HK1125630A

HK1125630A - Novel dual nk2/nk3-antagonists, pharmaceutical compositions comprising them, and processes for their preparations

Info

Publication number: HK1125630A
Application number: HK09104023.4A
Authority: HK
Inventors: D．亚斯兰德; M．曼特泽尔; J．让泽姆斯; W．本森; U．布鲁斯霍夫; M．菲尔吉斯; H．萨恩; R．布鲁克纳; M．阿道尔夫斯; A．阿塔利; D．赖歇; U．肖恩; A．C．麦克里里; P．斯米德
Original assignee: 索尔瓦药物有限公司
Priority date: 2006-02-01
Filing date: 2007-02-01
Publication date: 2009-08-14

Description

Novel dual NK2/NK 3-antagonists, pharmaceutical compositions containing them, and process for preparing them

The present invention relates to novel dual NK2/NK 3-antagonists as well as pharmaceutical compositions comprising such compounds. Furthermore, the present invention relates to methods for the preparation of such novel dual NK2/NK 3-antagonists.

Neurokinins (NKs), also known as tachykinins, include the naturally occurring neuropeptide substance P, neurokinin a and neurokinin B. Tachykinins act as agonists of receptors present in large mammals and humans, such as the neurokinin-1, NK-2 and NK-3 receptors. Artificially prepared compounds that antagonize tachykinin receptors are generally classified according to their relative ability to bind to one or more of the three receptor subtypes mentioned above. In this physiological process tachykinins play an important role in the transmission of pain, emesis, neurogenic inflammation, cystitis, inflammatory joint disease or asthmatic complaints.

A review article on NK receptor antagonists was recently published by Gerspacher (Progress in Medical Chemistry, 2005, Vol.43, 49 to 103), with reviews on selective (NK 1-or NK 2-or NK 3-receptor antagonists) and mixed (NK1/NK 2-; NK1/NK2/NK 3-; and NK2/NK3-) receptor antagonists.

Such mixed NK2/NK 3-receptor antagonists appear to be limited by both GSK and Sanofi approaches. GSK preferably modifies the selective antagonist talnetant structure stepwise by introducing various substituents NK3 meta to the quinoline portion of the molecule. One highly potent compound is as follows:

Sanofi-Syntheselabo in WO 2002/094821 (published 2002, 11/28) describes a series of piperidine-carboxamide derivatives having the following cyclic, nonlinear general structure:

Sanofi-Syntheselabo reported potent NK 2-receptor affinity (Ki value of 0.04nM) and potent NK 3-receptor affinity (Ki value of 0.04 nM).

However, compounds containing a linear nucleus with selective NK 3-receptor affinity or mixed NK2-/NK 3-receptor affinity have not been reported to date.

It is therefore an object of the present invention to provide novel active compounds containing a linear nucleus having antagonistic properties against the NK 2-and/or NK3 tachykinin receptors. Such compounds appear to be particularly suitable for the treatment of various disorders.

It has now surprisingly been found that: a group of novel linear nuclear compounds is characterized by antagonistic properties against the tachykinin receptor, in particular NK2 and/or NK 3-receptors. Thus, the family of compounds of the present invention appears to be particularly suitable for the treatment of peripheral disorders in which tachykinins, in particular neurokinin a and/or neurokinin B, act as transfer agents, for example for the treatment and/or prevention of any pathology involving neurokinin a and/or NK 2-receptors, or neurokinin B and/or NK 3-receptors, or both neurokinin a and neurokinin B and/or both NK2 and NK 3-receptors.

In more detail, the compounds of the invention appear to be particularly suitable for the treatment and/or prevention of pathologies of the respiratory system, gastrointestinal system, urinary system, immune system and cardiovascular system and central nervous system as well as pain, migraine, inflammation, nausea and vomiting, and skin diseases.

More specifically, the compounds of the invention appear to be particularly suitable for the treatment and/or prevention of the following pathologies: respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, cough and rhinitis; skin diseases, in particular inflammatory skin reactions, allergic skin reactions and psoriasis; arthropathy diseases, particularly arthritis (arthitis), vasculitis, and systemic lupus erythematosus; functional or inflammatory disorders of the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, crohn's disease, and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, the treatment of cancer, especially melanoma, glioma, small cell and large cell lung cancer, immune system disorders, bipolar disorder; migraine headache; pain, anxiety, depression, cognitive disorders, stress-related somatic disorders, psychoses, in particular schizophrenia, mania, schizoaffective disorders and panic disorders.

The subject of the invention is a compound of the general formula I,

wherein

R1 is selected from the group consisting of: alkyl and cycloalkyl radicals;

r2 is selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenearyl, alkenylene aryl, heteroaryl, and heterocycle;

r3 and R4 are independently selected from the group consisting of: hydrogen, halogen, hydroxy, cyano and carboxyalkyl;

x is selected from the group consisting of: CR6 and nitrogen;

r5 is selected from the group consisting of: optionally quilt (CO)_mNR9R10 substituted alkyl, optionally substituted (CO)_mNR9R10 substituted cycloalkyl, and NR7R 8;

r6 is selected from the group consisting of: hydrogen, alkyl, Cycloalkyl and (CO)_mNR9R10；

R7 and R8 are independently selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenearyl, alkyleneoxyalkyl, COalkyl, COaryl, or wherein R7 and R8 together form a 5-to 7-membered ring optionally containing additional heteroatoms, wherein such ring may be substituted with CONR9R10 and wherein no ring atoms in the 6-membered ring are substituted with carbonyl groups;

r9 and R10 are independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl, alkylenearyl, alkenyloxyalkyl, or wherein R9 and R10 together form a 5-to 7-membered ring optionally containing additional heteroatoms;

m is selected from 0 or 1;

and physiologically compatible acid addition salts of the compounds of formula I.

Furthermore, another subject of the invention is also pharmaceutical compositions comprising compounds of formula I.

Still another subject of the invention is a process for the preparation of the compounds of formula I.

Wherein the substituents in the compounds of formula I or in the other compounds described within the scope of the present invention are alkyl and/or alkylene groups or alkyl-and/or alkylene-containing groups, which substituents may each be straight-chain or branched and have from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 7 carbon atoms, even more preferably from 1 to 4 carbon atoms. Most preferred straight chain alkyl and/or alkylene groups are methyl and/or methylene respectively. Most preferred branched alkyl and/or alkylene groups are isopropyl and/or isopropylidene, respectively.

Wherein in the compounds of formula I or in other compounds described within the scope of the present invention the substituents are cycloalkyl and/or cycloalkylene or cycloalkyl-containing and/or cycloalkylene groups, such substituents may have from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 7 carbon atoms, even more preferably from 1 to 4 carbon atoms. Most preferred cycloalkyl and/or cycloalkylene groups are cyclopentyl and cyclohexyl and/or cyclopentylene and cyclohexylene, respectively.

Wherein in the compounds of formula I or in other compounds described within the scope of the present invention the substituents are alkenyl and/or alkenylene or alkenyl-and/or alkenylene groups, which substituents may each be straight-chain or branched and have from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms, more preferably from 2 to 7 carbon atoms, even more preferably from 2 to 4 carbon atoms. Most preferred alkenyl and/or alkenylene groups are vinyl and/or vinylene groups, respectively.

In the case where the substituents in the compounds of formula I are halogen or halogen-containing, fluorine, chlorine or bromine are suitable. Chlorine is preferred. Where the substituent in the compound of formula I is carboxyalkyl or carboxyalkyl containing, -OC (O) alkyl or C (O) Oalkyl is suitable, preferably OC (O) alkyl.

Where the substituents in the compounds of formula I are aryl and/or arylene groups or aryl and/or arylene-containing groups, monocyclic, bicyclic, tricyclic and tetracyclic aromatic ring systems are suitable. Phenyl is preferred.

Where the substituents in the compounds of formula I are heteroaryl and/or heteroarylene or contain heteroaryl and/or heteroarylene groups, monocyclic, bicyclic, tricyclic and tetracyclic aromatic ring systems containing at least one heteroatom, such as nitrogen, are suitable.

Where the substituents in the compounds of formula I are heterocyclic or heterocyclic-containing, monocyclic, bicyclic, tricyclic and tetracyclic non-aromatic ring systems containing at least one heteroatom, if not two or three or even four heteroatoms, such as nitrogen and/or sulfur and/or oxygen, are suitable. Monocyclic ring systems are preferred. Preferred heteroatoms are nitrogen and/or oxygen.

In the case where R7 and R8 and/or R9 and R10 together form a 5-to 7-membered ring and where such rings each independently optionally contain additional heteroatoms in particular embodiments, such heteroatoms may be selected from nitrogen, oxygen and sulfur, preferably oxygen.

In the case of alkyl and/or alkylene, aryl and/or arylene, heteroaryl and/or heteroarylene, heterocycles in the compounds of formula I or in other compounds described within the scope of the invention, all such substituents may be further substituted by any of the following groups: alkyl, alkenyl, hydroxy, SH, carbonylalkyl, carboxyalkyl, carbonylaryl, carboxyaryl, carbonylahetaryl, carboxyhetaryl, carbonylheterocycle, carboxyheterocycle, halogen, cyano, oxyalkyl, oxyalkenyl, aryl, hetaryl, NO₂、SO₂R11 and SO₃R11。

In a preferred embodiment of the invention, in the compounds of formula I, R1 is methyl.

In another preferred embodiment of the present invention, wherein R3 and R4 are independently selected from the group consisting of: hydrogen, fluorine, chlorine, preferably hydrogen or chlorine.

In a third preferred embodiment, the compound of formula I wherein X is CR6, R5 is NR7R8, R6 is (CO)_mNR9R10 and m is 1.

In another preferred embodiment of the invention, X in the compound is N and R5 is quilt (CO)_mNR9R10 substituted cycloalkyl and m ═ 1.

In a fourth preferred embodiment of the invention, in the compounds of formula I R7 and R8 together form a 6 membered ring, or R7 and R8 together form a 6 membered ring substituted by CONR9R 10.

In a fifth preferred embodiment of the invention, in the compounds of formula I, R9 and R10 are both methyl, or R9 and R10 together form a 6 membered ring, or R9 and R10 together form a 5 membered ring substituted by carbonyl.

In another preferred embodiment of the invention, R2 in the compound of formula I is selected from the group consisting of: c₁-C₂₀An alkyl group; c₃-C₂₀A cycloalkyl group; c₂-C₂₀An alkenyl group;

and

wherein R11 to R16 are each independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, hydroxyl, alkoxy, cyano, N (H) C (O) Oalkyl, aminoalkyl, dialkylamino, OCF₃、CF₃Carboxyalkyl, S (O)₂NH₂Phenyl, alkyl and cycloalkyl;

wherein R18 and R19 are each independently selected from the group consisting of: hydrogen, cyano and aryl;

wherein t is 0 or 1;

wherein each Q is independently selected from the group consisting of: CR11 and N;

wherein Y is selected from the group consisting of: CH. N and NO;

wherein Z is selected from the group consisting of: c-benzyl, NH, N-benzyl, N-alkyl, O and S;

wherein each V is independently selected from the group consisting of: n and CR 17; and is

Wherein R17 is selected from the group consisting of: hydrogen, alkyl, cycloalkyl, aryl and alkylthio.

In another preferred embodiment of the invention, R5 is selected from the group consisting of:

and

particular embodiments of the present invention are the following compounds:

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid methylamide; 1 ' - [4- (cyclohexanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; acetic acid 4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl ester; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-hydroxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; acetic acid 2- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl ester; 1 ' - [4- [ (3-chloro-4-fluoro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 5-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (5-chloro-2-fluoro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-1-carbonyl-3-cyano) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-hydroxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 4-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 4-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 5-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2, 3, 4-trifluoro-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1-oxy-pyridine-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (6-chloro-pyridine-3-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (3-benzyl-2-methylsulfanyl-3H-imidazole-4-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-oxo-2-phenyl-4H-chromene-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (cyclopropanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (cyclopentanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethyl-amide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-methylamino-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; n- [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -N-methyl-o-carbamoylbenzoic acid; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (biphenyl-4-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 3-diphenyl-propionyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - (3- (3, 4-dichloro-phenyl) -4- { [3- (4-hydroxy-phenyl) -propionyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1-methyl-1H-pyrrole-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (furan-2-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (2-biphenyl-4-yl-acetyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- { [3- (4-chloro-phenyl) -acryloyl ] -methyl-amino } -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1H-pyrrole-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (furan-2-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (thiophene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (thiophene-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (1H-indole-3-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-1H-indol-3-yl-acetyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (1H-indole-5-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyrazine-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-oxo-4H-chromene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-sulfamoyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (4-chloro-3-sulfamoyl-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-1H-imidazol-4-yl-acetyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-2-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-3-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-4-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (1-acetyl-piperidine-4-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (tetrahydro-pyran-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; (4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl) -carbamic acid tert-butyl ester; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3- { trifluoromethyl-methoxy } -benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - (3- (3, 4-dichloro-phenyl) -4- { [2- (2, 4-bis { trifluoromethyl } -phenyl) -acetyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- { [2- (2, 6-dihydroxy-pyrimidin-4-yl) -acetyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -piperidine-1-carboxylic acid tert-butyl ester; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (1H-imidazole-4-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; (1- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -2-phenyl-ethyl) -carbamic acid tert-butyl ester; [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamic acid tert-butyl ester; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (furazan-3-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 2-difluoro-benzo [1, 3] dioxol-5-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1H-pyrrole-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - (3- (3, 4-dichloro-phenyl) -4- { [3- (4-fluoro-phenyl) -5-methyl-isoxazole-4-carbonyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - (3- (3, 4-dichloro-phenyl) -4- { [5- (4-methoxy-phenyl) -oxazole-4-carbonyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (5-methyl-1-phenyl-1H- [1, 2, 3] triazole-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (benzofuran-5-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (5-methyl-benzo [ b ] thiophenyl-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (3, 5-bis-trifluoromethyl-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (2-bromo-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [3- (3, 4-dichloro-phenyl) -4- (methyl-pentafluorobenzoyl-amino) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 6-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (2, 4-dichloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (2, 6-chloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-trifluoromethyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-methyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (3-chloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (3, 4-dichloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (3-trifluoromethyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (4-chloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-trifluoromethyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 2-dimethyl-propionyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [3- (3, 4-dichloro-phenyl) -4- (methyl-phenylacetyl-amino) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-phenyl-cyclopropanecarbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (4-cyano-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-1-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (benzoyl-methyl-amino) -3-phenyl-butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid ethyl-methyl-amide; n- {2- (3, 4-dichloro-phenyl) -4- [4- (1-dimethylcarbamoyl-cyclohexyl) -piperazin-1-yl ] -butyl } -N-methyl-benzamide; 1 '- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4' ] bipiperidinyl-2-carboxylic acid dimethylamide; 1- [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide; 1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide; n- [4- [4- (cyclopropylmethyl-propionyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide; n- {2- (3, 4-dichloro-phenyl) -4- [4- (isopropyl-propionyl-amino) -piperidin-1-yl ] -butyl } -N-methyl-benzamide; n- {2- (3, 4-dichloro-phenyl) -4- [4- (phenyl-propionyl-amino) -piperidin-1-yl ] -butyl } -N-methyl-benzamide; n- [4- [4- (butyl-propionyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide; n- [4- [4- (butyl-cyclopropanecarbonyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide; n- [4- [4- (butyl-cyclohexanecarbonyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide; n- [4- [4- (benzoyl-butyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide; n- (2- (3, 4-dichloro-phenyl) -4- {4- [ (4-methoxy-butyl) -propionyl-amino) -piperidin-1-yl } -butyl) -N-methyl-benzamide; n- [4- {4- [ cyclopropanecarbonyl- (4-methoxy-butyl) -amino) -piperidin-1-yl } -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide; n- [4- {4- [ cyclohexanecarbonyl- (4-methoxy-butyl) -amino ] -piperidin-1-yl } -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide; n- [4- {4- [ benzoyl- (4-methoxy-butyl) -amino) -piperidin-1-yl } -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide; n- [4- {4- [ cyclohexyl (propionyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide; n- [4- {4- [ cyclohexyl (cyclopropylcarbonyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide; n- [4- {4- [ cyclohexyl (cyclohexylcarbonyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methyl-benzamide; n- [4- {4- [ benzoyl (cyclohexyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide; n- [2- (3, 4-dichlorophenyl) -4- {4- [ (1-methylpiperidin-4-yl) (propionyl) amino ] piperidin-1-yl } butyl ] -N-methylbenzamide; n- [4- {4- [ (cyclopropyl-carbonyl) (1-methylpiperidin-4-yl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide; n- [4- {4- [ (cyclohexylcarbonyl) (1-methylpiperidin-4-yl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide; n- {1- [4- [ benzoyl (methyl) amino ] -3- (3, 4-dichlorophenyl) butyl ] piperidin-4-yl } -N- (1-methylpiperidin-4-yl) benzamide; n- {2- (3, 4-dichloro-phenyl) -4- [4 ' - (pyrrolidine-1-carbonyl) - [1, 4 ' ] bipiperidinyl-1 ' -yl ] -butyl } -N-methyl-benzamide; 1- [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] -4- (2-oxo-pyrrolidin-1-yl) -piperidine-4-carboxylic acid dimethylamide; 3-cyano-naphthalene-1-carboxylic acid {2- (3, 4-dichloro-phenyl) -4- [4 ' - (piperidine-1-carbonyl) - [1, 4 ' ] bipiperidinyl-1 ' -yl ] -butyl } -methyl-amide; 1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dipropylamide; 1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-morpholin-4-yl-piperidine-4-carboxylic acid dimethylamide; 1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid isopropyl-methyl-amide; n- {2- (3, 4-dichloro-piperidine) -4- [4- (piperidine-1-carbonyl) -4-pyrrolidin-1-yl-piperidin-1-yl ] -butyl } -N-methyl-benzamide; 1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid diethylamide; n- {2- (3, 4-dichloro-phenyl) -4- [4- (morpholine-4-carbonyl) -4-pyrrolidin-1-yl-morpholin-1-yl ] -butyl } -N-methyl-benzamide; and physiologically compatible acid addition salts of these compounds.

The following compounds are particularly preferred:

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid methylamide; 1 ' - [4- (cyclohexanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; acetic acid 4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl ester; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-hydroxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; acetic acid 2- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl ester; 1 ' - [4- [ (3-chloro-4-fluoro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 5-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (5-chloro-2-fluoro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-1-carbonyl-3-cyano) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-hydroxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 4-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 4-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 5-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2, 3, 4-trifluoro-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (6-chloro-pyridine-3-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (cyclopentanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-methylamino-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; n- [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -N-methyl-o-carbamoylbenzoic acid; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - (3- (3, 4-dichloro-phenyl) -4- { [3- (4-hydroxy-phenyl) -propionyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1-methyl-1H-pyrrole-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (furan-2-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1H-pyrrole-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (furan-2-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (thiophene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (thiophene-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (1H-indole-5-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-oxo-4H-chromene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-sulfamoyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (4-chloro-3-sulfamoyl-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-2-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-3-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-4-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (tetrahydro-pyran-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; (4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl) -carbamic acid tert-butyl ester; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3- { trifluoromethyl-methoxy } -benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - (3- (3, 4-dichloro-phenyl) -4- { [2- (2, 4-bis { trifluoromethyl } -phenyl) -acetyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 2-difluoro-benzo [1, 3] dioxol-5-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (5-methyl-1-phenyl-1H- [1, 2, 3] triazole-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (benzofuran-5-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (2-bromo-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 6-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (2, 4-dichloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-trifluoromethyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-methyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (3-chloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (3-trifluoromethyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (4-cyano-benzoyl) -methyl-amino ] -3- (3, 4-dicyano-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (benzoyl-methyl-amino) -3-phenyl-butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid ethyl-methyl-amide; n- {2- (3, 4-dichloro-phenyl) -4- [4- (1-dimethylcarbamoyl-cyclohexyl) -piperazin-1-yl ] -butyl } -N-methyl-benzamide; 1 '- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4' ] bipiperidinyl-2-carboxylic acid dimethylamide; 1- [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide; 1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide; and physiologically compatible acid addition salts of these compounds.

The most preferred compounds of the invention are the following:

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (cyclohexanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; acetic acid 4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl ester; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-hydroxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; acetic acid 2- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl ester; 1 ' - [4- [ (3-chloro-4-fluoro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 5-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (5-chloro-2-fluoro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-1-carbonyl-3-cyano) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-hydroxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 4-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 4-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 5-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (6-chloro-pyridine-3-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- (cyclopentanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (furan-2-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-2-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-3-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3- { trifluoromethyl-methoxy } -benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (5-methyl-1-phenyl-1H- [1, 2, 3] triazole-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (benzofuran-5-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1 ' - [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide; 1- [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide; and physiologically compatible acid addition salts of these compounds.

The compounds of formula I and their acid addition salts can be prepared as follows: reacting a compound of the formula II

Wherein R1 to R4 are as defined above, with a compound of formula III,

wherein R5 is as defined above, results in the formation of a compound of the general formula I, which is optionally converted into its physiologically compatible acid addition salts.

In addition, compounds of formula I and their acid addition salts can be prepared as follows: reacting a compound of the formula III

Wherein R5 is as defined above, with a compound of the general formula IV,

wherein R1, R3 and R4 are as defined above, to give a compound of the general formula V,

then hydrolyzing the compound of the general formula V in an acid medium to obtain a compound of a general formula VI,

wherein R1 and R3 to R5 are as defined above. The compound of formula VI is then reacted with a compound of formula VII,

wherein R2 is as defined above, results in the formation of a compound of the general formula I, which is optionally converted into its physiologically compatible acid addition salts.

In addition, compounds of formula I and their acid addition salts can be prepared as follows: the compound of the general formula X is reacted,

wherein Q is selected from the group consisting of: halogen, preferably bromine or iodine; and a methanesulfonyl group; with a compound of the formula III,

a compound of the general formula I is formed, which is optionally converted into its physiologically compatible acid addition salts.

The compounds of formula II can be prepared as follows: reacting a compound of formula VII.

With a compound of the formula VII,

to obtain the compound of the formula IX,

the compound of formula IX is then oxidized to provide the compound of formula II.

The compounds of formula III are well known and may be prepared according to any of the following literature methods: med, chem, 1964, p.619(van de Westeringh); WO02/094821 (Sanofi); chem.1980, 45, p.3671 (j.t.tai); med chem.1974, 9, p.424 (b.devaux); med chem.2002, 45, p.3972(j.t. albert). The reaction scheme for the preparation of the compound of formula II is given in example 37.

The compound of formula IV can be prepared by selecting the appropriate R2 in analogy to the suggested procedure for the compound of formula II.

The compounds of the formula VII are known per se or can be prepared from known compounds by those skilled in the art in a manner known per se.

The compounds of formula X can be prepared as follows: the compound of the general formula IX is reacted,

with an H halide acid, preferably HBr or HI, to give a compound of formula X, wherein Q is halogen, preferably bromine or iodine, or, alternatively, with a chlorinated sulphonylmethane to give a compound of formula X, wherein Q is methanesulphonyl,

the compounds of the formula I can be isolated from the reaction mixture and purified by known methods. Acid addition salts can be converted into the free bases by customary methods and, if desired, such free bases can be converted into physiologically compatible acid addition salts by known methods. Physiologically compatible salts of the compounds of formula I are the conventional salts thereof with inorganic acids, for example sulfuric acid, phosphoric acid or hydrohalic acids, preferably hydrochloric acid, or with organic acids, for example lower aliphatic monocarboxylic, dicarboxylic or tricarboxylic acids, such as maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, sulfonic acids, for example lower alkanesulfonic acids, such as methanesulfonic acid or trifluoromethanesulfonic acid, or benzenesulfonic acids (optionally substituted on the phenyl ring by halogen or lower alkyl), such as p-toluenesulfonic acid, or with sulfonic acids.

The compounds of formula I contain an asymmetric carbon atom in the gamma-position of the ring nitrogen atom in the 4-position of the piperidine or piperazine ring, respectively, i.e. the carbon atom carrying the phenyl ring substituted by R3 and R4^*C. Thus, the compounds of formula I may exist in several stereoisomeric forms. The present invention includes both mixtures of optical isomers of formula I and isomerically pure compounds thereof. Preferably carrying therein the carbon atom of the phenyl ring substituted by R3 and R4^*C is a compound of formula I in S-configuration. If mixtures of optical isomers of the starting compounds (for example compounds of the formula II or compounds of the formula IV) are used in the synthesis of the compounds of the formula I, the compounds of the formula I are also obtained in the form of optical isomers. Starting from the starting compounds in a stereochemically homogeneous form, it is also possible to obtain stereochemically homogeneous compounds of the formula I. The stereochemically homogeneous compounds of the formula I can be obtained in a known manner from mixtures of optical isomers, for example by chromatographic separation on chiral separation materials, or by reaction with suitable optically active acids, for example tartaric acid or 10-camphorsulfonic acid, followed by fractional crystallization of the diastereomeric salts obtained and isolation of their optically active enantiomers.

The compounds of formula I and their acid addition salts have tachykinin receptor antagonistic properties and are therefore suitable for the treatment of pathological conditions in large mammals, especially humans, in which tachykinins are involved as transfer agents. The family of compounds of the invention is characterized by particularly advantageous action profiles, characterized by a high selectivity for the NK2 and/or NK 3-receptor. Furthermore, the family of compounds of the invention is characterized by good compatibility even after long-term administration, and relatively good oral availability. Due to their action profile, the compounds of the formula I are particularly suitable for inhibiting processes in which tachykinins, such as neurokinin A which binds the NK 2-receptor and/or neurokinin B which binds the NK 3-receptor, are involved. By having an advantageous effect directed to the peripheral region, the compounds of the formula I are particularly suitable for the treatment and/or prevention of any pathology in which neurokinin a and/or NK 2-receptors, or neurokinin B and/or NK 3-receptors, or both neurokinin a and neurokinin B and/or both NK2 and NK 3-receptors are involved. Some of the compounds of the present invention, particularly those wherein R2 is a cyano-substituted naphthalene ring system, are also suitable for inhibiting processes involving tachykinins, such as substance P binding to the NK 1-receptor. Due to the advantageous peripherally directed action, the compounds of formula I, wherein R2 is a cyano-substituted naphthalene ring system, are particularly suitable for the treatment and/or prevention of any pathology involving substance P and/or NK 1-receptor, or neurokinin a and/or NK 2-receptor, or neurokinin B and/or NK 3-receptor, or a combination of any two or all three of substance P, neurokinin a and neurokinin B and/or NK1, NK2 and NK 3-receptor.

More specifically, the compounds of the invention appear to be particularly suitable for the treatment and/or prevention of the following pathologies: respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, cough and rhinitis; skin diseases, in particular inflammatory skin reactions, allergic skin reactions and psoriasis; arthropathy diseases, particularly arthritis, vasculitis, and systemic lupus erythematosus; functional or inflammatory disorders of the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, crohn's disease, and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, the treatment of cancer, especially melanoma, glioma, small cell and large cell lung cancer, immune system disorders, bipolar disorder; migraine headache; pain, anxiety, depression, cognitive disorders, stress-related somatic disorders, psychoses, in particular schizophrenia, mania, schizoaffective disorders and panic disorders.

Functional disorders of the gastrointestinal tract treatable by the compounds of the present invention include, inter alia, disorders of the lower intestinal tract known as "irritable bowel syndrome" (═ IBS). Diagnosis of the typical symptoms of IBS, for example, in W.G. Thompson et al, Gastroenterology International2(1989)92-95 or in W.G.Thompson et al, GUT 45/II (1999) II43-II47, commonly referred to by the expert under the term "Rome criterion". The basic symptoms of IBS thus include lower abdominal pain, which appears to be caused by hypersensitivity of the visceral afferent nervous system, and large bowel movement abnormalities such as constipation, diarrhea, or alternating constipation and diarrhea. Other gastrointestinal inflammatory conditions which may be affected by the family of compounds of the invention are, for example, those of the small and large intestinal regions, generally covered by the term "inflammatory bowel disease" (═ IBD), such as Crohn's disease, ulcerative colitis. Due to its mechanism of action, the compounds of the invention also appear to be suitable for the treatment of other disorders in which tachykinins, in particular neurokinin a, are involved as transfer agents. Such disorders include, for example, neurogenic inflammation, inflammatory joint diseases such as rheumatoid arthritis, asthma discomfort, allergic disorders, immunoregulatory disorders, cystitis, or functional dyspepsia.

Another advantage of the compounds of the invention is the synergistic effect between NK 2-and NK 3-properties.

Another advantage of the compounds of the invention is their well-balanced combined NK 2-and NK 3-properties.

Description of pharmacological test methods

The example numbers given for the compounds of the formula I used as test substances in the pharmacological tests described below relate to the preparation examples described below.

1. Determination of the in vitro binding potency of test substances to the NK 1-receptor

The affinity of a test compound for the NK 1-receptor can be determined by determining the ability of the test compound to displace a radiolabeled ligand from its specific binding site. The assay was performed in Solvaypharmaceuticals, Weesp, The Netherlands.

The radiolabel used in this test is [2 ]³H]-substance P. The receptor was obtained from a CHO-cell (Chinese hamster ovary) membrane preparation in which the human NK 1-receptor was stably expressed. The [2 ] will film³H]Substance P is incubated in the absence or presence of various concentrations of test compound, diluted with a buffer system. The separation of bound radioactivity from non-radioactivity was performed by filtration through a glass fiber filter (Packard GF/B) and washing several times with ice cold buffer solution. Bound radioactivity was measured with a liquid scintillation counter (total binding). Non-specific binding was determined by incubation with the remaining (1. mu. mol/l) unlabeled P species.

Specific binding is given by total binding minus non-specific binding.

Plotting the radioactivity bound specifically against the concentration of test compound and calculating IC₅₀The value, i.e., the concentration at which 50% of the radioligand is displaced by test compound. The inhibition constants (Ki) were calculated according to the Cheng-Prusoff equation and are listed as their negative log values (pKi). The pKi value describes the potency of the test compound to bind to the receptor.

Table 1: in vitro binding potency of test substances to NK 1-receptor

Example numbering	1	4	8	9	10	11	14	15	24
Example numbering	1	4	8	9	10	11	14	15	24	pKi	7，1	7，2	7，4	7，6	7，1	8，2	7，0	7，6	7，1

Example numbering	49	55	56	65	70	80	82	83	89
Example numbering	49	55	56	65	70	80	82	83	89	pKi	7，0	7，0	7，2	7，1	7，2	7，1	7，1	7，1	7，0

Example numbering	92	93	98	101	102	103	105	108	116
Example numbering	92	93	98	101	102	103	105	108	116	pKi	7，0	8，1	8，3	8，7	8，7	7，3	7，6	7，9	7，1

Example numbering	125	126	127
Example numbering	125	126	127	pKi	7，9	8，2	7，1

For all the compounds of the examples, in each case by reaction at 10^-6To 10^-10At least three times for the test substances in the series of mol/l concentrationsMeasured to determine affinity to the human NK 1-receptor. The average results of all measurements are listed above. In this test mode, the compounds of example Nos. 1, 4, 8-11, 14, 15, 24, 49, 55, 56, 65, 70, 80, 82, 83, 89, 92, 93, 98, 101-127 exhibited pKi values of at least 7.0. The compounds of example nos. 11, 93, 98, 101, 102 and 126 show pKi values of at least 8.0.

2. Determination of the in vitro binding potency of test substances to the NK 2-receptor

The affinity of a test compound for the NK 2-receptor can be determined by determining the ability of the test compound to displace a radiolabeled ligand from its specific binding site.

The radiolabel used in this test is [2 ]³H]-SR 48968 (saredutan). The receptor was obtained from a CHO-cell (Chinese hamster ovary) membrane preparation in which the human NK 2-receptor was stably expressed. The [2 ] will film³H]-saredutant incubated in the absence or presence of various concentrations of test compound, diluted with a buffer system. The separation of bound radioactivity from non-radioactivity was performed by filtration through a glass fiber filter (Packard GF/B) and washing several times with ice cold buffer solution. Bound radioactivity was measured with a liquid scintillation counter (total binding). Non-specific binding was determined by incubation with the remaining (0.1. mu. mol/l) unlabeled saredutant.

Specific binding is given by total binding minus non-specific binding.

Table 2: in vitro binding potency of test substances to NK 2-receptor

Example numbering	1	2	3	4	5	6	7	8	9
Example numbering	1	2	3	4	5	6	7	8	9	pKi	9，8	9，4	8，8	9，6	9，0	9，2	8，7	9，1	9，2

Example numbering	10	11	12	13	14	15	16	17	18
Example numbering	10	11	12	13	14	15	16	17	18	pKi	8，9	8，7	8，7	9，0	9，1	9，2	9，0	7，5	8，9

Example numbering	19	20	21	22	23	24	25	26	27
Example numbering	19	20	21	22	23	24	25	26	27	pKi	8，5	7，6	7，9	7，8	8，7	8，3	8，3	8，3	7，8

Example numbering	28	29	30	31	32	33	34	35	36
Example numbering	28	29	30	31	32	33	34	35	36	pKi	7，7	8，6	8，6	8，4	7，8	7，1	7，8	8，5	8，8

Example numbering	37	38	39	40	41	42	43	44	45
Example numbering	37	38	39	40	41	42	43	44	45	pKi	8，8	8，8	7，7	7，9	8，5	7，8	9，6	8，3	8，6

Example numbering	46	47	49	50	51	52	53	55	56
Example numbering	46	47	49	50	51	52	53	55	56	pKi	8，2	8，5	8，0	7，4	7，1	7，8	7，8	8，2	7，6

Example numbering	58	59	61	63	64	65	66	67	68
Example numbering	58	59	61	63	64	65	66	67	68	pKi	7，0	7，0	7，4	8，4	7，9	7，6	7，8	8，2	8，7

Example numbering	69	70	71	72	73	74	75	76	77
Example numbering	69	70	71	72	73	74	75	76	77	pKi	7，0	7，6	8，3	8，5	7，9	8，4	8，3	7，8	8，5

Practice ofExample number	78	79	80	81	82	83	84	85	86
Practice ofExample number	78	79	80	81	82	83	84	85	86	pKi	8，8	8，7	8，7	7，9	8，6	8，3	7，9	7，9	7，9

Example numbering	87	89	90	91	92	93	94	95	96
Example numbering	87	89	90	91	92	93	94	95	96	pKi	8，1	7，9	7，9	8，1	7，7	7，8	8，5	9，0	8，7

Example numbering	97	98	99	100	101	102	103	104	105
Example numbering	97	98	99	100	101	102	103	104	105	pKi	8，7	8，3	9，2	8，5	9，4	8，3	8，7	8，7	8，7

Example numbering	108	116	124	125	126	127
Example numbering	108	116	124	125	126	127	pKi	8，4	8，3	9，0	7，3	8，0	8，7

For the compounds of example numbers 1-47, 49-53, 55, 56, 58, 59, 61, 63-104 and 124-127, in each case by reaction at 10^-6To 10^-10At least three measurements of the test substance in the series of mol/l concentrations are carried out to determine the affinity for the human NK 2-receptor. The average results of all measurements are listed above. All of the above test substances showed pKi values of at least 7.0 in this test mode. Example nos. 1-16, 18, 19, 23-26, 29-31, 35-38, 41, 43-47, 49, 55, 63, 67, 68, 71, 72, 74, 75, 77-80, 82, 83, 87, 91, 94-105, 108, 116, 124, 126 and 127 show pKi values of at least 8.0. Example nos. 1, 2, 4-6, 8, 9, 13-16, 95, 104 and 124 show pKi values of at least 9.0.

3. Determination of the in vitro binding potency of test substances to the NK 3-receptor

The affinity of a test compound for the NK 3-receptor can be determined by determining the ability of the test compound to displace a radiolabeled ligand from its specific binding site.

The radiolabel used in this test is [2 ]³H]-SR 142801 (osanetant). The receptor was obtained from a CHO-cell (Chinese hamster ovary) membrane preparation in which the human NK 3-receptor was stably expressed. The [2 ] will film³H]-osanetant incubated in the absence or presence of various concentrations of test compound, diluted with a buffer system. The separation of bound radioactivity from non-radioactivity was performed by filtration through a glass fiber filter (Packard GF/B) and washing several times with ice cold buffer solution. Bound radioactivity was measured with a liquid scintillation counter (total binding). Non-specific binding was determined by incubation with the remaining (1 μmol/l) unlabeled osanetant.

Specific binding is given by total binding minus non-specific binding.

Plotting the radioactivity bound specifically against the concentration of test compound and calculating IC₅₀The value, i.e., the concentration at which 50% of the radioligand is displaced by test compound. According to the Cheng-Prusoff formulaInhibition constants (Ki) were calculated and listed as negative log values (pKi). The pKi value describes the potency of the test compound to bind to the receptor.

Table 3: in vitro binding potency of test substances to NK 3-receptor

Example numbering	1	3	4	5	6	7	9	10	11
Example numbering	1	3	4	5	6	7	9	10	11	pKi	8，6	8，2	8，2	8，3	8，7	8，0	8，4	8，0	7，9

Example numbering	12	13	14	15	16	18	19	20	21
Example numbering	12	13	14	15	16	18	19	20	21	pKi	7，9	7，4	8，5	8，4	7，8	8，3	7，5	7，0	7，2

Example numbering	22	23	24	25	26	28	29	30	31
Example numbering	22	23	24	25	26	28	29	30	31	pKi	7，3	8，0	7，0	7，2	7，3	7，0	7，3	7，7	7，4

Example numbering	32	33	35	36	37	38	39	40	41
Example numbering	32	33	35	36	37	38	39	40	41	pKi	7，4	7，5	7，0	8，3	7，7	7，6	7，5	7，2	7，8

Example numbering	43	44	45	46	47	49	50	51	52
Example numbering	43	44	45	46	47	49	50	51	52	pKi	8，3	7，5	7，9	7，5	7，7	8，1	8，0	8，2	7，9

Example numbering	53	54	55	56	57	60	63	64	65
Example numbering	53	54	55	56	57	60	63	64	65	pKi	8，5	8，2	8，4	8，3	7，2	7，2	7，7	7，1	7，8

Example numbering	66	67	68	69	70	71	72	73	74
Example numbering	66	67	68	69	70	71	72	73	74	pKi	7，7	8，3	8，0	7，3	7，2	7，4	7，4	7，4	7，6

Example numbering	75	76	77	78	79	80	81	82	83
Example numbering	75	76	77	78	79	80	81	82	83	pKi	7，4	7，3	7，1	7，6	7，7	7，1	7，1	7，6	8，5

Example numbering	84	85	86	87	89	90	91	92	95
Example numbering	84	85	86	87	89	90	91	92	95	pKi	7，4	7，3	7，2	7，4	7，8	7，1	7，8	7，0	7，7

Example numbering	97	98	99	101	102	103	104	124	125
Example numbering	97	98	99	101	102	103	104	124	125	pKi	7，1	7，2	7，2	7，7	7，0	7，0	7，7	7，8	7，3

Example numbering	126
Example numbering	126	pKi	7，4

For the compounds of example numbers 1, 3 to 7, 9 to 16, 18, 19, 21 to 23, 25, 26, 29 to 33, 36 to 41, 43 to 47, 49 to 57, 60, 63 to 87, 89 to 91, 95, 97 to 104 and 124 in each case by way of example number 10^-6To 10^-10At least three measurements of the test substance in the series of mol/l concentrations are carried out to determine the affinity for the human NK 3-receptor. The average results of all measurements are listed above. All of the above test substances showed pKi values of at least 7.0 in this test mode. The compounds of example nos. 1, 3-10, 14, 15, 18, 23, 36, 43, 49-51, 53-56, 67, 68, and 83 exhibit pKi values of at least 8.0.

Functional cell assay for NK1-, NK 2-and NK 3-antagonism

Functional cell assays for the antagonistic effect of the compounds of the invention on human tachykinins were carried out in CHO cells expressing recombinant human NK1, NK2 or NK 3-receptors. Inhibition of ligand-induced increases in intracellular calcium flux and inhibition of ligand-induced mitogen-activated protein kinase (MAPK) phosphorylation are determined in these assays, which can be used as a measure of the functional activity of tachykinin antagonists. In addition, the antagonistic properties of the reference compound at different tachykinin receptors were characterized for comparison.

The effect of the test compounds was evaluated with Chinese Hamster Ovary (CHO) fibroblasts stably expressing cloned human NK1, NK2 or NK 3-receptors. NK receptors and G_qAnd (4) coupling. And a receptorBound ligand activation G_qProteins, lead to intracellular calcium flux and phosphorylation of MAPK. Two systems were used to determine the functional effect of the test compounds.

Measurement of Ca with FLIPR ²⁺ Show NK1 and NK2 activities

For these experiments, cells were seeded 24 hours prior to the experiment in black 96-well microplates. The cell density was 2.2X 10⁴Cells/well. All steps are performed under sterile conditions. To observe changes in intracellular calcium content, cells were loaded with calcium sensitive dyes. This dye (FLUO-4, from Molecular Probes) is excited at 488nm and emits light in the range 500nm to 560nm as long as complexes with calcium are formed. For dye loading, media was aspirated from the wells without disturbing the confluent cell layers, and 100 μ l of loading media (HBSS, 4 μ M FLUO-4, 0.005% (w/v) pluronic acid, 2.5mM probenecid, 20mM HEPES, pH 7.4) was dispensed into each well using an automated pipette system (Multidrop, Labsystems). Pluronic acid was added to increase dye solubility and cell uptake, while probenecid, an anion exchange inhibitor, was added to the loading medium to increase retention of the dye in the cells. Cells were incubated at 5% CO₂Incubate at 37 ℃ for 40 minutes in an incubator. After dye loading, cells were washed three times with wash-buffer (HBSS, 2.5mM probenecid, 20mM HEPES, pH 7.4) to reduce basal fluorescence. The buffer was aspirated in the final wash step and replaced with 100. mu.l of wash buffer. For this antagonistic screening pattern, substance P was added (final concentration: 10)^-8M; NK1 agonist) or NKA (final concentration: 10^-7M; NK2 agonist) was applied 7 minutes before 50 μ l of compound (final concentration 10 μ M to 1.4 nM). The FLIPR setting was set to 0.4 second contact time, filter 1, 50. mu.l of fluid addition, pipette height at 125. mu.l, dispense rate 40. mu.l/sec no mixing. The maximum fluorescence change was obtained using the statistical function of the FLIPR software and the data was plotted using GraphPad Prism 4. All points are expressed as percent inhibition relative to the control agonist. Use ofDetermination of IC by sigmoidal dose-response curve fitting₅₀The value is obtained. Antagonist potency (pA) was calculated using the following formula₂) The value:

pA₂＝-log(IC₅₀/(1+[L]/EC₅₀))，

wherein the IC of the compound is tested₅₀Obtained from the concentration-effect relationship, [ L ]]Concentration of agonist (substance P for NK1 assay, NKA for NK2 assay, NKb for NK3 assay), EC₅₀Potency (EC) of agonists on respective human cloned NK receptors₅₀Substance P: 10^-9.6M；EC₅₀NKA：10^-8.8M，EC₅₀NKB：10^-8.8M). The results are summarized in tables 4 and 5 below:

table 4: pA for NK1 ₂ Data:

example numbering	1	8	9	10	11	13	14	15	23
example numbering	1	8	9	10	11	13	14	15	23	pA₂	8，1	7，1	8，0	7，1	7，9	7，5	7，3	7，2	8，9

Example numbering	93	95	96	98	99	101	102	103	104
Example numbering	93	95	96	98	99	101	102	103	104	pA₂	8，1	7，2	7，5	8，8	7，3	7，2	8，7	7，5	7，7

Example numbering	105	108	116
Example numbering	105	108	116	pA₂	7，5	7，5	7，5

Table 5: pA for NK2 ₂ Data:

example numbering	1	2	3	4	5	6	7	8	9
example numbering	1	2	3	4	5	6	7	8	9	pA₂	9，7	9，3	8，7	8，6	8，5	8，8	8，6	8，6	8，6

Example numbering	10	11	12	13	14	15	16	17	18
Example numbering	10	11	12	13	14	15	16	17	18	pA₂	8，4	8，4	8，3	8，3	8，2	8，3	8，3	7，8	8，5

Example numbering	19	23	36	37	43	51	52	55	67
Example numbering	19	23	36	37	43	51	52	55	67	pA₂	9，3	8，9	9，3	8，8	9，2	7，4	8，4	8，7	7，6

Example numbering	68	83	93	94	95	96	97	98	99
Example numbering	68	83	93	94	95	96	97	98	99	pA₂	8，0	7，8	8，4	8，8	8，5	8，9	9，6	9，3	9，6

Example numbering	101	102	103	104	105	108	116
Example numbering	101	102	103	104	105	108	116	pA₂	10，0	7，4	8，7	7，8	10，1	9，0	8，9

Measurement of Ca with aequorin ²⁺ Indicating NK3 Activity

NK3 antagonism was determined in cell lines expressing the human NK3 receptor and a mitochondrially targeted apoaequorin (apoaequorin). In this system, cells expressing apoaequorin were incubated with coelenterazine, which is the chromophoric cofactor for aequorin. Upon incubation of cells with senktide, a potent NK3 agonist, intracellular calcium concentration increased. The trace amount of free calcium leads to a concentration-dependent activation of the catalytically active aequorin, which oxidizes coelenterazine and produces the apoaequorin coelenteramide, CO2 and light (λ max ═ 469 nm). Once a photon is emitted, the complex must dissociate and the apoaequorin must recombine with the cofactor before the complex can emit another photon. Thus, in this system, measurement of fluorescence (light emission) after addition of senktide reflects an increase in intracellular calcium due to NK3 receptor activation.

For this assay, cells were grown confluent and harvested with complexing ketone (5mM EDTA in PBS). The cells were centrifuged and resuspended in DMEM/F-12 (nutrient mixture according to Ham) without phenolsulfonphthalein, supplemented with 10% FCS to a density of 5X 10⁶Cells/ml. To load the cells, coelenterazine was added to a final concentration of 5 μm and the cells were stirred at room temperature for 4 hours. The loaded cells were diluted with DMEM/F12 without phenolsulfonphthalein and supplemented to a density of 2.8X 10⁵Cells/ml, pre-heated to 37 ℃ and stirred at room temperature for 60 min. For this antagonism screening format, 15. mu.l of cell suspension was added to 85. mu.l of compound (final concentration ranging from 4.5nM to 10. mu.M) in a white 96-well plate. After an incubation time of 20 minutes 50. mu.l of senktide (final concentration 5X 10-8M) were applied and chemiluminescence was immediately determined with a Microlumat (Berthold) for 20 seconds. All points are expressed as percent inhibition relative to the control agonist. IC (integrated circuit)₅₀Values were determined using a sigmoidal dose-response curve fit of GraphPad Prism 4. The antagonist potency (pA2) value was calculated using the following formula:

pA2＝pIC50+log[(L/EC50)-1]，

where pIC50 is the negative logarithm of the test compound IC50 value obtained from the concentration-action relationship, L is the concentration of senktide and EC50 is its potency at the human cloned NK3 receptor (EC50 senktide: 10-8.8M).

Table 6: pA for NK3 ₂ Data of

Example numbering	1	2	3	4	5	6	7	8	9
Example numbering	1	2	3	4	5	6	7	8	9	pA₂	8，6	7，5	8，2	8，2	8，5	8，7	8，1	8，4	8，0

Example numbering	10	11	12	13	14	15	16	17	18
Example numbering	10	11	12	13	14	15	16	17	18	pA₂	8，3	8，1	7，9	8，0	8，1	8，1	7，9	6，9	8，0

Example numbering	19	23	36	37	43	51	53	55	67
Example numbering	19	23	36	37	43	51	53	55	67	pA₂	7，3	7，9	7，2	7，5	7，5	7，5	7，3	8，1	7，8

Example numbering	97	101	102	103	104	105
Example numbering	97	101	102	103	104	105	pA₂	7，1	7，9	7，4	7，3	7，8	7，0

5. Determination of the functional NK 1-receptor antagonism of test compounds in tissues isolated from guinea pigs

The test compound NK 1-antagonism was determined in aortic ring preparations isolated from guinea pigs. The preparation was stored in an oxygen-treated nutrient solution (maintained at 37 ℃). To determine the contraction of the circular vessel muscle, the preparation was secured to a hook and connected to a force displacement sensor. The shrinkage/relaxation was recorded on a pen recorder (pen recorder). The preparation is provided with a medium tonus by the addition of phenylephrine.

NK 1-receptor was stimulated with NK 1-receptor agonist substance P, resulting in relaxation of muscle tone. This relaxation was measured before (predug) and after administration of the test compound and quantified as a percentage of the relaxation before administration. Application of 2-3 concentrations of test compound showed receptor stimulation concentration-dependent inhibition. Calculate half maximal Inhibitory Concentration (IC)₅₀) And its negative logarithm pIC₅₀＝-log(IC₅₀)。pIC₅₀Values represent the inhibitory potency of the test compounds on the NK 1-receptor.

Table 7: functional NK1 antagonism of test substances on isolated guinea pig tissue

Example numbering	11
Example numbering	11	pIC50	8，26

6. Determination of the functional NK 2-receptor antagonism of test compounds in tissues isolated from guinea pigs

Test compound NK2 antagonism was determined in gallbladder preparations isolated from guinea pigs. The preparation was stored in an oxygen-treated nutrient solution (maintained at 37 ℃). To determine the contraction of the circular gallbladder muscle, the preparation was secured to a hook and connected to a force displacement sensor. The contractions were recorded on a pen recorder (pen recorder).

Stimulation of the NK 2-receptor with the NK 2-receptor agonist neurokinin a results in muscle contraction. This contraction is measured before (before) and after administration of the test compound and quantified as a percentage of contraction relative to pre-administration. Application of 2-3 concentrations of test compound showed receptor stimulation concentration-dependent inhibition. Calculate half maximal Inhibitory Concentration (IC)₅₀) And its negative logarithm pIC₅₀＝-log(IC₅₀)。pIC₅₀Values represent the inhibitory potency of the test compounds on the NK 2-receptor.

Table 8: in vitro NK-2-receptor-antagonistic potency of test substances of the formula I on gallbladder of guinea pigs

Example numbering	1	2	3	4	6	10	11	36	43
Example numbering	1	2	3	4	6	10	11	36	43	pA2	8，17	8，96	8，96	8，86	8，88	8，78	8，03	9，05	10，41

7. Determination of the functional NK 3-receptor antagonism of test compounds in tissues isolated from guinea pigs

The test compound NK 3-antagonism was determined in ileal preparations isolated from guinea pigs. The preparation was stored in an oxygen-treated nutrient solution (maintained at 37 ℃). To determine the contraction of the longitudinal ileal muscle, the preparation was fixed to a hook and connected to a force displacement sensor. The contractions were recorded on a pen recorder (pen recorder).

With NK 3-receptor agonist [ MePhe⁷]Neurokinin B stimulates the NK 3-receptor, leading to muscle contraction. This contraction is measured before (before) and after administration of the test compound and quantified as a percentage of contraction relative to pre-administration. Application of 2-3 concentrations of test compound showed receptor stimulation concentration-dependent inhibition. Calculate half maximal Inhibitory Concentration (IC)₅₀) And its negative logarithm pIC₅₀＝-log(IC₅₀)。pIC₅₀Values represent the inhibitory potency of the test compounds on the NK 3-receptor.

Table 9: functional NK3 antagonism of test substances on isolated guinea pig tissue

Example numbering	1	3	4
Example numbering	1	3	4	pA2	8，4	8，5	8，0

8. Determination of the NK 3-receptor antagonistic potency (reduction of body temperature in senktide-induced gerbils) of the test substance in vivo

NK3 agonist lowered the temperature of gerbils. The low temperature induced by senktide can be antagonized by administering a compound having NK 3-antagonistic properties. Measuring the level of low temperature can indicate the activity of the test compound. The effect of the test compound itself was evaluated in the same experiment to exclude additional high temperature effects.

Male gerbils weighing between 60 and 90g were placed in groups at normal circadian rhythm and constant relative humidity levels (50. + -. 10%) at constant ambient temperature (room temperature: 21. + -. 2 ℃). Water and food are freely available. Reference agonist: senktide 0.03 mg/kgsc. Antagonists: see the example compounds in table X.

For each series of experiments, one state was always vehicle/vehicle group to determine normal body temperature and one state was always vehicle/senktide group to determine senktide induced hypothermia (═ 100%). Animals were weighed and labeled 60 minutes prior to agonist administration. For the oral (po) test, the test compound was administered at t-60 minutes. For parenteral or subcutaneous administration (i por sc, respectively), administration was carried out at t-30 minutes. Agonist senktide (sc) was administered at t 0 min. Temperature was measured at the mouth at t-15 minutes and registered with an accuracy of 0.1 ℃ after a 10 second reading. Thus, animals were measured every 60 seconds.

The vehicle/vehicle group was used as a reference to analyze the self-effect using the Dunett test; while the vehicle/senktide panel was used for comparison in the interaction assay (i.e., example compound/senktide panel).

Table 10: inhibition of temperature rise at t 60 minutes after oral administration (po)

Example numbering	Dosage: 30mg/kg	Dosage: 10mg/kg
Example numbering	Dosage: 30mg/kg	Dosage: 10mg/kg	1	54％	37％

Table 11: inhibition of temperature rise at a dose of 10mg/kg after parenteral administration (ip)

Example numbering	T 15 min after administration	T 30 min after administration
Example numbering	T 15 min after administration	T 30 min after administration	4	54％	68％
6	-	75％	4	54％	68％

9. Determination of the NK-3-receptor antagonistic potency (reduction of blood pressure in senktide-induced hypertensive guinea pigs) of the test substances in vivo

NK3 agonists elevate blood pressure in guinea pigs. Hypertension induced by senktide can be antagonized by administering a compound having NK 3-antagonistic properties. Measuring the level of hypertension can indicate the activity of the test compound. The effect of the test compound itself was evaluated in the same experiment to exclude additional hypertensive effects.

Male Dunkin Hartley guinea pigs weighing between 450-. The animals can breathe naturally.

The blood pressure is measured by a strain gauge sensor, wherein the strain gauge sensor is connected with a computer through an expander.

Two subsequent injections of the NK 3-receptor agonist senktide (0.4. mu.g/kg i.v.; 0.5ml/kg) were injected 15 minutes apart after hemodynamic stabilization and the peak-rising mean arterial blood pressure was determined for each injection. The mean value of the blood pressure rise was used as the hypertensive effect of the prodrug. 5 minutes thereafter, the test compound (0.1ml/min) was infused over 10 minutes, immediately followed by injection of 0.4. mu.g/kg senktide and determination of the mean arterial peak blood pressure rise. Cumulative test compound doses were applied for up to 5 cycles and the hypertensive effect of senktide was determined after each dose. The effect of the test compound on the peak of blood pressure rise induced by senktide is expressed as a percentage relative to the pre-dose value. ID₅₀Values (dose producing 50% inhibition of senktide response) were calculated from the dose response curve. The effect of vehicle on the senktide-induced blood pressure response was determined at regular baseline.

For oral administration, vehicle (1% methylcellulose) or test compound was administered in a dose volume of 5 ml/kg. 45 minutes thereafter, anesthesia was induced and catheters were inserted into the carotid artery and jugular vein. After 10 minutes of hemodynamic stability, two subsequent injections of the NK 3-receptor agonist senktide (0.4. mu.g/kg i.v.; 0.5ml/kg) were administered 15 minutes apart and the peak increase in mean arterial blood pressure was determined for each injection. The first senktide injection is about 80 to 90 minutes after dosing. The mean value of the blood pressure rise was used as the hypertensive effect of senktide in this animal. Mean values of the hypertension effects of senktide after vehicle treatment were used as control values (100%). The effect of each test compound on the peak of blood pressure rise induced by senktide is expressed as a percentage relative to the control value and the mean value of each dose group. The ID50 value (dose producing 50% inhibition of senktide response) was calculated from the dose response curve.

Senktide (0.8. mu.g/mL) was dissolved in saline. For intravenous administration, test compounds were dissolved in 40% hydroxypropyl- β -cyclodextrin (HPCD) containing 10% DMSO, diluted with saline and administered intravenously over the cumulative dose range. The animal vehicle groups received the corresponding HPCD/DMSO solutions in place of the test compounds. For oral administration, the test compound is suspended in 1% methylcellulose. The animal vehicle groups received the corresponding HPCD/DMSO solutions in place of the test compounds.

Table 12: inhibition of blood pressure after intravenous (iv) and oral (po) administration, ID₅₀Value representation

Example numbering	ID₅₀(iv)[mg/kg]	ID₅₀(po)[mg/kg]
Example numbering	ID₅₀(iv)[mg/kg]	ID₅₀(po)[mg/kg]	1	0，2557	6，3796
2	1，9809	-	1	0，2557	6，3796
2	1，9809	-	4	0，7564	2，3313
6	0，157	-	4	0，7564	2，3313
6	0，157	-	11	1，0554	10
13	0，5013	<10	11	1，0554	10
13	0，5013	<10	14	0，5168	6，811
15	0，3732	-	14	0，5168	6，811
15	0，3732	-	18	1，0108	-
19	0，3902	-	18	1，0108	-

10. Determination of NK 1-and NK 2-receptor antagonistic potency of test substances in vivo

The NK 1-and NK 2-antagonistic activity of the test substances was investigated in vivo in anesthetized guinea pigs after intravenous (i.v.) and oral (p.o.) administration, respectively. It is possible with this test mode to simultaneously detect in animals both the NK 2-antagonistic effect and the NK 1-antagonistic effect (rapid decrease in blood pressure) of three different organ systems (respiratory, colon and circulatory).

Pirbright-White guinea pigs weighing 500-700g were anesthetized with ketamine/xylazine (initial dose 67/13mg/kg, administered subcutaneously, with further doses as required). The animals were provided with intravenous catheters to administer substances and intra-arterial catheters to measure blood pressure. Animals were manually ventilated through a tracheal cannula and respiratory pressure was recorded by a pressure transducer. Balloons were introduced into the distal colon of the animal for manometer recording of colon movements with pressure sensors. Blood pressure, heart rate, respiratory pressure and colonic pressure were measured continuously for each animal and plotted on a recorder using a digital data processing system. Neurokinin A (NKA; 200 pmol/animal) was given as a bolus intravenous as a test stimulus to stimulate NK-1 and NK 2-receptors. NKA injections result in elevated respiratory (bronchoconstriction) and colonic pressures, as well as a biphasic decrease in blood pressure. First phase hypotension (the maximal hypotension phase within the first minute after NKA administration) is mediated by NK-1 receptors, as they can be completely blocked by specific NK-1 receptor antagonists. Second phase delayed hypotension (the maximal hypotension phase after 2-5 minutes) on the other hand is mediated by NK 2-receptors, since they can be completely blocked by specific NK 2-receptor antagonists. Of the test substancesDose is in ED₅₀Values are given which result in a reduction of the response to NKA test stimulation to 50% of the initial value, respectively, as characteristic variables for the individual measured parameters of bronchoconstriction, colonic pressure and blood pressure changes mediated by NK1 or NK 2.

The antagonistic effect of the test substances was first studied in an additive manner, with the NKA test stimulation taking 1 minute after the end of the administration of each dose of test substance. These ED50 values obtained from the additive dose-response curves are plotted in table 13.

Table 13: in vivo NK 1-and NK 2-receptor antagonistic potency of the test substances of the formula I after intravenous administration in guinea pigs

The measurements plotted in table 14 above indicate, among other things: the compound of example No. 11 produced significant NK-1-receptor-antagonistic activity on early hypotension after cumulative intravenous administration (antagonistic effect was detected 1 minute after the end of the administration of the test substance). The data further indicate that all of the example-numbered compounds produced significant NK 2-receptor antagonistic activity in colonic motility, late reduction in blood pressure, and respiratory impedance.

To additionally examine the change in the antagonistic effect of the test substances over time, the effect of NKA test stimulation was determined at various times (1, 30, 60, 90, 120, 150 and 180 minutes) after oral administration of the test substances. The antagonistic effect of the test substances was then determined when the "area under the curve" ("AUC") over the study period after administration of the test substances (1-180 min after administration) and the resulting ED50 values after oral administration were plotted in table 14.

Table 14: in vivo NK 1-and NK-2-receptor antagonistic potency of the test substances of the formula I after oral administration in guinea pigs

The compounds of the invention, in particular the compounds of example numbers 1, 4, 8 and 11 as shown in table 15, also have oral activity on NK 2. Example 11 also has activity as an NK1 receptor antagonist.

The compounds of formula I may be administered in the form of conventional pharmaceutical preparations. The dosage used may vary individually and will naturally vary depending on the type of condition to be treated, the substance used. However, pharmaceutical forms which usually contain 0.2 to 200mg, in particular 1 to 50mg, of active substance per single dose are suitable for administration to humans and large mammals. According to the present invention, the compounds may be contained in solid or liquid pharmaceutical preparations together with conventional pharmaceutical excipients and/or carriers. Examples of solid preparations are orally administrable preparations, such as tablets, coated tablets, capsules, powders or granules, or suppositories. In addition to customary pharmaceutical adjuvants, such as lubricants or tablet disintegrants, such preparations may also contain customary pharmaceutical inorganic and/or organic carriers, such as talc, lactose or starch. Liquid preparations such as suspensions or emulsions of the active substance may contain conventional diluents such as water, oils and/or suspending agents such as polyethylene glycol and the like. Other adjuvants such as antiseptic, correctant and the like may also be added.

The active substances can be mixed and formulated in a known manner together with pharmaceutical adjuvants and/or carriers. For the preparation of solid dosage forms, for example, the active ingredient may be mixed with the adjuvants and/or carriers in a conventional manner and may be wet granulated or dry granulated. The granules or powders can be poured directly into capsules or extruded by conventional methods to form tablet cores. Such formulations may be coated if desired by known methods.

The following examples are intended to further illustrate the invention without limiting its scope.

LC-MS data (API) were obtained from the following conditions:

instrument-description:

API 100 Single Quad，PE Applied Biosystems

PE 200 BI LC-Pump，PE Applied Biosystems

Gilson XL 215 Autosampler，Gilson Inc.

Sedex 75 Lightscattering-Detector，S.E.D.E.R.E

column: XTerra MS C18, 2.5um, 50 x 4.6mm

Protection of the column: XTerra MS C18, 3.5um, 20 x 3.9mm

Solvent A: 0.01M NH4ac pH 5.0+ 5% acetonitrile

Solvent B: acetonitrile

Gradient form:

100％ A ----10min---> 95％ B

2min isoconcentration of 95% B

100％ A <---0.5min---- 95％ B

100% A2.5 min isoconcentration

Flow rate: 1.0ml/min

Wavelength: 225nm

LC-MS data (ZQ) were obtained from the following conditions:

instrument-description:

ZQ Single Quad，Waters/Micromass

Alliance HT 2795，Waters

PL-ELS 1000 Lightscattering-Detector，Polymer Labs

column: XTerra MS C18, 2.5um, 50 x 4.6mm

Protection of the column: XTerra MS C18, 3.5um, 10 x 2.1mm

Solvent A: 0.01M NH4ac pH 5.0+ 5% acetonitrile

Solvent B: acetonitrile

Gradient form:

100% A1 min isoconcentration

100％ A ----6min---> 95％ B

1min isoconcentration of 95% B

100％ A <---1min---- 95％ B

100% A2 min isoconcentration

Flow rate: 1.0ml/min

Wavelength: 205-350nm

Example 1: n- [ (2S) -2- (3, 4-dichlorophenyl) -4-oxobutyl]-N-methyl- Synthesis of benzamide as starting Material for preparation of example Compounds 1, 2 and 99

To a solution of 15ml (0.172mol) oxalyl chloride in dichloromethane (200ml) cooled to-60/-70 ℃ was added dropwise over 75 minutes 30ml of DMSO in 100ml dichloromethane under nitrogen atmosphere to maintain the temperature at-60/-70 ℃. The reaction mixture was stirred at-70 ℃ for 20 minutes, then 31g (0.088mol) of N- [2- (3, 4-dichloro-phenyl) -4-hydroxy-butyl ] -N-methyl-benzamide in 200ml of dichloromethane were added in such a way as to maintain the temperature of the reaction mixture at-60 ℃ over 60 minutes. At this temperature 90ml of triethylamine in 40ml are added dropwise. The mixture was allowed to slowly return to room temperature and allowed to stand for 15 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in a mixture of 200ml of toluene and 200ml of ethyl acetate. The organic phase is washed with 100ml of saturated aqueous NaCl solution and then with 100ml of water 4 times. The recovered organic phase was dried over sodium sulfate and concentrated in vacuo to give 32.6g of a glassy material.

17.15g of this compound are suspended with stirring in 10ml of dichloromethane at room temperature. To the suspension was added 50ml of n-hexane and the mixture was left at 45 ℃ to give a slurry. To the slurry was added 40ml of n-hexane and the mixture was cooled to room temperature. The resulting suspension was filtered to give a solid, which was washed three times with 10ml of n-hexane. After dissolution in dichloromethane and subsequent concentration to dryness, 15g of a solid were obtained (melting point: 78-79 ℃): total yield: 90 percent of

Example 2: 1' - [ (3S) -4- [ benzoyl (methyl) amino]-3- (3, 4-dichlorobenzene) Alkyl) -butyl]-N, N-dimethyl-1, 4 '-bipiperidine-4' -carboxamide (example Compound 1) Synthesis of (2)

To a suspension of 15g (0.0428mol) of the aldehyde obtained in example 1, 14.9g (0.0540mol) of [1, 4 '] bipiperidinyl-4' -carboxylic acid dimethylamide hydrochloride and 5.3g of sodium acetate in 800ml THF are added 5ml of acetic acid with stirring, and the mixture is stirred at room temperature for 5 hours. To this mixture 18.5g (0.0876mol) of sodium triacetoxyborohydride are added in portions and the mixture is stirred at room temperature for a further 15 hours. The mixture was concentrated to dryness in vacuo and then redissolved in 300ml ethyl acetate, 50ml MTBE and 6g KOH (in 100ml water). The organic phase is washed with bicarbonate until pH5-6 and 3 times with 100ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness to give 27g of crude base as a foam. 17g of the crude base was dissolved in 30ml of dichloromethane at room temperature, and 13ml of 5N HCl was added thereto to obtain a solution. To this solution was added 500ml of MTBE and solids appeared. The suspension was heated to 50 ℃ and then cooled. The solid was recovered by filtration and washed 3 times with 100ml of MTBE. The solid was dissolved in 100ml methanol and concentrated to dryness to give 16.2g of compound, identified as dihydrochloride by elemental analysis.

Yield: 90 percent.

Optical rotation: -16.3 ° (c ═ 1% in methanol).

The crude base, purified by dissolution in water in the presence of concentrated HCl, after extraction with MTBE to remove the poorly soluble by-products and basification with aqueous KOH phase, followed by extraction of the base with dichloromethane, gave the pure base as a pale yellow compound in 90% yield.

Optical rotation: -17.8 ° (c ═ 1% in methanol).

¹HNMR (measured as alkali) (500MHz, CDCl)₃，30℃) δ：7.40-7.25(m，4.6H)，7.25-7.0(m，2.7H)，6.9，6.7(2xbs，0.7H)，3.82(bs，0.7H)，3.55(dd，0.7H)，3.5-3.25(m，4.4H)，3.2(bs，0.7H)，3.0(m，2H)，2.95-2.90(2xs，3H)，2.8-2.5(m，4.5H)，2.4-1.6(m，12H)，1.5(s，4H)，1，4(s，2H)。

¹³CNMR(125MHz，CDCl₃，30℃)δ：173.5，171.6，143.0，136.4.，132.4，130.5，128.4，126.8，66.9，57.1，56.1，53.3，51.7，47.3，41.7，38.7，37.7，33.6，30.9，26.9，25.2。

LC-MS: m +1 (monoisotopic) 573.

Retention time: 7.90min (API); 5.38min (ZQ).

Example 3: 1' - [ (3S) -4- [ benzoyl (methyl) amino group]-3- (3, 4-dichlorobenzene) Alkyl) -butyl]Combination of-N-methyl-1, 4 '-bipiperidine-4' -carboxamide (example Compound 2) Become into

To a suspension of 15g (0.0428mol) of the aldehyde obtained in example 1, 14.1g (0.0540mol) of [1, 4 '] bipiperidinyl-4' -carboxylic acid methylamide hydrochloride and 5.3g of sodium acetate in THF (800ml) was added 5ml of acetic acid with stirring, and the mixture was stirred at room temperature for 5 hours. To this mixture 18.5g (0.0876mol) of sodium triacetoxyborohydride are added in portions and the mixture is stirred at room temperature for a further 15 hours. The mixture was concentrated to dryness in vacuo and then redissolved in 300ml ethyl acetate, 50ml MTBE and 6g KOH (in 100ml water). The organic phase is washed with bicarbonate until pH5-6 and 3 times with 100ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness to give 27g of crude base as a foam. 17g of the crude base was dissolved in 30ml of dichloromethane at room temperature, and 13ml of 5N HCl was added thereto to obtain a solution. To this solution was added 500ml of MTBE and solids appeared. The suspension was heated to 50 ℃ and then cooled. The solid was recovered by filtration and washed 3 times with 100ml of MTBE. The solid was dissolved in 100ml methanol and concentrated to dryness to give 16.2g of compound, identified as dihydrochloride by elemental analysis.

Yield: 100 percent.

¹HNMR (measured as alkali) (500MHz, CDCl)₃₎ δ：7.45-6.70.(m，9H)，3.84(bs，0.7H)，3.55-2.8(m，4.3H)，2.78-2.75(2xs，3H)，2.7-2.5(m，3H)，2.4-1.6(m，14H)，1.5(s，4H)，1，4(s，2H)。

¹³CNMR(125MHz，CDCl₃，30℃)δ：176.9，171.6，143.0，136.4.，132.4，130.5，128.3，126.7，64.6，57.2，56.0，53.4，50.8，47.3，41.7，38.7，34.2，30.4，29.5，27.2，25.8，24.9

LC-MS：M+1：559。

Retention time: 6.98(API)

Example 4: 1- [ (3S) -4- [ benzoyl (methyl) amino group]-3- (3, 4-dichlorobenzene) Alkyl) -butyl]-N, N-dimethyl-4-pyrrolidin-1-ylpiperidine-4-carboxamide (example combination) Synthesis of substance 99);

wherein: method for preparing starting material N, N-dimethyl-4-pyrrolidine-1-yl piperidine-4-formamide Synthesis of

1-benzyl-4- [ (4-chlorobutyryl) amino]Piperidine-4-carboxylic acid ethyl ester

78.3g (0.298mol) of ethyl 4-amino-1-benzylpiperidine-4-carboxylate and 50ml of pyridine (0.6mol, 2eq) are dissolved in 1L of CH₂C₁₂In (1). The mixture was cooled to 5 ℃ and 0.37ml of the solution was added dropwise dissolved in 200ml of CH₂C₁₂Chlorobutyryl chloride (0.33mol, 1.1 eq). The mixture was stirred at room temperature for one week. 800ml of NaHCO are added₃The solution was saturated and the organic layer was separated. CH for aqueous layer₂C₁₂(2X 500ml) extraction. NaHCO for organic layer₃(2 x800ml) washed and evaporated to dryness. The mixture is purified over silica (eluent: CH)₂C₁₂(iv) MeOH, 100/0-97/3-95/5, v/v).

Yield: 113g (. about.quantitative yield) of a yellow semisolid.

1-benzyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxylic acid ethyl ester

12g of sodium hydride (290mmol, 1.2eq) are suspended in 600ml of THF. To the suspension was added 88.5g of ethyl 1-benzyl-4- [ (4-chlorobutyryl) -amino]Gel of piperidine-4-carboxylic acid ester (240mmol, 1eq) in 200ml THF. The mixture was stirred at room temperature overnight. NMR analysis showed a conversion of 60-70%. 5g additional sodium hydride (120mmol, 0.5eq) and 9g (60mmol, 0.3eq) sodium iodide were added and the mixture was stirred at room temperature for a further day. NMR analysis at this point showed complete conversion. The reaction was quenched with 1L of water. The mixture was extracted with ethyl acetate (3 × 1L). The organic layer was washed with 500ml of saturated aqueous solution of sodium chloride. The combined aqueous layers were extracted with dichloromethane (2 × 1L). The combined organic layers were evaporated to dryness. The crude mixture is further purified over silica (eluent: CH)₂C₁₂MeOH, 100/0 to 95/5, v/v) to give 68.4g of the title compound as a pale yellow solid (207mmol, 67%).

1-benzyl-N, N-dimethyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxamide

65g (200mmol, 1eq) of ethyl 1-benzyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxylate are dissolved in 600ml THF and 400ml 1M NaOH are added. The mixture was stirred under reflux overnight. TLC analysis showed incomplete conversion. 100ml of 1M additional NaOH were added and the mixture was stirred under reflux for a further 2.5 h. The mixture was cooled to room temperature and diluted with 500ml of water. MixingCH for things₂C₁₂(2X 500ml) extraction. The aqueous layer was cooled and neutralized with concentrated HCl (approximately 20 ml). The mixture was concentrated to dryness in vacuo.

The crude mixture was suspended in 1L. Dimethylamine HCl salt (21.9g, 270mmol, 1.35eq), TBTU (86.7g, 270mmol, 1.35eq) and triethylamine (138ml, 1.0mol, 5eq) were added. The mixture was stirred at room temperature overnight. Subjecting the mixture to CH₂C₁₂Diluted (500ml) and washed with water (500ml), NaHCO₃(500mL), water and saturated aqueous solution of sodium chloride (250 mL). The mixture was evaporated to dryness in vacuo. The crude mixture is purified over silica (eluent: CH)₂C₁₂/MeOH，95/5，v/v)。

Yield: 30.8g of 1-benzyl-N, N-dimethyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxamide as a pale yellow solid (93.5mmol, 52%).

N, N-dimethyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxamide

benzyl-N, N-dimethyl-4- (2-oxopyrrolidin-1-yl) piperidine-4-carboxamide (29g, 88mmol) was dissolved in tert-butanol/water (600ml, 9/1, v/v). Pd-C (6g, 10%, wet) was added and the mixture was stirred under a hydrogen atmosphere (5bar) at 50 ℃ for 16 h. NMR analysis showed complete conversion. Pd-C was removed by filtration through Celite (celite). The harvest of celite was washed with tert-butanol/water (100mL, 9/1, v/v). Volatiles were removed by evaporation in vacuo. The mixture is further purified over silica (eluent: CH)₂C₁₂a/3N methanolic ammonia solution, 95/5 to 90/10, v/v). The appropriate fractions were combined and concentrated to dryness.

Yield: 18g (75mmol, 86%) of a white solid.

N, N-dimethyl-4-pyrrolidin-1-ylpiperidine-4-carboxamides

To a suspension of 1g (4.2mmol) of N, N-dimethyl-4- (2-oxopyrrolidin-1-yl) -piperidine-4-carboxamide in absolute tetrahydrofuran (50ml) was added dropwise 1.8ml of Redal (sodium bis (2-methoxyethoxy) -dihydroaluminate) (3.5M/toluene, 6.3 mmol). The resulting solution was stirred vigorously at room temperature for 4 hours, and then quenched by the addition of 20g of NaF followed by the addition of 5ml of 80% aqueous tetrahydrofuran. The resulting slurry was stirred for an additional hour, then the solid was filtered off, washed gently with 2 × 50ml tetrahydrofuran, and the organic phase was evaporated under reduced pressure. The crude amine was further purified by column chromatography over silica gel (acetonitrile 6.25: ammonia 25% 1) to give a pale yellow oil which slowly crystallized on standing (330mg, 35%).

Melting point: at 150 ℃.

1- [ (3S) -4- [ benzoyl (methyl) amino group]-3- (3, 4-dichlorophenyl) -butane Base of]-N, N-dimethyl-4-pyrrolidin-1-ylpiperidine-4-carboxamide (example Compound 99) Synthesis of (2)

To a suspension of 150mg (0.0428mmol) of the aldehyde obtained in example 1, 96mg (0.0428mmol) of N, N-dimethyl-4-pyrrolidin-1-ylpiperidine-4-carboxamide and 0, 5g of sodium acetate in THF (21ml) at room temperature were added 0.05ml of acetic acid with stirring, and the mixture was stirred at room temperature for 5 hours. To this mixture was added 0.13g (0.062mmol) of sodium triacetoxyborohydride in portions and the mixture was stirred at room temperature for a further 15 hours. The mixture was concentrated to dryness in vacuo and then redissolved in 6ml of ethyl acetate, 10ml of MTBE and 0.12g of KOH (in 5ml of water). The organic phase is washed with sodium bicarbonate until pH5-6 and with 10ml of water3 times. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine is further purified by column chromatography over silica gel (ethyl acetate 10: triethylamine 1; R)_f0.35) to yield 109mg of a colorless amorphous foam (45%).

¹HNMR(500MHz，CDCl₃) δ：7.45-7.25(m，4.5H)，7.25-7.0(m，3H)，6.9，6.75(2xbs，0.6H)，3.85(bm，0.6H)，3.51(bdd，J＝12.5，10.1Hz，1H)，3.5-2.75(m，9H)，2.7(bs，2H)，2.6(bs，4H)，2.4-1.7(m，9H)，1.65(bs，4H).)。

¹³CNMR(125MHz，CDCl₃) δ：173.3，171.5，142.9，136.4，130.5，130.2，129.5，128.4，127.3，126.8，63.2，56.1，55.8，53.3，51.8，51.3，45.0，42.5，41.7，38.8，37.9，30.6，28.0，24.1。

LC-MS：M+1：559。

Retention time: 5.44 minutes (API).

Example 5: (2R) -1' - [ (3S) -4- [ benzoyl (methyl) amino]-3- (3, 4-bis) Chloro-phenyl) butyl]-N, N-dimethyl-1, 4' -bipiperidine-2-carboxamide (RS-configured entity) Synthesis of example Compound 100)

1g (7.75mmol) of L-pipecolic acid and 1.6g (8.0mmol) of N-Boc-piperidin-4-one are dissolved in 20ml of dichloromethane. To this solution was added 0.48ml of acetic acid and after 30 minutes 3.27g (2eq) of sodium triacetoxyborohydride. The resulting suspension was stirred at room temperature for 24 h. The reaction mixture was diluted with 30ml of saturated aqueous solution of sodium chloride and the product was extracted with 6 × 20ml of dichloromethane. The organic phase is passed through Na₂SO₄Drying and evaporation under reduced pressure gave 2.4g of [1, 4']-bipiperidinyl-2, 1 '-dicarboxylic acid 1' -tert-butyl ester.

2.4g (7.7mmol) of [1, 4']Bipiperidinyl-2, 1 '-dicarboxylic acid 1' -tert-butyl ester was dissolved in 20ml of dichloromethane, and 8ml (2M/THF, 16mmol) of dimethylamine, 1.75ml (16mmol) of N-methyl-morpholine and 2.1g (16mmol) of N-hydroxymethylbenzotriazole were added. Finally 3g (16mmol) of EDC HCl (ethyl-n' - (3-dimethylaminopropyl) -carbodiimide HCl salt) were added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with 50ml ethyl acetate and 2 × 20ml 10% K₂CO₃Aqueous wash. The organic phase is separated off, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude amide was purified by column chromatography over silica gel (ethyl acetate 2: ethanol 1, R)_f0.45) to give 1.4g of colorless solid 2-dimethylcarbamoyl- [1, 4']-piperidinyl-1' -carboxylic acid tert-butyl ester (53%).

[α]²² _D＝+47°，c＝1，MeOH。

1.4g (4.13mmol) of tert-butyl 2-dimethylcarbamoyl- [1, 4 '] -bipiperidinyl-1' -carboxylate are dissolved in 1ml of dichloromethane and 10ml of 6M HCl/isopropanol are then added. The reaction mixture was stirred at room temperature for 3h, during which time the product crystallized in the reaction medium. The suspension is diluted with 50ml of MTBE, stirred for more than 30 minutes and then filtered and washed with MTBE. The solid was dried under high vacuum for 1 hour to remove traces of volatiles to give 1.17g of a white powder [1, 4' ] -bipiperidinyl-2-carboxylic acid dimethylamide (91%).

To 150mg (0.0428mmol) of the aldehyde obtained in example 1, 135mg (0.0428mmol) of [1, 4 'at room temperature']To a suspension of bipiperidinyl-2-carboxylic acid dimethylamide and 0, 5g of sodium acetate in THF (21ml) were added under stirring 0.05ml of acetic acid and the mixture was stirred at room temperature for 5 hours. To this mixture was added 0.13g (0.062mmol) of sodium triacetoxyborohydride in portions and the mixture was stirred at room temperature for a further 15 hours. The mixture was concentrated to dryness in vacuo and then redissolved in 6ml of ethyl acetate, 10ml of MTBE and 0.12g of KOH (in 5ml of water). The organic phase is washed with sodium bicarbonate until pH5-6 and 3 times with 10ml of water. The organic solution was dried over sodium sulfate and concentratedAnd (5) condensing to be dry. The crude amine is further purified by column chromatography over silica gel (ethyl acetate 10: methanol 1: triethylamine 1; R)_f0.35) to yield 121mg of a colorless amorphous foam (49%).

[α]²² _D＝-46.5°：c＝1，CHCl₃。

¹HNMR(500MHz，CDCl₃) δ：7.45-7.3(m，4.5H)，7.25-7.0(m，2.8H)，6.9，6.75(2xbs，0.65H)，3.85(bm，0.65H)，3.6-3.4(m，1H)，3.55(dd，J＝13.1，9.5Hz，1H)，3.25(bs，3H)，3.0(m，2H)，2.9(s，3H)，2.75(m，2H)，2.6(bs，2H)，2.4(m，1H)，2.2(dt，J＝11.0，2.4Hz，1H)，2.18(m，1H)，2.0-1.3(m，14H)，1.25(m，1H)。

¹³CNMR(125MHz，CDCl₃) δ：173.1，171.6，142.9，136.4，132.7，132.5，130.5，130.2，129.5，128.4，127.2，126.7，63.9，58.7，55.9，53.8，53.6，53.4，45.5，42.3，41.4，38.8，36.8，36.2，34.5，33.5，30.8，30.3，28.9，25.8，24.3，23.9。

LC-MS：M+1＝573。

Retention time: 4.73 minutes (API).

Example 6: (2S) -1' - [ (3S) -4- [ benzoyl (methyl) amino]-3- (3, 4-bis) Chloro-phenyl) butyl]-N, N-dimethyl-1, 4' -bipiperidine-2-carboxamide (SS-configured entity) Synthesis of example Compound 100)

See the procedure of example 5. Using D-pipecolic acid instead of L-pipecolic acid, 1.267g of white crystalline amine salt (2S) -1' - [ (3S) -4- [ benzoyl (methyl) amino group]-3- (3, 4-dichloro-phenyl) butyl]-N, N-dimethyl-1, 4' -bipiperidine-2-carboxamide and purification including (ethyl acetate 10: methyl)Alcohol 1 is triethylamine 1; r_f0.35) to yield 69mg of colorless amorphous foam (28%).

[α]²² _D＝-16.2°，c＝1，CHCl₃。

¹HNMR(500MHz，CDCl₃) δ：7.45-7.3(m，4.5H)，7.25-7.0(m，2.8H)，6.9，6.75(2xbs，0.65H)，3.85(bm，0.65H)，3.6-3.4(m，1H)，3.55(m，1H)，3.23(bs，3H)，3.0(m，2H)，2.95(s，3H)，2.68(m，2H)，2.4(m，1H)，2.2(dt，J＝11.0，2.4Hz，1H)，2.18(m，1H)，2.0-1.3(m，14H)，1.25(m，1H)。

¹³CNMR(125MHz，CDCl₃) δ：173.1，171.7，142.8，136.0，132.5，130.6，130.2，129.5，128.4，127.2，126.7，63.8，58.7，56.0，54.1，53.4，53.2，45.5，42.5，41.5，38.9，36.8，36.2，34.5，33.7，30.7，30.2，28.9，25.7，24.2，23.8。

LC-MS：M+1＝573。

Retention time: 4.73 minutes (API).

Example 7: 1' - [ (3S) -4- [ benzoyl (methyl) amino]-3- (3, 4-dichloro-benzene Alkyl) -butyl]-N, N-dimethyl-1, 4' -bipiperidine-2-carboxamide (example Compound 100) Synthesis of (2)

See the procedure of example 5. Using (D-L) pipecolic acid instead of L-pipecolic acid or D-pipecolic acid, 1.267g of white crystalline amine salt (2) -1' - [ (3S) -4- [ benzoyl (methyl) amino group]-3- (3, 4-dichloro-phenyl) butyl]N, N-dimethyl-1, 4' -bipiperidine-2-carboxamide and its purification including (ethyl acetate 10: methanol 1: triethylamine 1; R)_f0.35) to yield 69mg of colorless amorphous foam (28%).

[α]² _D＝-16.2°，c＝1，CHCl₃。

LC-MS：M+1＝573。

Retention time: 4.73 minutes (API).

Example 8: n- [ (2S) -2- (3, 4-dichlorophenyl) -4- (4- {1- [ (dimethylamino) - Carbonyl radical]Cyclohexyl } piperazin-1-yl) butyl]-N-methylbenzamide (example Compound 96) Synthesizing;

wherein: starting material 1- (4-benzylpiperazin-1-yl) -N, N-dimethylcyclo-hexane-methyl Synthesis of amides

7.9g (0, 0262mol) of 1- (4-benzylpiperazin-1-yl) -cyclohexanecarboxamide (known from WO 0058292) in 120ml of anhydrous THF are added dropwise under nitrogen to a suspension of 2.83g (0.071mol) of 60% sodium hydride (in oil) in anhydrous THF (120ml) at room temperature, with stirring. The mixture was then heated to 60 ℃ for 2 hours with stirring. After the reaction mixture was cooled to room temperature, 6.33g of a solution of methyl iodide in anhydrous DMF (80ml) was added at room temperature and the reaction mixture was stirred for an additional 5 days. The reaction mixture was then poured onto 500g of ice water and the product was extracted with 500ml of MTBE. The organic layer was recovered and washed with 500ml of saturated aqueous solution of sodium chloride. The organic phase was then dried over sodium sulfate and concentrated to dryness. HPLC-MS showed the presence of the desired compound and its mono-methylated analogue.

Then purified by column chromatography on silica gel with n-hexane: 1/Ethyl acetate 9 the mixture was separated to give 3.2g of the desired compound (yield: 38%).

Wherein: synthesis of starting Material N, N-dimethyl-1-piperazin-1-ylcyclohexane-carboxamide Become into

3.2g (0.0097mol) of 1- (4-benzylpiperazin-1-yl) -N, N-dimethylcyclohexanecarboxamide are dissolved in 100ml of ethanol and 0.7ml of acetyl chloride are added. 1g of 10% palladium on charcoal was then added and the suspension was hydrogenated at 3 bar at room temperature for 15 hours. The catalyst was separated off by filtration and washed with 25ml of ethanol. The solvent was then evaporated to dryness to give 2.6g of N, N-dimethyl-1-piperazin-1-cyclohexane-carboxamide hydrochloride crystals (yield: 97%).

Melting point: 230-1 ℃.

N- [ (2S) -2- (3, 4-dichlorophenyl) -4- (4- {1- [ (dimethylamino) -carbonyl]Cyclohexane Radical } piperazin-1-yl) butyl]-synthesis of N-methylbenzamide (example compound 96);

to a suspension of 150mg (0.0428mmol) of the aldehyde obtained in example 1, 130mg (0.0428mmol) of N, N-dimethyl-1-piperazin-1-ylcyclohexane-carboxamide hydrochloride and 0, 5g of sodium acetate in THF (21ml) at room temperature were added with stirring 0.05ml of acetic acid, and the mixture was stirred at room temperature for 5 hours. To this mixture was added 0.13g (0.062mmol) of sodium triacetoxyborohydride in portions and the mixture was stirred at room temperature for a further 15 hours. The mixture was concentrated to dryness in vacuo and then redissolved in 6ml of ethyl acetate, 10ml of MTBE and 0.12g of KOH (in 5ml of water). The organic phase is washed with sodium bicarbonate until pH5-6 and 3 times with 10ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine is further purified by column chromatography over silica gel (ethyl acetate 10: methanol 1: triethylamine 1; R)_f0.35) to yield 260mg of a colorless amorphous foam (85%) as the dihydrochloride salt.

¹HNMR (measured as hydrochloride salt) (500MHz, CD)₃ OD) δ：7.65-6.95(m，8H)，3.82(m，2H)，3.80-3.5(m，3H)，3.2-2.9(m，15H)，2.8(m，2H)，2.5-1.1(m，12H)。

¹³CNMR(125MHz，CD₃ OD₎ δ：174.1，142.7，137.3.，133.8，132，5，132.1，129.7，129.1，128.1，127.7，58.2，56.0，53.7，51.7，47.3，42.1，39.2，28.5，27.1，25.1

LC-MS: m +1 (monoisotopic): 585.

retention time: 5.22 minutes (API).

Example 9: 1- [ (3S) -4- [ benzoyl (methyl) amino group]-3- (3, 4-dichlorobenzene) Alkyl) -butyl]-4-cyclohexyl-N, N-dimethyl-piperidine-4-carboxamide (example Compound) 95) Synthesis of (2)

5g (13.25mmol) of 4-phenyl-4-piperidinecarboxylic acid tosylate are dissolved in 50ml of dichloromethane, and then 3.75ml (27mmol) of triethylamine and 3.1g (14mmol) of di-tert-butyloxycarbonate are added. The reaction mixture was stirred for 16h, then diluted with 100ml of ethyl acetate and washed with 1 × 50ml of 10% aqueous acetic acid and 3 × 50ml of saturated aqueous sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 3.97g of N-Boc-4-phenyl-4-piperidinecarboxylic acid as white crystals (98%).

13mmol of N-Boc-4-phenyl-4-piperidinecarboxylic acid are dissolved in 100ml of ethanol and reacted with hydrogen (6 bar) in 5% -Rh/Al₂O₃The mixture is hydrogenated at 60 ℃ for 20 h. After filtration and evaporation of the solvent, 4.0g (100%) of pure crystalline N-Boc-4-cyclohexyl-4-piperidinecarboxylic acid was isolated.

Melting point: at 156 ℃.

1g (3.2mmol) of N-Boc-4-cyclohexyl-4-piperidine-carboxylic acid was dissolved in 20ml of dichloromethane and one drop of dimethylformamide was added. To the resulting solution was added 0.29ml (1.05eq) of oxalyl chloride and stirred for 30 minutes. 3.2ml of dimethylamine (2M/THF, 2eq) were added and the mixture was stirred for more than 30 minutes. The solution was diluted with 50ml ethyl acetate and washed with 2 × 20ml 10% aqueous potassium carbonate solution. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude amide is purified by column chromatography over silica gel (dichloromethane 20: acetone 1, R)_f0.3) to yield 217mg of N-Boc-4-cyclohexyl-4-piperidine-carboxylic acid dimethylamide as a colorless oil (20%).

217mg (0.64mmol) of N-Boc-4-cyclohexyl-4-piperidine-carboxylic acid dimethylamide are dissolved in 0.5ml of dichloromethane and 2ml of 6M HCl/isopropanol are added. The reaction mixture was stirred at room temperature for 3h, during which time the product crystallized in the reaction medium. The suspension is diluted with 20ml of MTBE, stirred for 30 more minutes and then filtered and washed with MTBE. The solid was dried under high vacuum for 1 hour to remove traces of volatiles to give 157mg of 4-cyclohexyl-4-piperidinecarboxylic acid dimethylformamide hydrochloride as a white powder (90%).

To a suspension of 95mg (0.027mmol) of the aldehyde obtained in example 1, 75mg (0.0428mmol) of 4-cyclohexyl-4-piperidinecarboxylic acid dimethylamide hydrochloride and 0, 3g of sodium acetate in THF (20ml) at room temperature were added 0.03ml of acetic acid with stirring, and the mixture was stirred at room temperature for 5 hours. To the mixture was added 0.1g (0.045mmol) of sodium triacetoxyborohydride in portions and the mixture was stirred at room temperature for a further 15 hours. The mixture was concentrated to dryness in vacuo and then redissolved in 6ml of ethyl acetate, 10ml of MTBE and 0.12g of KOH (in 5ml of water). The organic phase is washed with sodium bicarbonate until pH5-6 and 3 times with 10ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine is further purified by column chromatography over silica gel (ethyl acetate 10: triethylamine 1; R)_f0.35) to yield 102mg of a colorless amorphous foam (66%).

¹HNMR(500MHz，CDCl₃) δ：7.45-7.3(m，4.5H)，7.25-7.0(m，2.7H)，6.9，6.75(2xbs，0.65H)，3.8(m，0.5H)，3.6-3.4(m，1.5H)，3.15(m，0.6H)，3.0(s，6H)，2.9-2.5(m，4H)，2.2(m，0.6H)，2.1(bd，J＝12.5Hz，2H)，2.05-1.8(m，4H)，1.78(bd，J＝11.6Hz，2H)，1.6，(m，6H)，1.3-1.0(m，5H)。

¹³CNMR(125MHz，CDCl₃) δ：173.6，170.5，143.0，135.4，131.4，129.6，129.5，129.2，128.4，127.3，126.5，126.2，125.7，55.4，52.3，51.1，50.6，49.5，42.7，41.5，40.6，37.7，32.5，29.7，27.1，26.2，25.5。

LC-MS：M+1：572。

Retention time: 5.57 minutes (API).

Example 11: n- { (2S) -2- (3, 4-dichlorophenyl) -4- [ 4-pyrrolidin-1-yl -4- (pyrrolidin-1-ylcarbonyl) piperidin-1-yl]Butyl } -N-methylbenzamide (example) Synthesis of Compound 103)

Wherein: starting material 1-benzyl-4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) Synthesis of piperidines

2.34ml (0.0132mol) of N-benzylpiperidin-4-one, 4.4ml (0.0527mol) of pyrrolidine, 1.6ml (0.02mol) of chloroform and 38mg of N-benzyltriethylammonium chloride were stirred at 5 ℃. To this stirred mixture was added dropwise a solution of 2.6g of sodium hydroxide in water (5ml) while the temperature was maintained at 5 ℃. After stirring for 15 hours at 5 ℃ 50ml of water are added and the organic material is extracted 3 times with 10ml of dichloromethane. The organic phase is separated off and washed twice with 30ml of water. The organic phase is then separated, dried over sodium sulphate and concentrated to dryness to give 3.426g of an oil, NMR and MS showing the presence of the desired compound.

And (3) purification: 3g of the mixture were separated by MPLC on 112g of SiO2 using n-hexane-ethyl ester as eluent mixture to give 1.94g of the desired compound as a white solid.

(according to Lai, J.org.chem 1980, p. 3671).

Wherein: preparation of starting Material 4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) -piperidine Synthesis of

1.9g (0.00556mol) of 1-benzyl-4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) -piperidine were dissolved in 200ml ethanol at 30 ℃ and hydrogenated in the presence of 4 spoons of palladium hydroxide 20% on charcoal (60% moisture) at 40 ℃ for 6h at 4 bar. The catalyst was recovered by filtration and the solution was concentrated to dryness to give the desired debenzylated compound identified by NMR and MS, which was used without further purification.

N- { (2S) -2- (3, 4-dichlorophenyl) -4- [ 4-pyrrolidin-1-yl-4- (pyrrolidine-1-) Alkylcarbonyl) piperidin-1-yl]Process for preparation of butyl } -N-methylbenzamide (example Compound 103) Synthesizing;

to a suspension of 180mg (0.51mmol) of the aldehyde from example 1, 180mg (0.51mmol) of 4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) -piperidine and 0, 3g of sodium acetate in THF (20ml) at room temperature were added 0.03ml of acetic acid with stirring and the mixture was stirred at room temperature for 5 hours. To this mixture was added 0.2g (0.09mmol) of sodium triacetoxyborohydride in portions and the mixture was stirred at room temperature for a further 15 hours. The mixture was concentrated to dryness in vacuo and then redissolved in 6ml of ethyl acetate, 10ml of MTBE and 0.2g of KOH (in 5ml of water). The organic phase is washed with sodium bicarbonate until pH5-6 and 3 times with 10ml of water. The organic solution was dried over sodium sulfate and concentrated to dryness. The crude amine is further purified by column chromatography over silica gel (ethyl acetate 10: triethylamine 1; R)_f0.35) to yield 236mg of colorless amorphous foam (79%).

¹HNMR (measured as alkali) (500MHz, CDCl)₃) δ：7.45-6.70(m，8H)，3.85(m，2H)，3.6-3.4(m，4H)，3.3-2.5(m，10H)，2.35-1.9(m，8H)，1.78(s，4H)，1，67(s，4H)。

¹³CNMR(125MHz，CDCl₃₎ δ：172.4，171.6，143.0，136.5，132，4，130.5，129.4，128.3，127.3，126.7，62.9，56.1，53.3，51.7，51.1，47.5，45.1，41.7，38.7，27.9，27.4，24.0，23.2

LC-MS: m +1 (monoisotopic): 585.

retention time: 5.85 minutes (API).

Example 12: 3-cyano-N- { (2S) -2- (3, 4-dichlorophenyl) -4- [ 4-pyrrolidine -1-yl-4- (pyrrolidin-1-ylcarbonyl) piperidin-1-yl]Butyl } -N-methyl-1-naphthamide Synthesis of (example Compound 102)

Wherein: starting material 3-cyano-naphthalene-1-carboxylic acid [2S- (3, 4-dichloro-phenyl) -4-oxo Substituted-butyl]Synthesis of (meth) -amides

A solution of 12.2g DMSO in dichloromethane (100ml) was added dropwise to a solution of 7.3g oxalyl chloride in dichloromethane (100ml) with stirring at-70 ℃. The resulting mixture was stirred for a further 15 minutes, after which 20g of [2S- (3, 4-dichloro-phenyl) -4-hydroxy-butyl ] -methyl-carbamic acid tert-butyl ester in 200ml of dichloromethane were added. The mixture was stirred at-70 ℃ for a further hour, after which 40.3ml triethylamine in 50ml dichloromethane were added dropwise. The solution was stirred at-70 ℃ for 15 minutes and then allowed to warm to room temperature. The solvent was removed and the residue was dissolved in 300ml of toluene and 200ml of ethyl acetate. The resulting solution was washed six times with 200ml of saturated aqueous NaCl solution, dried over sodium sulfate and concentrated to dryness to give 19.7g of 3-cyano-naphthalene-1-carboxylic acid [2S- (3, 4-dichloro-phenyl) -4-oxo-butyl ] -methyl-amide.

3-cyano-N- { (2S) -2- (3, 4-dichlorophenyl) -4- [ 4-pyrrolidin-1-yl-4- (pyrazoyl) Pyrrolidin-1-ylcarbonyl) piperidin-1-yl]Butyl } -N-methyl-1-naphthamide (example combination) Object 102) synthesis;

253.8mg (0.0006mol) of 3-cyano-naphthalene-1-carboxylic acid [2S- (3, 4-dichloro-phenyl) -4-oxo-butyl ] -methyl-amide, 150mg (0.006mol) of 4-pyrrolidin-1-yl-4- (pyrrolidin-1-ylcarbonyl) -piperidine and 72mg (0.0012mol) of acetic acid are dissolved in 20ml of dichloromethane and stirred at room temperature for 30 minutes. Subsequently, 163.7mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture is then diluted with 40ml of ethyl acetate and the resulting phase is washed twice with 50ml of 10% aqueous potassium carbonate solution and once with 50ml of saturated aqueous sodium chloride solution. The organic phase was then separated and concentrated to dryness to give 280mg of the title base as an amorphous solid.

¹HNMR(500MHz，CDCl_3，) δ：8.24(0.35H)，8.19(0.65H)，7.97-6.50)(m，8H)，4.4(bs，0.65H)，3.85(bs，2H)，3.7-3.25(m，3.35H)，3.2(s，m，1H)，3.0-1.9(m，10H)，1.8(s，4H)，1.68(s，4H)。

¹³CNMR(125MHz，CDCl₃₎ δ：172.4，172.3，142.5，136.5，134.7，132.4，131.0，130.6，130.5，130.1，128.3，127.5，126.7，125.2，123.9，118.4，109.0，63.0，57.1，56.0，53.3，51.7，51.1，47.5，45.1，45.0，41.7，38.7，37.7，33.6，31.6，27.9，27.4，24.0

LC-MS: m +1 (monoisotopic): 573.

retention time: 7.90 minutes (API).

Example 13: n- { (2S) -2- (3, 4-dichlorophenyl) -4- [ 4' - (piperidin-1-ylcarbonyl) 1, 4 '-bipiperidin-1' -yl]Butyl } -N-methylbenzamide (Compounds of the examples) 104) Synthesis of (2)

Wherein: preparation of starting material 1 ' -benzyl-4 ' - (piperidin-1-ylcarbonyl) -1, 4 ' -bipiperidine Synthesis of

1 ' -benzyl-4 ' - (piperidin-1-ylcarbonyl) -1, 4 ' -bipiperidine is obtained by condensation of 2.34ml (0.00132mol) of N-benzylpiperidin-4-one, 5.3ml (0.00536mol) of piperidine, 1.6ml (0.002mol) of chloroform and 38mg of benzyltriethylammonium chloride. 4.445g of a crude mixture of oily substances are obtained (yield: 90%), of which 2g are subsequently purified in preparative HPLC with a gradient of formic acid-containing acetonitrile/water 2 times, giving 678mg of the product diformate after lyophilization of the fractions containing the pure desired compound.

Wherein: synthesis of starting Material 4 '- (piperidin-1-ylcarbonyl) -1, 4' -Bipiperidine

576mg of 1 ' -benzyl-4 ' - (piperidin-1-ylcarbonyl) -1, 4 ' -bipiperidinedicarboxylate were converted into the dihydrochloride, dissolved in 50ml of ethanol and hydrogenated in the presence of 50mg of 10% palladium on charcoal at 40 ℃ for 4 days. The catalyst was separated off by filtration and washed 3 times with 50ml of ethanol. The organic phases were combined again and concentrated to dryness to give 4 '- (piperidin-1-ylcarbonyl) -1, 4' -bipiperidine dihydrochloride as a solid.

N- { (2S) -2- (3, 4-dichlorophenyl) -4- [4 '- (piperidin-1-ylcarbonyl) -1, 4' -bi Piperidin-1' -yl radical]Synthesis of butyl } -N-methylbenzamide (example Compound 104)

127mg (0.00036mol) of the aldehyde from example 1, 160mg (0.0036mol) of solid 4 '- (piperidin-1-ylcarbonyl) -1, 4' -bipiperidine dihydrochloride and 35mg (0.0006mol) of acetic acid are dissolved in 20ml of dichloromethane and stirred at room temperature for 30 minutes. Subsequently, 85mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture is then diluted with 20ml of ethyl acetate and the resulting phase is washed twice with 50ml of 10% aqueous potassium carbonate solution and once with 50ml of saturated aqueous sodium chloride solution. The organic phase was then separated off and concentrated to dryness to give 206mg of the title base as a colourless foamy hydrochloride (quantitative yield).

¹HNMR(as hydrochloride)(500MHz，CDCl₃ OD) δ：7.65-6.95(m，8H)，3.8-3.55(m，8H)，3.35-3.25(2xs，3H)，3.2-2.4(m，13H)，2.35-2.15(m，2H)，1.95(s，4H)1.7(s，2H)，1，62(s，4H)。

LC-MS: m +1 (monoisotopic): 613.

retention time: 6.14 minutes (API).

Example 13: n- { (2S) -2- (3, 4-dichlorophenyl) -4- [ 4' - (pyrrolidin-1-yl) Carbonyl) -1, 4 '-bipiperidin-1' -yl]Butyl } -N-methylbenzamide (Compounds of the examples) 124) Synthesis of (2)

Wherein: synthesis of starting material 1 ' -benzyl-1, 4 ' -bipiperidine-4 ' -formamide

4, 5g (52.8mmol) piperidine, 5g (26.4mmol) N-benzyl-piperidin-4-one, 9, 5g (3eq) magnesium sulfate and 2.3ml N-dimethylacetamide were mixed together and then 2.6ml (1eq) 2-cyano-2-hydroxy-propane was added. The resulting suspension was stirred at 55 ℃ for more than 48h, whereupon the pasty suspension solidified. The crude product was mixed with 100ml of water and 100ml of ethyl acetate. The organic phase was washed with water (2 × 50ml), dried over sodium sulfate and evaporated to give 7g of crude aminonitrile.

1.3g (3, 6mmol) of the resulting aminonitrile are dissolved in 15ml of 90% wt. sulfuric acid and heated at 100 ℃ for 10 minutes. The resulting solution was poured onto ice and then basified to pH 9 with sodium hydroxide. The crude amine was extracted with ethyl acetate (3 × 30ml) and the organic phase was washed once with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. 1g (92%) of 1 ' -benzyl-1, 4 ' -bipiperidine-4 ' -carboxamide are obtained as pale yellow crystals.

Wherein: starting material N, N-diallyl-1 ' -benzyl-1, 4 ' -bipiperidine-4 ' -formyl Synthesis of amines

1, 75g (5, 83mmol) of 1 ' -benzyl-1, 4 ' -bipiperidine-4 ' -carboxamide are dissolved in 10ml of hexamethylphosphoramide. To this solution 466mg (2eq) sodium hydride (60% in oil) was added portionwise and the suspension was stirred at 60 ℃ for 2 hours. The resulting solution was then cooled to room temperature and 1ml (2eq) of allyl bromide was added over 6 hours via syringe pump. After 24h the reaction was quenched by addition of 10% aqueous ammonium chloride (50ml) and the product was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The crude compound was purified by column chromatography over silica gel (ethyl acetate 5: ethanol 1, R)_f0.3) to give 1g (45%) of the desiredN, N-diallyl-1 ' -benzyl-1, 4 ' -bipiperidine-4 ' -carboxamide.

Wherein: starting material 1 '-benzyl-4' - (2, 5-dihydro-1H-pyrrol-1-ylcarbonyl) Synthesis of 1, 4' -bipiperidine

1g (2, 6mmol) of N, N-diallyl-1 ' -benzyl-1, 4 ' -bipiperidine-4 ' -carboxamide are dissolved in 50ml of dichloromethane and the resulting refluxed solution is added portionwise in 36 hours to Grubbs-1 catalyst (1g, 50 mol%). The solvent was evaporated and the product was purified by column chromatography over silica gel (ethyl acetate, R)_f0.35) to yield 640mg (70%) of pure 1 ' -benzyl-4 ' - (2, 5-hydro-1H-pyrrol-1-ylcarbonyl) -1, 4 ' -bipiperidine.

Wherein: synthesis of starting material 4 '- (pyrrolidin-1-ylcarbonyl) -1, 4' -bipiperidine

0.64g (1, 81mmol) of 1 ' -benzyl-4 ' - (2, 5-dihydro-1H-pyrrol-1-ylcarbonyl) -1, 4 ' -bipiperidine are dissolved in 70ml of ethanol and 200mg of carbon (60% moisture) loaded with Pd (OH) 20% are added. The compound is hydrogenated with hydrogen at 5 atmospheres. After 4 hours, the catalyst was removed by filtration and the solvent was evaporated under reduced pressure to give 470mg (99%) of a blue-grey crystalline powder.

Melting point: 144 deg.c.

N- { (2S) -2- (3, 4-dichlorophenyl) -4- [ 4' - (pyrrolidin-1-ylcarbonyl) -1, 4- Bipiperidin-1' -yl]Synthesis of butyl } -N-methylbenzamide (example Compound 124)

150mg (0.005mol) of the aldehyde from example 1, 120mg (0.005mol) of 4 '- (pyrrolidin-1-ylcarbonyl) -1, 4' -bipiperidine and 35mg (0.0006mol) of acetic acid are dissolved in 20ml of dichloromethane and stirred at room temperature for 30 minutes. Subsequently, 85mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture is then diluted with 20ml of ethyl acetate and the resulting phase is washed twice with 50ml of 10% aqueous potassium carbonate solution and once with 50ml of saturated aqueous sodium chloride solution. The organic phase was then separated and concentrated to dryness to give the title compound. After purification 171mg of N- { (2S) -2- (3, 4-dichlorophenyl) -4- [4 ' - (pyrrolidin-1-ylcarbonyl) -1, 4 ' -bipiperidin-1 ' -yl ] butyl } -N-methylbenzamide (66%) were isolated.

¹HNMR(500MHz，CDCl₃) δ：7.45-7.3(m，4.6H)，7.25-7.0(m，2.8H)，6.9，6.75(2xbs，0.65H)，4.1-3.7(m，2H)，3.6-3.4(m，3.65H)，3.15(bs，0.65H)，3.0(bs，1H)，2.9-2.6(m，5H)，2.46(s，4H)，2.3-1.85(m，8H)，1.75(bs，7H)，1.5(m，4H)，1.4(m，2H)。

¹³CNMR(125MHz，CDCl₃) δ：172.4，171.6，142.9，136.4，132.4，130.5，130.2，129.4，128.3，127.2，126.7，66.4，57.1，56.1，55.7，53.3，51.6，51.1，47.8，47.2，42.5，41.6，38.7，33.6，30.9，27.4，27.1，26.9，25.1，23.2。

LC-MS：M+1＝598。

Retention time: 5.82 minutes (API).

Example 14: 1' - [ (3S) -4- [ benzoyl (methyl) amino]-3- (3, 4-dichlorobenzene) Alkyl) -butyl]-N-Ethyl-N-methyl-1, 4 '-bipiperidine-4' -carboxamide (example Compound) 95) According to another synthesis method

100mg (0.158mmol) of the amide 1' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl]-[1，4′]Bipiperidinyl-4' -carboxylic acid methylamide was dissolved in 1ml of anhydrous DMSO, and then 21mg (0.19mmol) of potassium tert-butoxide was added under an inert atmosphere. The resulting solution was stirred at room temperature for 1h, then 25mg (0.16mmol) of iodoethane were added and the reaction mixture was stirred at room temperature for a further 24 h. The reaction mixture was diluted with 10ml of 10% NH₄Aqueous Cl was diluted and the product was extracted with ethyl acetate (3 × 10 ml). The organic phase is passed through Na₂SO₄Dried and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (ethyl acetate 5: methanol 1, R)_f0.25) gave a colorless foam (31mg, 30%).

¹HNMR(500MHz，CDCl₃) δ：7.3(m，4.5H)，7.25-7.0(m，3H)，6.9，6.7(2xbs，0.6H)，3.9(bs，0.6H)，3.5(dd，J＝12.97，9.92Hz，1H)，3.4(m，3.5H)，3.2(bs，1H)，3.0-2.7(m，3H)，2.7(s，3H)，2.5(bs，4H)，2.4-1.6(m，10H)，1.5(s，4H)，1，4(s，2H)，1.1(bs，3H)。

¹³CNMR(125MHz，CDCl₃) δ：173.0，172.0，136.3，130.6，130.2，129.5，128.4，127.2，126.8，66.4，56.2，55.9，53.4，51.7，51.1，50.6，47.3，44.6，44.1，42.5，41.6，41.1，38.8，36.0，34.0，33.5，30.2，29.7，29.4，26.9，25.1，11.7。

LC-MS：M+1＝587。

Retention time: 5.59 minutes (API).

Example 14: 4- ({ [ (2S) -2- (3, 4-dichlorophenyl) -4- { 4' - [ (dimethylamide) Yl) -carbonyl]-1, 4 '-bipiperidin-1' -yl } butyl](methyl) amino } carbonyl) acetic acid phenyl ester (Compounds of examples)5) Synthesis of (2)

Wherein: starting material tert-butyl [ (2S) -2- (3, 4-dichlorophenyl) -4- { 4' - [ (dimethyl) Amino) -carbonyl]-1, 4 '-bipiperidin-1' -yl } butyl]Synthesis of methyl carbamate

To a suspension of 4g (0.0115mol) [2- (3, 4-dichloro-phenyl) -4-oxo-butyl ] -methyl-carbamic acid tert-butyl ester, 4.35g (0.0139mol) piperidinopiperidine ketamide hydrochloride [1, 4 '] bipiperidinyl-4' -carboxylic acid dimethylamide and 2g sodium acetate in 200ml THF, 1.5ml acetic acid was added. The reaction mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 4.88g (0.0231mol) of sodium triacetoxyborohydride in portions, and the solution was stirred at room temperature for 15 hours and then concentrated to dryness. The remaining material was dissolved in 100ml of MTBE and 5g of potassium hydroxide (in 50ml of water). The separated organic layer was then washed three times with 50ml of water, dried over sodium sulfate and concentrated to give 6.06g of foam, which was used in the next step without further purification. Yield: 92 percent of

Wherein: starting material 1' - [ (3S) -3- (3, 4-dichlorophenyl) -4- (methylamino) butane Base of]Synthesis of (E) -N, N-dimethyl-1, 4 '-bipiperidine-4' -carboxamide

6g (0.0105mol) of [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] -bipiperidin-1 ' -yl) -butyl ] -methyl-carbamic acid tert-butyl ester are dissolved at room temperature in 10ml of dichloromethane and 40ml of a 5N HCl-isopropanol (0.2mol) solution. 1 ' - [ (3S) -3- (3, 4-dichlorophenyl) -4- (methylamino) butyl ] -N, N-dimethyl-1, 4 ' -bipiperidine-4 ' -carboxamide hydrochloride precipitated and the mixture was stirred for 15 hours until complete reaction. The mixture was dropped into 150ml of MTBE and then stirred at room temperature for another 1 hour. The precipitate was isolated by filtration, washed 3 times with 10ml of MTBE and the solid obtained was dried under vacuum at 60 ℃ to give 4.1g of 1 ' - [ (3S) -3- (3, 4-dichlorophenyl) -4- (methylamino) butyl ] -N, N-dimethyl-1, 4 ' -bipiperidine-4 ' -carboxamide trihydrochloride.

Yield: 67%.

Optical rotation: -2.0 ° (c ═ 1% in methanol).

Wherein: 4- ({ [ (2S) -2- (3, 4-dichlorophenyl) -4- { 4' - [ (-N, N-dimethylamino) Yl) -carbonyl]-1, 4 '-bipiperidin-1' -yl } butyl](methyl) amino } carbonyl) acetic acid phenyl ester Synthesis of (2)

220mg (0.00038mol) of 1 ' - [ (3S) -3- (3, 4-dichlorophenyl) -4- (methylamino) butyl ] -N, N-dimethyl-1, 4 ' -bipiperidine-4 ' -carboxamide are dissolved at room temperature in 20ml of dichloromethane with stirring in the presence of 200. mu.l of triethylamine. To the reaction mixture, 98mg of 4-acetoxybenzoyl chloride in dichloromethane (20ml) was added dropwise at room temperature, followed by 200. mu.l of triethylamine. The reaction mixture was stirred at room temperature for 15 hours and concentrated in vacuo. The residue is dissolved in 50ml of ethyl acetate and 30ml of MTBE in the presence of 200mg of potassium hydroxide dissolved in 20ml of water. The organic phase is separated off and washed 4 times with 20ml of water. The organic layer was recovered, dried over sodium sulfate and concentrated to dryness to give 240mg (quantitative yield) of phenyl 4- ({ [ (2S) -2- (3, 4-dichlorophenyl) -4- {4 ' - [ (dimethylamino) carbonyl ] -1, 4 ' -bipiperidin-1 ' -yl } butyl ] (methyl) amino } carbonyl) acetate as a glassy material.

¹HNMR (measured as alkali) (500MHz, CDCl)₃₎ δ：7.45-7.1(m，7H)，7.0，6.8(2xbs，0.7H)，3.82(bs，0.7H)，3.55(dd，1H)，3.5-3.2(m，4H)，3.1(bs，0.7H)，3.0(m，2H)，2.95-2.90(2xs，3H)，2.8-2.5(m，4.5H)，2.3(s，3H)2.25-1.6(m，12H)，1.5(s，4H)，1，4(s，2H)。

¹³CNMR(125MHz，CDCl₃₎ δ：170.7，168.2，150.7，131.7.，121.5，120.9，66.1，55.2，56.1，52.6，51.7，50.9，50.4，46.6，40.9，38.0，36.9，29.9，26.2，24.4，20.4

LC-MS: m +1 (monoisotopic): 631.

retention time: 7.78 minutes (API).

Example 15: 1' - { (3S) -3- (3, 4-dichlorophenyl) -4- [ (4-hydroxybenzoyl) Yl) - (methyl) amino]Butyl } -N, N-dimethyl-1, 4 '-bipiperidine-4' -carboxamide (example) Synthesis of example Compound 6)

170mg (0.00027mol) of phenyl 4- ({ [ (2S) -2- (3, 4-dichlorophenyl) -4- {4 ' - [ (dimethylamino) -carbonyl ] -1, 4 ' -bipiperidin-1 ' -yl } butyl ] (methyl) amino } carbonyl) acetate are dissolved in 30ml of methanol in the presence of 300mg of potassium hydroxide at room temperature and stirred for 20 hours. The solution was then concentrated to dryness and dissolved in a solution of 50ml of ethyl acetate, 40ml of MTBE and 2g of ammonium chloride in water (20ml) until a pH of 7 was reached. The organic phase was separated, washed 3 times with 20ml of water, dried over sodium sulfate and concentrated in vacuo to give 102mg of the glassy compound 1 ' - { (3S) -3- (3, 4-dichlorophenyl) -4- [ (4-hydroxybenzoyl) (methyl) amino ] -butyl } -N, N-dimethyl-1, 4 ' -bipiperidine-4 ' -carboxamide (yield: 64%).

¹HNMR (measured as alkali) (500MHz, CDCl)₃) δ：7.40-6.70(m，7H)，(2xbs，0.7H)，3.88(bs，0.7H)，3.45(dd，1H)，3.5-3.25(m，4.H)，3.2(bs，0.7H)，3.0(m，2H)，2.95-2.90(2xs，3H)，2.8-2.5(m，4.5H)，2.4-1.6(m，12H)，1.5(s，4H)，1，4(s，2H)。

¹³CNMR(125MHz，CDCl₃) δ：173.5，172.8，172.4，160.1，158.8，132.9，131.56，131.4，130.9，129.8，127.1，70.6，65.9，55.6，53.4，51.7，47.3，38.7，37.8，31.9，26.7，26.0，24.9

LC-MS: m +1 (monoisotopic): 589.

retention time: 7.06 minutes (API).

Example 16: 1' - [ (3S) -4- [ benzoyl (methyl) amino]-3-phenylbutane Base of]-N, N-dimethyl-1, 4 '-bipiperidine-4' -carboxamide) synthesis

700mg (0.00108mol) of 1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid methylamide dihydrochloride are dissolved at room temperature in 100ml of ethanol. To this solution was added 50ml of water and 560mg of potassium hydroxide. The solution was hydrogenated in the presence of 5 spoons of 10% palladium on charcoal at 4 bar for 5 days at room temperature. The solution was recovered after filtration and the catalyst was separated off, concentrated to dryness and then dissolved in 60ml of MTBE. The organic phase was washed 3 times with 10ml of water, separated, dried over sodium sulfate and concentrated to dryness to give 405mg of the title product as an oily substance (yield: 74%). 390mg of this base were dissolved in 2ml of ethanol at 40 ℃ and 330. mu.l of HCl 5N in IPA were added with stirring to give a solution, to which 20ml of MTBE was added to produce a precipitate. After heating the solution to 50 ℃, the suspension was cooled to room temperature. The precipitate was recovered by filtration, washed twice with 10ml of methanol, dissolved in methanol and concentrated to dryness to give 435mg (98% yield) of colorless dihydrochloride as a foam.

¹HNMR (measured as alkali) (500MHz, CDCl)₃) δ：7.40-6.85(m，10H)，3.87(bs，0.7H)，3.58(dd，0.7H)，3.5-3.25(m，4.4H)，3.1(bs，0.7H)，2.96(m，2H)，2.95-2.85(bs，3H)，2.85-2.45(m，4.5H)，2.3-1.6(m，12H)，1.51(s，4H)，1，41(s，2H)。

¹³CNMR(125MHz，CDCl₃) δ：173.5，171.5，142.4，136.8.，129.2，128.7，128.5，128.2，128.0，126.7，66.9，57.6，56.4，53.4，51.8，47.3，42.4，38.5，37.7，33.6，31.1，26.9，25.1

LC-MS: m +1 (monoisotopic): 505.

retention time: 4.94 minutes (API).

Examples 17 to 36

Compounds 105 to 123 were obtained by reductive amination as outlined in method (a). Reductive amination of aldehydes with amines to give compounds of the formula I, examples 105 to 123

N- [ (2S) -4- {4- [ (cyclopropylmethyl) (propionyl) -amino]Piperidine-1- Phenyl } -2- (3, 4-dichlorophenyl) butyl]-N-methylbenzamide (example Compound 105) Synthesis of (2)

To a mixture of 105mg (0.3mmol) of N- [2- (3, 4-dichloro-phenyl) -4-oxo-butyl ] -N-methyl-benzamide (compound II), 70mg (0.33mmol) of N- (cyclopropylmethyl) -N-piperidin-4-ylpropanamide (compound III) and 37mg (0.45 mmol) of sodium acetate in 6ml of THF at room temperature is added with stirring 0.03ml (0.51mmol) of acetic acid. After stirring for 0.5h, 127mg (0.6mmol) of sodium triacetoxyborohydride are added to the mixture. After stirring for a further 15h, the mixture was concentrated to dryness in vacuo and redissolved in 20ml of dichloromethane. The organic solution was washed three times with potassium bicarbonate and then dried over sodium sulfate. After filtration the organic phase is concentrated to dryness under vacuum. The crude product was purified by column chromatography on silica gel using ethyl acetate/ethanol as eluent (100/0 to 80/20 v/v) to give 93mg of a colourless oil.

The following compounds were prepared following the reductive amination procedure described:

n- [ (2S) -2- (3, 4-dichlorophenyl) -4- {4- [ isopropyl (propionyl) amino ] piperidin-1-yl } butyl ] -N-methylbenzamide (compound example 106); n- [ (2S) -2- (3, 4-dichlorophenyl) -4- {4- [ phenyl (propionyl) amino ] piperidin-1-yl } butyl ] -N-methylbenzamide (compound example 107); n- [ (2S) -4- {4- [ butyl (propionyl) -amino ] piperidin-1-yl } -2- (3, 4-dichloro-phenyl) butyl ] -N-methylbenzamide (example 108); n- [ (2S) -4- {4- [ butyl- (cyclopropylcarbonyl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methyl-benzamide (example 109); n- [ (2S) -4- {4- [ butyl (cyclohexylcarbonyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide (example 110); n- [ (2S) -4- {4- [ benzoyl (butyl) -amino ] piperidin-1-yl } -2- (3, 4-dichloro-phenyl) butyl ] -N-methylbenzamide (example 111); n- [ (2S) -2- (3, 4-dichlorophenyl) -4- {4- [ phenyl (4-methoxybutyl) (propionyl) amino ] piperidin-1-yl } butyl ] -N-methylbenzamide (compound example 112); n- [ (2S) -4- {4- [ (cyclopropylcarbonyl) (4-methoxybutyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide (compound example 113); n- [ (2S) -4- {4- [ (cyclohexylcarbonyl) (4-methoxybutyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide (compound example 114); n- [ (2S) -4- {4- [ benzoyl (4-methoxybutyl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide (compound example 115); n- [ (2S) -4- {4- [ cyclohexyl (propionyl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methyl-benzamide (example 116); n- [ (2S) -4- {4- [ cyclohexyl (cyclopropylcarbonyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) cyclohexyl ] -N-methylbenzamide (example 117); n- [ (2S) -4- {4- [ cyclohexyl (cyclohexylcarbonyl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide (example 118); n- [ (2S) -4- {4- [ benzoyl (cyclohexyl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methyl-benzamide (compound example 119); n- [ (2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (1-methyl-piperidin-4-yl) (propionyl) amino ] piperidin-1-yl } butyl ] -N-methylbenzamide (compound example 120); n- [ (2S) -4- {4- [ (cyclopropylcarbonyl) (1-methylpiperidin-4-yl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide (compound example 121); n- [ (2S) -4- {4- [ (cyclohexylcarbonyl) (1-methylpiperidin-4-yl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide (compound example 122); and N- {1- [ (3S) -4- [ benzoyl (methyl) amino ] -3- (3, 4-dichlorophenyl) butyl ] piperidin-4-yl } -N- (1-methylpiperidin-4-yl) benzamide (compound example 123).

Example 37: preparation of starting material (compound III):

the commercially available compound III d is reacted with tert-butoxycarbonyl anhydride to give compound III c, which is then converted to intermediate III b under reductive amination conditions. The intermediate III b is acylated to the corresponding amide III a. The amide III a is then deprotected to give intermediate III.

Example 38: preparation of N- (cyclopropylmethyl) -N-piperidin-4-ylpropanamide

To a mixture of 1g (5mmol) of tert-butyl 4-oxopiperidine-1-carboxylate (compound IIIc), 0.39ml (4.5mmol) of 1-cyclopropylhexamethylenetetramine and 0.56g (6.8 mmol) of sodium acetate in 20ml of THF are added, with stirring, 0.44ml (7.75mmol) of acetic acid at room temperature. After stirring for 1 hour 1.93g (9.1mmol) of sodium triacetoxyborohydride are added to the mixture. After stirring for a further 15h, the mixture was concentrated to dryness in vacuo and redissolved in 50ml of ether. The organic solution is extracted three times with 30ml of 0.1n aqueous HCl solution. The combined aqueous layers were basified with aqueous sodium hydroxide solution and then extracted three times with 30ml of ether. The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give 1.1g of crude tert-butyl 4- [ (cyclopropylmethyl) amino ] piperidine-1-carboxylate (III b).

To a cold solution of 1.1g (4.3mmol) of crude tert-butyl 4- [ (cyclopropylmethyl) -amino ] piperidine-1-carboxylate (compound III b) and 1.13ml (6.5mmol) of N-ethyl-diisopropylamine in 25ml of dichloromethane at 5 ℃ were added 0.45ml (5.2mmol) of propionyl chloride (in 3ml of dichloromethane). After stirring for 2h the mixture was evaporated and redissolved in 50ml of ether. The organic phase is washed 2 times with 30ml of water, 2 times with 20ml of 0.1N aqueous sodium hydroxide solution, 2 times with 30ml of 0.1N aqueous hydrochloric acid solution, dried over sodium sulfate and concentrated to give 1.1g of the crude tert-butyl 4- [ (cyclopropylmethyl) (propionyl) amino ] cyclohexane-carboxylate (compound III a).

A solution of 1.1g of tert-butyl 4- [ (cyclopropylmethyl) (propionyl) amino ] -piperidine-1-carboxylate (compound III a) in 20ml of 4M hydrogen chloride in dioxane and 5ml of ethanol was stirred at room temperature for 15h, then evaporated and redissolved in 50ml of dichloromethane and washed successively 3 times with 20ml of aqueous potassium carbonate solution (10%), washed with 30ml of water, dried over sodium sulfate and concentrated under vacuum to give 0.45g of N- (cyclopropylmethyl) -N-piperidin-4-ylpropanamide (compound III) as a colourless oil.

The preparation of the desired 4-substituted piperidine (see above) is carried out according to the methods already described.

The compounds of formula I listed in table 14 below may be prepared according to, or analogously to, the methods described in the examples above.

Table 16 contains the mass spectrometry data, noting the observed retention time relative to molecular weight.

Table 16: MS data and retention time

Examples	Percentage of	Retention time	Molecular weight group
Examples	Percentage of	Retention time	Molecular weight group	1	100	5，43	573，6048
3	100	5，74	579，6522	1	100	5，43	573，6048
3	100	5，74	579，6522	4	100	5，47	591，5949
14	100	5，58	609，585	4	100	5，47	591，5949
14	100	5，58	609，585	19	100	4，86	574，5929
20	96，44	5，65	699，7872	19	100	4，86	574，5929
20	96，44	5，65	699，7872	21	92，45	5，77	717，7334
22	100	5，23	537，5718	21	92，45	5，77	717，7334
22	100	5，23	537，5718	23	100	5，65	565，6254
24	100	5，59	602，6465	23	100	5，65	565，6254
24	100	5，59	602，6465	25	100	5，29	617，6138
26	99，43	5，93	657，6009	25	100	5，29	617，6138
26	99，43	5，93	657，6009	27	100	5，99	649，7024
28	100	6，25	677，756	27	100	5，99	649，7024
28	100	6，25	677，756	29	100	5，26	617，6574
30	100	5，42	576，6087	29	100	5，26	617，6574
30	100	5，42	576，6087	31	100	5，27	563，566
32	100	5，75	623，6646	31	100	5，27	563，566
32	100	5，75	623，6646	33	100	6，06	663，7292
34	100	5，87	634，0877	33	100	6，06	663，7292
34	100	5，87	634，0877	35	100	5，36	562，5819
36	100	5，25	563，566	35	100	5，36	562，5819
36	100	5，25	563，566	37	100	5，43	579，633
38	100	5，36	579，633	37	100	5，43	579，633
38	100	5，36	579，633	39	100	5，74	612，6417
40	100	5，52	626，6685	39	100	5，74	612，6417
40	100	5，52	626，6685	41	100	5，3	612，6417
42	98，54	4，91	575，581	41	100	5，3	612，6417
42	98，54	4，91	575，581	43	100	5，03	574，5929
44	100	4，84	574，5929	43	100	5，03	574，5929

45	100	5，27	641，6358
45	100	5，27	641，6358	46	100	4，96	652，6837
47	100	5，13	687，1288	46	100	4，96	652，6837
47	100	5，13	687，1288	48	100	4，51	577，5968
49	100	5，06	588，6197	48	100	4，51	577，5968
49	100	5，06	588，6197	50	100	4，92	588，6197
51	100	4，85	588，6197	50	100	4，92	588，6197
51	100	4，85	588，6197	52	100	4，79	622，6771
53	99，7	5，01	581，6244	52	100	4，79	622，6771
53	99，7	5，01	581，6244	54	100	5，8	688，7359
55	100	5，9	657，6009	54	100	5，8	688，7359
55	100	5，9	657，6009	56	100	6，3	723，6258
57	100	4，59	621，6058	56	100	6，3	723，6258
57	100	4，59	621，6058	58	100	5，7	680，7565
59	98，64	4，7	563，57	58	100	5，7	680，7565
59	98，64	4，7	563，57	60	100	6，57	792，8871
61	100	5，79	688，7359	60	100	6，57	792，8871
61	100	5，79	688，7359	62	100	5，1	565，5422
63	100	5，79	653，594	62	100	5，1	565，5422
63	100	5，79	653，594	64	100	5，06	562，5819
65	100	5，7	672，6686	64	100	5，06	562，5819
65	100	5，7	672，6686	66	100	5，47	670，6775
67	100	5，52	668，7093	66	100	5，47	670，6775
67	100	5，52	668，7093	68	100	5，49	613，6258
69	100	6，05	643，7196	68	100	5，49	613，6258
69	100	6，05	643，7196	70	100	6，22	709，599
71	100	5，71	652，5009	70	100	6，22	709，599
71	100	5，71	652，5009	72	99，84	5，5	591，5949
73	100	5，95	663，5553	72	99，84	5，5	591，5949
73	100	5，95	663，5553	74	92，69	5，4	609，585
75	98，97	5，92	642，495	74	92，69	5，4	609，585
75	98，97	5，92	642，495	76	92，88	5，61	642，495
77	100	5，8	641，6019	76	92，88	5，61	642，495
77	100	5，8	641，6019	78	100	5，56	587，6316
79	100	5，5	591，5949	78	100	5，56	587，6316
79	100	5，5	591，5949	80	100	5，63	608，0499
81	100	5，86	642，495	80	100	5，63	608，0499
81	100	5，86	642，495	82	100	5，44	603，6306

83	100	5，77	641，6019
83	100	5，77	641，6019	84	100	5，66	608，0499
85	100	5，41	603，6306	84	100	5，66	608，0499
85	100	5，41	603，6306	86	98，96	5，82	641，6019
87	100	5，6	587，6316	86	98，96	5，82	641，6019
87	100	5，6	587，6316	88	100	5，67	553，6144
89	100	5，57	587，6316	88	100	5，67	553，6144
89	100	5，57	587，6316	91	100	5，31	598，6149
92	100	5，7	623，6646	91	100	5，31	598，6149

Example 39:

a capsule containing 1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

capsules each containing the following composition were prepared:

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide 20mg

Corn starch 60mg

Lactose 300mg

Proper amount of ethyl acetate

The active substance, corn starch and lactose were processed with ethyl acetate to a homogeneous pasty mixture. The paste was ground and the resulting granules were placed in a suitable pan and dried at 45 ℃ to remove the solvent. The dried granules were passed through a mill and mixed in a mixer with the following other adjuvants:

talcum powder 5mg

Magnesium stearate 5mg

Corn starch 9mg

And then filled into 400mg capsules (═ 0 capsules).

Example 40:

capsule containing 1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide

Capsules each containing the following composition were prepared:

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid methylamide 20mg

Corn starch 60mg

Lactose 300mg

Proper amount of ethyl acetate

talcum powder 5mg

Magnesium stearate 5mg

Corn starch 9mg

And then filled into 400mg capsules (═ 0 capsules).

Example 41:

a capsule containing 1 ' - [4- (cyclohexanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

capsules each containing the following composition were prepared:

1 ' - [4- (Cyclohexanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide 20mg

Corn starch 60mg

Lactose 300mg

Proper amount of ethyl acetate

talcum powder 5mg

Magnesium stearate 5mg

Corn starch 9mg

And then filled into 400mg capsules (═ 0 capsules).

Example 42:

a capsule containing 1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

capsules each containing the following composition were prepared:

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide 20mg

Corn starch 60mg

Lactose 300mg

Proper amount of ethyl acetate

talcum powder 5mg

Magnesium stearate 5mg

Corn starch 9mg

And then filled into 400mg capsules (═ 0 capsules).

The claims (modification according to treaty clause 19)

1. Compounds of the general formula I and the physiologically compatible acid addition salts of compounds of the formula I,

wherein

R1 is selected from the group consisting of: alkyl and cycloalkyl radicals;

x is selected from the group consisting of: CR6 and nitrogen;

R7 and R8 are independently selected from the group consisting of: alkyl, cycloalkyl, aryl, alkylenearyl, alkyleneoxyalkyl, COalkyl, COaryl, or wherein R7 and R8 together form a 5-to 7-membered ring optionally containing an additional heteroatom selected from nitrogen and oxygen, wherein such ring may be substituted with CONR9R10 and wherein no ring atoms in the 6-membered ring are substituted with carbonyl groups;

m is selected from 0 or 1.

2. The compound according to claim 1, wherein R1 is methyl.

3. The compound according to any one of claims 1 or 2, wherein R3 and R4 are independently selected from the group consisting of: hydrogen, fluorine, chlorine, preferably hydrogen or chlorine.

4. A compound according to any one of the preceding claims wherein X is CR6 wherein R5 is NR7R8 wherein R6 is (CO)_mNR9R10 and m is 1.

5. A compound according to any one of the preceding claims wherein X is N, wherein R5 is di (CO)_mNR9R10 substituted cycloalkyl and m ═ 1.

6. A compound according to any one of the preceding claims wherein R7 and R8 together form a 6 membered ring, or wherein R7 and R8 together form a 6 membered ring substituted by CONR9R 10.

7. A compound according to any one of the preceding claims wherein R9 and R10 are both methyl, or wherein R9 and R10 together form a 6 membered ring, or wherein R9 and R10 together form a 5-membered ring substituted with a carbonyl group.

8. A compound according to any preceding claim, wherein R2 is selected from the group consisting of:

C₁-C₂₀an alkyl group; c₃-C₂₀A cycloalkyl group; c₂-C₂₀An alkenyl group;

and

wherein each of R11 to R16 is independently selected from the group consisting of: hydrogen, fluorine, chlorine, bromine, hydroxyl, alkoxy, cyano, N (H) C (O) Oalkyl, aminoalkyl, dialkylamino, OCF₃、CF₃Carboxyalkyl, S (O)₂NH₂Phenyl, alkyl and cycloalkyl;

wherein t is 0 or 1;

wherein Y is selected from the group consisting of: CH. N and NO;

9. A compound according to any preceding claim, wherein R5 is selected from the group consisting of:

and

10. a compound according to any one of the preceding claims, selected from:

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid methylamide;

1 ' - [4- (cyclohexanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

acetic acid 4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl ester;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-hydroxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

acetic acid 2- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl ester;

1 ' - [4- [ (3-chloro-4-fluoro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 5-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (5-chloro-2-fluoro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-1-carbonyl-3-cyano) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-hydroxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 4-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 4-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 5-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2, 3, 4-trifluoro-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1-oxy-pyridine-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (6-chloro-pyridine-3-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (3-benzyl-2-methylsulfanyl-3H-imidazole-4-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-oxo-2-phenyl-4H-chromene-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- (cyclopropanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- (cyclopentanecarbonyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-methylamino-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

n- [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -N-methyl-o-carbamoylbenzoic acid;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (4-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (biphenyl-4-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3, 3-diphenyl-propionyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - (3- (3, 4-dichloro-phenyl) -4- { [3- (4-hydroxy-phenyl) -propionyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1-methyl-1H-pyrrole-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (furan-2-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (2-biphenyl-4-yl-acetyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- { [3- (4-chloro-phenyl) -acryloyl ] -methyl-amino } -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1H-pyrrole-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (thiophene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (thiophene-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (1H-indole-3-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-1H-indol-3-yl-acetyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (1H-indole-5-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyrazine-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (pyridine-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-oxo-4H-chromene-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-sulfamoyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (4-chloro-3-sulfamoyl-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-1H-imidazol-4-yl-acetyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-2-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-3-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-pyridin-4-yl-acetyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (1-acetyl-piperidine-4-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (tetrahydro-pyran-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

(4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -phenyl) -carbamic acid tert-butyl ester;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3- { trifluoromethyl-methoxy } -benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - (3- (3, 4-dichloro-phenyl) -4- { [2- (2- (2, 4-bis { trifluoromethyl } -phenyl) -acetyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - (3- (3, 4-dichloro-phenyl) -4- { [2- (2, 6-dihydroxy-pyrimidin-4-yl) -acetyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

4- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -piperidine-1-carboxylic acid tert-butyl ester;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (1H-imidazole-4-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

(1- { [2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamoyl } -2-phenyl-ethyl) -carbamic acid tert-butyl ester;

[2- (3, 4-dichloro-phenyl) -4- (4 ' -dimethylcarbamoyl- [1, 4 ' ] bipiperidinyl-1 ' -yl) -butyl ] -methyl-carbamic acid tert-butyl ester;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (furazan-3-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 2-difluoro-benzo [1, 3] dioxol-5-carbonyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (1H-pyrrole-3-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - (3- (3, 4-dichloro-phenyl) -4- { [3- (4-fluoro-phenyl) -5-methyl-isoxazole-4-carbonyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - (3- (3, 4-dichloro-phenyl) -4- { [5- (4-methoxy-phenyl) -oxazole-4-carbonyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (5-methyl-1-phenyl-1H- [1, 2, 3] triazole-4-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (benzofuran-5-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (5-methyl-benzo [ b ] thiophenyl-2-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (3, 5-bis-trifluoromethyl-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (2-bromo-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [3- (3, 4-dichloro-phenyl) -4- (methyl-pentafluorobenzoyl-amino) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 6-difluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (2, 4-dichloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (2, 6-dichloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-trifluoromethyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-methyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3-fluoro-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (3-chloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (3, 4-dichloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (3-methoxy-benzoyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (3-trifluoromethyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (4-chloro-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (4-trifluoromethyl-benzoyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ (2, 2-dimethyl-propionyl) -methyl-amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [3- (3, 4-dichloro-phenyl) -4- (methyl-phenylacetyl-amino) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (2-phenyl-cyclopropanecarbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (4-cyano-benzoyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - {3- (3, 4-dichloro-phenyl) -4- [ methyl- (naphthalene-1-carbonyl) -amino ] -butyl } - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- (benzoyl-methyl-amino) -3-phenyl-butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid ethyl-methyl-amide;

n- {2- (3, 4-dichloro-phenyl) -4- [4- (1-dimethylcarbamoyl-cyclohexyl) -piperazin-1-yl ] -butyl } -N-methyl-benzamide;

1 '- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4' ] bipiperidinyl-2-carboxylic acid dimethylamide;

1- [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide;

1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid dimethylamide;

n- [4- [4- (cyclopropylmethyl-propionyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide;

n- {2- (3, 4-dichloro-phenyl) -4- [4- (isopropyl-propionyl-amino) -piperidin-1-yl ] -butyl } -N-methyl-benzamide;

n- {2- (3, 4-dichloro-phenyl) -4- [4- (phenyl-propionyl-amino) -piperidin-1-yl ] -butyl } -N-methyl-benzamide;

n- [4- [4- (butyl-propionyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide;

n- [4- [4- (butyl-cyclopropanecarbonyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide;

n- [4- [4- (butyl-cyclohexanecarbonyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide;

n- [4- [4- (benzoyl-butyl-amino) -piperidin-1-yl ] -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide;

n- (2- (3, 4-dichloro-phenyl) -4- {4- [ (4-methoxy-butyl) -propionyl-amino ] -piperidin-1-yl ] -butyl) -N-methyl-benzamide;

n- [4- {4- [ cyclopropanecarbonyl- (4-methoxy-butyl) -amino ] -piperidin-1-yl } -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide;

n- [4- {4- [ cyclohexanecarbonyl- (4-methoxy-butyl) -amino ] -piperidin-1-yl } -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide;

n- [4- {4- [ benzoyl- (4-methoxy-butyl) -amino ] -piperidin-1-yl } -2- (3, 4-dichloro-phenyl) -butyl ] -N-methyl-benzamide;

n- [4- {4- [ cyclohexyl (propionyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide;

n- [4- {4- [ cyclohexyl (cyclopropylcarbonyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide;

n- [4- {4- [ cyclohexyl (cyclohexylcarbonyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide;

n- [4- {4- [ benzoyl (cyclohexyl) -amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide;

n- [2- (3, 4-dichlorophenyl) -4- {4- [ (1-methylpiperidin-4-yl) (propionyl) amino ] piperidin-1-yl } butyl ] -N-methylbenzamide;

n- [4- {4- [ (cyclopropylcarbonyl) (1-methylpiperidin-4-yl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide;

n- [4- {4- [ (cyclohexylcarbonyl) (1-methylpiperidin-4-yl) amino ] piperidin-1-yl } -2- (3, 4-dichlorophenyl) butyl ] -N-methylbenzamide;

n- {1- [4- [ benzoyl (methyl) amino ] -3- (3, 4-dichlorophenyl) butyl ] piperidin-4-yl } -N- (1-methylpiperidin-4-yl) benzamide;

n- {2- (3, 4-dichloro-phenyl) -4- [4 ' - (pyrrolidine-1-carbonyl) - [1, 4 ' ] bipiperidinyl-1 ' -yl ] -butyl } -N-methyl-benzamide;

1- [4- [ (3-cyano-naphthalene-1-carbonyl) -methyl-amino ] -3- (3, 4-dichloro-phenyl) -butyl ] -4- (2-oxo-pyrrolidin-1-yl) -piperidine-4-carboxylic acid dimethyl-amide;

3-cyano-naphthalene-1-carboxylic acid {2- (3, 4-dichloro-phenyl) -4- [4 ' - (piperidine-1-carbonyl) - [1, 4 ' ] bipiperidinyl-1 ' -yl ] -butyl } -methyl-amide;

1 ' - [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dipropylamide;

1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-morpholin-4-yl-piperidine-4-carboxylic acid dimethylamide;

1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid isopropyl-methyl-amide;

n- {2- (3, 4-dichloro-piperidine) -4- [4- (piperidine-1-carbonyl) -4-pyrrolidin-1-yl-piperidin-1-yl ] -butyl } -N-methyl-benzamide;

1- [4- (benzoyl-methyl-amino) -3- (3, 4-dichloro-phenyl) -butyl ] -4-pyrrolidin-1-yl-piperidine-4-carboxylic acid diethylamide;

n- {2- (3, 4-dichloro-phenyl) -4- [4- (morpholine-4-carbonyl) -4-pyrrolidin-1-yl-morpholin-1-yl ] -butyl } -N-methyl-benzamide;

and physiologically compatible acid addition salts of these compounds.

11. A compound according to claim 10 selected from:

1 ' - (3- (3, 4-dichloro-phenyl) -4- { [2- (2, 4-bis { trifluoromethyl } -phenyl) -acetyl ] -methyl-amino } -butyl) - [1, 4 ' ] bipiperidinyl-4 ' -carboxylic acid dimethylamide;

and physiologically compatible acid addition salts of these compounds.

12. A compound according to claim 10 selected from:

and physiologically compatible acid addition salts of these compounds.

13. A pharmaceutical composition comprising:

(a) a pharmacologically effective amount of a compound of formula I,

wherein

R1 is selected from the group consisting of: alkyl and cycloalkyl radicals;

x is selected from the group consisting of: CR6 and nitrogen;

m is selected from 0 or 1;

a physiologically acceptable acid addition salt thereof; and

(b) conventional pharmaceutically acceptable adjuvants and/or carriers.

14. A process for the preparation of a compound of the general formula I,

wherein

R1 is selected from the group consisting of: alkyl and cycloalkyl radicals;

x is selected from the group consisting of: CR6 and nitrogen;

m is selected from 0 or 1;

and the physiologically acceptable acid addition salts thereof;

it is characterized in that

(a) The compounds of formula I are prepared as follows: reacting a compound of formula II

With a compound of the formula III,

forming a compound of formula I, optionally converted into a physiologically compatible acid addition salt thereof; alternatively, the first and second electrodes may be,

(b) the compounds of formula I are prepared as follows: reacting a compound of formula III

With a compound of the general formula IV,

to obtain the compound of the general formula V,

then reacting the compound of formula VI with a compound of formula VII

Forming a compound of formula I, optionally converted into a physiologically compatible acid addition salt thereof;

(c) the compounds of formula I are prepared as follows: reacting a compound of formula X

Wherein Q is selected from the group consisting of: halogen, preferably bromine or iodine; and a methanesulfonyl group;

with a compound of the formula III,

15. Use of a compound according to any one of claims 1 to 12 for the preparation of a pharmaceutical formulation for the treatment and/or prevention of any pathology involving neurokinin a and/or nk.sub.2 receptor, or neurokinin B and/or nk.sub.3 receptor, or both neurokinin a and neurokinin B and/or both nk.sub.2 and nk.sub.3 receptors.

16. Use of a compound according to any one of claims 1 to 12, wherein R2 is a cyano-substituted naphthalene ring system, for the preparation of a pharmaceutical formulation for the treatment and/or prevention of any pathology involving substance P and/or the nk.sub.1 receptor, or neurokinin a and/or the nk.sub.2 receptor, or neurokinin B and/or the nk.sub.3 receptor, or a combination of any two or all three of substance P, neurokinin a and neurokinin B and/or the nk.sub.1, nk.sub.2 and nk.sub.3 receptors.

17. Use according to any one of claims 15 or 16 for the treatment and/or prevention of pathologies of the respiratory system, gastrointestinal system, urinary system, immune system and cardiovascular system and central nervous system as well as pain, migraine, inflammation, nausea and vomiting, and skin diseases.

18. Use according to any one of claims 15 to 17 for the treatment and/or prevention of respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, cough and rhinitis; skin diseases, in particular inflammatory skin reactions, allergic skin reactions and psoriasis; arthropathy diseases, particularly arthritis, vasculitis, and systemic lupus erythematosus; functional or inflammatory disorders of the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, crohn's disease, and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, the treatment of cancer, especially melanoma, glioma, small cell and large cell lung cancer, immune system disorders, bipolar disorder; migraine headache; pain, anxiety, depression, cognitive disorders, stress-related somatic disorders, psychoses, in particular schizophrenia, mania, schizoaffective disorders and panic disorders.

19. Method of treatment and/or prevention of any pathology involving neurokinin A and/or NK.sub.2 receptors, or neurokinin B and/or NK.sub.3 receptors, or both neurokinin A and neurokinin B and/or both NK.sub.2 and NK.sub.3 receptors in mammals and humans comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I,

wherein

R1 is selected from the group consisting of: alkyl and cycloalkyl radicals;

x is selected from the group consisting of: CR6 and nitrogen;

m is selected from 0 or 1;

20. A method of treatment or prevention of any pathology in mammals and humans, wherein said pathology involves substance P and/or NK.sub.1 receptor, or neurokinin A and/or NK.sub.2 receptor, or neurokinin B and/or NK.sub.3 receptor, or a combination of any two or all three of substance P, neurokinin A and neurokinin B and/or NK.sub.1, NK.sub.2 and NK.sub.3 receptors, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I,

wherein

R1 is selected from the group consisting of: alkyl and cycloalkyl radicals;

r2 is a cyano-substituted naphthalene ring system;

x is selected from the group consisting of: CR6 and nitrogen;

m is selected from 0 or 1;

21. A method of treatment or prophylaxis according to claim 18, wherein the following pathologies are involved: pathologies of the respiratory, gastrointestinal, urinary, immune and cardiovascular systems and the central nervous system as well as pain, migraine, inflammation, nausea and vomiting, and skin diseases.

22. A method of treatment or prophylaxis according to claim 18, wherein the following pathologies are involved: respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, cough and rhinitis; skin diseases, in particular inflammatory skin reactions, allergic skin reactions and psoriasis; arthropathy diseases, particularly arthritis, vasculitis, and systemic lupus erythematosus; functional or inflammatory disorders of the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, crohn's disease, and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, the treatment of cancer, especially melanoma, glioma, small cell and large cell lung cancer, immune system disorders, bipolar disorder; migraine headache; pain, anxiety, depression, cognitive disorders, stress-related somatic disorders, psychoses, in particular schizophrenia, mania, schizoaffective disorders and panic disorders.

Claims

wherein

R1 is selected from the group consisting of alkyl and cycloalkyl;

r2 is selected from the group consisting of alkyl, cycloalkyl, aryl, alkylenearyl, alkenylenearyl, heteroaryl, and heterocycle;

r3 and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, and carboxyalkyl;

x is selected from the group consisting of CR6 and nitrogen;

r5 is selected from the group consisting of optionally substituted (CO)_mNR9R10 substituted alkyl, optionally substituted (CO)_mNR9R10 substituted cycloalkyl, and NR7R 8;

r6 is selected from the group consisting of hydrogen, alkyl, Cycloalkyl and (CO)_mNR9R10；

R7 and R8 are independently selected from the group consisting of alkyl, cycloalkyl, aryl, alkylenearyl, alkyleneoxyalkyl, COalkyl, COaryl, or wherein R7 and R8 together form a 5-to 7-membered ring optionally containing additional heteroatoms, wherein such ring may be substituted with CONR9R10 and wherein no ring atoms in the 6-membered ring are substituted with carbonyl groups;

r9 and R10 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylenearyl, alkyleneoxyalkyl, or wherein R9 and R10 together form a 5-to 7-membered ring optionally containing additional heteroatoms;

m is selected from 0 or 1.

2. The compound according to claim 1, wherein R1 is methyl.

3. The compound according to any one of claims 1 or 2, wherein R3 and R4 are independently selected from the group consisting of hydrogen, fluoro, chloro, preferably hydrogen or chloro.

wherein each of R11 through R16 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, alkoxy, cyano, N (H) C (O) Oalkyl, aminoalkyl, dialkylamino, OCF₃、CF₃Carboxyalkyl, S (O)₂NH₂Phenyl, alkyl and cycloalkyl;

wherein R18 and R19 are each independently selected from the group consisting of hydrogen, cyano, and aryl;

wherein t is 0 or 1;

wherein each Q is independently selected from the group consisting of CR11 and N;

wherein Y is selected from the group consisting of CH, N, and NO;

wherein Z is selected from the group consisting of C-benzyl, NH, N-benzyl, N-alkyl, O and S;

wherein each V is independently selected from the group consisting of N and CR 17; and is

Wherein R17 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and alkylthio.

10. a compound according to any one of the preceding claims, selected from:

and physiologically compatible acid addition salts of these compounds.

11. A compound according to claim 10 selected from:

and physiologically compatible acid addition salts of these compounds.

12. A compound according to claim 10 selected from:

and physiologically compatible acid addition salts of these compounds.

13. A pharmaceutical composition comprising:

(a) a pharmacologically effective amount of a compound of formula I,

wherein

R1 is selected from the group consisting of alkyl and cycloalkyl;

x is selected from the group consisting of CR6 and nitrogen;

m is selected from 0 or 1;

a physiologically acceptable acid addition salt thereof; and

(b) conventional pharmaceutically acceptable adjuvants and/or carriers.

14. A process for the preparation of a compound of the general formula I,

wherein

R1 is selected from the group consisting of alkyl and cycloalkyl;

x is selected from the group consisting of CR6 and nitrogen;

r9 and R10 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, alkylenearyl, alkyleneoxyalkyl, or wherein R9 and R10 together form a 5-to 7-membered ring optionally containing additional heteroatoms:

m is selected from 0 or 1;

and the physiologically acceptable acid addition salts thereof;

it is characterized in that

(a) The compound of formula I is prepared by reacting a compound of formula II

With a compound of the formula III,

alternatively, the first and second electrodes may be,

(b) the compound of formula I is prepared by reacting a compound of formula III

With a compound of the general formula IV,

to obtain the compound of the general formula V,

then reacting the compound of formula VI with a compound of formula VII

(c) a compound of formula I is prepared by reacting a compound of formula X

Wherein Q is selected from the group consisting of halogen, preferably bromine or iodine; and a methanesulfonyl group;

with a compound of the formula III,

wherein

R1 is selected from the group consisting of alkyl and cycloalkyl;

x is selected from the group consisting of CR6 and nitrogen;

m is selected from 0 or 1;

wherein

R1 is selected from the group consisting of alkyl and cycloalkyl;

r2 is a cyano-substituted naphthalene ring system;

x is selected from the group consisting of CR6 and nitrogen;

m is selected from 0 or 1;

21. A method of treatment or prophylaxis according to claim 18, wherein pathologies of the respiratory system, of the gastrointestinal system, of the urinary system, of the immune system and of the cardiovascular system and of the central nervous system are involved, as well as pain, migraine, inflammation, nausea and vomiting, and skin diseases.

22. A method of treatment or prophylaxis according to claim 18, wherein the pathologies of respiratory diseases, in particular asthma, chronic obstructive pulmonary disease, chronic obstructive bronchitis, cough and rhinitis; skin diseases, in particular inflammatory skin reactions, allergic skin reactions and psoriasis; arthropathy diseases, particularly arthritis, vasculitis, and systemic lupus erythematosus; functional or inflammatory disorders of the gastrointestinal tract, in particular pseudomembranous colitis, gastritis, acute and chronic pancreatitis, ulcerative colitis, crohn's disease, and diarrhea; bladder diseases such as cystitis and interstitial cystitis; cardiovascular diseases such as hypertension, the treatment of cancer, especially melanoma, glioma, small cell and large cell lung cancer, immune system disorders, bipolar disorder; migraine headache; pain, anxiety, depression, cognitive disorders, stress-related somatic disorders, psychoses, in particular schizophrenia, mania, schizoaffective disorders and panic disorders.