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Definitions

• the present invention relates to the CGRP antagonists of general formula I.
• R 1 , R 2 , R 3 and R 4 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 exchanged by deuterium, medicaments containing these compounds, their use and processes for their preparation.
• R 1 is a group selected from
• R 2 is a group selected from
• R 3 is a group of the general formula II
• R 3.1 is H, C 1-3 -alkyl or R 3.1.1 -OC (O) -,
• R 3.1.1.1 a group selected from
• R 4 is a group of the general formulas
• YC and R 4.1 is H or d -3 alkyl, or
• R 4.1 represents a lone pair of electrons
• R 4.2 is H, C 1-3 -alkyl or R 4 ⁇ -OC (O) -,
• R 4.2.1.1 a group selected from
• R 4.3 is H, C 1-6 alkyl, H 2 NC 2-4 alkylene, (C 1-3 alkyl) -NH-C 2-4 alkylene, (C 1-3 alkyl) 2 NC 2-4 alkylene, H 2 NC (O) -C 1-3 alkylene, (C 1-3 alkyl) -NH-C (O) -C 1-3 alkylene, (C 1 3- alkyl) 2 NC (O) -C 1-3 alkylene or R 4.3.1 -C 2-4 alkylene,
• R 4.3.1 a group selected from
• R 5.1 is H, C 1-3 -alkyl, R is 5.II -OC (O) -, R is 5.M -OC (O) -C 1-3 -alkylene-NH-,
• R 5 is a group selected from
• R 5.2 H C 1-3 -alkyl, R 5.2.1 -OC (O) -C 1-3 -alkylene-NH-, R 5.2.1 -OC (O) -C 1-3 -alkylene-O -, R 5.2.1 -OC (O) -C 1-3 alkylene, R 5.2.I -OC (O) -C (O) - or
• R 3 1 , R 32 , R 42 , R 51 or R 52 is a radical other than H or d -3 alkyl
• a preferred first embodiment of the present invention consists in the compounds of the above general formula I, in which
• R 1 is a group selected from
• R is a group selected from
• R 3.1 is H, C 1-3 -alkyl- or HO-C (O) -,
• R 4 is a group of the general formulas III
• R 4.1 is H or C 1-3 alkyl, or
• R 4.1 represents a lone pair of electrons
• R 4.2 is H, C 1-3 -alkyl- or HO-C (O) -,
• R 3 1 , R 32 , R 42 , R 51 or R 52 is a radical other than H or d -3 alkyl
• 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
• R is a group selected from
• R 4 is a group of the general formulas III
• R 4.1 represents a lone pair of electrons
• R 4.2 is H, C 1-3 -alkyl- or R 4 ⁇ - (O) C-,
• R -, 4 4-. 2 2-. 1 1 represents HO, C 1-6 alkyl-O-, and
• R 4.3 is H, C 1-6 alkyl, H 2 NC 2-4 alkylene, (C 1-3 alkyl) -NH-C 2-4 alkylene,
• R 4.3.1 a group selected from
• R5 I R M - ⁇ oC (O) -, R 5.1.1 -OC (O) -C 1-3 -alkylene-NH-, R 5.M -OC (O) -C 1-3 -alkylene-O- .
• R is a group selected from
• R 5.2 R 1 -O-CfCO-C 1-3 -alkylene-NH-, R 1 -'-O-CCOJ-C 1-3 -alkylene-O-, R 5.2.1 -OC (O) -C 1 3 -alkylene-, R 5 Z 1 -OC (O) -C (O) - or R 5.2.1 -OC (O) -C 1-3 -alkylene-C (O) -,
• R is a group selected from
• R 1 is a group selected from
• »3 2 is H or C 1-3 alkyl when X is C,
• R 4 is a group of the general formulas
• N and R 4.1 represents a lone pair of electrons
• R 4.2 is H, C 1-3 -alkyl- or HO-C (O) -,
• 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
• R 3.1.1.1 a group selected from
• R 3.2 is H, C 1-3 -alkyl or R 32 ⁇ -OC (O) -,
• R 3.2.1.1 a group selected from
• R 4.1 is H or C 1-3 alkyl
• R 4.2 is H, C 1-3 -alkyl or R 4 ⁇ -OC (O) -,
• R 4.2.1.1 a group selected from
• R 4.3 is H, C 1-6 alkyl, H 2 NC 2-4 alkylene, (C 1-3 alkyl) -NH-C 2-4 alkylene,
• (C 1-3 -alkyl) 2 NC 2-4 -alkylene H 2 NC (O) -C 1-3 -alkylene, (C 1-3 -alkyl) -NH-C (O) -C 1-3 -alkylene-, (C 1-3 -alkyl) 2 NC (O) -C 1-3 -alkylene- or R 4.3.1 -C 2-4 -alkylene,
• r is a group selected from
• R 5 is a group selected from
• R 52.1.1 a group selected from
• R is a group selected from
• R 5.2.1 is a group of the formula
• R 3 1 , R 32 , R 42 , R 51 or R 52 is a radical other than H or C 1-3 alkyl
• a preferred 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
• R 4.1 is H or C 1-3 alkyl
• R 4.2 is H, C 1-3 -alkyl- or HO-C (O) -,
• radicals R 3-1 , R 32 , R 42 , R 51 or R 52 is a radical other than H, H 3 C- or C 1-3 -alkyl-, 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.
• R 1 is a group selected from
• R 2 is a group selected from
• R 3.2 is H or C 1-3 alkyl
• R 4.1 is H or C 1-3 alkyl
• R 4.3 is H, C 1-6 alkyl, H 2 NC 2-4 alkylene, (C 1-3 alkyl) -NH-C 2-4 alkylene, (C 1-3 alkyl) 2 NC 2-4 alkylene, H 2 NC (O) -C 1-3 alkylene, (C 1-3 alkyl) -NH-C (O) -C 1-3 alkylene, (C 1 3- alkyl) 2 NC (O) -C 1-3 alkylene or R 4.3.1 -C 2-4 alkylene,
• R5 .IR M - ⁇ oC (O) -, R 5.1.1 -OC (O) -C 1-3 -alkylene-NH-, R 5.1.1 -OC (O) -C 1-3 -alkylene-O -, R 5.1.1 -OC (O) -C 1-3 alkylene, R 5.II -OC (O) -C (O) - or R 5.1.1 -OC (O) -C 1-3 -alkylene-C (O) -,
• R 5 is a group selected from
• R5 .2 R 5.2.1 .oC (O) -C 1-3 -alkylene-NH-, R 5.2.1 -OC (O) -C 1-3 -alkylene-O-, R 5.2.1 -OC ( O) -C 1-3 -alkylene-, R 5.2.I -OC (O) -C (O) - or R 5.2.1 -OC (O) -C 1-3 -alkylene-C (O) -,
• R 5 is a group selected from
• R 5 . 2 . i . 2 ejne Q ru p pe selected from
• a preferred fourth embodiment of the present invention consists in the compounds of the above general formula I, in which
• R 1 is a group selected from
• R 4.1 is H or C 1-3 alkyl
• R 5 ⁇ HO-C (O) -C 1-3 -alkylene-NH-, HO-C (O) -C 1-3 -alkylene-O-, HO-C (O) -C 1-3 -alkylene -, HO-C (O) -C (O) - or HO-C (O) -C 1-3 -alkylene-C (O) -,
• R 1 is a group selected from
• R 4.3 is H, C 1-6 alkyl, (C 1-3 alkyl) 2 NC 2-4 alkylene, (C 1-3 alkyl) 2 NC (O) C 1-3 alkylene or R 4.3.1 -C 2-4 alkylene-,
• R 4.3.1 a group selected from
• R 5.1.1.1 a group selected from
• R 5.1.1.2 a group selected from
• R is a group selected from
• R is a group of the formula
• R 3 1 , R 32 , R 42 , R 51 or R 52 is a radical other than H, H 3 C- or d -3 -alkyl-, 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.
• R 1 is a group selected from
• R is a group selected from
• R 42 H or H 3 C-, "5.1 HO-C (O) -, HO-C (O) -C 1-3 -alkylene-NH-, HO-C (O) -C 1-3 -alkylene-N (C 1-3 alkyl) -, HO-C (O) -C 1-3 alkylene-O-, HO-C (O) -C 1-3 alkylene, HO-C (O) -C (O) -, HO-C (O) -C (O) -O-, HO-C (O) -C (O) -O-, HO-C (O) -C 1-3 -alkylene-C (O) - or HO-C (O) -C 1-3 -alkylene-C (O) -O-,
• radicals R 3-1 , R 32 , R 42 , R 51 or R 5.2 is a radical other than H, H 3 C- or d -3 -alkyl-,
• R 1 is a group selected from
• R is a group selected from
• R 4.3 is H, C 1-6 alkyl, (C 1-3 alkyl) 2 NC 2-4 alkylene, (C 1-3 alkyl) 2 NC (O) C 1-3 alkylene or R 4.3.1- C 2-4 -alkylene,
• R5 .IR M - ⁇ oC (O) -, R 5.1.1 -OC (O) -C 1-3 -alkylene-NH-, R 5.1.1 -OC (O) -C 1-3 -alkylene-O -, R 5.1.1 -OC (O) -C 1-3 alkylene, R 5.II -OC (O) -C (O) - or R 5.1.1 -OC (O) -C 1-3 -alkylene-C (O) -,
• R5 . 2 R 5.2.1 . O- C (O) -C 1-3 alkylene, R 5 Z 1 -OC (O) -C (O) - or R 5.2.1 -OC (O) -C 1-3 alkylene-C (O ) -,
• a preferred sixth embodiment of the present invention consists in the compounds of the above general formula I in which
• R 1 is a group selected from
• HO-C (O) -C 1-3 -alkylene HO-C (O) -C (O) - or HO-C (O) -C 1-3 -alkylene-C (O) -, l5.2 HO-C (O) -C 1-3 -alkylene, HO-C (O) -C (O) - or HO-C (O) -C 1-3 -alkylene-C (O) - .
• R 1 is a group selected from
• substituents are independent of each other. If, for example, several C 1-6 -alkyl groups as substituents are present in one group, then in the case of three substituents, d -6- alkyl could independently of one another be methyl, once n-propyl and once complete-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.
• 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.
• C 1-3 -AlkVl (even if they are part of other radicals) are branched and unbranched alkyl groups having 1 to 3 carbon atoms, under the term “C 1-6 -AikVl” branched and unbranched alkyl groups with 1 to 6 carbon atoms and by the term “C 1-8 -AikVl” branched and unbranched alkyl groups having 1 to 8 carbon atoms understood.
• Examples include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, tert-butyl, n-pentyl, / so-pentyl, neo-pentyl, hexyl, Heptyl and octyl.
• the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, f-Bu, etc. are also used for the abovementioned groups. Unless otherwise stated, the definitions include propyl, butyl,
• Pentyl, hexyl, heptyl and octyl all conceivable isomeric forms of the respective radicals.
• propyl includes n-propyl and / so-propyl
• butyl includes / so-butyl, sec-butyl and tert-butyl, etc.
• 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.
• propylene and butylene include all conceivable isomeric forms of the same carbon number.
• propylene also includes 1-methylethylene and butylene includes 1-methylpropylene, 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.
• 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,
• 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, succ
• Mandelic acid lactic acid, tartaric acid, citric acid or as salts with pharmaceutically acceptable bases such as alkali or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides or organic amines such as e.g. Diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and the like. available.
• bases such as alkali or alkaline earth metal hydroxides, for example sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides or organic amines such as e.g. 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 Chloric or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycolic or methanesulfonic acid
• pharmacologically acceptable acids - such as acid addition salts with hydrohalic acids - for example Chloric 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.
• the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chirality element is present in the compounds of general formula I, as well as the individual optically active enantiomers which make up the racemates mentioned.
• the 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 Chloric or hydrobromic acid - or organic acids - such as oxalic, fumaric, diglycol or methanesulfonic acid
• 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:
• any carboxylic acid functions, primary or secondary amino functions or hydroxyl functions which may be present in the residues of the amine of the formula HR 3 -R 4 may be protected by customary protective radicals and given if used protective residues are split off again after carrying out the reaction according to methods familiar to the person skilled in the art.
• 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- (1H-benzotriazol-1-yl) -N, NN I N I -tetramethyluronium hexa-fluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used.
• carbodiimides such as, for example, , Dicyclohexylcarbodiimide
• the couplings are usually with equimolar proportions of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 ° C and + 30 ° C, preferably -20 ° C and + 25 ° C performed. If necessary, preference is given to N-ethyldiisopropylamine (Hünig base) as additional auxiliary base.
• solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between -30 ° C and + 30 ° C, preferably -20 ° C and + 25 ° C performed.
• solvents such as dichloromethane,
• the mixed anhydride is obtained from the to be coupled carboxylic acid 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.
• 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 oxy devis 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 1H-imidazol-1-yl, a 1H-pyrazole optionally substituted by one or two methyl groups in the carbon skeleton 1-yl, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1, 2,3,4-tetrazole-1 -yl, a vinyl, propargyl, p-nitrophenyl,
• any carboxylic acid functions, primary or secondary amino functions or hydroxyl functions which may be present in the radicals of the general formula VI can be protected by conventional protective radicals and any protective radicals used after the reaction has been carried out can be cleaved again by methods familiar to the person skilled in the art.
• auxiliary bases are alkali metal and alkaline earth metal hydroxides, for example sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, eg.
• alkali metal acetate for example sodium or potassium acetate
• tertiary amines for example pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyldiisopropylamine, N-ethyldicyclohexylamine, 1, 4-di azabicyclo [2,2,2] octane or 1,8-diazabicyclo [5,4,0] undec-7-ene, as solvents, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or mixtures thereof; If alkali or alkaline-earth hydroxides, alkali metal carbonates or acetates are used as auxiliary bases, water may also be added as co-solvent to the reaction mixture.
• novel compounds of the general formula I according to the invention contain one or more chiral centers. For example, if there are two centers of chirality, then the compounds can occur 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.
• racemates which contain a basic or acidic function can also be resolved 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.
• 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
• the racemate of a compound of general formula I is reacted with one of the abovementioned optically active acids or bases in equimolar amounts in a solvent, and the obtained crystalline, diastereomeric, optically active salts using their different solubility.
• 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.
• methanol, ethanol or mixtures thereof for example in the volume ratio 50:50, are used.
• each of the optically active salts is dissolved in water, carefully neutralized with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, for example, with dilute hydrochloric acid or aqueous methanesulfonic acid, thereby giving the corresponding free compound in the (+) - or ( -) - Form received.
• a base such as sodium carbonate or potassium carbonate
• a suitable acid for example, with dilute hydrochloric acid or aqueous methanesulfonic acid
• hydroxycarboxylic acids of the general formula V required as starting compounds are obtained by reacting piperidines of the general formula VIII
• Y 1 and Y 2 denote nucleofuge groups which may be identical or different, preferably the chlorine atom, the p-nitrophenoxy or trichloromethoxy group,
• R 2 is defined as mentioned above and Z 1 represents a protective group for a carboxy group, for example a d -6- alkyl or an optionally substituted benzyl group, wherein the alkyl groups may be linear or branched and the benzyl group by a or two methoxy groups may be substituted.
• Z 1 preference is given to the methyl, ethyl, tert-butyl or benzyl group.
• the compounds of the general formula VIII are dissolved in a solvent, for example in dichloromethane, THF, pyridine or mixtures thereof, at a temperature between -20.degree. C. to 50.degree. C. in the presence of a base, for example triethylamine, pyridine or ethyldiisopropylamine, reacted with the carbonic acid derivatives of the general formula IX.
• a solvent for example in dichloromethane, THF, pyridine or mixtures thereof, at a temperature between -20.degree. C. to 50.degree. C. in the presence of a base, for example triethylamine, pyridine or ethyldiisopropylamine, reacted with the carbonic acid derivatives of the general formula IX.
• a base for example triethylamine, pyridine or ethyldiisopropylamine
• reaction of these intermediates with compounds of general formula X 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.
• a base such as triethylamine or pyridine
• an activating reagent e.g. 4-dimethylaminopyridine.
• the compounds of general formula X 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.
• a metal hydride e.g. NaH or KH be deprotonated
• the starting compounds of the formula VIII and IX are either commercially available, known from the literature or can be prepared by literature methods.
• N-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.
• alkali borohydrides such as sodium or potassium borohydride can be used.
• Further reducing agents are chlordialkyl boranes, such as chlorodicyclohexyl borane. When chiral chlorodialkyl boranes are used, such as chlorodialkyl boranes.
• B-Chlordiisopinocampheylborane used the compounds of general formula XIV can be isolated in enantiomerically pure form.
• the further reaction of compounds of general formula XIV to compounds of general formula X 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 protective groups with precursors.
• 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- ⁇ , ⁇ -dimethylbenzyloxycarbonyl or 3,5-dimethoxy- ⁇ , ⁇ -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
• Triethylsilyl triisopropyl, fert-butyldimethylsilyl or fert-butyldiphenylsilyl group, a fert-butyl, benzyl, 4-methoxybenzyl or 3,4-dimethoxybenzyl group in question.
• 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.
• the compounds of general formula I can, if they contain suitable basic functions, in particular for pharmaceutical applications in their physiologically acceptable salts with inorganic or organic acids are converted.
• suitable acids are hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, acetic, fumaric, succinic, lactic, mandelic, malic, citric, tartaric and maleic acids.
• novel compounds of the formula I if they contain carboxylic acid function, 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 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.
• the application also includes the individual diastereomeric antipode pairs or mixtures thereof, which are present when more than one chiral element is present in the compounds of general formula I, as well as the individual optically active enantiomers which make up the racemates mentioned.
• the compounds of the invention including their salts, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are exchanged by deuterium.
• 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.
• novel compounds and their physiologically acceptable salts have CG RP antagonistic properties and show good affinities in CGRP receptor binding studies.
• the compounds have CGRP antagonist properties in the pharmacological test systems described below.
• 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.
• BSS Balanced Salts Solution
• the cells are homogenized using an Ultra-Turrax and centrifuged for 10 minutes at 3000 xg. The supernatant is discarded and the pellet 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.
• the homogenate is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40) and homogenized for 30 seconds with an Ultra-Turrax. 230 ⁇ l of the homogenate are incubated for 180 minutes at room temperature with 50 pM 125 l-iodotyrosyl-calcitonin gene-related peptides (Amersham) and increasing concentrations of the test substances in a total volume of 250 ⁇ l. Incubation is terminated by rapid filtration through polyethyleneimine (0.1%) treated GF / B glass fiber filters using a cell harvester.
• assay buffer 50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, pH 7.40
• assay buffer 50 mM Tris, 150 mM NaCl, 5 mM MgCl 2 , 1 mM
• the protein bound radioactivity is determined using a gamma counter. Non-specific binding is defined as the bound radioactivity after the presence of 1 ⁇ M human CGRP-alpha during the incubation.
• the analysis of the concentration-binding curves is carried out by means of a computer-aided nonlinear curve fitting.
• SK-N-MC cells (1 million cells) are washed twice with 250 ⁇ l of incubation buffer (Hanks' HEPES, 1 rtiM 3-isobutyl-i-methylxanthine, 1% BSA, pH 7.4) and at 37 ° C for 15 minutes pre-incubated. After addition of CGRP (10 ⁇ l) 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.
• incubation buffer Hort' HEPES, 1 rtiM 3-isobutyl-i-methylxanthine, 1% BSA, pH 7.4
• Intracellular cAMP is then extracted by addition of 20 ⁇ l 1M 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 described in vitro test model CGRP antagonistic properties in a dose range between 10 ⁇ 12 to 10 ⁇ 5 M.
• the compounds according to the invention and their salts with physiologically tolerated acids are thus suitable for the acute and prophylactic treatment of headaches, in particular migraine, cluster headache and tension-type headaches.
• 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, especially thermal and radiation-related skin damage including sunburn, skin, prurigo, pruriginous toxidermia and severe itching, inflammatory diseases, eg inflammatory joint diseases ( Osteoarthritis, rheumatoid arthritis, neurogenic arthritis), generalized soft-tissue rheumatism (fibromyalgia), neurogenic inflammation of the oral mucosa, inflammatory lung disease, allergic rhinitis, asthma, COPD, diseases associated with excessive vasodilation and consequent reduced tissue perfusion, eg, shock and sepsis
• NIDDM Non-insul
• chronic pain disorders such as diabetic neuropathies, chemotherapy-induced neuropathies, HIV-induced neuropathies, postherpetic neuropathies by tissue trauma-induced neuropathies, trigeminal neural giene, temporomandibular dysfunctions, CRPS (complex regional pain syndrome), back pain, and visceral diseases such as irritable bowel syndrome (IBS), inflammatory bowel syndrome.
• 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 cancer 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.
• IBS irritable bowel syndrome
• the dosage required to achieve a corresponding effect is expediently by intravenous or subcutaneous administration 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, 1 to 3 times daily. If treatment with CGRP antagonists or / and CGRP release inhibitors is made in addition to a conventional hormone replacement, it is recommended to reduce the dosages given above, the dosage then being 1/5 of the lower limits specified above up to 1/1 of the above may be upper limits.
• CGRP is released by sensory nerves, such as the trigeminal nerve, which innervates part of the facial skin. It has already been shown that irritation of trigeminal ganglion in humans leads to an increase in plasma CGRP level and causes flushing ([4]: PJ Goadsby et al., Annais of Neurology, Vol. 23, No. 2, 1988, 193- 196).
• the CGRP antagonists of the invention are also active in a model for visceral pain in rodents.
• hypersensitivity of the visceral system is caused by irritation of the intestine by the instillation of chemicals, e.g. Butyrate, trinitrobenzenesulfonic acid or acetic acid.
• the hypersensitivity of the intestine is e.g. determined by the number of abdominal contractions. These arise after stretching a balloon introduced into the intestine and are elevated in a hypersensitive intestine (Bourdu et al., Gastroenterology 2005, 128, 1996-2008, Diop et al., J. Phamacol., Exp. Ther., 2002, 302, 1013 Plourde et al., Am J. Physiol 1997, 273, G191-G196).
• the CGRP antagonists of the present invention can be used for the treatment of IBS (irritable bowel syndrome).
• 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.
• Possible combinations of agents include antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine H1 receptor antagonists, ⁇ -blockers, ⁇ -agonists and ⁇ -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,
• the non-steroidal anti-inflammatory drugs aceclofenac, acemetacin, acetylsalicylic acid, acetaminophen (paracetamol), azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide, lomoxicam, 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
• 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.
• CGRP antagonists with vanilloid receptor antagonists e.g. VR-1 antagonists, glutamate receptor antagonists, e.g. mGlu5 receptor antagonists, mGlui receptor antagonists, iGlu ⁇ 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. B1 receptor antagonists, cannabinoid receptors, agonists, e.g. CB2 agonists, CB1
• 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.
• the compounds according to the invention can 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, with inhalation in particular aerosol formulations are suitable.
• 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.
• 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, i. in amounts sufficient to achieve the above 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.
• 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.
• compositions are preferably characterized by the
• 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 achieving the depot effect, such as
• Carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate 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.
• the core can also consist of several layers.
• the Drageum cover to achieve a depot effect consist of several layers wherein 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, e.g. 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.
• a sweetening agent such as saccharin, cyclamate, glycerol or sugar
• a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
• 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.
• excipients 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), excipients such as e.g.
• paraffins e.g., petroleum fractions
• oils of vegetable origin e.g., peanut or sesame oil
• mono- or polyfunctional alcohols e.g., ethanol or glycerin
• excipients such as e.g.
• ground natural minerals eg kaolins, clays, talc, chalk
• ground synthetic minerals eg fumed silica and silicates
• sugars eg pipe, milk and dextrose
• emulsifiers eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone
• lubricants eg Magnesium stearate, talc, stearic acid and sodium lauryl sulfate.
• 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 except the above excipients with different respectivelysaufêtem or dyes are added.
• the compounds of the formula I are administered by inhalation, it is particularly preferred if the administration takes place once or twice daily.
• 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 may be present in admixture with customary physiologically compatible excipients.
• 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.
• the following physiologically acceptable excipients can be used to prepare the inhalable powders according to the invention:
• Monosaccharides e.g., glucose or arabinose
• disaccharides e.g., lactose, sucrose, maltose
• oligo- and polysaccharides e.g., dextrans
• polyalcohols e.g., sorbitol, mannitol, xylitol
• salts e.g., sodium chloride, calcium carbonate
• 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 used as an excipient.
• the propellant-containing inhalable aerosols which can be used in the context of the use according to the invention can be dissolved in the 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 halohydrocarbons 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.
• propellant gases are fluorinated alkane derivatives selected from TG 134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,2,3,3,3-heptafluoropropane) and mixtures thereof.
• TG 134a 1,1,1,2-tetrafluoroethane
• TG227 1,2,3,3,3-heptafluoropropane
• propellant-containing inhalation aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as
• Co-solvents stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All of these ingredients are known in the art.
• Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic solutions.
• 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.
• 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.
• organic acids ascorbic acid, fumaric acid and citric acid are preferable.
• mixtures of the abovementioned acids in particular in the case of acids which, in addition to their acidification properties, also possess other properties, for example as flavorings, antioxidants or complexing agents, for example 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.
• auxiliaries and additives is meant in this context any pharmacologically acceptable substance that is not an active ingredient but 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.
• auxiliaries and additives include e.g. surfactants, e.g. Soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, chelating agents, antioxidants and / or preservatives which assure or prolong the useful life of the finished drug formulation, flavoring agents, vitamins and / or others known in the art
• the additives also include pharmacologically acceptable salts such as sodium chloride as isotonants.
• Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, 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.
• R r values are calculated using DC precast plates
• Kieselgel 60 F254 (E. Merck, Darmstadt, Article No. 1.05714) without chamber saturation.
• the Rf values determined under the name Polygram silica gel are determined using ready-to-use Polygram SIL G / UV254 (coated with 0.2 mm
• the Rf values determined under the name Polygram-Alox are determined using Polyglam Alox N / UV254 (finished with 0.2 mm aluminum oxide) DC ready-made foils
• 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.
• the acid, base and salt solutions used in the workup of the reaction solutions are aqueous systems of the indicated
• HPLC data are measured under the following parameters:
• Analytical column Zorbax column (Agilent Technologies), SB (stable bond) - C18; 3.5 ⁇ m; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 1.6 mL / min; Injection volume: 5 ⁇ L; Detection at 254 nm
• Analytical column Zorbax column (Agilent Technologies), SB (stable bond) - C18; 3.5 ⁇ m; 4.6 x 75 mm; Column temperature: 30 ° C; Flow: 0.8 mL / min; Injection volume: 5 ⁇ L; Detection at 254 nm
• 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.
• A4a) 1'-ethoxyoxalyl-r4,4'-bipiperidinyl-1-carboxylic acid-ferf-butyl ester To a cooled to 0 ° C solution of 4.0 g (14.9 mmol) of [4,4 '] Bipiperidinyl-1-carboxylic acid fert butyl ester and 2.15 mL (15.4 mmol) of triethylamine in 80 mL DCM were added dropwise 1.68 mL (15.0 mmol) of chloro-oxo-acetic acid ethyl ester. After completion of the addition, the cooling bath was removed and stirred for 1 h at RT.
• R f 0.5 (polygram-Alox, DCM / MeOH 50: 1)
• To 1.50 g (4.55 mmol) 4- (8-azabicyclo [3.2.1] oct-3-yl) -piperazine-1-carboxylic acid benzyl ester (A12b) in 10 mL DMF was added 1.29 g (9.30 mmol).
• K 2 CO 3 was added, then slowly added dropwise 0.56 mL (5.00 mmol) of ethyl bromoacetate and the reaction mixture stirred for a further 4 h at RT.
• A13a) 4-ferf-butoxycarbonylmethoxy-ri, 4'-piperidinyl-1'-carboxylic acid benzyl ester To a mixture of 2.58 g (11.06 mmol) 4-oxo-piperidine-1-carboxylic acid benzyl ester and 2.80 g (12.36 mmol) (piperidin-4-yloxy ) acetate-butyl acetate in 30 mL THF were added in portions 2.90 g (13.27 mmol) of sodium triacetoxyborohydride and the reaction mixture was stirred overnight at RT.
• 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.
• Triethylamine was added and stirred at RT for 10 min. 2.77 g (18.0 mmol) of piperidin-4-one (used as the hydrate of the hydrochloride salt) were added to the reaction mixture and it was stirred at RT overnight. The reaction solution was poured into 1 L of 7% K 2 CO 3 solution, the precipitated substance was filtered off, washed with water and at
• Example 2.1 4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1- (4-amino-S-chloro-S -trifluoromethylbenzyl ⁇ - ⁇ - ⁇ arboxynnethyl-anninoJ-i ⁇ '- bipiperidinyl-i'-yl] -
• reaction solution was filtered through a syringe filter and the crude product was purified by HPLC. The fractions containing the product were combined and freeze-dried.
• Example 7 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- [1- (2-ethoxycarbonyl-ethyl) -piperidin-4-yl] -piperazin-1-yl ⁇ -2-oxo-ethyl ester
• Triethylamine was added and stirred at RT for 10 min.
• To the reaction mixture was added 54 mg (0.20 mmol) of ethyl JBipiperidinyl-1-yl-oxo-acetic acid ethyl ester (amine A4) and shaken overnight at RT. After filtration through a syringe filter, the reaction solution was purified by HPLC without further work-up. The fractions containing the product were combined and freeze-dried. Yield: 88 mg (61% of theory)

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