EP1737860A1 - Antagonistes cgrp selectionnes, leur procede de production et leur utilisation comme medicaments - Google Patents

Antagonistes cgrp selectionnes, leur procede de production et leur utilisation comme medicaments

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Publication number
EP1737860A1
EP1737860A1 EP05729383A EP05729383A EP1737860A1 EP 1737860 A1 EP1737860 A1 EP 1737860A1 EP 05729383 A EP05729383 A EP 05729383A EP 05729383 A EP05729383 A EP 05729383A EP 1737860 A1 EP1737860 A1 EP 1737860A1
Authority
EP
European Patent Office
Prior art keywords
general formula
oxo
carboxylic acid
piperidine
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP05729383A
Other languages
German (de)
English (en)
Inventor
Klaus Rudolf
Stephan Georg Mueller
Philipp Lustenberger
Dirk Stenkamp
Gerhard Schaenzle
Kirsten Arndt
Henri Doods
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1737860A1 publication Critical patent/EP1737860A1/fr
Ceased legal-status Critical Current

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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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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    • 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]
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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
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to the CGRP antagonists of the general formula
  • A is a residue of the formula
  • X is an oxygen atom, a methylene or NH group
  • R 1 is a radical of the formula
  • the compounds of the general formula (I) are prepared by methods known in principle. The following processes have proven particularly useful for the preparation of the compounds of the general formula (I) according to the invention:
  • R 1 is defined as mentioned at the beginning
  • G is a nucleofugic group, which may be the same or different, preferably the phenoxy, 1 / - / - imidazol-1-yl, 1H-1, 2,4-triazol-1-yl, trichloromethoxy, or the 2,5-dioxopyrrolidin-1-yloxy group, with the proviso that X represents the NH group, or
  • G represents a nucleofugic group, which may be the same or different, preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group, with the proviso that X represents the oxygen atom,
  • R 2 and R 3 are defined as mentioned at the outset, with the proviso that R 2 and R 3 contain no further free primary or secondary aliphatic amino function.
  • Any primary or secondary amino function additionally present in the -NR 2 R 3 radical is provided with a suitable protective group.
  • the basically two-stage reactions are usually carried out as a one-pot process, preferably in such a way that in the first stage one of the two components (III) or. (.V) with equimolar amounts of the carbonic acid derivative of the general formula (IV) brings to reaction in a suitable solvent at a lower temperature, then adds at least equimolar amounts of the other component (III) or (V) and the reaction is ended at a higher temperature.
  • the reactions with bis (trichloromethyl) carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis (trichloromethyl) carbonate) of a tertiary base, for example triethylamine,, / -ethyldiisopropylamine, pyridine, 1, 5-diaza- bicyclo- [4.3.0] -non-5-ene, 1,4-diazabicyclo- [2.2.2] octane or 1,8-diazabicyclo- [5.4.0] -un-dec-7-ene.
  • a tertiary base for example triethylamine,, / -ethyldiisopropylamine, pyridine, 1, 5-diaza- bicyclo- [4.3.0] -non-5-ene, 1,4-diazabicyclo- [2.2.2] octane or 1,8-diazabicyclo- [5.4.0] -
  • solvents which should be anhydrous are tetrahydrofuran, dioxane, Dimethylformamide, dimethylacetamide, A / -methyl-2-pyrrolideone, 1,3-dimethyl-2-imidazolidinone or acetonitrile, when using bis- (trichloromethyl) carbonate as carbonyl component, anhydrous chlorinated hydrocarbons, for example dichloromethane, 1,2- Dichloroethane or trichlorethylene, preferred.
  • the reaction temperatures for the first reaction stage are between -30 ° C and + 25 ° C, preferably -5 ° C and + 10 ° C, for the second reaction stage between + 15 ° C and the boiling point of the solvent used, preferably between + 20 ° C and + 70 ° C
  • R 1 has the meanings mentioned above.
  • the coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2), for example carbodiimides, such as, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylamino propyl) carbodiimide, O- (1H-benzotriazol-1-yl) - ⁇ /, ⁇ / - ⁇ / ', ⁇ / , -tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1 H-benzotriazol-1 -yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used.
  • carbodiimides such as, for example, dicyclohexylcarbodi
  • the reaction rate can be increased by adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-di-hydro-1, 2,3-benzotriazine (HOOBt).
  • the couplings are normally made with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), ⁇ / methylpyrrolidone (NMP) or mixtures of these and at temperatures between -30 ° C and + 30 ° C, preferably -20 ° C and + 25 ° C, performed. If necessary, preference is given to additional auxiliary base / V-ethyldiisopropylamine (DIEA) (Hünig base).
  • DIEA V-ethyldiisopropylamine
  • R 2 and R 3 are defined as mentioned at the outset, with the proviso that R 2 and R 3 contain no free primary or secondary amine
  • Nu is a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group with 1 to 10 carbon atoms in the alkyl part, a phenylsulfonyloxy or naphthylsulfonyloxy group mono-, di- or trisubstituted, optionally by chlorine or bromine atoms, by methyl or nitro groups, it being possible for the substituents to be the same or different, a 1H-imidazole -1-yl-, a 1H-pyrazoI-1-yI-, a 1H-1, 2,4-triazol-1-yl-, 1 H-1, 2,3- optionally substituted by one or two methyl groups in the carbon skeleton Triazol-1-yl-, 1
  • R 1 is defined as mentioned at the beginning.
  • the reaction is carried out under Schotten-Baumann or Einhorn conditions, ie the components are in the presence of at least one equivalent of an auxiliary base at temperatures between -50 ° C and + 120 ° C, preferably -10 ° C and + 30 ° C , and optionally reacted in the presence of solvents.
  • Alkali and alkaline earth metal hydroxides for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. Sodium carbonate, potassium carbonate or cesium carbonate, alkali acetate, e.g.
  • Sodium or potassium acetate, and also tertiary amines for example pyridine, 2,4,6-tri-methylpyridine, quinoline, triethylamine, ⁇ / -ethyl-diisopropylamine, ⁇ / -ethyl-dicyclohexylamine, 1, 4-di-azabicyclo [ 2.2.2] octane or 1,8-diazabicyclo- [5.4.0] -undec-7-ene, as solvents, for example dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, et / -methylpyrrolidone or mixtures thereof into consideration; If alkali or alkaline earth hydroxides, alkali carbonates or acetates are used as auxiliary bases, water can also be added to the reaction mixture as a cosolvent.
  • solvents for example dichloromethan
  • A, X and R 1 are as defined at the outset, with an amine of the general formula HNR 2 R 3 , in which R 2 and R 3 are as defined at the outset, with the proviso that they are no further free primary or secondary aliphatic Amino function included.
  • the coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methods of Organic Chemistry, Volume 15/2), for example carbodiimides, such as, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl- (3-dimethylamino-propyl) - carbodiimide, O- (1H-benzotriazol-1-yl) - ⁇ /, A / - ⁇ /, A / '- tetramethyluronium hexafluorphos- phosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used.
  • DEC dicyclohexylcarbodiimide
  • DIC diis
  • the reaction rate can be increased by adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1, 2,3-benzotriazine (HOOBt).
  • HOBt 1-hydroxybenzotriazole
  • HOOBt 3-hydroxy-4-oxo-3,4-dihydro-1, 2,3-benzotriazine
  • the couplings are normally made with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane,
  • the mixed anhydride is obtained from the carboxylic acid of general formula (VIII) to be coupled and the carbonic acid monoisobutyl ester.
  • the preparation of this mixed anhydride and the coupling with the amines of the general formula HNR 2 R 3 takes place in a one-pot process, using the abovementioned solvents and at temperatures between -20 ° C. and + 25 ° C., preferably between 0 ° C. and +25 ° C.
  • A, X and R 1 are defined as mentioned at the outset and Nu is a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyloxy group having 1 to 10 carbon atoms in the alkyl part, one optionally by chlorine or Bromine atoms, phenylsulfonyloxy or naphthylsulfonyloxy group mono-, di- or tri-substituted by methyl or nitro groups, where the substituents may be the same or different, a 1H-imidazoI-1-yl, a 1H- optionally substituted by one or two methyl groups in the carbon skeleton Pyrazol-1-yl-, a 1 - / - 1, 2,4-triazol-1-yl-, 1 / - / - 1, 2,3-triazol-1-yl-, 1H-1, 2,3 , 4-tetrazol-1-yl
  • the reaction is carried out under Schotten-Baumann or Einhorn conditions, that is, the components are in the presence of at least one equivalent of an auxiliary base at temperatures between -50 ° C and + 120 ° C, preferably -10 ° C and + 30 ° C, and optionally reacted in the presence of solvents.
  • Alkali and alkaline earth metal hydroxides for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. B.
  • alkali acetate for example sodium or potassium acetate
  • tertiary amines for example pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, / V-ethyldiisopropylamine, ⁇ / -ethyldicyclohexylamine, 1, 4 -Di-azabicyclo [2.2.2] octane or 1,8-diaza-bicycio [5.4.0] - undec-7-ene, for example dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, ⁇ / -methylpyrrolidone or mixtures thereof; If alkali or alkaline earth hydroxides, alkali carbonates or acetates are used as auxiliary bases, water can also be added to the reaction mixture as a cosolvent
  • novel compounds of the general formula (I) according to the invention contain one or more centers of chirality. If, for example, there are two centers of chirality, the compounds can occur in the form of two diastereomeric pairs of antipodes.
  • the invention includes the individual isomers as well as their lo mixtures.
  • the respective diastereomers can be separated due to their different physicochemical properties, e.g. by fractional crystallization from suitable solvents, by high pressure liquid or column chromatography I5 using chiral or preferably achiral stationary phases.
  • Racemates falling under the general formula (I) can be separated, for example, by HPLC on suitable chiral stationary phases (for example Chiral AGP, Chiralpak AD). Racemates which contain a basic function can also be separated via the diastereomeric, optically active salts which, when reacted with an optically active acid, for example (+) - or (-) - tartaric acid, (+) - or (-) - Diacetyl tartaric acid, (+) - or (-) - monomethyl tartrate or (+) - camphorsulfonic acid are formed.
  • an optically active acid for example (+) - or (-) - tartaric acid, (+) - or (-) - Diacetyl tartaric acid, (+) - or (-) - monomethyl tartrate or (+) - camphorsulfonic acid are formed.
  • each of the optically active salts is dissolved in water with a Base, such as sodium carbonate or potassium carbonate, or with a suitable acid, for example with dilute hydrochloric acid or aqueous methanesulfonic acid, carefully neutralized and thereby obtain the corresponding free compound in the (+) or (-) form.
  • a Base such as sodium carbonate or potassium carbonate
  • a suitable acid for example with dilute hydrochloric acid or aqueous methanesulfonic acid
  • the starting compounds of the general formula (III) are obtained, insofar as they are not known from the literature or are even commercially available, in accordance with the processes specified in international patent application WO 98 / J11128] and DE 199 52
  • the starting compounds of the general formula (IV) are commercially available. Connections of the
  • A is defined as mentioned at the beginning and R represents an unbranched alkyl group, 5 preferably the methyl or ethyl group, can be prepared by resolution.
  • This racemate cleavage can be carried out using enzymatic methods, only one enantiomer of the racemate being transformed and the resulting mixture then using physicochemical methods, preferably using Using chromatographic methods, is separated.
  • a suitable enzyme system for this step is the enzyme Alcalase 2.4 L FG (Novozymes A / S; DK 2880 Bagsvaerd).
  • the compounds of the general formula (X) can then be converted into the enantiomerically pure compounds of the 5 general formula (V ) are transferred.
  • radical A contains no amino or methylamino group
  • diazotization of compounds of the general formula (X) with a suitable diazotization reagent, preferably sodium nitrite in an acidic medium can give the following: o Compounds of the general formula (XI). If enantiomerically pure compounds are used, the corresponding enantiomerically pure hydroxycarboxylic acid compounds are obtained, the reaction taking place with retention of the configuration.
  • A is defined as mentioned at the beginning and X denotes a chlorine, bromine or iodine atom, in analogy to methods known from the literature (Michael T. Crimmins, Kyle A. Emmitte and Jason D. Katz, Org. Lett. 2, 2165-2167 [2000]).
  • the resulting diastereomeric products can then be separated using physicochemical methods, preferably using chromatographic methods.
  • the hydrolytic cleavage of the chiral auxiliary, coupling with amines of the general formula HNR 2 R 3 and cleavage of the benzyl protecting group also opens access to enantiomerically pure hydroxycarboxylic acid compounds of the general formula (V).
  • the starting compounds of the general formula (VI) are obtained, for example, by reacting amines of the general formula HNR R 3 with 2- (alkoxycarbonylmethyl) -3-arylpropanoic acids and subsequent hydrolytic elimination of the alkyl group.
  • the required 2- (alkoxycarbonylmethyl) -3-aryl-propanoic acids o can be analogous to methods known from the literature (David A. Evans, Leester D. Wu, John JM Wiener, Jeffrey S. Johnson, David HB Ripin and Jason S. Tedrow, J Org. Chem 64, 6411-6417 [1999]; Saul G. Cohen and Aleksander Milovanovic, J. Am. Chem. SOG.
  • Carboxylic acids of the general formula (VIII) can be prepared from generally accessible starting materials by the processes specified in WO 98 / J11128].
  • the compounds of general formula (I) obtained can, if they contain suitable basic functions, be converted into their physiologically tolerable salts with inorganic or organic acids, in particular for pharmaceutical applications.
  • suitable acids for this purpose are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 5 acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
  • the present invention relates to racemates if the compounds of the general formula (I) have only one chiral element.
  • the application also includes the individual diastereomeric pairs of antipodes or their mixtures, which are present when more than one chiral element is present in the compounds of the general formula (I) and the individual optically active enantiomers from which the racemates mentioned are composed.
  • the new compounds of the general formula (I) and their physiologically tolerable salts have valuable pharmacological properties which are based on their selective CGRP-antagonistic properties.
  • the invention further relates to medicaments containing these compounds, their use and their preparation.
  • SK-N-MC cells are cultivated in "Dulbecco's modified Eagle Medium”. The medium of confluent cultures is removed. The cells are washed twice with PBS-50 buffer (Gibco 041-04190 M), detached by adding PBS buffer, mixed with 0.02% EDTA, and isolated by centrifugation. After resuspension in 20 ml "Balanced Salts Solution” [BSS (in mM): NaCl 120, KCI 5.4, NaHCO 3 16.2, MgSO 4 0.8, NaHPO 4 1.0, CaCI 2 1.8, D-Glucose 5.5, HEPES 30, pH 7.40] become the cells Centrifuged twice at 100 xg and resuspended in BSS.
  • BSS "Balanced Salts Solution”
  • the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000 xg. The supernatant is discarded and the pellet is re-centrifuged and resuspended in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1% bacitracin (1st ml / 1,000,000 cells). The homogenate is frozen at -80 ° C. Under these conditions, the membrane preparations are stable for more than 6 weeks.
  • the homogenate is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) and homogenized for 30 seconds with an Ultra-Turrax. 230 ⁇ l of the homogenate are incubated for 180 minutes at room temperature with 50 pM 125 l-iodotyrosyl-calcitonin gene-related peptides (Amersham) and increasing concentrations of the test substances in a total volume of 250 ⁇ l. The incubation is ended by rapid filtration through GF / B glass fiber filters treated with polyethyleneimine (0.1%) using a cell harvester. The radioactivity bound to protein is determined using a gamma counter. The bound radioactivity is defined as non-specific binding after the presence of 1 ⁇ M human CGRP-alpha during the incubation.
  • assay buffer 50 mM Tris, 150 mM NaCl, 5 mM MgCl
  • concentration-binding curves are analyzed with the aid of a computer-aided non-linear curve fitting.
  • SK-N-MC cells (1 million cells) are washed twice with 250 ⁇ l incubation buffer (Hanks ' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and at 37 ° C. for 15 minutes pre-incubated. After adding CGRP (10 ⁇ l) as an agonist in increasing concentrations (10 ⁇ 11 to 10 ⁇ 6 M) or additionally of substance in 3 to 4 different concentrations are incubated again for 15 minutes.
  • Intracellular cAMP is then extracted by adding 20 ⁇ l of 1M HCl and centrifugation (2000 ⁇ g, 4 ° C. for 15 minutes). The supernatants are frozen in 5 liquid nitrogen and stored at -20 ° C.
  • the cAMP contents of the samples are determined using a radioimmunoassay (from Amersham) and the pA 2 values of substances having an antagonistic effect are determined graphically, o
  • the compounds according to the invention show CGRP-antagonistic properties in a dose range between 10 -12 to 10- 5 M.
  • the compounds according to the invention and their salts with physiologically compatible acids are therefore suitable for the acute and prophylactic treatment of headaches, in particular migraine or cluster headaches.
  • the compounds according to the invention also have a positive influence on the following diseases: o non-insulin-dependent diabetes mellitus ("NIDDM”), complex regional pain syndrome (CRPS1), cardiovascular diseases, morphine tolerance, clostritium toxin-related diarrhea, skin diseases, in particular thermal and radiation-related skin damage including sunburn, inflammatory diseases, e.g. inflammatory joint diseases (arthritis), neurogenic inflammation
  • the compounds according to the invention generally have an alleviating effect on painful conditions.
  • the symptoms of menopausal hot flashes caused by vasodilation and increased blood flow in estrogen-deficient women and hormone-treated prostate cancer patients are influenced by the CGRP-antagonists of the present application preventively and acutely-therapeutic, whereby this Treatment approach before hormone substitution is characterized by low side effects.
  • the dosage required to achieve a corresponding effect is expediently 0.01 to 3 mg / kg body weight with intravenous or subcutaneous administration, preferably 0.01 to 1 mg / kg body weight, with oral administration 0.01 to 20 mg / kg body weight, preferably 0.1 to 10 mg / kg Body weight, and with nasal or inhalation administration 0.01 to 10 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight, each 1 to 3 times a day.
  • the treatment with CGRP antagonists or / and CGRP release inhibitors is carried out in addition to a conventional hormone substitution, it is advisable to reduce the doses given above, the dosage then being 1/5 of the lower limits specified up to 1/1 of the above specified upper limits.
  • the compounds produced according to the invention can be carried out either alone or, if appropriate, in combination with other active substances for the treatment of migraines intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aerosol formulations in particular being suitable for inhalation.
  • the combinations can be administered either simultaneously or sequentially.
  • Possible drug classes as combination partners are, for example, angiotensin! L receptor antagonists, ⁇ -agonists and ⁇ -antagonists, 5-HT-i B / i D agonists, AMPA antagonists, weak analgesics, antidepressants, antiemetics, anticonvulsants, antimuscarinics, ß-blockers , Calcium antagonists, corticosteroids, ergot alkaloids, histamine H1 receptor antagonists, neurokinin antagonists, neuroleptics, non-steroidal anti-inflammatory drugs, NO synthase inhibitors, prokinetics, selective serotonin reuptake inhibitors or other antimigraine drugs that are taken together with one or more inert customary carriers and / or diluents, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water
  • the non-steroidal antiinflammatory agents aceclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, lefloxamic acid, lefloxamide, , Phenylbutazone, piroxicam, sulfasalazine, tenoxicam, zomepirac or their physiologically tolerable salts, and meloxicam and other selective COX2 inhibitors, such as, for example, rofecoxib and celecoxib.
  • the dose for these active substances is expediently 1/5 of the usually recommended lowest dose up to 1/1 of the normally recommended dose, for example 20 to 100 mg sumatriptan.
  • the invention furthermore relates to the use of the 50 compounds according to the invention as valuable auxiliaries for the production and purification (affinity chromatography) of antibodies and, after suitable radioactive labeling, for example by tritiation of suitable precursors, for example by catalytic hydrogenation with trithium or replacement of halogen atoms by tritium, in RIA and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.
  • R f values are determined using ready-made silica gel 60 F254 TLC plates (E. Merck, Darmstadt, Item No. 1.05714) without chamber saturation.
  • the ratios given for the flow agents relate to volume units of the respective solvents.
  • the volume units given for NH 3 relate to a concentrated solution of NH 3 in water.
  • the acid, base and salt solutions used in the work-up of the reaction solutions are aqueous systems of the stated concentrations.
  • Silica gel from Millipore (MATREX TM, 35 to 70 ⁇ m) is used for chromatographic purifications.
  • HPLC data are measured using the parameters listed below:
  • Analytical column Zorbax column (Agilent Technologies), SB (stable bond) C18; 3.5 ⁇ m; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 ⁇ L; Detection at 254 nm
  • the same gradients that were used to collect the analytical HPLC data are generally used for preparative HPLC cleaning.
  • the products are collected in a mass-controlled manner, the product-containing fractions are combined and freeze-dried.
  • reaction mixture was purified directly by means of HPLC-MS (column: Agilent Zorbax Stable Bond RP C18, 5 ⁇ M, 30x100 mm; flow 30 mL / min; gradient: water / acetonitrile) and subsequent lyophilization. Yield: 77 mg (76% of theory)
  • Example 7 4- (5-oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) piperidine-1-carboxylic acid- (R) -1- (4-amino-3- chloro-5-trifluoromethyl-benzyl) -2- (1'-methyl- [4,4 , ] bipiperidinyl-1-yl) -2-oxo-ethyl ester
  • Formula (I) contain:
  • Composition 1 capsule for powder inhalation contains: Active ingredient 1.0 mg
  • the active ingredient is ground to the grain size required for inhalants.
  • the ground active ingredient is mixed homogeneously with the milk sugar.
  • the mixture o is filled into hard gelatin capsules.
  • 1 hub includes:
  • composition 1 vial contains: Active ingredient 0.1 g
  • Active ingredient sodium chloride and benzalkonium chloride are dissolved in water.
  • 1 hub includes:
  • the micronized active ingredient is homogeneously suspended in the mixture of lecithin and propellant.
  • the suspension is filled into a pressure vessel with a metering valve.
  • the active ingredient and excipients are dissolved in water and in a corresponding
  • composition o active substance 5 mg
  • Dissolve mannitol in water for injections Wfl
  • Add human serum albumin o Dissolve the active ingredient while heating; fill up to batch volume with Wfl; fill in vials; freeze-dry.
  • Polysorbate 80 Tween 80 20 mg
  • composition o active substance 20 mg
  • Example XI Mix active substance, corn starch and silica homogeneously; mix with magnesium stearate; Fill the mixture into hard gelatin capsules size 3 on a capsule filling machine.
  • Example XI Mix active substance, corn starch and silica homogeneously; mix with magnesium stearate; Fill the mixture into hard gelatin capsules size 3 on a capsule filling machine.
  • Dissolve mannitol in water for injections Wfl
  • Add human serum albumin Dissolve the active ingredient while heating; fill up to batch volume with Wfl; Fill into ampoules under nitrogen gas.

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Abstract

La présente invention concerne les antagonistes CGRP de la formule générale (I) où A, X et R<1> à R<3> ont la définition donnée dans la revendication 1, leurs tautomères, diastéréomères, énantiomères, hydrates, leurs mélanges et leurs sels ainsi que les hydrates des sels, notamment leurs sels physiologiquement compatibles avec des acides organiques ou inorganiques, les médicaments contenant ces composés, leur utilisation et leur procédé de production.
EP05729383A 2004-04-15 2005-04-09 Antagonistes cgrp selectionnes, leur procede de production et leur utilisation comme medicaments Ceased EP1737860A1 (fr)

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DE102004018796A DE102004018796A1 (de) 2004-04-15 2004-04-15 Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
PCT/EP2005/003759 WO2005100352A1 (fr) 2004-04-15 2005-04-09 Antagonistes cgrp selectionnes, leur procede de production et leur utilisation comme medicaments

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US7220862B2 (en) 2002-06-05 2007-05-22 Bristol-Myers Squibb Company Calcitonin gene related peptide receptor antagonists
US7842808B2 (en) 2002-06-05 2010-11-30 Bristol-Myers Squibb Company Anti-migraine spirocycles
US20040063735A1 (en) * 2002-06-05 2004-04-01 Chaturvedula Prasad V. Calcitonin gene related peptide receptor antagonists
US7595312B2 (en) 2002-10-25 2009-09-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions
TW200524601A (en) 2003-12-05 2005-08-01 Bristol Myers Squibb Co Heterocyclic anti-migraine agents
TW200533398A (en) 2004-03-29 2005-10-16 Bristol Myers Squibb Co Novel therapeutic agents for the treatment of migraine
DE102004015723A1 (de) 2004-03-29 2005-10-20 Boehringer Ingelheim Pharma Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US7384931B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7384930B2 (en) 2004-11-03 2008-06-10 Bristol-Myers Squibb Company Constrained compounds as CGRP-receptor antagonists
US7449586B2 (en) 2004-12-03 2008-11-11 Bristol-Myers Squibb Company Processes for the preparation of CGRP-receptor antagonists and intermediates thereof
US7439237B2 (en) * 2005-04-15 2008-10-21 Boehringer Ingelheim International Gmbh Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions
DE102005038831A1 (de) 2005-08-17 2007-02-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US7834007B2 (en) 2005-08-25 2010-11-16 Bristol-Myers Squibb Company CGRP antagonists
EP1770086A1 (fr) * 2005-09-29 2007-04-04 Boehringer Ingelheim Pharma GmbH & Co. KG Antagonistes CGRP selectionnés, leur procédé de préparation ainsi que leur utilisation comme médicaments
US8168592B2 (en) 2005-10-21 2012-05-01 Amgen Inc. CGRP peptide antagonists and conjugates

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DE59711622D1 (de) * 1996-09-10 2004-06-17 Boehringer Ingelheim Pharma Abgewandelte aminosäuren, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
DE10211770A1 (de) * 2002-03-14 2003-10-02 Boehringer Ingelheim Pharma Neue substituierte Piperidine, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
DE10227294A1 (de) * 2002-06-19 2004-01-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Zubereitungen zur intranasalen Applikation ausgewählter, von Aminosäuren abgeleiteter CGRP-Antagonisten sowie Verfahren zu deren Herstellung
DE10250080A1 (de) * 2002-10-25 2004-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US7595312B2 (en) * 2002-10-25 2009-09-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions

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