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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
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  • 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
  • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to new substituted piperidines of the general formula
• R is a saturated, mono- or di-unsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S, S-dioxido-thiadiaza heterocycle,
• heterocycles mentioned above are linked via a carbon or nitrogen atom and
• R 1 is phenyl, 1-naphthyl, 2-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3 -yl, 1-formyl-1H-indol-3-yl- , 4-imidazolyl-, 1-methyl-4-imidazolyl-, 2-thienyl-, 3-thienyl-, thiazolyl-, 1H-indazol-3-yl-, 1-methyl-1H-indazol-3 -yl-, benzo- [b] fur-3-yl, benzo [b] thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
• R 2 represents the hydrogen atom or a C 3 alkyl group
• one of the radicals A 1 and A 2 is the hydrogen atom and the other is the amino, the [1, 4 '] bipiperidinyl-1' -yl or an alkylamino group or the group
• R 3 represents the hydrogen atom or an alkyl radical
• Z is the carbonyl or sulfonyl group
• R 4 is an alkoxy, amino, alkylamino or dialkylamino group, a piperidinyl radical optionally substituted by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl or piperidinyl group, a 1-methyl -4-piperidinyloxy radical, a pyridinylamino, benzo [b] furanyl, 1, 2, 4-triazol-l-yl or lH-indolyl group, one optionally by a 4-alkyl-l-piperazinyl or 4-arylalkyl-1-piperazinyl radical substituted phenyl group or also a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, the
• the abovementioned alkyl and alkenyl groups or the alkyl groups contained in the abovementioned radicals contain 1 to 5 carbon atoms and can be branched or unbranched and the abovementioned aromatic and heteroaromatic radicals additionally by fluorine, chlorine or bromine atoms, by cyano or hydroxyl groups mono-, di- or tri-substituted and the substituents can be the same or different.
• 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 compounds of the general formula (I) 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.
• R is a mono- or di-unsaturated 5- to 7-membered aza, diaza, triaza or thiaza heterocycle, wherein the heterocycles mentioned above are linked via a carbon or nitrogen atom and
• an olefinic double bond of one of the abovementioned unsaturated heterocycles can be condensed with a benzene, pyridine, diazine or quinoline ring or with a 2 (1H) -oxoquinoline ring which is optionally substituted on the nitrogen atom by a methyl group or two olefinic rings Double bonds of one of the unsaturated heterocycles mentioned above can each be fused with a benzene ring,
• phenyl, pyridinyl, diazinyl, thienyl, pyrrolyl, 1, 3-thiazolyl, isoxazolyl, pyrazolyl or 1-methylpyrazolyl groups and benzo-, pyrido- and diazinocondensed heterocycles in the carbon skeleton additionally in the carbon skeleton by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, nitro, trifluoromethyl, hydroxyl, amino, acetylamino, acetyl, cyano or trifluoromethoxy groups may be mono-, di- or tri-substituted " , where the substituents can be the same or different,
• aromatic radicals are formed by fluorine, chlorine or bromine atoms, by branched or unbranched alkyl groups, can be mono-, di- or tri-substituted by alkoxy, trifluoromethyl, nitro, hydroxyl, amino or acetylamino groups, where the substituents can be the same or different,
• R 2 represents the hydrogen atom or the methyl group
• one of the radicals A 1 and A 2 represents the hydrogen atom and the other the amino, methylamino or ethylamino group, the [1,4 '] bipiperidinyl-1' -yl group or the group
• R 3 represents the hydrogen atom, the methyl or ethyl group
• Z is the carbonyl or sulfonyl group
• R 4 is an alkoxy, amino, alkylamino or dialkylamino group, a 1- or 4-piperidinyl optionally substituted by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl or 1-piperidinyl group Radical, an l-methyl-4-piperidinyloxy radical, a pyridinylamino, benzo [b] furanyl, 1, 2, 4-triazol-l-yl or lH-indolyl group, one optionally by a 4-methyl-1-piperazinyl or 4-phenylmethyl-1-piperazinyl radical substituted phenyl group or also a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, the
• the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned radicals contain 1 to 4 carbon atoms and can be branched or unbranched and the above-mentioned aromatic and heteroaromatic radicals additionally by fluorine, chlorine or bromine atoms, mono-, di- or tri-substituted by cyano or hydroxyl groups and the substituents can be the same or different,
• Particularly preferred compounds of the general formula I above are those in which R is a monounsaturated 5- to 7-membered diaza or triaza heterocycle,
• an olefinic double bond of one of the above-mentioned unsaturated heterocycles can be substituted with a benzene or quinoline ring or with a 2 (1H) -oxoquinoline ring optionally substituted on the nitrogen atom by a methyl group, or two olefinic double bonds of one of the above-mentioned unsaturated ones Heterocycles can each be fused with a benzene ring,
• phenyl groups contained in R and benzo-condensed heterocycles in the carbon skeleton additionally by fluorine, chlorine or bromine atoms, by methyl, methoxy, nitro, trifluoromethyl, hydroxyl, amino, acetylamino, acetyl, Cyan or trifluorometoxy groups can be mono-, di- or tri-substituted, it being possible for the substituents to be the same or different, but preferably unsubstituted or monosubstituted by a fluorine, chlorine or bromine atom, by a methyl or methoxy group,
• R 1 is optionally by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, nitro, hydroxy or Amino groups mono-, di- or tri-substituted phenyl group, where the substituents can be the same or different,
• R 2 represents the hydrogen atom or the methyl group
• one of the radicals A 1 and A 2 represents the hydrogen atom and the other the amino or methylamino group, the [1, 4 '] bipiperidinyl-1' -yl group or the group
• R 3 represents the hydrogen atom or the methyl group
• Z is the carbonyl or sulfonyl group
• R 4 is a branched or unbranched C 5 alkoxy group, a 1- or 4-piperidinyl radical optionally substituted by a 1-methyl -4-piperidinyl, 4-methyl-1-piperazinyl or 1-piperidinyl group, a 1 -Methyl-4-piperidinyloxy radical, a 2-pyridinylamino, benzo [b] furan-2-yl, 1,2,4-triazol-1-yl or IH-indol-2 -yl group, a phenyl group optionally substituted by a 4-methyl-1-piperazinyl or 4-phenylmethyl-1-piperazinyl radical or also a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, the
• the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned radicals contain 1 to 4 carbon atoms and are branched or unbranched and the above-mentioned aromatic and heteroaromatic radicals additionally by fluorine, chlorine or bromine atoms, by cyano - or hydroxyl groups can be mono-, di- or tri-substituted,
• R is 3,4-dihydro-2 (1H) -oxoquinazolin-3-yl-, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl-, 2,4-dihydro-5-phenyl -3 (3H) -oxo- 1,2, 4-triazol-2-yl-, 1,3-dihydro-2 (2H) -oxoimidazo [4, 5-c] quinolin-3-yl-, 1st , 3,4,5-tetrahydro-2-oxo-l, 3-benzodiazepin-3-yl-, 1,3-dihydro-5-methyl-2,4, (2H, 5H) -dioxoimidazo [4, 5-c ] quinolin-3-yl, 5, 7-dihydro-6-oxo-l, 3-dibenzodiazepin-5-yl or 1,3-di-hydro-2-oxobenzimidazol-1-yl group,
• bicyclic heterocycles mentioned in the carbon skeleton can additionally be monosubstituted by methoxy groups
• R 1 is a phenyl group which is mono-, di- or tri-substituted, optionally by fluorine, chlorine or bromine atoms, by hydroxyl or amino groups, it being possible for the substituents to be the same or different,
• R 2 represents the hydrogen atom or the methyl group
• one of the radicals A 1 and A 2 represents the hydrogen atom and the other amino or methylamino group, the [1, 4 '] bipiperidinyl-1' -yl group or the group
• R 3 represents the hydrogen atom or the methyl group
• Z is the carbonyl or sulfonyl group and R 4 is a branched or unbranched C- 4 alkoxy group, a 1- or 4-piperidinyl group optionally substituted by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl or 1-piperidinyl group, one 1-methyl-4-piperidinyloxy radical, a 2-pyridinylamino, benzo [b] furan-2-yl, 1,2,4-triazol-1-yl or IH-indol-2 -yl group, a phenyl group optionally substituted by a 4-methyl-1-piperazinyl or 4-phenylmethyl-1-piperazinyl radical or else a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, preferably 1 to 5 carbon atoms, the
• the above-mentioned alkyl groups or the alkyl groups contained in the above-mentioned radicals contain 1 to 4 carbon atoms and are branched or unbranched and the above-mentioned aromatic and heteroaromatic radicals additionally by fluorine, chlorine or bromine atoms, by cyano - or hydroxyl groups can be mono-, di- or tri-substituted,
• R is a saturated, mono- or di-unsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S, S-dioxido-thiadiaza heterocycle,
• heterocycles mentioned above are linked via a carbon or nitrogen atom and
• R 1 is phenyl, 1-naphthyl, 2-naphthyl, 1H-indol-3-yl, 1-methyl-IH-indol-3 -yl, 1-formyl-IH-indol-3 -yl- , 4-imidazolyl-, l-methyl-4-imidazolyl-, 2-thienyl-, 3-thienyl-, thia- zolyl-, lH-indazol-3-yl-, l-methyl-lH-indazol-3-yl-, benzo- [b] fur-3-yl-, benzo [b] thien-3-yl, pyridinyl-, Quinolinyl or isoquinolinyl group,
• R 2 is the hydrogen atom
• one of the radicals A 1 and A 2 is the hydrogen atom and the other is the amino, the [1, 4 '] bipiperidinyl-1' -yl or an alkylamino group or the group
• R 3 represents the hydrogen atom or an alkyl radical
• Z is the carbonyl or sulfonyl group and R 4 is an alkoxy, amino, alkylamino or dialkylamino group, a piperidinyl radical optionally substituted by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl or piperidinyl group, an l-methyl -4-piperidinyloxy radical or also a branched or unbranched alkyl radical comprising 1 to 4 carbon atoms, which in the ⁇ position is represented by a dialkylamino group, by a piperidinyl optionally substituted by a dimethylamino, 4-methyl-1-piperazinyl or piperidinyl group Radical or can be substituted by a 4-methyl-1-piperazinyl radical,
• 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:
• a la and A 2a have the meanings given at the beginning for A 1 and A 2 with the exception of an optionally alkyl-substituted amino group and R 1 and R 2 are defined as mentioned at the outset,
• 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. B. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylaminopropyl) carbodiimide, O- (IH-benzotriazol-l-yl) - N, NN ', N' -tetramethyluronium hexafluorophosphate - (HBTU) or (HBTU) tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used.
• DCC dicyclohexylcarbodiimide
• DI diisopropylcarbodiimide
• 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), N-methylpyrrolidone (NMP) or mixtures of these and at temperatures between - 30 and +30 ° C, preferably -20 and +25 ° C, carried out.
• solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures of these and at temperatures between - 30 and +30 ° C, preferably -20 and +25 ° C, carried out.
• N-ethyl-diisopropylamine (Hünig base) is preferred as an additional auxiliary base.
• DIEA N-ethyl-diisopropylamine
• Another coupling process for the synthesis of compounds of the general formula I is the so-called “anhydride process” (see also: M. Bodanszky, “Peptide Chemistry", Springer-Verlag 1988, pp. 58-59; M. Bodanszky, “Principles of Peptide Synthesis ", Springer-Verlag 1984, pp. 21-27) used.
• the “mixed anhydride” in the variant according to Vaughan is preferred (JR Vaughan Jr., J. Amer. Chem Soc.
• the mixed anhydride is obtained from the carboxylic acid of general formula (III) to be coupled and the carbonic acid monoisobutyl ester.
• This mixed anhydride is prepared and coupled with amines in a one-pot procedure, using the abovementioned solvents and at temperatures between -20 and + 25 ° C., preferably 0 and +25 ° C.
• a la and A 2a have the meanings given for A 1 and A 2 at the outset, with the exception of an optionally alkyl-substituted amino group, R 1 and R 2 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, a phenylsulfonyloxy or naphthylsulfonyloxy group which is mono-, di- or trisubstituted, optionally by chlorine or bromine atoms, by methyl or nitro groups, the substituents may be the same or different, an 1H-imidazol-1-yl-, an 1H-1, 2-4-triazol-1-yl-, an 1H-1, 2, 4-triazol-1-yl- , lH-l, 2,3-triazol-l-yl-,
• auxiliary bases are preferably alkali and alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, for. B.
• alkali acetates for example sodium or potassium acetate
• tertiary amines for example pyridine, 2, 4, 6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-di-azabicyclo [2, 2, 2] octane or 1, 8-diazabicyclo [5, 4, 0] undec-7-ene, for example dichloromethane as solvent , Tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof; If alkali or alkaline earth metal hydroxides, alkali carbonates or acetates are used as auxiliary bases, water can also be added to the reaction mixture as cosolvent.
• R 4 is a benzo [b] furanyl or IH indolyl group, one optionally substituted by a 4-alkyl-1-piperazinyl or 4-arylalkyl-1-piperazinyl radical
• Alkoxy-carbonylamino- or ⁇ [1 , 4 '] bipiperidinyl-1' - yl ⁇ - " acetyl ⁇ amino ⁇ group can be substituted, and Z represents the carbonyl group:
• radicals A1 and A2b represents the hydrogen atom and the other the radical
• R, R 1 , R 2 and R 3 are defined as 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. B. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylaminopropyl) carbodiimide, O- (1H-benzotriazol-1-yl) - N, NN ', N' -tetramethyluronium hexafluorophosphate - (HBTU) tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-dimethylamino) -phosphonium hexafluorophosphate (BOP) can be used.
• DCC dicyclohexylcarbodiimide
• DIC diisopropylcarbodiimide
• 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), N-methylpyrrolidone (NMP) or mixtures of these and at temperatures between -30 and +30 ° C, preferably -20 and +25 ° C, carried out.
• solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures of these and at temperatures between -30 and +30 ° C, preferably -20 and +25 ° C, carried out.
• DIEA N-ethyl-diisopropylamine
• the mixed anhydride is obtained from the carboxylic acid of general formula VI to be coupled and the carbonic acid mono-isobutyl ester
• the preparation of this mixed anhydride and the coupling with amines is carried out in a one-pot process, using the abovementioned solvents and at temperatures between -20 and + 25 ° C, preferably 0 and + 25 ° C.
• R 4 is a benzo [b] furanyl or IH indolyl group, a phenyl group optionally substituted by 4-alkyl-1-piperazinyl or 4-arylalkyl-1-piperazinyl radicals or a branched or unbranched branch comprising 1 to 7 carbon atoms
• 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, one optionally by chlorine or bromine atoms, by methyl or nitro groups mono-, di- or trisubstituted phenylsulfonylox - or naphthylsulfonyloxy group, where the substituents may be the same or different, an 1H-imidazol-1-yl, an 1H-pyrazol-1-yl- optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1, 2, 4-triazol-l-yl-, lH-l, 2,3-triazol-l-yl-, 1H-1, 2, 3, 4-tetrazol-l-yl-, a vinyl, propargyl, p-Nitrophenyl-, 2, 4-din
• th alkyl radical which in the ⁇ -position is represented by a pyridinyl, phenyl, phenoxy or phenylmethoxycarbonylamino group, by a dialkylamino group, by an optionally by a phenyl, pyridinyl, dimethylamino, 4-morpholinyl, 4-alkylhexahydro 1H-1,4-diazepin-1-yl-, 4-alkyl-1-piperazinyl-, 4- (alkylsulfonyl) -1-piperazinyl-, 4- (dialkylaminoalkyl) -1-piperazinyl-, 1-alkyl- 4-piperidinyl or piperidinyl group substituted piperidinyl or piperazinyl residue, by a 4-methyl-1-piperazinyl residue, by an N-methyl-N- (1 'methyl- [1, 4'] bipiperidinyl-1-yl) amino or 4- (1-piperid
• R, R 1 and R 2 are defined as mentioned at the outset, one of the radicals A 1b and A 2b the hydrogen atom and the other the radical
• R 3 represents the hydrogen atom or an alkyl radical.
• auxiliary bases are preferably alkali and alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, for. B.
• alkali acetates for example sodium or potassium acetate
• tertiary amines for example pyridine, 2, 4, 6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1 , 4-diazabicyclo [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, Dimethyl acetamide, N-methyl-pyrrolidone or mixtures thereof; If alkali or alkaline earth metal hydroxides, alkali carbonates or acetates are used as auxiliary bases, water can also be added to the reaction mixture as cosolvent.
• R 5 is a tert. -Alkyl group and R, R 1 , R 2 and R 3 are defined as mentioned above.
• Acidolysis with trifluoroacetic acid is preferred, with or without inert solvents, for example dichloromethane, and preferably in the absence of water. Suitable temperatures are between -50 and +90 ° C, preferably between 0 ° C and room temperature.
• the acidolysis of compounds of the general formula (X) with methanolic hydrogen chloride solution under reflux conditions has also proven successful, although experience has shown that an attack on carboxamide and ester functions cannot be completely ruled out, which is why the trifluoroacetic acid variant is generally the method of choice represents.
• R 3 is defined as mentioned at the outset
• Z is the carbonyl group
• R 4 is an alkoxy, amino, alkylamino or dialkylamino group, optionally by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl- or piperidinyl group substituted 1-piperidinyl residue, an l-methyl-4-piperidine yloxy radical, a pyridinylamino or 1, 2, 4-triazol-1-yl group:
• R, R 1 , R 2 and R 3 are as defined at the outset
• R f is an alkoxy, amino, alkylamino or dialkylamino group, a 1-piperidinyl radical optionally substituted by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl or piperidinyl group, a 1 Represents methyl-4-piperidinyloxy radical, a pyridinylamino or 1, 2, 4-triazol-l-yl group,
• X 1 and X 2 which may be the same or different, are a nucleofuge group, preferably the IH imidazol-1-yl, 1H-1,2,4-triazol-1-yl, trichloromethoxy, the 2nd , 5-Dioxopyrrolidin-l-yloxy group or the chlorine atom.
• 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 XII or VII with equimolar amounts of the carbonic acid derivative of the general formula XIII in a suitable solvent at a lower temperature Brings reaction, then adds at least equimolar amounts of the other component VII or XII and the reaction ended at a higher temperature.
• the component of the general formula XII corresponds to an alcohol
• the reaction can also be accelerated by catalytic amounts of the associated alcoholate or imidazole sodium - but if the compound of the general formula VII is a primary amine, catalysts are generally unnecessary.
• 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, N-ethyldiisopropylamine, pyridine, 1,5-diazabi- cyclo [4, 3, 0] non-5-ene, 1, 4-diazabicyclo [2, 2, 2] octane or 1,8-diazabicyclo [5, 4, 0] undec-7-ene.
• a tertiary base for example triethylamine, N-ethyldiisopropylamine, pyridine, 1,5-diazabi- cyclo [4, 3, 0] non-5-ene, 1, 4-diazabicyclo [2, 2, 2] octane or 1,8-diazabicyclo [5, 4, 0] undec-7-ene.
• Suitable solvents which should be anhydrous are tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile when using bis (trichloromethyl) -carbonate as carbonyl component are anhydrous chlorinated hydrocarbons, for example dichloromethane, 1, 2-dichloroethane or trichlorethylene, are preferred.
• the reaction temperatures for the first reaction stage are between -30 and +25 ° C, preferably -5 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
• Z represents the carbonyl group and R 4 represents an amino, alkylamino or dialkylamino group or a 1-piperidinyl radical optionally substituted by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl or piperidinyl group :
• R 4 represents an amino, alkylamino or dialkylamino group or a piperidinyl radical optionally substituted by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl or piperidinyl group,
• X 3 is the phenoxy group when X 4 is the (1H) -1, 2, 3, 4-tetrazol-1-yl radical, the 4-nitrophenoxy group when X 4 is the 4-nitrophenoxy group and the chlorine atom when X 4 represents the 2,4,5-trichlorophenoxy group.
• the reactions are two-stage with the intermediate formation of urethanes, which can be isolated.
• the reactions can also be carried out as a one-pot reaction.
• one of the two components XII 'or VII' is preferably reacted with equimolar amounts of the carbonic acid derivative of the general formula XV in a suitable solvent at a lower temperature. closing at least equimolar amounts of the other component VII 'or XII' and terminating the reaction at a higher temperature.
• the reactions are preferably carried out in anhydrous solvents, for example in tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile or anhydrous chlorinated hydrocarbons, for example dichloromethane , 1, 2-dichloroethane or trichlorethylene.
• the reaction temperatures for the first reaction stage are between -15 and + 40 ° C, preferably -10 and + 25 ° C, for the second reaction stage between +20 ° C and the boiling point of the solvent used, preferably between + 20 ° C and 100 ° C (See also: RW Adamiak and J.
• Z represents the sulfonyl group and R 4 represents an amino, alkylamino or dialkylamino group or a piperidinyl radical optionally substituted by a 1-methyl-4-piperidinyl, 4-methyl-1-piperazinyl or piperidinyl group:
• Z is the sulfonyl group and Nu 'is a leaving group, for example a halogen atom, such as chlorine, bromine or iodine atom, an alkyl or arylsulfonyloxy group or an alkoxy group each having up to 10 carbon atoms , e.g. B. the methoxy or ethoxy group, or a phenoxy or naphthoxy group optionally mono-, di- or tri-substituted by chlorine or bromine atoms, by methyl, nitro or hydroxyl groups, where the substituents may be the same or different,
• R 4 represents an amino, alkylamino or dialkylamino group or a piperidinyl radical optionally substituted by a 1-methyl-4-piperidinyl, methyl-1-piperazinyl or piperidinyl group.
• sodium or potassium acetate and tertiary amines, for example pyridine, 2, 4, 6-trimethylpyridine, quinoline, triethylamine, N-ethyldiisopropylamine, N-ethyl-dicyclo-hexylamine, 1, 4-diazabicyclo [2, 2, 2] octane or 1,8-diazabicyclo [5, 4, 0] undec-7-ene, as solvent, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dirthylformamide, dimethylacetamide, N-methylpyrrolidone or mixtures thereof in consideration; If alkali or alkaline earth metal hydroxides, alkali carbonates or acetates are used as auxiliary bases, water can also be added to the reaction mixture as cosolvent.
• tertiary amines for example pyridine, 2, 4, 6-trimethylpyridine, quinoline,
• the 2-hydroxyphenoxy group is preferred as the nucleofugic group Nu 'in compounds of the general formula XVI, and boiling dioxane as the solvent for the reaction with amines of the general formula XII'.
• R 4 is a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, which is in the ⁇ position by a dialkylamino group, by an optionally by a phenyl, pyridinyl, dimethylamino, 4-morpholinyl, 4-alkyl- hexahydro-lH-1, 4-diazepin-l-yl ⁇ , 4-alkyl-1-piperazinyl-, 4-
• Alkoxy-carbonyla ino- or ⁇ [1 , 4 '] bipiperidinyl-1' -yl ⁇ -acetyl ⁇ amino ⁇ group may be substituted:
• R 41 is a branched or unbranched alkylene radical comprising 1 to 7 carbon atoms, which is in the ⁇ -position by a tert.alkoxycarbonylamino or ⁇ [ 1, 4 '] bipiperidynyl-1' -yl ⁇ -acetyljamino ⁇ group can be substituted and Nu '' means a leaving group in the ⁇ position, 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 which is mono-, di- or tri-substituted, optionally by chlorine or bromine atoms, by methyl or nitro groups, it being possible for the substituents to be identical or different
• auxiliary bases are alkali and alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, but preferably alkali metal carbonates, e.g. B.
• alkali metal acetates such as sodium or potassium acetate
• tertiary amines such as pyridine, 2,, 6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diazabicyclo [2, 2, 2] octane or 1, 8-diazabicyclo [5, 4, 0] undec-7-ene, for example dichloromethane as solvent , Tetrahydrofuran, 1,4-dioxane, but preferably dipolar, aprotic solvents, for example acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, methyl isobutyl ketone or mixtures thereof; If alkali or alkaline earth metal hydroxides, alkali carbonates or acetates are used
• R, R 1 and R 2 are defined as stated at the beginning, with Ammonia, an alkylamine or with [1, 4 '] bipiperidinyl.
• the reaction is usually successful under mild conditions and without the addition of catalysts.
• the reaction can be carried out in general at temperatures between -10 ° C and 150 ° C, preferably +15 to +35 ° C, at pressures between normal pressure and 300 bar and without or in the presence of additional solvents.
• Alcohols such as methanol or ethanol and ethers such as diethyl ether, tetrahydrofuran or 1,4-dioxane are preferred as possible solvents.
• alkali or alkaline earth metal hydroxides such as sodium, potassium or barium hydroxide
• alkali metal alcoholates such as sodium ethylate or potassium methylate
• Triton B benzyltrimethylammonium hydroxide
• R 4 is a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, which in the ⁇ -position is a ⁇ [1, 4 '] bipiperidinyl-1' -yl ⁇ -acetyl ⁇ amino ⁇ residue and in the ⁇ position by a phenyl, pyridinyl, phenoxy, phenylmethoxycarbonylamino or N-alkylphenylamino group, by a dialkylamino group, by an optionally by a phenyl, pyridinyl, dimethylamino, 4 -Morpholinyl-, 4-alkyl-hexahydro-lH-l, 4-diaz-epin-1-yl-, 4-alkyl-1-piperazinyl -, 4- (alkylsulfonyl) -1-piperazinyl-, 4- ( Dialkylaminoalky
• R, R 1 and R 2 are defined as mentioned at the outset and R k is a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms which bears an amino group in the ⁇ position and in the ⁇ position by a phenyl, pyridinyl, Phenoxy, phenylmethoxycarbonylamino or N-alkylphenylamino group, by a dialkylamino group, by an optionally by a phenyl, pyridinyl, dimethylamino, 4-morpholinyl, 4-alkylhexahydro-1H-1, 4-diazepine-1 -yl-, 4-alkyl-1-piperazinyl-, 4- (alkylsulfonyl) -1-piperazinyl-, 4- (dialkylaminoalkyl) -1-piperazinyl-, 1-alkyl-4-piperidinyl- or 1-piperidinyl- Group-substit
• 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. B. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylaminopropyl) carbodiimide, O- (lH-benzotriazol-1-yl) - N, NN ', N' -tetramethyluronium hexafluorophosphate - (HBTU) tetrafluoroborate (TBTU) or IH-benzotriazol-l-yl-oxy-tris-dimethylamino) -phosphonium hexafluorophosphate (BOP) can be used.
• DCC dicyclohexylcarbodiimide
• DIC diisopropylcarbodiimide
• 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), N-methylpyrrolidone (NMP) or mixtures of these and at temperatures between -30 and +30 ° C, preferably -20 and +25 ° C, carried out.
• solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures of these and at temperatures between -30 and +30 ° C, preferably -20 and +25 ° C, carried out.
• DIEA N-ethyl-diisopropylamine
• the mixed anhydride is obtained from the carboxylic acid of general formula VI to be coupled and the carbonic acid mono-isobutyl ester.
• This mixed anhydride is prepared and coupled with amines in a one-pot process, using the abovementioned solvents and at temperatures between -20 and + 25 ° C., preferably 0 and + 25 ° C.
• R 3 and Z are defined as mentioned at the outset and R 4 is a 1, 2-ethylene group which is in the ⁇ position by an amino, [1, 4 '] bipiperidinyl-1-yl, phenylamino or N- Alkylphenylamino group, by a dialkylamino group, by an optionally by a phenyl, pyridinyl, dimethylamino, 4-morpholinyl, 4-alkylhexahydro-1H-1, 4-diazepin-1-yl, 4-A1- kyl-1-piperazinyl, 4- (alkylsulfonyl) -1-piperazinyl, 4- (dialkylaminoalkyl) -1-piperazinyl, 1-alkyl-4-piperidinyl or piperidinyl group substituted 1-piperidinyl or 1-piper - azinyl residue, through a 4-methyl-1-piperazinyl residue, an N-methyl-N- (1') bi
• R, R 1 and R 2 are defined as stated above and one of the radicals A 11 and A 21 represents the hydrogen atom and the other the group
• R 3 and Z have the meanings given above, with ammonia, a phenylamine or N-alkylphenylamine, with [1, 4 '] bipiperidinyl, with a dialkylamine, one optionally by a phenyl, pyridinyl, dimethylamino -, 4-morpholinyl, 4-alkyl-hexahydro-lH-l, 4-diazepin-l-yl, 4-alkyl-1-piperazinyl-, 4- (alkylsulfonyl) -1-piperazinyl-, 4- (dialkylaminoalkyl ) -1-piperazinyl, l-alkyl-4-piperidinyl or piperidinyl group substituted piperidine or piperazine, with 1-methylpiperazine, N-methyl-N- (1'-methyl- [1,4 '] bipiperidinyl-1 - yl) amine or 4- (1-piperidinylmethyl)
• the reaction is usually successful under mild conditions and without the addition of catalysts.
• the reaction can be carried out in general at temperatures between -10 ° C and 150 ° C, preferably +15 to +35 ° C, at pressures between normal pressure and 300 bar and without or in the presence of additional solvents.
• Alcohols such as methanol or ethanol and ethers such as diethyl ether, tetrahydrofuran or 1,4-dioxane are preferred as possible solvents.
• alkali or alkaline earth metal hydroxides such as sodium, potassium or barium hydroxide
• alkali alcoholates such as sodium ethylate or potassium methylate
• Triton B benzyltrimethylammonium hydroxide
• R 3 and Z are defined as mentioned at the outset and R 4 is a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, which is amino-substituted in the ⁇ -position and in the ⁇ -position by an amino, phenyl or pyridinyl -, phenoxy, phenylamino, phenylmethoxycarbonylamino or N-alkylphenylamino group, by a dialkylamino group, by an optionally by a phenyl, pyridinyl, dimethylamino, 4-morpholinyl, 4-alkylhexahydro-1H-1, 4-diazepin-l-yl-, 4-alkyl-1-piperazinyl-, 4- (alkylsulfon-yl) -1-piperazinyl-, 4- (dialkylaminoalkyl) -1-piperazinyl-, 1-alkyl-4- piperidinyl or pipe
• R, R 1 and R 2 and Z are defined as mentioned at the outset and R 4m is a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, which carries a tert.alkoxycarbonylamino group in the ⁇ -position and in the ⁇ -position by a Amino, phenyl, pyridinyl, phenoxy, phenylamino, phenylmethoxycarbonylmino or N-alkylphenylamino group, by a dialkylamino group, by an optionally by a phenyl, pyridinyl, dimethylamino, 4-morpholinyl, 4- Alkyl-hexahydro-1H-1,4-diazepin-l-yl-, 4-alkyl-1-piperazinyl-, 4- (alkylsulfonyl) -1-piperazinyl-, 4- (dialkylaminoalkyl) -1- piperazin
• Acidolysis with trifluoroacetic acid is preferred, with or without inert solvents, for example dichloromethane, and preferably in the absence of water. Suitable temperatures are between -50 and +90 ° C, preferably between 0 ° C and room temperature.
• the acidolysis of compounds of the general formula (XXVI) with methanolic hydrogen chloride solution under reflux conditions has also proven successful, although experience has shown that an attack on carboxamide and ester functions cannot be completely ruled out, which is why the Trifluoroacetic acid variant is usually the method of choice.
• n) For the preparation of compounds of the general formula (I) in which one of the two radicals A 1 and A 2 represents the hydrogen atom and the other the group
• R 3 and Z are defined as mentioned at the outset and R 4 is a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms, which is in the ⁇ -position by an amino or a ⁇ [1, 4 '] bipiperidinyl-1' -yl ⁇ -acetyl ⁇ amino ⁇ group and is substituted in the ⁇ -position by a free amino group:
• R, R 1 , R 2 and Z are defined as mentioned at the outset and R 4 is a branched or unbranched alkyl radical comprising 1 to 7 carbon atoms which is in the ⁇ -position by represents an amino or a ⁇ [1, 4 '] bipiperidinyl-1' -yl ⁇ -acetyl ⁇ amino ⁇ group and is substituted in the ⁇ -position by a phenylmethoxycarbonylamino group.
• Acidolysis is carried out using hydrogen bromide in organic acids, such as trifluoroacetic acid, pivalic acid, isobutyric acid, isovaleric acid, but preferably in acetic acid, and at temperatures between 0 and 40 ° C., but preferably at room temperature, and preferably in the presence of auxiliaries, such as anisole, Thioanisole, pentamethylbenzene or dimethyl sulfide.
• organic acids such as trifluoroacetic acid, pivalic acid, isobutyric acid, isovaleric acid, but preferably in acetic acid, and at temperatures between 0 and 40 ° C., but preferably at room temperature, and preferably in the presence of auxiliaries, such as anisole, Thioanisole, pentamethylbenzene or dimethyl sulfide.
• the new substituted piperidines of the general formula (I) according to the invention contain at least one chirality center. If one of the radicals R, A 1 or A 2 is also chiral, then the compounds can occur in the form of two diastereomeric pairs of antipodes.
• the invention includes the individual isomers as well as their 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 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 (eg Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic 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 (- ) -Diacetyltartaric acid, (+) - or (-) .
• suitable chiral stationary phases eg Chiral AGP, Chiralpak AD.
• Racemates which contain a basic or acidic 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 (- ) -Diacetyltartaric acid, (+) - or (-) .
• the racemate of a compound of the general formula (I) is reacted with one of the optically active acids or bases given above in an equimolar amount in a solvent and the crystalline, diastereomeric, optically active salts obtained using their different solubilities Cut.
• This reaction can be carried out in any type of solvent as long as they have a sufficient difference in the solubility of the salts. Methanol, ethanol or mixtures thereof, for example in a volume ratio of 50:50, are preferably used.
• Each of the optically active salts is then dissolved in water, neutralized with a base, such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution, and the corresponding free compound is thus obtained in the (+) or (-) form.
• the starting compounds of the general formula (III) can be obtained analogously to processes known from the literature from the above-described ⁇ -amino- ⁇ -oxo-arenebutanoic acids (see, for example: JE Nordlander, MJ Payne, FG Njoroge, VM Vishwanath, GR Han, GD Laikos and MA Balk, J. Org. Chem. 50, 3619
• the starting compounds of the general formula (IV) are obtained, insofar as they are not known from the literature or are even commercially available, in accordance with the processes specified in WO 98/11128 and DE 199 52 146.
• Starting compounds of the general formula (V) can be prepared in a conventional manner from compounds of the general formula (III) by derivatization.
• the carboxylic acids of the general formula (VI) required as starting compounds are commercially available or can be obtained by known methods.
• the carboxylic acid derivatives of the general formula (IX) are either known or are obtained in analogy to methods known from the literature from the starting compounds of the general formula (VI).
• the starting compounds of the general formula X can be prepared from corresponding precursors by processes a) and b) given above.
• the starting compounds of the general formulas (XII) and (XII 1 ) are either commercially available or can be obtained analogously to processes known from the literature.
• the starting compounds of the general formulas (XIII) and (XV) are also commercially available or known from the literature.
• the compounds of the general formula VII ′′ required as starting compounds can be obtained from amines of the general formula VII or VII ′ by reaction with sulfates of the general formula
• the starting materials of the general formula XVIII can be obtained from the compounds of the general formulas VII or VII 'described above by reaction, for example in the presence of triethylamine, with mostly commercially available compounds of the general formula
• X represents a halogen atom, such as chlorine, bromine or iodine.
• the starting compounds of the general formulas (XX) and (XX ') can be obtained by the processes specified in DE 199 52 146, but also arise in situ from appropriately substituted 4-aryl-4-oxobutyric acid piperidides, each of which has an amino position in the 2 position. , Alkylamino or dialkylamino group.
• the starting compounds of the general formulas (XXI) and (XXVII) fall under the definition of the general formula (I) and can be prepared by the processes described above.
• the starting compounds of the general formula (XXIII) can be easily prepared in a known manner, for example, from those compounds of the general formula (I) in which A 1 or A 2 denotes an optionally alkyl-substituted amino group by reaction with suitable acid chlorides or bromides ,
• the starting compounds of the general formula (XXV) are also easily obtained from compounds of the general formula (I) by reaction with suitably substituted, commercially available or by known processes. are carboxylic acids or carboxylic acid derivatives prepared under the conditions of process c) or d).
• the compounds of general formula I obtained can be converted into their physiologically tolerable salts with inorganic or organic acids, in particular for pharmaceutical applications.
• suitable acids for this are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
• the new compounds of the formula (I) can, if desired, be converted into their addition salts with inorganic or organic bases, in particular for pharmaceutical use into their physiologically tolerable addition salts.
• bases which can be used here are sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
• the new compounds of the general formula I and their physiologically tolerable salts have CGRP-antagonistic properties and show good affinities in CGRP receptor binding studies.
• the compounds have CGRP-antagonistic properties in the pharmacological test systems described below.
• 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 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, KC1 5.4, NaHC0 3 16.2, MgS0 4 0.8, NaHP0 4 1.0, CaCl 2 1.8, D-Glucose 5.5, HEPES 30, pH7 .40] the cells are centrifuged twice at 100 xg and resuspended in BSS.
• BSS "Balanced Salts Solution”
• the cells are homogenized using an Ultra-Turrax and centrifuged at 3000 xg for 10 minutes. The supernatant is discarded and the pellet 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), recentrifuged and resuspended (1 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
• concentration-binding curves are analyzed with the aid of a computer-aided non-linear curve fitting.
• the compounds of general formula I show IC5Q values ⁇ 10000 nM in the test described.
• 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
• Intracellular cAMP is then extracted by adding 20 ul IM HC1 and centrifugation (2000 x g, 4 ° C, 15 minutes). The supernatants are frozen in liquid nitrogen and stored at -20 ° C.
• the cAMP contents of the samples are determined by means of a radioimmunoassay (from Amersham) and the pA 2 values have an antagonistic effect
• the compounds of the general formula I show CGRP-antagonistic properties in a dose range between 10 ⁇ H to 10 ⁇ 5 M. Because of their pharmacological properties, the compounds of general formula I and their salts with physiologically compatible acids or bases are therefore suitable for the acute and prophylactic treatment of headaches, in particular migraine or cluster headaches.
• the compounds of the general formula I also have a positive effect on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM”), cardiovascular diseases, morphine tolerance, skin diseases, in particular thermal and radiation-related skin damage including sunburn, inflammatory diseases, for example inflammatory joint diseases (arthritis ), inflammatory lung diseases, allergic rhinitis, asthma, diseases that are associated with excessive vasodilation and the resulting reduced tissue blood flow, such as shock and sepsis.
• NIDDM non-insulin-dependent diabetes mellitus
• cardiovascular diseases in particular thermal and radiation-related skin damage including sunburn
• inflammatory diseases for example inflammatory joint diseases (arthritis ), inflammatory lung diseases, allergic rhinitis, asthma, diseases that are associated with excessive vasodilation and the resulting reduced tissue blood flow, such as shock and sepsis.
• inflammatory diseases for example inflammatory joint diseases (arthritis )
• inflammatory lung diseases for example inflammatory joint diseases (arthritis )
• the dosage required to achieve a corresponding effect is expediently 0.001 to 30 mg / kg of body weight in the case of intravenous or subcutaneous administration, preferably 0.01 to 5 mg / kg of body weight, and 0.01 to 50 mg in the case of oral, nasal or inhalation administration / kg body weight, preferably 0.1 to 30 mg / kg body weight, each 1 to 3 times a day.
• the compounds of general formula I prepared according to the invention optionally in combination with other active substances, such as, for example, antiemetics, prokinetics, Neuroleptics, antidepressants, neurokinin antagonists, anti-convulsants, histamine-HI receptor antagonists, antimuscarinics, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, ergot alkaloids, weak analgesics, non-steroidal antiphlogistics, corticosteroids, calcium antagonists, 5-antagonists HT ⁇ i ) agonists or other antimigraine agents, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, Incorporate water / sorbitol, water / polyethylene
• active substances
• active substances for example meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolon, carbinolamino nolamino nolamino nolaminophen , Phenytoin, valproate, amitryptilin, lidocaine, diltiazem or sumatriptan and other 5-HT ⁇ D agonists such as naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan.
• 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.
• Another object of the invention is the use of the compounds of general formula I as valuable tools for the production and purification (affinity chromatography) of Antibodies and, after suitable radioactive labeling, for example by direct labeling with 125j or 131j or by tritiation of suitable precursors, for example by replacing halogen atoms with tritium, in RIA and ELISA statements and as diagnostic or analytical aids in the neurotransmitter Research.
• the reaction mixture was freed from the solvent in vacuo, the residue was taken up in 200 ml of ethyl acetate and the resulting solution in succession with 50 ml of saturated sodium bicarbonate solution, 5%. Citric acid solution and saturated sodium bicarbonate solution are shaken out, dried over sodium sulfate and again evaporated in vacuo.
• the product obtained was purified on silica gel using dichloromethane / methanol / conc. Ammonia (90/10/1 v / v / v) purified by column chromatography for elution. After customary work-up of the suitable eluates, 1.05 g (48% of theory) of a colorless, crystalline product of R f 0.65 (FM ethyl acetate) was obtained.
• 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 is filled into hard gelatin capsules.
• 1 hub includes:
• Production method The active ingredient and benzalkonium chloride are dissolved in water and filled into Respimat® cartridges.
• 1 vial contains:
• Active ingredient sodium chloride and benzalkonium chloride are in
• 1 hub includes:
• 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 filled into a suitable container.
• Disodium hydrogen phosphate a2HP ⁇ 4 * 2H2 ⁇ 2 mg
• Dissolve polysorbate 80 sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (Wfl); Add human serum albumin; Dissolve active ingredient while heating; fill up to volume with Wfl; fill in ampoules.
• Dissolve mannitol in water for injections Wfl
• Wfl water for injections
• Human serum albumin Dissolve active ingredient while heating
• fill up to volume with Wfl fill in vials; freeze-dry.
• Dissolve mannitol in water for injections Wfl
• Add human serum albumin Dissolve active ingredient while heating
• fill up to volume with Wfl Fill into ampoules under nitrogen gas.

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• 1999
  • 1999-12-30 DE DE19963868A patent/DE19963868A1/de not_active Withdrawn
• 2000
  • 2000-12-22 SK SK941-2002A patent/SK9412002A3/sk not_active Application Discontinuation
  • 2000-12-22 JP JP2001550216A patent/JP2003519222A/ja active Pending
  • 2000-12-22 IL IL15037700A patent/IL150377A0/xx active IP Right Grant
  • 2000-12-22 PL PL00356400A patent/PL356400A1/xx not_active Application Discontinuation
  • 2000-12-22 AU AU35379/01A patent/AU783275B2/en not_active Ceased
  • 2000-12-22 MX MXPA02006509A patent/MXPA02006509A/es active IP Right Grant
  • 2000-12-22 UA UA2002076283A patent/UA75346C2/uk unknown
  • 2000-12-22 EA EA200200651A patent/EA005600B1/ru not_active IP Right Cessation
  • 2000-12-22 US US10/169,009 patent/US6949541B2/en not_active Expired - Lifetime
  • 2000-12-22 CA CA002395541A patent/CA2395541C/en not_active Expired - Fee Related
  • 2000-12-22 YU YU50002A patent/YU50002A/sh unknown
  • 2000-12-22 WO PCT/EP2000/013236 patent/WO2001049676A1/de active IP Right Grant
  • 2000-12-22 EE EEP200200369A patent/EE200200369A/xx unknown
  • 2000-12-22 CZ CZ20022628A patent/CZ20022628A3/cs unknown
  • 2000-12-22 NZ NZ519939A patent/NZ519939A/en unknown
  • 2000-12-22 CN CNB008181063A patent/CN1203069C/zh not_active Expired - Fee Related
  • 2000-12-22 KR KR1020027008495A patent/KR100736063B1/ko not_active IP Right Cessation
  • 2000-12-22 EP EP00991806A patent/EP1252153A1/de not_active Withdrawn
  • 2000-12-22 BR BR0017063-1A patent/BR0017063A/pt active Pending
  • 2000-12-22 HU HU0300002A patent/HUP0300002A3/hu unknown
  • 2000-12-27 AR ARP000106941A patent/AR027113A1/es not_active Suspension/Interruption
  • 2000-12-28 TW TW089128135A patent/TWI255267B/zh not_active IP Right Cessation
  • 2000-12-28 UY UY26513A patent/UY26513A1/es not_active Application Discontinuation
• 2002
  • 2002-06-20 BG BG106848A patent/BG106848A/bg active Pending
  • 2002-06-24 IL IL150377A patent/IL150377A/en not_active IP Right Cessation
  • 2002-06-27 HR HR20020560A patent/HRP20020560A2/hr not_active Application Discontinuation
  • 2002-06-27 ZA ZA200205181A patent/ZA200205181B/en unknown
  • 2002-06-28 NO NO20023161A patent/NO323700B1/no unknown
• 2003
  • 2003-09-01 HK HK03106237A patent/HK1054026A1/xx not_active IP Right Cessation

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