EP1086088A2

EP1086088A2 - Novel neurokinin antagonists, method for the production thereof and pharmaceutical compositions containing said compounds

Info

Publication number: EP1086088A2
Application number: EP99926368A
Authority: EP
Inventors: Franz Esser; Gerd Schnorrenberg; Horst Dollinger; Sven Lüttke; Birgit Jung; Georg Speck
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1998-05-30
Filing date: 1999-05-22
Publication date: 2001-03-28
Also published as: US20020147359A1; CA2333689A1; WO1999062893A3; DE19824470A1; WO1999062893A2; US6455700B1; US6277840B1; JP2002517386A; US20020133012A1; US20020010173A1; US6429328B2; US6103719A

Abstract

The invention relates to novel compounds of general formula (I) or the pharmaceutically acceptable salts thereof, wherein X = N-R3 or CH-R4, Y = CH¿2? or (CH2)2, Z = O or H2; and R?1, R2, R3, R4¿ and Ar have the meaning cited in the description. The invention also relates to the production and use thereof. The novel compounds are valuable neurokinin (tachykinin) antagonists.

Description

Novel neurokine antagonists, processes for their preparation and pharmaceutical compositions containing these compounds

The invention relates to new guanidine and amidine derivatives of the general formula I.

and their pharmaceutically acceptable salts, processes for their preparation and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.

The abbreviations used in this description and the claims are explained below:

Boc - t-butyloxycarbonyl

DC = thin layer chromatogram

DMF = dimethylformamide

EE = ethyl acetate

FAB-MS - Fast atom bombardment mass spectroscopy

RT = room temperature

TBTU = O-benzotriazolyl tetramethyluronium tetrafluoroborate

TEA - triethylamine

THF = tetrahydrofuran

A simplified representation is used to represent the formulas. All CH3 substituents are represented by a

For example, it shows the hyphen

For

or their pharmaceutically acceptable salts, wherein X is NR ³ or CH-R ⁴ , wherein

N - R ⁵

R —l '

\ NO . where R ⁵ , R ⁶ and R ⁷

.'- independently of one another H, alkyl, cycloalkyl, alkenyl, aryl,

Aralkyl, alkanoyl, benzoyl, heteroaryl, dialkylamino, dialkylaminoalkyl,

Trialkylammoniumalkyl,

Cyano, alkyloxycarbonyl, aralkyloxycarbonyl, OH, Oalkyl or OAryl, in which the alkyl groups contain 1 to 5 carbon atoms, the cycloalkyl groups

Contain 3 to 6 carbon atoms, the alkenyl groups contain 2 to 5 carbon atoms, aryl for phenyl, substituted by methyl or halogen (F, Cl, Br, J)

Phenyl or naphthyl; or R ⁵ and R ⁶ or R ⁶ and R ⁷ together the group - (CH2) 2 ^~ , - (CH2) 3 ^" '- (CH2) 4-

- form (CH ₂ ) 5 or - (CH ₂ ) 2 0 (CH ₂ ) 2;

NH or R ^{3 is} aryl;

and R ⁴ to R ⁷

are as defined above and

R ⁸ = H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6

Carbon atoms means or

R ⁷ + R ⁸ together form the group - (CH2) 2 ", - (CH2) 3-- - (CH2) 4-, - (CH2) 5" θder

- form (CH ₂ ) 2 0 (CH ₂ ) 2-;

or R is where R ^{5 is} as defined above;

Y represents CH ₂ or (CH ₂ ) 2;

Z represents 0 or H2;

Ar is unsubstituted or 1 to 5 times substituted phenyl, or unsubstituted or 1 or 2 times substituted naphthyl, [where the substituents of phenyl and naphthyl independently of one another are halogen (F, Cl, Br, J), OH, (C - C4) Aikyl, 0- (C -C ₄ ) alkyl, CF3, OCF ₃ or NR ⁹ R1 ° (where R ⁹ and R1 ° are independently H, methyl or acetyl)] or Ar by -OCH2O- or -0 Is (CH2) 2θ-substituted phenyl;

R ¹ phenyl (-C -C4) alkyl or phenyl (-C -C4) alkanoyl or

Naphthyl (C-) -C4) alkyl or naphthylacetyl means, wherein phenyl by

1 to 3 substituents can be substituted, where the substituents are independently halogen (F, Cl, Br, J),

(C ₁ -C) alkyl, 0- (-C-C ₄ ) alkyl, CF ₃ , OCF3 or NR ⁹ R ²⁰ (wherein R ⁹ and R20 are independently H, methyl or acetyl); and

R ² H, (C ₁ -C) alkyl, (C ₃ -C ₆ ) cycloalkyl, CH ₂ COOH, -CH ₂ C (0) NH ₂ ,

-OH or phenyl (-C-C4) alkyl means. The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P antagonism and neurokinin A or neurokinin B antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases.

Compounds of general formula I can have acid groups, mainly carboxyl groups, and / or basic groups such as e.g. Amino functions. Compounds of the general formula I can therefore be used as internal salts, as salts with pharmaceutically usable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid or organic acids (such as maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically usable acids Bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as Diethylamine, triethylamine, triethanolamine and others available.

The compounds according to the invention can be present as racemates, but they can also be obtained as pure enantiomers, ie in (R) or (S) form. Compounds which are present as racemates or as (S) form are preferred.

Test result for compound according to the invention: The receptor affinity for the NK-j receptor (substance

P receptor) is determined on human lymphoblastoma cells (IM-9) with cloned NK-] receptors, the displacement of ¹² 5j-labeled substance P being measured. The Kj values thus obtained show the effectiveness of the compounds.

Example No. Kj [nMol / L]

_ __

2 0.30

3 0.20

4 0.53

5 6.28

6 0.88

7 1.45

8 0.19

9 0.14

10 0.12 12 0.32

27 1.11

28 4.16

29 0.87

30 0.17

31 8.96

32 0.20

33 13.25

34 0.37

35 0.78

The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have both substance P antagonism and neurokinin A or neurokinin B antagonistic properties. They are useful for the treatment and prevention of neurokinin-mediated diseases: Treatment or prevention of inflammatory and allergic diseases of the respiratory tract, such as asthma, chronic bronchitis, hyper-reactive respiratory tract, emphysema, rhinitis, cough,

of the eyes, such as conjunctivitis and iritis,

the skin, such as dermatitis in contact eczema, urticaria, psoriasis, sunburn, insect bites, itching, sensitive or hypersensitive skin,

of the gastrointestinal tract, such as gastric and duodenal ulcers, ulcerative colitis. Crohn's Disease, Colon Irritable, M. Hirschsprung,

the joints, such as rheumatoid arthritis, reactive arthritis and Reiter's syndrome;

for the treatment of diseases of the central nervous system, such as dementia, Alzheimer's disease, schizophrenia, psychoses, depression, headache (e.g. migraine or tension headache), epilepsy; Parkinson's disease, stroke, treatment of herpes zoster and post-herpetic pain, tumors, collagenosis, urinary tract dysfunction, hemorrhoids, nausea and vomiting, e.g. through radiation or cytostatic therapy or movement and painful conditions of all kinds.

The invention therefore also relates to the use of the compounds according to the invention as medicinal products and pharmaceutical preparations which contain these compounds. Use in humans is preferred. The compounds according to the invention can be administered intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, if desired promoted by iontophoresis or enhancers known from the literature, and orally. For parenteral administration, the compounds of the formula I or their physiologically tolerable salts, possibly with the customary substances such as solubilizers, emulsifiers or other auxiliaries, are brought into solution, suspension or emulsion. Examples of possible solvents are water, physiological saline solutions or alcohols, for example Ethanol, propanediol or Glyceπn, sugar solutions such as glucose or mannitol solutions or a mixture of different solvents

In addition, the compounds can be applied by implants, for example made of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations

Preferred compounds of general formula 1 are those in which

X is NR ³ or CH-R ⁴ , wherein

3 ^N ~ ^R ~

\ NR ₆ , wherein R ⁵ , R ⁶ and R ⁷

Independently of one another H, alkyl, cycloalkyl, aryl, aralkyl, alkanoyl, benzoyl, dialkylamino, dialkylaminoalkyl, Tπalkylammoniumalkyl,

Cyano, alkyloxycarbonyl, aralkyloxycarbonyl, OH, Oalkyl or OAryl mean, in which the alkyl groups contain 1 to 4 carbon atoms, the cycloalkyl groups contain 3 to 6 carbon atoms, aryl represents phenyl or phenyl substituted by methyl or halogen (F, Cl, Br, J) , or R ⁵ and R ⁶ or R ⁶ and R ⁷ together form the group - (CH2) 2 ", - (CH2 - - (CH2 -, - (CH ₂ ) 5 -or - (CH ₂ ) 2 0 (CH ₂ ) 2 form,

or R ³

R ^{3 is} R ⁶ and R ⁴ , wherein R ⁵ to R ⁷

TR ⁷ ^N \ R ⁸

are as defined above and

R ⁸ = H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6

Carbon atoms means or

R ⁷ + R ⁸ together form the group - (CH2) 2 ", - (^ 2) 3- - (^ 2) 4-, - (CH2) 5 ^" θder

- form (CH ₂ ) 2 0 (CH ₂ ) 2-,

Y represents CH ₂ or (CH ₂ ) 2,

Z means 0 or H2,

Ar unsubstituted or 1- to 5-fold substituted phenyl [where the

Substituents of phenyl independently of one another halogen (F, Cl, Br, J) OH (C -C) alkyl, 0- (C -C ₄ ) alkyl, CF3, OCF3 or NR ⁹ R ^{1 0} (wherein R ⁹ and R ^{10 are} independently H, methyl or acetyl)] or Ar is phenyl substituted by -OCH2O- or -0 (CH2) 2θ;

R1 is phenyl (-C-C-4) alkyl or phenyl (C- _] -C4) alkanoyl, in which phenyl can be substituted by 1 to 3 substituents, in which the substituents independently of one another halogen (F, Cl, Br, J), ( C ₁ -C) alkyl, 0- (C -C) alkyl, CF ₃ , OCF3 or NR ^{1 9} R ²⁰ (wherein R ^{1 9} and R ^{20 are} independently H. methyl or acetyl); and

R ^{2 is} H, (C ₁ -C ₄ ) aikyl or (C ₃ -C ₆ ) cycloalkyl;

in particular those compounds in which X is NR ³ or CH-R ⁴ , in which

N -

- R is u

and R ⁵ to R ⁸ , Z, Ar, R1 and R ^{2 are} as defined above, and Y is CH2.

Of these compounds, preference is given to those in which Z is oxo and / or Ar is unsubstituted phenyl, in particular those in which Ar is phenyl mono- or disubstituted by halogen, preferably Ar is dichlorophenyl; and / or wherein R ^{1 is} substituted phenylacetyl (preferably 3,4-di-trifluoromethylphenyl acetyl) or in which R ^{1 is} substituted phenylethyl, in which the

Phenyl is substituted by 2 substituents which are independently halogen (F, Cl, Br, J), (C- | -C4) alkyl or CF3, in particular in which the substituents of phenyl CF3.

Are CH3 or F (preferably wherein the two substituents of phenyl are CF3); and / or wherein R ^{2 is} (C-) -C4) alkyl, preferably wherein R ^{2 is} methyl.

Compounds of formula I are preferred in which the group

R '

/

N.

V

is.

One aspect of the invention relates to compounds of the formula I in which X is the group CR ⁴ in which

R ⁴

R ⁵ R ⁶

-NN _χ

¥ ⁷ ^N \ R ⁸

is what R ⁵ , R ⁶ , R ⁷ and R ^{8 are} independently H, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; or

R ⁷ and R ⁸ together form the group (CH ₂ ) 2, (CH2) 3, (CH2) 4 or (CH2) s. Preferred are compounds in which R ⁵ and R ^{8 are} H and R ⁷ and R ⁸ together form the group (CH2) 2 or those in which R 1 and R ^{8 are} H and R ⁷ and R ^{8 are} cyclohexyl.

Another important aspect of the invention relates to compounds of the formula I in which X is the group NR ³ in which

N - R ^"

R

NO

1,

is what

R ⁵ and R ^{8 are} independently H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, phenyl, phenyl, benzyl or benzoyl substituted by methyl or halogen (F, Cl, Br, J), CN, alkyloxycarbonyl ( wherein the alkyl group contains 1 to 4 carbon atoms), benzyloxycarbonyl, alkoxy with 1 to 4 carbon atoms or dialkylamine

(wherein the alkyl groups contain 1 to 4 carbon atoms) R ^{7 is} H or alkyl of 1 to 4 carbon atoms; or R ⁵ and R ⁸ or R ⁸ and R ⁷ together form the group (CH2) 2, (CH2) 3. Form (CH2) 4 or (CH2) 5; or R ⁶ and R ⁷ together form the group - (CH) 2-0- (CH2) 2-. Of these compounds, preference is given to those in which a) R5 and R ⁸ independently of one another are H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, phenyl, phenyl substituted by methyl or halogen (F, Cl, Br, J), Are benzyl or benzoyl,

R ^{7 is} H or alkyl of 1 to 4 carbon atoms or

R ⁵ and R ⁸ or R ⁸ and R ⁷ together form the group

Form (Ch_2) 2, (CH2) 3, (CH2) 4 or (CH2) s, or R ⁶ and R ⁷ together form the group - (CH2) 2-0- (CH2) 2-,

b) R5 and R ^{8 are} independently H, alkyl having 1 to 4 carbon atoms, cyclohexyl, phenyl, phenyl substituted by methyl, benzyl or benzoyl,

R ^{7 is} H or methyl, or

R ⁵ and R ⁶ together form the group (CH2) 2 or R ⁸ and R ⁷ together form the group (CH2) s or - (CH) 2-0- (CH2) 2-,

c) R ^{5 is} H, alkyl having 1 to 4 carbon atoms, cyclohexyl, phenyl, benzyl or benzoyl substituted by methyl,

R ^{8 is} H, alkyl having 1 to 3 carbon atoms, cyclohexyl, phenyl, phenyl or benzyl substituted by methyl,

R ^{7 is} H or methyl, or

R ⁵ and R ⁸ together form the group - (CH2) 2- or R ⁸ and R ⁷ together form the group (CH2) 2-0- (CH2) 2-, d) R ⁸ and R ^{8 are} independently H, CH3, CH (CH3) 2, phenyl or benzyl, R ^{7 is} H or CH3, or R ⁸ and R ⁸ together form the group --CH2CH2- or R ⁸ and R ⁷ together form the group - (CH ₂ ) 2-0- (CH ₂ ) 2-.

Compounds of the general formula I in which X is the group are particularly preferred

NH

H ₂ NXN

NH

H

or

is. The following compounds are particularly preferred:

The compounds can be prepared in a manner known per se. Advantageous methods are shown and described in the following schemes. The compounds of the general formula

wherein

X denotes NR ³ , wherein

N - R ^'

R

N R is

can be prepared by reacting a compound of the general formula I, in which R ^{3 is} hydrogen, with the corresponding aminoiminomethanesulfonic acid, the corresponding carbodiimide or thiourea. This process is illustrated using methods A to C for compounds in which Y is CH2, Ar phenyl,

Z is oxo, R ^{"1 is} difluorophenylethyl and R ^{2 is} methyl. However, the process can be used analogously for all compounds of the formula I in which X is NR ³

Scheme 1 (Method A):

Method A:

Piperazine equipped with a protective group in the 1 position is reacted with 2-halogenophenylacetic acid ester to give N-protected piperazinylphenylacetic acid ester. This is saponified under suitable conditions, for example with sodium hydroxide solution, to give the corresponding carboxylic acid. This in turn is linked to an amine according to the invention, for example N-methyl-3,5-bis-trifluoromethylphenethylamine, by means of a suitable coupling reagent, such as TBTU. In the next step, the protective group is cleaved from the piperazine part of the molecule using a suitable cleaving reagent. In the last reaction step, the free piperazine-N is added Unsubstituted or substituted amino-iminomethanesulfonic acid (which is obtained, for example, by oxidation of the corresponding thiourea using H2O2) converted to the desired guanidine.

Compounds of the type of Examples 1-3 can advantageously be prepared by Method A.

Scheme 2 (Method B):

R ⁶ + + il _/ ^ 7

N = C = N (if R - alkyl, i = l,

R y 'if R = electrical pair, i = 0)

Method B:

The procedure is as for method A, except that in the last stage, instead of the substituted methanesulfonic acid, the reaction is carried out with carbodiimides. These are either N, N'disubstituted carbodiimides or N, N, N'-trisubstituted, which are then salt. for example as iodide. 2?

The compounds of the type of Examples 4 to 7 can advantageously be prepared by Method B.

Scheme 3 (Method C):

Method C:

The procedure is as in Method A, except that in the last step, instead of the substituted methanesulfonic acid, a substituted thiourea is reacted together with HgO.

Compounds of the type of Example 9 can advantageously be prepared by Method C.

The compound of the general formula

can be prepared by reacting the corresponding piperazine derivative or piperidine derivative with the corresponding amide. This method is illustrated using method D and analogous method E for compounds in which Y is CH2, Ar phenyl, Z oxo, Rl difluorophenylethyl and R ² methyl. However, the method can be used analogously for all compounds of the formula I in which X is NR ³ or CR ⁴ , especially for compounds in those.

NR ^*

R ³ -li is or

"' ^■

The reaction takes place in an inert solvent in the presence of a base.

Scheme 4 (Method D):

Method D:

Analogous to the last step in method A, piperazine protected in the 1 position is first reacted with unsubstituted or substituted aminoiminomethanesulfonic acid. If necessary, further substituents can be introduced into the resulting guanidine by alkylation or acylation. In the next step, the piperazine derivative with an unsubstituted piperazine-N is obtained by splitting off the protective group with a cleaving reagent.

The reaction partner for this piperazine derivative is obtained as shown in Scheme 4, right. (R) -mandelic acid is reacted with methanesulfonic acid halide to give (R) -2- (methanesulfonyloxy) acetic acid. This is now with a

Coupling reagent and the correspondingly substituted phenethylamine converted to the corresponding amide, or it is converted into the corresponding acid halide (e.g. with SOCI2 SO2CI2) and then with the appropriately substituted one

Phenethylamine converted into the corresponding amide. In the last step, the amide obtained in this way is reacted with the piperazine derivative described above, with the elimination of methanesulfonate, C-N formation occurs with simultaneous reversal of the chirality center. The reaction takes place in an indifferent solvent, e.g. DMF or acetonitrile in the presence of a base, e.g. TEA or N-methylmorpholine, at temperatures between 20 ° C and 120 ° C. The reaction time is between 0.5 h and 48 h.

Compounds of the type of Example 8 can advantageously be synthesized by Method D.

Scheme 5 (Method E):

The method is carried out analogously to method D. Compounds of the type of Example 36 can advantageously be prepared by Method E.

Examples

example 1

(R, S) -1 -Amιdιno-4- [2-phenylessιgsaure-N-methyl-N- (3,5-bιstπfluormethyl-phenyl-ethyl) -amιd] -pιperazιn, dihydrochloride

1, 09 g (R, S) -1- [2-phenylacetic acid-N-methyl-N- (3,5-bιstrιfluormethyl-phenylethyl) - amid] -pιperazιn (2 mmol) were with 5 ml of water, 5 ml of methanol , 1.1 g K2CO3

(8 mmol) and 0.5 g aminoiminomethanesulfonic acid (4 mmol) were added and the mixture was stirred at RT for 2 days. The reaction mixture was diluted with water and extracted several times with EA and ether. The organic phases were combined, dried with MgSO4 and evaporated to dryness. The solid residue was chromatographed on silica gel and the DC-uniform fractions obtained were combined and evaporated to dryness. The residue was dissolved in methanol, mixed with Etheπscher HCl, evaporated to dryness, stirred with ether, suction filtered and dried. 80 mg of the compound from Example 1 were thus obtained received (yield 7%)

Mp 128-138 ° C

FAB-MS (M + H) ⁺ = 516.4 Examples 2 and 3 were prepared in an analogous manner Example 2:

M.p .: 163-173 ° C FAB-MS: (M + H) ⁺ = 542.2.

Example 3:

Mp: 69-79 ° C

FAB-MS: (M + H) + = 530.2.

Example 4:

0.82 g of (R, S) -1- [2-phenylacetic acid-N-methyl-N- (3,5-bιstπfluormethyl-phenylethyl) - amid] -pιperazιn were with 20 ml CH2CI2, 0.5 ml TEA and 0.215 g N, N'-

Dnsopropylcarbodiimide was added and the reaction mixture was stirred at RT for 4 days. The mixture was then evaporated to dryness and the residue was chromatographed on silica gel. The TLC-uniform fractions were combined, concentrated, the residue was taken up in methanol, mixed with ethene HCl and again evaporated to dryness. The solid residue was evaporated stirred with ether, suction filtered and dried, 0.35 g of the compound from Example 4 being obtained as a racemate (yield 35%)

Mp 176-186 ° C (dec)

FAB-MS (M + H) ⁺ = 600.6

Examples 5 to 7 were prepared analogously to Example 4

Example 5

Mp 174-184 ° C (dec) FAB-MS (M + H) ⁺ = 600.6

Example 6:

Mp .: 145-158 [ _α ] 20 = 24.8 ° (DMSO) D

Example 7:

Mp .: 182-188 ° C (dec.) FAB-MS: (M + H) ⁺ = 680.3.

Example 8:

Preparation of 1 - (1-methylimidazolin-2-yl) piperazine: 1.86 Boc-piperazine was mixed with 25 ml of water, 25 ml of methanol, 2.77 g of K2CO3 and 1.5 g of imidazolin-2-sulfonic acid and stirred for 2 days at RT. After dilution with water, the mixture was extracted with EA and chromatographed on silica gel. This gave 0.8 g of 1 - (imidazolin-2-yl) -4-Boc-piperazine. 6.2 ml of DMF and 136 mg of NaH dispersion (60% strength) were added to this substance. After one hour, 0.214 ml of methyl iodide were added dropwise and the reaction mixture was left at RT for three days. Water was added, the mixture was extracted with EA and chromatographed on silica gel. In this way, 0.47 g of 1- (1-methylimidazolin-2-yl) -4-Boc-piperazine were obtained, which were treated with 5 ml of 4N HCl in dioxane at RT. After one hour, the mixture was concentrated, stirred with ether and concentrated to dryness in vacuo. Thus 0.38 g of 1 - (1-methylimidazolin-2-yl) piperazine, dihydrochloride was obtained as a solid substance (yield 15%).

0.73 g of (R) -mandelic acid-0-methanesulfonate-N-methyl-N- (3,5-bistrifluoromethylphenylethyl) -amide were mixed with 15 ml of DMF, 0.7 ml of TEA and 0.38 g

1- (1-Methylimidazolin-2-yl) piperazine, dihydrochloride are added and the mixture is stirred at 65 ° C. for 3 h. The reaction mixture was concentrated, the residue was first treated with NaHCO 3 solution and then extracted twice with EA. The organic

Phases were combined, concentrated under reduced pressure and the residue was chromatographed on silica gel. The product obtained in this way was dissolved in ether, washed with NaHCO 3, and evaporated to dryness with MgSO 4.

The residue was dissolved in methanol, excess ethereal HCl was added and the mixture was evaporated to dryness, giving 0.18 g of the compound of Example 8 (yield 19%).

Mp .: 115-125 ° C

FAB-MS: (M + H) ⁺ = 556.9. Example 9

0.31 g N, N'-dimethylthioohamstoff, 26 ml CH ₂ Cl2, 0.63 g Na ₂ S04, 1.25 g HgO, 0.77 g (S) -1 - [2-phenylacetic acid-N-methyl- N- (3,5-bιstπfluormethyl-phenylethyl) - amιd] -pιperazιn and 0.42 ml TEA were combined, stirred for 3 days at RT and then heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with water and EE treated. The separated organic phase was filtered and evaporated to dryness. The residue was chromatographed on silica gel. The eluate obtained was concentrated, dissolved in methanol, mixed with ethene HCl, evaporated to dryness again, the residue was washed with ether and dried. 0:15 g of compound Example 9 obtained as a white solid (yield 16%)

Mp 126-140 ° C

FAB-MS (M + H) ⁺ = 543.8

Example 10

Mp 131-141 ° C

[α] ²⁰ = 20 6 ° (DMSO) D

The following examples can be made by the methods described Example 11:

(+) - Enantiomer m.p .: 171-181 ° C

[α] 20 / D = 28.4 ° (DMSO).

Example 12:

MP: 240-245 ° C (dec.) FAB-MS: (M + H) ⁺ = 592.1.

Example 13:

Example 14

(+) - Enantιomeres FAB-MS (M + H) ⁺ = 584

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

Example 22:

Example 23:

Example 25:

Example 26

Example 27

Mp 124-128 FAB-MS (M + H) ⁺ = 648.2

Example 28

Mp 193-198 ° FAB-MS (M + H) ⁺ = 696.4

[α] ²⁰ = + 500 ° (DMSO) D Example 29:

Fp .: 146-149 ° [α] 20 = + 48.8 ° (DMSO)

D

Example 30:

Mp .: 90-100 ° [α] ²⁰ = + 23.6 ° (DMSO) D

Example 31:

Mp .: 170-180 ° FAB-MS: (M + H) ⁺ = 661.9 Example 32:

Mp .: 84-94 ° [α] ²⁰ = 20.4 ° (DMSO) D

Example 33:

Mp .: 169-179 ° [ _α ] 20 = 43.6 ° (DMSO) D

Example 34:

M.p .: 131 -141 '[α] ²⁰ = + 25.2 ° (DMSO) D Example 35:

Mp .: 146-148 ° FAB-MS: (M + H) ⁺ = 584, 586, 588

Example 36:

Mp .: 126-134 ° C.

3.8 g of 4-amino-1-benzylpiperidine (20 mmol) were dissolved together with 4.7 g of dicyclohexylcarbodiimide (23 mmol) in 80 ml of DMF and stirred at 80 ° C. for 12 hours. The solvent was evaporated in vacuo and the residue was flash chromatographed using ethyl acetate / methanol (1: 1) to give 5.4 g of 1-benzyl-4- (N ', N "-dicyclohexyl-guanidino) -piperidine (71% 5 g of this product (12.6 mmol) were dissolved in 60 ml of methanol and hydrogenated by means of 0.6 g of Pd-C at 2 bar H ₂ pressure. 4 g of 4- (N ', N "- dicyclohexyl -guanidino) -piperidine obtained (63%). 2.14 g of this product (7 mmol) were mixed with 2.9 g of (R) -2-methylsulfonyloxy-N-methyl-N- [2- (3,5-bistrifluoromethyl-ρhenyl) ethyl] phenylacetamide (6 mmol ), 60 ml DMF and 0.96 ml triethylamine combined and stirred at 65 ° C for 3 hours. The residue obtained after concentrating the crude product was chromatographed on silica gel with ethyl acetate / methanol (1: 1) as the eluent, after which 0.6 g of the desired substance were obtained.

Example 37:

Mp: 114-124 ° C. [Α] 20 / D = 41.4 ° (DMSO).

Pharmaceutical preparations

Initiation solution

200 mg active substance ^*

1.2 mg monopotassium dihydrogen phosphate = KH ₂ P0 ₄ )

0.2 mg dinate hydrogen phosphate =) (buffer)

NaH ₂ P0 2H ₂ 0)

94 mg Natπumchloπd) (isotonans) or)

520 mg glucose)

4 mg albumin (protease protection) q s sodium hydroxide solution) q s hydrochloric acid) ad pH 6 ad 10 ml water for injections

Release note

200 mg active substance ^*

94 mg of sodium chloride or

520 mg glucose

4 mg albumin q s sodium hydroxide solution) q s hydrochloric acid) ad pH 9 ad 10 ml water for initiation; purposes

Lvophilisate

200 mg active substance ^*

520 mg mannitol (isotonans / scaffold)

4 mg albumin Solvent 1 for lyophilisate 10 ml water for injections

Solvent 2 for Lyophilisate 20 mg Polysorbat®80 = Tween®80

(surfactant) 10 ml water for injections

* Active substance: according to the invention

Connection, e.g. one of Examples 1 to 35

Human dose of 67 kg: 1 to 500 mg

Claims

Claims:

1. Compound of the general formula

or their pharmaceutically acceptable salts, wherein

X is NR ³ or CH-R ⁴ , wherein

\ NR is _β , where R ⁵ , R ⁶ and R ⁷

/. R independently of one another H, alkyl, cycloalkyl, alkenyl, aryl,

Aralkyl, alkanoyl, benzoyl, heteroaryl, dialkylamino, dialkylaminoalkyl,

Trialkylammoniumalkyl,

Phenyl or naphthyl; or R ⁵ and R ⁶ or R ⁶ and R ⁷ together the group - (CH2) 2 ^~ _> - (CH2) 3 ^" '- (H2) 4 ^"

- form (CH ₂ ) 5- or - (CH ₂ ) 2 0 (CH ₂ ) 2;

R ^{5 is} R ⁶ and R ^{4 ~ N} _\ ^ ^N \, where R ⁵ to R ⁷

'\

are as defined above and

R ⁸ = H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6

Carbon atoms means or

R ⁷ + R ⁸ together form the group - (CH ^ -, - (^ 2) 3- - (^ 2) 4-, - (^ 2) 5- or

- form (CH ₂ ) 2 0 (CH ₂ ) 2-,

or R is as defined above,

Y represents CH2 or (CH2) 2,

Z represents 0 or H2;

Ar is unsubstituted or 1 to 5 times substituted phenyl, or unsubstituted or 1 or 2 times substituted naphthyl, [where the substituents of phenyl and naphthyl independently of one another are halogen (F, Cl Br, J), OH, (C ₁ - C ₄ ) alkyl, 0- (C ₁ -C) alkyl, CF3, OCF3 or NR ⁹ R ¹⁰ (in which R ⁹ and R ^{"10 are} independently H, methyl or acetyl)] or Ar by -OCH2O- or - 0 is (CH2) 2θ-substituted phenyl,

R ¹ phenyl (-C -C4) alkyl or phenyl (-C -C4) alkanoyl or

Naphthyl (-C -C4) alkyl or naphthylacetyl means, wherein phenyl through

(C ₁ -C ₄ ) alkyl, 0- (C ₁ -C) alkyl, CF3, OCF3 or NR1 ⁹ R ²⁰ (where R ¹⁹ and R ^{20 are} independently H, methyl or acetyl), and

R ² H, (C ₁ -C 4) alkyl, (C ₃ -C ₆ ) cycloalkyl, CH ₂ COOH, -CH ₂ C (0) NH ₂ ,

-OH or phenyl (-C-C4) alkyl means

2. A compound according to claim 1, wherein

X denotes NR ³ or CH-R ⁴ , wherein - R ⁵ ^R \ N, R is where R ⁵ , R ⁶ and R ⁷

/ -

R independently of one another H, alkyl, cycloalkyl, aryl,

Aralkyl, alkanoyl. Benzoyl, dialkylamino, dialkylaminoalkyl,

T alkylammoniumalkyl,

Cyano, alkyloxycarbonyl. Aralkyloxycarbonyl, OH, Oalkyl or OAryl, in which the alkyl groups contain 1 to 4 carbon atoms, the cycloalkyl groups

Contain 3 to 6 carbon atoms, aryl for phenyl or by methyl or

Halogen (F, Cl. Br, J) substituted phenyl; or R5 and R ⁶ or R ⁶ and R ⁷ together the group - (CH2) 2 ^~ , - (CH2) 3 ^_ '- (CH2) 4-

- form (CH ₂ ) 5- or - (CH ₂ ) 2 0 (CH ₂ ) 2;

NH or R ³

Is aryl;

R = R ⁶ and R ^_N _\ / ^N _\ , where R ⁵ to R ⁷

¥ R ⁷ \

R ⁸

are as defined above and

R ⁸ = H, alkyl with 1 to 5 carbon atoms or cycloalkyl with 3 to 6

Carbon atoms means or

R ⁷ + R ⁸ together form the group - (CH _) _ :, - (^ 2) 3-. - (^ 2) 4-, - (CH2) 5 "θder

- form (CH ₂ ) 2 0 (CH ₂ ) 2-;

Y represents CH ₂ or (CH2) 2;

Z represents 0 or H2;

Ar unsubstituted or 1- to 5-fold substituted phenyl [where the

Substituents of phenyl independently of one another halogen (F, Cl, Br, J), OH, (C -C) alkyl, 0- (C ₁ -C) alkyl, CF3, OCF3 or NR ⁹ R ¹⁰ (wherein

R ⁹ and R1 ° are independently H, methyl or acetyl)] or Ar is phenyl substituted by -OCH2O- or -0 (CH2) 2θ;

R ¹ is phenyl (Cι--C 4) alkyl or phenyl (C- _| -C4) alkanoyl, wherein phenyl may be substituted by 1 to 3 substituents, wherein the substituents are independently halogen (F, Cl, Br, J), (C ₁ -C ₄ ) alkyl, 0- (-C-C-4) alkyl, CF ₃ , OCF3 or NR ^{1 9} R ²⁰ (wherein R ¹⁹ and R ^{20 are} independently H, methyl or acetyl); and

R ^{2 is} H, (C ₁ -C ₄ ) alkyl or (C ₃ -C ₆ ) cydoalkyl.

3. A compound according to claim 1 or 2 wherein

N- R ³ or CH -R ⁴ means, wherein

NO ⁵

3 rows

NR ⁶ is

/.

R

and R ⁵ to R ⁸ Z Ar, R ^ and R ^{2 are} as defined in claim 1 or 2, and Y is CH ₂

4 A compound according to any one of claims 1 to 3, wherein Z is oxo

5 A compound according to any one of claims 1 to 4, wherein Ar is unsubstituted phenyl

6 A compound according to any one of claims 1 to 4, wherein Ar is phenyl mono- or disubstituted by haloagen

7 A compound according to claim 6, wherein Ar is dichlorophenyl

8 A compound according to any one of claims 1 to 7, wherein R ^{1 is} substituted phenylacetyl

9 A compound according to claim 8, wherein R1 is 3,4-dι-Tπfluormethylphenyl-acetyl

10 A compound according to any one of claims 1 to 7, wherein R1 is substituted phenylethyl, wherein the phenyl is substituted by 2 substituents which are independently halogen (F, Cl Br, J), (-C-C-4) alkyl or CF3

11 A compound according to claim 10, wherein the substituents of the phenyl are CF3 CH3 or F.

12 A compound according to claim 11, wherein the two substituents of phenyl are CF3

13 A compound according to any one of claims 1 to 12, wherein R ^{2 is} (C <| -C4) alkyl

14 A compound according to claim 13 wherein R ^{2 is} methyl

15. A compound according to any one of claims 1 to 7 and 10 to 14, wherein the group

R '

/

N

V

is.

16. A compound according to any one of claims 1 to 15, wherein X is CR ⁴ , wherein

R ⁴

is what

R ⁵ , R ⁶ , R ⁷ and R ^{8 are} independently H, alkyl of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; or R ⁷ and R ⁸ together form the group (CH2) 2. Form (^ 2) 3, (CH2) 4 or (CH2) 5.

17. A compound according to claim 16, wherein R ⁵ and R ^{6 are} H and R ⁷ and R ⁸ together form the group (CH2) 2.

18. A compound according to claim 16, wherein R ⁵ and R ^{6 are} H and R ⁷ and R ^{8 are} cyclohexyl.

^{1 9} - Compound according to any one of claims 1 to 15, wherein X is the group NR ³ , wherein

/ _7th

R

is what

R5 and ^R6 are independently H, alkyl having 1 to 4 carbon atoms, cycloalkyl substituted with 3 to 6 carbon atoms, phenyl, with methyl or halogen (F, Cl. Br, I) phenyl, benzyl or benzoyl, CN, alkyloxycarbonyl (wherein the alkyl group contains 1 to 4 carbon atoms), benzyloxycarbonyl, alkoxy with 1 to 4 carbon atoms or dialkylamine

(wherein the alkyl groups contain 1 to 4 carbon atoms) R ^{7 is} H or alkyl of 1 to 4 carbon atoms; or R ⁵ and R ⁶ or R ⁶ and R ⁷ together form the group (CH.2) 2. Form (CH-2) 3, (CH2) 4 or (CH2) 5; or

R ⁶ and R ⁷ together form the group - (CH) 2-0- (CH2) 2 ^_ .

20. The compound of claim 19, wherein

R ⁵ and R ^{8 are} independently H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, phenyl, benzyl or benzoyl substituted by methyl or halogen (F, Cl, Br, J); R ^{7 is} H or alkyl of 1 to 4 carbon atoms; or R ⁵ and R ⁸ or R ⁸ and R ⁷ together form the group,

Form (CH2) 2, (CH_2) 3, (CH2) 4 or (CH2) s; or R ⁶ and R ⁷ together form the group - (CH2) 2-0- (CH2) 2-.

21. The compound of claim 20, wherein

R ⁵ and R ^{8 are} independently H, alkyl of 1 to 4 carbon atoms, cyclohexyl, phenyl, methyl-substituted phenyl, benzyl or benzoyl;

R ^{7 is} H or methyl; or

R ⁵ and R ⁸ together form the group (CH2) 2 or R ⁸ and R ⁷ together form the group (CH2) s or - (CH) 2 ~ 0- (CH2) 2-.

22. The compound of claim 21, wherein

R ^{5 is} H, alkyl of 1 to 4 carbon atoms, cyclohexyl, phenyl substituted by methyl, benzyl or benzoyl;

R ^{8 is} H, alkyl of 1 to 3 carbon atoms, cyclohexyl, phenyl, methyl substituted phenyl or benzyl;

R ^{7 is} H or methyl; or

R ⁵ and R ⁸ together form the group - (CH2) 2- or R ⁶ and R ⁷ together form the group (CH2) 2-0- (CH2) 2-.

23. The compound of claim 22, wherein

R ⁵ and R ^{8 are} independently H, CH3, CH (CH3) 2, phenyl or benzyl, R ^{7 is} H or CH3, or R ⁵ and R ⁸ together form the group -CH2CH2- or R ⁸ and R ⁷ together form the Form group - (CH2) 2-0- (CH2) 2-.

24. A compound according to claim 19, wherein X is the group

NH N Λ N

H

or

is.

5. A compound according to claim 1

33

or

6. A process for the preparation of a compound of general formula I according to any one of claims 1 to 25, characterized in that

a) an amide of the general formula

in an inert solvent in the presence of a base with a piperidine or piperazine of the general formula

is implemented; or b) for the preparation of a compound of general formula I, wherein

X denotes NR ³ , wherein

a compound of the general formula I, in which R ^{3 is} hydrogen, is reacted with the corresponding aminoiminomethanesulfonic acid, the corresponding carbodiimide or thiourea and the compound thus obtained is isolated in free form or in the form of a salt.

27. The method according to claim 26, characterized in that for the preparation of a compound of general formula I, wherein

X denotes NR ³ , wherein

-, N - R ⁵ ^{R "} ^ - R ^{6 ιst} - _! '

a compound of the general formula I, in which R ^{3 is} hydrogen, is reacted with the corresponding aminoiminomethanesulfonic acid, the corresponding carbodiimide or thiourea.

28. The method according to claim 26, characterized in that

for the preparation of a compound of general formula I, wherein

X denotes NR ³ , wherein

Λ

an amide of the general formula

is reacted with the corresponding piperazine.

29. The method according to claim 26, characterized in that for the preparation of a compound of general formula I, wherein X CR ⁴ means where

an amide of the general formula

is reacted with the corresponding piperidine.

30. A pharmaceutical preparation containing a compound according to any one of claims 1 to 25 and pharmaceutically acceptable carriers and excipients.

31. Use of a compound according to any one of claims 1 to 25 for the manufacture of a pharmaceutical preparation for the therapy of and for the prevention of neurokinin-mediated diseases.