EP1931646A2 - Selected cgrp antagonists, a method for the production thereof and use in the form of drugs - Google Patents

Abstract

The invention relates to CGRP-antagonists of general formula (I), wherein R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>3</SUP>, R<SUP>4</SUP> and R<SUP>5</SUP> are defined in claim 1, to the tautomers, isomers, diastereomers, enantiomers, hydrates, mixtures salts and salt hydrates thereof, in particular to 10 salts thereof, which are physiologically compatible with acids or inorganic or organic bases and to compounds of general formula (I), wherein one or several hydrogen atoms are substituted by deuterium. Drugs containing said compounds, the use thereof and a method for the production thereof are also disclosed.

Description

 SELECTED CGRP-ANT AGONISTS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS DRUGS

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

in which R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in claim 1, their tautomers, their isomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, as well as those compounds of the general formula I in which one or more hydrogen atoms are replaced by deuterium, medicaments containing these compounds, their use and processes for their preparation.

STATE OF THE ART

International patent applications PCT / EP97 / 04862 and PCTVE P04 / 000087 already describe CGRP antagonists for the treatment of migraine.

DETAILED DESCRIPTION OF THE INVENTION

In the above general formula I mean in a first embodiment

R ^{1 is} a group selected from

wherein

H, halogen, HO-, F ₃ C- or C _1-6 -alkyl-O-,

R is a group of the general formulas II

wherein

R ^{1 is} H, halogen, C _1-3 alkyl-O, C _1-3 alkyl or F ₃ C-, R ² - ² H, H ₂ N, HO-, H ₃ CO-, HC (O) -O- or C _1-3 -alkyl-C (O) -O-,

R ² - represents ³ H, halogen, C _1-3 -alkyl- or F ₃ C-,

R ^{3 is} a group of the general formulas III

wherein

X N or C,

R ³ - ¹ H, C _1-3 -alkyl or R ^{3 / M} - (O) C-,

R ³ - ¹ - ¹ HO- or Ci- ₆ -alkyl-O-,

R ^{3 2 is} a lone pair when X = N, or

R ^{3 is 2} H or C _1-3 alkyl when X is C,

R ^{4 is} a group selected from

R ⁵ R ^{5 1} -O-C (O) - and

R ⁵ -, D-β-alkyl, phenyl, pyridyl-C _1-3 alkylene- ¹ H indanyl, HO-C ₂ - ₄ alkylene, C _1-6 alkyl-OC _2-4 -alkylene-, HO-C _2-4 -alkylene-OC _2-4 -alkylene, C _1-6 -alkyl-C _2-4 -alkylene-OC _2-4 -alkylene-, H ₂ NC _2-4 - alkylene, (C _1-6 alkyl) -NH-C _2-4 alkylene, (C _1-6 alkyl) ₂ NC _2-4 alkylene, H ₂ NC (O) -C _1-3 alkylene, (C _1-6 alkyl) -NH-C (O) -C _1-3 alkylene, (C _1-6 alkyl) ₂ NC ( O) -C _1-3 -alkylene, C _1-6 -alkyl-C (O) -OC _1-3 -alkylene, C _1-6 -alkyl-OC (O) -OC _1-3 -alkylene , R ^{5 1} - alkylene- _4, - ¹ -C (O) -C _1-3 alkylene- or -C ₂ R ^5.1.2

»5.1.1 a group selected from

a group selected from

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

A second embodiment of the present invention consists in the compounds of the above general formula I, in which

R ^{1 is} a group selected from

wherein

R ^{1.1 represents} H or H ₃ CO-,

R ^{2 is} a group selected from

R ³ -R ⁴ together form a group selected from

R ⁵ R ^5.1 -OC (O) - and

R ^5.1 is H, C _1-8 alkyl, phenyl, indanyl, pyridyl-C _1-3 -alkylene, HO-C ₂ - ₄ alkylene, C _1-6 alkyl-OC _2-4 - alkylene, HO-C ₂ - ₄ -alkylene-OC ₂ - ₄ -alkylene, C _1-6 -alkyl-C _2-4 -alkylene-OC _2-4 -alkylene, H ₂ NC _2-4 -alkylene -, (C _1-6 -alkyl) -NH-C _2-4 -alkylene, (C _1-6 -alkyl) ₂ NC _2-4 -alkylene, H ₂ NC (O) -C _1-3 - alkylene, (C _1-6 alkyl) -NH-C (O) C _1-3 alkylene, (C _1-6 alkyl) ₂ NC (O) C _1-3 alkylene, C _1-6 -alkyl-C (O) -OC _1-3 -alkylene, C _1-6 -alkyl-OC (O) -OC _1-3 -alkylene, R ^5.1.1 -C (O) -C _1-3 alkylene or

R ^5.1.2 -C _2-4 -alkylene,

R ^{5.1 .1} a group selected from

a group selected from

mean,

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

A third embodiment of the present invention consists in the compounds of the above general formula I, in which

R ^{1 is} a group selected from

a group selected from

R ³ -R ⁴ together form a group selected from

R ⁵ R ^5.1 -OC (O) - and

R ^{5.1 is} H, C _1-6 -alkyl, phenyl, indanyl, pyridyl-CH ₂ -, C _1-3 -alkyl-OC _2-4 -alkylene, C _1-3 -alkyl-OC _2-4 -alkylene-OC _2-4 -alkylene, (C _1-3 -alkyl) ₂ NC ₂ - ₄ -alkylene-, (C _1-3 -alkyl) ₂ NC (O) -C _1-3 -alkylene-, C _1-6 -alkyl-C (O) -OC _1-3 -alkylene, C _1-3 -alkyl-OC (O) -OC _1-3 -alkylene, R ^5.1.1 -C (O) - C _1-3 alkylene- or R ^5.1.2 -C ₂ - ₄ alkylene,

R ^5.1.1 a group selected from

a group selected from

and mean,

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

As very particularly preferred compounds of the above general formula I, for example, the following compounds may be mentioned:

their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases.

USED TERMS AND DEFINITIONS

Unless otherwise indicated, all substituents are independent of each other. If a group, for example more C _1-6 -alkyl groups as substituents, as in the case of three substituents _C1-6 alkyl may independently of one another once methyl, one n-propyl and one tert-butyl. In the context of this application, in the definition of possible substituents, these can also be represented in the form of a structural formula. As used herein, an asterisk ( ^* ) in the structural formula of the substituent is understood to be the point of attachment to the remainder of the molecule.

Also included in the subject matter of this invention are the compounds of the invention, including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.

The term "C _1-3 -alkyl" (including those which are part of other radicals) are to be understood as meaning branched and unbranched alkyl groups having 1 to 3 carbon atoms, branched and unbranched alkyl groups having 1 to 3 by the term "C _1-6 -alkyl" 6 and understood by the term "d-β-alkyl" branched and unbranched alkyl groups having 1 to 8 carbon atoms. Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, terf-butyl, n-pentyl, / so-pentyl, neo-pentyl, hexyl, Heptyl or octyl. Optionally, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups. Unless otherwise stated, the definitions propyl, butyl, pentyl, hexyl, heptyl and octyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and tert-butyl, etc.

The term "C _1-3 -alkylene" (even if they are part of other radicals) are branched and unbranched alkylene groups having 1 to 3 carbon atoms and the term "C ₂ - ₄ -alkylene" branched and unbranched alkylene groups having 2 to 4 Understood carbon atoms. For example: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene. Unless otherwise stated, the definitions propylene and butylene include all conceivable isomeric forms of the same carbon number. For example, propylene also includes 1-methylethylene and butylene includes 1-methyl-propylene, 1, 1-dimethylethylene, 1, 2-dimethylethylene.

It should also be mentioned that in the context of the present invention the terms "alkylene" and "alkylenyl" are used synonymously. "Halogen" in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.

Compounds of general formula I may have acid groups, mainly carboxyl groups, and / or basic groups such as e.g. Amino functions. Compounds of general formula I can therefore be used as internal salts, as salts with pharmaceutically usable inorganic acids such as hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or organic acids such as malic acid, succinic acid, Acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid, citric acid or as salts with pharmaceutically usable bases such as alkali metal or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and the like. available.

The invention relates to the respective compounds optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid

The compounds of the invention may exist as racemates if they possess only one chiral element, but they may also be present as pure enantiomers, i. in (R) or (S) form. Preference is given to compounds which are present as racemates or as (R) -form.

However, the application also includes the individual pairs of diastereomeric antipodes or mixtures thereof which are present when more than one chiral element is present in the Compounds of the general formula I is present, as well as the individual optically active enantiomers, from which the mentioned racemates are composed.

The invention relates to the respective compounds optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example chlorine or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid.

Methods of Preparation

The compounds of general formula I are prepared by methods known in principle. The following processes have proved particularly suitable for the preparation of the compounds of general formula I according to the invention:

(a) For the preparation of compounds of general formula I in which all radicals are defined as mentioned in the introduction:

Coupling of a carboxylic acid of general formula IV

in which R ¹ and R ² are defined as mentioned above, with an amine of the general formula V

HR ³ R ⁴ R ⁵ ,

in which R, R and R are as defined above, wherein the linking takes place via the nitrogen atom of R ³ . Prior to carrying out the reaction, any carboxylic acid functions, primary or secondary amino functions or hydroxyl functions which are protected by customary protecting groups can be protected in the residues of the amine of the formula HR ³ -R ⁴ -R ⁵ and any protective groups used after the reaction has been carried out according to methods familiar to the person skilled in the art be split off again.

The coupling is preferably carried out using methods known from peptide chemistry (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), where, for example, carbodiimides, such as, for example, Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl (3-dimethylamino-propyl) -carbodiimide, O- (1 / - / - benzotriazol-1-yl) - / V, / V- / V, / V tetramethyluronium hexa-fluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP). 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 used with equimolar proportions of the coupling components as well as the coupling reagent in

Solvents such as dichloromethane, Tetra h yd rofu ran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), Λ / -methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 ° C and + 30 ° C, preferably -20 ° C and + 25 ° C, performed. If necessary, als / ethyldiisopropylamine (Hünig base) is preferred as additional auxiliary base.

Another coupling method for the synthesis of compounds of the general formula I is the so-called "anhydride method" (see also: M. Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, pages 58-59, M. Bodanszky, "Principles of Peptide Synthesis ", Springer-Verlag 1984, p 21-27). Preference is given to the "mixed anhydride process" in the variant according to Vaughan (JR Vaughan Jr., J. Amer.Chem.Soc.73, 3547 (1951)) using isobutyl chloroformate in the presence of bases such as 4-methylmorpholine or 4-ethylmorpholine, the mixed anhydride is obtained from the carboxylic acid to be coupled of the general formula V and the carbonic monoisobutyl ester. The preparation of this mixed anhydride and the coupling with the amines of general formula VI is carried out 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. (b) For the preparation of compounds of the general formula I in which all radicals are defined as mentioned in the introduction:

Coupling of a compound of general formula VI

in which R ¹ and R ² are defined as mentioned above and Nu is a leaving group, for example a halogen atom, such as the chlorine, bromine or iodine atom, an alkylsulfonyl oxygruppe having 1 to 10 carbon atoms in the alkyl moiety, optionally by chlorine or bromine atoms, by Methyl- or nitro groups mono-, di- or trisubstituted phenylsulfonyloxy or naphthylsulfonyloxy group, where the substituents may be identical or different, a 1 / - / imidazol-1-yl, optionally substituted by one or two methyl groups in the carbon skeleton 1 H-pyrazol-1-yl, a 1 H-1, 2,4-triazol-1-yl, 1 / - / - 1, 2,3-triazol-1-yl, 1 / - / - 1, 2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a Dimethylaminyloxy, 2 (1 / - /) - oxopyridin-1-yl-oxy, 2,5-dioxopyrrolidine-1-ynyloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group, with an amine the general formula V

HR ³ R ⁴ R ⁵ ,

in which all radicals are defined as mentioned above and wherein the linkage via the nitrogen atom of the amine R ³ takes place.

Before carrying out the reaction, any carboxylic acid functions, primary or secondary amino functions or hydroxyl functions which may be present in the radicals of the general formula V may be protected by conventional protecting groups and any protecting groups used may be cleaved off after the reaction has been carried out by methods familiar to the person skilled in the art. The reaction is under Schotten-Baumann or Einhorn conditions carried out, that is, the components in the presence of at least one equivalent of an auxiliary base at temperatures between -50 ° C and + 120 ° C, preferably from -10 ⁰ C and + 30 ° C, and optionally reacted in the presence of solvents. Preferred auxiliary bases are alkali metal and alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, eg. As sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetate, for example sodium or potassium acetate, and tertiary amines, for example pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, Λ / -Ethyldiisopropylamin, Λ / -Ethyldicyclohexylamin, 1, 4 Di-azabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] undec-7-ene as solvent, for example dichloromethane,

Tetrahydrofuran, 1, 4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, Λ / -methylpyrrolidone or mixtures thereof into consideration; If alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or acetates are used as auxiliary bases, water may also be added to the reaction mixture as cosolvent.

The novel compounds of the general formula I according to the invention contain one or more chiral centers. For example, if there are two chiral centers, then the compounds can be in the form of two diastereomeric antipode pairs. The invention includes the individual isomers as well as their mixtures.

The separation of the respective diastereomers is possible 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.

The separation of racemates covered by the general formula I succeeds, 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 (-) - monomethyl tartrate or (+) - or (-) - camphorsulfonic acid, or an optically active base, for example with (R) - (+) - 1-phenylethylamine, (S) - (-) - 1-phenylethylamine or (S) -brucine. According to a conventional isomer separation process, the racemate of a compound of the general formula I is reacted with one of the abovementioned optically active acids or bases in an equimolar amount in a solvent and the resulting crystalline, diastereomeric, optically active salts are separated by utilizing their different solubilities. This reaction can be carried out in any kind of solvents as long as they have a sufficient difference in the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in the volume ratio 50:50, are used. 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 such as dilute one

Hydrochloric acid or aqueous methanesulfonic acid, carefully neutralized, thereby obtaining the corresponding free compound in the (+) - or (-) - form.

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

The hydroxycarboxylic acids of the general formula V required as starting compounds are obtained by reacting piperidines of the general formula VII

^R1 - ^^, NH

in the R ¹ is defined as mentioned above, with carbonic acid derivatives of the general formula VIII

O γ ²

in which Y ¹ and Y ² denote nucleofuge groups which may be identical or different, preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group,

and with compounds of general formula IX

in which R ² is defined as mentioned above and Z ^{1 represents} a protective group for a carboxy group, for example a Ci_6-alkyl or an optionally substituted benzyl group, wherein the alkyl groups may be linear or branched and the benzyl group by one or two Methoxy groups can be substituted, available. Z ¹ is preferably the methyl, ethyl, tert-butyl or benzyl group. Before carrying out the reaction, any hydroxy functions which may be present in the radical R ^{2 of} a compound of the formula (VI) may be protected by customary protective radicals and any protective radicals used may be cleaved off after the reaction has been carried out by methods familiar to the person skilled in the art.

In a first step, the compounds of the general formula VII are dissolved in a solvent, for example in dichloromethane, THF, pyridine or mixtures thereof, at a temperature between -20 ° C. and 50 ° C. in the presence of a base, for example triethylamine, pyridine or ethyldiisopropylamine, reacted with the carbonic acid derivatives of general formula VIII. The resulting intermediate can be purified or further reacted without purification. The reaction of these intermediates with compounds of general formula IX is also carried out in one of the abovementioned solvents, and at the abovementioned temperatures, in the presence of a base, such as triethylamine or pyridine, with or without the addition of an activating reagent, e.g. 4-dimethylaminopyridine. For activation, the compounds of general formula IX may also be reacted by means of a metal hydride, e.g. NaH or KH be deprotonated, in which case the presence of the base or the activating reagent can be dispensed with.

The starting compounds of the formula VII and VIII are either commercially available, known from the literature or can be prepared by methods known from the literature.

Access to compounds of the general formula IX consists in the reaction of aldehydes of the general formula X.

in which R ² is defined as mentioned above, with Λ / acetylglycine in acetic anhydride as solvent in the presence of alkali metal acetate, preferably sodium or potassium acetate, at a suitable temperature, preferably at 80 to 130 ° C.

The azlactones formed primarily are without isolation to the compounds of the general formula XI

in which R ² is defined as mentioned above, hydrolyzed. By further reaction in the presence of aqueous mineral acids such as sulfuric, phosphoric or hydrochloric acid, but preferably of hydrochloric acid, compounds of general formula XII

in which R j2 is defined as mentioned at the beginning.

These are then reacted with suitable reducing agents in the compounds of general formula XIII

in which R ² is defined as mentioned above, transferred.

As the reducing agent, alkali borohydrides such as sodium or potassium borohydride can be used. Further reducing agents are chlordialkylboranes, such as chlorodicyclohexylborane. Become chiral Chlordialkylborane, such as B-Chlordiisopinocampheylboran used, the compounds of general formula XIII can be isolated in enantiomerically pure form. The further reaction of compounds of general formula XIII to compounds of general formula IX is carried out in an alcoholic medium, preferably in methanol or ethanol, in the presence of a suitable acid, such as hydrochloric acid. Alternatively, the reaction can be carried out by reaction in alcoholic solvents, preferably methanol, with thionyl chloride.

All compounds of the general formula I which contain primary or secondary amino, hydroxy or hydroxycarbonyl functions are preferably obtained from precursors provided with protective groups. Suitable protective groups for amino functions are, for example, a benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-biphenylyl-α, α-dimethylbenzyloxycarbonyl or 3,5-dimethoxy-α, α-dimethylbenzyloxycarbonyl group, an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety, for example the methoxycarbonyl, ethoxycarbonyl , n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl or terf-butyloxycarbonyl group, the allyloxycarbonyl, 2,2,2-trichloro (1, 1 -dimethylethoxy) carbonyl or 9-fluorenylmethoxycarbonyl group or a formyl, acetyl or trifluoroacetyl group.

Suitable protective groups for hydroxy functions are, for example, a trimethylsilyl, triethylsilyl, triisopropyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl group, a tert-butyl, benzyl, 4-methoxybenzyl or 3,4-dimethoxybenzyl group. The protective group for hydroxycarbonyl functions is, for example, an alkyl group having a total of 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, 2,2,2-trichloroethyl -, benzyl or 4-methoxybenzyl group in question.

If they contain suitable basic functions, the compounds of the general formula I obtained can, in particular for pharmaceutical applications, be converted into their physiologically acceptable salts with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, Lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid into consideration.

In addition, the novel compounds of the formula I, if they contain carboxylic acid functions, can be converted into their addition salts with inorganic or organic bases, in particular for the pharmaceutical application, into their physiologically tolerable addition salts. Suitable bases for this purpose, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine into consideration.

The present invention relates to racemates, provided that the compounds of general formula I have only one chiral element. However, the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chiral element is present in the compounds of general formula I, as well as the individual optically active enantiomers which make up the racemates mentioned.

Also included in the subject matter of this invention are the compounds of the invention, including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.

The novel compounds of the general formula I and their physiologically tolerable salts have valuable pharmacological properties which are based on their selective CGRP antagonistic properties. Another object of the invention are these compounds containing drugs, their use and their preparation.

The above-mentioned novel compounds and their physiologically acceptable salts have CGRP-antagonistic properties and show good affinities in

CGRP receptor binding studies. The compounds have CGRP antagonist properties in the pharmacological test systems described below. To demonstrate the affinity of the above-mentioned compounds for human CGRP receptors and their antagonistic properties, the following experiments were carried out:

A. Binding Studies with SK-N-MC Cells Expressing Human CGRP Receptor

SK-N-MC cells are cultured 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), removed by addition of PBS buffer, mixed with 0.02% EDTA, and isolated by centrifugation. After resuspension in 20 ml Balanced Salts Solution [BSS (in mM): NaCl 120, KCl 5.4, NaHCO ₃ 16.2, MgSO ₄ 0.8, NaHPO ₄ 1.0, CaCl ₂ 1.8, D-glucose 5.5, HEPES 30, pH 7.40]. The cells are centrifuged twice at 100 xg and resuspended in BSS. After determining the number of cells, the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000 xg. The supernatant is discarded and the pellet recentrifuged and resuspended in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl ₂ , 1 mM EDTA, pH 7.40) supplemented with 1% bovine serum albumin and 0.1% bacitracin (1 ml / 1000000 cells). The homogenate is frozen at -80 ° C. The membrane preparations are stable under these conditions 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. Incubation is terminated by rapid filtration through polyethyleneimine (0.1%) treated GF / B glass fiber filters using a cell harvester. The protein bound radioactivity is determined using a gamma counter. Non-specific binding is defined as the bound radioactivity after the presence of 1 μM human CGRP-alpha during the incubation.

The analysis of the concentration-binding curves is carried out by means of a computer-aided non-linear curve fitting. The compounds mentioned in the introduction show IC ₅₀ values <1000 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 of 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 addition of CGRP (10 μl) as agonist in increasing concentrations (10 ^-11 to 10 ^-6 M) or additionally of substance in 3 to 4 different concentrations, the mixture is incubated again for 15 minutes.

Intracellular cAMP is then extracted by addition of 20 μl of 1 M HCl and centrifugation (2000 x g, 4 ° C for 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 radioimmunoassay (Amersham) and the pA ₂ values of antagonistic substances are determined graphically.

The compounds of the invention show in the process described in i / rtro test model CGRP-antagonistic properties in a dosage range between 10 ^{~ -12} and 10 ^-5 M.

INDICATIONS

Because of their pharmacological properties, the compounds according to the invention and their salts with physiologically tolerated acids are thus suitable for the acute and prophylactic treatment of headaches, in particular migraine, cluster headache and tension-type headaches. Furthermore, the compounds according to the invention also have a positive influence on the following diseases: non-insulin-dependent diabetes mellitus ("NIDDM"), cardiovascular diseases, morphine tolerance, Clostridium toxin-induced diarrheal diseases, skin disorders, in particular thermal and radiation-related skin damage including sunburn, skin, prurigo, pruriginous toxidermias as well as severe itching, inflammatory Diseases such as inflammatory joint diseases (osteoarthritis, rheumatoid arthritis, neurogenic arthritis), generalized soft tissue rheumatism (fibromyalgia), neurogenic inflammations of the oral mucosa, inflammatory lung disease, allergic rhinitis, asthma, COPD, diseases that are associated with excessive vasodilation and consequent reduced tissue perfusion , eg shock and sepsis, chronic pain disorders such as diabetic neuropathies, chemotherapy-induced neuropathies, HIV-induced neuropathies, postherpetic neuropathies due to tissue trauma-induced neuropathies, trigeminal neuralgia, temporomandibular dysfunctions, complex regional pain syndrome (CRPS), back pain, and visceral diseases , such as irritable bowel syndrome (IBS), inflammatory bowel syndrome. In addition, the compounds according to the invention have a soothing effect on pain conditions in general. The symptoms of menopausal, caused by vasodilation and increased blood flow hot flushes of estrogen-deficient women and hormone-treated prostate carcinoma patients and castrates is influenced by the CGRP antagonists of the present application preventively and acutely therapeutically favored, this therapy approach is characterized by hormone substitution by side effects.

The compounds according to the invention are preferably suitable for the acute and prophylactic treatment of migraine and cluster headache, for the treatment of irritable bowel syndrome (IBS) and for the preventive and acute therapeutic treatment of hot flushes of estrogen-deficient women.

The dosage required to achieve a corresponding effect is expediently when administered intravenously or subcutaneously from 0.0001 to 3 mg / kg

Body weight, preferably 0.01 to 1 mg / kg body weight, and by oral, nasal or inhalative administration 0.01 to 10 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight, in each case 1 to 3 times a day.

If treatment with CGRP antagonists or / and CGRP release inhibitors is made in addition to conventional hormone replacement, it is recommended that the dosages given above be reduced, with the dosage then being 1/5 of the above lower limits up to 1/1 of the above may be upper limits. Another object of the invention is the use of the compounds of the invention as valuable tools for generating and purifying (affinity chromatography) of antibodies and, after appropriate 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 and analytical tools in neurotransmitter research.

COMBINATIONS

Possible combinations of agents include antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine H1 receptor antagonists, β-blockers, α-agonists and α-antagonists, ergot alkaloids, weak analgesics, non-steroidal anti-inflammatory drugs, corticosteroids, calcium Antagonists, 5-HT _{1B /} i _D agonists or other antimigraine agents, which together with one or more inert customary carriers and / or diluents, for example corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, Water / ethanol, water / - glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable mixtures, in common pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, solutions, metered-dose aerosols or suppositories can be incorporated.

For the abovementioned combinations, the non-steroidal anti-inflammatory drugs aceclofenac, acemetacin, acetylsalicylic acid, acetaminophen (paracetamol), azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid are thus used as further active substances , Naproxen, phenylbutazone, piroxicam, sulfasalazine, zomepirac or their pharmaceutically acceptable salts, as well as meloxicam and other selective COX2 inhibitors, such as rofecoxib, valdecoxib, parecoxib, etoricoxib and celecoxib, as well as substances containing earlier or later steps in the prostaglandin Inhibit synthesis or prostaglandin receptor antagonists such as EP2 receptor antagonists and I P receptor antagonists. Furthermore, ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isomethepten, pizotifen, botox, gabapentin, pregabalin, duloxetine, topiramate, riboflavin, montelukast, lisinopril, micardis, prochlorperazine, dexamethasone, Flunarizine, dextropropoxyphene,

Meperidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenytoin, valproate, amitryptiline, imipramine, venlafaxine, lidocaine or diltiazem and other 5-HT _{1B / D} i agonists such as almotriptan, eletriptan, frovatriptan, Naratriptan, rizatriptan, sumatriptan and zolmitriptan are used.

In addition, CGRP antagonists with vanilloid receptor antagonists, e.g. VR-1 antagonists, glutamate receptor antagonists, e.g. mGlu5 receptor antagonists, inGlui receptor antagonists, iGluδ receptor antagonists, AMPA receptor antagonists, purine receptor blockers, such as e.g. P2X3 antagonists, NO synthase inhibitors, e.g. iNOS inhibitors, calcium channel blockers, e.g. PQ-type blockers, N-type blockers, potassium channel openers, e.g. KCNQ channel openers, sodium channel blockers, e.g. PN3 channel blockers, NMDA receptor antagonists, acid-sensing ion channel antagonists, e.g. ASIC3 antagonists, bradykinin receptor antagonists such as e.g. Bi receptor antagonists, cannabinoid receptors agonists, such as e.g. CB2 agonists, CB1 agonists, somatostatin receptor agonists, e.g. sst2 receptor agonists are given.

The dose for these active substances is expediently 1/5 of the usually recommended lowest dosage up to 1/1 of the normally recommended dosage, so for example 20 to 100 mg sumatriptan.

PRESENTATIONS

The compounds according to the invention may be administered either alone or optionally in combination with other active substances for the treatment of migraine intravenously, subcutaneously, intramuscularly, intraarticularly, intrarectally, intranasally, by inhalation, topically, transdermally or orally, in particular aerosol formulations being suitable for inhalation. The combinations may be administered either simultaneously or sequentially. Suitable application forms are, for example, tablets, capsules, solutions, juices, emulsions or inhalable powders or aerosols. In this case, the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50 wt .-% of the total composition, ie in amounts which are sufficient to achieve the above-mentioned dosage range.

Oral administration may be in the form of a tablet, as a powder, as a powder in a capsule (e.g., hard gelatin capsule), as a solution or suspension. In the case of an inhalative administration, the active substance combination can be carried out as a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.

Therefore, pharmaceutical formulations are preferably characterized by the content of one or more compounds of the formula I according to the above preferred embodiments.

It is particularly preferred if the compounds of the formula I are administered orally, it is particularly preferred if the administration takes place once or twice daily. Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or means for obtaining the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Similarly, the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used. Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, for example flavorings, such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

The capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules. Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.

As adjuvants there may be mentioned, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), oils of vegetable origin (e.g., peanut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerin), carriers such as e.g. ground natural minerals (eg kaolins, clays, talc, chalk) synthetic minerals (eg fumed silica and silicates), sugars (eg pipe, milk and dextrose) emulsifiers (eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg Magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

In the case of oral administration, the tablets may, of course, besides the abovementioned excipients also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes. It is likewise preferred if the compounds of the formula I are administered by inhalation, it is particularly preferred if the administration takes place once or twice daily. For this purpose, the compounds of the formula I must be provided in inhalable dosage forms. Suitable inhalable dosage forms are inhalable powders, propellant-containing metered-dose inhalers or propellant-free inhalable solutions which, if appropriate, are present in admixture with conventional physiologically compatible excipients.

In the context of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions. The administration forms which can be used in the context of the present invention will be described in detail in the following part of the description.

Inhalation powders If the compounds of the formula I are mixed with physiologically acceptable

The following physiologically acceptable excipients can be used to prepare the inhalable powders according to the invention: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and polysaccharides (eg dextrans), polyalcohols (eg sorbitol, Mannitol, XyNt), salts (eg sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Preferably, mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. Lactose, most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention. Process for the preparation of the inhalable powders according to the invention by grinding and

Micronization as well as final mixing of the ingredients are known in the art.

Propellant-containing inhalation aerosols The propellant-containing aerosols which can be used in the context of the use according to the invention

Inhalation aerosols may be dissolved in propellant gas or in dispersed form. The propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons. Hydrogens such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The abovementioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The propellant-containing inhalation aerosols which can be used in the context of the use according to the invention may also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusting agents. All of these ingredients are known in the art.

LPG-free inhalation solutions

The use according to the invention of compounds of the formula I is preferably carried out for the preparation of propellant-free inhalable solutions and inhalable suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic

Solutions into consideration. The solvent may be water only or it may be a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids. To adjust this pH, acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferable. Optionally, mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorings, antioxidants or

Have complexing agents, such as citric acid or ascorbic acid. Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH. Cosolvents and / or further auxiliaries can be added to the propellant-free inhalable solutions which can be used in the context of the inventive use. Preferred cosolvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. By auxiliaries and additives is meant in this context any pharmacologically acceptable substance which is not an active ingredient but which can be formulated together with the active ingredient (s) in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy. The auxiliaries and additives include, for example, surfactants, such as soybean lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or preservatives, the

Ensure or prolong the duration of use of the finished drug formulation, flavorings, vitamins and / or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonants. The preferred excipients include antioxidants, such as ascorbic acid, if not already for the

Adjusting the pH used, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins found in the human organism. Preservatives may be used to protect the formulation from contamination by germs. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.

For the above-described forms of treatment, ready-to-use packs of a medicament for the treatment of respiratory disorders, including an enclosed description containing, for example, the words respiratory disease, COPD or asthma, a pteridine and one or more combination partners selected from the group described above, are provided. EXPERIMENTAL PART

As a rule, IR, H-NMR and / or mass spectra are available for the compounds prepared. Unless otherwise indicated, R _r values are calculated using

DC precast plates Kieselgel 60 F254 (E. Merck, Darmstadt, Article No. 1.05714) without

Chamber saturation determined.

The ratios indicated for the flow agents relate to volume units of the respective solvents. The indicated volume units at NH ₃ refer to a concentrated solution of NH ₃ in water.

Unless otherwise stated, the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the indicated

Concentrations.

For chromatographic purifications, silica gel from Millipore (MATREX ™, 35-70 μm) is used.

The indicated HPLC data are measured under the following parameters:

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

Method B:

Analytical column: Zorbax column (Agilent Technologies), SB (stable bond) C18; 3.5 μm; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 1.6 ml_ / min; Injection volume: 5 μl_; Detection at 254 nm

Method C:

Analytical column: Zorbax column (Agilent Technologies), SB (stable bond) C18; 3.5 μm; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 1.6 ml_ / min; Injection volume: 5 μl_; Detection at 254 nm

Method D:

Analytical column: Symmetry C8 Waters - 4.6 X 150 mm; 5 micron, flow: 1.3 ml / min, column temperature: 25 ° C, detection at 254 nm. Preparative HPLC purifications generally use the same gradients used in the collection of analytical HPLC data. The collection of products is mass-controlled, the product-containing fractions are combined and freeze-dried.

If further information on the configuration is missing, it remains unclear whether they are pure enantiomers or whether partial or even complete racemization has occurred.

The test descriptions use the following abbreviations:

Cyc cyclohexane

DCM dichloromethane

DIPE diisopropyl ether

DMF Λ /, Λ / -dimethylformamide

EtOAc ethyl acetate

EtOH ethanol

AcOH acetic acid i.vac. in vacuo (in vacuum)

MeOH methanol

MTBE terf-butyl methyl ether

NaOAc sodium acetate

RT room temperature

TBTU O- (Benzotriazol-1-yl) - / V, / V, / V, / V-tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

Module A1

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1 ^■ carboxy-2- (3-ethyl-4 -hydroxy-5-methyl-phenyl) -ethyl ester

A1 a) 2-ethyl-6-methyl-phenol

To a solution of 30 g (222 mmol) of 2-ethyl-6-methyl-aniline in 135 ml of EtOH was added 19.4 mL (0.23 mmol) concentrated HCl and a solution of 16.1 g (0.23 mmol) sodium nitrite in water at 0 ° C ( about 70 mL) was added and stirred for 15 min. This mixture was added at 45 ° C to a solution of 10.5 mL of concentrated H ₂ SO ₄ in 300 mL of water and heated to 70 ° C at the end of the addition. The aqueous phase was cooled to rt and exhaustively extracted with EtOAc. The combined organic phases were extracted with 1 M NaOH solution. The aqueous phase was washed with DCM, acidified to pH 1 with 4N HCl solution and extracted with DCM. The organic phase was washed with saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated i.vac. concentrated. The crude product was used without further purification in the subsequent reaction step. Yield: 12.0 g (40% of theory)

A1 b) 4-bromo-2-ethyl-6-methylphenol

To a solution of 33.6 g (247 mmol) of 2-ethyl-6-methyl-phenol in 350 ml of chloroform was added dropwise at RT a solution of 12.7 ml (247 mmol) of bromine in 10 ml of chloroform and the mixture was stirred for 2 h. The reaction mixture was washed with an aqueous

NaHSO ₃ solution and stirred for 20 min. The phases were separated and the organic phase washed with saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated i. Vac. concentrated. Column chromatography (silica gel, Cyc / EtOAc 9: 1) gave the product.

Yield: 39.8 g (75% of theory)

ESI-MS: (M + H) ⁺ = 214/216 (Br)

Retention time (HPLC-MS): 6.3 min (method D)

A1 c) 2-Benzyloxy-5-bromo-1-ethyl-3-methyl-benzene

A suspension of 39.8 g (185 mmol) of 4-bromo-2-ethyl-6-methylphenol, 63.9 g (0.46 mmol) of K ₂ CO ₃ and 22.0 mL (185 mmol) of benzyl bromide in 450 mL of acetonitrile was refluxed for 3 h heated, cooled to RT and i.vac. concentrated. The residue was treated with EtOAc, the organic phase washed with water and saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated i. Vac. concentrated.

Yield: 54.5 g (96% of theory)

ESI-MS: (M + H) ⁺ = 304/306 (Br)

Retention time (HPLC-MS): 9.4 min (method D) A1 d) (Z, E) -2-acetylamino-3- (4-benzyloxy-3-ethyl-5-methyl-phenyl) -acrylic acid methyl ester

Prepared analogously to Example 1 b from 50.4 g (165.1 mmol) of 2-benzyloxy-5-bromo-1-ethyl-3-methylbenzene and 28.9 g (198.2 mmol) of 2-acetylamino-acrylic acid methyl ester. Yield: 41.0 g (68% of theory)

ESI-MS: (M + H) ⁺ = 368

Retention time (HPLC-MS): 4.5 min (method C)

A1 e) 3- (4-Benzyloxy-3-ethyl-5-methylphenyl) -2-oxo-propionic acid

To a solution of 41.0 g (11 1.6 mmol) of (Z, E) -2-acetylamino-3- (4-benzyloxy-3-ethyl-5-methyl-phenyl) -acrylic acid methyl ester in 300 mL of 1,4-dioxane was added 200 4 M HCl and the reaction solution heated to 130 ° C (bath temperature) for 7 h. The organic phase was separated hot, i.vac. concentrated and the residue obtained from toluene recrystallized.

Yield: 9.6 g (28% of theory)

ESI-MS: (M + H) ⁺ = 312

Retention time (HPLC-MS): 4.1 min (method C)

Alf) (R) -3- (4-Benzyloxy-3-ethyl-5-methylphenyl) -2-hydroxypropionic acid

Under an argon atmosphere, a solution of 9.59 g (30.7 mmol) of 3- (4-benzyloxy-3-ethyl-5-methylphenyl) -2-oxo-propionic acid in 25 ml of THF was admixed with 4.26 ml (31.0 mmol) of triethylamine. Stirred for 5 min and cooled to -30 ° C (internal temperature). A solution of 19.7 g (61.0 mmol) of (IR) -β-chlorodiisopinocampheylborane in 35 ml was added dropwise and the reaction solution was stirred for 30 minutes without cooling after the end of the addition. It was mixed with 15 mL 4N NaOH (temperature rise to 20 ° C), stirred for 5 min, cooled to 0 ° C, treated with 50 mL MTBE and stirred for 20 min. The organic phase was separated and dried over Na ₂ SO ₄ . After removal of the drying and solvent, the residue was further reacted without purification. Yield: 10.3 g (100% of theory)

ESI-MS: (MH) ^" = 313

Retention time (HPLC-MS): 4.2 min (method C)

A1g) (R) -3- (4-Benzyloxy-3-ethyl-5-methylphenyl) -2-hydroxypropionic acid methyl ester Prepared analogously to Example 1 e from 10.3 g (30.7 mmol) of (R) -3- (4-benzyloxy-3-ethyl-5-methyl-phenyl) -2-hydroxy-propionic acid and 4.71 ml_ (64.5 mmol) of thionyl chloride. The crude product obtained was further reacted without purification.

A1 h) 4- (2-oxo-1,2,4,5,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2-

(4-benzyloxy-3-ethyl-5-methylphenyl) -1-methoxycarbonyl ethyl ester To a solution of 75 ml of pyridine heated to 60 ° C. (bath temperature), a solution of 7.12 g (34.3 mmol) of 4 was added over the course of 10 minutes -Nitrophenyl chloroformate in 30 mL THF was added, stirred for 10 min and then added dropwise a solution of 10.0 g of the crude product of Example A1g in 50 mL pyridine. The mixture was stirred for a further 1 hour, treated with 6.72 g (27.4 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and the bath temperature was raised to 100 ° C. ( 2 h). The resulting precipitate was filtered, the filtrate i.vac. The residue is combined with 150 mL EtOAc, the organic phase is washed twice with 50 mL each time of 1 M KHSC 2 solution and 10 times with 50 mL 15% K ₂ CO ₃ solution each time and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue was purified by chromatography (silica gel, EtOAc / Cyc 2: 1). Yield: 2.28 g (14% of theory)

ESI-MS: (M + H) ⁺ = 600

Retention time (HPLC-MS): 5.4 min (method C)

Al i) 4- (2-oxo-1,2,4,5,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2-

(4-benzyloxy-3-ethyl-5-methyl-phenyl) -1-carboxy-ethyl ester

To a solution of 800 mg (1.33 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-benzyloxy-3-ethyl-5-methyl-phenyl) -1-methoxycarbonyl-ethyl ester in 15 mL THF was added a solution of 50 mg (2.09 mmol) LiOH in 5 mL water and the reaction mixture at RT for 1 h touched. It was concentrated i.vac, the residue was taken up in 50 mL of water and treated with 2 M HCl until the acid reaction. The precipitate was filtered off, washed with water and dried. Further purification was carried out by boiling with 150 ml of water, filtration and renewed drying.

Yield: quantitative

ESI-MS: (M + H) ⁺ = 586

Retention time (HPLC-MS): 4.8 min (method C) A1k) 4- (2-Oxo-1,2,4,5,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -1 ^■ carboxy-2- (3 ethyl-4-Hydroxy-5-methyl-phenyl) -ethyl ester

810 mg (1.38 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-benzyloxy 3-ethyl-5-methyl-phenyl) -1-carboxy-ethyl ester in 25 ml of MeOH were admixed with 80 mg of 10% Pd / C and hydrogenated at RT and 3 bar of hydrogen until the reaction was stopped. The catalyst was filtered off with suction and the solvent i.vac. concentrated. The residue was triturated with DIPE, filtered off with suction and dried. Yield: 639 mg (93% of theory)

ESI-MS: (M + H) ⁺ = 496 retention time (HPLC-MS): 3.7 min (Method C)

Module A2

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1-carboxy-2- (4-hydroxy-3 methoxy-5-methyl-phenyl) -ethyl ester

A2a) 4-bromo-2-methoxy-6-methyl-phenol

To a solution of 42.3 g (0.31 mol) of 2-methoxy-6-methyl-phenol in 450 mL of AcOH was added dropwise within 5.5 h a solution of 56.2 g (0.32 mol) Λ / -Bromosomuccinimid in 1700 mL of AcOH and the mixture 16 Stirred at RT. The reaction mixture was i.vac. concentrated and the residue taken up in DCM. The organic phase was washed with 5% NaHCO ₃ and saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated i.vac. concentrated. The red oil was used without further purification in the subsequent reaction step.

Yield: 65.9 g (66% of theory)

R _f = 0.32 (silica gel, hexane / EtOAc 4: 1)

Retention time (HPLC-MS): 1 1.1 min (method D)

A2b) 2-Benzyloxy-5-bromo-1-methoxy-3-methylbenzene To a solution of 65.9 g (0.26 mol) of 4-bromo-2-methoxy-6-methyl-phenol in 330 mL of DMF at RT 45.7 g (0.33 mol) K ₂ CO ₃ and a solution of 40.3 mL (0.33 mol) Benzyl bromide was added and the mixture stirred for 18 h at RT. The mixture was filtered, i.vac. concentrated and the residue taken up in diethyl ether. The organic phase was washed with water, 5% Na ₂ CO ₃ and NaCl solution, dried over Na ₂ SO ₄ and concentrated i.vac. concentrated. The crude product was used without further purification in the subsequent reaction step. Yield: 92.2 g (81% of theory)

R _f = 0.56 (silica gel, hexane / EtOAc 4: 1) retention time (HPLC-MS): 16.3 min (method D)

A2c) 4-benzyloxy-3-methoxy-5-methylbenzaldehvd

To a solution of 61.2 g (1 19.5 mmol) 2-benzyloxy-5-bromo-1-methoxy-3-methylbenzene in 240 mL THF at -75 ° C 96 mL (240 mmol) n-butyllithium (2.5 M in hexane) and the mixture stirred at -75 ° C for 15 min. A solution of 31 mL (402 mmol) of DMF in 30 mL of THF was added dropwise, the mixture warmed to 0 ° C and stirred for a further 2 h. The reaction was treated with saturated NH ₄ Cl solution, diluted with 150 mL of water and the phases were separated. The aqueous phase was exhaustively extracted with diethyl ether. The combined organic phases were washed with saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated i.vac. concentrated. Column chromatography (silica gel, hexane / EtOAc 85:15) gave the product as a yellow oil. Yield: 27.1 g (88% of theory)

R _f = 0.32 (silica gel, hexane / EtOAc 4: 1)

Retention time (HPLC-MS): 13.3 min (method D)

A2d) 2-Acetylamino-3- (4-benzyloxy-3-methoxy-5-methyl-phenyl) -acrylic acid A suspension of 27.0 g (105.4 mmol) of 4-benzyloxy-3-methoxy-5-methylbenzaldehyde, 18.5 g (158.0 mmol) of N-acetylglycine and 12.96 g (158.0 mmol) of NaOAc in 120 mL of acetic anhydride was heated to 1 15 ° C under nitrogen for 3.5 h. At 100 ° C., 60 ml of water were slowly added dropwise and the mixture was stirred for 1 h. The reaction mixture was cooled to RT, poured into water, and the aqueous phase exhaustively extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated i. Vac. concentrated. The residue became triturated with isopropanol, the resulting solid washed with isopropanol, diethyl ether and a little acetone and i.vac. dried at 45 ° C. Yield: 21.2 (57% of theory)

R _f = 0.24 (silica gel, hexane / EtOAc 4: 1) retention time (HPLC-MS): 9.4 min (method D)

A2e) 3- (4-Benzyloxy-3-methoxy-5-methylphenyl) -2-oxo-propionic acid The product was prepared analogously to Example 1c starting from 20.0 g (56.3 mmol) of 2-acetylamino-3- ( 4-benzyloxy-3-methoxy-5-methyl-phenyl) -acrylic acid. The crude product was used without further purification in the subsequent reaction step. Yield: 15.6 g (53% of theory)

Retention time (HPLC-MS): 1 1.9 min (method D)

A2f) (R) -3- (4-Benzyloxy-3-methoxy-5-methylphenyl) -2-hydroxypropionic acid The product was prepared analogously to Example 1 d starting from 16.0 g (50.90 mmol) 3- (4- Benzyloxy-3-methoxy-5-methylphenyl) -2-oxo-propionic acid. Yield: 7.63 g (47% of theory)

Retention time (HPLC-MS): 9.8 min (method D)

A2g) methyl (R) -3- (4-benzyloxy-3-methoxy-5-methylphenyl) -2-hydroxypropionate

The product was prepared analogously to Example 1 e starting from 7.6 g (24.02 mmol) of (R) -3- (4-benzyloxy-3-methoxy-5-methylphenyl) -2-hydroxypropionic acid. Yield: 6.84 g (86% of theory) retention time (HPLC-MS): 1 1.7 min (method D)

A2h) 4- (2-oxo-1,2,4,5,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2-

(4-benzyloxy-3-methoxy-5-methylphenyl) -1-methoxycarbonyl ethyl ester The product was prepared analogously to Example 1f starting from 6.8 g (20.6 mmol) of (R) -3- (4-benzyloxy-3-methoxy 5-methylphenyl) -2-hydroxypropionic acid methyl ester in acetonitrile.

Yield: 8.16 g (66% of theory)

ESI-MS: (M + H) ⁺ = 602

Retention time (HPLC-MS): 14.1 min (method D) A2i) 4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-benzyloxy-3-methoxy -5-methyl-phenyl) -1-carboxy-ethyl ester

The product was analogously to Example 1g starting from 8.16 g (13.65 mmol) of 4- (2-oxo-1, 2,4,5-tetrahydro-1, 3-benzdiazepin-3-yl) piperidine-1-carboxylic acid ( R) -2- (4-benzyloxy-3-methoxy-5-methylphenyl) -1-methoxycarbonyl ethyl ester.

Yield: 7.83 g (98% of theory)

ESI-MS: (M + H) ⁺ = 588

Retention time (HPLC-MS): 12.2 min (method D)

A2k) 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1-carboxy-2- (4-hydroxypropyl) -3-methoxy-5-methyl-phenyl) -ethyl ester

The product was reacted analogously to Example 1 h starting from 7.80 g (13.27 mmol) of 4- (2-oxo

1, 2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-benzyloxy-3-methoxy-5-methylphenyl) -1 -carboxy-ethyl ester.

Yield: 5.33 g (80% of theory)

ESI-MS: (M + H) ⁺ = 498

Retention time (HPLC-MS): 8.4 min (method D)

example 1

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- [4- (4-ethoxycarbonyl-phenyl) piperazin-1-yl] -1- (4-hydroxy-3,5-dimethyl-benzyl) -2-oxo-ethyl ester

1 a) 2-Benzyloxy-5-bromo-1,3-dimethylbenzene

To a solution of 50.0 g (249 mmol) of 2,6-dimethyl-4-bromophenol in 500 ml of DMF was added 39.9 g (286 mmol) of K ₂ CO ₃ and stirred for 20 min. Then 34.0 mL (286 mmol) of benzyl chloride were slowly added dropwise and the reaction mixture for 3 h at 100 ° C bath temperature. After completion of the reaction was poured onto 500 ml_ of water and extracted exhaustively with EtOAc. The organic phases were combined, dried over Na ₂ SO ₄ and concentrated i.vac. concentrated. Yield: quantitative GC-MS: (M ⁺ ) = 290/292 (Br)

R _f = 0.87 (silica gel, Cyc / EtOAc 3: 1)

1 b) 2-Acetylamino-3- (4-benzyloxy-3,5-dimethyl-phenyl) -acrylic acid methyl ester Under a nitrogen atmosphere, a mixture of 40.0 g (137 mmol) of 2-benzyloxy-5-bromo-1, 3-dimethylbenzene and 24.1 g (165 mmol) of methyl 2-acetylaminoacrylate in 420 ml of triethylamine and 200 ml of acetonitrile were treated with 3.5 g (11.2 mmol) of tri-o-tolylphosphine and 2.5 g (1.1 mmol) of Pd (OAc) ₂ and 18 h stirred at 80 ° C. The precipitate was filtered off with suction, the filtrate i.vac. concentrated and mixed with 800 ml_ DCM and 800 ml_ water. The organic phase was separated, filtered off with suction through Na ₂ SO ₄ , the solvent i.vac. removed, the residue stirred with EtOAc, filtered off with suction and i. vac dried.

Yield: 31.1 g (64% of theory)

ESI-MS: (M + H) ⁺ = 354

Retention time (HPLC-MS): 8.6 min (method A)

1 c) 3- (4-Benzyloxy-3,5-dimethylphenyl) -2-oxo-propionic acid

31.1 g (88.1 mmol) of methyl 2-acetylamino-3- (4-benzyloxy-3,5-dimethylphenyl) acrylate in 150 ml of 1,4-dioxane were admixed with 125 ml of 4 M HCl, 7 h under reflux and stirred overnight at RT. The precipitate was filtered off, washed with water and dried at 45 ° C in a vacuum oven. Yield: 14.3 g (54% of theory)

EI-MS: (M) ⁺ = 298

Retention time (HPLC-MS): 9.0 min (Method A)

1 d) (R) -3- (4-Benzoyl-3,5-dimethylphenyl) -2-hydroxypropionic acid

Under a nitrogen atmosphere, a solution of 14.3 g (47.8 mmol) of 3- (4-benzyloxy-3,5-dimethyl-phenyl) -2-oxo-propionic acid and 8.3 mL (59.8 mmol) of triethylamine in 170 mL of THF at - 35 ° C with a solution of 22.1 (69.0 mmol) (IR) -ß-Chlordiisopino- campheylborane in 70 mL THF within 30 min. After the end of the addition the cold bath was removed and the reaction solution was stirred at RT overnight. The reaction mixture was made alkaline at 0 ° C with 70 ml_ 1 M NaOH, mixed with 100 mL MTBE, stirred for 15 min and the phases were separated. The organic phase was washed with 50 ml of water and three times with 50 ml of 1 M NaOH each time. The combined aqueous phases were washed with half-conc. HCl, extracted exhaustively with EtOAc and dried the combined organic phases over Na ₂ SO ₄ . After removal of the drying and solvent, the residue was further reacted without purification.

Yield: 14.0 g (98% of theory) ESI-MS: (MH) ^" = 299

Retention time (HPLC-MS): 7.9 min (Method A)

1 e) (R) -3- (4-Benzyloxy-3,5-dimethylphenyl) -2-hydroxypropionic acid methyl ester

To a cooled to 0 ° C solution of 14.0 g (23.3 mmol) of (R) -3- (4-benzoyl-3,5-dimethyl-phenyl) -2-hydroxy-propionic acid in 150 mL MeOH was added dropwise 2.0 mL (27.4 mmol) SOCb was added and the reaction mixture stirred for 1 h at RT. The

Reaction solution was i. vac. concentrated and the residue chromatographically

(Silica gel, Cyc / EtOAc 3: 1).

Yield: 5.7 g (78% of theory) ESI-MS: (M + NH ₄ ) ⁺ = 332

Retention time (HPLC-MS): 9.1 min (Method A)

1f) 4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-benzyloxy-3,5 -dimethyl-phenyl) -1-methoxycarbonyl-ethyl ester Under a nitrogen atmosphere, 1.93 g (9.58 mmol) of 4-nitrophenyl chloroformate were added to a solution of 1.17 g (9.58 mmol) of 4-dimethylaminopyridine in 50 ml of pyridine, 1.5 h at RT stirred, with 3.0 g (9.58 mmol) of (R) -3- (4-benzyloxy-3,5-dimethyl-phenyl) -2-hydroxy-propionic acid methyl ester and stirred for 20 min at RT. Subsequently, 2.35 g (9.58 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added and the mixture was stirred at RT for 20 h. The reaction mixture was i. vac. the residue was taken up in EtOAc, the organic phase was washed with 10% KHSO ₄ and saturated NaHCO ₃ solution and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue was purified by chromatography (silica gel, gradient Cyc / EtOAc 1: 1 to 1: 2). Yield: 3.21 g (57% of theory)

ESI-MS: (M + H) ⁺ = 586

Retention time (HPLC-MS): 10.4 min (Method A)

1g) 4- (2-oxo-1,2,5,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2-

(4-benzyloxy-3,5-dimethyl-phenyl) -1-carboxy-ethyl ester

A solution of 3.21 g (5.48 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- ( 4-benzyloxy-3,5-dimethyl-phenyl) -1-methoxycarbonyl ethyl ester in 80 ml of THF was treated with a solution of 200 mg (8.35 mmol) of LiOH in 40 ml of water and stirred at RT for 1 h. The reaction mixture was i. vac. concentrated, the residue taken up in 100 mL of water, acidified with 2 M HCl, the precipitate was filtered off and dried in a vacuum oven at 40 ° C. Yield: quantitative

ESI-MS: (M + H) ⁺ = 572 retention time (HPLC-MS): 9.2 min (Method A)

1 h) 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-hydroxypropyl-3, 5-dimethyl-phenyl) -1-carboxy-ethyl ester

3.72 g (6.51 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4 -benzyloxy-3,5-dimethyl-phenyl) -1-carboxy-ethyl ester in 50 mL DCM were mixed with 300 mg of 10% Pd / C and at RT and 3 bar hydrogen until

Reaction stop shaken. The catalyst was filtered off with suction and the solvent i.vac. concentrated. The residue was triturated with DIPE and filtered with suction.

Yield: 2.41 g (77% of theory) ESI-MS: (M + H) ⁺ = 482

Retention time (HPLC-MS): 7.0 min (method A)

1 i) 4- (2-Oxo-1, 2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- [4- (4-ethoxycarbonyl -phenyl) -piperazin-1-yl1-1- (4-hydroxy-3,5-dimethyl-benzyl) -2-oxo-ethyl ester

A solution of 200 mg (0.42 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- ( 4-hydroxy-3,5-dimethyl-phenyl) -1-carboxy-ethyl ester, 148 mg (0.46 mmol) of TBTU and 65 μL (0.46 mmol) of triethylamine in 2 mL of DMF was stirred at RT for 10 min. Then the addition of 108 mg (0.46 mmol) of 4-piperazin-1-yl-benzo acid ethyl ester and the reaction solution was stirred for 2 h. The reaction solution was purified by HPLC without further work-up; the fractions containing the product were combined and lyophilized. Yield: 216 mg (75% of theory) ESI-MS: (M + H) ⁺ = 698

Retention time (HPLC-MS): 4.4 min (method B)

Example 1.1

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- [4- (4-carboxy-phenyl) piperazin-1-yl] -1- (4-hydroxy-3,5-dimethyl-benzyl) -2-oxo-ethyl ester

To a solution of 50 mg (0.07 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2- [4- (4-ethoxycarbonyl-phenyl) -piperazin-1-yl] -1- (4-hydroxy-3,5-dimethyl-benzyl) -2-oxo-ethyl ester in 2 mL THF was added a solution of 2.6 mg ( 0.11 mmol) LiOH in 1 mL of water and the reaction mixture shaken overnight. To complete the reaction, 6.5 μL (0.08 mmol, 35% in

Water) H ₂ O ₂ and shaken for a further 4 h at RT. One narrowed i.vac. The residue was taken up in water and acidified with formic acid. The resulting

Precipitate was filtered off with suction and dried.

Yield: 37 mg (77% of theory)

ESI-MS: (M + H) ⁺ = 670

Retention time (HPLC-MS): 4.0 min (method B)

Example 2

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1- (4-amino-3-chloro-5 -trifluoromethyl-benzyl) -2- [4- (4-ethoxycarbonyl-phenyl) -piperazin-1-yl] -2-oxo-ethyl ester

2a) (Z, E) -2-Acetylamino-3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -acrylic acid To a suspension of 50.0 g (224 mmol) of 4-amino-3-chloro-5 trifluoromethylbenzaldehyde and 27.5 g (335 mmol) NaOAc in 202 mL acetic anhydride were 39.7 g (335 mmol)

Λ / -Acetylglycine and the reaction mixture heated to 1 15 ° C for 1 h. After cooling to 80 ° C 100 ml_ water were added dropwise, the temperature of the mixture was maintained at 80 ° C. The suspension was reheated to 95 ° C. for 40 minutes and then added to a mixture of 250 ml of toluene and 500 ml of water. The suspension was stirred at RT, the precipitate was filtered off with suction and dried at 60 ° C in a convection oven.

Yield: 48.8 g (68% of theory) ESI-MS: (M + H) ⁺ = 321/323 (Cl)

R _f = 0.37 (silica gel, DCM / MeOH / AcOH 90: 10: 1)

2b) 3- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-oxo-propionic acid A suspension of 97.0 g (300 mmol) of (Z, E) -2-acetylamino-3- (4-amino 3-chloro-5-trifluoromethyl-phenyl) -acrylic acid in 900 ml of 1,4-dioxane and 1050 ml of 4 M HCl was heated to 100 ° C. for 8 hours. I.vac was concentrated to ca. 600 ml, cooled to RT, the precipitated substance was filtered off, washed twice with 100 ml of water each time and dried at 50.degree. The residue was taken up in 850 ml of toluene, heated to reflux and then cooled in an ice bath. The resulting precipitate was filtered, washed with PE and dried in a convection oven at 50 ° C. Yield: 63.0 g (74% of theory) ESI-MS: (MH) ^" = 280/282 (CI)

R _f = 0.21 (silica gel, DCM / MeOH / NH ₃ 80: 20: 2)

2c) (/?) - 3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-hydroxypropionic acid To a solution of 63.0 g (224 mmol) of 3-cooled to about -30 ° C. (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-oxo-propionic acid and 31.2 ml (224 mmol) triethylamine in 300 ml THF was added dropwise to a solution of 100.0 g (312 mmol) of (IR) -B-chlorodiisopinocampheylborane in 150 ml of THF and the reaction mixture kept at this temperature for 1.5 h and then warmed to RT over a further hour. To the reaction mixture was added 80 mL 4 M NaOH, stirred for 5 min, cooled to 0 ° C, treated with 300 mL MTBE, stirred again for 20 min at this temperature and then the phases were separated. The organic phase was exhaustively extracted with water, the combined aqueous phases acidified with 4 M HCl, exhaustively extracted with MTBE and the combined organic phases dried over Na ₂ SO ₄ . The THF / MTBE / NaOH phase was acidified with 4 M HCl, the phases separated and the organic phase i.vac. concentrated. Both residues were combined and further reacted without purification. R _f = 0.20 (silica gel, DCM / MeOH / NH ₃ 80: 20: 2)

2d) (/?) - 3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-hydroxypropionic acid methyl ester

The crude product from Example 2c (62 g) was dissolved in 300 ml of MeOH and 3.65 ml (50 mmol) of SOCl _{2 were} slowly added dropwise to this solution. The reaction mixture was stirred at RT for a further 3 h, then i.vac. concentrated, the residue taken up in DCM and filtered through silica gel. The solution was i.vac. concentrated and the residue purified by chromatography (silica gel, DCM / MeOH / NH ₃ 80: 20: 2). The fractions containing the product were combined, i.vac. concentrated, the residue mixed with PE, filtered off with suction and dried. Yield: 43.1 g (65% of the theory over 2 steps) ESI-MS: (M + H) ⁺ = 298/300 (Cl) R _f = 0.86 (silica gel, DCM / MeOH / NH ₃ 80: 20: 2)

2e) 4- (2-Oxo-1,2,4,5,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2-

(4-amino-3-chloro-5-trifluoromethylphenyl) -1-methoxycarbonyl ethyl ester Under a nitrogen atmosphere, a solution of 13.5 g (65.0 mmol) was added to 100 ml of pyridine at 60 ° C. (bath temperature) over the course of 10 min. Chloroformic acid 4-nitrophenyl ester in 40 mL THF added, stirred for 10 min, then a solution of 18.0 g (60.5 mmol) of (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2 Methylhydroxy-propionate in 50 ml of pyridine and the reaction mixture kept at this temperature for 1.5 h. The addition of 15.9 g (65.0 mmol) of 3-piperidine-4 was then carried out in portions. yl-1, 3,4,5-tetrahydro-1,3-benzodiazepin-2-one. The temperature of the reaction mixture was raised to 100 ° C, this held for 6 h at this temperature and then stirred at RT overnight. One narrowed i.vac. , the residue was taken up in 200 ml of EtOAc, the organic phase was washed twice with 100 ml of 1 M KHSO ₄ solution, 10 times each with 50 ml of 15% K ₂ CO ₃ solution and dried over Na ₂ SO ₄ . To

Removal of the dry and solvent, the residue was reacted further without purification.

Yield: 33.1 g (96% of theory) ESI-MS: (M + H) ⁺ = 569/571 (Cl) R _f = 0.72 (silica gel, DCM / Cyc / MeOH / NH ₃ 70: 15: 15: 2)

2f) 4- (2-Oxo-1,2,5,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2-

(4-Amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester To a solution of 33.0 g (58.0 mmol) of 4- (2-oxo-1, 2,4,5-tetrahydro-1, 3-benzdiazepin-3-yl) -piperidine-1-carboxylic acid (/?) - 2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-methoxycarbonyl-ethyl ester in 200 mL of THF a solution of 2.11 g (88.0 mmol) of LiOH in 100 ml of water was added and the reaction solution was stirred at RT for 3.5 h. THF was i.vac. The aqueous residue was washed twice with MTBE, acidified with 2 M HCl, extracted exhaustively with DCM and the combined organic phases were dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue was dissolved at 65 ° C. in 80 ml of isopropanol and slowly cooled to RT overnight. The suspension was cooled in an ice bath, filtered off with suction, washed with a little isopropanol and DIPE and dried. Yield: 26.2 g (81% of theory) ESI-MS: (M + H) ⁺ = 555/557 (Cl)

R _f = 0.18 (silica gel, DCM / Cyc / MeOH / NH ₃ 70: 15: 15: 2)

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

2g) 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1- (4-amino-3-chloro -5-trifluoromethyl-benzyl) -2- [4- (4-ethoxycarbonyl-phenyl) -piperazine

1 -yli-2-oxo-ethyl ester

A solution of 200 mg (0.36 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- ( 4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester, 128 mg (0.40 mmol) TBTU and 56 μL (0.40 mmol) triethylamine in 2 mL DMF stirred at RT for 10 min. Then, 94 mg (0.40 mmol) of ethyl 4-piperazin-1-yl-benzoate were added and the reaction solution was stirred for 2 hours. The reaction solution was purified by HPLC without further work-up; the fractions containing the product were combined and lyophilized. Yield: 265 mg (95% of theory)

ESI-MS: (M + H) ⁺ = 771/773 (CI)

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

The following examples describe the preparation of pharmaceutical application forms which contain as active ingredient any compound of the general formula I:

Example I

Capsules for powder inhalation with 1 mg of active ingredient

Composition: 1 capsule for powder inhalation contains: active ingredient 1.0 mg lactose 20.0 mg

Hard gelatine capsules 50.0 mg

71.0 mg

Method of preparation: The active substance is ground to the particle size required for inhalation. The ground active substance is mixed homogeneously with the milk sugar. The mixture is filled into hard gelatin capsules.

Example Il

Inhalation solution for Respimat ^® with 1 mg active substance

Composition: 1 stroke contains: Active ingredient 1.0 mg

Benzalkonium chloride 0.002 mg

Disodium edetate 0.0075 mg

Water purified ad 15.0 μl

Production method:

The active substance and benzalkonium chloride are dissolved in water and dissolved in Respimat ^® -

Bottled cartridges.

Example IM

Inhalation solution for nebulizers containing 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 ad 20.0 ml

Method of Preparation:

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

Example IV

Propellant metered dose inhaler with 1 mg active substance

Composition:

1 stroke contains: active substance 1.0 mg

Lecithin 0.1%

Propellant ad 50.0 μl

Method of Preparation: The micronized drug is homogeneously suspended in the mixture of lecithin and propellant. The suspension is filled into a pressure vessel with metering valve.

Example V

Nasal spray with 1 mg of active ingredient

Composition:

Active ingredient 1.0 mg

Sodium chloride 0.9 mg

Benzalkonium chloride 0.025 mg

Disodium edetate 0.05 mg

Water cleaned ad 0.1 ml

Production method:

The active ingredient and the excipients are dissolved in water and filled into a corresponding container.

Example VI

Injection solution with 5 mg active substance per 5 ml

Composition:

Active substance 5 mg

Glucose 250 mg

Human serum albumin 10 mg

Glykofurol 250 mg

Water for injections ad 5 ml

production:

Glykofurol and glucose in water for injection dissolve (WfI); Add human serum albumin; Dissolve active ingredient with heating; fill with WfI on batch volume; Fill into ampoules under nitrogen fumigation. Example VII

Injection solution with 100 mg active substance per 20 ml

Composition:

Active substance 100 mg

Monopotassium dihydrogenphosphate = KH ₂ PO ₄ 12 mg

Disodium hydrogen phosphate = Na ₂ HPO ₄ ^* 2H ₂ O 2 mg

Sodium chloride 180 mg Human serum albumin 50 mg

Polysorbate 80 20 mg

Water for injections ad 10 ml

Preparation: Dissolve polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate in water for injections (WfI); Add human serum albumin; Dissolve active ingredient with heating; fill with WfI on batch volume; fill in ampoules.

Example VIII

Lyophilisate with 10 mg active substance

Composition: Active substance 10 mg

Mannitol 300 mg

Human serum albumin 20 mg

Water for injections ad 2 ml

production:

Dissolve mannitol in water for injections (WfI); Add human serum albumin; Dissolve active ingredient with heating; fill with WfI on batch volume; to fill in vials; freeze-dry. Solvent for lyophilisate: Polysorbate 80 = Tween 80 20 mg

Mannitol 200 mg

Water for injections ad 10 ml

production:

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

Example IX

Tablets containing 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

production:

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

Example X

Capsules with 20 mg active substance

Composition:

Active substance 20 mg

Corn starch 80 mg

Silica, highly dispersed 5 mg

Magnesium stearate 2.5 mg production:

Mix active substance, corn starch and silica homogeneously; mix with magnesium stearate; Fill the mixture on a capsule filling machine into size 3 hard gelatin capsules.

Example Xl

Suppository with 50 mg active substance

Composition:

Active substance 50 mg

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

production:

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

Example XII

Injection solution with 10 mg active substance per 1 ml_

Composition:

Active substance 10 mg Mannitol 50 mg

Human serum albumin 10 mg

Water for injections ad 1 ml

Preparation: Dissolve mannitol in water for injection (WfI); Add human serum albumin; Dissolve active ingredient with heating; fill with WfI on batch volume; Fill into ampoules under nitrogen fumigation.

Claims

1. CGRP antagonists of the general formula I. in the R ^{1 is} a group selected from and wherein H, halogen, HO-, F ₃ C- or C _1-6 -alkyl-O-, a group of general formulas wherein H, halogen, C _1-3 -alkyl-O-, C _1-3 -alkyl- or F ₃ C-, H, H ₂ N, HO, H ₃ CO, HC (O) -O- or C _1-3 -alkyl-C (O) -O-, H is halogen, C _1-3 -alkyl or F ₃ C-, a group of general formulas wherein N or C, H, C _1-3 alkyl or R ^a - ^{1 1} - (O) C-, HO- or d _-6- alkyl-O-, R ^{3.2 is} a lone pair when X = N, or R ^{3.2 represents} H or C _1-3 alkyl when X is C, R ^{4 is} a group selected from R ⁵ R ^5.1 -O-C (O) -, R ^5.1 is H, C _1-8 alkyl, phenyl, indanyl, pyridyl-C _1-3 -alkylene, HO-C ₂ - ₄ alkylene, C _1-6 alkyl-OC _2-4 - alkylene, HO-C ₂ - ₄ -alkylene-OC ₂ - ₄ -alkylene, C _1-6 -alkyl-C _2-4 -alkylene-OC _2-4 -alkylene, H ₂ NC _2-4 -alkylene -, (C _1-6 -alkyl) -NH-C _2-4 -alkylene, (C _1-6 -alkyl) ₂ NC _2-4 -alkylene, H ₂ NC (O) -C _1-3 - alkylene, (C _1-6 alkyl) -NH-C (O) -C _1-3 alkylene, (C _1-6 alkyl) ₂ NC (O) C _1-3 alkylene, C _1-6 alkyl C (O) -OC _1-3 alkylene, C _1-6 alkyl OC (O) -OC _1-3 alkylene, R ^5.1.1 -C (O) -C _1-3 alkylene or R ^5.1.2 -C _2-4 alkylene, R ^5.1.1 a group selected from R ^{5.1.2 represents} a group selected from mean, their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases. 2. Compounds of general formula I according to claim 1, in which R ^{1 is} a group selected from wherein Represents H or H ₃ CO-, a group selected from R ³ -R ⁴ together form a group selected from R ⁵ R ^{5 1} -O-C (O) - and R ^5.1 is H, C _1-8 alkyl, phenyl, indanyl, pyridyl-C _1-3 -alkylene, HO-C ₂ - ₄ alkylene, C _1-6 alkyl-OC _2-4 - alkylene, HO-C ₂ - ₄ -alkylene-OC ₂ - ₄ -alkylene, C _1-6 -alkyl-C _2-4 -alkylene-OC _2-4 -alkylene, H ₂ NC _2-4 -alkylene -, (C _1-6 alkyl) -NH-C _2-4 alkylene, (C _1-6 alkyl) ₂ NC _2-4 alkylene, H ₂ NC (O) -C _1-3 alkylene, (C _1-6 alkyl) -NH-C (O) -C _1-3 alkylene, (C _1-6 alkyl) ₂ NC ( O) -C _1-3 -alkylene, C _1-6 -alkyl-C (O) -OC _1-3 -alkylene, C _1-6 -alkyl-OC (O) -OC _1-3 -alkylene , R ^5.1.1 -C (O) -C _1-3 alkylene or R ^5.1.2 -C _2-4 alkylene, R ^5.1.1 a group selected from R represents a group selected from mean, their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases. 3. Compounds of general formula I according to claim 1, in which R ^{1 is} a group selected from and a group selected from R-R together select a group R ⁵ R ^{5 .1} -OC (O) - and R ^5.1 is H, C _1-6 alkyl, phenyl, indanyl, pyridyl-CH ₂ -, C _1-3 alkyl-OC ₂ - ₄ alkylene, C _1-3 alkyl-OC _2-4 (Ci. ₃ alkyl) -alkylene-OC _2-4 -alkylene, ₂ NC _2-4 alkylene, (C _1-3 alkyl) ₂ NC (O) -C _1-3 alkylene-, C _1-6 -alkyl-C (O) -OC _1-3 -alkylene, C _1-3 -alkyl-OC (O) -OC _1-3 -alkylene, R ^5.1.1 -C (O) -C _1-3 alkylene or R ^5.1.2 -C _2-4 alkylene, R ⁵ _{.1 .1} a group selected from R ^{5.1.2 represents} a group selected from mean, their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases. 4. The following compounds of general formula I according to claim 1: their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts, and the hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases. 5. Physiologically acceptable salts of the compounds according to any one of claims 1 to 4 with inorganic or organic acids or bases. 6. Medicament, comprising a compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5, optionally together with one or more inert carriers and / or diluents. 7. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the acute and prophylactic treatment of headache, in particular migraine, cluster headache and tension headache. 8. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for combating non-insulin-dependent diabetes mellitus (NIDDM). 9. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of cardiovascular diseases, morphine tolerance, Chlostridiumtoxin-related diarrheal diseases, skin diseases, especially thermal and radiation-related damage including sunburn, lesions, prurigo, Pruriginous toxidermias and severe itching, of inflammatory diseases, eg inflammatory joint diseases such as osteoarthritis, rheumatoid arthritis or neurogenic arthritis, generalized soft-tissue rheumatism (fibromyalgia), neurogenic inflammations of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma and COPD, diseases resulting in excessive vasodilation and consequent reduced vascular blood flow, in particular shock or sepsis, accompanied by chronic pain disorders such as diabetic neuropathies, chemotherapy-induced neuropathies, HIV-induced neuropathies, postherpetic neuropathies, tissue trauma-induced neuropathies, trigeminal neuralgia, temporomandibular dysfunctions, CRPS, back pain, visceral diseases such as neuropathy. IBS (irritable bowel syndrome) or inflammable bowel syndrome, for the relief of pain in general or for preventive or acute therapeutic influence caused by vasodilation and increased blood flow symptoms of hot flashes of menopausal, estrogen-deficient women and hormone-treated prostate cancer patients and castrates. 10. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS). 1 1. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the preventive and acute therapeutic treatment of hot flashes of estrogen-deficient women. 12. A process for the preparation of a medicament according to claim 6, characterized in that a compound according to at least one of claims 1 to 5 is incorporated into one or more inert carriers and / or diluents in a non-chemical way. 13. A process for the preparation of compounds of general formula I according to any one of claims 1 to 5, characterized in that (a) a carboxylic acid of general formula IV in which R ¹ and R ^{2 are} as defined in claim 1, with an amine of the general formula V HR ³ R ⁴ R ⁵ , in which R ³ , R ⁴ and R ^{5 are} as defined in claim 1, wherein the linking takes place via the nitrogen atom of R ³ and wherein before carrying out the reaction in the residues of the amine of the formula HR ³ -R ⁴ - R ⁵ optionally existing carboxylic acid functions, primary or secondary amino functions or hydroxy functions protected by protecting groups and any protecting groups used after the reaction is split off again, or (b) a compound of general formula VI in which R ¹ and R ^{2 are} as defined in claim 1 and Nu represents a leaving group, with an amine of the general formula V HR ^J 3-R _D ⁴ 4-R _D 5 in which all the radicals are defined as defined in claim 1, wherein the linking via the nitrogen atom of the amine R ³ takes place and wherein before carrying out the reaction in the radicals of the amine of the general formula V optionally present carboxylic acid functions, primary or secondary amino functions or Protected hydroxy functions by protective residues and any protective residues used after the reaction is again split off, wherein the required as starting compounds hydroxycarboxylic acids of the general formula V by reacting piperidines of the general formula VII ^R1 - ^^, NH in which R ^{1 is} as defined in claim 1, with carbonic acid derivatives of the general formula VIII O V ¹ ' ^/ ^ V ^{2 YY} , in which Y ¹ and Y ² denote nucleofuge groups which may be identical or different, and with compounds of general formula IX in which R ^{2 is} as defined in claim 1 and Z ^{1 represents} a protecting group for a carboxy group, can be obtained, wherein before carrying out the reaction in the radical R ^{2 of} a compound of formula VI optionally present by a hydroxy Protected protecting residue and optionally used protection residues are split off again after the reaction, and an access to compounds of the general formula IX in the reaction of aldehydes of the general formula X. in which R ^{2 is} as defined in claim 1, with Λ / acetylglycine in acetic anhydride as solvent in the presence of alkali metal acetate, and the primarily resulting azlactones without isolation to the compounds of general formula XI in which R ^{2 is} as defined in claim 1, are hydrolyzed, and / or if desired, a compound of 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 the pharmaceutical application, into its physiologically tolerated salts.