six-membered heteroaryl-Co-2 alkylene group containing one, two or three N atoms and which may be benzo-fused, in addition, (g) optionally substituted with 1 or 2 radicals R 1 is 4-substituted nine- or ten-membered heteroaryl radical containing one, two or three N atoms,
  • Heterocycle which contains at least one N, O or S atom and in which additionally a -CH 2 unit can be replaced by a -C (O) group,
  • R 1 - 1 halogen, -CN, C 3 - 6 -cycloalkyl, -OR 1 - 1 - 1 , -SR 1 - 1 - 1 , -C (O) R 1 1 1 , -S (O) 2 -R 1 - 1 2 ,
  • R 1 - 1 - 1 (a) H, (b) Ci- 4 alkyl,
  • each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,
  • R 1 - 1 - 1 - 2 are independently halogen or Ci -4 alkyl
  • R 1 - 1 - 2 (a) Ci- 4 alkyl, (b) d-C3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each
  • Methyl group may be substituted by 1, 2 or 3 fluorine atoms, or
  • R 1 "1" 3 and R 1 "1" 4 together with the N-atom to which they are attached form a 5- or 6-membered heterocyclic ring which additionally contains one further heteroatom selected from N, O and S. can, or
  • p i . 1 . 4 . 1 una epending another are halogen, -NH 2, -NH (Ci -4 alkyl), -N (d -4 alkyl) 2 or -SO 2 -R 1 - 1 2,
  • R 1 - 2 halogen, -CN, OH, -O-CH 3 or phenyl,
  • R 1 - 3 (a) halogen, -CN, -OR 1 - 1 - 1 , -SR 1 - 1 - 1 , -CO 2 R 1 - 1 1 , C 1-6 alkyl or
  • each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms, or
  • R 2 and R 3 together with the carbon atom to which they are attached, an optionally substituted by a radical R 2 1 substituted Cs ⁇ -Cycloalkylenoli in which a - A -
  • -CH 2 unit can be replaced by a heteroatom O, N, S or by a group CO, SO or SO 2 ,
  • R 5 (a) H, halogen, -CN, -OH,
  • Ci -3 alkyl five-membered heteroaryl group which is selected from the group consisting of pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
  • Ci -3 alkyl six-membered heteroaryl group which is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
  • R 5 - 1 -NH 2 -NH (Ci -6 alkyl), - N (Ci -6 alkyl) 2, ⁇ / -Acetidinyl, ⁇ / -pyrrolidinyl, ⁇ / -piperidinyl, ⁇ / -morpholinyl, - OH, -O-Ci -8- alkyl or -OC 3-7 -cycloalkyl,
  • R 5 - 2 -NH 2 -NH (Ci -6 alkyl), - N (Ci -6 alkyl) 2, ⁇ / -Acetidinyl, ⁇ / -pyrrolidinyl, ⁇ / ⁇ piperidinyl or / and -morpholinyl
  • R 6 (a) H, halogen, -CN, -OH,
  • R 7 (a) H, halogen, -CN, -OH,
  • Ci -3 alkyl five-membered heteroaryl group which is selected from the group consisting of pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or (k) a six-membered heteroaryl group which is optionally substituted by one or two C 1-3 -alkyl groups and is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
  • R 7 - 2 -NH 2 -NH (Ci -6 alkyl), - N (Ci -6 alkyl) 2, ⁇ / -Acetidinyl, ⁇ / -pyrrolidinyl, ⁇ / ⁇ piperidinyl or / -morpholinyl,
  • R 8 is H, F, Cl, CH 3 ,
  • An embodiment 2 of the present invention consists in the compounds of the above general formula I in which R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 and X 3 as described above under the embodiment ⁇ _ mentioned are defined and
  • R 1 is (a) optionally substituted with a radical R 1 is substituted C 1 -6 alkyl group,
  • R 1 is 4-substituted nine- or ten-membered heteroaryl radical containing one, two or three N atoms,
  • Heterocycle which contains at least one N, O or S atom and in which additionally a -CH 2 unit can be replaced by a -C (O) group,
  • R 1 - 1 (a) -CN, C 3- 6 cycloalkyl, -OR 1 - 1 - 1, -NR 1 R 3 1 1 - 1 4, or (b) d-3-alkyl, wherein each methylene group with 1 or 2 fluorine atoms and each
  • Methyl group may be substituted by 1, 2 or 3 fluorine atoms,
  • Methyl group may be substituted by 1, 2 or 3 fluorine atoms,
  • R 1 - 1 - 3 , R 1 - 1 - 4 independently
  • R 1 - 1 - 3 and R 1 - 1 - 4 form, together with the N-atom to which they are attached, a 5- or 6-membered heterocyclic ring which additionally contains a further heteroatom selected from N, O and S. can, or
  • R 1 - 2 halogen, -CN, -OH, -O-CH 3 or phenyl,
  • R 1 - 3 independently (a) halogen, -CN, -OR 1 - 1 - 1 , d -6- alkyl or
  • each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms, and
  • R 1 - 4 - 1 H or d- 4 alkyl mean
  • An embodiment 3 of the present invention consists in the compounds of the above general formula I, in which R 1 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 and X 3 mentioned above under the embodiment 1_ or 2 are defined and
  • An embodiment 4 of the present invention consists in the compounds of the above general formula I, in which R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , X 1 , X 2 and X 3 as described above under the embodiment I -, 2 or 3 mentioned are defined and
  • An embodiment 5 of the present invention consists in the compounds of the above general formula I, in which R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , X 1 , X 2 and X 3 as described above under the embodiment I , 2, 3 or 4 mentioned are defined and
  • R 5 (a) H, halogen, -CN or
  • An embodiment 6 of the present invention consists in the compounds of the above general formula I, in which R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , X 1 , X 2 and X 3 as described above under the embodiment I -, 2, 3, 4 or 5 mentioned are defined and
  • R 6 is (a) H, halogen, -CN, -OH, (b) Ci -3 alkyl,
  • An embodiment 7 of the present invention consists in the compounds of the above general formula I in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 and X 3 as described above under the embodiment I -, 2, 3, 4, 5 or 6 mentioned are defined and
  • R 7 (a) H, halogen, -CN, (b) d-C3 alkyl, or -O-Ci -3 alkyl, wherein each methylene group having 1 or 2 fluorine atoms and each methyl group with 1, 2 or 3 fluorine atoms could be,
  • An embodiment 8 of the present invention consists in the compounds of the above general formula I, in which R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , X 1 , X 2 and X 3 as described above in the embodiment I -, 2, 3, 5, 6 or 7 mentioned are defined and
  • R 4 H means
  • An embodiment 9 of the present invention consists in the compounds of general formula Ia
  • R 1 , R 2 , R 3 , R 6 , R 7 and X 1 are as defined above in the embodiment I, 2, 3, 6, or 7,
  • R 1 , R 6 , R 7 and X 1 are defined as mentioned above under the embodiment I, 2, 6, 7 or 8,
  • An embodiment ⁇ ⁇ _ of the present invention consists in the compounds of the general formula I, Ia or Ib, in which R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 and X 3 as described above under the embodiment I, 2, 3, 4, 5, or 8 mentioned are defined and
  • R 7 is -CN, -CF 3 , Cl or Br,
  • One embodiment of the present invention consists in the compounds of general formula I, Ia or Ib above in which R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 and X 3 are as are defined above in the embodiment I, 3, 4, 5, 6, 7, 8, 9, W or 1_1_ mentioned and
  • R 1 is (a) optionally substituted with a radical R 1 is substituted C 1 -6 alkyl group,
  • an optionally substituted by a group R 1 is 2-substituted C 3-6 cycloalkyl group, can be a -CH 2 moiety replaced by a -C (O) group,
  • R 1 - 1 (a) -CN, C 3 - 6 -cycloalkyl, -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , or
  • each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms,
  • R 1 4 is independently (a) F, Cl, Br, -OH, -O-Ci -3 alkyl, -NH 2, -NHCH 3, -N (CHa) 2, -NH-C (O) -C -4 alkyl, de-alkyl, or
  • An embodiment of the present invention consists in the compounds of the above general formula I, Ia or Ib, in which R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 and X 3 are as are defined above in the embodiment I, 3, 4, 5, 6, 7, 8, 9, W or 1_1_ mentioned and
  • R 1 (a) an optionally substituted by a radical R 1-1 substituted C- ⁇ -6-alkyl group
  • R 1 is 4-substituted six-membered heteroaryl residue selected from the group consisting of
  • R 1 is 4-substituted 5- or 6-membered heterocycle which is selected from the group consisting of
  • R 1 - 1 (a) -CN, cyclopropyl, CF 3 , -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N (CHa) 2 , or
  • each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group by 1, 2 or 3 fluorine atoms, R 1 - 2 is -OH or -O-CH 3 ,
  • An embodiment M of the present invention consists in the compounds of the above general formula I, Ia or Ib, in which R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 and X 3 as above are defined under the embodiment I, 3, 4, 5, 6, 7, 8, 9, 1_0 or 1_1_ and
  • R 1 is selected from the group consisting of
  • 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.
  • alkyl Ci alkyl groups having 1 to 3 carbon atoms, branched, the term “C-M-alkyl” and unbranched alkyl groups having 1 to 4 carbon atoms, the term “C 1-6 -alkyl” is understood to mean branched and unbranched alkyl groups having 1 to 6 carbon atoms and branched and unbranched alkyl groups having 1 to 8 carbon atoms by the term "C 1-8 -alkyl”.
  • Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, te / f-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl.
  • the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups.
  • the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals.
  • propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and te / f-butyl.
  • the above-mentioned terms also include those radicals in which each methylene group may be substituted with up to two and each methyl group with up to three fluorine atoms.
  • the term "Co- 2- alkylene” is understood to mean branched and unbranched alkylene groups having from 0 to 2 carbon atoms, a co-alkylene group being a bond. Examples include: methylene, ethylene and ethane-1, 1-diyl.
  • the abovementioned terms also include those radicals in which each methylene group may be substituted by up to two fluorine atoms.
  • C 3-7 -cycloalkyl (including those which are part of other groups) means cyclic alkyl groups having 3 to 7 carbon atoms and the term “C 3-6 -cycloalkyl” means cyclic alkyl groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise described, the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • Cs-e-cycloalkylene (even if they are part of other radicals) are understood as meaning cyclic alkylene groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Unless otherwise described, the cyclic alkyl groups may be substituted with one or more groups selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • C 2 - 6 alkenyl (including those which are part of other radicals) are understood to mean branched and unbranched alkenyl groups having 2 to 6 carbon atoms, provided they have at least one double bond. Alkenyl groups having 2 to 4 carbon atoms are preferred. Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise described, the definitions propenyl, butenyl, pentenyl and hexenyl include all conceivable isomeric forms of the respective radicals. For example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-butenyl, 2-butenyl and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, etc.
  • C 2 - 4 -alkynyl (including those which are part of other radicals) are understood to mean branched and unbranched alkynyl groups having 2 to 4 carbon atoms, provided they have at least one triple bond. For example, this will be called: ethynyl, propynyl or butynyl. Unless otherwise stated, the definitions of propynyl and butynyl include all conceivable isomeric forms of the respective radicals.
  • propynyl includes 1-propynyl and 2-propynyl
  • butinyl includes 1-butynyl, 2-butynyl and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl, etc.
  • Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.
  • heterocyclic rings or “heterocycle” is meant stable 4-, 5- or 6-membered monocyclic heterocyclic ring systems which may be both saturated and monounsaturated and which may bear, in addition to carbon atoms, one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Both nitrogen and sulfur heteroatoms can optionally be oxidized.
  • the above heterocycles may be linked via a carbon atom or via a nitrogen atom with the remainder of the molecule. Examples include the following compounds:
  • Cyclic imides include, for example, succinimide, maleimide and phthalimide.
  • aryl (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6 or 10 carbon atoms. For example, phenyl, 1-naphthyl or 2-naphthyl be mentioned; preferred aryl radical is phenyl.
  • the aromatics may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, / so-propyl, te / f-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, Bromine and iodine, where the radicals may be the same or different.
  • heteroaryl is understood as meaning five- or six-membered heterocyclic aromatics which may contain one, two, three or four heteroatoms selected from the group oxygen, sulfur and nitrogen and additionally contain so many conjugated double bonds that an aromatic system is formed becomes. These heteroaryls may additionally be benzo-fused with a phenyl ring to form nine- or ten-membered bicyclic heteroaryls. Examples of five- or six-membered heterocyclic aromatics include:
  • heteroaryls may be substituted by one or more radicals selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluoro, Chlorine, bromine and iodine, where the radicals may be the same or different.
  • a nitrogen atom present in the heteroaryl radical may be oxidized to form an N-oxide.
  • oxo group an oxygen substituent on a carbon atom resulting in the formation of a carbonyl group -C (O) -.
  • Introduction of an oxo group as a substituent on a non-aromatic carbon atom results in conversion of a -CH 2 group to a -C (O) group.
  • the introduction of an oxo group on an aromatic carbon atom leads to the conversion of a -CH group into a -C (O) group and may result in the loss of aromaticity.
  • Suitable inorganic acids are, for example, hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, organic acids being, for example, malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid into consideration.
  • the compounds of general formula I contain suitable carboxylic acid functions, in particular for pharmaceutical applications in their physiologically acceptable salts with inorganic or organic bases.
  • suitable inorganic bases are alkali metal or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc hydroxides or ammonium hydroxides;
  • suitable organic amines are, for example, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.
  • the compounds of the invention may exist as racemates if they possess only one chiral element, but they may also be present as pure enantiomers, i. in (R) or (S) form.
  • the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chiral element is present in the compounds of general formula I, as well as the individual optically active enantiomers which make up the racemates mentioned.
  • the compounds of general formula I are obtained by processes known per se, for example by the following processes:
  • the coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example carbodiimides, e.g. Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylamino-propyl) -carbodiimide, 0- (1H-benzotriazol-1-yl) - / V, / V, ⁇ Metramethyluronium hexafluorophosphate (HBTU) or tetra - Fluoroborate (TBTU) or 1 H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used.
  • DEC Dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • the reaction rate can be increased by adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt).
  • the couplings are normally carried out with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / -methylpyrrolidone (NMP) or mixtures thereof.
  • solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / -methylpyrrolidone (NMP) or mixtures thereof.
  • an auxiliary base such as diisopropylethylamine (DIPEA, Hünig base) is additionally used.
  • An alternative method of preparing compounds of general formula I is to link carboxylic acids of general formula V wherein all of the radicals are as defined above with amines of general formula IV in which all radicals are as defined above.
  • reaction of a phenol of general formula VIII in which all radicals are defined as mentioned above with a nitrile of general formula X in which all radicals are as defined above is carried out by known methods, for example in a solvent such as tetrahydrofuran, dimethylformamide or dimethyl sulfoxide and expediently in the presence of a base such as triethylamine, sodium hydroxide or potassium carbonate at a temperature of 20 0 C to 160 0 C. If the phenol of the general formula VIII is liquid, the reaction can also be carried out without solvent and additional base.
  • ketones are obtained, for example, from the reaction of a nitrile of the general formula IX with an alkyl Grignard reagent, which can be converted by means of reductive amination into the compounds of the general formula III.
  • the reductive amination is carried out by known methods, for example with a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or Natriumcyanoborhydrid conveniently in a solvent such as tetrahydrofuran or dichloromethane optionally with the addition of acetic acid.
  • a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or Natriumcyanoborhydrid conveniently in a solvent such as tetrahydrofuran or dichloromethane optionally with the addition of acetic acid.
  • the ketones obtained can also be converted into oximes. The subsequent reduction of the oximes then provides compounds of the general formula
  • CHO cells expressing the cynomolgus B1 receptor are termed "HAM 'S S-12
  • the cells are homogenized in suspension, the homogenate is centrifuged and resuspended. After determination of the protein content, 200 ⁇ l of the homogenate (50 to 250 ⁇ g protein / assay) are incubated for 60-180 minutes at room temperature with 0.5 to 5.0 nM kallidine (DesArg10, Leu9), [3,4-prolyl-3,43H (N) ] and increasing concentrations of the test substance are incubated in a total volume of 250 ⁇ l. Incubation is terminated by rapid filtration through GF / B glass fiber filters pre-treated with polyethyleneimines (0.3%). The radioactivity bound to the protein is measured with a TopCount NXT.
  • Non-specific binding is defined as the bound radioactivity in the presence of 1.0 ⁇ M (DesArgi O) kallidine.
  • the analysis of the concentration-binding curve can be carried out by means of a computer-aided non-linear curve fitting in order to determine the corresponding K 1 value for the test substance.
  • the new compounds and their physiologically acceptable salts are suitable for the treatment of diseases and
  • Another object of the present invention comprises the compounds of the invention of the above-mentioned general formula I for use as a medicament.
  • the substances are suitable for the treatment of (a) acute pain, such as toothache, peri- and postoperative pain, traumatic pain, muscle pain, Burn pain, pain in sunburn, trigeminal neuralgia, pain in colic, as well as in spasms of the gastrointestinal tract or the uterus;
  • intestinal pain such as chronic pelvic pain, gynecological pain, pain before and during menstruation, pain in pancreatitis, peptic ulcer, interstitial cystitis, renal colic,
  • neuropathic pain such as painful polyneuropathies, pain in diabetic neuropathy, AIDS-associated neuropathic pain, non-herpes associated neuralgia, post-zoster neuralgia, nerve injury, traumatic brain injury, pain due to nerve damage as a result of toxins or chemotherapy, in phantom pain, pain in multiple sclerosis, nerve root detachment and painful traumatic individual nerve damage, and central pain such as after stroke, spinal cord injury or tumors;
  • inflammatory / pain receptor mediated pain associated with diseases such as osteoarthritis, rheumatoid arthritis, rheumatic fever, Tendo synovitis, bursitis, tendonitis, gout and gouty arthritis, traumatic arthritides, vulvodynia, lesions, and
  • tumor pain associated with cancers such as lymphocytic or myeloid leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, lymphogranulomatosis, lymphosarcoma, solid malignant tumors, and extensive metastases;
  • headache disorders of various causes such as cluster headache, migraine (with or without aura), and tension-type headache
  • pain conditions of mixed cause such as chronic low back pain, including lumbago, or fibromyalgia.
  • the compounds are suitable for treatment (h) inflammatory or inflammatory effects of sunburn and burns, gingivitis, edema after trauma from burns, cerebral edema and angioedema, bowel disease including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory diseases of the skin (such as psoriasis and eczema), vascular connective tissue disorders, strains and fractures, as well as musculoskeletal diseases with inflammatory phenomena such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoid arthritis, spondylarthritis, but also osseoarthritis, and inflammatory connective tissue diseases of other causes, and collagenoses of any genesis such as systemic lupus erythematosus, scleroderma, polymyosit
  • bronchial asthma including allergic asthma (atopic and non-atopic) and bronchospasm on exertion, occupational asthma, viral or bacterial exacerbation of existing asthma and other non-allergic conditional asthmatic diseases;
  • chronic bronchitis and chronic obstructive pulmonary disease including pulmonary emphysema, viral or bacterial exacerbation of chronic bronchitis or chronic obstructive bronchitis, adult respiratory distress syndrome (ARDS), bronchitis, pneumonia, allergic rhinitis (seasonal and perennial), vasomotor rhinitis and pneumoconiosis diseases such as aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tobaccoosis, byssinosis, exogenous allergic alveolitides, pulmonary fibrosis, bronchiectasis, lung diseases in alpha-anti-tritrypsin deficiency and cough;
  • COPD chronic obstructive pulmonary disease
  • diabetes mellitus and its consequences such as, for example, diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy) and diabetic symptoms in insulitis (for example hyperglycemia, diuresis, proteinuria and increased renal nitrite and kallikrein excretion);
  • insulitis for example hyperglycemia, diuresis, proteinuria and increased renal nitrite and kallikrein excretion
  • sepsis and septic shock after bacterial infections or after trauma
  • Periarteritis nodosa Temporal arteritis, Wegner's granulomatosis, giant cell arrhythmias, arteriosclerosis, erythema nodosum;
  • the substances are suitable for causal treatment in terms of slowing down or stopping the progression of chronic progressive diseases, in particular osteoarthritis, rheumatoid arthritis and spondylarthritis.
  • Another object of the present invention comprises the use of the compounds of the invention of the above-mentioned general formula I for the preparation of a medicament for a therapeutic application in the indications mentioned above.
  • the compounds of general formula I according to the invention are preferably used for the treatment of osteoarthritis, rheumatoid arthritis or COPD.
  • treatment or “therapy” is understood to mean a therapeutic treatment of patients with overt, acute or chronic indications, on the one hand the symptomatic (palliative) treatment for the alleviation of the disease symptoms and on the other hand the causal or curative treatment of the indication with the aim to terminate the pathological condition, to reduce the severity of the pathological condition or to delay the progression of the pathological condition, depending on the type or severity of the indication included.
  • Another object of the present invention is the use of a compound of general formula I for the manufacture of a medicament for the acute and prophylactic treatment of acute pain, intestinal pain, neuropathic pain, inflammatory / pain receptor-mediated pain, tumor pain, headache disorders and pain conditions of mixed cause and another of the above-mentioned diseases.
  • the use is characterized in that it provides the administration of an effective
  • Amount of a compound of general formula I or a physiologically acceptable salt thereof includes a patient who requires such treatment.
  • patient is preferably understood to mean a human.
  • these substances are also useful in the veterinary treatment of pets, exotic animals and livestock.
  • the compounds of the invention For the treatment of pain, it may be advantageous to combine the compounds of the invention with invigorating substances such as caffeine or other analgesic agents. If suitable active ingredients are available for the treatment of the cause of the pain, these can be combined with the compounds according to the invention.
  • Non-steroidal anti-inflammatory drugs such as propionic acid derivatives, which may be selected from the group consisting of alminoprofen, bucloxinic acid, carprofen, fenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and tiaprofenoic acid; Acetic acid derivatives which may be selected from the group consisting of indomethacin, acemetacin, alcofenac, isoxepac, sulindac and tolmetin; Fenamic acid derivatives which may be selected from the group consisting of meclofenamic acid, mefenamic acid and tolfenamic acid; Biphenyl-carboxylic acid derivatives; Oxicams, which may be selected from the group consisting of meloxicam, piroxicam and tenoxicam; SalIDs, such as propionic acid derivatives, which may be selected from the group consist
  • Opiate receptor agonists which may be selected, for example, from the group consisting of such as morphine, darvon, tramadol and buprenorphine.
  • Cannabinoid agonists such as GW-1000.
  • Sodium channel blockers which may be selected, for example, from the group consisting of carbamazepine, mexiletine, pregabalin, tectin and ralfinamide.
  • N-type calcium channel blockers such as ziconotide.
  • Serotonergic and noradrenergic modulators which may be selected, for example, from the group consisting of duloxetine and amitriptyline.
  • Corticosteroids which may be selected, for example, from the group consisting of betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
  • Histamine H1 receptor antagonists which may be selected, for example, from the group consisting of brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, Promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine.
  • Leukotriene antagonists and 5-lipoxygenase inhibitors which may for example be selected from the group consisting of zafirlukast, montelukast, pranlukast and zileuton.
  • Local anesthetics which may be selected, for example, from the group consisting of ambroxol and lidocaine.
  • TRPV1 antagonists which may be selected, for example, from the group consisting of AZD-1386, JTS-653 and PHE-377.
  • Nicotine receptor agonists such as A-366833.
  • P2X3 receptor antagonists such as A-317491.
  • anti-NGF antibodies and NGF antagonists which may for example be selected from the group consisting of JNJ-42160443 and PPH 207.
  • NK1 and NK2 antagonists such as CP-728663.
  • NMDA antagonists which may for example be selected from the group consisting of CNS-5161, AZ-756 and V-3381.
  • Potassium channel modulators such as CL-888.
  • GABA modulators such as baclofen.
  • Anti-migraine therapeutics which may be selected, for example, from the group consisting of sumatriptan, zolmitriptan, naratriptan and eletriptan.
  • the compounds of the general formula I according to the invention for the treatment of one or more of the respiratory diseases mentioned above, it may be advantageous to use the compounds of the general formula I according to the invention with other active compounds for the treatment of To combine respiratory diseases. If suitable active substances are available for the treatment of the cause of the respiratory diseases, these can be combined with the compounds according to the invention.
  • the compounds of the general formula I can also be used in combination with other pharmacologically active substances.
  • active substances which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, further PDE4 inhibitors, LTD4 receptor (CysLTI, CysLT2, CysLT3) antagonists, inhibitors of MAP kinases such as, for example, p38, ERK1 , ERK2, JNK1, JNK2, JNK3 or SAP, LTB4 receptor (BLT1, BLT2) antagonists, EGFR inhibitors, H1 receptor antagonists, antihistamines, H4 receptor antagonists, PAF antagonists and PI3-kinase inhibitors CXCR1 and / or CXCR2 Receptor antagonists and substances for cough.
  • active substances which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, further PDE4 inhibitors, LTD4 receptor (CysLTI, Cys
  • the compounds of general formula I can also be used in the form of two- or three-fold combinations thereof, such as, for example, combinations of compounds of formula I with one or two compounds selected from the group consisting of
  • betamimetics corticosteroids, PDE4 inhibitors, EGFR inhibitors and LTD4 antagonists
  • anticholinergics betamimetics, corticosteroids, PDE4 inhibitors, EGFR inhibitors and LTD4 antagonists
  • PDE4 inhibitors corticosteroids, EGFR inhibitors and LTD4 antagonists
  • EGFR inhibitors and LTD4 antagonists CCR3 inhibitors, iNOS inhibitors (inducible nitric oxide synthase inhibitors), (6R) -L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as "BH4" ) and its derivatives, which are mentioned in WO 2006/120176, and SYK inhibitors (spike tyrosine kinase inhibitors),
  • Anticholinergics betamimetics, corticosteroids, PDE4 inhibitors and MRP4 inhibitors.
  • compounds which are selected from the group consisting of arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterols, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol are preferably used according to the invention , Mabuterol, meluadrin, metaproterenol, milveterol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, soterenol, sulfonterol, terbutaline, tiaramide, toluubuterol and zinte
  • the acid addition salts of the betamimetics are preferably selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate,
  • Hydrocitrate hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • anticholinergics are preferably compounds which are selected from the group consisting of tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, aclidinium salts, preferably the bromide salt, glycopyrronium salts , preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R) -1-phenethyl-3- (9H-xanthene-9-carbonyloxy) -1-azoniabicyclo [2.2.2] octane salts.
  • tiotropium salts preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, aclidinium salts, preferably
  • the cations are the pharmacologically active ingredients.
  • the above-mentioned salts may preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate , Succinate, benzoate or p-toluenesulfonate, with chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate being preferred as counterions,
  • the chlorides, bromides, iodides and methanesulfonates are particularly preferred
  • Other anticholinergics may be selected from Group consisting of
  • corticosteroids preferably compounds are used which are selected from the group consisting of beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone and tipredane or Pregna-1,4-diene-3,20-dione, 6-fluoro-11-hydroxy-16, 17 - [(1-methylethylidene) -bis (oxy)] - 21 - [[4 - [(nitrooxy) methyl ] benzoyl] oxy] -, (6-alpha, 1 1-beta, 16-alpha) - (9CI) (NCX-1024) 16,17-butylidenedioxy-6,9-difluoro
  • any reference to steroids includes reference to their optional salts or derivatives, hydrates or solvates.
  • Examples of possible salts and derivatives of steroids may be: alkali metal salts, such as, for example, sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or even furoates.
  • Preferred PDE4 inhibitors according to the invention are compounds selected from the group consisting of enprofylline, theophylline, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, apremilast, arofylline, atizoram, oglemilast and tetomilast or
  • Cis [4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid]
  • Cis [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]
  • acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, Hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • compounds which are selected from the group consisting of ketuximab are preferably used as EGFR inhibitors.
  • Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention.
  • LTD4-receptor antagonists are preferably compounds which are selected from the group consisting of montelukast, pranlukast and zafirlukast, or (E) -8- [2- [4- [4- (4-
  • acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate,
  • alkali metal salts such as, for example, sodium or potassium salts, alkaline earth salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or else furoate.
  • compounds which are selected from the group consisting of compounds are preferably used as histamine H1 receptor antagonists Epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, olopatadine, desloratidine and meclozin, optionally in the form of their Racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • the acid addition salts are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.
  • the histamine H4 receptor antagonists used are preferably compounds such as (5-chloro-1H-indol-2-yl) - (4-methyl-1-piperazinyl) -methanone (JNJ-7777120), optionally in the form of their racemates , Enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, solvates or hydrates.
  • Acid addition salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate are preferred according to the invention
  • MAP kinase inhibitors it is preferable to use compounds which are selected from the group consisting of:
  • compounds which are selected from the group consisting of: saredutant, nepadutant and figopitant, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs, are used as neurokinin (NK1 or NK2) antagonists.
  • saredutant nepadutant and figopitant
  • enantiomers diastereomers
  • diastereomers optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs
  • substances which are selected from the group consisting of hydrocodone, caramiphene, carbetipentane and dextramethorphan, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of their pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates, are preferably used as substances for coughing ,
  • Preferred substances of the invention are CXCR1 or CXCR2 antagonists, compounds according to the invention are preferably used, e.g. 3 - [[3 - [(dimethylamino) carbonyl] -2-hydroxyphenyl] amino] -4 - [[(R) -1- (5-methylfuran-2-yl) propyl] amino] cyclobut-3 en-1, 2-dione (SCH-527123), optionally in the form of its racemates, enantiomers, diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates.
  • compounds according to the invention are preferably used, e.g. 3 - [[3 - [(dimethylamino) carbonyl] -2-hydroxyphenyl] amino] -4 - [[(R) -1- (5-methylfuran-2-yl) propyl] amino] cyclobut-3 en-1, 2-dione (
  • the dose required to produce an analgesic effect is advantageously 0.01 to 3 mg / kg body weight, preferably 0.1 to 1 mg / kg when given intravenously, and 0.1 to 8 mg / kg body weight, preferably 0.5 to 3 mg / kg, respectively, when given orally 1 to 3 times a day.
  • the compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, in particular aerosol formulations being suitable for inhalation.
  • customary carriers and / or diluents for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl alcohol.
  • mass spectra and / or 1 H-NMR spectra are available for the compounds prepared.
  • the ratios indicated for the flow agents relate to volume units of the respective solvents.
  • the volume units given for ammonia refer to a concentrated solution of ammonia in water.
  • the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the concentrations indicated.
  • silica gel from Millipore (MATREX TM, 35 to 70 ⁇ m) or Alox (E. Merck, Darmstadt, aluminum oxide 90 standardized, 63 to 200 ⁇ m, article no: 1.01097.9050) is used.
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid gradient:
  • Plasticizer A water / 0.1% trifluoroacetic acid
  • Plasticizer B acetonitrile / 0.1% trifluoroacetic acid
  • Plasticizer A water / 0.1% trifluoroacetic acid
  • Plasticizer B acetonitrile / 0.1% trifluoroacetic acid
  • Method 5 Column: YMC Pack ODS-AQ, 3.5 ⁇ M, 4.6 x 75 mm
  • Plasticizer A water / 0.15% formic acid
  • Plasticizer B acetonitrile
  • Plasticizer A water / 0.15% formic acid Plasticizer B: acetonitrile Temperature: RT Gradient:
  • Method 7 Column: X Terra C18, 3.5 ⁇ M, 4.6 x 50 mm
  • Plasticizer A water / 0.1% trifluoroacetic acid
  • Plasticizer B acetonitrile / 0.1% trifluoroacetic acid
  • Method 8 Column: X Bridge C18, 2.5 ⁇ M, 3.0 x 3.0 mm
  • Plasticizer A water / 0.032% ammonia
  • Plasticizer B acetonitrile
  • Plasticizer A water / 0.1% ammonia solvent
  • B acetonitrile / 0.1% ammonia gradient:
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid gradient:
  • Method 1 Column: Varian XRS C18, 5 ⁇ M, 4.6 x 50 mm
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile
  • Plasticizer A water / 0.1% trifluoroacetic acid
  • Plasticizer B acetonitrile
  • Plasticizer hexane (+ 0.2% diethylamine) / (methanol / ethanol 1/1) isocratic: 90:10
  • Plasticizer hexane (+ 0.2% diethylamine) / isopropanol isocratic: 55:45 flow rate: 12 ml / min column: Daicel AD-H 250 ⁇ 20 mm, 5 ⁇ m (column temperature: 20 ° C.).
  • Example 1 Pyrimidine-5-carboxylic acid N, N - (1 - ((5- (2-chloro-4-methoxyphenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide
  • Reaction product was purified by HPLC with 5-95% acetonitrile: water + 0.1% ammonia.
  • Example 5 Pyrimidine-5-carboxylic acid N- (1- (1- (5- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) amide
  • the catalyst was then filtered off and the filtrate was evaporated to dryness.
  • the catalyst was then filtered off and the filtrate was evaporated to dryness.
  • Example 8 Pyrimidine-5-carboxylic acid N- (1- (1- (5- (4- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethylcarbamoyl) cyclopropyl) amide, enantiomer 2
  • Example (1 d) Analogously to Example (1 d), starting from 1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethanamine, enantiomer 2, (from 7a) and 1 - [(pyrimidine-5 -carbonyl) -amino] -cyclopropanecarboxylic acid (from 1b) the title compound.
  • Example (1 d) Analogously to Example (1 d) starting from 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methyl) cyclopropanecarboxamide (from 4c) and 5- (trifluoromethyl ) - nicotinic acid the title compound.
  • Example 70 2-Chloro-N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) thiazole-5-carboxamide
  • Example 72 Pyrimidine-5-carboxylic acid N- (1 - ((5- (2- (difluoromethyl) -4-methoxyphenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide
  • Example 73 Pyrimidine-5-carboxylic acid N N - (1 - ((3-chloro-5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide
  • Example (1d) Analogously to Example (1d), starting from (3-chloro-5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methanamine (from 73b) and 1 - [(pyrimidine-5-carbonyl) -amino] -cyclopropanecarboxylic acid (from 1 b) the title compound.
  • Example 75 Pyrimidine-5-carboxylic acid N- (1 - ((3-fluoro-5- (2 (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide
  • Example 77 Pyrimidine-5-carboxylic acid (1- ⁇ 1- [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl ⁇ -cyclopropyl) -amide
  • Example (1 d) Analogously to Example (1 d), starting from 1- (3-fluoro-5- (2- (trifluoromethyl) phenoxy) -pyridin-2-yl) ethanamine (from 77d) and 1 - [(pyrimidine-5-carbonyl) - amino] -cyclopropanecarboxylic acid (from 1 b) the title compound.
  • the catalyst was then filtered off and the filtrate was evaporated to dryness.
  • Example 80 3-Ethoxy-N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) isothiazole-5-carboxamide
  • Example 83 Pyrimidine-5-carboxylic acid N- (1- ((5- (2-cyano-4-methoxyphenoxy) pyridin-2-yl) methylcarbamoyl) cyclopropyl) amide
  • Example 84 (R) -5-Chloro- N - (1- (1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyridin-2-yl) ethylcarbamoyl) cyclopropyl) nicotinamide
  • Example 87 Pyrimidine-5-carboxylic acid- (R) -N- (1- (1- (1- (5- (2-cyano-4-methoxyphenoxy) -pyridin-2-yl) -ethylcarbamoyl) -cyclopropyl) -amide
  • Example 90 Pyrimidine-5-carboxylic acid N- (1 - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) methylcarbamoyl) cyclopropyl) amide
  • Example (4c) Analogously to Example (4c) was starting from te / f-butyl-1 - ((5- (4-methoxy-2- (trifluoromethyl) - phenoxy) pyrimidin-2-yl) methylcarbamoyl) cyclopropylcarbamate and trifluoroacetic the
  • Example (76a) Analogously to Example (76a), starting from cyanoacetic acid, 1-chloro-N, N, 2-trimethyl-propylamine, TEA and 1-amino-N - ((5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidine) 2-yl) - methyl) cyclopropanecarboxamide (from 91 b) the title compound was prepared.
  • Example 95 Pyrimidine-5-carboxylic acid N- (1- (1- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethylcarbamoyl) cyclopropyl) amide
  • Example 96 N- (1- (1- (5- (5- (4-Methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethylcarbamoyl) cyclopropyl) isoxazole-5-carboxamide
  • Example (4c) Analogously to Example (4c) was starting from te / f-butyl-1- (1- (5- (4-methoxy-2- (trifluoromethyl) - phenoxy) pyrimidin-2-yl) ethylcarbamoyl) cyclopropylcarbamate trifluoroacetate and trifluoroacetic the Title compound prepared.
  • Example (1d) Analogously to Example (1d), starting from 1-amino-N- (1- (5- (4-methoxy-2- (trifluoromethyl) phenoxy) pyrimidin-2-yl) ethyl) cyclopropanecarboxamide (from 101 b) and 3, 3,3-trifluoropropionic acid produced the title compound.
  • Example 100 Pyrimidine-5-carboxylic acid N- (1 - ((6- (2-chloro-4-methoxyphenoxy) pyridazin-3-yl) methylcarbamoyl) cyclopropyl) amide
  • Example 101 Pyrimidine-5-carboxylic acid (1 - ⁇ [5- (4-methoxy-2-trifluoromethyl-phenoxy) -pyrazino-2-ylmethyl] -carbamoyl ⁇ -cyclopropyl) -amide
  • Example 103 Pyrimidine-5-carboxylic acid- (1 - ⁇ 1- [5- (4-fluoro-2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl ⁇ -cyclopropyl) -amide
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example 104 Pyrimidine-5-carboxylic acid- (1 - ⁇ 1 - [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl ⁇ -cyclopropyl) -amide.
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example 105 Pyrimidine-5-carboxylic acid- (1 - ⁇ [5- (2-ethyl-4-methoxy-phenoxy) -pyridin-2-yl-methyl] -carbamoyl ⁇ -cyclopropyl) -amide.
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example 106 Pyrimidine-5-carboxylic acid- (1 - ⁇ 1- [5- (4-bromo-2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl ⁇ -cyclopropyl) -amide.
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example 107 Pyrimidine-5-carboxylic acid- (1 - ⁇ 1- [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl ⁇ -cyclopropyl) -amide.
  • Example (1d) Analogously to Example (1d), the title compound was prepared by amide linkage using TBTU.
  • Example 108 Pyrimidine-5-carboxylic acid 1- (1- ⁇ 1- [5- (4-bromo-2-trifluoromethyl-phenoxy) -3-fluoro-pyridin-1-yl] -ethylcarbamoyl-1-cyclopropoxy-amide
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example 109 Pyrimidine-5-carboxylic acid (1- ⁇ 1- [5- (4-chloro-2-trifluoromethyl-phenoxy) -pyridine] -yl-1-ethylcarbamoyl-1-cyclopropyl-amide
  • Example (1d) Analogously to Example (1d), the title compound was prepared by amide linkage using TBTU.
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example 11 1 2-Methoxy-pyrimidine-5-carboxylic acid- (1 - ⁇ 1- [5- (2-chloro-phenoxy) -3-fluoro-pyridine] -yl-1-ethylcarbamoyl-1-cyclopropyl-amide
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example 1 12 2-Methylamino-pyrimidine-5-carboxylic acid- (1 - ⁇ 1- [5- (2-chloro-phenoxy) -3-fluoro-pyridine-1-yl-ethylcarbamoyl-1-cyclopropyl-amide
  • Example 113 2-Methyl-pyrimidine-5-carboxylic acid- (1 - ⁇ 1- [5- (2-chloro-phenoxy) -3-fluoro-pyridin-2-yl] -ethylcarbamoyl ⁇ -cyclopropyl) -amide
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example 114 Pyrimidine-5-carboxylic acid- (1 - ⁇ 1- [5- (2-bromo-4-methoxy-phenoxy) -pyridin-2-yl] -ethylcarbamoyl ⁇ -cyclopropyl) -amide
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example 115 2-Methyl-pyrimidine-5-carboxylic acid- (1 - ⁇ 1 - [3-fluoro-5- (2-trifluoromethyl-phenoxy-pyridine-1-yl-ethylcarbamoyl-1-cyclopropyl-amide
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example 1 16 2-Methoxy-pyrimidine-5-carboxylic acid- (1 - ⁇ 1 - [3-fluoro-5- (2-trifluoromethyl-phenoxy-pyridine-1-yl-ethylcarbamoyl-1-cyclopropyl-amide
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example 1 17 Pyrimidine-5-carboxylic acid- (1 - ⁇ 1- [3-chloro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-yl] -ethylcarbamoyl ⁇ -cyclopropyl) -amide
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example 1 18 Pyrimidine-5-carboxylic acid 1- (1- ⁇ 1- [5- (4-bromo-2-trifluoromethyl-phenoxy) -3-chloro-pyridin-1-yl-ethylcarbamoyl-1-cyclopropyl-amide
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example 1 19 2-Methylamino-pyrimidine-5-carboxylic acid- (1 - ⁇ 1 - [3-fluoro-5- (2-trifluoromethyl-phenoxy-pyridine-1-yl-ethylcarbamoyl-1-cyclopropyl-amide
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example 120 Pyrimidine-5-carboxylic acid (1 - ⁇ [3-chloro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-ylmethyl] -carbamoyl ⁇ -cyclopropyl) -amide
  • Example (1 d) Analogously to Example (1 d), the title compound was prepared by amide linkage using TBTU.
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example 122 2-Methoxy-pyrimidine-5-carboxylic acid (1 - ⁇ [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridin-2-ylmethyl] -carbamoyl ⁇ -cyclopropyl) -amide
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.
  • Example 124 2-Methyl-pyrimidine-5-carboxylic acid- (1 - ⁇ [3-fluoro-5- (2-trifluoromethyl-phenoxy) -pyridine] -ylmethyl-1-carbamoyl-1-cyclopropyl-amide
  • Example (4d) Analogously to Example (4d), the title compound was prepared by amide linkage using TBTU.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne les composés représentés par la formule générale (I) dans laquelle R1, R2, R3, R4, R5, R6, R7, X1, X2 et X3 ont la signification donnée dans le descriptif, et les énantiomères, les diastéréomères, les mélanges et les sels, notamment les sels physiologiquement acceptables de ces composés, contenant des acides ou bases organiques ou inorganiques, présentant des propriétés précieuses. L'invention concerne également la préparation de ces composés, des médicaments contenant les composés pharmacologiquement actifs, et la préparation et l'utilisation de ces médicaments.
PCT/EP2010/052235 2009-02-26 2010-02-23 Composés servant d'antagonistes de bradykinine b1 WO2010097373A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP09153779 2009-02-26
EP09153779.5 2009-02-26

Publications (1)

Publication Number Publication Date
WO2010097373A1 true WO2010097373A1 (fr) 2010-09-02

Family

ID=42342566

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/052235 WO2010097373A1 (fr) 2009-02-26 2010-02-23 Composés servant d'antagonistes de bradykinine b1

Country Status (1)

Country Link
WO (1) WO2010097373A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020039088A3 (fr) * 2018-08-24 2020-04-02 Xeniopro GmbH Nouveaux composés

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066577A1 (fr) * 2002-02-08 2003-08-14 Merck & Co., Inc. Derives du n-biphenylmethyl aminocycloalkanecarboxamide avec une substitution methyle, utiles comme antagonistes de la bradykinine
WO2004019868A2 (fr) * 2002-08-29 2004-03-11 Merck & Co., Inc. Derives n-biarylmethyl aminocycloalcanecarboxamide
WO2005085198A2 (fr) * 2004-03-02 2005-09-15 Merck & Co., Inc. Derives d'amino cyclopropane carboxamide utilises comme antagonistes de la bradykinine
WO2006120176A2 (fr) 2005-05-11 2006-11-16 Nycomed Gmbh Combinaison d'un inhibiteur de pde4 et un derive de tetrahydrobiopterine
WO2009027450A1 (fr) * 2007-08-29 2009-03-05 Boehringer Ingelheim International Gmbh Nouveaux antagonistes de la bradykinine b1

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066577A1 (fr) * 2002-02-08 2003-08-14 Merck & Co., Inc. Derives du n-biphenylmethyl aminocycloalkanecarboxamide avec une substitution methyle, utiles comme antagonistes de la bradykinine
WO2004019868A2 (fr) * 2002-08-29 2004-03-11 Merck & Co., Inc. Derives n-biarylmethyl aminocycloalcanecarboxamide
WO2005085198A2 (fr) * 2004-03-02 2005-09-15 Merck & Co., Inc. Derives d'amino cyclopropane carboxamide utilises comme antagonistes de la bradykinine
WO2006120176A2 (fr) 2005-05-11 2006-11-16 Nycomed Gmbh Combinaison d'un inhibiteur de pde4 et un derive de tetrahydrobiopterine
WO2009027450A1 (fr) * 2007-08-29 2009-03-05 Boehringer Ingelheim International Gmbh Nouveaux antagonistes de la bradykinine b1

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HOUBEN-WEYL: "Methoden der Organischen Chemie", vol. 15/2

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020039088A3 (fr) * 2018-08-24 2020-04-02 Xeniopro GmbH Nouveaux composés
CN112888479A (zh) * 2018-08-24 2021-06-01 赛尼欧普罗有限责任公司 用于治疗病态状况的芳香型分子

Similar Documents

Publication Publication Date Title
EP2401256B1 (fr) Composés comme antagonistes de la bradykinine B1
EP2539323B1 (fr) Composés comme antagonistes de la bradykinine B1
EP2606042B1 (fr) Composés de tétrahydrofuranyl disubstitués en tant qu'antagonistes du récepteur b1 de la bradykinine
EP2670736B1 (fr) 9-[4-(3-chloro-2-fluoro-phényl-amino)-7-méthoxy-quinazoline-6-yloxy]-1,4-diazaspiro[5.5]undécane-5-one dimaléate, preparation et utilisation du 9-[4-(3-chloro-2-fluoro-phényl-amino)-7-méthoxy-quinazoline-6-yloxy]-1,4-diazaspiro[5.5]undécane-5-one dimaléate en tant que medicament
WO2010015523A1 (fr) Hétérocycles à substitution cyclohexyloxy, médicaments contenant ces composés, leur utilisation et procédé pour les préparer
WO2010097374A1 (fr) Composés servant d'antagonistes de bradykinine b1
EP2606043B1 (fr) Dérivés de pyridazine en tant qu'antagonistes du récepteur de la bradykinine b1
EP2313397B1 (fr) Hétérocycles substitués par cyclohexyloxy, médicament contenant ces liaisons, leur utilisation et leur procédé de fabrication
WO2010097373A1 (fr) Composés servant d'antagonistes de bradykinine b1
AU2015271888B2 (en) Compounds as bradykinin B1 antagonists
OA16324A (en) Disubstituted tetrahydrofuranyl compounds as antagonists of the bradykinin B1 receptor.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10705161

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10705161

Country of ref document: EP

Kind code of ref document: A1