EP1737860A1

EP1737860A1 - Selected cgrp-antagonists, their preparation processes and their use as medicaments

Info

Publication number: EP1737860A1
Application number: EP05729383A
Authority: EP
Inventors: Klaus Rudolf; Stephan Georg Mueller; Philipp Lustenberger; Dirk Stenkamp; Gerhard Schaenzle; Kirsten Arndt; Henri Doods
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2004-04-15
Filing date: 2005-04-09
Publication date: 2007-01-03
Also published as: WO2005100352A8; DE102004018796A1; JP2007532601A; US20050250763A1; WO2005100352A1; CA2563386A1

Abstract

CGRP-antagonists are disclosed having the general formula (I), in which A, X and R1-R3 have the definition given in claim 1, as well as their tautomers, diastereomers, enantiomers, hydrates, mixtures and salts, as well as their salt hydrates, in particular their physiologically compatible salts with inorganic or organic acids, medicaments containing these compounds, their use and their preparation processes.

Description

Selected CGRP antagonists, processes for their preparation and their use as medicines

The present invention relates to the CGRP antagonists of the general formula

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts, in particular their physiologically tolerable salts with inorganic or organic acids, medicaments containing these compounds, their use and processes for their preparation.

In the above general formula (I)

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

-NR -2r R-) 3 a radical of the formula

- ^ - N ^ {N-CH ₃ - -N VN NH - -NN- NH

Examples of particularly preferred compounds of the above general formula (I) are as follows:

^S N MX

11

413 tioo 562

431 ju ς o 580

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts, the compounds

(1) 4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinoiin-3-yl) piperidine-1-carboxylic acid- (R) - 1 - (4-amino-3- chloro-5-trifluoromethyl-benzyl) -2- [1, 4 '] bipiperidinyl-1' -yl-2-oxoethyl ester,

(2) 4- (2-Oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R) - 1- (4-amino-3- chloro-5-trifluoromethyl-benzyl) -2- [4- (4-methyl-piperazin-1-yl) - piperidin-1-yl] -2-oxo-ethyl ester, (3) 4- (2-Oxo-1, 2-dihydro-imidazo [4,5-c] quinolin-3-yl) piperidine-1-carboxylic acid- (R) - 1- (4-amino-3- chloro-5-trifluoromethyl-benzyl) -2- [4- (1-methyl-piperidin-4-yl) - piperazin-1-yl] -2-oxo-ethyl ester,

5

(4) 4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidin-1-carboxylic acid- (R) - 1 - (4-amino-3- chloro-5-trifluoromethyl-benzyl) -2- (1 '-methyl- [4,4'] bipiperidinyl-1-yl) - 2-oxo-ethyl ester,

0 (5) 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- [4- (4-methyl-piperazin-1-yl) - piperidin-1-yl] -2-oxo-ethyl ester,

(6) 4- (5-Oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) piperidine-1-carboxylic acid (R) -5 1 - (4-amino -3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-methyl-piperidin-4-yl) - pi perazi n-1 -yl] -2-oxo-ethyl ester,

(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) -

: o 2-oxo-ethyl ester,

(8) 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, 4 '] bipiperidinyl-1' -yl-2-oxoethyl ester,

! 5

(9) 4- (5-Oxo-3-phenyl-4,5-dihydro- [1,2,4] triazoI-1-yl) -piperidine-1-carboxylic acid- (R) - 1- (4-amino -3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-aza-bicyclo [2.2.2] oct-3-yi) - piperazin-1-yl] -2-oxo-ethyl ester,

o their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts are of outstanding importance. 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:

5 (a) For the preparation of compounds of the general formula

in which X represents the oxygen atom or the NH group and A and R ¹ to R ³ are defined as mentioned above:

Implementation of a piperidine of the general formula

in which R ¹ is defined as mentioned at the beginning,

(i) with a carbonic acid derivative of the general formula

in which 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

(ii) with a carbonic acid derivative of the general formula

in which 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,

and with a compound of the general formula

in which X represents the oxygen atom or an NH group and A, 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. Examples of 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 (See also: HA Staab and W. Rohr, "Syntheses with Heterocyclic Amides (Azolides)", Newer Methods in Preparative Organic Chemistry, Volume V, pp. 53-93, Verlag Chemie, Weinheim / Bergstr. , 1967; P. Majer and RS Randad, J. Org. Chem. 59, pp. 1937-1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara and H. Ogura, Tetrahedron Letters 24 (42), 4569-4572 (1983); SR Sandler and W. Karo in "Organic Functional Group Preparations", Vol. II, pp. 223-245, Academis Press, New York 1971).

(b) For the preparation of compounds of the general formula

in which X denotes the methylene group and A and R ¹ to R ³ are defined as mentioned at the outset, with the proviso that the molecule contains no further free primary or secondary aliphatic amino function:

Coupling of a carboxylic acid of the general formula

in which A, R ² and R ³ are defined as mentioned at the outset, with a piperidine of the general formula

X — NH _{ι (|||)}

in which 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) -Λ /, Λ / -Λ / ', Λ / ^, -tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1 H-benzotriazol-1 -yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used. 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), Λ / 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).

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). The "mixed anhydride process" is preferred in the variant according to Vaughan (JR Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which using isobutyl chlorocarbonate in the presence of bases such as 4- Methylmorpholine or 4-ethylmorpholine, the mixed anhydride from the carboxylic acid to be coupled general formula (VI) and the carbonic acid monoisobutyl ester is obtained. 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 ° C. and + 25 ° C.

(c) For the preparation of compounds of the general formula

in which X denotes the methylene group and A and R ² and R ³ are defined as mentioned at the outset, with the proviso that these groups contain no free primary or secondary amine:

Coupling a compound of the general formula

in which A, 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, and 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-, 1H- 1, 2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, one Is dimethylaminyloxy, 2 (1H) -oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1 / - / - benzotriazole-1-yloxy or azide group,

with a piperidine of the general formula

R '

^NH , (lll)

in which 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, Λ / -ethyl-diisopropylamine, Λ / -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.

(d) For the preparation of compounds of the general formula

in the A, X and R) 1 D R3 are defined as mentioned at the beginning:

5 coupling of a carboxylic acid of the general formula

in which 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) -Λ /, A / -Λ ^/, A / '- tetramethyluronium hexafluorphos- phosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used. 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 made with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane,

-5 tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), Λ / -MethyIpyrrolidon (NMP) or mixtures of these and at temperatures between -30 and + 30 ° C, preferably -20 and + 25 ° C, performed. If necessary, preference is given to additional auxiliary base / V-ethyldiisopropylamine (DIEA) (Hünig base).

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). The "mixed anhydride process" is preferred in the variant according to Vaughan (JR Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which using butyl chloro-carbonate in the presence of bases such as 4- Methylimorpholine or 4-ethylmorpholine, 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.

(e) For the preparation of compounds of the general formula

0

in which A, X and R ¹ to R ³ are defined as mentioned at the outset, with the proviso that there is no free primary or secondary amine in the molecule:

! 5

Coupling a compound of the general formula

in which 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, vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, dimethylaminyloxy, 2 ( 1H) -oxopyridin-1-yloxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group,

with an amine of the general formula HNR R ³ , in which R ² and R ^{3 are} as defined in the introduction, with the proviso that no free carboxylic acid and / or no further free primary or secondary aliphatic amino function is contained.

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. sodium carbonate, potassium carbonate or cesium carbonate, alkali acetate, for example sodium or potassium acetate, and tertiary amines, for example pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, / V-ethyldiisopropylamine, Λ / -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, Λ / -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.

5

The 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.

.5 According to a conventional method for isomer separation, the racemate of a compound of general formula (I) is reacted with one of the optically active acids given above in an equimolar amount in a solvent and the crystalline, diastereomeric, optically active salts obtained are separated using their different solubilities , This implementation can be done in any kind of

50 solvents are carried out as long as they have a sufficient difference in the solubility of the salts. Methanol, ethanol or mixtures thereof are preferably used, for example in a volume ratio of 50:50. Then 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.

5

In each case only the (R) - or (S) -enantiomer or a mixture of two optically active diastereomeric compounds falling under the general formula (I) is also obtained by carrying out the syntheses described above with a suitable (R) - or (S) -configured reaction component. O

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 | 146 [. The starting compounds of the general formula (IV) are commercially available. Connections of the

5 general formula (V) can be prepared according to methods familiar to the peptide chemist from protected phenylalanines and amines of the general formula HNR ² R ³ .

The phenyalanine derivatives required for the preparation of the optically pure compounds of the general formula (V) 0 can be obtained from the compounds of the general formula

in which 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.

If the group X in compounds of the general formula (V) represents the oxygen atom, the hydroxycarboxylic acids of the general formula required for the synthesis can

in which A is defined as mentioned at the beginning, can be obtained from compounds of the general formula (X), with the proviso that R represents the hydrogen atom 5.

Provided that 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.

! 5 Another access to compounds of the general formula (XI) in which the radicals A are defined as mentioned at the beginning is the alkylation of the compound

with appropriately substituted benzyl chlorides, benzyl bromides or benzyl iodides of the general formula

, A

<X, (XMI)

in which 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).

Compounds of the general formula (XI), in which the radicals A are defined as mentioned at the outset, can furthermore be boiled off by boiling 2-acetylamino-3-phenyl-acrylic acids of the general formula

by means of strong acids and subsequent reduction of the resulting 2-hydroxy-3-phenyl-acrylic acids.

5

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. 90, 3495-3502 [1968]; Hiroyuki Kawano, Youichi Ishii, Takao Ikariya, Masahiko Saburi, Sadao Yoshikawa, Yasuzo Uchida and Hidenori Kumobayashi,

5 Tetrahedron Letters 28, 1905-1908 [1987]). 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. Examples of 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. However, 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.

5 Also included in the subject matter of this invention are the compounds according to the invention, including their salts, in which one or more hydrogen atoms have been replaced by deuterium.

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.

5 The new compounds mentioned above 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. O

The following experiments were carried out to demonstrate the affinity of the abovementioned compounds for human CGRP receptors and their antagonistic properties:

! 5 A. Binding studies with SK-N-MC cells (expressing the human CGRP receptor)

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. After determining the cell number, 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.

After thawing, 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 μl 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 μl. 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 μM human CGRP-alpha during the incubation.

The concentration-binding curves are analyzed with the aid of a computer-aided non-linear curve fitting.

The compounds mentioned at the beginning show IC50 values 100 10000 nM in the test described.

B. CGRP antagonism in SK-N-MC cells

SK-N-MC cells (1 million cells) are washed twice with 250 μl 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 μl) 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 μl 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

In the described in vitro test model, the compounds according to the invention show CGRP-antagonistic properties in a dose range between 10 ^-12 to 10- ⁵ M.

5 Because of their pharmacological properties, 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. Furthermore, 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

: 5 fertilize the oral mucosa, inflammatory lung diseases, allergic rhiriitis, asthma, diseases that are associated with excessive vasodilation and the resulting reduced tissue perfusion, eg shock and sepsis. In addition, 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.

If 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, α-agonists and α-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 / sorbitol, water / polyethylene Glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, can be incorporated into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories.

5

For the combinations mentioned above, 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.

Furthermore, candesartan, eprosartan, irbesartan, losartan, olmesartan, 5 tasosartan, telmisartan, valsartan, duloxetine, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrotinol, botoxin, timololtenpene, timololtenpene, timolapteninol, botoxoltenptenol, botoxetol, pomotol, pomotol Topiramate, riboflavin, montelukast, lisinopril, prochlorperazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol,: o atenolol, clonidine, indoramine, carbamazepine, phenytoin, valproate, amitocaindiliazin or other ditiazine-5 _{B /} _D i agonists such as almotriptan, Donitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan and their physiologically tolerable salts are used.

! 5 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.

Experimental part

IR, ¹ H-NMR and / or mass spectra are generally available for the compounds produced.

Unless otherwise stated, 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. Unless otherwise noted, 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 ™, 35 to 70 μm) is used for chromatographic purifications.

The HPLC data given are measured using the parameters listed below:

'.0

Method A:

Analytical column: Zorbax column (Agilent Technologies), SB (stable bond) C18; 3.5 μm; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 μL; Detection at 254 nm

The same gradients that were used to collect the analytical HPLC data are generally used for preparative HPLC cleaning. The The products are collected in a mass-controlled manner, the product-containing fractions are combined and freeze-dried.

If more detailed information on the configuration is missing, it remains open whether the enantiomers are pure or whether partial or even complete racemization has occurred.

The following abbreviations are used in the test descriptions:

DCM dichloromethane

DMAP 4-dimethylaminopyridine

DMF / V, A / -dimethylformamide

EtOAc ethyl acetate

HCI hydrochloric acid

LiOH lithium hydroxide

MeOH methanol

RT room temperature

TBTU 2- (1 / - / - benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

example 1

4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R) -1 - (4-amino-3-chloro-5 -trifluoromethyl-benzyl) -2- [1, 4 '] bipiperidinyl-1'-yl-2-oxo-ethyl ester

(1 a) 4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidin-1-carboxylic acid- (R) -

2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-ethoxycarbonyl-ethyl ester To the mixture of 0.79 g (6.42 mmol) DMAP and 100 mL pyridine were added 1.29 g (6.42 mmol) 4-chloroformic acid-4 -nitrophenyl ester added and 1 h at RT touched. A solution of 2.0 g (6.42 mmol) of (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-hydroxy-propionic acid ethyl ester in 15 ml of pyridine was then added dropwise with stirring at RT and a further 2 h at RT stirred. The mixture was then mixed with 1.72 g (6.42 mmol) of 3-piperidin-4-yl-1,3-dihydro-imidazo [4,5-c] quinoline

5 2-one added and stirred for 2 days at RT. The reaction mixture was concentrated under reduced pressure, 200 mL EtOAc and 200 mL 15% K ₂ CO ₃ solution were added, the organic phase was separated off, dried and concentrated. The residue was purified by column chromatography (silica gel, gradient DCM to DCM / MeOH / NH ₃ 0: 95: 5). o Yield: 1.2 g (31% of theory)

ESI-MS: (M + H) ⁺ = 606/608 (Cl)

Retention time (HPLC): 6.7 min (method A)

(1b) 4- (2-Oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidin-1-carboxylic acid- (R) - 5 2- (4-amino- 3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester

1.20 g (1.98 mmol) of 4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-amino -3-chloro-5-trifluoromethyl-phenyl) -1-ethoxycarbonyl-ethyl ester, dissolved in 30 mL THF, was added at RT with a solution of 74 mg (3.0 mmol) LiOH in 30 mL water and 3 h at RT touched. The reaction mixture: o Was concentrated under reduced pressure, the residue was mixed with 100 ml of water and acidified with 1 M HCl. The precipitate was filtered off, washed with 50 ml of water and dried in a forced air drying cabinet. Yield: 0.88 g (77% of theory)

ESI-MS: (M + H) ⁺ = 578/580 (Cl)

! 5 retention time (HPLC): 5.8 min (method A)

(1 c) 4- (2-Oxo-1, 2-dihydro-imidazo [4,5-c] quinolin-3-yl) piperidine-1-carboxylic acid- (R) - 1 - (4-amino-3 -chloro-5-trifluoromethyl-benzyl) -2- [1, 4 '] bipiperidinyl-1' -yl-2-oxoethyl ester so A mixture of 80 mg (0.138 mmol) 4- (2-oxo-1, 2 -dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy- ethyl ester, 23.6 mg (0.14 mmol) [1, 4'Ppiperidinyl, 46.6 mg (0.14 mmol) TBTU, 0.041 mL (0.28 mmol) triethylamine and 1.8 mL DMF was added overnight at RT touched. The reaction mixture was purified directly by means of HPLC-MS (column: Agilent Zorbax Stable Bond RP C18, 5 μM, 30x100 mm; flow 30 mL / min; gradient: water / acetonitrile) and subsequent lyophilization. Yield: 77 mg (76% of theory)

ESI-MS: (M + H) ⁺ = 728/730 (Cl)

Retention time (HPLC): 4.8 min (method A)

Example 2

4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R) -1 - (4-amino-3-chloro-5 -trifluoromethyl-benzyl) -2- [4- (4-methyl-piperazin-1-yl) -piperidin-1-yl] -2-oxo-ethyl ester

Analogously to Example (1c), 4- (2-oxo-1, 2-dihydro-imidazo-

[4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-amino-3-chloro-5-trifluoromethylphenyl) -1-carboxy-ethyl ester and 25 mg (0.14 mmol) of 1-methyl-4-piperidin-4-yl-piperazine received the product.

Yield: 76 mg (74% of theory)

ESI-MS: (M + H) ⁺ = 743/745 (Cl)

Retention time (HPLC): 5.5 min (method A)

Example 3

: 5

4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R) -1 - (4-amino-3-chloro-5 -trifluoromethyl-benzyl) -2- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -2-oxo-ethyl ester

Analogously to Example (1c), 4- (2-oxo-1, 2-dihydro-imidazo-

[4,5-c] quinolin-3-yl) piperidine-1-carboxylic acid- (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester and 26 mg (0.14 mmol) 1- (1-methyl-piperidin-4-yl) - piperazine received the product.

Yield: 68 mg (66% of theory)

ESI-MS: (M + H) ⁺ = 743/745 (Cl)

Retention time (HPLC): 4.0 min (method A)

Example 4

4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-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

Analogously to Example (1c), 4- (2-oxo-1,2-dihydro-imidazo-

[4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-amino-3-chloro-5-trifluoromethylphenyl) -1-carboxy-ethyl ester and 25 mg (0.14 mmol) of 1-methyl- [4,4 '] bipiperidinyl das

Received product.

Yield: 73 mg (71% of theory)

ESI-MS: (M + H) ⁺ = 742/744 (Cl)

Retention time (HPLC): 4.9 min (method A) Example 5

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- [4- (4-methyl-piperazin-1-yl) piperidin-1-yl] -2-oxo-ethyl ester

(5a) 4- (5-oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) -piperidine-1-carboxylic acid- (R) -

2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-ethoxycarbonyl-ethyl ester Analogously to example (1a), 2.0 g (6.42 mmol) became (R) -3- (4-amino-3-chloro -5-trifluoromethyl-phenyl) -2-hydroxy-propionic acid ethyl ester and 2.41 g (65%, 6.42 mmol) of 5-phenyl-2-piperidin-4-yl-2,4-dihydro-1,2,4-triazole -3-one will receive the product. Yield: 1.0 g (27% of theory)

ESI-MS: (M + H) ⁺ = 582/584 (Cl)

Retention time (HPLC): 8.9 min (method A)

(5b) 4- (5-oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) piperidine-1-carboxylic acid- (R) -

2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester Analogously to example (1 b), from 1.0 g (1.72 mmol) 4- (5-oxo-3-phenyl-4, 5-dihydro- [1, 2,4] triazol-1-yl) piperidine-1-carboxylic acid- (R) -2- (4-amino-3-chloro-5-trifluoromethylphenyl) -1-ethoxycarbonyl- ethyl ester and 64 mg (2.60 mmol) LiOH the product can be obtained.

Yield: 0.91 g (96% of theory)

ESI-MS: (M + H) ⁺ = 554/556 (Cl)

Retention time (HPLC): 7.5 min (method A) (5c) 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- [4- (4-methyl-piperazin-1-yl) - piperidin-1-yl] -2-oxo-ethyl ester

Analogously to Example (1c), 4- (5-oxo-3-phenyl-4,5-dihydro) was obtained from 77 mg (0.14 mmol).

[1,2,4] triazol-1-yl) -piperidine-1-carboxylic acid- (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester and 25 mg (0.14 mmol) 1-methyl-4-piperidin-4-yl-piperazine received the product.

Yield: 84 mg (84% of theory)

ESI-MS: (M + H) ⁺ = 719/721 (Cl)

Retention time (HPLC): 5.4 min (method A)

Example 6

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- [4- (1-methyl-piperidin-4-yl) piperazin-1-yl] -2-oxo-ethyl ester

Analogously to example (1c), 77 (0.14 mmol) of 4- (5-oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) -piperidine-1-carboxylic acid were converted from 77 mg (0.14 mmol). (R) -2- (4-amino-3-chloro-5-trifluoromethylphenyl) -1-carboxy-ethyl ester and 26 mg (0.14 mmol) 1- (1-methyl-piperidin-4-yl) -piperazine das Received product. Yield: 84 mg (84% of theory) ESI-MS: (M + H) ⁺ = 719/721 (Cl)

Retention time (HPLC): 5.0 min (method A)

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

Analogously to example (1c), 77 (0.14 mmol) of 4- (5-oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) -piperidine-1-carboxylic acid were (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester and 25 mg (0.14 mmol) of 1-methyl- [4,4 '] bipiperidinyl give the D product.

Yield: 76 mg (76% of theory)

ESI-MS: (M + H) ⁺ = 718/720 (Cl)

Retention time (HPLC): 6.0 min (method A)

5 Example 8

4- (5-oxo-3-phenyl-4,5-dihydro- [1, 2,4] triazol-1-yl) piperidine-1-carboxylic acid- (R) -1 - (4-amino-S- chloro-δ-trifluoromethyl-benzy ^ -fl ^ 'Jbipiperidinyl-l'-yl ^ -oxo-ethyl ester

Analogously to example (1c), 77 (0.14 mmol) of 4- (5-oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) -piperidine-1-carboxylic acid were converted from 77 mg (0.14 mmol). (R) -2- (4-amino-3-chloro-5-trifluoromethylphenyl) -1-carboxy-ethyl ester and 24 mg (0.14 mmol) [1, 4 '] bipiperidinyl give the product> 5. Yield: 71 mg (73% of theory)

ESI-MS: (M + H) ⁺ = 704/706 (Cl)

Retention time (HPLC): 6.0 min (method A)

5 Example 9

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- [4- (1-aza-bicyclo [2.2.2] oct-3-yl) piperazin-1-yl] -2-oxo-ethyl ester o

[1,2,4] triazoi-1-yl) -piperidine-1-carboxylic acid- (R) -2- (4-amino-3-chloro-5-trifluoromethyl-5 phenyl) -1-carboxy-ethyl ester and 27 mg (0.14 mmol) 3-piperazin-1-yl-1-aza-bicyclo-

[2.2.2] octane received the product.

Yield: 13 mg (13% of theory)

ESI-MS: (M + H) ⁺ = 731/733 (CI)

Retention time (HPLC): 5.6 min (method A) o

The following examples describe the production of pharmaceuticals

Forms of use that are any compound of the general as an active ingredient

Formula (I) contain:

: 5 Example I:

Capsules for powder inhalation with 1 mg of active ingredient

Composition: 1 capsule for powder inhalation contains: Active ingredient 1.0 mg

Milk sugar 20.0 mg

Hard gelatin capsules 50.0 mg

5 71.0 mg

Production method:

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.

Example II:

Inhalation solution for Respimat® with 1 mg of active ingredient 5

Composition:

1 hub includes:

Active ingredient 1.0 mg

Benzalkonium chloride 0.002 mg

; o Disodium edetate 0.0075 mg

Water cleaned ad 15.0 μl

Production method:

! 5 The active ingredient and benzalkonium chloride are dissolved in water and filled into Respimat® cartridges.

Example III

50 inhalation solution for nebulizer with 1 mg of active ingredient

Composition: 1 vial contains: Active ingredient 0.1 g

Sodium chloride 0.18 g

Benzalkonium chloride 0.002 g

Water purified to 20.0 ml

Production method:

Active ingredient, sodium chloride and benzalkonium chloride are dissolved in water.

Example IV:

0

Propellant aerosol with 1 mg of active ingredient

Composition:

1 hub includes:

5 active ingredient 1.0 mg

Lecithin 0.1%

LPG ad 50.0 μl

Production method:

! 0 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.

Example V

! 5 nasal spray with 1 mg of active ingredient

Composition:

Active ingredient 1.0 mg

Sodium chloride 0.9 mg

50 benzalkonium chloride 0.025 mg

Disodium edetate 0.05 mg

Water purified to 0.1 ml Production method:

The active ingredient and excipients are dissolved in water and in a corresponding

Container filled.

5 Example VI:

Solution for injection with 5 mg active substance per 5 ml

Composition: o active substance 5 mg

Glucose 250 mg

Human serum albumin 10 mg

Glykofurol 250 mg

Water for injections ad 5 ml

production:

Dissolve glycofurol and glucose 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.

Example VII:

Solution for injection with 100 mg active substance per 20 ml

! 5 composition:

Active substance 100 mg

Monopotassium dihydrogen phosphate = KH2PO4 12 mg

disodium hydrogen

10 phosphate = Na2HPθ4-2H2θ 2 mg

Sodium chloride 180 mg

Human serum albumin 50 mg

Polysorbate 80 20 mg Water for injections ad 20 ml

production:

Dissolve polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate 5 in water for injections (Wfl); Add human serum albumin; Dissolve the active ingredient while heating; fill up to batch volume with Wfl; fill in ampoules.

Example VIII:

)

Lyophilisate with 10 mg active substance

Composition:

Active substance 10 mg

5 mannitol 300 mg

Human serum albumin 20 mg

production:

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.

Solvent for lyophilisate:

Polysorbate 80 = Tween 80 20 mg

5 mannitol 200 mg

Water for injections ad 10 ml

production:

Dissolve polysorbate 80 and mannitol in water for injections (Wfl); fill in ampoules.

Example IX Tablets with 20 mg of active substance

Composition:

Active substance 20 mg

Lactose 120 mg

Corn starch 40 mg

Magnesium stearate 2 mg

Povidone K 25 18 mg

D Manufacturing:

Mix active substance, lactose and corn starch homogeneously; granulate with an aqueous solution of povidone; mix with magnesium stearate; squeeze on a tablet press; Tablet weight 200 mg.

5 Example X:

Capsules with 20 mg of active substance

Composition: o active substance 20 mg

Corn starch 80 mg

Silica, finely divided 5 mg

Magnesium stearate 2.5 mg

5 Manufacturing:

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:

Suppositories with 50 mg of active substance Composition:

Active substance 50 mg

Hard fat (Adeps solidus) q.s. ad 1700 mg

5 Manufacturing:

Melt hard fat at approx. 38 ° C; Disperse the ground active substance homogeneously in the melted hard fat; After cooling to approx. 35 ° C, pour into pre-cooled molds.

Example XII:

Solution for injection with 10 mg active substance per 1 ml

Composition:

I5 active substance 10 mg

Mannitol 50 mg

Human serum albumin 10 mg water for injections ad 1 ml

10 Manufacturing:

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.

Claims

claims

1. CGRP antagonists of the general formula

in the o A a residue of the formula

5 X is an oxygen atom, a methylene or NH group,

R ^{1 is} a radical of the formula

0 o H ^H oHdΩeΓr and NR R is a radical of the formula

- ^ - N) (N-CH ₃ - rN V - N NH - ^ - NN - NH

I o means

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts.

15 2. The compounds of general formula (I) according to claim 1, which are numbered consecutively in the table of the description with (1) to (2353),

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts. 0

3. The following compounds of general formula (I) according to claim 1:

(1) 4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinoiin-3-yl) piperidine-1-carboxylic acid- (R) - 1 - (4-amino-3- chloro-5-trifluoromethyl-benzyl) -2- [1, 4 '] bipiperidinyl-1' -yl-2-oxo-5 ethyl ester, (2) 4- (2-oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) piperidine-1-carboxylic acid- (R) - 1- (4-amino-3- chloro-5-trifluoromethyl-benzyl) -2- [4- (4-methyl-piperazin-1-yl) - piperidin-1-yl] -2-oxo-ethyl ester,

5 (3) 4- (2-Oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidine-1-carboxylic acid- (R ^ - 1- (4-amino-3 -chloro-5-trifluoromethyl-benzyl) -2- [4- (1-methyl-piperidin-4-yl) - piperazin-1 -yl] -2-oxo-ethyl ester,

(4) 4- (2-Oxo-1,2-dihydro-imidazo [4,5-c] quinolin-3-yl) -piperidin-1-carboxylic acid- (R) - IO 1- (4-amino-3 -chloro-5-trifluoromethyl-benzyl) -2- (1 '-methyl- [4,4'] bipiperidinyl-1-yl) -

2-oxo-ethyl ester,

(5) 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- [4- (4-methyl-piperazin-1-yl) -

15 piperidin-1-yl] -2-oxo-ethyl ester,

(6) 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- [4- (1-methyl-piperidin-4-yl) - piperazin-1-yl] -2-oxo-ethyl ester, 0

(7) 4- (5-Oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) -piperidine-l-carboxylic acid- (R) - 1 - (4-amino -3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-methyl- [4,4'] bipiperidinyl-1-yl) - 2-oxo-ethyl ester, 5 (8) 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, 4 '] bipiperidinyl-1' -yl-2-oxoethyl ester,

(9) 4- (5-Oxo-3-phenyl-4,5-dihydro- [1,2,4] triazol-1-yl) -piperidine-l-carboxylic acid- (R) - 0 1 - (4- amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-aza-bicyclo [2.2.2] oct-3-yl) - piperazin-1-yl] -2-oxo-ethyl ester, their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts.

4. Physiologically acceptable salts of the compounds according to one of claims 1 to 3 with inorganic or organic acids.

5. Medicament containing a compound according to any one of claims 1 to 3 or a physiologically acceptable salt according to claim 4 in addition to optionally one or more inert carriers and / or diluents.

6. Use of a compound according to at least one of claims 1 to 4 for the manufacture of a medicament for the acute and prophylactic treatment of headaches, in particular migraine or cluster headache.

7. Use of a compound according to at least one of claims 1 to 4 for the manufacture of a medicament for combating non-insulin-dependent diabetes mellitus (NIDDM).

8. Use of a compound according to at least one of claims 1 to 4 for the manufacture of a medicament for the treatment of CRPS1 (complex regional pain syndrome), cardiovascular diseases, morphine tolerance, chlostritium toxin-related diarrheal diseases, skin diseases, in particular thermal and radiation-related damage including sunburn, from inflammatory diseases such as, in particular, inflammatory joint diseases such as arthritis, from neurogenic inflammations of the oral mucosa, from inflammatory lung diseases, from allergic rhinitis, from asthma, from diseases which lead to excessive vasodilation and the resultant reduced vascular blood flow, such as especially shock or sepsis, for the relief of pain in general or for preventive or acute therapeutic influence on the symptoms of heat wall caused by vasodilation and increased blood flow menopausal, estrogen-deficient women and hormone-treated prostate cancer patients.

9. A method for producing a medicament according to claim 5, characterized in that a compound according to at least one of claims 1 to 4 is incorporated into one or more inert carriers and / or diluents in a non-chemical way.

10. A process for the preparation of the compounds of general formula (I) according to at least one of claims 1 to 4, characterized in that

(a) for the preparation of compounds of the general formula

in which X represents the oxygen atom or the NH group and A and R to R ^{3 are} as defined in claim 1, a piperidine of the general formula

R ¹

^NH . (III)

in which R ¹ is defined in claim 1,

(i) with a carbonic acid derivative of the general formula

in which G denotes a nucleofugic group, which may be the same or different, with the proviso that X represents the NH group, or

(ii) with a carbonic acid derivative of the general formula

in which G represents a nucleofugic group, which may be the same or different, with the proviso that X represents the oxygen atom,

and with a compound of the general formula

in which X represents the oxygen atom or an -NH group and A, R ² and R ^{3 are} as defined in claim 1, with the proviso that R ² and R ³ contain no further free primary or secondary aliphatic amino function; or

(b) for the preparation of compounds of the general formula

in which X represents the methylene group and A and R ¹ to R ^{3 are} as defined in claim 1, with the proviso that no further free primary or secondary aliphatic amino function contain a carboxylic acid of the general formula

in which A, R ² and R ^{3 are} as defined in claim 1, with a piperidine of the general formula ^"

R

NH (III)

in which R is coupled as defined in claim 1; or

I O (c) for the preparation of compounds of the general formula

in which X represents the methylene group and A, R ² and R ^{3 are} as defined in claim 1, with the proviso that these groups contain no free primary or secondary amine, a compound of the general formula

0 in which A, R ² and R ^{3 are} as defined in claim 1, with the proviso that R ² and R ³ contain no free primary or secondary amine, and Nu is a leaving group, with a piperidine of the general formula R

NH (III)

in which R ¹ is defined in claim 1 is coupled; or

(d) for the preparation of compounds of the general formula

in which A, X and R ¹ to R ^{3 are} as defined in claim 1, a carboxylic acid of the general formula

in which A, X and R ^{1 are} as defined in claim 1, with an amine of the general formula HNR ² R ³ , in which R ² and R ^{3 are} as defined in claim 1, with the proviso that they are no further free primary or contain secondary aliphatic amino function is coupled; or

(e) for the preparation of compounds of the general formula

in which A, X and R ¹ to R ^{3 are} as defined in claim 1, with the proviso that no free primary or secondary amine is present, a compound of the general formula

in which A, X and R ^{1 are} as defined in claim 1 and Nu is a leaving group, with an amine of the general formula HNR ² R ³ , in which R ² and R ^{3 are} as defined in claim 1, with the proviso that no free carboxylic acid and / or no further free primary or secondary aliphatic amino function is contained, is coupled, and

if necessary, a protective residue used in the reactions described above is split off again and / or

any precursor functions used are modified in a connection thus obtained and / or

if desired, a compound of the general formula (I) thus obtained is separated into its stereoisomers and / or

a compound of the general formula (I) thus obtained is converted into its salts, in particular for its pharmaceutical use into its physiologically tolerable salts.