EP1940824A1

EP1940824A1 - Selected cgrp antagonists method for production and use thereof as medicament

Info

Publication number: EP1940824A1
Application number: EP06807391A
Authority: EP
Inventors: Stephan Georg Mueller; Klaus Rudolf; Philipp Lustenberger; Gerhard Schaenzle; Dirk Stenkamp; Henri Doods; Kirsten Arndt
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2005-10-21
Filing date: 2006-10-19
Publication date: 2008-07-09
Also published as: TW200800962A; US7625886B2; AR058127A1; CA2626009A1; US20070099903A1; JP2009511621A; DE102005050892A1; WO2007045672A1

Abstract

The invention relates to the CGRP antagonists of general formula (I), where R1, R2, R3 and R4 are as defined in claim 1, the tautomers, isomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof and the hydrates of the salts, in particularly the physiologically-acceptable salts with inorganic or organic acids or bases and any compound of general formula (I), in which one or more hydrogen atoms are exchanged for deuterium, medicaments comprising said compounds the use and methods for production thereof.

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 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.

STATE OF THE ART

International patent applications PCT / EP97 / 04862 and PCT / EP03 / 11762 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

and embedded image in which

Represents H or H ₃ CO-,

R is a group selected from

wherein

Represents H or H ₃ C-,

a group of general formulas II

3.1

-N

-R ⁴

L3.2

wherein

N or C,

H or C _1-3 alkyl,

a lone pair when X = N, or

Is H or Ci _-3 alkyl, when X = C, represents R ^{4 is} phenyl or

R ^{4 is} a group of the general formulas

wherein

C and

, 4.1 H or Ci _-3 alkyl, or

N and

, 4.1 a lone pair of electrons,

with the proviso that X and Y are not N at the same time,

4.2

R ^{4 is} H or C _1-3 alkyl,

4.3

H, Ci- ₆ alkyl, H ₂ NC ₂ - ₄ alkylene, (Ci _-3 alkyl) -NH-C ₂ - ₄ alkylene, (Ci _-3 alkyl) ₂ NC ₂ - ₄ - alkylene, H ₂ NC (O) -C _-3 alkylene, (Ci _-3 alkyl) -NH-C (O) -C _-3 alkylene, (Ci _-3 alkyl) ₂ -NC ( O) -C _-3 alkylene, Ci _-3 alkyl OC (O) -C _-3 -alkylene-O- or R ⁴ - alkylene- ¹ -C ³ _2-4,

R _S 4.3.1 represents a group selected from - A -

R ⁵ - ¹ Ci _-6 alkyl, Ci _-6 alkyl-O-, _Ci-6-alkyl-C (O) -O-, R ^{5 / M} -OC (O) -,

R ⁵ - ¹ - ¹ -OC (O) -C _-3 -alkylene-NH-, R ^{5 / M} -OC (O) -C _-3 -alkylene-O-, R ⁵ - ¹ - ¹ -OC (O ) -Ci- _3- alkylene, R ^{5 / M} -O-C (O) -C (O) - or

R ⁵ - ¹ - ¹ -OC (O) -Ci _-3 -alkylene-C (O) -,

R ⁵ - ¹ - alkylene- ¹ H, d-β-alkyl, phenyl, indanyl, pyridyl-Ci _-3, HO-C ₂ - ₄ alkylene,

Ci _-6 alkyl-OC ₂ - alkylene- _4, H ₂ NC _{_2-4} alkylene, (Ci _-6 alkyl) -NH-C ₂ - ₄ alkylene, (Ci _-6 alkyl) ₂ -NC ₂ - ₄ -alkylene-, H ₂ NC (O) -Ci _-3 -alkylene-,

(Ci _-6 alkyl) -NH-C (O) -C _-3 alkylene, (Ci _-6 alkyl) ₂ -N-C (O) -C _-3 alkylene, _Ci-6-alkyl-C (O) -O-Ci _-3 alkylene, Ci _-6 alkyl-OC (O) -O-Ci _-3 alkylene, R ⁵ - ¹ - ^{1 / l} -C (O) -C _{1- 3} -alkylene- or R ⁵ - ¹ - ¹ - ² -C _2-4 -alkylene-,

p ⁵ . ⁱ . ⁱ . ^I _e _ne group selected

»5.1.1.2 a group selected from

_R5 . ² R ⁵ - ² - ¹ -OC (O) -Ci _-3 -alkylene, R ^{52 1} -O-C (O) -C (O) -, R ⁵ - ^{2 1} -OC (O) -Ci _{- 3} -alkylene-C (O) - or R ⁵ - ^{2 1} -C (O) -,

R ⁵ is - ² - ¹ H, Ci-8-alkyl, phenyl, indanyl, pyridyl-Ci _-3 -alkylene, HO-C ₂ - ₄ alkylene, H ₂ NC _2-4 alkylene, (Ci _-6 alkyl) -NH-C _2-4 alkylene,

(Ci _-6 alkyl) ₂ NC _2-4 alkylene, H ₂ NC (O) -C _-3 alkylene, (C ^ alkyl), -NH-C (O) -C 3 alkylene , (Ci _-6 alkyl) ₂ NC (O) -C _-3 alkylene-, Ci _-6 alkyl-C (O) -O-Ci _-3 alkylene, Ci _-6 alkyl-OC (O) -O-Ci _-3 alkylene-,

j5.2.1.1 a group selected from

a group represents selected

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

Represents H or H ₃ CO-,

R ^{2 is} a group selected from

R) 3 -RR _> 4 together form a group of the general formulas IV

wherein

4.2

H or H ₃ C-,

4.3

H, Ci- ₆ alkyl, H ₂ NC ₂ - ₄ alkylene, (Ci _-3 alkyl) -NH-C ₂ - ₄ alkylene, (Ci _-3 alkyl) ₂ NC ₂ - ₄ - alkylene, H ₂ NC (O) -C _-3 alkylene, (Ci _-3 alkyl) -NH-C (O) -C _-3 alkylene, (Ci _-3 alkyl) ₂ NC (O ) -Ci- _3- alkylene or R ⁴ - ³ - ¹ -C _2-4 -alkylene,

a group represents selected

R ⁵ - ¹ Ci _-3 alkyl, Ci _-3 alkyl-O-, Ci _-3 alkyl-C (O) -O- or R ^{5 / M} -OC (O) -, R ⁵ - ¹ - ¹ -OC (O) -C _-3 -alkylene-NH-, R ^{5 / M} -OC (O) -C _-3 -alkylene-O- or R ⁵ - ¹ - ¹ -OC (O) -C _-3 alkylene-,

Ci _-3 alkyl OC ₂ - ₄ alkylene, (Ci _-3 alkyl) ₂ NC ₂ - ₄ alkylene, (Ci _-3 alkyl) ₂ NC (O) -C _-3 alkylene-, Ci _-3 alkyl-C (O) -O-Ci _-3 alkylene, Ci _-3 alkyl OC (O) -O-Ci _-3 alkylene, R ⁵ - ^{1 / M is} -C (O ) -Ci ₃ -alkylene- or R ⁵ - ¹ - ¹ - ² -C _2-4 -alkylene-,

R ⁵ - ¹ - ¹ - ^{1 is} a group selected from

R is a group selected from

R ^5-2 -C ¹ _-3 -alkyl-C (O) -, R ^5-2 ^{/ 1} -OC (O) -C ₃ -alkylene, R ^{52 1} -O-C (O) -C (O) - or R ⁵ - ^{2 / l} -OC (O) -Ci _-3 -alkylene-C (O) -,

R ⁵ is - ² - ¹ is H, Ci-8-alkyl, phenyl, indanyl, pyridyl-Ci _-3 -alkylene, HO-C _2-4 alkylene-, (Ci _-3 alkyl) ₂ NC _2-4 alkylene, (Ci _-3 alkyl) ₂ NC (O) -C _-3 alkylene, Ci _-3 alkyl-C (O) -O-Ci _-3 alkylene, Ci _-3 alkyl OC (O) -O-Ci _-3 alkylene, R ⁵ - ^{2 1} - ¹ -C (O) -C _-3 alkylene- or R ⁵ - ² - ¹ - ² -C _2-4 -alkylene-,

p ⁵ . ² . ⁱ . ⁱ _e _ne Q _rU pp _e selected

and ₁ 5.2.1.2 represents a group selected from

mean,

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-R together form a group of general formulas IV

wherein

4.2

H or H ₃ C-,

R ⁴ -, Ci- ₆ alkyl, (Ci _-3 alkyl) ₂ NC ₂ H ³ - ₄ alkylene, (Ci _-3 alkyl) ₂ NC (O) -C alkylene- _-3 or R ⁴ - ³ - ¹ -C ₂ - ₄ -alkylene-,

R ^{4-3'1 represents} a group selected from

and

_R5 .IR ⁵ - ¹ - ¹ -OC (O) - or R ⁵ - ^{1 / l} -OC (O) -C _-3 alkylene-,

R ⁵ - ¹ -, Ci- alkylene- H ¹ ₈ alkyl, phenyl, indanyl, pyridyl-Ci _-3, HO-C ₂ - ₄ alkylene, Ci _-6 alkyl-OC ₂ - ₄ alkylene, H ₂ NC _2-4 alkylene, (Ci _-6 alkyl) -NH-C _2-4 alkylene, (Ci _-6 alkyl) ₂ NC _2-4 alkylene, H ₂ NC (O) -C _-3 alkylene, (Ci _-6 alkyl) -NH-C (O) -C alkylene- _-3, (Ci _-6 alkyl) ₂ NC (O) -C _-3 alkylene-, Ci _-6 alkyl-C (O) -O-Ci _-3 alkylene, Ci _-6 alkyl-OC (O) -O-Ci _-3 alkylene-,

R ⁵ - ¹ - ^{1 / l} -C (O) -C _-3 alkylene- or R ⁵ - ¹ - ¹ - alkylene- ² -C _2-4

»5.1.1.1 a group selected from

j5.1.1.2 a group selected from

_R5 . ² R ⁵ - ² - ¹ -OC (O) -Ci _-3 -alkylene, R ^{52 1} -O-C (O) -C (O) - or

R ⁵ - ² - ¹ -OC (O) -Ci _-3 -alkylene-C (O) -,

R ⁵ - ² - ^1H, d-β-alkyl, phenyl, indanyl, pyridyl-Ci _-3 -alkylene, HO-C ₂ - ₄ alkylene, Ci _-6 alkyl-OC ₂ - ₄ alkylene, H ₂ NC ₂ - ₄ alkylene, (Ci _-6 alkyl) -NH-C ₂ - ₄ alkylene, (Ci _-6 alkyl) ₂ NC ₂ - alkylene- _4, H ₂ NC (O) -C _-3 alkylene, (C ^ alkyl), -NH-C (0) -C-3-alkylene, (C ^ alkyl) 2N-C (O) -C-3- alkylene, _Ci-6-alkyl-C (O) -O-Ci _-3 alkylene, Ci ^ alkyl-0-C (0) -0-Ci-3-alkylene,

R ⁵ - ² - ^{1 / l} -C (O) -C _-3 alkylene- or R ⁵ - ² - ¹ - ² C _2-4 alkylene-,

p ⁵ . ² . ⁱ . ⁱ _e _ne Q _rU pp _e selected

p ⁵ . ² . ⁱ . ² _e _ne Q _rU pp _e represents selected

means

A fourth embodiment of the present invention consists in the compounds of the above general formula I in which R ^{1 is} a group

R is a group selected from H ₀

R-R together select a group

R-R together form a group of general formulas IV

wherein

R ⁴ - ³ H, Ci- ₆ alkyl, (H ₃ C) ₂ NC ₂ - ₃ alkylene, (H ₃ C) ₂ NC (O) -Ci _-2 alkylene, Ci _-2 alkyl -OC (O) -O-C ₂ - ₃ alkylene or R ⁴ - ³ - ¹ C ₂ - ₃ alkylene, R ^{4 "3" 1 is} a group selected from

R ⁵ - ¹ H ₃ C-, H ₃ CO-, Ci _-2 alkyl-C (O) -O-, R ^{5 / M} -OC (O) -,

R ⁵ - ¹ -, Ci _-6 alkyl, (H ₃ C) ₂ NC ₂ H ¹ - alkylene- _3, (H ₃ C) ₂ NC (O) -C _-2 alkylene-, Ci _-2 -Alkyl-OC (O) -O-Ci- _2- alkylene or R ⁵ - ^{1 / M-} C _2-3 -alkylene-,

p ⁵ . ⁱ . ⁱ . ⁱ _e _ne Q _rU pp _e selected

and

R ⁵ - ² H ₃ CC (O) -, R ⁵ - ^{2 1} -OC (O) -Ci- _2- alkylene, R ^{52 1} -O-C (O) -C (O) - or R ⁵ - ^{2 1} -OC (O) -Ci- _2- alkylene-C (O) -,

R ⁵ is - ² - ¹ is H, Ci _-6 alkyl, alkylene- (H ₃ C) ₂ NC _2-3, (H ₃ C) ₂ NC (O) -C _-2 alkylene-,

Ci _-2 alkyl-OC (O) -O-Ci _-2 -alkylen- or R ⁵ _-2 ^{/ M} -C _2-3 -alkylen-,

p ⁵ . ² . ⁱ . ⁱ _e _ne Q _rU pp _e d _ars selected

and

means

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

USED TERMS AND DEFINITIONS

Unless otherwise indicated, all substituents are independent of each other. If a group eg several be Ci _-6 alkyl groups as substituents, it might in the case of three substituents Ci _-6 alkyl 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 according to 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 "phenyl" is understood to mean both unsubstituted and mono- or disubstituted phenyl groups. Suitable substituents, which may be identical or different, are fluorine, chlorine or bromine atoms, C ₃ -C ₃ -alkyl, F ₃ C, C 1 -C ₃ -alkyl-O or F ₃ CO groups.

The term "C _1-2 -alkyl" (even if they are part of other radicals) are branched and unbranched alkyl groups having 1 or 2 carbon atoms, by the term "C _1-3 -alkyl" branched and unbranched alkyl groups having 1 to 3 carbon atoms, the term "CI_ ₆ alkyl" refers to branched and unbranched alkyl groups having 1 to 6 carbon atoms and by the term "C _1-8 alkyl" are meant 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, tert-butyl, n-pentyl, / so-pentyl, neo-pentyl or hexyl. If appropriate, the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, tert-Bu, etc. are also used for the abovementioned groups. Unless otherwise specified, the definitions of propyl, butyl, pentyl and hexyl 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.

Branched and unbranched alkylene groups with 1 or 2 carbon atoms, branched and unbranched alkylene groups with 1 to 3 carbon atoms, under the term "d-3-alkylene" by the term "d- _2- alkylene" (even if they are part of other radicals), the term "C ₂ - ₃ alkylene" are meant branched and unbranched alkylene groups with 2 or 3 carbon atoms and by the term "C _{_2-4} -alkylene" are meant branched and unbranched alkylene groups with 2 to 4 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-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,

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.

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 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. 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 V

in which R ¹ and R ² are defined as mentioned above, with an amine of the general formula VI HR ³ -R ⁴

in the R ³ and R ^{4 are} as defined above, wherein the link on the

Nitrogen atom of 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 residues of the amine of the formula HR ³ -R ^{4 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 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). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt), the Reaction rate can be increased. 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), 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 Methylmorpholine or 4-ethylmorpholine, 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.

(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 VII

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 phenyl sulfonyloxy or naphthylsulfonyloxy group, wherein the substituents may be the same or different, a 1 / - / - imidazol-1-yl, a 1 / - / - pyrazol-1-yl, optionally substituted by one or two methyl groups in the carbon skeleton 1 / - / - 1, 2,4-triazol-1-yl, 1 / - / - 1, 2,3-triazol-1-yl, 1 / - / - 1, 2,3,4-tetrazole 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, 1 / - / - benzotriazol-1-yloxy or azide group, with an amine of general formula VI

HR ³ -R ⁴

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 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.

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; 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, 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.

In each case only the [R] or (S) -enantiomer or a mixture of two optically active, diastereomeric compounds covered by the general formula I is also obtained thereby. that one carries out 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 VIII

V- ^{^} NH

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

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 X.

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. For Z ^1, preference is given to 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 general formula VIII in a solvent, for example in dichloromethane, THF, pyridine or mixtures thereof a temperature between -20 ° C to 50 ° C in the presence of a base, for example triethylamine, pyridine or ethyldiisopropylamine, reacted with the carbonic acid derivatives of the general formula IX. The resulting intermediate can be purified or further reacted without purification. The 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 such as 4-dimethylaminopyridine. For activation, the compounds of general formula X can also be deprotonated by means of a metal hydride, such as NaH or KH, in which case the presence of the base or of the activating reagent can be dispensed with.

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

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

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 general formula XII

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 XIII

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

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

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 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-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-butyloxy carbonyl group, the allyloxycarbonyl, 2,2,2-trichloro (1, 1-dimethylethoxy) carbonyl or 9-fluorenylmethoxycarbonyl group or a formyl, acetyl or trifluoroacetyl group in question.

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 tolerated salts with inorganic or organic acids. Examples of suitable acids are hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, acetic, fumaric, succinic, lactic, mandelic, malic, citric, tartaric and maleic acids.

In addition, the 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. 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 new compounds and their physiologically acceptable salts have CGRP antagonistic properties and show good affinities in CGRP receptor binding studies. The compounds have CGRP antagonistic properties in the pharmacological test systems described below.

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 at -80 ° C frozen. 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 adding CGRP (10 μl) as an agonist in increasing

Concentrations (10 ^{~ 11} to 10 ^{~ 6} M) or additionally of substance in 3 to 4 different concentrations are incubated again for 15 minutes.

Intracellular cAMP is then extracted by addition of 20 μl of 1 M HCl and centrifugation (2000 xg, 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-related diarrheal diseases, skin disorders, especially thermal and radiation-related skin damage including sunburn, skin, prurigo, pruriginous toxidermias as well as severe itching, inflammatory diseases, eg inflammatory joint diseases (osteoarthritis, rheumatoid arthritis, neurogenic arthritis), generalized soft tissue rheumatism (fibromyalgia), neurogenic inflammations of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, COPD, diseases associated with excessive vasodilation and concomitant reduced tissue perfusion, eg, shock and sepsis, chronic pain disorders, such as diabetic neuropathies, chemotherapy-induced neuropathies, HIV-induced neur Post-herpetic neuropathies include 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 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.

The dosage required to achieve a corresponding effect is expediently in the case of intravenous or subcutaneous administration of 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, 1 to 3 times daily.

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-i _{B /} i _D agonists or other antimigraine agents, which together with one or more inert customary carriers and / or diluents, for example corn starch, milk sugar, 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 conventional pharmaceutical preparations such as tablets, dragees, capsules , Powders, suspensions, solutions, metered 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,

Isomethioptes, Pizotifen, Botox, Gabapentin, Pregabalin, Duloxetine, Topiramate, Riboflavin, Montelukast, Lisinopril, Micardis, Prochlorperazine, Dexamethasone, Flunarizine, Dextropropoxyphene, Meperidine, Metoprolol, Propranolol, Nadolol, Atenolol, Clonidine, Indoramine, Carbamazepine, Phenytoin, Valproate, Amitriptyline, Imipramine, venlafaxine, lidocaine or diltiazem and other 5-HT _{1B /} _D i agonists such as almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan be used.

In addition, CGRP antagonists may be useful with vanilloid receptor antagonists such as VR-1 antagonists, glutamate receptor antagonists such as mGlu5 receptor antagonists, mGlui receptor antagonists, iGluδ receptor antagonists, AMPA receptor antagonists, purine receptor blockers such as P2X3 Antagonists, NO synthase inhibitors such as iNOS inhibitors, calcium channel blockers such as PQ-type blockers, N-type blockers, potassium channel openers such as KCNQ channel openers, sodium channel blockers such as PN3 Channel blockers, NMDA receptor antagonists, acid-sensing ion channel antagonists such as ASIC3 antagonists, bradykinin receptor antagonists such as B1 receptor antagonists, cannabinoid receptor agonists such as CB2 agonists, CB1 agonists, somatostatin receptor agonists such as 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, 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. 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 auxiliaries, 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. 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. Likewise, 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.

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. AIs are, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), carriers such as natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg finely divided silicic acid 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, of course, the tablets may also contain additives other than those mentioned. Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives 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 may be present in admixture with customary 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 powder

If the compounds of the formula I are present in admixture with physiologically acceptable excipients, the inhalable powders according to the invention can be used to prepare them the following physiologically acceptable excipients are used: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride , Calcium carbonate) or mixtures of these excipients with each other. 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. Methods for producing the inhalable powders according to the invention by grinding and micronizing as well as by final mixing of the constituents are known from the prior art.

Propellant-containing inhalation aerosols

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. 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 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.

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. The solvent can only be water or it is 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, it is also possible to use 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. 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, which ensure or extend the useful life 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. 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.

EXPERIMENTAL PART

As a rule, IR, 1 H-NMR and / or mass spectra are available for the compounds prepared. Unless otherwise noted are the refurbishment of the

Reaction solutions used acidic, base and salt aqueous systems of the indicated concentrations.

Unless otherwise stated, R _r values are determined using GCF Finished Tops Kieselgel 60 F254 (E. Merck, Darmstadt, Article No. 1.05714) with no chamber saturation.

The R _r values determined under the name Polygram are determined using

DC finished films Polygram SIL G / UV ₂₅₄ (coated with 0.2 mm silica gel) from the company

Macherey-Nagel (Düren, Item No. 805 021) levied. 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.

For chromatographic purifications silica gel from Millipore (MATREX ™, 35-

70 μm). For chromatographic purifications, alumina (Alox) from ICN

Biomedicals (Eschwege, article number 02090). According to the manufacturer, the required activity level is generated before use.

The indicated HPLC data are measured under the following parameters: Method A:

Analytical column: Merck Chromolith Speed ROD, RP18e; 4.6 x 50 mm; Column temperature: 30 ° C; Flow: 1.5 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: 0.8 ml_ / min; Injection volume: 5 μl_; 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:

AcOH acetic acid

CDI Λ /, / V-carbonyldiimidazole

Cyc cyclohexane

DCM dichloromethane

DIPE diisopropyl ether

DMF Λ /, Λ / -dimethylformamide

EtOAc ethyl acetate

EtOH ethanol

HCl hydrochloric acid

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

MeOH methanol

PE petroleum ether

RT room temperature

TBME te / t-butyl methyl ether

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

THF tetrahydrofuran example 1

4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2- [4- (4-fluoro-phenyl) -piperazine-1-yl] -1- (4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl) -2-oxo-ethyl ester

1 a) 4-methyl-3 / - / - benzoxazol-2-one

To a solution of 50.0 g (0.39 mol) of 5-amino-m-cresol and 210 ml (1.2 mol) in 1 L

DCM was added dropwise at 0 ° C 76.0 g (0.45 mol) of CDI in 1 L DCM. After completion of the reaction, 250 ml of water were added to the reaction mixture, the organic phase was separated off and washed twice with 250 ml of 1 M KHSO ₄ solution and 250 ml of water each time and dried over MgSO ₄ . After removal of the drying agent and solvent, the residue obtained was dissolved in 200 mL EtOAc, heated under reflux, treated with 100 mL PE, slowly cooled to RT, the resulting precipitate was filtered off with suction and dried.

Yield: 39.2 g (67% of theory)

ESI-MS: (M + H) ⁺ = 150

R _f = 0.65 (silica gel, DCM / Cyc / MeOH / NH 2 70: 15: 15: 2)

1 b) 6-Bromo-4-methyl-3 / - / - benzoxazol-2-one

To a solution of 29.5 g (197.8 mmol) of 4-methyl-3H-benzoxazol-2-one in 200 mL of AcOH was added 35.8 g (199.1 mmol) of Λ / bromosuccinimide and stirred at RT overnight. The reaction solution was admixed with 800 ml of water, stirred at RT for 15 min, the precipitate was filtered off with suction, washed with water and dried at 60 ° C. in a vacuum drying cabinet.

Yield: 43.0 g (95% of theory)

ESI-MS: (M + H) ⁺ = 226/228 (Br)

R _f = 0.35 (silica gel, DCM / Cyc / MeOH / NH 2 70: 15: 15: 2) 1 c) (Z, E) -2-Acetylamino-3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -acrylic acid methyl ester

Under a nitrogen atmosphere, to a solution of 38.3 g (168.0 mmol) of 6-bromo-4-methyl-3 / - / - benzoxazol-2-one and 28.0 g (191.7 mmol) 2-acetylamino-acrylic acid methyl ester in 800 ml_ acetonitrile and 480 ml of triethylamine 5.4 g (23.9 mmol) of Pd (OAc) ₂ and 7.5 g (24.0 mmol) of tri-o-tolyl-phosphane, the reaction mixture stirred for 18 h at 80 ° C and then i.vac. concentrated. The residue was treated with 100 ml of water and 50 ml of EtOAc and the precipitate was filtered off. The crystals were dissolved in MeOH / DCM 1: 1 under reflux, mixed with activated charcoal, filtered off and the filtrate was concentrated to dryness.

Yield: 31.2 g (64% of theory)

ESI-MS: (M + H) ⁺ = 291

R _f = 0.38 (silica gel, DCM / Cyc / MeOH / NH ₃ 70: 15: 15: 2)

1 d) 3- (4-Methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -2-oxo-propionic acid

To a solution of 31.2 g (107.5 mmol) of (Z, E) -2-acetylamino-3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -acrylic acid methyl ester in 320 ml 1, 4-dioxane was added to 160 mL of 4 M HCl and the reaction solution heated under reflux for 5 h. It was concentrated i.vac, filtered off the precipitate, washed with water and dried at 60 ° C in a vacuum oven.

Yield: 24.9 g (98% of theory)

ESI-MS: (M + H) ⁺ = 236

R _f = 0.38 (silica gel, DCM / Cyc / MeOH / NH ₃ 70: 15: 15: 2)

1 e) (Fi) -2-Hydroxy-3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -propionic acid Under a nitrogen atmosphere were added to a cooled to -35 ° C solution of 24.9 g (105.9 mmol) of 3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -2-oxo-propionic acid and 20.0 mL (143.9 mmol) of triethylamine in 400 mL of THF over 15 min a solution of 60.0 g (187.1 mmol) of (IR) -B-chlorodiisopinocampheylborane in 200 ml of THF was added dropwise and the reaction solution was stirred at RT overnight. Subsequently, the reaction solution at 5 ° C was carefully made alkaline with 1 M NaOH, mixed with 400 mL EtOAc and stirred for 15 min. The organic phase was separated, extracted twice with 100 ml of 1 M NaOH and with 100 ml of water. The combined aqueous phases were mixed with concentrated HCl and extracted twice with 150 ml of EtOAc. The combined organic phases were dried over MgSO ₄ and concentrated i.vac. concentrated. Yield: 20.8 g (83% of theory) ESI-MS: (M + H) ⁺ = 238 R _f = 0.10 (silica gel, DCM / Cyc / MeOH / NH ₃ 70: 15: 15: 2)

1f) (R) -2-Hydroxy-3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -propionic acid methyl ester 23.0 g (97.0 mmol) of (R) -2-hydroxy -3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -propionic acid were dissolved in 200 ml methanolic HCl (1.3 M), stirred at RT overnight and then concentrated i.vac. concentrated. The residue was admixed with 200 ml of EtOAc, washed with 15% K ₂ CO ₃ solution and the organic phase was dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue was treated with DIPE, the crystals were filtered off and dried at 50 ° C in a vacuum oven. Yield: 14.6 g (60% of theory) ESI-MS: (M + H) ⁺ = 252

R _f = 0.44 (silica gel, DCM / Cyc / MeOH / NH ₃ 70: 15: 15: 2)

1g) 4- (2-Oxo-1, 2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -1-carboxy-2- (4- methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -ethyl ester

4.1 g (20.1 mmol) of 4-nitrophenyl chloroformate in 20 ml of THF were metered in under nitrogen atmosphere at 60 ° C. bath temperature over 10 minutes to 40 ml of pyridine, stirred for 5 minutes, then 5.0 g (19.9 mmol) of (R) -2- Methyl hydroxy-3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) propionate and 20 ml of pyridine were added and the reaction mixture was stirred at 60 ° C. for 1.5 h. The reaction solution was admixed with 4.9 g (20.0 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and stirred at 100 ° C. for 2 h. After completion of the reaction, 150 ml of EtOAc were added, washed three times with 70 ml of 1 M KHSO ₄ solution and 12 times with 50 ml each of 15% K ₂ CO ₃ solution, and the organic phase was dried over MgSO ₄ . After removal of the drying agent and solvent, the residue was dissolved in 60 ml of THF, combined with 250 mg of LiOH in 10 ml of water and the reaction mixture was stirred at RT for 3 h. One removed i.vac. the THF, added 60 mL of TBME to the aqueous residue, filtered insoluble matters, separated the organic phase, and acidified the aqueous phase with 1 M HCl. After 1 h at RT, the resulting precipitate was filtered off, washed with water and dried at 60 ° C in a vacuum oven. Yield: 2.5 g (25% of theory) ESI-MS: (MH) ^" = 507 R _f = 0.10 (silica gel, DCM / Cyc / MeOH / NH ₃ 70: 15: 15: 2)

1 h) of 4- (2-oxo-1,2,4,5,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid - (I?) - 2- [4- (4- fluorophenyl) -piperazin-1-yl1-1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester. To a solution of 600 mg (1.18 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (I?) - 1-carboxy-2- (4 methyl 2-oxo-2,3-dihydrobenz-oxazol-6-yl) -ethyl ester, 417 mg (1.30 mmol) TBTU, 183 μl (1.30 mmol) triethylamine in 10 mL DMF were added 234 mg (1.30 mmol) 1. (4-fluoro-phenyl) -piperazine and the reaction mixture was shaken at RT. The reaction solution was purified by HPLC without further work-up, the fractions containing the product were combined and lyophilized.

Yield: 490 mg (62% of theory)

ESI-MS: (M + H) ⁺ = 671

Retention time (HPLC): 4.0 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-acetyl-piperazine- 1 -yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

Prepared analogously to Example 1 h from 600 mg (1.18 mmol) 4- (2-oxo-1, 2,4,5-tetrahydro-1,3-benzdiazepin-3-yl) -piperidine-1-carboxylic acid - (/? ) -1-Carboxy-2- (4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl) -ethyl ester and 275 mg (1.30 mmol) of 1- (4-piperidin-4-yl-piperazine -1-yl) ethanone. Yield: 420 mg (51% of theory)

ESI-MS: (M + H) ⁺ = 702

Retention time (HPLC): 2.7 min (Method B)

Example 1.2

4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid - (I?) - 1 - (4-methyl-2-oxo 2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-2- [4- (1-oxo-1λ ⁴ -thiomorpholin-4-yl) -piperidin-1-yl] -ethyl ester

1.2a) 4- (2-Oxo-1,2,4,5,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1- (4-methyl-2-) oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-2- (4-oxopiperidin-1-yl) -ethyl ester To a solution of 500 mg (0.98 mmol) of 4- (2-oxo -1, 2,4,5, -tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1-carboxy-2- (4-methyl-2-oxo-2, 3-dihydrobenz-oxazol-6-yl) -ethyl ester, 350 mg (1.09 mmol) TBTU, 300 μL (2.15 mmol) triethylamine in 10 mL DMF, 200 mg (1.30 mmol) piperidin-4-one (used as hydrate of the hydrochloride - Salt) and the reaction mixture stirred for 4 h at RT. The reaction solution was i.vac. concentrated, the residue taken up in DCM, the organic phase washed with saturated NaHCCv solution and dried over NaaSCu. After removal of the drying agent and solvent, the residue was purified by chromatography (silica gel, gradient DCM / MeOH 20: 1 to DCM / MeOH 10: 1). The fractions containing the product were concentrated, the residue was stirred with DIPE, filtered off with suction and dried. Yield: 480 mg (83% of theory)

ESI-MS: (MH) ^" = 588

Retention time (HPLC): 3.2 min (method B) 1.2b) 4- (2-Oxo-1,2,4,5,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1- (4-methyl-2 - oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-2- [4- (1-oxo-1, ^4- thio-morpholin-4-yl) -piperidin-1-yl-1. ethyl ester

A solution of 80 mg (0.14 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1 - ( 4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo

2- (4-oxo-piperidin-1-yl) -ethyl ester and 32 mg (0.27 mmol) thiomorpholine-1-oxide in 5 ml_

DCM was stirred at RT overnight. After cooling the solution to 0 ° C, 15 μL

(0.27 mmol) of AcOH and 50 mg (0.33 mmol) of sodium triacetoxyborohydride were added and the

Reaction mixture stirred for 4 h at this temperature. One narrowed i.vac. The residue was taken up in 1 ml of MeOH, filtered from insoluble components, and purified

Crude product via HPLC. The fractions containing the product were combined and lyophilized.

Yield: 24 mg (26% of theory)

ESI-MS: (M + H) ⁺ = 693 retention time (HPLC): 2.7 min (Method B)

Example 1.3

4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid - (I?) - 2- (4-acetoxy-1,4 ' -bipiperidinyl-1'-yl) -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

To a solution of 100 mg (0.20 mmol) 4- (2-oxo-1,2,4,5,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1 -carboxy-2- (4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl) -ethyl ester, 70 mg (0.22 mmol) TBTU, 35 μL (0.25 mmol) triethylamine in 1.5 mL DMF became 50 mg (0.22 mmol) of acetic acid [1, 4 '] bipiperidinyl-4-yl-ester and the reaction mixture was stirred overnight at RT. The reaction solution was combined with 100 ml of water and 100 ml of saturated NaHCO ₃ solution, extracted three times with 70 ml of EtOAc each time and the combined organic phases were dried over MgSO ₄ . After removal of the drying and solvent, the residue became chromatographic (Silica gel, gradient DCM to DCM / MeOH / NH ₃ 50: 47: 3). The fractions containing the product were combined, i.vac. concentrated, the residue triturated with DIPE, filtered off with suction and dried. Yield: 20 mg (14% of theory) ESI-MS: (M + H) ⁺ = 717

R _f = 0.49 (silica gel, DCM / Cyc / MeOH / NH ₃ 70: 15: 15: 2)

Example 2

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- [4- (4-ethoxycarbonylmethyl-piperazine- 1 -yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl) -2-oxo-ethyl ester

To a solution of 100 mg (0.20 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (/?) - 1-carboxy-2- (4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl) -ethyl ester, 71 mg (0.22 mmol) TBTU and 31 μl (0.22 mmol) triethylamine in 1 ml DMF 56 mg (0.22 mmol) of (4-piperidin-4-yl-piperazin-1-yl) -acetic acid ethyl ester and the reaction mixture shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were concentrated and lyophilized.

Yield: 60 mg (41% of theory)

ESI-MS: (M + H) ⁺ = 746

Retention time (HPLC): 2.5 min (method B)

Example 2.1

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- [4- (4-carboxymethyl-piperazine- 1 -yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester O

° Λ

XX

To a solution of 20 mg (0.03 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2- [4- (4-ethoxycarbonylmethyl-piperazin-1-yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo ethyl ester in 1 ml of THF, a solution of 1 mg (0.04 mmol) of LiOH in 0.5 ml of water was added and the reaction mixture was stirred at RT overnight. To complete the reaction, 1 mg of LiOH was added again and the mixture was stirred at RT for 3 h. The solvents were removed in a nitrogen stream and lyophilized the residue. The product was obtained as lithium salt. Yield: 15 mg (80% of theory)

ESI-MS: (M + H) ⁺ = 718

Retention time (HPLC): 2.5 min (method B)

Example 3

4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- [4 - ((S) -2- methoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

To a solution of 200 mg (0.39 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (/?) - 1-carboxy-2- (4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl) -ethyl ester, 140 mg (0.44 mmol) TBTU and 61 μL (0.44 mmol) triethylamine in 2 mL DMF were added 93 mg (0.44 mmol) of (S) -1-piperidin-4-yl-pyrrolidine-2-carboxylic acid methyl ester and the reaction mixture shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were concentrated and lyophilized. Yield: 218 mg (79% of theory)

ESI-MS: (M + H) ⁺ = 703 retention time (HPLC): 2.5 min (Method A)

Example 3.1

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (□) -2- [4- ((S) -2 -carboxy-pyrrolidin-1-yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

To a solution of 200 mg (0.29 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - / 2 - - [4 - ((S) -2-methoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) 2-oxo-ethyl ester in 9 ml of THF, a solution of 17 mg (0.71 mmol) of LiOH in 3 ml of water was added and the reaction mixture was stirred at RT for 66 h. The solvents were removed in a stream of nitrogen and the residue was purified by HPLC. The fractions containing the product were combined and lyophilized. Yield: 49 mg (25% of theory)

ESI-MS: (M + H) ⁺ = 689

Retention time (HPLC): 2.5 min (Method A)

Example 3.2

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

2-dimethylcarbamoylmethoxycarbonyl-pyrrolidin-1-yl) piperidin-1-yl] -1- (4-methyl-2-oxo-

2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

To a solution of 34 mg (0.05 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - / 2 - - [4 - ((S) -2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) 2-oxo-ethyl ester, 18 mg (0.06 mmol) TBTU and 8 μl triethylamine in 2 ml DMF were added 6 mg (0.06 mmol) 2-hydroxy-Λ /, Λ / -dimethyl-acetamide and the reaction mixture overnight shaken at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were combined and lyophilized. Yield: 22 mg (58% of theory) ESI-MS: (M + H) ⁺ = 774

Retention time (HPLC): 2.5 min (Method A)

Example 4

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (?) -2- [4- ((R) -2 -ethoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydrobenzoxazole)

6-ylmethyl) -2-oxo-ethyl ester

Prepared analogously to Example 3 from 200 mg (0.39 mmol) of 4- (2-oxo-1, 2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (? ) -1-Carboxy-2- (4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-yl) -ethyl ester and 99 mg (0.44 mmol) of (R) -1-piperidine-4- yl-pyrrolidine-2-carboxylic acid ethyl ester. After purification via HPLC (solvent mixture contains 0.1% trifluoroacetic acid), the product was obtained as the trifluoroacetate salt. Yield: 275 mg (84% of theory) ESI-MS: (M + H) ⁺ = 717 Retention time (HPLC): 2.6 min (Method A)

Example 4.1

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - / 2 - [4 - ((R) - 2 -carboxy-pyrrolidin-1-yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

Prepared analogously to Example 3.1 from 265 mg (0.37 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) - 2- [4 - ((R) -2-ethoxy-carbonyl-pyrrolidin

1 -yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester and 22 mg (0.92 mmol) LiOH ,

Yield: 85 mg (33% of theory)

ESI-MS: (M + H) ⁺ = 689 retention time (HPLC): 2.5 min (Method A)

Example 4.2

4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- [4 - ((R) -2- dimethylcarbamoylmethoxycarbonyl-pyrrolidin-1-yl) piperidin-1-yl] -1- (4-methyl-2-oxo-

2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

Prepared analogously to Example 3.2 from 85 mg (0.12 mmol) 4- (2-oxo-1,2,4,5,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) - 2- [4 - ((R) -2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl] -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazole-6 -ylmethyl) -2-oxo-ethyl ester and 15 mg (0.14 mmol) 2-hydroxy-Λ /, Λ / -dimethyl-acetamide. After purification via HPLC (solvent mixture contains 0.1% trifluoroacetic acid), the product was obtained as Trifluoracetat- SaIz.

Yield: 21 mg (19% of theory) ESI-MS: (M + H) ⁺ = 774

Retention time (HPLC): 2.5 min (Method A)

Example 5

1 '- {(R) -3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -2- [4- (2-oxo-1, 2,4,5-) tetrahydro-1,3-benzodiazepine-S-yO-piperidine-i-carbonyloxyj-propionyl-1-yl-bipiperidinyl-2-carboxylate

H °

A solution of 300 mg (0.59 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (I?) - 1 -carboxy-2- (4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl) -ethyl ester, 210 mg (0.65 mmol) TBTU and 100 μL (0.72 mmol) triethylamine in 20 mL THF became 1 Stirred at RT. Then, 220 mg (0.70 mmol) of ethyl [1,4-bis] piperidinyl-4-carboxylate (used as bis-hydrochloride salt) and 400 μL (2.87 mmol) of triethylamine were added. The reaction mixture was stirred at RT for 24 h. It was diluted with EtOAc, the organic phase was washed with saturated NaHCO ₃ solution and dried over NaaSCu. After removal of the drying agent and solvent, the residue was purified by chromatography (Alox, activity level M-III, gradient DCM / EtOH 20: 1 to DCM / EtOH 10: 1). The fractions containing the product were combined, i.vac. concentrated, the residue triturated with diethyl ether, filtered off with suction and dried. Yield: 240 mg (56% of theory)

ESI-MS: (M + H) ⁺ = 731

Retention time (HPLC): 3.0 min (method B)

Example 5.1 1 '- {(R) -3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -2- [4- (2-oxo-1, 2,4,5-) tetrahydro-1,3-benzodiazepine-S-yl-1-piperidine-i-carbonyloxy-propionyl-1'-bipiperidinyl-M-carboxylic acid

To a solution of 190 mg (0.26 mmol) of 1 '- {(R) -3- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl) -2- [4- ( 2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxonyloxy] -propionyl} -1,4'-bipiperidinyl-4-carboxylic acid ethyl ester in 10 mL THF a solution of 12 mg (0.50 mmol) of LiOH in 2 ml of water and the reaction solution was stirred at RT for 3 h. It was diluted with water, removed i.vac. the THF, added 4M HCl to the weakly acidic reaction, washed with DCM, and saturated the aqueous phase with solid NaCl, whereupon an oily precipitate separated. It was decanted from the solvent, the residue was taken up in DCM / MeOH and the organic phase was dried over Na ₂ SO ₄ . After removal of the drying and solvent, the product was obtained as the hydrochloride salt. Yield: 175 mg (87% of theory) ESI-MS: (MH) ^" = 701

Retention time (HPLC): 2.8 min (method B)

Example 6

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid - (I?) - 1 - (4-methyl-2-oxo) 2,3-dihydro-benzoxazol-6-ylmethyl) -2- [1 '- (2-morpholin-4-yl-ethoxycarbonylmethyl) -4,4'-bipiperidinyl-1-yl] -2-oxo-ethyl ester

6a) 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (1'-ethoxycarbonylmethyl-4, 4'-bipiperidinyl-1-yl) -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

A solution of 350 mg (0.69 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (□) - 1 -carboxy-2- (4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl) -ethyl ester, 244 mg (0.76 mmol) TBTU and 138 μl (1.04 mmol) triethylamine in 15 mL THF became 1 Stirred at RT. Then, 175 mg (0.69 mmol) of [4,4 '] bipiperidinyl-1-yl-acetic acid ethyl ester were added. The reaction mixture was stirred at RT for 4 h. One removed i.vac. the solvent, the residue was taken up in 30 mL EtOAc, the organic phase was washed with 30 mL 5% 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 DCM / EtOH 19: 1 to DCM / EtOH 9: 1). The fractions containing the product were combined and purified i.vac. concentrated. Yield: 240 mg (47% of theory) ESI-MS: (M + H) ⁺ = 745

Retention time (HPLC): 3.1 min (method B)

6b) 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) piperidine-1-carboxylic acid (R) -2- (1'-carboxymethyl-4, 4'-bipiperidinyl-1-yl) -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester

To a solution of 240 mg (0.32 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - / 2 - - (1 '- ethoxycarbonylmethyl-4,4'-bipiperidinyl-1-yl) -1- (4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl) -2-oxo-ethyl ester in 10 mL THF was added to a solution of 39 mg (1.61 mmol) of LiOH in 5 ml of water, and the reaction solution was stirred at RT for 1 h. It was mixed with 1.61 mL of 1 M HCl and concentrated i.vac. The residue was mixed with a little water, stirred, the water was decanted off and the residue was dried in air. Yield: 240 mg (47% of theory)

ESI-MS: (M + H) ⁺ = 717 retention time (HPLC): 2.9 min (Method B)

6c) 4- (2-Oxo-1, 2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1- (4-methyl-2-oxo -2,3-dihydro-benzoxazol-6-ylmethyl) -2- [1 '- (2-morpholin-4-yl-ethoxycarbonylmethyl) -4,4'-bipiperidinyl-1-yl1-2-oxo-ethyl ester A solution of 90 mg (0.13 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2- ( 1'-carboxymethyl-4,4'-bipiperidinyl-1-yl) -1- (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-ylmethyl) -2-oxo-ethyl ester, 48 mg ( 0.15 mmol) of TBTU and 26 μl (0.19 mmol) of triethylamine in 1.4 ml of DMF was stirred at RT for 1 h. Then, 18 μL (0.15 mmol) of 2-morpholin-4-yl-ethanol was added. The reaction mixture was stirred at RT for 16 h. It was mixed with 4 drops of formic acid, filtered through a syringe filter and purified via HPLC. The product-containing fractions were combined, made _ß with 5% NaHCO solution alkaline, extracted with 50 mL EtOAc and the organic phase over Na ₂ SO ₄ dried. After removal of the drying agent and solvent, the residue was triturated with DIPE, filtered off with suction and dried. Yield: 47 mg (45% of theory)

ESI-MS: (M + H) ⁺ = 830

Retention time (HPLC): 2.6 min (method B)

Example 7

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (I?) - 1 - (2-methoxy-7-methyl) 1 / - / - benzimidazol-5-ylmethyl) -2- (4-morpholin-4-yl-piperidin-1-yl) -2-oxo-ethyl ester

7a) (Z, E) -2-Acetylamino-3- (4-amino-methyl-5-nitro-phenyl) -acrylic acid methyl ester Under argon atmosphere, to a solution of 9.0 g (39.0 mmol) of 4-bromo-2-methyl 6-nitro-phenylamine and 10.0 g (69.9 mmol) of 2-acetylamino-acrylic acid methyl ester in 100 mL acetonitrile and 100 mL triethylamine 0.7 g (2.9 mmol) Pd (OAc) ₂ and 0.9 g (2.9 mmol) tri-o-tolyl Phosphane given. The reaction mixture was stirred for 24 h at 90 ° C bath temperature, i.vac. The residue is combined with 200 ml of water and 200 ml of EtOAc, and the precipitate is filtered off. The crystals were dissolved in 500 mL MeOH at reflux, filtered hot and the filtrate i.vac. concentrated to dryness. Yield: 8.0 g (70% of theory) ESI-MS: (M + H) ⁺ = 294 7b) 3- (4-Amino-3-methyl-5-nitro-phenyl) -2-oxo-propionic acid To a solution of 8.0 g (53.1 mmol) of (Z, E) -2-acetylamino-3- (4- amino-methyl-5-nitro-phenyl) -acrylic acid methyl ester in 60 ml of 1,4-dioxane, 60 ml of a 4 M HCl were added, the mixture was stirred at reflux for 3 hours, the reaction solution was concentrated i.vac and the residue was admixed with ice. The precipitate was filtered off, washed with ice-water and dried.

Yield: 6.5 g (95% of theory) EI-MS: (M) ⁺ = 238

7c) (R) -3- (4-Amino-3-methyl-5-nitro-phenyl) -2-hydroxypropionic acid Under a nitrogen atmosphere were added to a cooled to -35 ° C solution of 6.5 g (26.0 mmol) 3- (4-amino-3-methyl-5-nitro-phenyl) -2-oxo-propionic acid and 4.5 mL (32.4 mmol) triethylamine in 100 mL THF within 15 min a solution of 12.0 g (37.4 mmol) (IR) - B-Chlordiisopinocampheylboran in 40 mL THF was added dropwise and the reaction solution was stirred at RT overnight. Subsequently, the reaction solution at 5 ° C was carefully mixed with 60 mL 1 M NaOH and 150 mL diethyl ether and stirred for 15 min. The organic phase was separated, extracted three times with 40 mL 1 M NaOH and once with 40 mL water. The combined aqueous phases were washed with half-conc. Acidified with ice bath cooling and extracted twice with 120 mL EtOAc. The combined organic phases were dried over Na ₂ SO ₄ and concentrated i.vac. concentrated. The crude product was obtained, which was reacted further without purification. Yield: 6.0 g (67% of theory)

7d) (Fi) -3- (4-amino-3-methyl-5-nitro-phenyl) -2-hydroxypropionic acid methyl ester To 90 ml of MeOH were added under ice-acetone cooling 4.0 mL (54.8 mmol) SOCl ₂ and at 0 ° C 6.0 g (17.5 mmol) of (R) -3- (4-amino-3-methyl-5-nitro-phenyl) -2-hydroxy-propionic acid in 10 mL MeOH slowly added dropwise. The reaction solution was stirred at 0 ° C. for 1 h and at RT for 1 h, and then i.vac. concentrated. The residue was combined with EtOAc, washed with saturated NaHSO ₄ 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 DCM / MeOH 100: 1 to 50: 1). Yield: 3.4 g (76% of theory) ESI-MS: (M + H) ⁺ = 255 R _f = 0.43 (polygram, DCM / MeOH 50: 1)

7e) 4- (2-Oxo-1,2,4,5,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (/?) - 2-

(4-Amino-3-methyl-5-nitrophenyl) -1-methoxycarbonyl ethyl ester Under a nitrogen atmosphere, 1.8 g (14.7 mmol) of 4-dimethylaminopyridine in 25 ml of pyridine under ice-bath cooling, first with 2.7 g (13.4 mmol) of 4-chloroformate -nitrophenylester, stirred for 30 min at RT, then with 3.4 g (13.2 mmol) of methyl (R) -3- (4-amino-3-methyl-5-nitro-phenyl) -2-hydroxy-propionate in 15 ml_ pyridine, stirred again for 2 h at RT, and then with 3.5 g (14.3 mmol) of 3-piperidin-4-yl-1, 3,4,5-tetrahydro-1, 3-benzdiazepin-2-one added and Stirred for 5 h at RT. After completion of the reaction, the reaction mixture was i.vac. the residue is combined with EtOAc, the organic phase is washed with 10% KHSO ₄ solution and saturated NaHSO ₄ solution and dried over Na ₂ SO ₄ . After removal of the drying agent and solvent, the residue was purified by chromatography (silica gel, DCM / MeOH 25: 1). Yield: 3.7 g (50% of theory) ESI-MS: (M + H) ⁺ = 526

R _f = 0.42 (polygram, DCM / MeOH 25: 1)

7f) 4- (2-Oxo-1, 2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (3,4-diamino-5 methyl-phenyl) -1-methoxycarbonyl-ethyl ester

A suspension of 2.00 g (3.24 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (/?) - 2- (4-Amino-3-methyl-5-nitrophenyl) -1-methoxycarbonyl ethyl ester and 300 mg of 10% Pd / C in 100 ml of MeOH were hydrogenated at 50 ° C. and 50 psi hydrogen pressure for 3.5 h. The catalyst was filtered, the filtrate i.vac. concentrated and the residue purified by chromatography (silica gel, gradient DCM / MeOH 30: 1 to DCM / MeOH 15: 1).

Yield: 1.35 g (84% of theory) ESI-MS: (M + H) ⁺ = 496

7g) 4- (2-Oxo-1,2,4,5,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (I-) -1-methoxycarbonyl-2- (2-) methoxy-7-methyl-1 / - / - benzimidazol-5-yl) -ethyl ester A solution of 1.00 g (2.02 mmol) of 4- (2-oxo-1, 2,4,5-tetrahydro-1,3-bis) benzdiazepin-3-yl) - piperidine-1-carboxylic acid- (R) -2- (3,4-diamino-5-methylphenyl) -1-methoxycarbonyl-ethyl ester and 2.00 mL (15.01 mmol) tetramethoxymethane in 20 mL MeOH was used in Of 40 mg (0.21 mmol) of toluenesulfonic acid hydrate heated under reflux for 1 h. One narrowed i.vac. and the residue purified by chromatography (Alox, activity level M-III, DCIWMeOH 20: 1).

Yield: 0.99 g (92% of theory) ESI-MS: (M + H) ⁺ = 536

7h) 4- (2-oxo-1,2,4,5,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid - (I?) - 1 - carboxy-2- (2-) Methoxy-7-methyl-1H-benzimidazol-5-yl) ethyl ester To a solution of 0.98 g (1.83 mmol) 4- (2-oxo-1,2,4,5,5-tetrahydro-1,3-benzodiazepine 3-yl) -piperidine-1-carboxylic acid- (R) -1-methoxycarbonyl-2- (2-methoxy-7-methyl-1 / - / - benzimidazol-5-yl) -ethyl ester in 18 mL THF a solution of 0.10 g (4.18 mmol) of LiOH in 6 mL of water and the reaction solution was stirred at RT overnight. It was mixed with 1.05 mL 4 M HCl and removed i.vac. the THF. The oily residue was decanted off, this was dissolved in DCM / MeOH and the organic phase dried over Na ₂ SO ₄ . After removal of the drying and solvent, the desired product was obtained.

Yield: 0.80 g (80% of theory)

ESI-MS: (MH) ^" = 520

Retention time (HPLC): 2.7 min (Method B)

7i) 4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1- (2-methoxy-7-methyl -1 / - / - benzimidazol-5-ylmethyl) -2- (4-morpholin-4-yl-piperidin-1-yl) -2-oxo-ethyl ester To a solution of 90 mg (0.16 mmol) 4- (2 -Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -1-carboxy-2- (2-methoxy-7-methyl-1 Ethyl benzoate, benzimidazol-5-yl), 60 mg (0.19 mmol) TBTU and 30 μL (0.22 mmol) triethylamine in 1 mL DMF were added 40 mg (0.24 mmol) 4-piperidin-4-yl-morpholine and the reaction mixture was stirred at RT overnight. The reaction mixture was purified by HPLC without working up; the fractions containing the product were combined and lyophilized.

Yield: 44 mg (40% of theory)

ESI-MS: (M + H) ⁺ = 674

Retention time (HPLC): 6.9 min (method C) Example 7.1

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid - (□) -2- (4,4-dimethyl-1, 4'-bipiperidinyl-1'-yl) -1- (2-methoxy-7-methyl-1 / - / - benzimidazol-5-ylmethyl) -2-oxo-ethyl ester

Prepared analogously to Example 7i from 90 mg (0.16 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -1 -carboxy-2- (2-methoxy-7-methyl-1H-benzimidazol-5-yl) -ethyl ester and 55 mg (0.20 mmol) 4,4-dimethyl- [1,4 '] bipiperidinyl (used as bis- Hydrochloride salt) using 100 μl (0.72 mmol) triethylamine.

Yield: 38 mg (33% of theory)

ESI-MS: (M + H) ⁺ = 700

Retention time (HPLC): 7.4 min (method C)

Example 7.2

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid- (R) -2- (4-methoxy-1, 4'- bipiperidinyl-1'-yl) -1- (2-methoxy-7-methyl-1 / - / - benzimidazol-5-ylmethyl) -2-oxo-ethyl ester

Prepared analogously to Example 7i from 90 mg (0.16 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid (R) -1 -carboxy-2- (2-methoxy-7-methyl-1H-benzimidazol-5-yl) -ethyl ester and 55 mg (0.20 mmol) 4-methoxy- [1,4 '] bipiperidinyl (incorporated as the bis-hydrochloride salt) using 100 μL (0.72 mmol) triethylamine.

Yield: 44 mg (38% of theory)

ESI-MS: (M + H) ⁺ = 702 retention time (HPLC): 7.1 min (method C)

Example 7.3

4- (2-Oxo-1,2,4,5-tetrahydro-1,3-benzadiazepin-3-yl) -piperidine-1-carboxylic acid - (¢) -2- [4- (4-ethoxycarbonylmethyl-piperazine -1-yl) -piperidin-1-yl] -1- (2-methoxy-7-methyl-1 / - / - benzimidazol-5-ylmethyl) -2-oxo-ethyl ester

Prepared analogously to Example 7i from 150 mg (0.27 mmol) of 4- (2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -1 -carboxy-2- (2-methoxy-7-methyl-1H-benzimidazol-5-yl) -ethyl ester and 85 mg (0.33 mmol) of (4-piperidin-4-yl-piperazin-1-yl) -acetic acid ethyl ester.

Yield: 21 mg (10% of theory)

ESI-MS: (M + H) ⁺ = 759

Retention time (HPLC): 7.2 min (method C)

The following examples describe the preparation of pharmaceutical

Use forms containing as active ingredient any compound of 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

Production method:

The active ingredient 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 hub 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 ingredient and benzalkonium chloride are dissolved in water and filled into Respimat ^® 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

Production method:

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

Example IV

Propellant metered dose inhaler with 1 mg active substance

Composition:

1 hub contains:

Active ingredient 1.0 mg

Lecithin 0.1%

Propellant ad 50.0 μl

Production method:

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 substance and the excipients are dissolved in water and in a corresponding

Bottled 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

Herstellunq:

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 20 ml

production:

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

production:

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

wherein

R ¹ - ^{1 represents} H or H ₃ CO-,

R ^{2 is} a group selected from

wherein R ^{2 is} ¹ H or H ₃ C-,

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

3.1

-N-

-R ⁴

wherein

X N or C,

R ^{3 is} ¹ H or C _1-3 alkyl,

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} phenyl or

R ^{4 is} a group of the general formulas III

wherein

C and

R ⁴ - ¹ H or C _1-3 alkyl, or N and

R ^{4 1 is} a lone pair of electrons,

with the proviso that X and Y are not N at the same time,

4.2

H or C _1-3 alkyl,

R ⁴ - ³ H, Ci- ₆ alkyl, H ₂ NC ₂ - ₄ alkylene, (Ci _-3 alkyl) -NH-C ₂ - ₄ alkylene,

(Ci _-3 alkyl) ₂ NC _{_2-4} alkylene, H ₂ NC (O) -C _-3 alkylene, (Ci _-3 alkyl) -NH-C (O) -C alkylene _-3 -, (Ci _-3 alkyl) ₂ -N-C (O) -C _-3 alkylene, Ci _-3 alkyl OC (O) -C _-3 -alkylene-O- or R ⁴ - ³ - ¹ - C _2-4 alkylene,

R ^{4'3 1 represents} a group selected from

R ⁵ - ¹ Ci- ₆ alkyl, _{Ci-6-alkyl-O-,} _Ci-6-alkyl-C (O) -O-, R ^{5 / M} -OC (O) -,

R ^{5 1} - ¹ -OC (O) -C _-3 -alkylene-NH-, R ^{5 / M} -OC (O) -C _-3 -alkylene-O-, R ⁵ - ^{1 / l} -OC (O) -Ci- _3- alkylene, R ⁵ - ^{1 1} -OC (O) -C (O) - or

R ⁵ - ^{1 / l} -OC (O) -Ci _-3 -alkylene-C (O) -,

R ⁵ - ¹ - alkylene- ¹ H, d-β-alkyl, phenyl, indanyl, pyridyl-Ci _-3, HO-C _2-4 alkylene-,

Ci _-6 alkyl-OC _2-4 alkylene, H ₂ NC _2-4 alkylene, (Ci _-6 alkyl) -NH-C _2-4 alkylene, (Ci _-6 alkyl) ₂ -NC _2-4 -alkylene, H ₂ NC (O) -Ci _-3 -alkylene,

(Ci _-6 alkyl) -NH-C (O) -C _-3 alkylene, (Ci _-6 alkyl) ₂ -N-C (O) -C _-3 alkylene, _Ci-6-alkyl-C (O) -O-Ci _-3 alkylene, Ci _-6 alkyl-OC (O) -O-Ci _-3 alkylene, R ⁵ - ¹ - ^{1 / l} -C (O) -C _-3 -alkylene- or R ⁵ - ¹ - ¹ - ² -C _2-4 -alkylene-,

p ⁵ . ⁱ . ⁱ . ⁱ _e _ne Q _rU pp _e selected

p ⁵ . ⁱ . ⁱ . ² _e j _ne Q _rU pp _e selected from

_R5 . ² R ⁵ - ² - ¹ -OC (O) -Ci _-3 -alkylene, R ^{52 1} -O-C (O) -C (O) -, R ⁵ - ^{2 1} -OC (O) -Ci _{- 3} -alkylene-C (O) - or R ^{52 1} -C (O) -,

R ⁵ is - ² - ^1H, _d-8 alkyl, phenyl, indanyl, pyridyl-Ci _-3 -alkylene, HO-C _{_2-4} alkylene, Ci _-6 alkyl-OC _{_2-4} alkylene, H ₂ NC ₂ - ₄ alkylene, (Ci _-6 alkyl) -NH-C ₂ - ₄ alkylene,

(Ci _-6 alkyl) ₂ NC ₂ - alkylene- _4, H ₂ NC (O) -C alkylene- _-3, (Ci ^ alkyl) -NH-C (0) -C-3-alkylene, , (Ci ^ alkyl) 2N-C (O) -C 3 alkylene, _Ci-6-alkyl-C (O) -O-Ci _-3 alkylene, Ci _-6 alkyl-OC (O ) -O-Ci- _3- alkylene, R ⁵ - ² - ^{1 1} -C (O) -Ci- _3- alkylene or R ⁵ - ² - ¹ - ² -C _2-4 -alkylene-,

p ⁵ . ² . ⁱ . ⁱ _e _ne Q _rU pp _e selected

j ⁵ . ² . ⁱ . ² _e _ne Q _rU pp _e represents selected

means

2. Compounds of general formula I according to claim 1, in which

R ^{1 is} a group selected from

wherein

ϊ1.1 represents H or H ₃ CO-,

R is a group selected from

R-R together form a group of general formulas IV

-N -Λ R ⁴ - ² ^ N - ^^ Λ

5.2

N-

wherein 4.2

H or H ₃ C-,

R ⁴ - ³ H, Ci- ₆ alkyl, H ₂ NC ₂ - ₄ alkylene, (Ci _-3 alkyl) -NH-C ₂ - ₄ alkylene, (Ci _-3 alkyl) ₂ NC _{_2-4} alkylene, H ₂ NC (O) -C _-3 alkylene-,

(Ci _-3 alkyl) -NH-C (O) -C _-3 alkylene, (Ci _-3 alkyl) ₂ NC (O) -C _-3 alkylene- or R ⁴ - ³ - ¹ -C _2-4 -alkylene,

R ^{4-3'1 represents} a group selected from

and

R ⁵ - ¹ Ci _-3 alkyl, Ci _-3 alkyl-O-, Ci _-3 alkyl-C (O) -O- or R ^{5 / M} -OC (O) -, R ⁵ - ¹ - ¹ -OC (O) -C _-3 -alkylene-NH-, R ⁵ - ¹ - ¹ -OC (O) -C _-3 -alkylene-O- or R ⁵ - ¹ - ¹ -OC (O) -C _-3 -alkylene,

R ⁵ - ¹ - alkylene- ¹ H, d-β-alkyl, phenyl, indanyl, pyridyl-Ci _-3, HO-C _2-4 alkylene, Ci _-3 alkyl-OC _2-4 alkylene-, (Ci _-3 alkyl) ₂ NC _2-4 alkylene, (Ci _-3 alkyl) ₂ NC (O) -C _-3 alkylene, Ci _-3 alkyl-C (O) -O-Ci _-3 alkylene, Ci _-3 alkyl OC (O) -O-Ci _-3 alkylene, R ⁵ - ¹ - ^{1 / l} -C (O) -C _-3 alkylene- or R ⁵ - ¹ - ¹ - alkylene- ² -C _2-4

R ⁵ - ¹ - ¹ - ^{1 is} a group selected from

R ⁵ .II2 _e j _ne Q _rU pp _e selected

I ⁵² Ci _-3 -Alkyl-C (O) -, R ⁵ - ² - ¹ -OC (O) -Ci _-3 -alkylene, R ^{52 1} -O-C (O) -C (O) - or R ⁵ - ² - ¹ -OC (O) -Ci _-3 -alkylene-C (O) -,

R ⁵ is - ² - ¹ H, Ci- alkylene- ₈ alkyl, phenyl, indanyl, pyridyl-Ci _-3, HO-C ₂ - ₄ alkylene, Ci _-3 alkyl OC ₂ - ₄ alkylene-, (Ci _-3 alkyl) ₂ NC _{_2-4} alkylene, (Ci _-3 alkyl) ₂ NC (O) -C alkylene- _-3, Ci _-3 alkyl-C (O) -O-Ci- _3- alkylene, R ⁵ - ² - ^{1 / l} -C (O) -C _-3 alkylene- or R ⁵ - ² - ¹ - ² -C _{_2-4} alkylene-,

R ⁵ . ² . ^I. ^I _e _ne group selected

p ⁵ . ² . ⁱ . ² _e j _ne Q _rU pp _e d _ars tellt selected from

means

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 form a group of general formulas IV

wherein

, 4.2 H or H ₃ C-,

R, 4 ⁴ .3 ^J H, Ci- ₆ alkyl, (Ci _-3 alkyl) ₂ NC _{_2-4} alkylene, alkylene (Ci _-3 alkyl) ₂ NC (O) -C _-3 - or R ⁴ - ³ - ¹ -C _2-4 -alkylene-,

R represents a group selected from

R ⁵ - ¹ R ⁵ - ^{1 1} -OC (O) - or R ^{5 / M} -OC (O) -Ci _-3 -alkylene-, R ⁵ - ¹ -, Ci- alkylene- H ¹ ₈ alkyl, phenyl, indanyl, pyridyl-Ci _-3, HO-C ₂ - ₄ alkylene, Ci _-6 alkyl-OC ₂ - ₄ alkylene, H ₂ NC ₂ - ₄ alkylene, (Ci _-6 alkyl) -NH-C ₂ - ₄ alkylene, (Ci _-6 alkyl) ₂ NC ₂ - alkylene- _4, H ₂ NC (O) -C _-3 alkylene, (Ci _-6 alkyl) -NH-C (O) -C alkylene- _-3, (Ci _-6 alkyl) ₂ NC (O) -C _-3 alkylene-, Ci _-6 alkyl-C (O) -O-Ci _-3 alkylene, Ci _-6 alkyl-OC (O) -O-Ci _-3 alkylene, R ⁵ - ¹ - ^{1 / 1} -C (O) -Ci- _3- alkylene or R ^{5 / M} - ² -C _2-4 -alkylene,

R ⁵ - ¹ - ¹ - ^{1 is} a group selected from

p ⁵ . ⁱ . ⁱ . ² _e j _ne Q _rU pp _e selected from

_R5 . ² R ⁵ - ² - ¹ -OC (O) -Ci ₃ -alkylene, R ^{52 1} -O-C (O) -C (O) - or R ⁵ - ^{2 / l} -OC (O) -Ci _-3 -alkylene-C (O) -,

R ⁵ is - ² - ¹ is H, Ci- alkylene- ₈ alkyl, phenyl, indanyl, pyridyl-Ci _-3, HO-C _2-4 alkylene, Ci _-6 alkyl-OC _2-4 alkylene, H ₂ NC _2-4 alkylene, (Ci _-6 alkyl) -NH-C _2-4 alkylene, (Ci _-6 alkyl) ₂ NC _2-4 alkylene, H ₂ NC (O) -C _-3 alkylene, (C ^ alkyl), -NH-C (O) -C-3-alkylene, (Ci _-6 alkyl) ₂ NC (O) -C _-3 - alkylene-,

Ci _-6 alkyl-C (O) -O-Ci _-3 alkylene, Ci _-6 alkyl-OC (O) -O-Ci _-3 alkylene, R ⁵ - ² - ^{1 1} C ( O) -Ci- _3- alkylene or R ⁵ - ² - ¹ - ² -C _2-4 -alkylene-,

j5.2.1.1 a group selected from

j5.2.1.2 represents a group selected from

means

4. Compounds of general formula I according to claim 1, in which

R ^{1 is} a group

a group selected from

R-R together select a group

R-R together form a group of general formulas IV

wherein

, 4.3 H, Ci- ₆ alkyl, (H ₃ C) ₂ NC ₂ - ₃ alkylene, (H ₃ C) ₂ NC (O) -Ci _-2 alkylene,

Ci _-2 alkyl-OC (O) -O-C ₂ - ₃ alkylene or R 4. ^4-3.1 -C _2-3 alkylene,

a group selected from

and

H ₃ C-, H ₃ CO-, Ci _-2 alkyl-C (O) -O-, R ⁰ ^ -O-C (O) -,

"5.1.1 H, Ci- ₆ alkyl, alkylene- (H ₃ C) ₂ NC _2-3, (H ₃ C) ₂ NC (O) -C _-2 alkylene-,

Ci _-2 alkyl-OC (O) -O-Ci _-2 alkylene- or R 5. ^8-1. ^1-1. ^1-1 -C _2-3 alkylene-,

a group selected from

and

R "H ₃ CC (O) -, R ⁵ Al -OC (O) -Ci _-2 -alkylene, R ⁰ ^ -OC (O) -C (O) - or

_R ^ _O-C (O) -Ci- _2- alkylene-C (O) -,

5.2.1 ₁ H, Ci- ₆ alkyl, (H ₃ C) ₂ NC ₂ - alkylene- _3, (H ₃ C) ₂ NC (O) -C _-2 alkylene-,

Ci _-2 alkyl-OC (O) -O-Ci _-2 -alkylen- or R ⁵ ^ ¹ - ¹ -C _2-3 -alkylen-,

₁ 5.2.1.1 represents a group selected from

and

means

5. The following compounds of general formula I according to claim 1:

6. Physiologically acceptable salts of the compounds according to any one of claims 1 to 5 with inorganic or organic acids or bases.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a physiologically acceptable salt according to claim 6, optionally together with one or more inert carriers and / or diluents.

8. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the acute and prophylactic treatment of headache, in particular migraine, cluster headache and tension headache.

9. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for combating non-insulin-dependent diabetes mellitus (NIDDM).

10. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of cardiovascular diseases, morphine tolerance, Chlostridiumtoxin-related diarrhea, 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 , accompanied by an excessive vasodilation and consequent reduced vascular blood flow, in particular shock or sepsis, of chronic pain disorders such as diabetic neuropathies, by Ch neuropathies, HIV-induced neuropathies, postherpetic neuropathies, tissue trauma-induced neuropathies, trigeminal neuralgias, temporomandibular dysfunctions, CRPS, back pain, visceral disorders such as IBS (irritable bowel syndrome) or inflammable bowel syndrome Painful conditions in general or for preventive or acute therapeutic influence on the symptoms caused by vasodilation and increased blood flow of hot flashes of menopausal, estrogen-deficient women and hormone-treated prostate cancer patients and castrates.

1 1. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS).

12. Use of a compound according to at least one of claims 1 to 6 for the manufacture of a medicament for the preventive and acute therapeutic treatment of

Hot flashes of women who are more susceptible to estrogen.

13. A process for the preparation of a medicament according to claim 7, characterized in that a compound according to at least one of claims 1 to 6 is incorporated into one or more inert carriers and / or diluents by non-chemical means.