DE4406885A1 - New acyl-(chloro-benzyl-oxo-tetra:hydro)-quinolinyl-aminoacid derivs. - Google Patents

Abstract

Amino acid derivs. of formula R1COAR2 (I) and their salts are new. R1 = vinyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, arylvinyl, heteroarylvinyl, aryloxyalkyl, aralkoxy, 3-8C cycloalkyl, (3-8C cycloalkyl)alkyl, bicycloheptyl or bicycloheptylalkyl (both opt. substd. by 1-3 Me), or adamantyl, adamantylalkyl, decahydronaphthyl, decahydronaphthylalkyl, tetrahydronaphthyl, tetrahydronaphthylalkyl, diphenylalkyl, di(arylalkyl)aminoalkyl or arylalkylaminoalkyl; aryl = phenyl (opt. substd. by 1-3 of halogen, trihalomethyl alkoxy, alkyl, OH, NO2, alkanoyl and CN) or naphthyl; heteroaryl = indolyl (opt. 1-substd. by alkyl or benzyl), pyridyl, pyrrolyl, imidazolyl or thienyl; alkyl and alkoxy have 1-3 C; A = an opt. protected D- or L-amino acid selected from Ala, Val, Leu, Ile, Ser, Thr, allothreonine, Cys, Met, Phe, Trp, N-formyl-Trp, Tyr, Pro, didehydroproline, hydroxyproline, azetidine-2-carboxylic acid, thioproline (Trp), aminoproline, pGlu, 2-aminobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, Glu, Asp, Gln, Asn, Lys, Arg, His, Orn, hydroxypiperidine-carboxylic acid, mercaptoproline, Tpr(O), Met(O), Tpr(O2) and Met(O2); R2 = a gp. of formula (II); R = F, Cl, Br or Et or OMe; m = 1-5.

Description

The invention relates to new amino acid derivatives general formula I.

and their pharmaceutically acceptable salts, processes to their manufacture and these connections containing pharmaceutical compositions. The Connections are valuable neurokinin (Tachykinin) antagonists.

In European patent applications EP 394 989 and EP 443 132 peptides with neurokinin antagonistic effect described.

In German patent application P 43 15 437.9 connections are described that differ from these Peptides differ significantly in the term R². The new compounds of the present invention are a selection from the general definition the connections from P 43 15 437.9.

The in this description and the claims for the abbreviations used correspond to the amino acids the usual three-letter code as z. B. in Europ. J. Biochem., 138, 9 (1984). The other abbreviations are explained below:

Boc = t-butoxycarbonyl
Bzl = benzyl
CDI = carbonyldiimidazole
DCCI = dicyclohexylcarbodiimide
DCH = dicyclohexylurea
HOBt = 1-hydroxybenztriazole
Hyp = (2S, 4R) -hydroxyproline
THF = tetrahydrofuran
TEA = triethylamine
TFA = trifluoroacetic acid
Z = benzyloxycarbonyl
Me = methyl
Ac = acetyl
Et = ethyl
DMF = dimethylformamide
DPPA = diphenylphosphoryl azide
PPA = polyphosphoric acid
RT = room temperature
TBTU = benzotriazolyl tetramethyl uronium tetrafluoroborate.

The term amino acid includes (if below Text is not expressly stated otherwise) natural and unnatural amino acids, both the D- as well as the L-form, especially α-amino acids, and their isomers.

If an amino acid is specified without a prefix (e.g. Orn) this stands for the L-shape of the Amino acid. The D shape is expressly stated.

The invention relates to new amino acid derivatives general formula I.

or their pharmaceutically acceptable salts, wherein
R¹ vinyl, aryl, heteroaryl, aralkyl, heteroaralkyl, arylvinyl, heteroarylvinyl, aryloxyalkyl, arylalkyloxy, (C₃- C₈) cycloalkyl, (C₃-C₈) cycloalkylalkyl, unsubstituted or substituted by 1-3 methyl groups, bicycloheptyl or bicycloheylyl, adamantylantamyl, adamantyl , Decalin alkyl, tetralin, tetralin alkyl, diphenylalkyl, di (arylalkyl) aminoalkyl or arylalkylaminoalkyl (in which aryl represents phenyl, 1-, 2- or 3-times substituted phenyl or naphthyl; the substituents of the phenyl group independently of one another are halogen, trihalomethyl, alkoxy, alkyl Are hydroxyl, nitro, alkylcarbonyl or cyano; heteroaryl is indolyl, indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl substituted by alkyl or benzyl in position 1; and the alkyl or alkoxy group contains 1 to 3 carbon atoms);
A D- or L-alanine (Ala), (D- or L-valine (Val), D- or L-leucine (Leu), D- or L-isoLeucine (Ile), D- or L-serine (Ser ), D- or L-threonine (Thr), D- or L-alloThreonine, D- or L-cysteine (Cys), D- or L-methionine (Met), D- or L-phenylalanine (Phe), D - or L-tryptophan (Trp), N-formyl protected Trp, D- or L-tyrosine (Tyr), D- or L-proline (Pro), D- or L-didehydroproline (ΔPro) such as 3, 4- Didehydroproline (Δ (3,4) -Pro), D- or L-hydroxyproline (Pro (OH)) such as 3-hydroxyproline (Pro (3OH)) and 4-hydroxyproline (Pro (4OH)), D- or L -Azetidine-2-carboxylic acid (Azt), D- or L-thioproline (Tpr), D- or L-aminoproline (Pro (NH₂)) such as 3-aminoproline (Pro (3NH₂)) and 4-aminoproline (Pro ( 4NH₂)), D- or L-pyroglutamic acid (pGlu), D- or L-2-aminoisobutyric acid (Aib), D- or L-2,3-diaminopropionic acid, D- or L-2,4-diaminobutyric acid, D- or L-glutamic acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine (Gln), D- or L-Asp aragin (Asn), D- or L-lysine (Lys), D- or L-arginine (Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L- Hydroxypiperidinecarboxylic acid such as 5-hydroxypiperidine-2-carboxylic acid, D- or L-mercaptoproline (Pro (SH)) such as 3-mercaptoproline (Pro (3SH)) and 4-mercaptoproline (Pro (4SH)), Tpr (O), Met (O), Tpr (O₂) or Met (O₂), and their geometric isomers, the hydroxyl and amino groups contained by customary protective groups (e.g. B. acyl, carbamoyl or aralkyl (especially benzyl) can be protected;
R² for an amine of the formula

stands in what
G is fluorine, chlorine, bromine, methyl, ethyl or methoxy;
m means 1, 2, 3, 4 or 5.

Compounds of the general formula I can Own acid groups, mainly Carboxyl groups, or phenolic hydroxyl groups, and / or basic groups such as B. Guanidino or Amino functions. Compounds of the general formula I can therefore either 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 for example maleic acid, fumaric acid, Citric acid, tartaric acid or acetic acid) or as Salts with pharmaceutically usable bases such as Alkali or alkaline earth metal hydroxides or Carbonates, zinc or ammonium hydroxides or organic amines such as B. diethylamine, Triethylamine, triethanolamine and the like. a. available.  

The chirality centers in the new Amino acid derivatives can each be R, S or R, S configuration.

Of the compounds of the formula I according to the invention, preference is given to those in which
R¹ vinyl, aryl, heteroaryl, aralkyl, heteroaralkyl, arylvinyl, heteroarylvinyl, aryloxyalkyl, arylalkyloxy, di (arylalkyl) aminoalkyl or arylalkylaminoalkyl (where aryl is phenyl, 1-, 2- or 3-times substituted phenyl or naphthyl; the substituents of the Phenyl group are independently halogen, trihalomethyl, alkoxy, alkyl or cyano; heteroaryl is indolyl, indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl substituted in position 1 by alkyl or benzyl; and the alkyl or alkoxy group contains 1 to 3 carbon atoms) means;
A D- or L-alanine (Ala), (D- or L-valine (Val), D- or L-leucine (Leu), D- or L-isoLeucine (Ile), D- or L-serine (Ser ), D- or L-threonine (Thr), D- or L-alloThreonine, D- or L-cysteine (Cys), D- or L-methionine (Met), D- or L-phenylalanine (Phe), D - or L-tryptophan (Trp), N-formyl protected Trp, D- or L-tyrosine (Tyr), D- or L-proline (Pro), D- or L-didehydroproline (ΔPro) such as 3,4- Didehydroproline (Δ (3,4) -Pro), D- or L-hydroxyproline (Pro (OH)) such as 3-hydroxyproline (Pro (30H)) and 4-hydroxyproline (Pro (40H)), D- or L -Azetidine-2-carboxylic acid (Azt), D- or L-thioproline (Tpr), D- or L-aminoproline (Pro (NH₂)) such as 3-aminoproline (Pro (3NH₂)) and 4-aminoproline (Pro ( 4NH₂)), D- or L-pyroglutamic acid (pGlu), D- or L-2-aminoisobutyric acid (Aib), D- or L-2,3-diaminopropionic acid, D- or L-2,4-diaminobutyric acid, D- or L-glutamic acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine (Gln), D- or L-Asp aragin (Asn), D- or L-lysine (Lys), D- or L-arginine (Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L- Hydroxypiperidinecarboxylic acid such as 5-hydroxypiperidine-2-carboxylic acid, D- or L-mercaptoproline (Pro (SH)) such as 3-mercaptoproline (Pro (3SH)) and 4-mercaptoproline (Pro (4SH)), Tpr (O), Met (O), Tpr (O₂) or Met (O₂), and their geometric isomers, the hydroxyl and amino groups contained by conventional protective groups (e.g. B. acyl, carbamoyl or aralkyl (especially benzyl) can be protected, especially those in which
R¹ aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxyalkyl, arylalkyloxy, di (arylalkyl) aminoalkyl (where aryl is phenyl or 1- or 2-fold substituted phenyl; the substituents of the phenyl group are independently halogen or alkoxy; heteroaryl for indolyl, in Position 1 is alkyl or benzyl-substituted indolyl or pyridyl; and the alkyl or alkoxy group contains 1 to 3 carbon atoms) means, in particular

preferably wherein R¹

is;
and / or in what
A is an amino acid which has no or a polar functional group in the side chain, such as OH, COOH, NH₂, guanidine, CONH₂, SH; especially
wherein the functional group in the side chain of A is OH, or
wherein A is Ser, Thr, Trp (For) or Tyr, or
wherein A is Pro or 4-hydroxyproline, preferably.
wherein A is 4-hydroxyproline with a 2-S configuration, in particular

is.

Of the compounds of formula I according to the invention are further preferred those

• a. where m is 1 or 2,
• b. wherein G is chlorine, bromine or ethyl, and
• c. where G is fluorine and m 5.

The amino acids given are preferably in S configuration before.

The compounds of the invention are valuable Neurokinin (tachykinin) antagonists who especially substance P antagonism, but also Neurokinin A or Neurokinin B antagonistic Possess properties. They are useful for Treatment of and for prevention Neurokinin-mediated diseases like Respiratory diseases, e.g. B. asthma, bronchitis, Rhinitis, cough or sputum as well as from inflammatory eye diseases such as Conjunctivitis, from inflammatory skin diseases like for example dermatitis and urticaria, by others Inflammatory diseases such as polyarthritis or Osteoarthritis, from gastrointestinal diseases like Irritant colon and vomiting, as well as painful conditions such as B. Migraines.

The invention therefore also relates to the use of Compounds according to the invention as remedies and pharmaceutical preparations containing these Connections included. Application is preferred on people. The application of the invention Connections can be intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, inhalative, transdermal, if necessary through Iontophoresis or enhancers known from the literature promoted, and orally.  

The connections become parenteral administration of formula I or their physiologically compatible Salts, possibly with the usual substances such as solubilizers, emulsifiers or others Excipients in solution, suspension or emulsion brought. As solvents such. B. in question: Water, physiological saline or Alcohols, e.g. B. ethanol, propanediol or glycerol, Sugar solutions such as glucose or mannitol solutions or a mixture of different ones Solvents.

In addition, the connections can be made by implants, e.g. B. from polylactide, polyglycolide or Polyhydroxybutyric acid or intranasal Preparations are applied.

The compounds of the invention can generally known methods of amino acid and Peptide chemistry can be made.

The components R¹-COOH, the amino acid H-A-OH and the amine H-R² linked together. It can optionally first with the carboxylic acid R¹-COOH a suitably protected form of H-A-OH coupled and after deprotection with the amine H-R² be condensed, or it may be the most suitable first protected amino acid H-A-OH reacted with H-R² and after deprotection of this product with R¹-COOH be coupled.

The base body of the amines H-R² can be obtained by methods known per se be, e.g. B. according to A.L. Davis et al., J. Med. Chem. 18, 752 (1975) and (T.J. McCord et al., J.  Heterocycl. Chem. 9, 119 (1972). This manufacture can by the reaction scheme shown below be summarized. The introduction of the Benzyl group R 'in a compound of general Formula XI is carried out by reaction with NaH and Hal R ′ (Hal: chlorine, bromine or iodine). This implementation can without or with the use of a protective group (Sch) on exocyclic N are carried out.

Suitable protective groups (Sch) are base stable Protecting groups such as the Boc group.  

example 1

The starting compound is (±) -3-amino-7-chloro 1,2,3,4-tetrahydroquinolin-2-one, its preparation is described in the literature (T.J McCord et al., J. Heterocycl. Chem. 9, 119 (1972); A.L. Davis et al., J. Med. Chem. 18, 752 (1975)).

11.1 g of this compound are mixed dissolved from 125 ml of dioxane and 125 ml of water, with (Boc) ₂O added and 2.9 g of soda with stirring registered. After stirring for an hour The precipitate that has precipitated becomes room temperature suction filtered, washed with water and dried. This gives (±) -3-Boc-amino-7-chloro-1,2,3,4- tetrahydroquinolin-2-one. 0.9 g of the obtained The compound is dissolved in 15 ml of DMF and 0.13 g NaH dispersion (60% in oil) added. After 0.5 Hours is a solution of 0.38 ml of 2-chlorine benzyl chloride, dissolved in 5 ml DMF, and 5 Stirred for hours at room temperature. Then moved one sucks with 200 ml ice-cold water obtained crystals, washed with water and it dries. This gives (±) -3-Boc-amino-1- (2- chlorobenzyl) -7-chloro-1,2,3,4-tetrahydroquinoline-2- on.  

1.2 g of the compound thus obtained are with 32.5 ml of 4N HCl in dioxane and 2.3 ml of anisole were added and stirred for 1.5 hours at room temperature. The Reaction mixture is made under reduced pressure concentrated, the residue stirred with 150 ml ether, the crystals obtained are filtered off with ether washed and dried. This gives (±) -3- Amino-1- (2-chlorobenzyl) -7-chloro-1,2,3,4- tetrahydroquinolin-2-one hydrochloride.

Coupling step:

0.88 g of the hydrochloride obtained are with 0.72 g (2S, 4R) -N- (1-methylindol-3-yl-carbonyl) -4- hydroxyproline, 40 ml DMF, 0.8 ml TEA and 0.84 g TBTU united, by adding TEA the pH to 8.5 set to 9 and 1.5 hours at room temperature touched. The reaction mixture is in 400 ml saturated NaHCO₃ solution stirred in the resulting precipitate is suctioned off with water, Washed ethyl acetate and ether and dried. Consequently connection 1 is approx. 1: 1 R / S- Obtained mixture of diastereomers.  

Summary of examples in analog Way can be made:

Table 1

Example 12

Pharmaceutical preparations Solution for injection

200 mg of active substance (active substance: compounds according to the invention, for example those of Example 1).
1.2 mg monopotassium dihydrogen phosphate = KH₂PO₄
0.2 mg disodium hydrogen phosphate = (buffer) NaH₂PO₄ · 2H₂O
94 mg sodium chloride (isotonans) or
520 mg glucose
4 mg albumin (protease protection)
qs sodium hydroxide solution
qs hydrochloric acid ad pH 6
ad 10 ml water for injections.

Solution for injection

200 mg of active substance (active substance: compounds according to the invention, for example those of Example 1).
94 mg sodium chloride or
520 mg glucose
4 mg albumin
qs sodium hydroxide solution
qs hydrochloric acid ad pH 9
ad 10 ml water for injections.

Lyophilisate

200 mg of active substance (active substance: compounds according to the invention, for example those of Example 1).
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 = Twen®80 (surfactant)
10 ml water for injections

Human dose of 67 kg: 1 to 500 mg.

Claims (15)

1. Amino acid derivative of the general formula I or its pharmaceutically acceptable salt, wherein
R¹ vinyl, aryl, heteroaryl, aralkyl, heteroaralkyl, arylvinyl, heteroarylvinyl, aryloxyalkyl, arylalkyloxy, (C₃- C₈) cycloalkyl, (C₃-C₈) cycloalkylalkyl, unsubstituted or substituted by 1-3 methyl groups, bicycloheptyl or bicycloheylyl, adamantylantamyl, adamantyl , Decalin alkyl, tetralin, tetralin alkyl, diphenylalkyl, di (arylalkyl) aminoalkyl or arylalkylaminoalkyl (in which aryl represents phenyl, 1-, 2- or 3-times substituted phenyl or naphthyl; the substituents of the phenyl group independently of one another are halogen, trihalomethyl, alkoxy, alkyl Are hydroxyl, nitro, alkylcarbonyl or cyano; heteroaryl is indolyl, indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl substituted by alkyl or benzyl in position 1; and the alkyl or alkoxy group contains 1 to 3 carbon atoms);
A D- or L-alanine (Ala), (D- or L-valine (Val), D- or L-leucine (Leu), D- or L-isoLeucine (Ile), D- or L-serine (Ser ), D- or L-threonine (Thr), D- or L-alloThreonine, D- or L-cysteine (Cys), D- or L-methionine (Met), D- or L-phenylalanine (Phe), D - or L-tryptophan (Trp), N-formyl protected Trp, D- or L-tyrosine (Tyr), D- or L-proline (Pro), D- or L-didehydroproline (ΔPro) such as 3,4- Didehydroproline (Δ (3,4) -Pro), D- or L-hydroxyproline (Pro (OH)) such as 3-hydroxyproline (Pro (30H)) and 4-hydroxyproline (Pro (40H)), D- or L -Azetidine-2-carboxylic acid (Azt), D- or L-thioproline (Tpr), D- or L-aminoproline (Pro (NH₂)) such as 3-aminoproline (Pro (3NH₂)) and 4-aminoproline (Pro ( 4NH₂)), D- or L-pyroglutamic acid (pGlu), D- or L-2-aminoisobutyric acid (Aib), D- or L-2,3-diaminopropionic acid, D- or L-2,4-diaminobutyric acid, D- or L-glutamic acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine (Gln), D- or L-Aspa ragin (Asn), D- or L-lysine (Lys), D- or L-arginine (Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L- Hydroxypiperidinecarboxylic acid such as 5-hydroxypiperidine-2-carboxylic acid, D- or L-mercaptoproline (Pro (SH)) such as 3-mercaptoproline (Pro (3SH)) and 4-mercaptoproline (Pro (4SH)), Tpr (O), Met (O), Tpr (O₂) or Met (O₂), and their geometric isomers, the hydroxyl and amino groups contained by conventional protective groups (e.g. B. acyl, carbamoyl or aralkyl (especially benzyl) can be protected;
R² for an amine of the formula stands in what
G is fluorine, chlorine, bromine, methyl, ethyl or methoxy;
m means 1, 2, 3, 4 or 5. 2. A compound according to claim 1, wherein
R¹ vinyl, aryl, heteroaryl, aralkyl, heteroaralkyl, arylvinyl, heteroarylvinyl, aryloxyalkyl, arylalkyloxy, di (arylalkyl) aminoalkyl or arylalkylaminoalkyl (where aryl is phenyl, 1-, 2- or 3-times substituted phenyl or naphthyl; the substituents of the Phenyl group are independently halogen, trihalomethyl, alkoxy, alkyl or cyano; heteroaryl is indolyl, indolyl, pyridyl, pyrrolyl, imidazolyl or thienyl substituted in position 1 by alkyl or benzyl; and the alkyl or alkoxy group contains 1 to 3 carbon atoms) means;
A D- or L-alanine (Ala), (D- or L-valine (Val), D- or L-leucine (Leu), D- or L-isoLeucine (Ile), D- or L-serine (Ser ), D- or L-threonine (Thr), D- or L-alloThreonine, D- or L-cysteine (Cys), D- or L-methionine (Met), D- or L-phenylalanine (Phe), D - or L-tryptophan (Trp), N-formyl protected Trp, D- or L-tyrosine (Tyr), D- or L-proline (Pro), D- or L-didehydroproline (ΔPro) such as 3,4- Didehydroproline (Δ (3,4) -Pro), D- or L-hydroxyproline (Pro (OH)) such as 3-hydroxyproline (Pro (30H)) and 4-hydroxyproline (Pro (40H)), D- or L -Azetidine-2-carboxylic acid (Azt), D- or L-thioproline (Tpr), D- or L-aminoproline (Pro (NH₂)) such as 3-aminoproline (Pro (3NH₂)) and 4-aminoproline (Pro ( 4NH₂)), D- or L-pyroglutamic acid (pGlu), D- or L-2-aminoisobutyric acid (Aib), D- or L-2,3-diaminopropionic acid, D- or L-2,4-diaminobutyric acid, D- or L-glutamic acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine (Gln), D- or L-Asp aragin (Asn), D- or L-lysine (Lys), D- or L-arginine (Arg), D- or L-histidine (His), D- or L-ornithine (Orn), D- or L- Hydroxypiperidinecarboxylic acid such as 5-hydroxypiperidine-2-carboxylic acid, D- or L-mercaptoproline (Pro (SH)) such as 3-mercaptoproline (Pro (3SH)) and 4-mercaptoproline (Pro (4SH)), Tpr (O), Met (O), Tpr (O₂) or Met (O₂), and their geometric isomers, the hydroxyl and amino groups contained by conventional protective groups (e.g. B. acyl, carbamoyl or aralkyl (especially benzyl) can be protected. 3. A compound according to claim 1 or 2, wherein
R¹ aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxyalkyl, arylalkyloxy, di (arylalkyl) aminoalkyl (where aryl is phenyl or 1- or 2-fold substituted phenyl; the substituents of the phenyl group are independently halogen or alkoxy; heteroaryl for indolyl, in Position 1 is alkyl or benzyl-substituted indolyl or pyridyl; and the alkyl or alkoxy group contains 1 to 3 carbon atoms) means, in particular 4. A compound according to claim 3, wherein R¹ is. 5. Connection according to one of claims 1 to 4, where A is an amino acid that has no or one polar functional group in the side chain bears, such as OH, COOH, NH₂, guanidine, CONH₂, SH. 6. A compound according to claim 5, wherein the functional group in the side chain of A OH is. 7. Connection according to one of claims 1 to 5, where A is Ser, Thr, Trp (For) or Tyr. 8. Connection according to one of claims 1 to 5, where A is pro or 4-hydroxyproline. 9. A compound according to claim 8, wherein A is 4-hydroxyproline having a 2-S configuration, in particular is. 10. A compound according to any one of claims 1-9, wherein m 1 or 2. 11. A compound according to any one of claims 1-10, wherein G is chlorine, bromine or ethyl. 12. A compound according to any one of claims 1-9, wherein G Is fluorine and m 5. 13. A method of making a compound according to one of claims 1 to 12 or salts thereof, characterized in that according to known Methods step by step the respective Amino acids, carboxylic acids and amines condensed and the compound thus obtained in free form or isolated in the form of the desired salt. 14. Pharmaceutical preparation containing one A compound according to any one of claims 1 to 12. 15. Use of a connection according to one of the Claims 1 to 12 for therapy from and Prevention of neurokinin-mediated Diseases.