HK1127601A

HK1127601A - Selected cgrp antagonists, methods for the production thereof and their use as medicaments

Info

Publication number: HK1127601A
Application number: HK09106682.1A
Authority: HK
Inventors: Stephan Georg Mueller; Klaus Rudolf; Philipp Lustenberger; Gerhard Schaenzle; Marco Santagostino; Dirk Stenkamp; Kirsten Arndt; Henri Doods
Original assignee: 贝林格尔‧英格海姆国际有限公司
Priority date: 2005-08-17
Filing date: 2006-08-15
Publication date: 2009-10-02

Description

Selected CGRP antagonists, method for the production thereof and use thereof as medicaments

The invention relates to CGRP antagonists of general formula (I)

Wherein R is¹，R²，R³And R⁴The tautomers, isomers, diastereomers, enantiomers, hydrates, mixtures thereof, and salts thereof, and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases, as defined in claim 1, and the compounds of the general formula I in which one or more of the hydrogen atoms are replaced by deuterium, the pharmaceutical compositions containing these compounds, the use thereof and the production thereof.

Prior Art

CGRP antagonists for the treatment of migraine have been described in International patent applications PCT/EP97/04862 and PCT/EP 03/11762.

Detailed Description

In formula I above, in a first embodiment

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³represents a group of the formula II

Wherein

X represents N or C, and X represents N or C,

R^3.1representation H, C_1-3-alkyl or R^3.1.1-O-C(O)，

R^3.1.1Representation H, C_1-6Alkyl, H₂N-C_2-4Alkylene group, (C)_1-3-alkyl) -NH-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-3-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^3.1.1.1-C_2-4-an alkylene group,

R^3.1.1.1represents a group selected from the group consisting of,

and

if X is equal to N, R^3.2Represents a pair of free electrons, or

If X is ═ C, R^3.2Representation H, C_1-3-alkyl or R^3.2.1-O-C(O)，

R^3.2.1Representation H, C_1-6Alkyl, H₂N-C_2-4Alkylene group, (C)_1-3-alkyl radical)-NH-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-3-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^3.2.1.1-C_2-4-an alkylene group,

R^3.2.1.1represents a group selected from the group consisting of,

and

R⁴represents a group of the formula III

Wherein

Y represents C, and

R^4.1represents H or C_1-3-alkyl, or

Y represents N, and

R^4.1which represents a pair of free electrons that are,

provided that X and Y do not simultaneously represent N,

R^4.2representation H, C_1-3-alkyl or R^4.2.1-O-C(O)，

R^4.2.1Representation H, C_1-6Alkyl, H₂N-C_2-4Alkylene group, (C)_1-3-alkyl) -NH-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-3-alkyl) -NH-C (O) -C_1-3An alkylene group,(C_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^4.2.1.1-C_2-4-an alkylene group,

R^4.2.1.1represents a group selected from the group consisting of,

and

and is

R^4.3Representation H, C_1-6Alkyl, H₂N-C_2-4Alkylene group, (C)_1-3-alkyl) -NH-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-3-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^4.3.1-C_2-4-an alkylene group,

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1representation H, C_1-3-alkyl, R^5.1.1-O-C(O)、R^5.1.1-O-C(O)-C_1-3alkylene-NH, R^5.1.1-O-C(O)-C_1-3alkylene-N (C)_1-3-alkyl), R^5.1.1-O-C(O)-C_1-3alkylene-O, R^5.1.1-O-C(O)-C_1-3Alkylene radical, R^5.1.1-O-C(O)-C(O)、R^5.1.1-O-C(O)-C(O)-O、R^5.1.1-O-C(O)-C_1-3alkylene-C (O) or R^5.1.1-O-C(O)-C_1-3alkylene-C (O) -O,

R^5.1.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-C_1-3Alkylene, HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.1.1.1-C(O)-C_1-3Alkylene or R^5.1.1.2-C_2-4-an alkylene group,

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2representation H, C_1-3-alkyl, R^5.2.1-O-C(O)-C_1-3alkylene-NH, R^5.2.1-O-C(O)-C_1-3alkylene-O, R^5.2.1-O-C(O)-C_1-3Alkylene radical, R^5.2.1-O-C (O) or R^5.2.1-O-C(O)-C_1-3-alkylene-C (O),

R^5.2.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-C_1-3-AAlkyl, HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4alkylene-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.2.1.1-C(O)-C_1-3Alkylene or R^5.2.1.2-C_2-4-an alkylene group,

R^5.2.1.1represents a group selected from the group consisting of,

and

R^5.2.1.2represents a group selected from the group consisting of,

andor

R^5.2.1Represents a group of the formula

Provided that R is^3.1，R^3.2，R^4.2，R^5.1Or R^5.2At least one group in the group (a) represents H or C_1-3-a group other than an alkyl group,

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

A preferred first embodiment of the present invention are the compounds of the above general formula I, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³represents a group of the formula II

Wherein

X represents N or C, and X represents N or C,

R^3.1representation H, C_1-3Alkyl or HO-C (O),

if X is equal to N, R^3.2Represents a pair of free electrons, or

If X is ═ C, R^3.2Representation H, C_1-3-alkyl radicalOr HO-C (O),

R⁴represents a group of the formula III

Wherein

Y represents C, and

R^4.1represents H or C_1-3-alkyl, or

Y represents N, and

R^4.1which represents a pair of free electrons that are,

provided that X and Y do not simultaneously represent N,

R^4.2representation H, C_1-3Alkyl or HO-C (O),

R^5.1representation H, C_1-3Alkyl, HO-C (O) -C_1-3alkylene-NH, HO-C (O) -C_1-3alkylene-N (C)_1-3Alkyl), HO-C (O) -C_1-3alkylene-O, HO-C (O) -C_1-3Alkylene, HO-C (O) -O, HO-C (O) -C_1-3alkylene-C (O) or HO-C (O) -C_1-3alkylene-C (O) -O,

R^5.2representation H, C_1-3Alkyl, HO-C (O) -C_1-3alkylene-NH, HO-C (O) -C_1-3alkylene-O, HO-C (O) -C_1-3Alkylene, HO-C (O) or HO-C (O) -C_1-3alkylene-C (O) with the proviso that R^3.1，R^3.2，R^4.2，R^5.1Or R^5.2At least one group in the group (a) represents H or C_1-3-a group other than an alkyl group,

A second embodiment of the present invention are compounds of formula I above, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³represents a group of the formula II

Wherein

X represents N or C, and X represents N or C,

R^3.1representation H, C_1-3-alkyl or R^3.1.1-(O)C，

R^3.1.1Denotes HO, C_1-6-an alkyl-O group, wherein,

if X is equal to N, R^3.2Represents a pair of free electrons, or

If X is ═ C, R^3.2Represents H or C_1-3-an alkyl group,

R⁴represents a group of the formula III

Or

Wherein

Y represents C, and

R^4.1represents H or C_1-3-alkyl, or

Y represents N, and

R^4.1which represents a pair of free electrons that are,

provided that X and Y do not simultaneously represent N,

R^4.2representation H, C_1-3-alkyl or R^4.2.1-(O)C，

R^4.2.1Denotes HO, C_1-6-alkyl-O, and

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1represents R^5.1.1-O-C(O)、R^5.1.1-O-C(O)-C_1-3alkylene-NH, R^5.1.1-O-C(O)-C_1-3alkylene-O, R^5.1.1-O-C(O)-C_1-3Alkylene radical, R^5.1.1-O-C (O) or R^5.1.1-O-C(O)-C_1-3-alkylene-C (O),

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2represents R^5.2.1-O-C(O)-C_1-3alkylene-NH, R^5.2.1-O-C(O)-C_1-3alkylene-O, R^5.2.1-O-C(O)-C_1-3Alkylene radical, R^5.2.1-O-C (O) or R^5.2.1-O-C(O)-C_1-3-alkylene-C (O),

R^5.2.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-C_1-3Alkylene, HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.2.1.1-C(O)-C_1-3Alkylene or R^5.2.1.2-C_2-4-an alkylene group,

R^5.2.1.1represents a group selected from the group consisting of,

and

R^5.2.1.2represents a group selected from the group consisting of,

and

A second preferred embodiment of the present invention are the compounds of the above general formula I, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³represents a group of the formula II

Wherein

X represents N or C, and X represents N or C,

R^3.1representation H, C_1-3Alkyl or HO-C (O),

if X is equal to N, R^3.2Represents a pair of free electrons, or

If X is ═ C, R^3.2Represents H or C_1-3-an alkyl group,

R⁴represents a group of the formula III

Or

Wherein

Y represents C, and

R^4.1represents H or C_1-3-alkyl, or

Y represents N, and

R^4.1which represents a pair of free electrons that are,

provided that X and Y do not simultaneously represent N,

R^4.2representation H, C_1-3Alkyl or HO-C (O),

R^5.1represents HO-C (O), HO-C (O) -C_1-3alkylene-NH, HO-C (O) -C_1-3alkylene-O, HO-C (O) -C_1-3Alkylene, HO-C (O) or HO-C (O) -C_1-3-alkylene-C (O),

R^5.2represents HO-C (O) -C_1-3alkylene-NH, HO-C (O) -C_1-3alkylene-O, HO-C (O) -C_1-3Alkylene, HO-C (O) or HO-C (O) -C_1-3-alkylene-C (O),

A third embodiment of the present invention are compounds of formula I above, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^3.1Representation H, H₃C or R^3.1.1-O-C(O)，

R^3.1.1Representation H, C_1-6Alkyl radicals, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^3.1.1.1-C_2-4-an alkylene group,

R^3.1.1.1represents a group selected from the group consisting of,

and

R^3.2representation H, C_1-3-alkyl or R^3.2.1-O-C(O)，

R^3.2.1Representation H, C_1-6Alkyl radicals, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^3.2.1.1-C_2-4-an alkylene group,

R^3.2.1.1represents a group selected from the group consisting of,

and

R^4.1represents H or C_1-3-an alkyl group,

R^4.2representation H, C_1-3-alkyl or R^4.2.1-O-C(O)，

R^4.2.1Representation H, C_1-6Alkyl radicals, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^4.2.1.1-C_2-4-an alkylene group,

R^4.2.1.1represents a group selected from the group consisting of,

and

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1representation H, H₃C、R^5.1.1-O-C(O)、R^5.1.1-O-C(O)-C_1-3alkylene-NH, R^5.1.1-O-C(O)-C_1-3alkylene-N (C)_1-3-alkyl), R^5.1.1-O-C(O)-C_1-3alkylene-O, R^5.1.1-O-C(O)-C_1-3Alkylene radical, R^5.1.1-O-C(O)-C(O)、R^5.1.1-O-C(O)-C(O)-O、R^5.1.1-O-C(O)-C_1-3alkylene-C (O) or R^5.1.1-O-C(O)-C_1-3alkylene-C (O) -O,

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2is selected from the group consisting ofThe group of (A) a group of (B),

and

R^5.2representation H, H₃C、R^5.2.1-O-C(O)-C_1-3alkylene-NH, R^5.2.1-O-C(O)-C_1-3alkylene-O, R^5.2.1-O-C(O)-C_1-3Alkylene radical, R^5.2.1-O-C (O) or

R^5.2.1-O-C(O)-C_1-3-alkylene-C (O),

R^5.2.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-C_1-3Alkylene, HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4alkylene-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.2.1.1-C(O)-C_1-3Alkylene or R^5.2.1.2-C_2-4-an alkylene group,

R^5.2.1.1represents a group selected from the group consisting of,

and

R^5.2.1.2represents a group selected from the group consisting of,

andor

R^5.2.1Represents a group of the formula,

with the proviso that at least one radical R^3.1，R^3.2，R^4.2，R^5.1Or R^5.2Represents H or C_1-3-a group other than an alkyl group,

A preferred third embodiment of the present invention are the compounds of the above general formula I, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^3.1Representation H, H₃C or HO-C (O),

R^3.2representation H, C_1-3Alkyl or HO-C (O),

R^4.1represents H or C_1-3-an alkyl group,

R^4.2representation H, C_1-3Alkyl or HO-C (O),

R^5.1representation H, H₃C、HO-C(O)、HO-C(O)-C_1-3alkylene-NH, HO-C (O) -C_1-3alkylene-N (C)_1-3Alkyl), HO-C (O) -C_1-3alkylene-O, HO-C (O) -C_1-3Alkylene, HO-C (O) -O, HO-C (O) -O-, HO-C (O) -C_1-3alkylene-C (O) or HO-C (O) -C_1-3alkylene-C (O) -O,

R^5.2representation H, H₃C、HO-C(O)-C_1-3alkylene-NH, HO-C (O) -C_1-3alkylene-O, HO-C (O) -C_1-3Alkylene, HO-C (O) or HO-C (O) -C_1-3-alkylene-C (O),

provided that R is^3.1，R^3.2，R^4.2，R^5.1Or R^5.2At least one group of (A) represents H, H₃C or C_1-3-a group other than an alkyl group,

A fourth embodiment of the present invention are compounds of formula I above, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^3.1The expression "H" is used to indicate the formula,

R^3.2represents H or C_1-3-an alkyl group,

R^4.1represents H or C_1-3-an alkyl group,

R^4.2the expression "H" is used to indicate the formula,

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2.1.1represents a group selected fromThe mass of the balls is obtained by mixing the raw materials,

and

R^5.2.1.2represents a group selected from the group consisting of,

and

A preferred fourth embodiment of the present invention are compounds of the above general formula I, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together areRepresents a group of the formula IV

Wherein

R^3.1The expression "H" is used to indicate the formula,

R^3.2represents H or C_1-3-an alkyl group,

R^4.1represents H or C_1-3-an alkyl group,

R^4.2the expression "H" is used to indicate the formula,

R^5.2represents H-O-C (O) -C_1-3alkylene-NH, HO-C (O) -C_1-3alkylene-O, HO-C (O) -C_1-3Alkylene, HO-C (O) or HO-C (O) -C_1-3-alkylene-C (O),

A fifth embodiment of the invention are compounds of formula I above, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^3.1Represents H or R^3.1.1-O-C(O)，

R^3.1.1.1represents a group

R^3.2Representation H, H₃C or R^3.2.1-O-C(O)，

R^3.2.1Representation H, C_1-6Alkyl radicals, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene group, (C)_1-3-alkyl radical)₂N-C(O)-C_1-3Alkylene or R^3.2.1.1-C_2-4-an alkylene group,

R^3.2.1.1represents a group

R^4.2Represents H or H₃C，

R^4.3Representation H, C_1-6Alkyl radicals, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^4.3.1-C_2-4-an alkylene group,

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1representation H, H₃C、R^5.1.1-O-C(O)、R^5.1.1-O-C(O)-C_1-3alkylene-NH, R^5.1.1-O-C(O)-C_1-3alkylene-N (C)_1-3-alkyl), R^5.1.1-O-C(O)-C_1-3alkylene-O, R^5.1.1-O-C(O)-C_1-3Alkylene radical, R^5.1.1-O-C(O)-C(O)、R^5.1.1-O-C(O)-C(O)-O-、R^5.1.1-O-C(O)-C_1-3alkylene-C (O) or R^5.1.1-O-C(O)-C_1-3alkylene-C (O) -O,

R^5.1.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-CH₂、HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.1.1.1-C(O)-C_1-3Alkylene or R^5.1.1.2-C_2-4-an alkylene group,

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2representation H, H₃C、R^5.2.1-O-C(O)-C_1-3Alkylene radical, R^5.2.1-O-C (O) or R^5.2.1-O-C(O)-C_1-3-alkylene-C (O),

R^5.2.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-CH₂、HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4alkylene-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.2.1.1-C(O)-C_1-3Alkylene or R^5.2.1.2-C_2-4-an alkylene group,

R^5.2.1.1represents a group selected from the group consisting of,

R^5.2.1.2represents a group selected from the group consisting of,

andor

R^5.2.1Represents a group of the formula

A fifth preferred embodiment of the present invention are compounds of formula I above wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^3.1Represents H or HO-C (O),

R^3.2representation H, H₃C or HO-C (O),

R^4.2represents H or H₃C，

R^5.1Represents HO-C (O), HO-C (O) -C_1-3alkylene-NH, HO-C (O) -C_1-3alkylene-N (C)_1-3Alkyl), HO-C (O) -C_1-3alkylene-O, HO-C (O) -C_1-3Alkylene, HO-C (O) -O, HO-C (O) -C_1-3alkylene-C (O)Or HO-C (O) -C_1-3alkylene-C (O) -O,

R^5.2represents HO-C (O) -C_1-3Alkylene, HO-C (O) or HO-C (O) -C_1-3-alkylene-C (O),

A sixth embodiment of the invention are compounds of formula I above, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2represents R^5.2.1-O-C(O)-C_1-3Alkylene radical, R^5.2.1-O-C (O) or R^5.2.1-O-C(O)-C_1-3-alkylene-C (O),

R^5.2.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-CH₂、HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.2.1.1-C(O)-C_1-3Alkylene or R^5.2.1.2-C_2-4-an alkylene group,

R^5.2.1.1represents a group selected from the group consisting of,

R^5.2.1.2represents a group selected from the group consisting of,

and

A sixth preferred embodiment of the present invention are compounds of formula I above wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

A seventh embodiment of the present invention are compounds of formula I above, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

The following compounds are also indicated as examples of the most preferred compounds of formula I above:

Terms and definitions used

Unless otherwise specified, all substituents are independent of each other. For example, if a group has more than one C_1-6Alkyl as a substituent at three C_1-6In the case of alkyl substituents, each substituent, independently of the others, may represent methyl and one may represent n-propylAnd one may represent a tert-butyl group.

Within the scope of the present description, in the definition of possible substituents, these substituents may also be represented in the form of structural formulae. Asterisks in the structural formulae of substituents, if present (^*) It is understood as a point of attachment to the rest of the molecule.

Also included in the subject matter of the invention are compounds according to the invention, including salts thereof, in which one or more hydrogen atoms (e.g., 1, 2, 3, 4 or 5 hydrogen atoms) are replaced by deuterium.

The term "C_1-3Alkyl "(also included as part of another group) means branched and straight-chain alkyl groups having 1 to 3 carbon atoms, the term" C_1-6Alkyl refers to branched and straight-chain alkyl groups having 1 to 6 carbon atoms, the term "C_1-8Alkyl "refers to branched and straight-chain alkyl groups having from 1 to 8 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. The following abbreviations may also optionally be used for the above groups: me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. Unless otherwise specified, the definitions propyl, butyl, pentyl, hexyl, heptyl and octyl include all possible isomeric forms of the groups described. Thus, for example, propyl includes n-propyl and isopropyl, and butyl includes isobutyl, sec-butyl, tert-butyl, and the like.

The term "C_1-3Alkylene "(also included as part of another group) refers to branched and straight chain alkylene groups having 1 to 3 carbon atoms, the term" C_2-4By alkylene is meant having

Branched and straight chain alkylene of 2 to 4 carbon atoms. Examples include: methylene, ethylene, ethane-1, 1-diyl, propylene, propane-2, 2-diyl, 1-methylethylene, butylene, 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene. Unless otherwise stated, the definitions propylene and butylene include all possible isomeric forms having the same carbon number. Thus, for example, propylene also includes 1-methylethylene and butylene includes 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene.

It should also be noted that within the scope of the present invention, the terms "alkylene" and "alkylidene" are used synonymously.

The compounds of formula I may have acidic groups, mainly carboxyl groups, and/or basic groups, such as amino functions. The compounds of the general formula I can thus be formed as internal salts, as salts with pharmaceutically usable inorganic acids, such as hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or organic acids, such as malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid, citric acid, or as salts with pharmaceutically usable bases, such as hydroxides of alkali metals or alkaline earth metals (e.g. sodium hydroxide or potassium hydroxide), or carbonates, ammonia, zinc hydroxide or ammonium hydroxide or organic amines, such as diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine.

The invention relates to said compounds, optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates, in the form of tautomers as well as in the form of the free base or of the corresponding acid addition salts with pharmacologically acceptable acids, for example with hydrohalic acids (for example hydrochloric acid or hydrobromic acid) or organic acids (for example oxalic acid, fumaric acid, diglycolic acid or methanesulfonic acid).

The compounds of the invention can be present as racemates, which can also be obtained as pure enantiomers if they have only one chiral element, i.e. in (R) -or (S) -form, preferably as racemates or in (R) -form.

But the application also includes individual diastereoisomeric pairs of enantiomers or mixtures thereof, which occur when there is more than one chiral element in the compound of formula I, as well as individual optically active enantiomers, and hence the racemates mentioned.

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

Preparation method

The compounds of the general formula I are prepared in a manner known in principle. The following methods have proven particularly useful for the preparation of compounds of the general formula I according to the invention:

(a) for the preparation of compounds of the general formula I, wherein all radicals are as defined above: coupling of carboxylic acids of the formula V with amines of the formula VI

In the formula V, R¹And R²Are as defined above in the description and are,

H-R³-R⁴，

wherein R is³And R⁴Are as defined above, linked by R³Is carried out by the nitrogen atom of (1).

Prior to carrying out the reaction, is present in the formula H-R³-R⁴Any carboxylic acid functional group, primary or secondary amino functional group or hydroxyl functional group in the amine group may be protected by a conventional protecting group, and the protecting group used may be cleaved again, if necessary after the reaction has been carried out, according to a method familiar to those skilled in the art.

The coupling is preferably carried out using methods known from peptide chemistry (cf., for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides, such as Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC) or ethyl- (3-dimethylaminopropyl) -carbodiimide, O- (1H-benzotriazol-1-yl) -N, N-N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) or the tetrafluoroborates (TBTU) thereof, or 1H-benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP). The reaction rate can be increased by adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3, 4-dihydro-1, 2, 3-benzotriazine (HOObt). The coupling is usually carried out in a solvent such as dichloromethane, tetrahydrofuran, acetonitrile, Dimethylformamide (DMF), Dimethylacetamide (DMA), N-methyl-tetrahydropyrrolidone (NMP) or mixtures thereof, in equimolar amounts of the coupling components and the coupling reagent, at a temperature between-30 ℃ and +30 ℃, preferably between-20 ℃ and +25 ℃. If necessary, it is preferred to use N-ethyl-diisopropylamine (Hunig's base) as further auxiliary base.

The so-called "anhydride method" is used as a further coupling method for the Synthesis of compounds of the general formula I (see: M.Bodanszky, "Peptide Chemistry", Springer-Verlag 1988, pages 58 to 59; M.Bodanszky, "Principles of Peptide Synthesis", Springer-Verlag 1984, pages 21 to 27). Preference is given to the mixed anhydride preparation according to the Vaughan variant (J.R.Vaughan Jr.J.Amer.chem.Soc.73, 3547(1951)) in which isobutyl chlorocarbonate is used to obtain the mixed anhydride of the carboxylic acid of the formula V to be coupled with monoisobutyl carbonate in the presence of a base such as 4-methylmorpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with the amines of the formula VI is carried out in a one-pot process using the abovementioned solvents and at temperatures between-20 ℃ and +25 ℃, preferably between 0 ℃ and +25 ℃.

(b) For the preparation of compounds of the general formula I, wherein all radicals are as defined above:

reacting a compound of the formula VII

Wherein R is¹And R²Are all asAs defined above, and Nu represents a leaving group, for example a halogen atom, for example a chlorine, bromine or iodine atom, an alkylsulfonyloxy group having from 1 to 10 carbon atoms in the alkyl moiety, a phenylsulfonyloxy group or a naphthylsulfonyloxy group, which is optionally mono-, di-or trisubstituted by a chlorine or bromine atom, by a methyl or nitro group, where the substituents may be identical or different, a 1H-imidazol-1-yl group, a 1H-pyrazol-1-yl group optionally substituted by one or two methyl groups in the carbon skeleton, a 1H-1, 2, 4-triazol-1-yl group, a 1H-1, 2, 3, 4-tetrazol-1-yl group, a vinyl group, a propargyl group, a p-nitrophenyl group, a2, 4-dinitrophenyl group, a2, 3-triazol-1-yl group, a 1H-1, 2, 3, 4-tetrazol-1-yl group, Trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridyl, dimethylaminoxy (dimethylaminyloxy), 2(1H) -oxopyridin-1-yl-oxy, 2, 5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azido group, coupling with an amine of the formula VI

H-R³-R⁴，

Wherein all radicals are as defined above and the linkage is via the amine R³Is carried out by the nitrogen atom of (1).

Any carboxylic acid functional, primary or secondary amino or hydroxyl groups present in the amine groups of formula VI may be protected prior to the reaction by conventional protecting groups, and after the reaction has been carried out, any protecting groups used may be cleaved again using methods familiar to those skilled in the art.

The reaction is carried out under Schotten-Baumann or Einhorn conditions, i.e.the components are reacted in the presence of at least one equivalent of a secondary base at a temperature between-50 ℃ and +120 ℃, preferably between-10 ℃ and +30 ℃ and optionally in the presence of a solvent. The auxiliary bases used are preferably alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, such as sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetates, such as sodium or potassium acetate, and tertiary amines, such as pyridine, 2, 4, 6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1, 4-diazabicyclo [ 2.2.2 ] octane or 1, 8-diazabicyclo [ 5.4.0 ] undec-7-ene, the solvents used may be, for example, dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or alkali metal acetates are used as auxiliary bases, water can also be added to the reaction mixture as a cosolvent.

The novel compounds of the general formula I according to the invention contain one or more chiral centers. For example, if two chiral centers are present, the compound may exist as two diastereomeric pairs of enantiomers. The present invention includes individual isomers as well as mixtures thereof.

Diastereomers may be separated on the basis of their different physico-chemical properties, for example by fractional crystallization from a suitable solvent, by high pressure liquid chromatography or column chromatography, using chiral, or preferably achiral, stationary phases.

The racemates contained by formula I can be separated, for example, by HPLC on a suitable chiral stationary phase (e.g., chiral AGP, Chiralpak AD). Racemates containing basic or acidic functional groups can also be separated via diastereomeric optically active salts formed upon reaction with an optically active acid, such as (+) or (-) -tartaric acid, (+) or (-) -diacetyltartaric acid, (+) or (-) -monomethyl tartrate or (+) or (-) -camphorsulfonic acid, or an optically active base, such as (R) - (+) -1-phenylethylamine, (S) - (-) -1-phenylethylamine or (S) -guacamine (brucine).

According to a conventional method for separating isomers, a racemate of a compound of the general formula I is reacted with an equimolar amount of one of the above optically active acids or bases in a solvent, and the resulting crystalline diastereomeric optically active salts are separated by their different solubilities. This reaction can be carried out in any type of solvent, provided that the solubility of the salts differs significantly. Preference is given to using methanol, ethanol or mixtures thereof, for example in a ratio of 50:50 by volume. Each optically active salt is then dissolved in water, carefully neutralized with a base, such as sodium or potassium carbonate, or with a suitable acid, such as dilute aqueous hydrochloric or methanesulfonic acids, and the corresponding compound is obtained in its free (+) or (-) form.

The (R) or (S) enantiomer alone, or a mixture of two optically active diastereoisomeric compounds, encompassed by formula I, may also be synthesized as described above to obtain the appropriate reaction components in the (R) or (S) configuration.

The hydroxycarboxylic acids of the formula V which are necessary as starting compounds can be obtained by reacting piperidines of the formula VIII with carbonic acid derivatives of the formula IX and with compounds of the formula X

R in the formula VIII¹As defined above in the foregoing description,

in formula IX Y¹And Y²Denotes a nucleofugic group, which may be the same or different, and is preferably a chlorine atom, a p-nitrophenoxy group or a trichloromethoxy group,

in the formula X, R²As defined above, and Z¹Representing a protecting group for a carboxyl group, e.g. C_1-6Alkyl or optionally substituted benzyl, wherein alkyl may be straight or branched chain and benzyl may be substituted by one or two methoxy groups.

Z¹Preferably methyl, ethyl, tert-butyl or benzyl. The group R present in the compound of formula (VI) before the reaction is carried out²The hydroxyl group in (A) may be protected by a conventional protecting groupProtection and, after the reaction is complete, the protecting groups used can be cleaved again in a manner familiar to the person skilled in the art.

In a first step, a compound of formula VIII is reacted with a carbonic acid derivative of formula IX in a solvent, e.g. in dichloromethane, THF, pyridine or a mixture thereof, at a temperature between-20 ℃ and 50 ℃ in the presence of a base, e.g. triethylamine, pyridine or ethyldiisopropylamine. The intermediate thus formed can be purified or further reacted without purification. The reaction of this intermediate with the compound of the general formula X, also in one of the solvents mentioned above, and at the temperatures indicated above, is carried out in the presence of a base, such as triethylamine or pyridine, with or without addition of an activating reagent, such as 4-dimethylaminopyridine. For its activation, the compounds of the formula X can also be deprotonated using metal hydrides, such as NaH or KH, in which case, however, the presence of a base or an activating agent is not necessary.

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

A route to compounds of formula X comprising reacting an aldehyde of formula XI

(wherein R is²As defined hereinbefore) with N-acetylglycine in the presence of an alkali metal acetate, preferably sodium or potassium acetate, as solvent at a suitable temperature, preferably from 80 to 130 ℃.

The initially formed azalide (azlactone) is hydrolyzed without isolation to a compound of the formula XII

Wherein R is²As previously defined. By further reaction in the presence of aqueous mineral acids, such as sulfuric acid, phosphoric acid or hydrochloric acid, but preferably hydrochloric acid, compounds of the formula XIII are obtained

Wherein R is²As previously defined.

Then, it is converted into the compound of the formula XIV with a suitable reducing agent

Wherein R is²As previously defined.

Suitable reducing agents are alkali metal borohydrides, such as sodium borohydride or potassium borohydride. Other suitable reducing agents are chlorodialkylboranes, such as chlorodicyclohexylborane. If chiral chlorodialkylboranes such as B-chlorodiisopinosyl borane are used, the compounds of the formula XIV can be separated in enantiomerically pure form. The further reaction of the compound of formula XIV to form the compound of 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 may be carried out by reaction with thionyl chloride in an alcohol solvent, preferably methanol.

All compounds of the formula I which contain primary or secondary amino, hydroxyl or hydroxycarbonyl functions are preferably obtainable from precursors having protecting groups. Examples of amino-functional protecting groups include benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-biphenyl- α, α -dimethyl-benzyloxycarbonyl or 3, 5-dimethoxy- α, α -dimethyl-benzyloxycarbonyl, alkoxycarbonyl having a total of from 1 to 5 carbon atoms in the alkyl moiety, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxy-carbonyl or tert-butoxycarbonyl, allyloxycarbonyl, 2, 2, 2-trichloro- (1, 1-dimethylethoxy) carbonyl or 9-fluorenylmethoxycarbonyl, or formyl, acetyl or trifluoroacetyl.

Examples of hydroxy protecting groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl, tert-butyl, benzyl, 4-methoxybenzyl or 3, 4-dimethoxybenzyl.

Examples of hydroxycarbonyl protecting groups include alkyl groups having a total of 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, allyl, 2, 2, 2-trichloroethyl, benzyl, or 4-methoxybenzyl.

The compounds of the general formula I obtained, if they contain suitable basic functional groups, can be converted into their physiologically acceptable salts with inorganic or organic acids, in particular for pharmaceutical use. Suitable acids include, for example, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, acetic, fumaric, succinic, lactic, mandelic, malic, citric, tartaric, or maleic acid.

Furthermore, if they contain carboxylic acid functions, the novel compounds of the formula I can be converted into their addition salts with inorganic or organic bases, in particular for pharmaceutical use, into their physiologically acceptable addition salts. Bases suitable for use herein include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.

If the compounds of the formula I have only one chiral element, the invention relates to racemates. However, the present application also includes individual diastereoisomeric pairs of enantiomers or mixtures thereof, which may be present if there is more than one chiral element in the compound of formula I, as well as mixtures thereof, and the individual optically active enantiomers which thus constitute the racemates mentioned.

Also included as subject matter of the invention are compounds according to the invention, including salts thereof, wherein one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by deuterium.

The novel compounds of the general formula I and their physiologically acceptable salts have valuable pharmacological properties on the basis of their selective CGRP-antagonistic properties. The invention further relates to medicaments containing such compounds, their use and their preparation.

The above-mentioned novel compounds and their physiologically acceptable salts have CGRP-antagonistic properties and show good affinity in CGPR receptor binding studies. These compounds exhibit CGRP-antagonistic properties in the pharmacological test system described below.

The following experiments were performed to confirm the affinity of the above mentioned compounds for the human CGRP receptor and their antagonistic properties:

A. binding studies with SK-N-MC cells (expressing human CGRP receptor)

SK-N-MC cells were cultured in "Dulbecco's modified Eagle Medium". Removing the medium from the fused culture. The cells were washed twice with PBS buffer (Gibco 041-04190M), lysed by addition of PBS buffer mixed with 0.02% EDTA, and separated by centrifugation. Resuspended in 20 ml "balanced salt solution" [ BSS (in mM): NaCl 120, KCl 5.4, NaHCO₃ 16.2，MgSO₄ 0.8，NaHPO₄ 1.0，CaCl₂1.8, D-glucose 5.5, HEPES 30, pH 7.40]After (c), the cells were centrifuged twice at 100 × g and resuspended in BSS. After the cell number has been determined, the cells are homogenized using an Ultra-Turrax and centrifuged at 3000 Xg for 10 minutes. The supernatant was discarded, and the pellet was placed in Tris buffer (10mM Tris, 50mM NaCl, 5mM MgCl) containing 1% bovine serum albumin and 0.1% bacitracin₂1mM EDTA, pH 7.40)Enrichment was re-centrifuged and re-suspended (1 ml/1000000 cells). The homogenate was frozen at-80 ℃. The cell membrane preparation was stable for more than 6 weeks under these conditions.

After thawing, the homogenate was washed with assay buffer (50mM Tris, 150mM NaCl, 5mM MgCl)₂1mM EDTA, pH 7.40) at 1:10 and homogenized for 30 seconds at Ultra-Turrax. 230 microliters of homogenate are incubated with 50pM 125I-iodotyrosyl-calcitonin-gene-related peptide (Amersham) at ambient temperature for 180 minutes, and increasing concentrations of test substance in a total volume of 250 microliters. The incubation was stopped by rapid filtration through a GF/B-glass fiber filter that had been treated with polyethyleneimine (0.1%) using a cell harvester. Bound radioactivity on the protein was measured using a gamma counter. Non-specific binding is defined as the radioactivity bound during culture in the presence of 1. mu.M human CGRP-alpha.

Concentration binding curves were analyzed using computer-assisted nonlinear curve fitting.

In said assay, the above-mentioned compounds show IC₅₀The value is less than or equal to 10000 nM.

B. CGRP antagonism in SK-N-MC cells

SK-N-MC cells (1 million cells) were washed twice with 250. mu.l of culture buffer (HEPES from Hanks, 1mM 3-isobutyl-1-methylxanthine, 1% BSA, pH7.4) and pre-incubated at 37 ℃ for 15 minutes. In addition as an increasing concentration (10)^-11To 10^-6M) or otherwise with 3 to 4 different concentrations of this substance, the mixture is incubated for a further 15 minutes.

Intracellular cAMP was then extracted by addition of 20. mu.l of 1M HCl and then centrifuged (2000 Xg, 4 ℃ C. over 15 minutes). The supernatant was frozen in liquid nitrogen and stored at-20 ℃.

cAMP content in a sample is determined by radioimmunoassay (Mess rs. Amersham) and antagonizes pA of the agent₂The value being determined graphically。

In the in vitro test model, the compounds of the invention are at 10^-12To 10^-5The CGRP-antagonistic properties are shown between the dose ranges of M.

Indications of

Due to their pharmacological profile, the compounds according to the invention and their salts with physiologically acceptable acids are suitable for the acute and prophylactic treatment of headache (in particular migraine, cluster headache and tension headache). Furthermore, the compounds according to the invention also have a positive effect on: non-insulin dependent diabetes mellitus ("NIDDM"), cardiovascular disease, morphine tolerance, diarrhea caused by clostridium toxin, skin disease (especially heat and radiation induced skin damage including sunburn, lichen disease, prurigo, pruritic toxic dermatitis (pruritic toxidermies) and severe itching irritation), inflammatory disease (e.g., inflammatory disease of joints (osteoarthritis, rheumatoid arthritis, neuroarthritis), systemic soft tissue rheumatism (fibromyalgia), neuroinflammation of oral mucosa, inflammatory lung disease, allergic rhinitis, asthma, COPD, diseases caused by excessive vasodilation and resulting decrease in blood supply to tissues (e.g., shock and sepsis), chronic pain (e.g., diabetic neuropathy), chemotherapy-induced neuropathy, HIV-induced neuropathy, post-herpetic neuropathy, Neuropathy caused by tissue trauma, trigeminal neuralgia, temporomandibular dysfunction, CRPS (combined regional pain disorder), back pain, and visceral diseases such as Irritable Bowel Syndrome (IBS) and inflammatory bowel syndrome. In addition, the compounds according to the invention have a general pain-relieving effect. Hot flashes in estrogen-deficient women due to vasodilation and increased blood flow and the advantageous effect of prophylactic and acute therapeutic application of the CGRP antagonists of the present application in prostate cancer patients and castors, which treatment is distinguished from hormone replacement by no 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 prevention and acute treatment of hot flushes in women with estrogen deficiency.

The dosage required to achieve the corresponding effect is suitably from 0.0001 to 3 mg/kg of body weight, preferably from 0.01 to 1 mg/kg of body weight, when administered intravenously or subcutaneously, and from 0.01 to 10 mg/kg of body weight, preferably from 0.1 to 10 mg/kg of body weight, when administered orally, nasally or by inhalation, in each case from 1 to 3 times a day.

If treatment with CGRP antagonists and/or CGRP release inhibitors is used to supplement conventional hormone replacement, it is advisable to lower the above indicated dose, in which case the dose may be 1/5 from the above lower limit up to 1/1 from the indicated upper limit.

CGRP is released by sensory nerves, such as the trigeminal nerve, which innervates a portion of the facial skin. Stimulation of the trigeminal ganglion in humans has been shown to result in increased plasma levels of CGRP and to cause redness of the face ([4 ]: P.J. Goadsby et al, Annals of Neurology, Vol.23, No. 2, 1988, 193- "196).

To demonstrate that hot flashes can be successfully treated by the aid of CGRP antagonists of general formula I which stimulate the trigeminal ganglia to cause increased release of endogenous CGRP in marmosets, resulting in increased blood flow through the cutaneous vessels. Efficacy is characterized by the determination of a specific dose administered intravenously, which reduces blood flow through facial skin by 50% of the increase caused by endogenous CGRP. A detailed description of this process is disclosed in European patent EP 1207884B 1.

The CGRP antagonists according to the invention are also active in visceral pain patterns in rodents. In this model, the hypersensitivity of the visceral system is achieved by stimulating the intestine with instillation chemicals, such as butyrate, trinitrobenzene sulfonic acid or acetic acid. Intestinal hypersensitivity is measured, for example, by the number of abdominal contractions. This occurs after the expansion of the balloon introduced into the intestine and increases in the allergic intestine (Bourdu et al, Gastroenterology, 2005, 128, 1996-2008; Diop et al, J.Phamacol. exp. ther.2002, 302, 1013-1022; Plourde et al, am.J.Physiol.1997, 273, G191-G196).

Since the CGRP antagonist according to the present invention reverses the intestinal hypersensitivity in the above-mentioned mode, it can be used for the treatment of IBS (irritable bowel syndrome).

The invention further relates to the use of the compounds of the invention as valuable adjuvants in the manufacture and purification (affinity chromatography) of antibodies and in RIA and ELISA assays, for example by tritiation of suitable precursors (for example by catalytic hydrogenation of tritium or replacement of the halogen atom by tritium), after suitable radiolabelling, and as diagnostic or analytical adjuvants in neurotransmitter research.

Combination of

Active substance classes which can be used in combination include antiemetics, prokinetic (prokinetic), neuroleptics, antidepressants, neurokinin antagonists, antispasmodics, histamine-H1-receptor antagonists, beta-blockers, alpha-agonists and alpha-antagonists, ergot alkaloids, mild analgesics, non-steroidal anti-inflammatory agents, corticosteroids, calcium antagonists, 5-HT_1B/1DAgonists or other antimigraine agents which may be formulated with one or more inert conventional carriers and/or diluents (e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetostearyl alcohol, carboxymethyl cellulose or fatty substances such as solid fats or suitable mixtures thereof) into conventional galenic preparations (e.g. tablets or coated, capsules, powders, suspensions, solutions, metered aerosols or suppositories).

Thus, other active substances which may be used in the above combinations include, for example, the non-steroidal anti-inflammatory agents aceclofenac, acemetacin, acetylsalicylic acid, acetamidophenol (paracetamol), azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulfasalazine, zomepirac or a pharmaceutically acceptable salt thereof and meloxicam and other selective COX 2-inhibitors, such as, for example, rofecoxib, valdecoxib, parecoxib, etoricoxib and celecoxib, as well as substances which inhibit the early or late stages of prostaglandin synthesis or prostaglandin receptor antagonists such as EP 2-receptor antagonists and IP-receptor antagonists.

Ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, thiothidine, botulinum toxin (botox), gabapentin, pregabalin, duloxetine, topiramate, riboflavin (riboflavin), montelukast, lisinopril, telmisartan, norgestrel (prochloroperazine), dexamethasone, flunarizine, dexpropoxyphene, pethidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenytoin, sodium valproate, amitriptyline (amitriptiline), imipramine, venlafaxine, lidocaine or diltiazem(and other 5-HT)_1B/1DAgonists such as almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.

In addition, CGRP-antagonists can be added as well as the following: vanilloid receptor antagonists such as VR-1 antagonists, glutamate receptor antagonists such as mGlu 5-receptor antagonists, mGlu 1-receptor antagonists, iGlu 5-receptor antagonists, AMPA-receptor antagonists, purine receptor blockers such as P2X3 antagonists, NQ-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-sensitive 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.

The dosage of these actives is suitably 1/5 at the lowest normally recommended dose to 1/1 at the normally recommended dose, meaning, for example, 20 to 100mg sumatriptan.

Preparation

The compounds prepared according to the invention can be administered by intravenous, subcutaneous, intramuscular, intra-articular, intrarectal, intranasal route, by inhalation, topically, transdermally or orally, alone or optionally in combination with other active substances for the treatment of migraine, whereas aerosol formulations are particularly suitable for inhalation. The compositions may be administered simultaneously or sequentially.

Suitable forms for administration are, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. In each case, the proportion of the pharmaceutically active compounds should be in the range from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight, of the total composition, i.e. in an amount sufficient to achieve the dosage ranges mentioned below.

Oral administration may be in the form of tablets, powders in capsules (e.g., hard gelatin capsules), or as solutions or suspensions. When administered by inhalation, the active substance combination can be administered as a powder, an aqueous or aqueous-alcoholic solution or via a propellant gas formulation.

Preferred pharmaceutical preparations are therefore characterized in that they contain one or more compounds of the formula I according to the preferred embodiments described above.

It is particularly preferred if the compounds of the formula I are administered orally, and it is also particularly preferred if they are administered once or twice a day. Corresponding tablets may, for example, be obtained by mixing the active substance with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binding agents, such as starch or gelatin, lubricating agents, such as magnesium stearate or talc and/or agents delaying release, such as carboxymethylcellulose, ethylcellulose, or polyvinyl acetate.

Corresponding coated tablets can be prepared by coating cores, manufactured analogously to the tablets, with substances which are customarily used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of multiple layers for delayed release or to prevent incompatibilities. Similarly, to achieve delayed release the tablet coating may consist of multiple layers, and the excipients mentioned above for tablets may be used.

Syrups containing the active substance or a composition thereof according to the invention may additionally contain sweetening agents, for example saccharin, cyclamate, glycerol or sugar, and taste enhancers (for example, flavoring agents such as vanillin or orange extract (orange extract), it may furthermore also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Capsules containing one or more active substances or compositions of active substances may be prepared, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and packaging them in gelatin capsules. Suitable suppositories may be prepared, for example, by mixing them with a predetermined carrier, for example, neutral fats or polyethylene glycols or derivatives thereof.

Excipients that may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut or sesame oil), mono-or polyhydric alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose and glucose), emulsifiers (e.g., lignin, spent sulfite liquor, methyl cellulose, starch and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

For oral administration, these tablets may, of course, contain, in addition to the aforementioned defined carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate in combination with various additives such as starch (preferably potato starch), gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used in the manufacture of tablets. In the case of aqueous suspensions, the active substances may be mixed with various odorants or colorants in addition to the above-mentioned excipients.

It is likewise preferred if the compounds of the formula I are administered by inhalation, particularly preferably if they are administered once or twice a day. To achieve this, the compounds of formula I must be formulated into inhalable dosage forms. Inhalable formulations include inhalable powders, propellant-containing metered aerosols or propellant-free inhalable solutions, optionally mixed with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrated or sterile ready-to-use inhalable solutions. Dosage forms that can be used within the scope of the present invention are described in detail in the next section of the specification.

Inhalable powder

If the compounds of the formula I are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare the inhalable powders according to the invention: monosaccharides (e.g., glucose or arabinose), disaccharides (e.g., lactose, sucrose, maltose), oligo-and polysaccharides (e.g., dextran), polyols (e.g., sorbitol, mannitol, xylitol), salts (e.g., sodium chloride, calcium carbonate) or mixtures of these excipients. Preferably, mono-or di-saccharides are used, with lactose or glucose being particularly preferably used (but not exclusively) in their hydrate form. The invention is particularly preferably used with lactose, lactose monohydrate being particularly preferred. The process for the manufacture of the inhalable powders according to the invention by grinding and micronization and by finally mixing the ingredients together is known in the prior art.

Inhalable aerosols containing propellant

The propellant gas-containing inhalation aerosols which can be used according to the invention can contain I dissolved in the propellant gas or in dispersed form therein. Propellant gases which can be used for the preparation of inhalation aerosols are known from the prior art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as, preferably, fluorinated derivatives of methane, ethane, propane, butane, cyclopentane or cyclobutane. The propellant gases mentioned above may be used alone or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from the group consisting of TG134a (1, 1, 1, 2-tetrafluoroethane), TG227(1, 1, 1, 2, 3, 3, 3-heptafluoropropane) and mixtures thereof. The propellant gas-containing inhalation aerosols which can be used according to the scope of application of the invention may also contain further constituents such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and pH regulators. All these ingredients are known in the prior art.

Propellant-free inhalable solutions

The use of the compounds of the formula I according to the invention is preferably used for the preparation of propellant-free inhalable solutions and inhalable suspensions. Solvents useful for this purpose include aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water alone or a mixture of water and ethanol. The pH of the solution or suspension is adjusted to 2 to 7, preferably 2 to 5, using a suitable acid. The pH can be adjusted using an acid selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and the like. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which have formed acid addition salts with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid, and citric acid are preferable. Mixtures of the above acids may be used if desired, especially in the case of acids having other properties than their acidifying properties (e.g. as fragrances, antioxidants or complexing agents), for example citric acid or ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used for adjusting the pH.

Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions used in the present invention. Preferred cosolvents are solvents containing hydroxyl groups or other polar groups, for example alcohols, especially isopropanol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context are to be understood as meaning pharmaceutically acceptable substances which are not active substances but can be formulated with one or more active substances in pharmacologically suitable solvents in order to modify the properties of the active substance preparation. Preferably such substances have no pharmacological effect or no noteworthy or at least no adverse pharmacological effect on the relevant treatment. Excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and/or preservatives that ensure or prolong the shelf life of the finished pharmaceutical formulation, flavoring agents, vitamins and/or other additives known in the art. These additives also include pharmacologically acceptable salts such as sodium chloride as an isotonic agent. Preferred excipients include antioxidants such as ascorbic acid (e.g., with the proviso that it is not used to adjust pH), vitamin a, vitamin E, tocopherol, and similar vitamins and provitamins present in the human body. Preservatives can be used to protect the formulation from contamination by pathogens. Suitable preservatives are known from the prior art, especially cetylpyridinium chloride, benzalkonium chloride and benzoic acid or benzoates such as sodium benzoate in concentrated solutions known from the prior art.

Experimental part

In general, the compounds prepared have been obtained¹H-NMR and mass spectrometry. Unless otherwise stated, R_fValues were measured using an off-the-shelf TLC silica gel plate 60F 254(e.merck, Darmstadt, item No. 1.05714) without saturation using an expansion tank.

R measured by the name Polygram silica gel_fValues obtained using a ready-made Polygram SIL G/UV254 TLC film (coated with 0.2 mm silica gel) manufactured by Macherey-Nagel (Duren, item number 805021).

Rf values, as measured under the name Polygram Alox, were obtained using a Polygram Alox N/UV254 TLC film (coated with 0.2 mm alumina) off-the-shelf manufactured by Macherey-Nagel (Duren, item number 802021).

The proportions given for the eluent relate to the ratio of the volume units of the solvent given. To NH₃The given volume ratio unit is related to NH₃Concentrated solution in water.

Unless otherwise stated, the acid, base and salt solutions used to treat the reaction solutions are aqueous systems of the concentrations given.

Silica gel (MATREX) manufactured by Millipore^TM35-70 microns) was used for chromatographic purification.

Alumina (Alox) manufactured by ICN Biomedicals (Eschwege, item No. 02090) was used for chromatographic purification. The required active phases (active phases II-III) are generated before use according to the manufacturer's instructions.

The HPLC data provided are measured under the parameters listed below:

the method A comprises the following steps:

and (3) analyzing the column: merck Chromolith Speed ROD, RP18 e; 4.6X 50 mm; column temperature: 30 ℃; flow rate: 1.5 ml/min; injection volume: 5 microliter; detection at 254 nm

Time [ min ] volume ratio of bulk acetonitrile (with 0.1% formic acid) of water (with 0.1% formic acid)

Percentage by volume

0 90 10

4.5 10 90

5 10 90

5.5 90 10

The method B comprises the following steps:

and (3) analyzing the column: zorbax columns (Agilent Technologies), SB (Stable bond) -C18; 3.5 microns; 4.6X 75 mm; column temperature: 30 ℃; flow rate: 1.6 ml/min; injection volume: 5 microliter; detection at 254 nm

Percentage by volume

0 95 5

4.5 10 90

5.0 10 90

5.5 90 10

The method C comprises the following steps:

and (3) analyzing the column: zorbax columns (Agilent Technologies), SB (Stable bond) -C18; 3.5 microns; 4.6X 75 mm; column temperature: 30 ℃; flow rate: 0.8 ml/min; injection volume: 5 microliter; detection at 254 nm

Time [ min ] water (with 0.1% formic acid) acetonitrile (with 0.1% formic acid)

Volume percent of volume percent

0 95 5

9 10 90

10 10 90

11 90 10

In preparative HPLC purification, the same gradient as used to obtain analytical HPLC data is typically used.

The product was collected under mass spectrometry control, and the product-containing fractions were pooled and lyophilized.

In the absence of any further data on configuration, it is not clear whether pure enantiomers are involved or whether partial or even total racemisation occurs.

The following abbreviations are used in the experimental description:

boc tert-butyloxycarbonyl group

Cyc cyclohexane

DCM dichloromethane

DIPE diisopropyl ether

DMF N, N-dimethylformamide

EtOAc ethyl acetate

EtOH ethanol

h hours

HCl hydrochloric acid

HOAc acetic acid

Vac. in vacuum (under vacuum)

min for

MeOH methanol

MTBE methyl-tert-butyl ether

NaOH sodium hydroxide

PE Petroleum Ether

RT ambient temperature

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

TFA trifluoroacetic acid

THF tetrahydrofuran

The preparation of the starting compounds is described below:

amine 1

3- [4, 4' ] Bipiperidinyl-1-yl-propionic acid ethyl ester

A1a)1 '- (2-ethoxycarbonyl-ethyl) - [4, 4' ] bipiperidinyl-1-carboxylic acid tert-butyl ester

4.4 ml (40.6 mmol) of ethyl acrylate are added to a solution of 10.0 g (37.3 mmol) of tert-butyl [4, 4' ] bipiperidinyl-1-carboxylate in 100 ml of EtOH and the reaction mixture is refluxed for 2 hours. To complete the reaction, 1 ml (9.2 mmol) of ethyl acrylate was added, and the mixture was refluxed for 1 hour and left at room temperature overnight. The solvent was removed in vacuo and the crude product was reacted further without purification.

Yield: 14.0 g (100% of theory)

ESI-MS：(M+H)⁺＝369

A1b)3- [4, 4' ] bipiperidinyl-1-yl-propionic acid ethyl ester

28 ml of TFA were added dropwise to a solution of 14.0 g of the crude product from example A1a in 250 ml of DCM, and the reaction mixture was stirred at room temperature for 4 hours. The mixture was evaporated in vacuo, the residue was dissolved in 200 ml of DCM and the solution was added portionwise to 20 g of Na₂CO₃In a solution of 120 ml of water. The organic phase was separated, the aqueous phase was extracted twice more with DCM and the combined organic phases were taken up with Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was dried and reacted without further purification.

Yield: 8.8 g (88% of theory)

ESI-MS：(M+H)⁺＝269

Amine 2

3- (4-piperazin-1-yl-piperidin-1-yl) -propionic acid ethyl ester

A2a)3- [4- (4-benzyl-piperazin-1-yl) -piperidin-1-yl ] -propionic acid ethyl ester

5.5 ml (50.8 mmol) of ethyl acrylate are added to a solution of 11.7 g (44.9 mmol) of 1-benzyl-4-piperidin-4-yl-piperazine in 120 ml of anhydrous EtOH and the reaction mixture is refluxed for 1 hour and then stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dried under oil pump vacuum for 1 hour. The crude product was reacted further without purification.

Yield: 16.5 g (99% of theory)

ESI-MS：(M+H)⁺＝360

A2b)3- (4-piperazin-1-yl-piperidin-1-yl) -propionic acid ethyl ester

A suspension of 16.5 g of the crude product from example A2a and 1.6 g of 10% Pd/C in 200 ml of EtOH was hydrogenated at 50 ℃ and 50psi hydrogen pressure for 4 hours. The catalyst was removed by suction filtration and the filtrate was concentrated to about 120 ml and mixed with 72 ml of an ethanolic solution of HCl (1.3M). The precipitate formed is filtered off with suction and dried in vacuo. The product was obtained as the bis-hydrochloride salt.

Yield: 12.6 g (83% of theory)

ESI-MS：(M+H)⁺＝270

Amine 3

3- (4-piperidin-4-yl-piperazin-1-yl) -propionic acid ethyl ester

A3a)3- [4- (1-benzyl-piperidin-1-yl) -piperazin-1-yl ] -propionic acid ethyl ester

12.5 ml (73.0 mmol) of ethyldiisopropylamine and 5.0 ml (46.1 mmol) of ethyl acrylate are added to a solution of 11.0 g (33.2 mmol) of 1- (1-benzyl-piperidin-4-yl) -piperazine (used as bis-hydrochloride salt) in 40 ml of EtOH and the reaction mixture is heated to 90 ℃ (bath temperature) over 3 hours. After cooling, mix with water, extract the mixture thoroughly with EtOAc, and let the combined organic phases stand Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was chromatographed (silica gel, DCM/EtOH/NH)₃100:10:1) purification.

Yield: 6.8 g (56% of theory)

ESI-MS：(M+H)⁺＝360

R_f0.64 (silica gel, DCM/MeOH/NH)₃ 90:9:1)

A3b)3- (4-piperidin-4-yl-piperazin-1-yl) -propionic acid ethyl ester

A suspension of 5.13 g (14.3 mmol) of ethyl 3- [4- (1-benzyl-piperidin-4-yl) -piperazin-1-yl ] -propionate and 1.0 g of 10% Pd/C in 100 ml EtOH was hydrogenated at 50 ℃ under 50psi hydrogen pressure for 2 h. The catalyst was filtered off and the filtrate was evaporated to dryness. The oily product was allowed to react further without purification.

Yield: 3.6 g (93% of theory)

ESI-MS：(M+H)⁺＝270

Amine 4

[4, 4' ] Bipiperidinyl-1-yl-oxo-acetic acid ethyl ester

A4a)1 '-ethoxyoxalyl- [4, 4' ] bipiperidinyl-1-carboxylic acid tert-butyl ester

1.68 ml (15.0 mmol) of chloro-oxo-acetic acid ethyl ester were added dropwise to 4.0 g (14.9 mmol) [4, 4']A solution of tert-butyl bipiperidinyl-1-carboxylate and 2.15 ml (15.4 mmol) of triethylamine in 80 ml of DCM is cooled to 0 ℃. After the addition had ceased, the cooling bath was removed and the mixture was stirred at room temperature for 1 hour. The reaction mixture is mixed with water, the organic phase is separated off and taken up with Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was dissolved in EtOAc, the solution was filtered through silica gel and evaporated to dryness in vacuo.

Yield: 3.1 g (57% of theory)

ESI-MS：(M+H)⁺＝386

A4b) [4, 4' ] Bipiperidinyl-1-yl-oxo-acetic acid ethyl ester

5.0 ml TFA was added dropwise to 3.1 g (8.36 mmol) of 1 '-ethoxyoxalyl- [4, 4']A solution of tert-butyl bipiperidinyl-1-carboxylate in 40 ml DCM was added and the reaction mixture was stirred at room temperature for 4 hours. The mixture was evaporated in vacuo, the residue was dissolved in 50 ml of DCM and the solution was added portionwise to 4.0 g of Na₂CO₃In an ice-cooled solution of 20 ml water. The organic phase was separated, the aqueous phase was extracted twice more with DCM and the combined organic phases were taken up with Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the product was obtained as an oil, which was allowed to react further without purification.

Yield: 2.3 g (84% of theory)

ESI-MS：(M+H)⁺＝269

Amine 5

4- [4, 4' ] bipiperidinyl-1-yl-4-oxo-butyric acid ethyl ester

A5a)1 '- (3-carboxy-propionyl) - [4, 4' ] bipiperidinyl-1-carboxylic acid tert-butyl ester

A solution of 4.1 g (40.7 mmol) of succinic anhydride in 50 ml of THF is added dropwise at room temperature to 10.0 g (37.3 mmol) [4, 4']A solution of tert-butyl bipiperidinyl-1-carboxylate in 100 ml THF and the reaction mixture was stirred at room temperature overnight. To complete the reaction, 2.0 g (19.9 mmol) of succinic anhydride was added and the mixture was stirred at 50 ℃ for 4 hours and at room temperature overnight. 200 ml of 7.5% K are added₂CO₃The solution was dissolved and the aqueous phase was washed with 200 ml EtOAc. At 200 ml 7.5% K₂CO₃The organic phase is extracted with the solution and the combined aqueous phases are acidified with citric acid. The mixture was extracted thoroughly with EtOAc and the combined organic phases were evaporated in vacuo.

Yield: 11.7 g (85% of theory)

ESI-MS：(M+H)⁺＝369

A5b)4- [4, 4' ] bipiperidinyl-1-yl-4-oxo-butyric acid ethyl ester

A solution of 11.7 g (31.7 mmol) of tert-butyl 1 '- (3-carboxy-propionyl) - [4, 4' ] bipiperidinyl-1-carboxylate in 250 ml of HCl in ethanol (1.25M) was stirred at room temperature overnight. The solvent was removed in vacuo and the product was obtained as the hydrochloride salt and allowed to react further without purification.

Yield: 4.3 g (46% of theory)

ESI-MS：(M+H)⁺＝297

Amine 6

([1, 4' ] Bipiperidinyl-4-yl-tert-butoxycarbonylamino) -acetic acid ethyl ester

A6a) (1 '-benzyl- [1, 4' ] bipiperidinyl-4-yl) -carbamic acid tert-butyl ester

A solution of 5.0 g (25.0 mmol) of tert-butyl piperidin-4-yl-carbamate and 4.46 ml (25.0 mmol) of 1-benzyl-piperidin-4-one in 150 ml of THF is adjusted to pH 5 with AcOH and then with 5.61 g (26.5 mmol) of NaBH (OAc) under ice cooling₃The mixture was mixed in portions over 3 hours. The reaction mixture was stirred at room temperature overnight, followed by 500 ml of 30% K₂CO₃The solution was made basic, stirred at room temperature for 1 hour, extracted three times with 100 ml each of EtOAc, and the combined organic phases were taken over Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted further without purification.

Yield: 7.0 g (75% of theory)

A6b)1 '-benzyl- [1, 4' ] bipiperidinyl-4-ylamine

7.0 g (18.7 mmol) of (1 '-benzyl- [1, 4']Bipiperidin-4-yl) -carbamic acid tert-butyl ester with 14.3 ml (185 mmol) of TFA in 80 ml of DCM was refluxed overnight. The mixture was evaporated in vacuo and the residue was taken up with 200 ml of 30% K₂CO₃The solutions were mixed and extracted three times with 100 ml each time of EtOAc, the first 100 ml of extract was discarded. The combined organic phases were washed with Na₂SO₄Dried, filtered and evaporated to dryness. The product was reacted further without purification.

Yield: 5.1 g (100% of theory)

A6c) (1 '-benzyl- [1, 4' ] bipiperidinyl-4-ylamino) -acetic acid ethyl ester

2.79 g (13.17 mmol) NaBH (OAc)₃1.8 g (6.58 mmol) of 1 ' -benzyl- [1, 4 ' cooled to 0 ℃ are added portionwise ']Bipiperidin-4-ylamine, 2.69 ml (13.0 mmol) of oxo-acetic acid ethyl ester (used as a 50% solution in toluene) and 1 ml (17.45 mmol) of AcOH in 250 ml of THF, and the reaction mixture was stirred at room temperature overnight. It was evaporated in vacuo and the residue was dissolved in EtOAc and saturated with K₂CO₃The organic phase was washed with a solution and Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by HPLC. The product-containing fractions were combined, the organic solvent (acetonitrile) was removed in vacuo, the aqueous residue was extracted thoroughly with DCM, and the combined organic phases were dried over MgSO₄And (5) drying. After removal of the drying agent and solvent, the product was obtained as a yellow oil.

Yield: 1.25 g (53% of theory)

ESI-MS：(M+H)⁺＝360

R_f0.35 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

A6d) [ (1 '-benzyl- [1, 4' ] bipiperidinyl-4-yl) -tert-butoxycarbonyl-amino ] -acetic acid ethyl ester

3.34 ml (30.0 mmol) of triethylamine are added dropwise to 1.20 g (3.34 mmol) of (1 '-benzyl- [1, 4']Bipiperidin-4-ylamino) -acetic acid ethyl ester in 15 ml DCM was then added in portions 0.73 g (3.34 mmol) Boc-anhydride. The reaction mixture was stirred at room temperature for 70 hours and then evaporated to dryness in vacuo. The residue was dissolved in EtOAc at 15% K₂CO₃Washed with Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted further without purification.

Yield: 1.3 g (85% of theory)

A6e) ([1, 4' ] Bipiperidinyl-4-yl-tert-butoxycarbonyl-amino) -acetic acid ethyl ester

A suspension of 1.30 g (2.83 mmol) of ethyl [ (1 '-benzyl- [1, 4' ] bipiperidinyl-4-yl) -tert-butoxycarbonyl-amino ] -acetate with 0.16 g of 10% Pd/C in 25 ml EtOH is hydrogenated at 50 ℃ and 50psi hydrogen pressure for 5 h. The catalyst was removed by suction filtration and the filtrate was evaporated to dryness. The product was obtained as a colorless oil and was allowed to react further without purification.

Yield: 1.00 g (96% of theory)

ESI-MS：(M+H)⁺＝370

Amine 7

(4-methyl-4-piperazin-1-yl-piperidin-1-yl) -acetic acid ethyl ester

A7a) 1-benzyl-4-piperazin-1-yl-piperidine-4-carbonitrile

A mixture of 11.0 g (49.8 mmol) 1-benzyl-4-hydroxy-piperidine-4-carbonitrile and 22.0 g (255 mmol) piperazine in 200 ml MeOH was refluxed for 2 hours. The precipitate was filtered off with suction and evaporated in vacuoThe filtrate was dried, the residue was dissolved in a small amount of water, extracted thoroughly with DCM, and the combined organic phases were taken up with Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by chromatography (Alox, DCM/MeOH 30: 1).

Yield: 2.38 g (16% of theory)

ESI-MS：(M+H)⁺＝285

R_f＝0.37(Polygram-Alox，DCM/MeOH 25:1)

A7b)1- (1-benzyl-4-methyl-piperidin-4-yl) -piperazine

15 ml of methylmagnesium chloride solution (45 mmol, 3M in THF) are added at room temperature to 2.37 g (7.92 mmol) of 1-benzyl-4-piperazin-1-yl-piperidine-4-carbonitrile in 100 ml of anhydrous THF, and the reaction mixture is stirred for 3 hours. With saturated NH₄The Cl solution was mixed, the mixture stirred for another 10 min, the aqueous phase was washed with EtOAc, mixed with 4M NaOH solution until a basic reaction, extracted thoroughly with DCM, and the combined organic phases were taken over Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted further without purification.

Yield: 0.64 g (30% of theory)

ESI-MS：(M+H)⁺＝274

A7c)4- (1-benzyl-4-methyl-piperidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester

1.35 g (6.00 mmol) of Boc-anhydride was added to 1.63 g (5.66 mmol) of 1- (1-benzyl-4-methyl-piperidin-4-yl) -piperazine in 50 ml of THF and the reaction mixture was stirred at room temperature for 3 hours. It was then evaporated to dryness in vacuo and the residue was reacted further without purification.

Yield: 2.10 g (100% of theory)

ESI-MS：(M+H)⁺＝374

A7d)4- (4-methyl-piperidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester

A suspension of 2.28 g (5.62 mmol) of tert-butyl 4- (1-benzyl-4-methyl-piperidin-4-yl) -piperazine-1-carboxylate with 300 mg of 10% Pd/C in 50 ml MeOH is hydrogenated at 50 ℃ and 3447hPa hydrogen pressure for 3 h. To complete the reaction, 0.47 ml of concentrated HCl was added and the mixture was hydrogenated at 50 ℃ and 3447hPa hydrogen pressure for 3 hours. The catalyst is filtered off, the filtrate is evaporated off in vacuo, the residue is stirred with diethyl ether, filtered off with suction and dried.

Yield: 1.54 g (86% of theory)

ESI-MS：(M+H)⁺＝284

A7e)4- (1-ethoxycarbonylmethyl-4-methyl-piperidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester

A mixture of 1.53 g (4.78 mmol) of 4- (4-methyl-piperidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester and 1.1 ml (5.55 mmol) of oxo-acetic acid ethyl ester (50% in toluene) in 50 ml of THF is stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ℃, 1.25 g (5.90 mmol) of sodium triacetoxyborohydride was added in portions, and after the cooling bath was removed, the mixture was stirred at room temperature overnight. This was mixed with 10 ml of 20% NaHCO₃The solutions were mixed, extracted thoroughly with EtOAc and the combined organic phases were taken over Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by chromatography (Alox, DCM/EtOH 100: 1).

Yield: 0.47 g (27% of theory)

ESI-MS：(M+H)⁺＝370

A7f) (4-methyl-4-piperazin-1-yl-piperidin-1-yl) -acetic acid ethyl ester

To 0.46 g (1.25 mmol) of 4- (1-ethoxycarbonylmethyl-4-methyl-piperidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester in 5 ml of DCM was added 2 ml of TFA at 0 ℃ and the reaction mixture was stirred at room temperature for 2 hours. It was evaporated to dryness in vacuo and the crude product, which had been obtained as the bis-trifluoroacetate salt, was reacted further without purification.

Yield: 0.65 g (100% of theory)

ESI-MS：(M+H)⁺＝270

Amine 8

[4- (4-methyl-piperidin-4-yl) -piperazin-1-yl ] -acetic acid ethyl ester

A8a) [4- (1-benzyl-4-methyl-piperidin-4-yl) -piperazin-1-yl ] -acetic acid ethyl ester

Prepared in analogy to example A7e from 0.62 g (2.27 mmol) 1- (1-benzyl-4-methyl-piperidin-4-yl) -piperazine (example A7b) and 0.55 ml (2.77 mmol) of oxo-acetic acid ethyl ester (50% in toluene). The crude product was purified by chromatography (Alox, gradient PE/EtOAc 2:1 to 1: 1).

Yield: 0.45 g (50% of theory)

ESI-MS：(M+H)⁺＝360

R_f＝0.56(Polygram-Alox，PE/EtOAc 1:1)

A8b) [4- (4-methyl-piperidin-4-yl) -piperazin-1-yl ] -acetic acid ethyl ester

A suspension of 0.44 g (1.10 mmol) [4- (1-benzyl-4-methyl-piperidin-4-yl) -piperazin-1-yl ] -acetic acid ethyl ester with 100mg 10% Pd/C in 20 ml EtOH was hydrogenated at 50 ℃ and 3447hPa hydrogen pressure for 12 h. The catalyst was filtered off and the filtrate was evaporated to dryness. The product was reacted further without purification.

Yield: 0.29 g (97% of theory)

ESI-MS：(M+H)⁺＝270

Amine 9

(S) -4-methyl-1-piperidin-4-yl-piperazine-2-carboxylic acid ethyl ester

A9a) (S) -piperazine-1, 2, 4-tricarboxylic acid 1-benzyl ester-4-tert-butyl-2-ethyl ester

11.2 g (34.9 mmol) of TBTU and 5.5 ml (39.6 mmol) of triethylamine are added to a mixture of 12.2 g (32.8 mmol) of 1-benzyl (S) -piperazine-1, 2, 4-tricarboxylate-4-tert-butyl ester and 30 ml of EtOH in 150 ml of THF, cooled to 0 ℃ and stirred at this temperature for a further 30 minutes and then at room temperature for 68 hours. 600 ml of diethyl ether are added to the reaction mixture, which is admixed with 200 ml of saturated NaHCO₃The solutions were mixed, the aqueous phase was separated, the organic phase was washed with saturated NaCl solution and Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by chromatography (silica gel, gradient PE/EtOAc 4:1 to 7: 3).

Yield: 11.35 g (88% of theory)

ESI-MS：(M+H)⁺＝393

R_f0.38 (Polygram-silica gel, PE/EtOAc 3:1)

A9b) (S) -piperazine-1, 2-dicarboxylic acid 1-benzyl ester-2-ethyl ester

To a mixture of 3.27 g (8.33 mmol) of (S) -piperazine-1, 2, 4-tricarboxylic acid 1-benzyl ester-4-tert-butyl ester-2-ethyl ester and 30 ml of DCM cooled to 0 ℃ was added 10 ml of TFA, and the mixture was stirred for 10 minutes under ice-cooling and at room temperature for 2 hours. The mixture was evaporated to dryness in vacuo at 30 ℃ and the residue was once more dissolved in EtOAc and once more evaporated in vacuo. The crude product obtained as trifluoroacetate salt was reacted further without purification.

A9c) (S) -4-methyl-piperazine-1, 2-dicarboxylic acid 1-benzyl ester-2-ethyl ester

1.00 g (12.2 mmol) NaOAc and 10 g of molecular sieves A3 were added to a mixture of 4.4 g of the crude product from A9b) and 1.2 ml (16.0 mmol) of formaldehyde (37% in water) in 80 ml of THF, and the reaction mixture was stirred at room temperature for 2 hours. After cooling to 0 ℃ 3.39 g (16.0 mmol) of sodium triacetoxyborohydride are added in portions and the mixture is stirred at this temperature for 30 minutes and at room temperature for 68 hours. Filtering out insoluble components, and adding saturated K₂CO₃The solution was added to the filtrate, stirred for 15 minutes, mixed with EtOAc, the organic phase separated and washed with Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by chromatography (Alox, PE/EtOAc 2: 1).

Yield: 2.04 g (81% of theory)

ESI-MS：(M+H)⁺＝307

R_f＝0.73(Polygram-Alox，PE/EtOAc 1:1)

A9d) (S) -4-methyl-piperazine-2-carboxylic acid ethyl ester

A suspension of 2.04 g (6.66 mmol) of 1-benzyl (S) -4-methyl-piperazine-1, 2-dicarboxylate 2-ethyl ester with 200 mg of 10% Pd/C in 100 ml of EtOH was hydrogenated at 50 ℃ and 3447hPa hydrogen pressure for 6 hours. The catalyst was filtered off, the filtrate was evaporated to dryness in vacuo, and the residue was reacted further without purification.

Yield: 1.06 g (92% of theory)

ESI-MS：(M+H)⁺＝173

A9e) (S) -1- (1-tert-Butoxycarbonyl-piperidin-4-yl) -4-methyl-piperazine-2-carboxylic acid ethyl ester

A mixture of 0.90 g (5.23 mmol) of (S) -4-methyl-piperazine-2-carboxylic acid ethyl ester and 1.20 g (6.02 mmol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in 20 ml EtOH was mixed with 50 μ l of formic acid and 3 g of molecular sieve a3 and the reaction mixture was allowed to stand at room temperature for 66 hours. The molecular sieves were filtered off, the mixture was mixed with 100mg of 10% Pd/C and hydrogenated at 50 ℃ and 3447hPa hydrogen pressure for 4 hours. The catalyst was removed by suction filtration and the filtrate evaporated in vacuo and the residue purified by chromatography (silica gel, gradient DCM/EtOH 98:2 to 75: 25).

Yield: 0.35 g (19% of theory)

ESI-MS：(M+H)⁺＝356

R_f＝0.5(Polygram-Alox，DCM/MeOH 50:1)

A9f) (S) -4-methyl-1-piperidin-4-yl-piperazine-2-carboxylic acid ethyl ester

A mixture of 0.34 g (0.96 mmol) of ethyl (S) -1- (1-tert-butoxycarbonyl-piperidin-4-yl) -4-methyl-piperazine-2-carboxylate in 6 ml of an ethanolic HCl solution (1.25M) was refluxed for 1 hour. After the reaction mixture was cooled, the precipitate was filtered off with suction and dried. The product was obtained as the tri-hydrochloride salt.

Yield: 0.33 g (95% of theory)

ESI-MS：(M+H)⁺＝256

Amine 10

(S) -1- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester

A10a) (S) -piperazine-1, 3-dicarboxylic acid 1-tert-butyl ester-3-ethyl ester

A suspension of 4.00 g (10.2 mmol) of (S) -piperazine-1, 2, 4-tricarboxylic acid-1-benzyl ester-4-tert-butyl ester-2-ethyl ester (example A9a) with 200 mg of 10% Pd/C in 100 ml EtOH was hydrogenated at 50 ℃ and 3447hPa hydrogen pressure for 2 hours. The catalyst was filtered off, the filtrate was evaporated to dryness in vacuo, and the residue was reacted further without purification.

Yield: 2.61 g (98% of theory)

ESI-MS：(M+H)⁺＝259

A10b) (S) -4- (1-methyl-piperidin-4-yl) -piperazine-1, 3-dicarboxylic acid 1-tert-butyl ester-3-ethyl ester

A mixture of 2.65 g (10.05 mmol) of (S) -piperazine-1, 3-dicarboxylic acid 1-tert-butyl ester-3-ethyl ester and 1.36 ml (11.06 mmol) of 1-methyl-piperidin-4-one in 100 ml of THF is stirred at room temperature for 1 hour. After cooling to 0 ℃, 3.00 g (14.16 mmol) of sodium triacetoxyborohydride are added in portions and the reaction mixture is stirred at room temperature overnight. To complete the reaction, 1.00 g (4.72 mmol) of sodium triacetoxyborohydride and 0.3 ml of AcOH were further added, and the mixture was stirred at room temperature for another 48 hours. 40 ml of saturated K are added₂CO₃Solution, the mixture was stirred for 15 min, extracted thoroughly with EtOAc, and the combined organic phases were taken over Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by chromatography (Alox, DCM/EtOH 100: 1).

Yield: 1.93 g (53% of theory)

ESI-MS：(M+H)⁺＝356

A10c) (S) -1- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester

A mixture of 1.88 g (5.18 mmol) of (S) -4- (1-methyl-piperidin-4-yl) -piperazine-1, 3-dicarboxylic acid 1-tert-butyl ester-3-ethyl ester, 3 ml of EtOH and 15 ml of HCl in ethanol (1.25M) was stirred at room temperature overnight. To complete the reaction, the mixture was refluxed for 1 hour. After the reaction mixture was cooled, the precipitate was filtered off with suction and dried. The product was obtained as the bis-hydrochloride salt.

Yield: 1.35 g (79% of theory)

ESI-MS：(M+H)⁺＝256

Amine 11

(S) -4- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester

A11a) (S) -4- (1-methyl-piperidin-4-yl) -piperazine-1, 2-dicarboxylic acid 1-benzyl ester-2-ethyl ester

A mixture of 4.20 g (10.13 mmol) of 1-benzyl-2-ethyl (S) -piperazine-1, 2-dicarboxylate (example 49b, used as trifluoroacetate salt) and 1.37 ml of 1-methyl-piperidin-4-one in 100 ml of THF is stirred at room temperature for 1 hour. After cooling to 0 ℃, 3.00 g (14.16 mmol) of sodium triacetoxyborohydride are added in portions and the reaction mixture is stirred at room temperature overnight. It was mixed with 40 ml of saturated K₂CO₃The solution was mixed and stirred for a further 15 minutes, extracted thoroughly with EtOAc and the combined organic phases were taken over Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by chromatography (Alox, DCM/EtOH 100: 1).

Yield: 2.17 g (55% of theory)

ESI-MS：(M+H)⁺＝390

R_f＝0.43(Polygram-Alox，DCM/MeOH 50:1)

A11b) (S) -4- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester

A suspension of 2.15 g (5.52 mmol) of 1-benzyl-2-ethyl (S) -4- (1-methyl-piperidin-4-yl) -piperazine-1, 2-dicarboxylate and 100mg of 10% Pd/C in 50 ml of EtOH was hydrogenated at 50 ℃ and 3447hPa hydrogen pressure for 2 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. The product was reacted further without purification.

Yield: 1.35 g (96% of theory)

ESI-MS：(M+H)⁺＝256

Amine 12

(3-piperazin-1-yl-8-aza-bicyclo [3.2.1] oct-8-yl) -acetic acid ethyl ester

A12a)3- (4-benzyloxycarbonyl-piperazin-1-yl) -8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

5.00 g (22.2 mmol) of 3-oxo-8-aza-bicyclo [3.2.1]A mixture of tert-butyl octa-8-carboxylate and benzyl piperazine-1-carboxylate in 60 ml of THF was adjusted to pH 5 with AcOH and stirred at room temperature for 1 hour. The mixture was mixed with 5.64 g (26.6 mmol) of sodium triacetoxyborohydride in portions under ice-cooling, and the reaction mixture was stirred at room temperature overnight. It was mixed with 150 ml of 15% K₂CO₃The solutions were mixed, the organic phase was separated, the aqueous phase was extracted thoroughly with EtOAc and the combined organic phases were taken over Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by chromatography (silica gel, EtOAc).

2 isomeric products can be isolated:

isomer A:

yield: 2.10 g (22% of theory)

ESI-MS：(M+H)⁺＝430

R_f0.55 (silica gel, EtOAc)

Retention time (HPLC): 3.2 minutes (method B)

Isomer B:

yield: 2.20 g (23% of theory)

ESI-MS：(M+H)⁺＝430

R_f0.68 (silica gel, EtOAc)

A12b) benzyl 4- (8-aza-bicyclo [3.2.1] oct-3-yl) -piperazine-1-carboxylate

6.01 ml (78.0 mmol) of TFA are slowly added to 2.10 g (4.89 mmol) of 3- (4-benzyloxycarbonyl-piperazin-1-yl) -8-aza-bicyclo [3.2.1]Tert-butyl octane-8-carboxylate (isomer a) in 60 ml of DCM and the reaction mixture was stirred at room temperature for 2 hours. It was evaporated to dryness in vacuo and the residue was dissolved in 15% K₂CO₃In solution, extracted thoroughly with DCM and the combined organic phases taken over Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the product is reacted further without purification.

Yield: 1.50 g (93% of theory)

ESI-MS：(M+H)⁺＝330

R_f0.16 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

A12c) benzyl 4- (8-ethoxycarbonylmethyl-8-aza-bicyclo [3.2.1] oct-3-yl) -piperazine-1-carboxylate

1.29 g (9.30 mmol) of K₂CO₃1.50 g (4.55 mmol) of 4- (8-aza-bicyclo [3.2.1] in 10 ml of DMF]To octyl-3-yl) -piperazine-1-carboxylic acid benzyl ester (a12b), then 0.56 ml (5.00 mmol) of ethyl bromoacetate were slowly added dropwise, and the reaction mixture was stirred at room temperature for another 4 hours. The insoluble material was filtered off, mixed with EtOAc and the organic phase was washed with saturated NaHCO₃Washed twice with Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted further without purification.

Yield: 1.75 g (92% of theory)

ESI-MS：(M+H)⁺＝416

R_f0.72 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

A12d) (3-piperazin-1-yl-8-aza-bicyclo [3.2.1] oct-8-yl) acetic acid ethyl ester

A suspension of 1.70 g (4.09 mmol) of benzyl 4- (8-ethoxycarbonylmethyl-8-aza-bicyclo [3.2.1] oct-3-yl) -piperazine-1-carboxylate (A12C) in 200 mg of 10% Pd/C in 30 ml of EtOH was shaken at room temperature under 3000hPa hydrogen pressure for 3 hours. The catalyst was removed by suction filtration and the filtrate was evaporated to dryness. The product was reacted further without purification.

Yield: 1.10 g (96% of theory)

ESI-MS：(M+H)⁺＝282

R_f0.21 (silica gel, DCM/MeOH/NH)₃ 80:20:2)

Amine 13

([1, 4' ] Bipiperidinyl-4-yloxy) -acetic acid ethyl ester

A13a) 4-tert-Butoxycarbonylmethoxy- [1, 4 '] bipiperidinyl-1' -carboxylic acid benzyl ester

2.90 g (13.27 mmol) of sodium triacetoxyborohydride are added portionwise to a mixture of 2.58 g (11.06 mmol) of benzyl 4-oxo-piperidine-1-carboxylate and 2.80 g (12.36 mmol) of tert-butyl (piperidin-4-yloxy) -acetate in 30 ml of THF, and the reaction mixture is stirred at room temperature overnight. This was mixed with 50 ml of 1M NaOH, the mixture was stirred at room temperature for 1 hour, mixed with EtOAc, the organic phase was separated and washed with Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by chromatography (Alox, DCM/MeOH 100: 1).

Yield: 3.10 g (65% of theory)

ESI-MS：(M+H)⁺＝433

A13b) ([1, 4' ] bipiperidinyl-4-yloxy) -acetic acid tert-butyl ester

A suspension of 3.08 g (7.12 mmol) of benzyl 4-tert-butoxycarbonylmethoxy- [1, 4 '] bipiperidinyl-1' -carboxylate with 300 mg of 10% Pd/C in 60 ml MeOH is hydrogenated at 50 ℃ and 3447hPa hydrogen pressure for 2 hours. The catalyst was removed by suction filtration and the filtrate was evaporated to dryness. The product was reacted further without purification.

Yield: 2.15 g (99% of theory)

ESI-MS：(M+H)⁺＝299

A13c) ([1, 4' ] bipiperidinyl-4-yloxy) -acetic acid ethyl ester

20 ml of HCl in ethanol (1.25M) were added to 2.02 g (6.63 mmol) of ([1, 4' ] bipiperidinyl-4-yloxy) -acetic acid tert-butyl ester in 20 ml of EtOH and the reaction mixture was refluxed for 3 hours. After cooling to 0 ℃, the precipitate formed is filtered off with suction and dried under high vacuum. The product obtained as bis-hydrochloride salt was reacted further without purification.

Yield: 1.74 g (76% of theory)

ESI-MS：(M+H)⁺＝271

Amine 14

[1, 4' ] Bipiperidinyl-4-yl-acetic acid ethyl ester

A14a) (1 '-benzyl- [1, 4' ] bipiperidinyl-4-yl) -acetic acid ethyl ester

50 ml of DCM and 11.7 ml (62.5 mmol) of 1-benzyl-piperidin-4-one are added to 11.8 g (56.8 mmol) of piperidin-4-yl-acetic acid ethyl ester in 100 ml of THF and the reaction mixture is stirred at room temperature for 2 hours. The mixture is mixed in portions with 13.7 g (62.5 mmol) of sodium triacetoxyborohydride and stirred at room temperature for a further 36 hours. 100 ml of 10% NaOH was added to the reaction mixtureIt is extracted twice with 100 ml of MTBE each time, and the combined organic phases are taken over Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by HPLC.

Yield: 3.27 g (17% of theory)

ESI-MS：(M+H)⁺＝345

R_f0.55 (silica gel, EtOAc/MeOH/NH)₃ 90:10:1)

A14b) [1, 4' ] Bipiperidinyl-4-yl-acetic acid ethyl ester

A suspension of 3.24 g (9.41 mmol) of (1 '-benzyl- [1, 4' ] bipiperidinyl-4-yl) -acetic acid ethyl ester with 300 mg of 10% Pd/C in 50 ml EtOA is hydrogenated at room temperature and a hydrogen pressure of 3000hPa until the theoretical amount of hydrogen has been absorbed. The catalyst was removed by suction filtration, the filtrate was evaporated to dryness and the residue was mixed with 50 ml of EtOH and HCl in ethanol (1.25M). The mixture was evaporated to dryness in vacuo, the residue was stirred with 100 ml of DIPE/isopropanol (2:1), the precipitate was filtered off and dried at 35 ℃ in a circulating air drying cabinet. The product was obtained as the bis-hydrochloride salt.

Yield: 2.90 g (94% of theory)

ESI-MS：(M+H)⁺＝255

R_f0.05 (silica gel, EtOAc/MeOH/NH)₃ 70:30:3)

Amine 15

3- [1, 4' ] bipiperidinyl-4-yl-propionic acid ethyl ester

A15a)4- (2-methoxycarbonyl-ethyl) - [1, 4 '] bipiperidinyl-1' -carboxylic acid tert-butyl ester

Under nitrogen atmosphere, 4.00 g (19.3 mmol)Mol) 3-piperidin-4-yl-propionic acid methyl ester with 3.85 g (19.3 mmol) of tert-butyl 4-oxo-piperidine-1-carboxylate in 50 ml of THF, adjusted to pH 5 with AcOH and the mixture was stirred at room temperature for 1 hour. After cooling to 0 ℃, the mixture was mixed in portions with 5.15 g (24.3 mmol) of sodium triacetoxyborohydride and the reaction mixture was stirred at room temperature overnight. Within 10 minutes, 90 ml of 30% K are added dropwise₂CO₃Solution, the mixture was extracted three times with EtOAc, and the combined organic phases were taken over Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted further without purification.

Yield: 5.40 g (79% of theory)

ESI-MS：(M+H)⁺＝355

R_f0.63 (silica gel, DCM/MeOH/NH)₃ 80:20:2)

A15b)3- [1, 4' ] bipiperidinyl-4-yl-propionic acid ethyl ester

5.40 g (15.2 mmol) of tert-butyl 4- (2-methoxycarbonyl-ethyl) - ([1, 4 '] bipiperidinyl-1' -carboxylate in 150 ml of HCl in ethanol (1.25M) are stirred at room temperature overnight.

Yield: 2.30 g (79% of theory)

ESI-MS：(M+H)⁺＝269

Retention time (HPLC): 1.2 minutes (method B)

Amine 16

4- (4-piperazin-1-yl-piperidin-1-yl) -butyric acid ethyl ester

A16a)4- [4- (4-benzyl-piperazin-1-yl) -piperidin-1-yl ] -butyric acid ethyl ester

A mixture of 3.11 g (12.0 mmol) 1-benzyl-4-piperidin-4-yl-piperazine and 7.50 ml (12.0 mmol, 15% in water) 4-oxo-butyric acid in 70 ml THF is adjusted to pH 5 with AcOH under nitrogen atmosphere and stirred at room temperature for 1 hour. After cooling to 0 ℃, 5.35 g (24.0 mmol) of sodium triacetoxyborohydride are added in portions and the reaction mixture is stirred at room temperature overnight. 80 ml of 30% K are added dropwise within 15 minutes₂CO₃The solution, the aqueous phase was washed twice with EtOAc and evaporated in vacuo to half. Adding 1M KHSO₄The solution was filtered off with suction to remove the precipitate formed, the filtrate was washed with EtOAc and the aqueous phase was evaporated to dryness in vacuo. The residue was dissolved in 150 ml of HCl in ethanol (1.25M) and the reaction mixture was stirred at room temperature overnight. It was evaporated to dryness in vacuo and the residue was dissolved in a small amount of 15% K₂CO₃In solution, extracted thoroughly with EtOAc and the combined organic phases are taken over Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted further without purification.

Yield: 2.90 g (65% of theory)

ESI-MS：(M+H)⁺＝374

A16b)4- (4-piperazin-1-yl-piperidin-1-yl) -butyric acid ethyl ester

A suspension of 2.90 g (7.76 mmol) of ethyl 4- [4- (4-benzyl-piperazin-1-yl) -piperidin-1-yl ] -butyrate with 300 mg of 10% Pd/C in 60 ml MeOH was hydrogenated at room temperature under 3447hPa hydrogen pressure for 24 h. The catalyst was removed by suction filtration, the filtrate evaporated to dryness and the residue dissolved in DIPE and a small amount of isopropanol and mixed with 4M HCl in 1, 4-dioxane. The precipitate was filtered off with suction and dried. The product was obtained as the bis-hydrochloride salt.

Yield: 2.50 g (90% of theory)

ESI-MS：(M+H)⁺＝284

Retention time (HPLC): 0.7 minute (method B)

Amine 17

4-piperazin-1-yl-piperidine-1-carboxylic acid benzyl ester

A17a)4- (1-benzyloxycarbonyl-piperidin-4-yl) -piperazine-1-carboxylic acid tert-butyl ester

A solution of 7.18 ml (48.0 mmol) of benzyl chloroformate in 50 ml of DCM was added dropwise under ice cooling to 12.3 g (45.7 mmol) of tert-butyl 4-piperidin-4-yl-piperazine-1-carboxylate and 8.2 ml (50 mmol) of N-ethyldiisopropylamine in 200 ml of DCM, and the reaction mixture was stirred at room temperature overnight. It was diluted with 200 ml of 15% K₂CO₃Washing with the solution, separating the organic phase, and adding Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted further without purification.

Yield: 16.0 g (87% of theory)

A17b) benzyl 4-piperazin-1-yl-piperidine-1-carboxylate

To 16.0 g (39.7 mmol) of tert-butyl 4- (1-benzyloxycarbonyl-piperidin-4-yl) -piperazine-1-carboxylate in 200 ml of DCM was added 25 ml of TFA at room temperature, and the reaction mixture was stirred at room temperature overnight. It was evaporated to dryness in vacuo, the residue was dissolved in 200 ml of water and 200 ml of EtOAc, and the aqueous phase was separated from 50 ml of 15% K₂CO₃The solution was mixed, extracted twice with 200 ml each time of EtOAc, and the combined organic phases were taken over Na₂SO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted without purification.

Yield: 4.00 g (33% of theory)

ESI-MS：(M+H)⁺＝304

The preparation of the final compound is described below:

example 1

1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-4-carboxylic acid ethyl ester

1a) (Z, E) -2-acetylamino-3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -acrylic acid

39.7 g (335 mmol) of N-acetylglycine are added to a suspension of 50.0 g (224 mmol) of 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde and 27.5 g (335 mmol) of NaOAc in 202 ml of acetic anhydride, and the reaction mixture is heated at 115 ℃ for 1 hour. After cooling to 80 ℃, 100 ml of water are added dropwise while keeping the temperature of the mixture at 80 ℃. The suspension was heated to 95 ℃ for a further 40 minutes and then added to a mixture of 250 ml of toluene and 500 ml of water. The suspension was stirred at room temperature, the precipitate filtered off with suction and dried at 60 ℃ in a circulating air drying cabinet.

Yield: 48.8 g (68% of theory)

ESI-MS：(M+H)⁺＝321/323(Cl)

R_f0.37 (silica gel, DCM/MeOH/AcOH 90:10:1)

1b)3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-oxo-propionic acid

A suspension of 97.0 g (300 mmol) of (Z, E) -2-acetylamino-3- (4-amino-3-chloro-5-tri-fluoromethyl-phenyl) -acrylic acid in 900 ml of 1, 4-dioxane and 1050 ml of 4M HCl was heated to 100 ℃ over 8 hours. The mixture is evaporated down to about 600 ml in vacuo, cooled to room temperature, the precipitated material is filtered off, washed twice with 100 ml of water each time and dried at 50 ℃. The residue was dissolved in 850 ml of toluene, heated under reflux and then cooled in an ice bath. The precipitate formed was filtered, washed with PE and dried in a circulating air drying cabinet at 50 ℃.

Yield: 63.0 g (74% of theory)

ESI-MS：(M-H)^-＝280/282(Cl)

R_f0.21 (silica gel, DCM/MeOH/NH)₃ 80:20:2)

1c) (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-hydroxy-propionic acid

A solution of 100.0 g (312 mmol) of (1R) -B-chlorodiisopinocampheylborane in 150 ml of THF is added dropwise to a solution of 63.0 g (224 mmol) of 3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-oxo-propionic acid and 31.2 ml (224 mmol) of triethylamine in 300 ml of THF cooled to about-30 ℃ and the reaction mixture is kept at this temperature for 1.5 hours and then heated at room temperature for one hour. When 80 ml of 4M NaOH was added to the reaction mixture, it was stirred for 5 minutes, cooled to 0 ℃, mixed with 300 ml of MTBE, stirred at this temperature for a further 20 minutes, and the liquid phase was separated. The organic phase was extracted thoroughly with water, the combined aqueous phases were acidified with 4M HCl, extracted thoroughly with MTBE, and the combined organic phases were taken up with Na₂SO₄And (5) drying. The THF/MTBE/NaOH phase was acidified with 4M HCl, the liquid phase was separated and the organic phase was evaporated in vacuo. The two residues were combined and reacted further without purification.

R_f0.20 (silica gel, DCM/MeOH/NH)₃ 80:20:2)

1d) (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-hydroxy-propionic acid methyl ester

The crude product from example 1c (62 g) was dissolved in 300 ml MeOH and 3.65 ml (50 mmol) SOCl was slowly added dropwise₂To this solution. The reaction mixture was stirred at room temperature for a further 3 hours, then evaporated to dryness in vacuo, the residue was dissolved in DCM and filtered over silica gel. The solution was evaporated in vacuo and the residue was chromatographed (silica gel, DCM/MeOH/NH)₃80:20: 2)). The fractions containing the product were combined, evaporated to dryness in vacuo, the residue was mixed with PE, filtered off with suction and dried.

Yield: 43.1 g (65% of theory, 2 steps)

ESI-MS：(M+H)⁺＝298/300(Cl)

R_f0.86 (silica gel, DCM/MeOH/NH)₃ 80:20:2)

1e)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-methoxycarbonyl-ethyl ester

Under a nitrogen atmosphere, a solution of 13.5 g (65.0 mmol) of 4-nitrophenyl chloroformate in 40 ml of THF is metered into 100 ml of pyridine over 10 minutes at 60 ℃ (bath temperature), the mixture is stirred for 10 minutes, then a solution of 18.0 g (60.5 mmol) of methyl (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-hydroxy-propionate in 50 ml of pyridine is added dropwise, and the reaction mixture is left at this temperature for 1.5 hours. 15.9 g (65.0 mmol) of 3-piperidin-4-yl-1, 3, 4, 5-tetrahydro-1, 3-benzodiazepine are then added in portions-2-ketones. The temperature of the reaction mixture was increased to 100 ℃ and the mixture was kept at this temperature for 6 hours and then stirred at room temperature overnight. The mixture was evaporated to dryness in vacuo, the residue was dissolved in 200 ml of EtOAc and the organic phase was evaporated to 10 ml of 1M KHSO each time₄The solution was washed twice with 50 ml each time of 15% K₂CO₃Dissolving ten times in Na₂SO₄And (5) drying. In thatAfter removal of the drying agent and solvent, the residue is reacted further without purification.

Yield: 33.1 g (96% of theory)

ESI-MS：(M+H)⁺＝569/571(Cl)

R_f0.72 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

1f)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester

A solution of 2.11 g (88.0 mmol) of LiOH in 100 ml of water is added to 33.0 g (58.0 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-methoxy-carbonyl-ethyl ester in 200 ml THF and the reaction solution was stirred at room temperature for 3.5 hours. The THF was removed in vacuo, the aqueous residue was washed twice with MTBE, acidified with 2M HCl, extracted thoroughly with DCM, and the combined organic phases were taken up with Na₂SO₄And (5) drying. After the drying agent and solvent were removed, the residue was dissolved in 80 ml of isopropanol at 65 ℃ and slowly cooled to room temperature overnight. The suspension was cooled in an ice bath, filtered off with suction, washed with a little isopropanol and DIPE and dried.

Yield: 26.2 g (81% of theory)

ESI-MS：(M+H)⁺＝555/557(Cl)

R_f0.18 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

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

1g)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-oxo-2- (4-oxo-piperidin-1-yl) -ethyl ester

7.40 g (23.0 mmol) of TBTU and 5.84 ml (40.0 mmol) of triethylamine are added to 10.0 g (18.0 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 50 ml DMF and stirring at room temperature for 10 min. 2.77 g (18.0 mmol) piperidin-4-one (used as the hydrate of its hydrochloride salt) were added to the reaction mixture and it was stirred at room temperature overnight. The reaction solution was poured into 1 liter of 7% K₂CO₃On the solution, the precipitated material was filtered off, washed with water and dried at 60 ℃ for 6 hours. Further purification was performed by column chromatography (silica gel, EtOAc).

Yield: 7.5 g (65% of theory)

ESI-MS：(M+H)⁺＝636/638(Cl)

R_f0.25 (silica gel, EtOAc)

1h) 1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-4-carboxylic acid ethyl ester

62.9 mg (0.4 mmol) of ethyl piperidine-4-carboxylate with 11. mu.l (0.2 mmol) of AcOH are added to 127 mg (0.2 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2-oxo-2- (oxo-piperidin-1-yl) -ethyl ester in 2 ml THF/MeOH (2:1) and the reaction mixture was stirred at room temperature for 2 hours. It is then allowed to cool to 0 ℃ and, after 2 hours, is admixed with 10.6 mg (0.16 mmol) of NaBH₃CN was mixed and stirred at 0 deg.C overnight. The solvent was evaporated, the residue was dissolved in 2 ml DMF and the crude product was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 68 mg (44% of theory)

ESI-MS：(M+H)⁺＝777/779(Cl)

Retention time (HPLC): 7.0 minutes (method C)

Example 1.1

1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-4-carboxylic acid

A solution of 7.2 mg (0.3 mmol) of LiOH in 1 ml of water is added to 140 mg (0.18 mmol) of 1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-4-carboxylic acid ethyl ester in 1 ml THF and the reaction mixture was stirred at room temperature for 3 hours. 1 ml of HCl (1M) was added and the crude product was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 53 mg (39% of theory)

ESI-MS：(M+H)⁺＝749/751(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Example 2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (ethoxycarbonylmethyl-amino) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester

2a)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (ethoxycarbonylethoxycarbonyl-methylamino) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester

128 mg (0.40 mmol) of TBTU and 56. mu.l (0.40 mmol) of triethylamine are added to 200 mg (0.36 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 2 ml DMF and stirred at room temperature for 10 min. 148 mg (0.40 mmol) ([1, 4']Bipiperidin-4-yl-tert-butoxycarbonyl-amino) -acetic acid ethyl ester (amine a6) was added to the reaction mixture, and it was stirred at room temperature overnight. The reaction solution was evaporated in vacuo, the residue was dissolved in EtOAc, the precipitate formed was filtered off with suction and dried. The product is reacted further withoutPurification is required.

Yield: 330 mg (100% of theory)

2b)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (ethoxycarbonylmethyl-amino) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester

0.5 ml TFA was added to 330 mg (0.36 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (tert-butoxycarbonyl-ethoxycarbonyl-methylamino) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester in 5 ml of DCM at 0 ℃ and the reaction mixture was stirred at room temperature overnight. It was evaporated to dryness in vacuo and the residue was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 263 mg (90% of theory)

ESI-MS：(M+H)⁺＝806/808(Cl)

Retention time (HPLC): 2.6 minutes (method A)

Example 2.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (carboxymethyl-amino) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester

9.4 mg (0.39 mmol) of LiOH solution are added to 212 mg (0.26 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (ethoxycarbonyl-methylamino) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester in 9 ml THF and the reaction mixture was stirred at room temperature overnight. To complete the reaction, 6.3 mg (0.26 mmol) of LiOH were added and the mixture was stirred at room temperature overnight. The reaction mixture was purified by HPLC without further treatment. The fractions containing the product were combined and lyophilized to obtain the product as trifluoroacetate salt.

Yield: 130 mg (55% of theory)

ESI-MS：(M+H)⁺＝778/780(Cl)

Retention time (HPLC): 2.7 minutes (method A)

Example 3

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

632 mg (1.97 mmol) of TBTU and 0.34 ml (1.97 mmol) of ethyldiisopropylamine are added to 1.0 g (1.80 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino)To a solution of the group-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 10 ml THF was added and the mixture was stirred at room temperature for 10 minutes. 500 mg (1.97 mmol) [4, 4']Bipiperidin-1-yl-ethyl acetate was added to the reaction mixture, and it was stirred at room temperature overnight. The mixture was evaporated in vacuo and the residue was dissolved in DCM and taken up in 1M KHSO₄Solution with 15% K₂CO₃The organic phase was washed with a solution and Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by HPLC. The fractions containing the product were combined, evaporated to dryness in vacuo, the residue triturated with DIPE, filtered off with suction and dried.

Yield: 150 mg (11% of theory)

ESI-MS：(M+H)⁺＝791/793(Cl)

R_f0.46 (silica gel, DCM/Cyc/MeOH/NH)₃ 70：15：15:2)

Example 3.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

A solution of 1 mg (0.04 mmol) of LiOH in 1 ml of water is added to 30 mg (0.04 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester to a solution in 2 ml THF andthe reaction mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and the residue was mixed with a small amount of water and 1M HCl until an acidic reaction was obtained. The precipitate formed was filtered off with suction and dried.

Yield: 20 mg (66% of theory)

ESI-MS：(M+H)⁺＝763/765(Cl)

R_f0.31 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 3.2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-methoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

100mg (0.31 mmol) of TBTU and 0.06 ml (0.34 mmol) of ethyldiisopropylamine are added to 200 mg (0.26 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester to a solution in 15 ml THF and the mixture was stirred at room temperature for 10 minutes. 1 ml (24.6 mmol) of MeOH was added to the reaction mixture, and it was stirred at room temperature overnight. It is evaporated to dryness in vacuo, the residue is dissolved in 2 ml of DMF and the crude product is purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 80 mg (39% of theory)

ESI-MS：(M+H)⁺＝777/779(Cl)

R_f0.60 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

The following compounds are prepared in an analogous manner in each case from 200 mg of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester with 1 ml of the respective alcohol:

example 3.7

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2-oxo-2- (1 '-phenoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -ethyl ester

50 mg (0.16 mmol) of TBTU and 37. mu.l (0.26 mmol) of triethylamine are added to 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethylTo a solution of yl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester in 1.5 ml THF was stirred at room temperature for 1 hour. 14.8 mg (0.16 mmol) of phenol were added and the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered through a syringe filter, and the crude product was purified by HPLC. The eluted fractions containing the product were combined and lyophilized. The residue was dissolved in DCM, evaporated to dryness in vacuo, triturated with DIPE, filtered off with suction and dried.

Yield: 48 mg (44% of theory)

ESI-MS：(M+H)⁺＝839/841(Cl)

R_f0.47 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Retention time (HPLC): 3.2 minutes (method B)

The following compounds are prepared in an analogous manner in each case from 100mg (examples 3.8 to 3.12), 120 mg (example 3.13) or 90 mg (examples 3.14 and 3.15) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester with the amounts of the alcohol components necessary in each case:

example 3.16

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (2, 2-dimethylpropionyloxy-methoxycarbonyl-methyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester

27 mg (0.20 mmol) of K₂CO₃With 28 microliters (0.20 mmol) of 2, 2-dimethyl-propionic acid chloromethyl ester to 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester to a solution in 2 ml DMF and the reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated in vacuo, the residue was dissolved in 50 ml DCM, the organic phase was washed with 20 ml water and Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was chromatographed (silica gel, DCM/MeOH/NH)₃97:3: 0.3). The fractions containing the product were combined, the residue evaporated to dryness, triturated with a small amount of diethyl ether/DIPE, filtered off with suction and dried.

Yield: 38 mg (34% of theory)

ESI-MS：(M+H)⁺＝877/879(Cl)

R_f0.47 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Retention time (HPLC): 3.3 minutes (method B)

Example 3.17

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acidAcid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-dimethylcarbamoylmethoxy-carbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

48 mg (0.15 mmol) of TBTU, 21. mu.l (0.15 mmol) of triethylamine and 15 mg (0.15 mmol) of 2-hydroxy-N, N-dimethyl-acetamide are added to 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester to a solution in 1 ml DMF and the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered through a syringe filter, and the crude product was purified by HPLC. The fractions containing the product were combined and evaporated to dryness in vacuo.

Yield: 23 mg (21% of theory)

ESI-MS：(M+H)⁺＝848/850(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Example 4

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-ethoxycarbonylmethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester

0.52 g(1.62 mmol) TBTU with 0.28 ml (1.61 mmol) ethyldiisopropylamine was added to 0.80 g (1.44 mmol) 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester to a solution in 30 ml THF and stirred at rt for 10 min. 0.40 g (1.57 mmol) of (4-piperazin-1-yl-piperidin-1-yl) -acetic acid ethyl ester was added to the reaction mixture, and it was stirred at room temperature overnight. Add 40 mL EtOAc at 15% K₂CO₃The organic phase was washed with solution and MgSO₄And (5) drying. After removal of the drying agent and solvent, the residue was chromatographed (silica gel, gradient DCM to DCM/EtOH/NH)₃70:30: 3).

Yield: 0.68 g (60% of theory)

ESI-MS：(M+H)⁺＝792/794(Cl)

R_f0.70 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 4.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester

A solution of 25 mg (1.02 mmol) of LiOH in 20 ml of water is added to 380 mg (0.48 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-ethoxycarbonylmethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester in 20 ml THF and the reaction mixture was stirred at room temperature overnight. The organic solvent was removed in vacuo and combined with 20 ml of water and 1.1 ml of 1M HCl. The mixture was evaporated in vacuo, the residue was dissolved in 5 ml DMF and the crude product was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 114 mg (31% of theory)

ESI-MS：(M+H)⁺＝764/766(Cl)

R_f0.07 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 4.2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-butoxycarbonylmethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester

51 mg (0.16 mmol) of TBTU and 29. mu.l (0.34 mmol) of triethylamine are added to 80 mg (0.11 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester in 1.5 ml DMF and the mixture shaken at room temperature for 30 min. 100 microliters (1.09 mmol) of 1-butanol was added to the reaction mixture and allowed to shake at room temperature overnight. After being filtered by the syringe, the mixture is,the crude product was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 46 mg (54% of theory)

ESI-MS：(M+H)⁺＝820/822(Cl)

R_f0.67 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

The following compounds are prepared in an analogous manner in each case from 80 mg of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]2-oxo-ethyl ester with 100. mu.l of the respective alcohol component:

the following compounds are prepared in an analogous manner in each case from 80 mg of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]2-oxo-ethyl ester with 1.5 equivalents (examples 4.5 and 4.6) and 1.6 equivalents (examples 4.7 and 4.8) of the respective alcohol component:

example 4.9

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (2-morpholin-4-yl-ethoxycarbonylmethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

50 mg (0.16 mmol) of TBTU and 37. mu.l (0.34 mmol) of triethylamine are added to 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester in 5 ml THF and stirred at rt for 30 min. 19 μ l (0.16 mmol) of 2-morpholin-4-yl-ethanol are added to the reaction mixture and the suspension is stirred at room temperature for 1.5 hours. 3 ml of DMF were added and the mixture was stirred at room temperature for a further 4 hours. The reaction mixture was evaporated down in vacuo and the residue was dissolved in 1.5 ml MeOH, filtered through a syringe filter and purified by HPLC. The product-containing eluate was evaporated to dryness in vacuo, the residue triturated with DIPE, filtered off with suction and dried in vacuo at 50 ℃.

Yield: 47 mg (41% of theory)

ESI-MS：(M+H)⁺＝877/879(Cl)

R_f0.31 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Retention time (HPLC): 2.7 minutes (method B)

Example 4.10

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2-oxo-2- (4- {1- [2- (2-oxo-pyrrolidin-1-yl) -ethoxycarbonylmethyl]-piperidin-4-yl } -piperazin-1-yl) -ethyl ester

Analogously to example 4.9, 80 mg (0.11 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine are prepared-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester with 18 μ l (0.16 mmol) 1- (2-hydroxy-ethyl) -pyrrolidin-2-one using 1.5 ml DMF as solvent.

Yield: 39 mg (43% of theory)

ESI-MS：(M+H)⁺＝875/877(Cl)

R_f0.40 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Retention time (HPLC): 2.9 minutes (method B)

Example 4.11

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (3-morpholin-4-yl-propoxycarbonyl-methyl) -piperidine-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

Analogously to example 4.9, from 90 mg (0.12 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester with 22 mg (0.15 mmol) 3-morpholin-4-yl-propan-1-ol, using 1.5 ml DMF as solvent. After purification by HPLC, the product was dissolved in DCM as 5% NaHCO₃The organic phase is extracted with Na₂SO₄And (5) drying. After the drying agent and solvent were removed, the residue was stirred with DIPE, filtered off with suction and dried in air.

Yield: 48 mg (46% of theory)

ESI-MS：(M+H)⁺＝891/893(Cl)

R_f0.17 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Retention time (HPLC): 2.7 minutes (method B)

Example 4.12

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (2, 2-dimethyl-propionyloxymethoxycarbonyl-methyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

42 mg (0.30 mmol) of K₂CO₃With 43 microliters (0.30 mmol) of 2, 2-dimethyl-propionic acid chloromethyl ester to 150 mg (0.20 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester in 5 ml DMF and the reaction mixture was stirred at room temperature overnight. It is evaporated to dryness in vacuo and the residue is taken up with 30 ml of 15% K₂CO₃The solutions were mixed and the precipitated product was filtered off with suction and chromatographed (silica gel, gradient DCM to DCM/MeOH/NH)₃50:47: 3).

Yield: 50 mg (29% of theory)

ESI-MS：(M+H)⁺＝878/880(Cl)

R_f0.63 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 4.13

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (1-ethoxycarbonyloxy-ethoxycarbonyl-methyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

Analogously to example 4.12, prepared from 150 mg (0.20 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-Yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester with 40 μ l (0.30 mmol) of 1-chloroethyl-ethyl carbonate.

Yield: 50 mg (29% of theory)

ESI-MS：(M+H)⁺＝880/882(Cl)

R_f0.68 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 4.14

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-diethylcarbamoylmethoxy-carbonylmethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester

50 mg (0.16 mmol) of TBTU, 25. mu.l (0.18 mmol) of triethylamine and 30 mg (0.23 mmol) of N, N-diethyl-2-hydroxy-acetamide are added to 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoro-methyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester in 1 ml DMF and the reaction mixture was stirred at room temperature for 20 h. The reaction solution was poured into saturated NaHCO₃On the solution, the precipitate formed is filtered off with suction and dried. The crude product was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 36 mg (31% of theory)

ESI-MS：(M+H)⁺＝877/879(Cl)

Retention time (HPLC): 3.2 minutes (method B)

The following compounds are prepared in an analogous manner in each case from 100mg of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester with the corresponding amounts of the respective alcohol components:

example 5

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-ethoxycarbonylmethyl-piperazin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

64 mg (0.20 mmol) of TBTU and 28. mu.l (0.20 mmol) of triethylamine are added to 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-l-o-l-1, 2, 4, 5-tetrahydro-l-e-1, 3-benzodiazepines-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 1 ml DMF and stirred at room temperature for 10 min. 51 mg (0.20 mmol) of (4-piperidin-4-yl-piperazin-1-yl) -acetic acid ethyl ester were added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 91 mg (64% of theory)

ESI-MS：(M+H)⁺＝792/794(Cl)

R_f0.48 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 5.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-carboxymethyl-piperazin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

A solution of 3.6 mg (0.15 mmol) of LiOH in 1 ml of water is added to 70 mg (0.09 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-ethoxycarbonylmethyl-piperazin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester in 10 ml DTH and the reaction mixture was stirred at room temperature overnight. THF removal in a nitrogen streamThen mixed with a small amount of water, followed by addition of formic acid until an acidic reactant is obtained, then acetonitrile is added, and the product is subjected to freeze-drying.

Yield: 52 mg (76% of theory)

ESI-MS：(M-H)^-＝762/764(Cl)

R_f0.14 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 5.2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-dimethylcarbamoylmethoxycarbonyl-methyl-piperazin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

90 mg (0.28 mmol) of TBTU, 39. mu.l (0.15 mmol) of triethylamine and 29 mg (0.28 mmol) of 2-hydroxy-N, N-dimethyl-acetamide are added to 190 mg (0.25 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-carboxymethyl-piperazin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester in 5 ml DMF and the reaction mixture was stirred at room temperature overnight. The reaction solution was filtered through a syringe filter, and the crude product was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 106 mg (50% of theory)

ESI-MS：(M+H)⁺＝849/851(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Example 6

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (2-ethoxycarbonyl-ethyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester

64 mg (0.20 mmol) of TBTU and 28. mu.l (0.20 mmol) of triethylamine are added to 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 1 ml DMF and stirred at room temperature for 10 min. 54 mg (0.20 mmol) of 3- [4, 4']Bipiperidin-1-yl-propionic acid ethyl ester (amine a1) was added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 42 mg (29% of theory)

ESI-MS：(M+H)⁺＝805/807(Cl)

R_f0.58 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 6.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (2-carboxy-ethyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester

A solution of 1.4 mg (0.06 mmol) of LiOH in 1 ml of water is added to 30 mg (0.04 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (2-ethoxycarbonyl-ethyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester in 10 ml THF and the reaction mixture was stirred at room temperature overnight. THF was removed in a nitrogen stream, then a small amount of water was added followed by formic acid until an acidic reactant was obtained, followed by acetonitrile, and the crude product was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 28 mg (97% of theory)

ESI-MS：(M+H)⁺＝777/779(Cl)

R_f0.15 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 7

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (2-ethoxycarbonyl-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

64 mg (0.20 mmol) of TBTU and 111. mu.l (0.80 mmol) of triethylamine are added to 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 1 ml DMF and stirred at room temperature for 10 min. 122 mg (0.20 mmol) of ethyl 3- (4-piperazin-1-yl-piperidin-1-yl) -propionate (amine A2, used as tris-trifluoroacetate) were added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 45 mg (31% of theory)

ESI-MS：(M+H)⁺＝806/808(Cl)

R_f0.57 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 7.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (2-carboxy-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

Analogously to example 6.1, prepared from 30 mg (0.04 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl2- {4- [1- (2-ethoxycarbonyl-ethyl) -piperidin-4-yl ] -piperidine]-piperazin-1-yl } -2-oxo-ethyl ester with 1.4 mg (0.06 mmol) of LiOH.

Yield: 15 mg (51% of theory)

ESI-MS：(M-H)^-＝776/778(Cl)

R_f0.13 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 7.2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (4- {1- [2- (2-dimethylamino-ethoxycarbonyl) -ethyl]-piperidin-4-yl } -piperazin-1-yl) -2-oxo-ethyl ester

48 mg (0.15 mmol) of TBTU and 21. mu.l (0.15 mmol) of triethylamine are added to 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (2-carboxy-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester in 1 ml DMF and stirred at room temperature for 10 min. 15 μ l (0.15 mmol) of 2-dimethylamino-ethanol was added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 22 mg (20% of theory)

ESI-MS：(M+H)⁺＝849/851(Cl)

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

The following compounds are prepared in an analogous manner in each case from 100mg (examples 7.3 and 7.4) or 95 mg (example 7.5) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (2-carboxy-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester with their respective amounts of the respective alcohol components:

example 8

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [4- (2-ethoxycarbonyl-ethyl) -piperazin-1-yl]-piperidin-1-yl } -2-oxo-ethyl ester

64 mg (0.20 mmol) of TBTU and 28. mu.l (0.20 mmol) of triethylamine are added to 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepineHetero compound-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 1 ml DMF and stirred at room temperature for 10 min. 54 mg (0.20 mmol) of ethyl 3- (4-piperidin-4-yl-piperazin-1-yl) -propionate (amine A3) were added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 77 mg (53% of theory)

ESI-MS：(M+H)⁺＝806/808(Cl)

R_f0.58 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 8.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [4- (2-carboxy-ethyl) -piperazin-4-yl]-piperidin-1-yl } -2-oxo-ethyl ester

Analogously to example 6.1, prepared from 60 mg (0.07 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [4- (2-ethoxycarbonyl-ethyl) -piperazin-1-yl]Piperidin-1-yl } -2-oxo-ethyl ester with 2.9 mg (0.12 mmol) of LiOH.

Yield: 40 mg (70% of theory)

ESI-MS：(M-H)^-＝776/778(Cl)

R_f0.14 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 9

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((R) -2-ethoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

64 mg (0.20 mmol) of TBTU and 28. mu.l (0.20 mmol) of triethylamine are added to 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 1 ml DMF and stirred at room temperature for 10 min. 45 mg (0.20 mmol) of (R) -1-piperidin-4-yl-pyrrolidine-2-carboxylic acid ethyl ester were added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 77 mg (56% of theory)

ESI-MS：(M+H)⁺＝763/765(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Example 9.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((R) -2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

Analogously to example 6.1, prepared from 60 mg (0.08 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((R) -2-ethoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester with 2.9 mg (0.12 mmol) LiOH.

Yield: 42 mg (73% of theory)

ESI-MS：(M+H)⁺＝735/737(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Example 9.2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((R) -2-dimethylcarbamoylmethoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

25 mg (0.08 mmol) of TBTU and 11. mu.l (0.08 mmol) of triethylamine are added to 50 mg (0.07 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((R) -2-carboxy-pyrrolidin-1-yl) -pyridin-1-yl]-2-oxo-ethyl ester in 1 ml DMF and stirred at room temperature for 10 min. 8.1 mg (0.08 mmol) of 2-hydroxy-N, N-dimethyl-acetamide was added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 38 mg (68% of theory)

ESI-MS：(M+H)⁺＝820/822(Cl)

Retention time (HPLC): 2.9 minutes (method A)

Example 9.3

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [ (R) -2- (2-morpholin-4-yl-ethoxycarbonyl) -pyrrolidin-1-yl]-piperidin-1-yl } -2-oxo-ethyl ester

Analogously to example 9.2, prepared from 50 mg (0.07 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((R) -2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester with 10.3 mg (0.08 mmol) 2-morpholin-4-yl-ethanol.

Yield: 35 mg (61% of theory)

ESI-MS：(M+H)⁺＝848/850(Cl)

Retention time (HPLC): 2.6 minutes (method A)

Example 10

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((S) -2-methoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

Analogously to example 9, from 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester with 42 mg (0.20 mmol) of (S) -1-piperidin-4-yl-pyridylalane-2-carboxylic acid methyl ester.

Yield: 80 mg (59% of theory)

ESI-MS：(M+H)⁺＝749/751(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Example 10.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((S) -2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

A solution of 2.9 mg (0.12 mmol) of LiOH in 1 ml of water is added to 60 mg (0.08 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((S) -2-methoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester in 3 ml THF and the reaction mixture was stirred at room temperature overnight. The solvent was removed in a stream of nitrogen, the residue was dissolved in 1 ml of water, formic acid was added until an acidic reaction was obtained, and the mixture was extracted thoroughly with EtOAc. Adding Na to the combined organic extracts₂SO₄Dried, filtered and evaporated to dryness in vacuo. The residue was dissolved in a small amount of water and acetonitrile and lyophilized.

Yield: 51 mg (87% of theory)

ESI-MS：(M+H)⁺＝735/737(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Example 10.2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((S) -2-dimethylcarbamoylmethoxycarbonyl-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

Analogously to example 9.2, a solution prepared from 70 mg (0.10 mmol) of 4- (2-oxo-1, 2,4, 5-tetrahydro-1, 3-benzodiazepines-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((S) -2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester with 11 mg (0.11 mmol) 2-hydroxy-N, N-dimethyl-acetamide.

Yield: 45 mg (58% of theory)

ESI-MS：(M+H)⁺＝820/822(Cl)

Retention time (HPLC): 3.0 minutes (method A)

Example 10.3

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [ (S) -2- (morpholin-4-yl-ethoxycarbonyl) -pyrrolidin-1-yl]-piperidin-1-yl } -2-oxo-ethyl ester

Analogously to example 9.2, from 70 mg (0.10 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- ((S) -2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester with 13.2 mg (0.11 mmol) 2-morpholin-4-yl-ethanol.

Yield: 54 mg (59% of theory)

ESI-MS：(M+H)⁺＝848/850(Cl)

Retention time (HPLC): 2.6 minutes (method A)

Example 11

(R) -1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-2-carboxylic acid methyl ester

64 mg (0.20 mmol) of TBTU and 56. mu.l (0.40 mmol) of triethylamine are added to 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 1 ml DMF and stirred at room temperature for 10 min. 57 mg (0.20 mmol) of (R) - [1, 4']Bipiperidinyl-2-carboxylic acid methyl ester (used as acetate) was added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 59 mg (43% of theory)

ESI-MS：(M+H)⁺＝763/765(Cl)

R_f0.50 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 11.1

(R) -1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperazinesPyridine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-2-carboxylic acid

Analogously to example 6.1, prepared from 40 mg (0.05 mmol) of (R) -1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-2-carboxylic acid methyl ester with 1.9 mg (0.08 mmol) of LiOH.

Yield: 10 mg (25% of theory)

ESI-MS：(M-H)^-＝747/749(Cl)

R_f0.27 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 12

(S) -1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-2-carboxylic acid methyl ester

In analogy to example 11, from 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester and 45 mg (0.20 mmol) of (S) - [1, 4' ] bipyridinyl-2-carboxylic acid methyl ester.

Yield: 33 mg (24% of theory)

ESI-MS：(M+H)⁺＝763/765(Cl)

R_f0.44 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 12.1

(S) -1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-2-carboxylic acid

In analogy to example 6.1, from 20 mg (0.03 mmol) of (S) -1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1, 4' -bipiperidinyl-2-carboxylic acid methyl ester with 1.2 mg (0.05 mmol) of LiOH.

Yield: 3 mg (15% of theory)

ESI-MS：(M-H)^-＝747/749(Cl)

Rf 0.29 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 13

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-ethoxyoxalyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

64 mg (0.20 mmol) of TBTU and 70. mu.l (0.50 mmol) of triethylamine are added to 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -1-carboxy-ethyl ester in 2 ml DMF and stirred at room temperature for 10 min. 54 mg (0.20 mmole) [4, 4']Bipiperidin-1-yl-oxo-acetic acid ethyl ester (amine a4) was added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 88 mg (61% of theory)

ESI-MS：(M+H)⁺＝805/807(Cl)

Retention time (HPLC): 4.5 minutes (method B)

Example 13.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-oxalyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

Analogously to example 6.1, prepared from 40 mg (0.05 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-ethoxyoxalyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester will be combined with 3.6 mg (0.15 mmol) LiOH.

Yield: 26 mg (67% of theory)

ESI-MS：(M+H)⁺＝777/779(Cl)

Retention time (HPLC): 5.0 minutes (method C)

Example 13.2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-dimethylcarbamoyl-methoxyoxalyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

Analogously to example 7.2, from 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-oxalyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester with 15 mg (0.15 mmol) 2-hydroxy-N, N-dimethyl-acetamide.

Yield: 70 mg (63% of theory)

ESI-MS：(M+H)⁺＝862/864(Cl)

Retention time (HPLC): 4.1 minutes (method B)

Example 13.3

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (2-morpholin-4-yl-ethoxyoxalyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester

Analogously to example 9.2, from 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-oxalyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester with 18 μ l (0.15 mmol) 2-morpholin-4-yl-ethanol.

Yield: 69 mg (60% of theory)

ESI-MS：(M+H)⁺＝890/892(Cl)

Retention time (HPLC): 3.6 minutes (method B)

Example 14

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (3-ethoxycarbonyl-propionyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester

64 mg (0.20 mmol) of TBTU with 28. mu.l (0.50 mmol) of triethylamine are added to a solution of 100mg (0.18 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester in 1 ml of DMF and stirred at room temperature for 10 min. 59 mg (0.20 mmol) of ethyl 4- [4, 4' ] bipiperidinyl-1-yl-4-oxo-butyrate (amine A5) are added to the reaction mixture and allowed to shake at room temperature overnight. After filtration through a syringe filter, the reaction solution was purified by HPLC without further treatment. The eluted fractions containing the product were combined and lyophilized.

Yield: 61 mg (41% of theory)

ESI-MS：(M+H)⁺＝833/835(Cl)

R_f0.61 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 14.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (3-carboxy-propionyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester

A solution of 1.9 mg (0.08 mmol) of LiOH in 1 ml of water is added to 40 mg (0.05 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (3-ethoxycarbonyl-propionyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester in 10 ml THF and the reaction mixture was stirred at room temperature overnight. Removing the solvent in a nitrogen stream to leave a residueDissolved in 1 ml of water, mixed with formic acid until an acidic reactant is obtained, and mixed with 1 ml of acetonitrile and lyophilized. The residue was dissolved in 1 ml DMF and purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 19 mg (39% of theory)

ESI-MS：(M+H)⁺＝805/807(Cl)

Rf ═ 0.16 (silica gel, DCM/MeOH/NH)₃ 90:10:1)

Example 14.2

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- { 1' - [3- (2-morpholin-4-yl-ethoxycarbonyl) -propionyl]-4, 4' -bipiperidin-1-yl } -2-oxo-ethyl ester

Analogously to example 9.2, from 100mg (0.12 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (3-carboxy-propionyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester with 17 μ l (0.14 mmol) 2-morpholin-4-yl-ethanol.

Yield: 16 mg (14% of theory)

ESI-MS：(M+H)²⁺＝459/460(Cl)

Retention time (HPLC): 3.7 minutes (method B)

Example 15

4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

15a)4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-ethoxycarbonyl-ethyl ester

1.29 g (6.42 mmol) of 4-nitrophenyl chloroformate are added to a solution of 0.79 g (6.42 mmol) of DMAP in 50 ml of pyridine and stirred at room temperature for 1 hour. A solution of 2.00 g (6.42 mmol) of (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-hydroxy-propionic acid ethyl ester in 15 ml of pyridine is added dropwise and the reaction mixture is stirred at room temperature for 2 hours. 1.77 g (6.42 mmol) of 7-methoxy-3-piperidin-4-yl-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine are then added in portions-2-ketones. The suspension was stirred at room temperature for 72 hours and then evaporated to dryness in vacuo. The residue was mixed with 200 ml of EtOAc, at 200 ml of 15% K₂CO₃The solution is washed, the organic phase is separated off and evaporated in vacuo. The residue was chromatographed (silica, gradient DCM to MeOH/NH)₃95:5) purifying.

Yield: 1.80 g (46% of theory)

ESI-MS：(M+H)⁺＝613/615(Cl)

Rf 0.50 (silica gel, DCM/MeOH9:1)

15b)4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester

A solution of 0.11 g (4.50 mmol) of LiOH in 50 ml of water is added to 1.80 g (2.94 mmol) of 4- (7-methoxy-2-oxo-1, 3, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-ethoxycarbonyl-ethyl ester in 50 ml THF and the reaction mixture was stirred at room temperature for 3 hours. THF was removed in vacuo, diluted with 100 ml of water, and acidified with 1M HCl. The precipitated material was filtered off with suction, washed with 50 ml of water and dried in a vacuum drying oven at 65 ℃.

Yield: 1.60 mg (93% of theory)

ESI-MS：(M+H)⁺＝585/587(Cl)

15c)4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

Analogously to example 9, from 100mg (0.17 mmol) of 4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester with 48 mg (0.19 mmol) [4, 4']Bipiperidin-1-yl-acetic acid ethyl ester.

Yield: 58 mg (41% of theory)

ESI-MS：(M+H)⁺＝821/823(Cl)

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

Example 15.1

4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

A solution of 1 mg (0.04 mmol) of LiOH in 1 ml of water is added to 20 mg (0.02 mmol) of 4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester to a solution in 1 ml THF and the reaction mixture was stirred at room temperature overnight. To complete the reaction, a solution of 1 mg of LiOH in 1 ml of water was added once more and the mixture was stirred at room temperature for a further 3 hours. The solvent was removed in a stream of nitrogen, the residue was dissolved in a mixture of acetonitrile and water, and the product was subjected to freeze-drying.

Yield: 14 mg (72% of theory)

ESI-MS：(M+H)⁺＝793/795(Cl)

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

Example 15.2

4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (2-morpholin-4-yl-ethoxycarbonyl-methyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester

113 mg (0.35 mmol) of TBTU, 84. mu.l (0.60 mmol) of triethylamine and 39 mg (0.30 mmol) of 2-morpholin-4-yl-ethanol are added to 230 mg (0.29 mmol) of 4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester to a solution in 5 ml DMF and the reaction mixture was stirred at room temperature overnight. The reaction solution was poured into saturated NaHCO₃The precipitated product was filtered off with suction over the solution and dried at 40 ℃. The crude product was dissolved in 25 ml of anhydrous isopropanol and precipitated as a salt as 0.5M HCl in isopropanol. The precipitate was filtered off, washed with 5 ml isopropanol and 30 ml DIPE and dried overnight at 30 ℃ in a vacuum drying oven.

Yield: 90 mg (34% of theory)

ESI-MS：(M+H)⁺＝906/908(Cl)

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

Example 16

4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-ethoxycarbonylmethyl-piperazin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

Analogously to example 9, from 100mg (0.17 mmol) of 4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester with 49 mg (0.19 mmol) (4-piperidin-4-yl-piperazin-1-yl) -acetic acid ethyl ester.

Yield: 62 mg (44% of theory)

ESI-MS：(M+H)⁺＝822/824(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Example 16.1

4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-carboxymethyl-piperazin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester

Analogously to example 15.1, prepared from 20 mg (0.02 mmol) of 4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino)-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-ethoxycarbonylmethyl-piperazin-1-yl) -piperidin-1-yl]-2-oxo-ethyl ester with 2 mg (0.08 mmol) LiOH.

Yield: 19 mg (99% of theory)

ESI-MS：(M+H)⁺＝794/796(Cl)

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

Example 17

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-methyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

17a) (Z, E) -2-acetylamino-3- (4-amino-3-chloro-5-methyl-phenyl) -acrylic acid methyl ester

Under nitrogen atmosphere, 15.4 g (49.1 mmol) of tri-o-tolyl-phosphine and 11.0 g (49.0 mmol) of Pd (OAc)₂To a mixture of 72.8 g (330 mmol) of 4-bromo-2-chloro-6-methyl-aniline and 58.0 g (397 mmol) of methyl 2-acetylamino-acrylate in 970 ml of triethylamine and 1.2 l of acetonitrile and the reaction mixture is stirred at 80 ℃ for 18 h. After the reaction was cooled, the solution was filtered, evaporated to dryness in vacuo and the residue was stirred with 350 ml water and 350 ml EtOAc. The solvent was decanted off and the residue was stirred once more with 300 ml EtOAc, filtered off with suction, washed with a small amount of EtOAc and MTBE and dried at 60 ℃.

Yield: 40.6 g (44% of theory)

ESI-MS：(M+H)⁺＝283/285(Cl)

R_f0.47 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

17b)3- (4-amino-3-chloro-5-methyl-phenyl) -2-oxo-propionic acid

A solution of 28.0 g (99.0 mmol) of (Z, E) -2-acetylamino-3- (4-amino-3-chloro-5-methyl-phenyl) -acrylic acid methyl ester in 250 ml of 1, 4-dioxane and 125 ml of HCl (4M) was stirred under nitrogen at 80 ℃ for 6 hours. The solvent was removed in vacuo, the residue triturated with isopropanol and DIPE, the precipitate removed by suction filtration and dried at 60 ℃. The product was obtained as its hydrochloride salt and allowed to react further without purification.

Yield: 26.0 g (99% of theory)

ESI-MS：(M-H)^-＝226/228(Cl)

R_f0.15 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

17c) (R) -3- (4-amino-3-chloro-5-methyl-phenyl) -2-hydroxy-propionic acid methyl ester

A solution of 27.0 g (84.2 mmol) of (1R) -B-chlorodi-isopinocampheylborane in 75 ml of THF is added dropwise over 15 minutes to a solution of 13.0 g (49.2 mmol) of 3- (4-amino-3-chloro-5-methyl-phenyl) -2-oxo-propionic acid and 17.0 ml (122.3 mmol) of triethylamine in 175 ml of THF cooled to about-30 ℃ under nitrogen. After the addition was stopped, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. 150 ml of 1M NaOH was added dropwise to the reaction mixture under ice cooling. 200 ml of EtOAc are added, the mixture is stirred for a further 15 minutes, the aqueous phase is separated off and the organic phase is washed twice with 50 ml of 1M NaOH each time, once with 40 ml of water and made acidic with 4 MHCl. The organic phase is separated off over MgSO₄Dried and evaporated to dryness in vacuo. The residue was mixed with 250 ml of methanolic HCl (1.25M) and stirred at room temperature overnight. The reaction mixture was evaporated in vacuo, the residue was dissolved in a small amount of PE and EtOAc, placed on silica gel and eluted with PE/EtOAc (2:1). The fractions containing the product were combined and evaporated to dryness.

Yield: 6.0 g (50% of theory)

ESI-MS：(M+H)⁺＝244/246(Cl)

R_f0.74 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

17d)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-methyl-phenyl) -1-carboxy-ethyl ester

In analogy to example 1e, from 6.0 g (24.6 mmol) of (R) -3- (4-amino-3-chloro-5-methyl-phenyl) -2-hydroxy-propionic acid methyl ester and 6.1 g (24.9 mmol) of 3-piperidin-4-yl-1, 3, 4, 5-tetrahydro-1, 3-benzodiazepine-2-ketones. The crude methyl ester product was dissolved in 100 ml THF and mixed with a solution of 1.0 g (40.9 mmol) LiOH in 50 ml water. The reaction mixture was stirred at room temperature for 15 hours, diluted with water, and the organic solvent was removed in vacuo. The aqueous phase was washed with 60 ml EtOAc, acidified with 21 ml 4M HCl, and stirred at room temperature for 15 min. The mixture was extracted three times with 150 ml each of DCM and the combined organic phases were washed with MgSO₄And (5) drying. After removal of the drying agent and solvent, the residue was chromatographed (silica gel, gradient DCM to DCM/MeOH/NH)₃70:27: 3).

Yield: 0.88 g (7% of theory)

ESI-MS：(M+H)⁺＝501/503(Cl)

R_f0.17 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

17e)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-methyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

Analogously to example 5, from 100mg (0.20 mmol) of 4- (2-oxo-1, 3, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-methyl-phenyl) -1-carboxy-ethyl ester with 56 mg (0.22 mmol) [4, 4']Bipiperidin-1-yl-acetic acid ethyl ester.

Yield: 19 mg (13% of theory)

ESI-MS：(M+H)⁺＝737/739(Cl)

R_f0.72 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 17.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-methyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

A solution of 7.0 mg (0.29 mmol) of LiOH in 5 ml of water is added to 80 mg (0.11 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-methyl-benzyl) -2- (1 '-ethoxycarbonyl-methyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester in 10 ml THF and the reaction mixture in the chamberStir at room temperature overnight. The THF was removed in vacuo, the aqueous residue was mixed with 0.35 ml of 1M HCl and evaporated in vacuo. The residue was purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 8 mg (10% of theory)

ESI-MS：(M+H)⁺＝709/711(Cl)

R_f0.21 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 18

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (3-chloro-4-hydroxy-5-methyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

18a) 2-benzyloxy-5-bromo-1-chloro-3-methyl-benzene

7.0 ml (57.7 mmol) of benzyl bromide are added to 10.2 g (46.1 mmol) of 4-bromo-2-chloro-6-methyl-phenol and 30.0 g (217 mmol) of K₂CO₃In a suspension in 130 ml DMF and the reaction mixture was stirred at room temperature overnight. The insoluble components were filtered off, the filtrate was evaporated to dryness in vacuo, mixed with water and extracted thoroughly with EtOAc. The combined organic phases were washed with Na₂SO₄Dried, filtered and evaporated to dryness. The product was reacted further without purification.

Yield: 14.0 g (98% of theory)

R_f0.91 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

18b) (Z, E) -2-acetylamino-3- (4-benzyloxy-3-chloro-5-methyl-phenyl) -acrylic acid methyl ester

Under nitrogen atmosphere, 4.4 g (14.0 mmol) of tri-o-tolyl-phosphine and 3.2 g (14.3 mmol) of Pd (OAc)₂To a mixture of 28.0 g (89.9 mmol) 2-benzyloxy-5-bromo-1-chloro-3-methyl-benzene and 15.0 g (103 mmol) methyl 2-acetamido-acrylate in 260 ml triethylamine and 400 ml acetonitrile was added and the reaction mixture was stirred at 80 ℃ for 18 h. After cooling, the reaction solution was evaporated to dryness in vacuo, the residue was stirred with 100 ml of water, 50 ml of EtOAc and 50 ml of PE, and the insoluble components were filtered off. The residue was dissolved in DCM/MeOH (5:1), mixed with activated carbon, filtered and evaporated to dryness in vacuo. The crude product was reacted further without purification.

Yield: 12.5 g (37% of theory)

ESI-MS：(M+H)⁺＝374/376(Cl)

R_f0.67 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

18c)3- (4-benzyloxy-3-chloro-5-methyl-phenyl) -2-oxo-propionic acid

To a solution of 18.4 g (49.2 mmol) of (Z, E) -2-acetylamino-3- (4-benzyloxy-3-chloro-5-methylphenyl) -acrylic acid methyl ester in 150 ml of 1, 4-dioxane was added 75 ml of 4M HCl and the reaction mixture was refluxed overnight. The 1, 4-dioxane was removed in vacuo and the precipitated product was filtered off, dissolved again in DIPE and added MgSO₄And (5) drying. After the drying agent and solvent are removed, the residue is reacted further without purification.

Yield: 15.5 g (99% of theory)

ESI-MS：(M-H)^-＝317/319(Cl)

R_f0.20 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

18d) (R) -3- (4-benzyloxy-3-chloro-5-methyl-phenyl) -2-hydroxy-propionic acid methyl ester

A solution of 27.6 g (86.0 mmol) of (1R) -B-chlorodiisopinocampheylcholine borane in 100 ml of THF is added dropwise over 15 minutes to a solution of 15.5 g (48.6 mmol) of 3- (4-benzyloxy-3-chloro-5-methyl-phenyl) -2-oxo-propionic acid and 9.2 ml (66.2 mmol) of triethylamine in 200 ml of THF cooled to about-30 ℃ under nitrogen. After the addition had ceased, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Under ice-cooling, 240 ml of 1M NaOH was added dropwise to the reaction mixture. 400 ml of EtOAc are added, the mixture is stirred for 15 minutes, the aqueous phase is separated off and the organic phase is washed twice with 100 ml of 1M NaOH each time and once with 100 ml of water. The combined aqueous phases were acidified with semi-concentrated HCl, extracted twice with 150 ml of EtOAc each time, and the combined organic phases were extracted with MgSO₄And (5) drying. After the drying agent and solvent were removed, the oily residue was mixed with 150 ml of methanolic HCl (1.25M) and the reaction mixture was stirred at room temperature overnight. It is evaporated to dryness in vacuo and the residue is taken up with 70 ml of 15% K₂CO₃The solutions were mixed and extracted twice with 50 ml of EtOAc each time. The combined organic phases were washed with MgSO₄Dried, filtered and evaporated to dryness in vacuo. The product was reacted further without purification.

Yield: 7.0 g (43% of theory)

ESI-MS：(M+NH₄)⁺＝352/354(Cl)

R_f0.87 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

18e)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-benzyloxy-3-chloro-5-methyl-phenyl) -1-carboxy-ethyl ester

In analogy to example 1e, was prepared from 7.0 g (20.9 mmol) of (R) -3- (4-benzyloxy-3-chloro-5-methyl-phenyl) -2-hydroxy-propionic acid methyl ester and 5.2 g (21.2 mmol) of 3-piperidin-4-yl-1, 3,4, 5-tetrahydro-1, 3-benzodiazepines-2-ketones. The crude methyl ester product was dissolved in 150 ml THF and mixed with a solution of 0.5 g (20.7 mmol) LiOH in 50 ml water. The reaction mixture was stirred at room temperature overnight, diluted with water, and the organic solvent was removed in vacuo. The aqueous phase was washed twice with 60 ml each time of EtOAc, acidified with 21 ml of 4M HCl, and the oil thus formed was extracted thoroughly with EtOAc. The combined organic phases were washed with MgSO₄Dried, filtered and the solvent evaporated in vacuo. The residue was triturated with DIPE and filtered under suction.

Yield: 3.3 g (26% of theory)

ESI-MS：(M+H)⁺＝592/594(Cl)

R_f0.35 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

18f)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1-carboxy-2- (3-chloro-4-hydroxy-5-methyl-phenyl) -ethyl ester

2.75 g (4.65 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine are reactedA suspension of (R) -2- (4-benzyloxy-3-chloro-5-methyl-phenyl) -1-carboxy-ethyl-3-piperidine-1-carboxylate with 1.0 g rhodium on alumina in 150 ml MeOH was hydrogenated at 40 ℃ and 50psi hydrogen pressure for 18 h. To complete the reaction, 0.5 g more rhodium on alumina was added and the mixture was hydrogenated for a further 6 hours. The catalyst was removed by suction filtration and the filtrate was evaporated to dryness in vacuo. The residue contaminated with about 50% of its corresponding methyl ester was dissolved in 25 ml of THF and mixed with a solution of 250 mg (10.23 mmol) LiOH in 15 ml of water, and the reaction mixture was stirred at room temperature for 3 hours. THF is removed in vacuo, andwater and 10.5 ml of 1M HCl are mixed and the precipitated product is filtered off with suction and then washed with a little water and dried at 60 ℃.

Yield: 2.1 g (90% of theory)

ESI-MS：(M+H)⁺＝502/504(Cl)

R_f0.12 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

18g)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (3-chloro-4-hydroxy-5-methyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester

Analogously to example 5, from 100mg (0.20 mmol) of 4- (2-oxo-1, 3, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1-carboxy-2- (3-chloro-4-hydroxy-5-methyl-phenyl) -ethyl ester with 51 mg (0.20 mmol) [4, 4']Bipiperidin-1-yl-acetic acid ethyl ester.

Yield: 14 mg (9% of theory)

ESI-MS：(M+H)⁺＝738/740(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Example 18.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -1- (3-chloro-4-hydroxy-5-methyl-benzyl) -2-oxo-ethyl ester

A solution of 2.0 mg (0.08 mmol) of LiOH in 1 ml of water is added to 38 mg (0.05 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (3-chloro-4-hydroxy-5-methyl-benzyl) -2- (1 '-ethoxycarbonylmethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester to a solution in 1 ml THF and the reaction mixture was shaken at room temperature for 3 hours. The reaction solution was acidified with 1M HCl and purified by HPLC. The eluted fractions containing the product were combined and lyophilized.

Yield: 30 mg (82% of theory)

ESI-MS：(M+H)⁺＝710/712(Cl)

R_f0.20 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 19

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-ethoxycarbonylmethyl-4-methyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester

0.25 ml (1.18 mmol) of triethylamine is added to 250 mg (0.45 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (c) (d)Example 1f), 250 mg (0.50 mmol) of ethyl (4-methyl-4-piperazin-1-yl-piperidin-1-yl) -acetate (example A7f) and 160 mg (0.50 mmol) of TBTU in a mixture of 2 ml of DMF and the reaction mixture was stirred at room temperature for 4 h. It was evaporated to dryness in vacuo and the residue was purified by HPLC; the eluted fractions containing the product were combined and lyophilized.

Yield: 225 mg (62% of theory)

ESI-MS：(M+H)⁺＝806/808(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Example 19.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-4-methyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester

A solution of 10.0 mg (0.42 mmol) of LiOH in 5 ml of water is added to 100mg (0.12 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 10 ml of THF-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-ethoxycarbonyl-methyl-4-methyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester and the reaction mixture was stirred at room temperature for 3 hours. Mixed with 0.42 ml (0.42 mmol) 1M HCl and the mixture evaporated in vacuo. The residue was dissolved in a small amount of DCM/MeOH (1:1), filtered through a small amount of silica gel, and eluted with DCM/MeOH (1: 1). The filtrate was evaporated to dryness in vacuo and dried under high vacuum.

Yield: 95 mg (98% of theory)

ESI-MS：(M+H)⁺＝778/780(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Example 20

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-ethoxycarbonylmethyl-piperazin-1-yl) -4-methyl-piperidin-1-yl]-2-oxo-ethyl ester

0.10 ml (0.72 mmol) of triethylamine are added to 250 mg (0.45 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f), 140 mg (0.49 mmol) [4- (4-methyl-piperidin-4-yl) -piperazin-1-yl]Ethyl acetate (example A8b) and 160 mg (0.50 mmol) of TBTU in 2 ml of DMF and the reaction mixture is stirred at room temperature for 18 h. It was evaporated in vacuo and the residue was purified by chromatography (Alox, gradient DCM/MeOH 40:1 to 30: 1). The fractions containing the product were combined, evaporated to dryness in vacuo and purified by HPLC; the eluted fractions containing the product were combined and lyophilized.

Yield: 178 mg (49% of theory)

ESI-MS：(M+H)⁺＝806/808(Cl)

Retention time (HPLC): 3.8 minutes (method B)

Example 20.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-carboxymethyl-piperazin-1-yl) -4-methyl-piperidin-4-yl]-2-oxo-ethyl ester

Analogously to example 19.1, from 100mg (0.12 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (4-ethoxycarbonylmethyl-piperazin-1-yl) -4-methyl-piperidin-1-yl]-2-oxo-ethyl ester with 10.0 mg (0.42 mmol) LiOH.

Yield: 42 mg (44% of theory)

ESI-MS：(M+H)⁺＝778/780(Cl)

Retention time (HPLC): 3.3 minutes (method B)

Example 21

(S) -1- (1- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -piperidin-4-yl) -4-methyl-piperazine-2-carboxylic acid ethyl ester

0.40 mm ofL (2.88 mmol) of triethylamine are added to 260 mg (0.46 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f), 210 mg (0.58 mmol) of (S) -4-methyl-1-piperidin-4-yl-piperazine-2-carboxylic acid ethyl ester (example A9f) and 170 mg (0.53 mmol) of TBTU in a mixture of 2.4 ml of DMF and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was purified by HPLC without further treatment; the eluted fractions containing the product were combined and lyophilized.

Yield: 227 mg (61% of theory)

ESI-MS：(M+H)⁺＝792/794(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Example 21.1

(S) -1- (1- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -piperidin-4-yl) -4-methyl-piperazine-2-carboxylic acid

0.5 mg (1.00 mmol) of a 2M LiOH solution are added to 80.0 mg (0.10 mmol) of (S) -1- (1- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 1 ml THF-3-yl) -piperidine-1-carbonyloxy]-propionyl } -piperidin-4-yl) -4-methyl-piperazine-2-carboxylic acid ethyl ester and mixing the reactionThe mixture was stirred at room temperature for 20 hours. It was purified by HPLC without work-up; the eluted fractions containing the product were combined and lyophilized.

Yield: 50 mg (65% of theory)

ESI-MS：(M+H)⁺＝764/766(Cl)

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

Example 22

(S) -4- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester

0.25 ml (2.88 mmol) of triethylamine is added to 200 mg (0.36 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f), 150 mg (0.58 mmol) of (S) -1- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester (example a10c) and 140 mg (0.44 mmol) of TBTU in a mixture of 2.0 ml of DMF and the reaction mixture was stirred at room temperature for 5 h. It was purified by HPLC without further treatment; the eluted fractions containing the product were combined and lyophilized.

Yield: 84 mg (29% of theory)

ESI-MS：(M+H)⁺＝792/794(Cl)

Retention time (HPLC): 3.5 minutes (method B)

Example 22.1

(S) -4- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid

0.26 ml (0.13 mmol) of a 0.5M LiOH solution is added to 50.0 mg (0.06 mmol) of (S) -4- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 0.8 ml THF-3-yl) -piperidine-1-carbonyloxy]-propionyl } -1- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester and the reaction mixture was stirred at room temperature overnight. To complete the reaction, 50 μ l (0.1 mmol) of 0.5M LiOH solution were added and stirred at room temperature for a further 4 hours, and the reaction mixture was then purified by HPLC without work-up; the eluted fractions containing the product were combined and lyophilized.

Yield: 22 mg (46% of theory)

ESI-MS：(M+H)⁺＝764/766(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Example 23

(S) -1- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -4- (1-methyl-piperidin-4-yl)) -piperazine-2-carboxylic acid ethyl ester

0.30 ml (2.16 mmol) of triethylamine are added to 700 mg (1.26 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f), 430 mg (1.41 mmol) of (S) -4- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester (example a11b) and 450 mg (1.40 mmol) of TBTU in a mixture of 7 ml of DMF and the reaction mixture was stirred at room temperature for 18 h. It was evaporated in vacuo and the residue was taken up with saturated NaHCO₃The solution was stirred together, extracted thoroughly with EtOAc, and the combined organic phases were taken over Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by HPLC; the eluted fractions containing the product were combined and lyophilized.

Yield: 670 mg (67% of theory)

ESI-MS：(M+H)⁺＝792/794(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Example 23.1

(S) -1- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -4- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid

In analogy to example 22.1, prepared from 80.0 mg (0.10 mmol) of (S) -1- { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -4- (1-methyl-piperidin-4-yl) -piperazine-2-carboxylic acid ethyl ester with 0.46 ml (0.23 mmol) of a 0.5M LiOH solution.

Yield: 53 mg (69% of theory)

ESI-MS：(M+H)⁺＝764/766(Cl)

Retention time (HPLC): 2.9 minutes (method B)

Example 24

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (8-ethoxycarbonylmethyl-8-aza-bicyclo [3.2.1]Oct-3-yl) -piperazin-1-yl]-2-oxo-ethyl ester

113 mg (0.40 mmol) of (3-piperazin-1-yl-8-aza-bicyclo [3.2.1]Oct-8-yl) -acetic acid ethyl ester (example A12d) was added to 200 mg (0.45 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f), 128 mg (0.40 mmol) of TBTU and 56 μ l (0.40 mmol) of triethylamine in a mixture of 2 ml of DMF and the reaction mixture was stirred at room temperature for 2 h. It was purified by HPLC without further treatment; combination of Chinese herbsAnd contains the eluted fraction of the product and is evaporated to dryness in vacuo.

Yield: 156 mg (53% of theory)

ESI-MS：(M+H)⁺＝818/820(Cl)

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

Example 24.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (8-carboxymethyl-8-aza-bicyclo [3.2.1]Oct-3-yl) -piperazin-1-yl]-2-oxo-ethyl ester

A solution of 1.92 mg (0.08 mmol) of LiOH in 1 ml of water is added to 40.0 mg (0.05 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 1 ml of THF-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (8-ethoxycarbonyl-methyl-8-aza-bicyclo [3.2.1]Oct-3-yl) -piperazin-1-yl]-2-oxo-ethyl ester and the reaction mixture was shaken at room temperature overnight. The solvent was removed in a nitrogen stream and the residue was purified by HPLC; the eluted fractions containing the product were combined and lyophilized.

Yield: 13 mg (34% of theory)

ESI-MS：(M+H)⁺＝790/792(Cl)

Retention time (HPLC): 2.7 minutes (method B)

Example 25

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (4-ethoxycarbonylmethoxy-1, 4 '-bipiperidin-1' -yl) -2-oxo-ethyl ester

0.30 ml (2.16 mmol) of triethylamine are added to 300 mg (0.54 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f), 220 mg (0.64 mmol) ([1, 4']Bipiperidin-4-yloxy) -acetic acid ethyl ester (example a13c) and 200 mg (0.62 mmol) of TBTU in 3 ml of DMF were taken and the reaction mixture was stirred at room temperature for 4 hours. With ice and saturated NaHCO₃The solutions were mixed and the precipitate was filtered off. It was dissolved in DCM with a little EtOH and Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by HPLC; the eluted fractions containing the product were combined and lyophilized.

Yield: 170 mg (39% of theory)

ESI-MS：(M+H)⁺＝807/809(Cl)

Retention time (HPLC): 3.7 minutes (method B)

Example 25.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (4-carboxymethoxy-14 '-Bipiperidin-1' -yl) -2-oxo-ethyl ester

A solution of 8.00 mg (0.33 mmol) of LiOH in 2.5 ml of water is added to 100mg (0.12 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 8 ml of THF-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (4-ethoxycarbonyl-methoxy-1, 4 '-bipiperidin-1' -yl) -2-oxo-ethyl ester and the reaction mixture is stirred at room temperature for 3 hours. 0.34 ml (0.34 mmol) of 1M HCl was added and the mixture was evaporated in vacuo. The residue was dissolved in DCM/MeOH, filtered through a small amount of silica gel, and eluted with DCM/MeOH (7: 3). It was evaporated to dryness in vacuo and the residue was dried under high vacuum.

Yield: 61 mg (63% of theory)

ESI-MS：(M+H)⁺＝779/781(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Example 26

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (4-ethoxycarbonylmethyl-1, 4 '-bipiperidin-1' -yl) -2-oxo-ethyl ester

200 μ l (1.43 mmol) of triethylamine and 414 mg (1.29 mmol) of TBTU are addedTo 30 ml of THF and 650 mg (1.17 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 5 ml of DMF-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f) and the reaction mixture was stirred at room temperature for 30 min. Then 422 mg (1.29 mmol) of [1, 4 'in 10 ml DCM were added']Bipiperidin-4-yl-acetic acid ethyl ester (example a14b) and 330 μ l (2.38 mmol) of triethylamine and the mixture stirred at room temperature for a further 18 h. 50 ml of half-saturated NaHCO were added₃The mixture was extracted twice with 50 ml each time of EtOAc, the combined organic phases were washed with 50 ml of saturated NaCl solution and Na₂SO₄And (5) drying. After removal of the drying agent and solvent, the residue was chromatographed (silica gel, EtOAc/MeOH/NH)₃95:5:0.5) purification. The fractions containing the product were combined, evaporated to dryness in vacuo, the residue triturated with DIPE, filtered off with suction and dried.

Yield: 646 mg (70% of theory)

ESI-MS：(M+H)⁺＝791/793(Cl)

R_f0.33 (silica gel, EtOAc/MeOH/NH)₃ 90:10:1)

Example 26.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (4-carboxymethyl-1, 4 '-bipiperidin-1' -yl) -2-oxo-ethyl ester

A solution of 5.00 mg (0.21 mmol) of LiOH in 3 ml of water was addedTo 100mg (0.13 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 10 ml THF-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (4-ethoxycarbonyl-methyl-1, 4 '-bipiperidin-1' -yl) -2-oxo-ethyl ester and the reaction mixture is stirred at room temperature for 2 days. The mixture was evaporated to dryness in vacuo and the residue was dissolved in 1 ml DMF and purified by HPLC; the eluted fractions containing the product were combined and lyophilized.

Yield: 22 mg (22% of theory)

ESI-MS：(M+H)⁺＝763/765(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Example 27

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (2-ethoxycarbonyl-ethyl) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester

Analogously to example 24, from 500 mg (0.90 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f) with 341 mg (1.00 mmol) of 3- [1, 4']Bipiperidin-4-yl-propionic acid ethyl ester (example A15 b).

Yield: 340 mg (47% of theory)

ESI-MS：(M+H)⁺＝805/807(Cl)

Retention time (HPLC): 3.6 minutes (method B)

Example 27.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (2-carboxy-ethyl) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester

A solution of 2.40 mg (0.10 mmol) of LiOH in 1 ml of water is added to 50 mg (0.06 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 3 ml of THF-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (2-ethoxycarbonyl-ethyl) -1, 4 '-bipiperidin-1' -yl]-2-oxo-ethyl ester and the reaction mixture was stirred at room temperature for 4 hours. THF was removed in a nitrogen stream and the residue was dissolved in a small amount of water and purified by HPLC; the eluted fractions containing the product were combined and lyophilized.

Yield: 38 mg (79% of theory)

ESI-MS：(M+H)⁺＝777/779(Cl)

Retention time (HPLC): 3.4 minutes (method B)

Example 28

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acidAcid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (3-ethoxycarbonyl-propyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

283 mg (1.00 mmol) of ethyl 4- (4-piperazin-1-yl-piperidin-1-yl) -butyrate (example A16b) are added to 500 mg (0.90 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1f), 321 mg (1.00 mmol) of TBTU and 0.14 ml (1.00 mmol) of triethylamine in 10 ml of DMF and the reaction mixture was stirred at room temperature for 2 h. It was purified by HPLC without further treatment; the fractions containing the product were combined, evaporated in vacuo and the residue was taken up with saturated NaHCO₃The solutions were stirred together, filtered, and dried.

Yield: 165 mg (22% of theory)

ESI-MS：(M+H)⁺＝820/822(Cl)

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

Example 28.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (3-carboxy-propyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

Analogously to example 27.1, prepared from 50 mg (0.06 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (3-ethoxycarbonyl-propyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester with 2.40 mg (0.10 mmol) LiOH.

Yield: 29 mg (60% of theory)

ESI-MS：(M+H)⁺＝792/794(Cl)

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

Example 29

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (1-ethoxycarbonyl-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

29a)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2-oxo-2- (4-piperidin-4-yl-piperazin-1-yl) -ethyl ester

1.00 g (1.80 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -2- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -1-carboxy-ethyl ester (example 1)f) A mixture of 546 mg (1.80 mmol) of benzyl 4-piperazin-1-yl-piperidine-1-carboxylate (example a17b), 643 mg (2.00 mmol) of TBTU and 0.35 ml (2.50 mmol) of triethylamine in 10 ml of DMF was stirred at room temperature overnight. It was mixed with 150 ml of 15% K₂CO₃The solutions were mixed, the precipitate was removed by suction filtration, washed with 30 ml of water and the crude product was dried in a drying cabinet at 40 ℃.

Yield: 1.50 g (99% of theory)

ESI-MS：(M+H)⁺＝840/842(Cl)

Retention time (HPLC): 3.7 minutes (method B)

A suspension of 750 mg (0.89 mmol) of the product described above with 600 mg of Raney nickel in 50 ml of MeOH is hydrogenated at room temperature and 3447hPa for 30 h. The catalyst was removed by suction filtration, evaporated to dryness in vacuo and the residue purified by HPLC. The fractions containing the product were combined, evaporated to dryness in vacuo and the residue was taken up in 15% K₂CO₃The solution was made basic, extracted with 100 ml EtOAc, the organic phase separated and washed with Na₂SO₄And (5) drying. After the drying agent and solvent were removed, the residue was triturated with 30 ml of DIPE, filtered off with suction and dried.

Yield: 280 mg (44% of theory)

ESI-MS：(M+H)⁺＝706/708(Cl)

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

29b)4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (1-ethoxycarbonyl-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

140 mg (0.20 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiAza derivatives-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2-oxo-2- (4-piperidin-4-yl-piperazin-1-yl) -ethyl ester, 60.8 mg (0.44 mmol) K₂CO₃And a mixture of 29. mu.l (0.22 mmol) of ethyl 2-bromopropionate in 1.8 ml of DMF, shaking at 50 ℃ for 2 hours. The reaction mixture was purified by HPLC without work-up; the eluted fractions containing the product were combined and lyophilized.

Yield: 111 mg (69% of theory)

ESI-MS：(M+H)⁺＝806/808(Cl)

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

Example 29.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (1-carboxy-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

A solution of 2.4 mg (0.10 mmol) of LiOH in 0.8 ml of water is added to 50 mg (0.06 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 1 ml of THF-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (1-ethoxycarbonyl-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester, and the reaction mixture was shaken at room temperature for 2 hours, and at 50 ℃ for 4 hours. It was then purified by HPLC without work-up; the washes containing the product were combinedRemoving part, and lyophilizing.

Yield: 42 mg (87% of theory)

ESI-MS：(M+H)⁺＝778/780(Cl)

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

Example 30

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (1-ethoxycarbonyl-1-methyl-ethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

140 mg (0.20 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2-oxo-2- (4-piperidin-4-yl-piperazin-1-yl) -ethyl ester (example 29a), 60.8 mg (0.44 mmol) of K₂CO₃And a mixture of 45. mu.l (0.30 mmol) of ethyl 2-bromo-2-methyl-propionate in 1.8 ml of DMF, shaking at 50 ℃ for 12 hours, followed by 48 hours at room temperature. The precipitate was filtered off and the filtrate was purified by HPLC without workup; the fractions containing the product were combined, evaporated to dryness in vacuo and the residue taken up in saturated NaHCO₃The solution is made alkaline and the precipitate is filtered off with suction, washed with 20 ml of water and dried at 40 ℃.

Yield: 85 mg (52% of theory)

ESI-MS：(M+H)⁺＝820/822(Cl)

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

Example 31

1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -4-methyl-1, 4' -bipiperidinyl-4-carboxylic acid ethyl ester

127 mg (0.20 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepineA mixture of (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2-oxo-2- (4-oxo-piperidin-1-yl) -ethyl (example 1g), 68.5 mg (0.40 mmol) of ethyl 4-methyl-piperidine-4-carboxylate and 11 μ l (0.2 mmol) of AcOH in 2 ml of DCM was stirred at room temperature for 2 hours, cooled to 0 ℃, stirred for 2 hours, then mixed with 57.7 mg (0.26 mmol) of sodium triacetoxyborohydride and stirred at 0 ℃ overnight. The reaction mixture was purified by HPLC without work-up; the eluted fractions containing the product were combined and lyophilized.

Yield: 85 mg (54% of theory)

ESI-MS：(M+H)⁺＝791/793(Cl)

Retention time (HPLC): 7.7 minutes (method B)

The following compounds are prepared in an analogous manner from 127 mg of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in each case-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trisFluoromethyl-benzyl) -2-oxo-2- (4-oxo-piperidin-1-yl) -ethyl ester (example 1g) was prepared with the amounts of amine component required in each case:

example 32

1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carbonyloxy]-propionyl } -4-methyl-1, 4' -bipiperidinyl-4-carboxylic acid

A solution of 2.99 mg (0.08 mmol) of LiOH in 1 ml of water is added to 40 mg (0.05 mmol) of 1' - { (R) -3- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2- [4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine in 0.8 ml of THF-3-yl) -piperidine-1-carbonyloxy]-propionyl } -4-methyl-1, 4' -bipiperidinyl-4-carboxylic acid ethyl ester and the reaction mixture is stirred at room temperature for 1 hour and at 50 ℃ for 8 hours. It was purified by HPLC without work-up; the eluted fractions containing the product were combined and lyophilized.

Yield: 18 mg (47% of theory)

ESI-MS：(M+H)⁺＝763/765(Cl)

Retention time (HPLC): 3.5 minutes (method B)

The following compounds were prepared in an analogous manner from in each case 40 mg of their corresponding ethyl esters, the hydrolysis only needing 1 hour at room temperature:

example 33

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- {4- [1- (5-methyl-2-oxo-1, 3-dioxol-4-ylmethoxycarbonylmethyl) -piperidin-4-yl]-piperazin-1-yl } -2-oxo-ethyl ester

185 mg (0.24 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine are reacted-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester (example 4.1), 25 mg (0.25 mmol) of KHCO₃And 50 mg (0.26 mmol) of 4-bromomethyl-5-methyl-1, 3-dioxol-2-one in 1 ml of DMFThe mixture was shaken at room temperature overnight. The reaction mixture was filtered through a syringe filter and purified by HPLC; the eluted fractions containing the product were combined and lyophilized.

Yield: 14 mg (7% of theory)

ESI-MS：(M+H)⁺＝876/878(Cl)

R_f0.54 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 33.1

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepin-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (5-methyl-2-oxo-1, 3-dioxol-4-ylmethoxycarbonylmethyl) -4, 4' -bipiperidin-1-yl ] -2-oxo-ethyl ester

Analogously to example 33, from 150 mg (0.20 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester (example 3.1) with 50 mg (0.26 mmol) of 4-bromomethyl-5-methyl-1, 3-dioxol-2-one.

Yield: 8 mg (5% of theory)

ESI-MS：(M+H)⁺＝875/877(Cl)

R_f0.74 (silica gel, DCM/Cyc/MeOH/NH)₃ 70:15:15:2)

Example 34

4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (4- {1- [2- (2-methoxy-ethoxy) -ethoxycarbonylmethyl]-piperidin-4-yl } -piperazin-1-yl) -2-oxo-ethyl ester

13 μ l (0.11 mmol) of 2- (2-methoxy-ethoxy) -ethanol was added to 75 mmol (0.10 mmol) of 4- (2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [4- (1-carboxymethyl-piperidin-4-yl) -piperazin-1-yl]-2-oxo-ethyl ester (example 4.1), 35 mg (0.11 mmol) of TBTU and 28 μ l (0.20 mmol) of triethylamine in a mixture of 1 ml of DMF and the reaction mixture is stirred at room temperature for 1 hour. It was purified by HPLC without work-up; the eluted fractions containing the product were combined and lyophilized.

Yield: 22 mg (26% of theory)

ESI-MS：(M+H)⁺＝866/868(Cl)

Retention time (HPLC): 3.2 minutes (method B)

Example 35

4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepine-3-yl) -piperidine-1-carboxylic acid (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- [1 '- (2-morpholin-4-yl-ethoxycarbonylmethyl) -4, 4' -bipiperidin-1-yl]-2-oxo-ethyl ester

230 mg (0.29 mmol) of 4- (7-methoxy-2-oxo-1, 2, 4, 5-tetrahydro-1, 3-benzodiazepineA mixture of (R) -1- (4-amino-3-chloro-5-trifluoromethyl-benzyl) -2- (1 '-carboxymethyl-4, 4' -bipiperidin-1-yl) -2-oxo-ethyl ester (example 15.1), 113 mg (0.35 mmol) of TBTU, 84 μ l (0.60 mmol) of triethylamine and 39.3 mg (0.30 mmol) of 2-morpholin-4-yl-ethanol in 5 ml of DMF is stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCO₃The precipitated product was filtered off with suction over the solution and dried at 40 ℃. It was dissolved in 25 ml of isopropanol and precipitated as the hydrochloride salt by addition of 0.5M HCl in isopropanol. It is filtered off with suction, washed with 5 ml of isopropanol and 30 ml of DIPE and dried at 30 ℃ in a vacuum drying cabinet.

Yield: 90 mg (34% of theory)

ESI-MS：(M+H)⁺＝906/908(Cl)

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

The following examples describe the preparation of pharmaceutical formulations containing any one of the compounds of formula I as the active substance:

example I

Capsules for powder inhalation containing 1 mg of active substance

Composition (A):

1 capsule for powder inhalation comprising:

active substance 1.0 mg

Lactose 20.0 mg

Hard gelatinCapsule50.0 mg

71.0 mg

The preparation method comprises the following steps:

the active substance is ground to the desired particle size of the inhalation substance. The milled active was homogeneously mixed with lactose. The mixture was filled into hard gelatin capsules.

Example II

For supplying toInhalable solutions containing 1 mg of active substance

Composition (A):

1 spray contains:

active substance 1.0 mg

Benzalkonium chloride 0.002 mg

Disodium edetate 0.0075 mg

Adding 15.0 microliter of pure water

The preparation method comprises the following steps:

dissolving the active substance and benzalkonium chloride in water, and fillingIn the cartridge.

Example III

Inhalable solutions for nebulisers containing 1 mg of active substance

Composition (A):

1 vial containing:

active substance 0.1 g

Sodium chloride 0.18 g

Benzalkonium chloride 0.002 g

Adding 20.0 ml of pure water

The preparation method comprises the following steps:

the active substance, sodium chloride and benzalkonium chloride are dissolved in water.

Example IV

Propellant gas-operated metered aerosols containing 1 mg of active substance

Composition (A):

1 spray contains:

active substance 1.0 mg

Lecithin 0.1%

Propellant gas plus 50.0 microliter

The preparation method comprises the following steps:

the micronized active substance is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension was filled into a pressurized container with a metering valve.

Example V

Nasal spray containing 1 mg of active substance

Composition (A):

active substance 1.0 mg

Sodium chloride 0.9 mg

Benzalkonium chloride 0.025 mg

Disodium edetate 0.05 mg

Adding 0.1 ml of pure water

The preparation method comprises the following steps:

the active substance and excipients are dissolved in water and filled into suitable containers.

Example VI

Injection solutions containing 5 mg of active substance per 5 ml

Composition (A):

active substance 5 mg

Glucose 250 mg

Human serum albumin 10 mg

Sugar Furfural 250 mg

Adding water for injection to 5 ml

Preparation:

dissolving sugar furfural (glycofurol) and glucose in water for injection (WfI); adding human serum albumin; dissolving the active substance under heating; to WfI to complement to the specified volume; transfer to an ampoule under nitrogen.

Example VII

Injection solutions containing 100mg of active substance per 20 ml

Composition (A):

active substance 100mg

KH potassium dihydrogen phosphate₂PO₄12 mg of

Disodium hydrogen phosphate Na ═ Na₂HPO₄·2H₂O12 mg

180 mg of sodium chloride

Human serum albumin 50 mg

Tween 8020 mg

20 ml of water for injection is added

Preparation:

dissolving tween 80, sodium chloride, monopotassium phosphate and disodium phosphate in water for injection (WfI); adding human serum albumin; dissolving the active substance under heating; to WfI to complement to the specified volume; transfer to ampoule.

Example VIII

Lyophilisate containing 10 mg of active substance

Composition (A):

active substance 10 mg

Mannitol 300 mg

Human serum albumin 20 mg

Adding water for injection to 2 ml

Preparation:

dissolving mannitol in water for injection (WfI); adding human serum albumin; dissolving the active substance under heating; to WfI to complement to the specified volume; transferring to a small glass bottle; and (5) freeze-drying.

Solvent for lyophilizate:

tween 80-Tween 8020 mg

Mannitol 200 mg

10 ml of water for injection is added

Preparation:

dissolving tween 80 and mannitol in water for injection (WfI); transfer to ampoule.

Example IX

Tablet containing 20 mg of active substance

Composition (A):

active substance 20 mg

Lactose 120 mg

Corn starch 40 mg

Magnesium stearate 2 mg

Povidone K2518 mg

Preparation:

mixing active substance, lactose and corn starch uniformly; granulating with Povidone aqueous solution; mixing with magnesium stearate; pressing in a tablet press; tablet weight 200 mg.

Example X

Capsule containing 20 mg of active substance

Composition (A):

active substance 20 mg

Corn starch 80 mg

Highly dispersed silicic acid 5 mg

Magnesium stearate 2.5 mg

Preparation:

uniformly mixing an active substance, corn starch and silicic acid; mixing with magnesium stearate; the mixture was filled into size 3 hard gelatin capsules in a capsule filling machine.

Example XI

Suppository containing 50 mg of active substance

Composition (A):

active substance 50 mg

Hard fat (solid animal fat) in a sufficient amount of 1700 mg

Preparation:

melting the hard fat at about 38 ℃; uniformly dispersing the milled active in the molten hard fat; after cooling to about 35 ℃, it is poured into a pre-cooled mold.

Example XII

Injectable solution containing 10 mg of active substance per 1 ml

Composition (A):

active substance 10 mg

Mannitol 50 mg

Human serum albumin 10 mg

1 ml of water for injection is added

Preparation:

dissolving mannitol in water for injection (WfI); adding human serum albumin; dissolving the active substance under heating; to WfI to complement to the specified volume; transfer to an ampoule under nitrogen.

Claims

1. CGRP antagonists of general formula I

Wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³represents a group of the formula II

Wherein

X represents N or C, and X represents N or C,

R^3.1representation H, C_1-3-alkyl or R^3.1.1-O-C(O)，

R^3.1.1.1represents a group selected from the group consisting of,

and

R^3.2if X is N, it represents a pair of free electrons, or

R^3.2When X is ═ C, it represents H, C_1-3-alkyl or R^3.2.1-O-C(O)，

R^3.2.1Representation H, C_1-6Alkyl, H₂N-C_2-4Alkylene group, (C)_1-3-alkyl) -NH-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-3-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^3.2.1.1-C_2-4-an alkylene group,

R^3.2.1.1represents a group selected from the group consisting of,

and

R⁴represents a group of the formula III

Wherein

Y represents C, and

R^4.1represents H or C_1-3-alkyl, or

Y represents N, and

R^4.1which represents a pair of free electrons that are,

provided that X and Y do not simultaneously represent N,

R^4.2representation H, C_1-3-alkyl or R^4.2.1-O-C(O)，

R^4.2.1Representation H, C_1-6Alkyl, H₂N-C_2-4Alkylene group, (C)_1-3-alkyl) -NH-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-3-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^4.2.1.1-C_2-4-an alkylene group,

R^4.2.1.1represents a group selected fromThe mass of the balls is obtained by mixing the raw materials,

and

and is

R^4.3Representation H, C_1-6Alkyl, H₂N-C_2-4Alkylene group, (C)_1-3-alkyl) -NH-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-3-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^4.3.1-C_2-4-alkylene, and

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-C_1-3Alkylene, HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4alkylene-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl radical-C(O)-O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.2.1.1-C(O)-C_1-3Alkylene or R^5.2.1.2-C_2-4-an alkylene group,

R^5.2.1.1represents a group selected from the group consisting of,

and

R^5.2.1.2represents a group selected from the group consisting of,

andor

R^5.2.1Represents a group of the formula

2. Compounds of the general formula I according to claim 1, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³represents a group of the formula II

Wherein

X represents N or C, and X represents N or C,

R^3.1representation H, C_1-3-alkyl or R^3.1.1-(O)C，

R^3.1.1Denotes HO, C_1-6-an alkyl-O group, wherein,

R^3.2if X is N, it represents a pair of free electrons, or

R^3.2When X is C, it represents H or C_1-3-an alkyl group,

R⁴represents a group of the formula III

Or

Wherein

Y represents C, and

R^4.1represents H or C_1-3-alkyl, or

Y represents N, and

R^4.1which represents a pair of free electrons that are,

provided that X and Y do not simultaneously represent N,

R^4.2representation H, C_1-3-alkyl or R^4.2.1-(O)C，

R^4.2.1Denotes HO, C_1-6-alkyl-O, and

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2.1.1represents a group selected from the group consisting of,

and

R^5.2.1.2represents a group selected from the group consisting of,

and

3. Compounds of the general formula I according to claim 1, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^3.1Representation H, H₃C or R^3.1.1-O-C(O)，

R^3.1.1.1represents a group selected from the group consisting of,

and

R^3.2representation H, C_1-3-alkyl or R^3.2.1-O-C(O)，

R^3.2.1.1represents a group selected from the group consisting of,

and

R^4.1represents H or C_1-3-an alkyl group,

R^4.2representation H, C_1-3-alkyl or R^4.2.1-O-C(O)，

R^4.2.1.1represents a group selected from the group consisting of,

and

R^4.3representation H, C_1-6Alkyl, H₂N-C_2-4Alkylene group, (C)_1-3-alkyl) -NH-C_2-4-AAlkyl, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-3-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^4.3.1-C_2-4-alkylene, and

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1representation H, H₃C、R^5.1.1-O-C(O)、R^5.1.1-O-C(O)-C_1-3alkylene-NH, R^5.1.1-O-C(O)-C_1-3alkylene-N (C)_1-3-alkyl), R^5.1.1-O-C(O)-C_1-3alkylene-O, R^5.1.1-O-C(O)-C_1-3Alkylene radical, R^5.1.1-O-C(O)-C(O)、R^5.1.1-O-C(O)-C(O)-O、R^5.1.1-O-C(O)-C_1-3alkylene-C (O) or

R^5.1.1-O-C(O)-C_1-3alkylene-C (O) -O,

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2representation H, H₃C、R^5.2.1-O-C(O)-C_1-3alkylene-NH, R^5.2.1-O-C(O)-C_1-3alkylene-O, R^5.2.1-O-C(O)-C_1-3Alkylene radical, R^5.2.1-O-C (O) or R^5.2.1-O-C(O)-C_1-3-alkylene-C (O),

R^5.2.1.1represents a group selected from the group consisting of,

and

R^5.2.1.2represents a group selected from the group consisting of,

andor

R^5.2.1Represents a group of the formula,

4. Compounds of the general formula I according to claim 1, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IVBall

Wherein

R^3.1The expression "H" is used to indicate the formula,

R^3.2represents H or C_1-3-an alkyl group,

R^4.1represents H or C_1-3-an alkyl group,

R^4.2the expression "H" is used to indicate the formula,

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2.1.1represents a group selected from the group consisting of,

and

R^5.2.1.2represents a group selected from the group consisting of,

and

5. Compounds of the general formula I according to claim 1, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^3.1Represents H or R^3.1.1-O-C(O)，

R^3.1.1.1represents a group

R^3.2Representation H, H₃C or R^3.2.1-O-C(O)，

R^3.2.1.1represents a group

R^4.2Represents H or H₃C，

R^4.3Representation H, C_1-6Alkyl radicals, (C)_1-3-alkyl groups)₂N-C_2-4Alkylene group, (C)_1-3-alkyl groups)₂N-C(O)-C_1-3Alkylene or R^4.3.1-C_2-4-alkylene, and

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1representation H, H₃C、R^5.1.1-O-C(O)、R^5.1.1-O-C(O)-C_1-3alkylene-NH, R^5.1.1-O-C(O)-C_1-3alkylene-N (C)_1-3-alkyl), R^5.1.1-O-C(O)-C_1-3alkylene-O, R^5.1.1-O-C(O)-C_1-3Alkylene radical, R^5.1.1-O-C(O)-C(O)、R^5.1.1-O-C(O)-C(O)-O-R^5.1.1-O-C(O)-C_1-3alkylene-C (O) or R^5.1.1-O-C(O)-C_1-3alkylene-C (O) -O,

R^5.1.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-methyl, HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.1.1.1-C(O)-C_1-3Alkylene or R^5.1.1.2-C_2-4-an alkylene group,

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2.1representation H, C_1-8-alkyl, phenyl, indanyl, pyridyl-methyl, HO-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4Alkylene radical, C_1-6-alkyl-O-C_2-4alkylene-O-C_2-4Alkylene radical, H₂N-C_2-4Alkylene group, (C)_1-6-alkyl) -NH-C_2-4Alkylene group, (C)_1-6-alkyl groups)₂N-C_2-4Alkylene radical, H₂N-C(O)-C_1-3Alkylene group, (C)_1-6-alkyl) -NH-C (O) -C_1-3Alkylene group, (C)_1-6-alkyl groups)₂N-C(O)-C_1-3Alkylene radical, C_1-6-alkyl-C (O) -O-C_1-3Alkylene radical, C_1-6alkyl-O-C (O) -O-C_1-3Alkylene radical, R^5.2.1.1-C(O)-C_1-3Alkylene or R^5.2.1.2-C_2-4-an alkylene group,

R^5.2.1.1represents a group selected from the group consisting of,

and

R^5.2.1.2represents a group selected from the group consisting of,

andor

R^5.2.1Represents a group of the formula

6. Compounds of the general formula I according to claim 1, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

Wherein

R^4.3.1represents a group selected from the group consisting of,

and

R^5.1.1.1represents a group selected from the group consisting of,

R^5.1.1.2represents a group selected from the group consisting of,

and

R^5.2.1.1represents a group selected from the group consisting of,

R^5.2.1.2represents a group selected from the group consisting of,

and

7. Compounds of the general formula I according to claim 1, wherein

R¹Represents a group selected from the group consisting of,

and

wherein

R^1.1Represents H or H₃C-O，

R²Represents a group selected from the group consisting of,

and

R³-R⁴together represent a radical of the formula IV

8. The compound of claim 1, selected from

9. Physiologically acceptable salts of compounds of the general formula I according to any of claims 1 to 8 with inorganic or organic acids or bases.

10. Pharmaceutical composition comprising a compound according to at least one of claims 1 to 8, or a physiologically acceptable salt according to claim 9, optionally together with one or more inert carriers and/or diluents.

11. Use of a compound according to at least one of claims 1 to 9 for the preparation of a pharmaceutical composition for the acute and prophylactic treatment of headache, in particular migraine, cluster headache and tension headache.

12. Use of a compound according to at least one of claims 1 to 9 for the preparation of a pharmaceutical composition for the treatment of non-insulin dependent diabetes mellitus.

13. Use of a compound according to at least one of claims 1 to 9 for the preparation of a pharmaceutical composition for the treatment of: cardiovascular diseases, morphine tolerance, diarrhoea caused by clostridial toxins, skin diseases, especially damage caused by heat and radiation, including sunburn, lichen diseases, prurigo-toxic dermatitis and severe itching, inflammatory diseases, such as arthritic diseases, for example osteoarthritis, rheumatoid arthritis or neurotic arthritis, systemic soft tissue rheumatism (fibromyalgia), oral mucosal neuroinflammation, inflammatory lung diseases, allergic rhinitis, asthma and COPD, diseases associated with excessive vasodilation and thus decreased blood flow in blood vessels, such as shock or sepsis, chronic pain such as diabetic neuropathy, chemotherapy-induced neuropathy, HIV-induced neuropathy, post-herpetic neuropathy, neuropathy induced by tissue trauma, trigeminal neuralgia, temporomandibular dysfunction, CRPS, back pain, and visceral diseases such as IBS (irritable bowel syndrome) or inflammatory bowel syndrome; for pain relief in general or for prophylactic or acute therapeutic treatment of hot flush syndrome in women with estrogen deficiency in postmenopausal women and in hormone-treated prostate cancer patients and castrated persons, due to vasodilation and increased blood flow.

14. Use of a compound according to at least one of claims 1 to 9 for the preparation of a pharmaceutical composition for the treatment of Irritable Bowel Syndrome (IBS).

15. Use of a compound according to at least one of claims 1 to 9 for the preparation of a pharmaceutical composition for the prevention and acute therapeutic management of hot flashes in women with estrogen deficiency.

16. A process for the preparation of a pharmaceutical composition according to claim 10, characterized in that a compound according to at least one of claims 1 to 9 is incorporated by non-chemical means into one or more inert carriers and/or diluents.

17. A process for preparing compounds of the general formula I as claimed in one of claims 1 to 9, characterized in that

(a) Reacting a carboxylic acid of the formula V

In the formula V, R¹And R²Are each as defined in claim 1, with amines of the formula VI

H-R³-R⁴，

In the formula VI R³And R⁴Are as defined in claim 1, wherein the linkage is via R³And before the reaction has taken place, any carboxylic acid functional, primary or secondary amino or hydroxyl groups present in the groups of the amines of the formula VI are protected by a protective group and after the reaction has ended, the protective group used is cleaved again, or

(b) Reacting a compound of the formula VII

Wherein R is¹And R²As defined in claim 1 and Nu represents a leaving group, with an amine of the formula VI³-R⁴，

Wherein all radicals are as defined in claim 1, wherein the linkage is via the amine R³And any carboxylic acid functional groups, primary or secondary amino functional groups or hydroxyl groups present in the groups of the amines of the general formula VI are protected by a protecting group before the reaction is carried out and any protecting groups used are cleaved again after the reaction has ended, wherein

The hydroxycarboxylic acid of the formula V required as starting compound is a piperidine of the formula VIII

Wherein R is¹As defined in claim 1, with carbonic acid derivatives of the formula IX

Wherein Y is¹And Y²Denotes a nucleofugic group, which may be the same or different,

and with a compound of the formula X to obtain

Wherein R is²As defined in claim 1, and Z¹Represents a carboxyl protecting group and may be present in the group R of the compound of formula VI before the reaction is carried out²Any hydroxyl groups in (a) are protected by a protecting group and, after the reaction has ended, any protecting groups used are cleaved again and

a route to a compound of formula X comprising reacting an aldehyde of formula XI

Wherein R is²As defined in claim 1, with N-acetylglycine in acetic anhydride as solvent, in the presence of alkali metal acetates, and/or

Optionally resolving the compound of formula I thus obtained into its stereoisomers, and/or

The compounds of the general formula I thus obtained are converted into their salts, in particular into physiologically acceptable salts for pharmaceutical use.