WO2000014109A1

WO2000014109A1 - Basic products having antagonistic activity on the nk-1 receptor and their use in pharmaceutical compositions

Info

Publication number: WO2000014109A1
Application number: PCT/EP1999/006541
Authority: WO
Inventors: Karsten Gröger; Alessandro Sisto
Original assignee: Menarini Ricerche S.P.A.
Priority date: 1998-09-08
Filing date: 1999-09-06
Publication date: 2000-03-16
Also published as: ITFI980201A0; IT1304898B1; AU5745799A; ITFI980201A1

Abstract

Compounds of formula (I) presenting an aliphatic or aromatic amino group are described. The compounds are useful in the treatment of pathologies wherein the Substance P receptor plays a role and in particular for the treatment of inflammations of respiratory tract, as asthma and rhinitis, in the treatment of emesis induced by administration of chemiotherapics and in the treatment of tumour syndrome.

Description

BASIC PRODUCTS HAVING ANTAGONISTIC ACTIVITY ON THE NK-1 RECEPTOR AND THEIR USE IN PHARMACEUTICAL COMPOSITIONS Field of the invention The present invention refers to antagonists of the NK-1 receptor having basic characteristics and to their use in pharmaceutical compositions useful in the treatment of pathologies wherein the receptor of Substance P plays a role and in particular for the treatment of inflammation of the aerial ways, as asthma and rhinitis, of the emesis induced by the administration of chemiotherapics, and in the tumour syndromes. In particular the present invention refers to compounds presenting a basic amino group, aliphatic or aromatic, of general formula (I)

(I) wherein: n = 0,1 ,2,3 p = 0,1 ,2,3,4 R1 is: a) a basic moiety chosen in the group consisting of:

- amino possibly mono- or di-substituted with C^alkyl group or with an aromatic heterocycle such as triazole, pyridine, pirimidine;

- a basic aliphatic heterocycle chosen in the group consisting of: piperidine, piperazine, morpholine, quinuclidine, possibly substituted with C .₃ alkyl, phenyl, benzyl, C^aminoalkyl or with an aliphatic heterocycle chosen between piperidine and morpholine, such aliphatic heterocycle being possibly linked to the (CH₂)_nCONH through a group (CH₂)_q-X₂ wherein q is 1 , 2, 3, 4 and X₂ is a group - CONH- or -NHCO- - a basic, aromatic heterocycle, chosen in the group consisting of pyridine and quinoline possibly substituted with one or more alkyl groups containing up to 3 carbon atoms b) an aryl- or arylalkyl-radical wherein the aryl-moiety is chosen in a group consisting of: pyrrole, benzofuran, biphenyl, benzene, indole, naphthalene, imidazole, furan, thiophene, indane and wherein the aromatic moiety can be optionally substituted on the ring with one or more substituents chosen among: halogen, C^ alkyl optionally substituted with no more than three F, C^ oxyalkyl, possibly substituted with no more than three F, -NHR7, -N(R7)2, -CONHR7, - COR7, -COOR7, -R8COOR7.-OR8COOR7, -R8COR7, -R8CONHR7, -NHCOR7, - nitro, wherein R7 is hydrogen or C^ alkyl and R₈ is a C,^ alkyldiene linear o branched; R2 is a moiety of general formula:

^R _/X,

(CH₂)m

wherein m= 0,1 ,2,3, R6 is : a) a basic moiety chosen in the group consisting of : - amine possibly mono- or di-substituted with C1-3 alkyl o with an aromatic heterocycle such as triazole, pyridine, pirimidine;

- basic aliphatic heterocycle chosen in the group consisting of : piperidine, piperazine, morpholine, quinudidina, possibly substituted with C1-3 alkyl, phenyl, benzyl, C1-4 aminoalkyl or with an aliphatic heterocyle chosen among piperidine or morpholine; such aliphatic heterocycle being possibly linked to the (CH2)mX1-₉ through a group (CH2)q-X2- wherein q is 1 ,2,3,4 and X2 is a group CONH o NHCO.

- a basic, aromatic heterocycle chosen in the group consisting of pyridine and quinoline possibly substituted with one or more alkyl group containing up to 3 carbon atoms; b) an aryl- or aryl-alkyl radical wherein the aryl moiety is chosen in the group consisting of pyrrole, benzofuran, biphenyle, benzene, indole, naphthalene, imidazole, furan, thiophene, indane and wherein the aromatic moiety can be possibly substituted on the ring with one or more substituents chosen among: halogen, C^ alkyl possibly substituted with no more than three F, C^ oxyalkyl, possibly substituted with no more than three F atoms, -NHR7, -N(R7)2, -CONHR7, -COR7, -COOR7, -R8COOR7.-OR8COOR7, -R8COR7, -R8CONHR7, -NHCOR7, -nitro, wherein R7 is hydrogen or a C^ alkyl and Rs is a C^ linear or branched alkylidene, and Xι is -CONH- o NHCO-; R3 is chosen n the group:

- naphthyl-methyle, benzyl substituted with one or two halogen atoms, indol- methyl;

- R5 is H or meythyl; - R4 is an aryl or aryl-alkyl group with up to 15 carbon atoms wherein the aryl moiety is chosen in the group consisting of: pyridine, pyrrole, benzofuran, biphenyle, benzene, indole, naphthalene, imidazole, quinoline, furan, thiophene, indane and wherein the aromatic moiety can be possibly substituted on the ring with one or more substituents chosen among halogen, C_1-6 alkyl possibly substituted with up to three F atoms, C^ oxyalkyl, -NHR7, -N(R7)2, -CONHR7, - COR7, -COOR7, -R8COOR7,-ORδCOOR7, -R8COR7, -R8CONHR7, -NHCOR7, - NO2, wherein R7 is H or a C^ alkyl and Rβ is a linear or branched C_1-6 alkylidiene; with the proviso that - when RQ is a moiety as above defined R1 is an aryl or aryl-alkyl as above defined;

- when Re is an aryl or aryl-alkyl as above defined R1 is a basic moiety as above defined.

The presence of the amino-group gives to the compounds specific basic characteristics. The present invention refers also to the pharmaceutically acceptable salts of the compounds of formula (I) with organic or inorganic acids chosen in the group consisting of: hydrochloric, sulforic, phosphoric, hydrobromic, acetic, trifluoroacetic, oxalic, malonic, malic, succinic, tartaric, citric acid. The compounds of formula (I) having antagonistic activity on the receptors of tachykinins, are useful in the treatment of such pathologies where the tachykinins play a pathogen role, in particular arthritis, asthma, rhinitis, and more generally the inflamations of the respiratory tract, emesis caused by the administration of antitumourals, Huntington's disease, neuritis, neuralgia, hemicrania, hypertension, urinary incontinence, urticaria, symptoms indicating carcinoid syndrome, influenza and common cold, illnesses of the immune system. State of the art

Tachykinins are a family of at least three peptides known as Substance P, Neurokinin A (NKA) and Neurokinin B (NKB). The studies in the field of tachykinins antagonists, at the beginning based essentially on the single or multiple substitution of the aminoacids in the sequence of the peptide agonists of Substance P and the other tachykinins, resulted in the discovery of nonapeptides containing one or more D-tripthophane units (Regoli et al. Pharmacol 28,301 (1984). On the other side the problems deriving from the use of peptides having high molecular weight (multiple sites of enzymatic hydrolysis attack, low bioavailability, quick secretion from liver and kidneys) induced the researchers to look for the shortest peptide fragment capable of antagonistic action.

Tripeptides presenting the lateral chain of a natural basic aminoacid have also been described as tachykinins antagonists (EP 394989; J.Med. Chem. 1993, 36, 2266-2278).

Recently antagonists non containing natural aminoacids, and therefore non presenting the drawbacks of metabolic instability typical of the peptides and characterised by the presence of an aliphatic ring preferably 1 ,1 or 1 ,2 disubstituted cyclohexane directly linked to the backbone of the peptide or pseudopeptide structure have been described (WO 9413694, WO 9515311 , WO 9519966). Anyhow it is still necessary to make available other tachykinins antagonists having superior properties.

Detailed description of the invention

Surprisingly it was found, and this is an essential characteristic of the present invention, that compounds of formula (I), as above defined, having non-peptide structure and presenting an aliphatic or aromatic basic group are very efficient as tachykinin antagonists having better inhibiting action of the tachykinin/NK1 receptor binding, high stability and good solubility in water.

In particular, and surprisingly, when tested "in vivo" on guinea pigs for the inhibition of the broncospasm following agonist i.v. administration, the compounds are active both by intravenous as by oral administration, at a dosage lower than 1 μmoli/kg , while the compounds described in WO 9515311 and WO 9519966 have a lower affinity for the NK1 receptor, in the nanomolar range, and when tested "in vivo" according to the above said test show an ED50 higher than 1 μmoli/kg. An essential advantage of the presently claimed compounds is also their good solubility in water (> 10 mg /ml) while the compounds described in the state of the art show a solubility in water of 1-10 μg/ml.

More particularly the present application refers to compounds of formula (I):

(I) wherein R-| , R2, R3, R4, Rs, are as previously defined.

A preferred selection of compounds according to the present invention is represented by the compounds wherein:

R₂ is as initially defined and: R1 and R6 are: a basic moiety chosen in the group consisting of: o

- dimethylamina, amino-triazole,

- an aliphatic heterocycle chosen in the group consisting of: piperidine, morpholine, piperazine possibly substituted with methyl, aminoethyl, phenyl, benzyl or piperidine; or 3-(4-methyl-piperazin-1-yl)propyl-aminocarbonyl - pyridine

- a radical indol-3-yl;

R4 is an aryl-methyl group wherein the aryl is chosen in a group consisting of: benzene, naftalene, pyridine and indole and wherein the aromatic moiety can be possibly substituted on the ring with one or more substituents chosen in the group consisting of: halogen, C_1-6 alkyl possibly substituted with no more then three F atoms, C^ oxyalkyl. Possibly substituted with no more then three F atoms, - NHR7, -N(R7)2, -CONHR7, -COR7, -COOR7, -R8COOR7,-OR8COOR7, - R8COR7, -R8CONHR7, -NHCOR7, -NO2, wherein R7 is hydrogen or a C„ alkyl and R8 is a C^ linear or branched alkylidene; - R3, R5,m, n, p, X1 are as above defined with the proviso that:

- when R1 is a basic moiety, as above defined, R6 is indol-3-yl and vice-versa.

In the compounds according to the present application the C^ alkyl is preferably chosen in the group consisting of: methyl, ethyl, propyl, butyl; the C^oxyalkyl is preferably chosen in the group consisting of metoxy, ethoxy, propyloxy; the alkyl moiety of the aryl-alkyl group in R1 , R6 and R4 is preferably methyl or ethyl; C,^ linear or branched alkylidene is preferably chosen in the group consisting of: methylidene, ethylidene and propylidene; the definition halogen means chlorine, fluorine, bromine and iodine. A particular selection of the present invention are the compounds wherein: n = 0;

R₂ is as initially defined and:

Re is: a basic moiety chosen in the group consisting of: - dimethyiamine, 3-amino-[1 ,2,4]triazole

- an aliphatic heterocycle chosen in the group consisting of. 1 -piperidine, 4- morpholine, piperazine, 3-quinuclidine, 4-quinuclidine, 4-methyl-piperazine, 4- phenyl-piperazine, 4-benzylpiperazine, 4-aminoethyl-piperazine, 4-(1-piperidyl)- piperidine, 3-(4-methyl-piperazin-1 -yl)propyl-aminocarbonyl

-pyridine R, is indol-3-yl

R₃ is a group 2-naphthyl,3,4dichlorobenzyl, 4-bromobenzyl, 3-indolyl

R₄ is a methylaryl wherein the aryl moiety is chosen in the group consisting of: phenyl, 2-naphthyl, phenyl substituted with 4-CI, 3,4-diCI, 2,4-diCI, 4-Br, 4-I, 4-

CH₃, 4-CF₃, 3,5-diCF₃; - R_5> m, p, X, are as above defined.

Another preferred selection of compounds according to the invention is represented by the compounds wherein:

R₂ is as initially defined and: m = 0; X1 = CONH R6 is a radical indol-3-yl;

R1 is a basic moiety chosen in the group consisting of:

- dimethylamine, 3-amino-[1 ,2,4]triazole,

- an aliphatic heterocycle chosen in the group consisting of. 1 -piperidine, 4- morpholine, piperazine, 3-quinuclidine, 4-quinuclidine, 4-methyl-piperazine, 4- phenyl-piperazine, 4-benzylpiperazine, 4-aminoethyl-piperazine, 4-(1-piperidyl)- piperidine,

- pyridine

R3 is a group 2-naphthyl, 3,4-dichlorobenzyl, 4-bromobenzyl, 3-indolyl R4 is a methyl-aryl group wherein the aryl is chosen among: phenyl, 2-naphthyl, phenylsubstituted with 4-CI, 3,4-di-CI, 2,4-di-CI, 4-Br, 4-I, 4-CH3, 4-CF3, 3,5-di- CF3;

- R5, n, p are as above defined.

Considering the asymmetric centres of formula (I), the invention refers only to the isomers wherein the carbon atom bound to R3 has configuration S. The compounds according to the invention showed antagonistic activity on the action of Subtance P, Neurokinin A and Neurokinin B. Therefore they can be used as pharmaceutical products for the treatment or the prevention of those pathologies wherein Substance P, Neurokinin A and Neurokinin B act as neuromodulators. Examples of the above said pathologies are: diseases of the respiratory tract, as asthma and allergic rhinitis, ophthtalmic illnesses, as conjunctivitis, cutaneous illnesses as allergic and contact dermatitis and psoriasis, intestinal illnesses, as ulcerative colitis, Crohn's disease, emesis induced by administration of anti- tumoural medicaments. The present compounds can be used also in the treatment of tumours wherein the cells present a functionally expressed NK-1 receptor (astrocytomas, gliomas). The compounds of formula (I) are prepared according to the process described in the following Example 1. Example 1 Preparation of N^α(N^α(1 (H)indol-3-yl-carbonv0-L-Asparaqinvirβ-N-(2(morpholin-4- yl)ethyl^')l}L-3-r(3.4-dichloro)phenyllalanine-N-methyl-N-(4-bromobenzvπ amide. 1) To a solution of 3-indolyl carboxylic acid [I3C-OH] (1 ,1 g, 6,8 mmoles) in a mixture of 5 ml N,N-dimethyl-formamide (DMF) and 10 ml methylene dichloride (DCM), 1-hydroxybenzotriazole (HOBt) (1 ,1 g, 8,2 mmoles) and 1-ethyl-3-(3'- dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCI) (1 ,6 g, 8,3 mmoles) are added at room temperature and under vigorous stirring.

The mixture is stirred for 2 h at room temperature, thereafter the hydrochloride of α methyl ester of aspartic-β-t-butyl ester [HCI.H-Asp(OtBu)-OMe] (2 g, 8.3 mmoles) is added followed by addition drop by drop of diisopropylethylamine [DIPEA] up to pH 8. The solution is left under stirring for 24 h. After elimination of the solvent under reduced pressure, the residue was treated with ethyl acetate (5 ml) and extracted with an aqueous solution of NaHC03 5% (3 X 50ml), thereafter with a saturated aqueous solution of NaCI (3 x 50ml), with an aqueous solution of H2SO4 0,05 M (3 x 50 ml) and in the end again with the saturated solution of NaCI (3 x 50ml). The organic phase was anhydrified on Na2S04 and then dried giving 2 g (5.7 mmoles, yield 83% ) of the methyl ester of Nα(1 (H)indol-3-yl- carbonyl)-L-(β-tbutylester)-Aspartic acid [!3C-Asp(OtBu)-OMe] For the liquid chormatography under high pressure (HPLC) a column Phase Sep.

Spherisorb ODS-2 5m 46 x 250 mm was used with the following eluents:

A= 0,1 trifluoroacetic acid in acetonitrile:

B= 0,1 trifluoroacetic acid in water. Linear gradient from 20% A to 80% A in 25 min, isocratic at 80% A for 10 min flow 1 ml/min; UV-identification at 230 nm.

The HPLC analysis shows a single peak at tR= 5,3 min.

A solution of the previously obtained compound (2 g, 5,7 mmoles) in 15 ml methanole and 0.5 M NaOH up to pH 9 is stirred for 3 h at room temperature. The solution is extracted with EtOAc (15 ml x 3) and acidified up to pH 3 with HCI 0,1

N, maintaining the solution at 0°C and under vigorous stirring.

The product is isolated by extraction with ethyl acetate (20 ml) and washed with water (3 x15 ml) and a saturated solution of NaCI (3 x15 ml). The organic phase was anhydrified on Na2SO4 and dried giving 1.4 g (4,1 mmoles, yield 72% ) of β- t-butylester of N^α(1 (H)indol-3-yl-carbonyl)-L-aspartic acid [l3C-Asp(OtBu)-OH]. TLC (chloroform, methyl alcohol 80/20 v/v (CM))= 0,29 HPLC analysis according to step 1 shows a single peak at TR= 4,4 min. 3) To a solution of 4-bromobenzylamina (2 g, 9 mmoles) hydrochloride and tert- butyl-dicarbonate (4 g, 18 mmoles ) in 30 ml of 2-propanol an aqueous solution of NaOH is added, up to pH 10. The solution was left under stirring at room temperature for 4 h. The solvent was eliminated under reduced pressure and the residue collected with ethyl acetate (50 ml). The organic solution was washed with an aqueous solution of NaHCO3 5% (3 X 50ml), then with an aqueous solution saturated in NaCI (3 x 50ml), with an aqueous solution of H2SO4 0,05 M (3 x 50 ml) and finally again with the aqueous solution saturated in NaCI (3 x 50ml); the solution was anhydrified on Na2SO4 and dried. The desired products was isolated by precipitation with diethyl eter/n-hexane to give 1.5 g (4,6 mmoles, yield 52%), di-tert-butyl-N-(4-bromobenzyl)carbamate). The HPLC analysis according to the conditions described in step (1 ) shows a single peak at tR= 6,8 min. 4) To a solution of the compound obtained in step (3) (1 ,5 g, 4,6 mmoles) in tetrahydrofuran THF (20 ml), at 0° C under strong stirring and nitrogen current methyl iodide (2,9 ml, 46 mmoles) and sodium hydride (0,4 g of a suspension in mineral oil) are added. The solution is left under stirring at room temperature for 4 h. The reaction is interrupted by addition of ethyl acetate (40 ml) and water (40ml). The two phases are separated and the organic phase is extracted with an aqueous solution of NaHCO3 5% (3 X 30ml), thereafter with an aqueous solution saturated in NaCI (3 x 30ml), with an aqueous solution of H2SO4 0,05 M (3 x 30 ml) and finally again with the aqueous solution saturated in NaCI (3 x 30ml). The organic phase is anhydrified on Na2SO4 and dried giving 1 g of tert-butyl-N- Methyl-N-(4-bromobenzyl)carbamate) (3 mmoles; yield 65%). TLC(Chloroform, methyl alcohol 95/5 v/v)=0,85

The HPLC analysis according to the conditions given in step (1) shows a single peak at tR= 7,8 min. 5) A solution of the product obtained in step (4) (1 g, 3 mmoles) in 50 ml of ethyl acetate saturated with HCI (about 2N) is left under stirring at room temperature for 30 min. The solvent is eliminated under light nitrogen flow and the residue is resuspended several times with ethyl eter (4x30ml), thereafter the solvent is eliminated giving 0,800 mg of N-methyl-N-(4-bromobenzyl) amine hydrochloride (yield 96%).

TLC(Chloroform, methyl alcohol 95/5 v/v): Rf= 0,15;

The HPLC according to the conditions given in step (1 ) shows a single peak at tR=1 ,8 min.

6) To a solution of Nαtert-butyloxycarbonyl-L-3-(3,4-dichlorophenyl)alanine (0,23 g, 0,7 mmoles) in a mixture DMF/DCM (2 ml / 5ml) HOBt (0,11 g, 0,8 mmoles) and WSC.HCI (0,17 g, 0,9 mmoles) are added. The solution is left under stirring at 0°C for 30' and is thereafter added with 0,2 g of the product obtained in previous step (4) (0.73 mmoles) and 0,28 ml DIPEA. After 3 h stirring at room temperature, the solvent was eliminated by evaporation under reduced pressure and collected with ethyl acetate.

The organic solution was extracted with an aqueous solution of NaHCO3 al 5% (3 X 50ml), with an aqueous solution saturated in di-NaCI (3 x 50ml), with an aqueous solution of H2SO4 0,05 M (3 x 50 ml) and finally again with the aqueous solution saturated in NaCI (3 x 50ml). The organic phase was anhydrified on Na2SO4 and dried giving 0,37 g of N (tert-butyloxycarbonyl)-L-3- (3,4dichlorophenyl)alanine N-methyl, N(4-bromobenzyl) amide (0,67 mmoles; yield 95%)

The HPLC analysis according to the conditions given in step (1 ) shows a single peak at tR= 8,6 min.

7) A solution of the product obtained in the previous step (6) in 20 ml ethyl acetate saturated with HCI (about 2N) is left under stirring at room temperature for 30 min.

The solvent is eliminated under light nitrogen flow and the residue is suspended several times in ethyl eter (4x30ml) and dried giving 0,32 mg L-3-(3,4 dichlorophenyl)alanine N-methyl-N-(4-bromobenzyl) amide hydrochloride (yield 98%). TLC(Chloroform, methyl alcohol 95/5 v/v): Rf= 0,15;

The HPLC according to the conditions given in step (1 ) shows a single peak (large) at tR= 5.9 min.

8) To a solution of the compound obtained in step (2) (0,22 g, 0,66 mmoles) in a mixture DMF/DCM (2 ml / 5ml) HOBt (0,11 g, 0,8 mmoles) and WSC.HCI (0,15 g, 0,8 mmoles) are added. The solution is left under stirring at 0°C for 30' and is thereafter added with 0,32 g of the compound obtained in step (6) (0.66 mmoles) and 0,35 ml DIPEA. After 3 h stirring at room temperature, the solvent was eliminated by evaporation under reduced pressure and collected with ethyl acetate. The organic solution was extracted with an aqueous solution of NaHCO3 5% (3 X 50ml), with an aqueous solution saturated in NaCI (3 x 50ml), with an aqueous solution of H2SO4 0,05 M (3 x 50 ml) and finally again with the aqueous solution saturated in NaCI (3 x 50ml). The organic phase was anhydrified on Na2S04 and dried giving 0,4 g Nα{Nα [1(H)indol-3-yl-carbonyl]L-Aspartyl-(β- tbutyl ester)} L-3-(3,4-dichlorophenyl)alanine N-methyl, N-(4-bromobenzyl) amide (0,52 mmoles; yield 79%)

The HPLC according to the conditions given in step (1b) shows a single peak at tR= 8,1 min.

9) A solution of the product obtained in previous step (8) (0,4 g, 0,52 mmoles) in a mixture of trifluoroacetic acid/DCM (10 ml/10 ml) is left under stirring at room temperature for 30 min. The solvent was eliminated under light nitrogen flow and the residue is resuspended several times in ethyl eter (4x30ml) and dried giving

0,32 mg of N^α{ N^α [1(H)indol-3-yl-carbonyl]L-Aspartyl}L-3-(3,4- dichlorophenyl)alanine N-methyl, N-(4-bromobenzyl) amide (0,45 mmoles; yield 86%).

TLC(Chloroform, metyl alcohol 95/5 v/v): Rf= 0,15; The HPLC analysis according to the conditions of step (1) shows a single peak at tR= 6,3 min.

10) To a solution of the product obtained in step (9) (0,32 g, 0,45 mmoles) in 2 ml DMF cooled at 0°C 2, 1-hydroxybenzotriazole (0,07 g, 0,55 mmoles) and (WSC.HCI) (0,1 g, 0,55 mmoles) are added. The solution is left under stirring for 5 h and then 2-aminoethylmorpholine (0,17 g, 1 ,35 mmoles) is added. The mixture is left under stirring for 1 h at room temperature. After elimination of the solvent under reduced pressure the residue is purified by inverted chromatography using a column Hibar Merck filled with Lichosorb RP-18 to 5 μm, by isocratic elution at 60% diacetonitrile in water, 0,01 % of trifluoroacetic acid, flow 8ml/min. The fractions corresponding to the product peak are pooled together, concentrated to small volume under reduced pressure and liophilysed several times giving 0,089 (0,1 mmoles, yield 22%) of Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N- (2(morpholin-4-yl)ethyl)]}-L-3-[(3,4-dichloro)phenyl]alanine-N-methyl-N-(4- bromobenzyl) amide; [MH]⁺ 781 The HPLC analysis according to the conditions of step (1 ) shows a single peak at tR= 6,1 min.

Following the same path of synthesis above described, or with obvious modifications thereof the hereinafter reported products were prepared, the retention times tR are obtained, if not differently indicated, with a column lichrospher 100RP-18e (5 μm) 4 x 250, 220 nm, fl.rate = 1 ml/min, with eluents A e B as described in Example 1 (acetonitrile = AN) with absorption UV at 220 nm; the [MH]+ values were obtained with electro-spray ionisation technique.

The compounds were isolated as trifluoroacetic acid salts, but whatever other organic or inorganic acid could be used giving the corresponding salts. Example 2: Na{Na(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3-[(3,4-dichloro)phenyl]alanine-N-methyl-N-(4-bromobenzyl) amide: 60%

AN (0,1 % acid TFA) column Lichosorb RP-18 4μm, flow 1 ml/min; tR = 4.93 min;

[MH]+ 785

Example 3: Nα{Nα(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-bromobenzyl) amide: 60% AN

(0,1% acid TFA) column Lichosorb RP-18 4μm 250x 4mm, flow 1 ml/min; tR = 5.03 min; [MH]⁺ 767

Example 4: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-bromobenzyl) amide: 60% AN (0,1% acid TFA) column Lichosorb RP-18 4 μm 250x 4mm, flow 1 ml/min; tR = 5.03 min;

[MH]⁺ 763

Example 5: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-iodobenzyl) amide; 60% AN (0,1% acid TFA) column Lichosorb RP-18 4 μm 250x 4mm, flow 1 ml/min; tR = 5.04 min; [MH]⁺ 811

Example 6: N^α{N (1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-bromobenzyl) amide: to 20 a 80% AN (0,1% acid TFA) in 20 min e 80% AN for 10 min; column Lichrocart RP-18 5μm

250x 4mm, flow 1 ml/min; tR = 16.69 min; [MH]⁺ 763 Example 7: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-chlorobenzyl) amide: 60% AN (0,1% acid TFA) column Lichosorb RP-18 4μm, flow 1 ml/min; tR = 5.18 min;

[MH]⁺ 723

Example 8: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3-(2-naphthyi)alanine-N-methyl-N-(4-chlorobenzyl) amide: 50% AN (0.1% TFA), tR = 5.34 min. with column Vydac 218TP54 (5um), 4.6 x 250 mm, fl.rate = 1 ml/min. [MH]⁺ 719

Example 9: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-chlorobenzyl) amide: 50% AN (0.1% TFA), tR = 5.29 min. with column Vydac 218TP54 (5um), 4.6 x 250 mm, fl.rate = 1 ml/min. [MH]⁺ 719

Example 10: N<*{N«(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(1 - methylpiperazin-4-yl)ethyl)]}-L-3-(2-naphthyl]alanine-N-methyl-N-(4-chlorobenzyl) amide: 55% AN (0.1% TFA), tR = 4.02 min; [MH]⁺ = 736 Example 11 : N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: to 20 a 80% AN (0,1% acid TFA) in 20 min e 80% AN for 10 min; column lichrocart RP-18

5μm 250x 4mm, flow 1 ml/min; tR = 16.55 min; [MH]⁺ 702

Example 12: N«{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperidin-1 -yl) ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 50% AN

(0.1% TFA), tR = 10.30 min; [MH]⁺ = 701

Example 13: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 55% AN (0.1 %

TFA), tR = 7.63 min; [MH]⁺ = 699 ExajτιpJe__l4:N^α{N (1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3-(3,4-dichloro-phenyl)alanine-N-methyl-N-(4-methylbenzyl) amide: to 40 a

60% AN (0.1% TFA) in 20 min, tR = 14.89 min; [MH]⁺ = 717

Example 15: Nα{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperazin-1-yl) ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 55% AN (0.1% TFA), tR = 8.7 min; [MH]⁺ = 702

Example 16: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide : : from20 to 80% AN (0,1% acid TFA) in 20 min e 80% AN for 10 min; column lichrocart RP-18 5μm

250x 4mm, flow 1 ml/min; tR = 16.18 min; [MH]⁺ 699 Example 17: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(1 - methylpiperazin-4-yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 60% AN (0.1% TFA), tR = 5.34 min; [MH]⁺ = 716

Example 18: N«{N«(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(1 - benzylpiperazin-4-yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4- trifluoromethylbenzyl) amide: 60% AN (0.1% TFA), tR = 9.25 min; [MH]⁺ = 803

Exam^ple 19: Nα{N<*(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide: 50% AN (0.1% TFA), tR = 10.62 min; [MH]⁺ = 757 Example 20: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide: 50% AN

(0.1% TFA), tR = 5.88 min; [MH]⁺ = 753

Example 21 : Nα{Nα(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide: 55% AN (0.1 % TFA), tR = 9.22 min; [MH]⁺ = 753

Example 22: N«{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperazin-1 - yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide: 50% AN (0.1% TFA), tR = 5.68 min; [MH]⁺ = 756 Example 23: N»{N«(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(1 - methylpiperazin-4-yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4- trifluoromethylbenzyl) amide: 50% AN (0.1% TFA), tR = 5.61 min; [MH]⁺ = 770 Example 24: N<*{N«(1 (H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-(2(1 - methylpiperazin-4-yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 50% AN (0.1% TFA), tR = 4.49 min; [MH]⁺ = 716 Example 25: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3-((3,4-dichloro)phenyl)alanine-N-methyl-N-(benzyl) amide: 50% AN (0.1 % TFA), tR = 5.9 min. with column Vydac 218TP54 (5um), 4.6 x 250 mm, 220 nm, fl.rate = 1 ml/min. [MH]⁺ 685

Example 26: Nα{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- lo

yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide: 60% AN (0,1% acid TFA) column Lichosorb RP-18 4μm, flow 1 ml/min; tR = 5.22 min; [MH]⁺ 689 Example 27: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperidin-1 - yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide: 50% AN (0.1 M CH3COO-NH4+), tR = 14.96 min; [MH]⁺ = 688

Example 28: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Aspartil[β-(4-amminoethyl- piperazin-1-yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 30 -40% AN -20' - 40-80% -AN - 5'-(0.1 % TFA), tR = 23.5 min. Vydac 218TP54

(5um) 4.6 x 250 mm, 220 nm, fl.rate = 1 ml/min; [MH]⁺ = 756 Example 29: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Aspartil[β-(4-methyl-piperazin-1- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: : 50% AN (0.1%

TFA), tR = 5.72 min; [MH]⁺ = 673

Example 30: N {N^α(1 (H)indol-3-yl-carbonyl)-L-(α-amminoesandioil [δ-(4-methyl- piperazin-1-yl)])}-L-3(2-naphthyl)alanine-N-methyl-N-benzyl amide; 50% AN (0.1% TFA), tR = 5.72 min; [MH]⁺ = 687

Example 31 : N^α{N«(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2((4- phenyl)piperazin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 60% AN (0.1 % TFA), tR = 9.02 min; [MH]⁺ = 778

Example 32: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-(piperidin-1 - yl)piperidin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4- trifluoromethylbenzyl) amide: 50% AN (0.1% TFA), tR = 6.46 min; [MH]⁺ = 838 Example 33: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2((4- phenyl)piperazin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4- trifluoromethylbenzyl) amide: 50% AN (0.1% TFA), tR = 11.72 min; [MH]⁺ = 832 Example 34: Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2((4- benzyl)piperazin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4- trifluoromethylbenzyl) amide: 60% AN (0.1% TFA), tR = 5.32 min; [MH]⁺ = 846. Example 35: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide: 50% AN (0.1 % TFA), tR = 5.8 min. with column Vydac 218TP54 (5um), 4.6 x 250 mm, fl.rate = 1 ml/min.

[MH]⁺ 685.

Example 36: N^α{Nα(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide: 48% AN (0.1 M CH3COO- NH4+), tR = 8.37 min ; [MH]⁺ = 685

Example 37: N^α{N (1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperazin-1- yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide: 40% AN (0,1% acid TFA) column Lichosorb (4μm), 70x 4 mm, flow 1 ml/min; tR = 1.72 min; [MH]⁺719

Example 38: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3-((3,4-dichloro)phenyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 60% AN (0.1 % TFA), tR = 6.51 min. with column Vydac 218TP54 (5um),

4.6 x 250 mm, fl.rate = 1 ml/min. [MH]⁺ 777

Example 39: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3-((3,4-dichloro)phenyl)alanine-N-methyl-N-((2,4-dichloro)benzyl) amide: 60% AN (0.1% TFA), tR = 6.84 min. with column Vydac 218TP54 (5um),

4.6 x 250 mm, fl.rate = 1 ml/min. [MH]⁺ 777

Example 40: N^α{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3-((3,4-dichloro)phenyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 60% AN (0.1% TFA), tR = 6.51 min. with column Vydac 218TP54 (5um), 4.6 x 250 mm, fl.rate = 1 ml/min. [MH]⁺ 771

Example 41 : N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 60% AN (0.1% TFA), tR = 5.97 min. with column Vydac 218TP54 (5um), 4.6 x 250 mm, fl.rate = 1 ml/min. [MH]⁺ 757 Example 42: N<*{N<*(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piridin-2- yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 60% AN (0,1 % acid TFA) column Lichosorb (4μm), 250x 4 mm, flow 1 ml/min; tR = 5.26 min; [MH]⁺ 749

Example 43: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- lo

yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 60% AN (0,1% acid TFA) column Lichosorb (4μm), 250x 4 mm, flow 1 ml/min; tR = 5.38 min; [MH]⁺ 753

Example 44: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 60% AN

(0,1% acid TFA) column Lichosorb RP-18 4μm 250x 4mm, flow 1 ml/min; tR = 5.38 min; [MH]⁺ 753

Example 45: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3(4-bromo-phenyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 55% AN (0,1% acid TFA) column Lichosorb RP-18 4μm 250x 4mm, flow 1 ml/min; tR =

5.26 min; [MH]⁺ 791

Example 46: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperazin-1- yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide: 60% AN (0,1% acid TFA) column Lichosorb (4μm), 250x4 mm, flow 1 ml/min; tR = 3.38 min; [MH]⁺ 756

Example 47: N^α{N (1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-methyl- piperazin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,5- ditrifluoromethyl)benzyl) amide: 60% AN (0.1% TFA), tR = 4.42 min; [MH]⁺ = 838 Example 48: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-benzyl- piperazin-1 -yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide:

55% AN (0.1% TFA), tR = 6.04 min; [MH]⁺ = 792

Example 49: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-benzyl- piperazin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,5- ditrifluoromethyl)benzyl) amide: 60% AN (0.1% TFA), tR = 7.44 min; [MH]⁺ = 914 Example 50: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-benzyl- piperazin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-bromobenzyl) amide:

55% AN (0.1% TFA), tR = 7.25 min; [MH]⁺ = 856

Example 51 : N^α{N^α(1(H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-(2(4-benzyl- piperazin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 55% AN (0.1 % TFA), tR = 6.20 min; [MH]⁺ = 792

Example 52: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-(piperid-1 - yl)piperid-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-benzyl amide: 45% AN (0.1% TFA), tR = 5.69 min; [MH]⁺ = 770 Example 53: Nα{Nα(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2- dimethylammino-ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 50% AN (0.1% TFA), tR = 8.42 min; [MH]⁺ = 661

Example 54: Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-methyl- piperazin-1-yl)ethyl)]}-L-Tryptophan-N-methyl-N-((3,5-ditrifluoromethyl)benzyl) amide 55% AN (0.1 % TFA), tR = 5.56 min; [MH]⁺ = 812

Example 55: N^α{N«(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(3- dimethylammino-propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl) amide: 50% AN (0.1% TFA), tR = 7.11 min; [MH]⁺ = 675

Example 56: N<*{N< (1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-(piperid-1- yl)piperid-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl) amide: 45% AN (0.1% TFA), tR = 5.1 min; [MH]⁺ = 784

Example 57: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(3-(4- methylpiperazin-1-yl)propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4- methyl)benzyl) amide: 45% AN (0.1 % TFA), tR = 6.05 min; [MH]⁺ = 730 Example 58: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(3-(1 H-

[1 ,2,4]triazol-3-yl-ammino)propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4- methyl)benzyl) amide: to 20 a 80% AN (0.1% TFA) in 20 min, tR = 14.0 min. with column Vydac Peptide&Protein, 4.6 x 250 mm, fl.rate = 1 ml/min; [MH]⁺ 714 Example 59: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(3-((3-(4-methyl- piperazin-1-yl)propil)amminocarbonil)propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-

((4-methyl)benzyl) amide: 45% AN (0.1% TFA), tR = 5.36 min ; [MH]⁺ = 815

Example 60: N^α{N«(1 (H)indol-3-yl-carbonyl)-L-Glutamminil[β-N-(2-(4-(piperidin-1 - yl)piperidin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl) amide: 45% AN (0.1 % TFA), tR = 8.90 min; [MH]⁺ = 798 Example 61 : N«{N^α(1 (H)indol-3-yl-carbonyl)-L-Glutamminil[β-N-(3-(4- methylpiperazin-1-yl)propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4- methyl)benzyl) amide: 45% AN (0.1 % TFA), tR = 6.83 min; [MH]⁺ = 744 Example 62: Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,5-bis trifluoromethyl)benzyl) amide: to 20 a 80% AN (0,1% acid TFA) in 20 min e 80% AN for 10 min; column lichrocart RP-18 5μm 250x 4mm, flow 1 ml/min; tR = 19.29 min; [MH]⁺ 825 Example 63: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,5-bis trifluoromethyl)benzyl) amide: to 20 a 80% AN (0,1% acid TFA) in 20 min e 80% AN for 10 min; column lichrocart

RP-18 5μm 250x 4mm, flow 1 ml/min; tR = 18.82 min; [MH]⁺ 821 Example 64: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((1-naphthyl)methyl) amide: to 20 a 80% AN (0,1% acid TFA) in 20 min e 80% AN for 10 min; column lichrocart RP-18 5μm 250x 4mm, flow 1 ml/min; tR = 19.45 min; [MH]⁺ 739

Example 65 : N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((1-naphthyl)methyl) amide 55% AN (0.1%

TFA), tR = 6.55 min; [MH]⁺ = 735

Example 66: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((1-naphthyl)methyl) amide: 50% AN

(0.1 % TFA), tR = 8.78 min; [MH]⁺ = 735

Example 67: N^α{N^α(1(H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-((R)quinuclidin-3- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 55% AN (0.1%

TFA), tR = 7.43 min; [MH]⁺ = 699 Example 68: N^α{N^α(1 (H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 55% AN

(0.1% TFA), tR = 8.27 min; [MH]⁺ = 703

Example 69: N^α{N^α(1 (H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-((S)quinuclidin-3- yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 55% AN (0.1 % TFA), tR = 7.96 min; [MH]⁺ = 699

Example 70: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ- 3(piperidin-1-yl)propanoil))]}-L-3(2-naphthyI)alanine-N-methyl-N-(4-methylbenzyl) amide: 60% AN (0.1 % TFA), tR = 5.49 min; [MH]⁺ = 701 Example 71 : N^α{N (1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-4- quinuclidin-carbonyl]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide: 50% AN (0.1% TFA), tR = 5.46 min; [MH]⁺ = 685

Example 72: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-4- quinuclidin-carbonyl]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 50% AN (0.1 % TFA), tR = 7.02 min; [MH]⁺ = 699

Example 73: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-omitil[Nβ-4-quinuclidin-carbonyl]}- L-3(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide: 55% AN

(0.1 % TFA), tR = 6.27 min; [MH]⁺ = 781

Example 74: N^α{N^α(1(H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-3(1- methylpiperazin-4-yl)propanoil]}-L-3(2-naphthyl)alanine-N-methyl-N-(4- methylbenzyl) amide: 50% AN (0.1 % TFA), tR = 4.76 min; [MH]⁺ = 716 Example 75: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ- 3(piperidin-1-yl)propanoil]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide: 60% AN (0,1 % acid TFA) column Lichosorb (4μm), 250x4 mm, flow 1 ml/min; tR = 4.52 min; [MH]⁺ 687

Example 76-12270: N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ- 3(piperidin-1-yl)propanoil]}-L-tryptophan-N-methyl-N-(4-methylbenzyl) amide: to 20 a 80% AN (0.1% TFA) in 20 min, tR = 16.58 min; [MH]⁺ = 678 Example 77: N^α{N^α(1 (H)indol-3-yl-carbonyI)-D-(α,β)diamminopropanoil[Nβ- 3(morpholin-4-yl)propanoil]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 50% AN (0.1% TFA), tR = 5.28 min; [MH]⁺ = 703

Example 78: N^α{N^α(1 (H)indol-3-yl-carbonyl)-D-(α,β)diamminopropanoil[Nβ-

3(piperidin-1-yl)propanoil]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 50% AN (0.1 % TFA), tR = 6.05 min; [MH]⁺ = 701

Example 79: N^α{N^α(1 (H)indol-3-yl-carbonyl)-D-(α,β)diamminopropanoil[Nβ-3(4- methylpiperazin-1-yl)propanoil))]}-L-3(2-naphthyl)alanine-N-methyl-N-(4- methylbenzyl) amide: 50% AN (0.1 % TFA), tR = 4.55 min; [MH]⁺ = 716 Example 80: N^α{N^α(1 (H)indol-3-yl-carbonyl)-D-(α,β)diamminopropanoil[Nβ- 2(piperazin-1-yl)etanoil)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 50% AN (0.1% TFA), tR = 4.86 min; [MH]⁺ = 688

Example 81 : Nα{Nα(1(H)indol-3-yl-carbonyl)-L-Lisin[Nβ-3(piperidin-1- yl)propanoil]}-L-3(2-naphthyl)alanine -N-methyl-N-(4-methylbenzyl) amide: 55% AN (0.1% TFA), tR = 7.8 min; [MH]⁺ = 743

Example 82: N«{N^α(1 (H)indol-3-yl-carbonyl)-L-Lisin[Nβ-3(4-methylpiperazin-1 - yl)propanoil]}-L-3(2-naphthyl)alanine -N-methyl-N-(4-methylbenzyl) amide: 55%

AN (0.1 % TFA), tR = 9.32 min; [MH]⁺ = 758

Example 83: N«{N«(1 (H)indol-3-yi-carbonyl)-L-Lisin[Nβ-3(4-(piperidin-1 - yl)piperidin-1 -yl)propanoil]}-L-3(2-naphthyl)alanine -N-methyl-N-(4-methylbenzyl) amide: 45% AN (0.1% TFA), tR = 10.48 min ; [MH]⁺ = 826 Example 84: N^α{N^α[3(piperidin-1-yl)propanoil]-L-(α,β)diamminopropanoil[Nβ- [1(H)indol-3-yl-carbonyl]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: to 20 a 80% AN (0.1% TFA) in 20 min, tR = 19.95 min [MH]⁺ = 701 Example 85: N^α{N^α[3(piperidin-1 -yl)propanoil]-L-(α,β)diamminopropanoil[Nβ- [1 (H)indol-3-yl-carbonyl]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide: 40% AN (0,1% acid TFA) column Lichosorb (4μm), 70x 4 mm, flow 1 ml/min; tR = 2.10 min; [MH]⁺ 687.

The evaluation of the antagonistic activity on NK1 receptors was performed with binding "in vitro" tests and "in vivo" tests on the inhibition of bronchospasm induced by the agonist via intravenous administration and extravasation of plasma proteins in guinea pigs bronchi (PPE bronchi).

The test of inhibition of [3H]SP binding to cell IM9 was performed on intact cell as described in WO 95/15311 and WO 95/19965 and the affinity was measured as pKi.

The antibronchospastic effect was evaluated using the method described in Perretti et al in European Journal of Pharmacology 273 (1995) 129-135. The antagonistic effect is determined as ED50 , expressed in nmoles/Kg, defined as the dosage necessary to decrease by 50% the bronchoconstrictive effect of the agonist at a given time.

The extravasation of the plasma proteins in guinea pigs bronchi was performed according to R. Cirillo et al. European J Pharmacology 341 (1998), 201-209. The antagonistic effect was measured as %inhibition of a dosage of 10mg/kg per os of antagonist on the extravasation of plasma proteins in bronchi induced by an NK1 agonist.

Table

Claims

1 1 . Compounds, containing an aliphatic or aromatic amino group, of general

2 formula (I)

5 (I)

6 wherein: n = 0,1 ,2,3

7 p = 0,1 ,2,3,4

8 R-| is:

9 a) a basic moiety chosen in the group consisting of: lo a) a basic moiety chosen in the group consisting of: l i - amino possibly mono- or di-substituted by C,.₃alkyl group or by an aromatic

12 heterocycle such as triazole, pyridine, pirimidine;

13 - a basic aliphatic heterocycle chosen in the group consisting of : piperidine,

14 piperazine, morpholine, quinuclidine, possibly substituted with C_1-3 alkyl, phenyl,

15 benzyl, C^aminoalkyl or with an aliphatic heterocycle chosen between piperidine

16 and morpholin, such aliphatic being possibly linked to the (CH₂)_nCONH, through a

17 group (CH₂)_q-X₂ wherein q is 1 , 2, 3, 4 and X₂ is a group -CONH- or -NHCO-

18 - a basic, aromatic heterocycle, chosen in the group consisting of pyridine and

19 chinoline possibly substituted with one or more alkyl groups containing up to 3

20 carbon atoms

2i b) an aryl- or arylalkyl-radical wherein the aryl-moiety is chosen in a group

22 consisting of: pirrolo, benzofuran, biphenyl, benzene, indole, naftalene, imidazole,

23 furan, thiophene, indane and wherein the aromatic moiety can be optionally

24 substituted on the

25 the ring with one or more substituents chosen among: halogen, C^ alkyl possibly

26 substituted with no more than three F, C^ oxyalkyl, possibly substituted with no more than three F atoms, -NHR7, -N(R7)2, -CONHR7, -COR7, -COOR7, - R8COOR7.-OR8COOR7, -R8COR7, -R8CONHR7, -NHCOR7, -nitro, wherein R7 is hydrogen or a C^ alkyl and R8 is a C^ linear or branched alkyldene, R2 is a moiety of general formula:

wherein m= 0,1 ,2,3, R6 is : a) a basic moiety chosen in the group consisting of : - amine possibly mono- or di-substituted with C1 -3 alkyl o with an aromatic heterocycle such as triazole, pyridine, pirimidine; - basic aliphatic heterocycle chosen in the group consisting of: piperidine, piperazine, morpholine, quinuclidina, possibly substituted with C1 -3 alkyl, phenyl, benzyl, C1 -4 aminoalkyl or with an aliphatic heterocyle chosen among piperidine or morpholine; such aliphatic heterocycle being possibly linked to the (CH2)mX1- through a group (CH2)q-X2- wherein q is 1 ,2,3,4 and X2 is a group CONH o NHCO. - a basic, aromatic heterocycle chosen in the group consisting of pyridine and quinoline possibly substituted with one or more alkyl group containing up to 3 carbon atoms; b) an aryl- or aryl-alkyl radical wherein the aryl moiety is chosen in the group consisting of pyrrole, benzofuran, biphenyle, benzene, indole, naphthalene, imidazole, furan, thiophene, indane and wherein the aromatic moiety can be possibly substituted on the ring with one or more substituents chosen among: halogen, C^ alkyl possibly substituted with no more than three F, C^ oxyalkyl, possibly substituted with no more than three F atoms, -NHR7, -N(R7)2, -CONHR7, -COR7, -COOR7, -R8COOR7.-OR8COOR7, -R8COR7, -R8CONHR7, -NHCOR7, -nitro, wherein R7 is hydrogen or a C^ alkyl and Rδ is a C^ linear or branched alkylidene, and X1 is -CONH- or NHCO-; R3 is chosen n the group: - naphthyl-methyle, benzyl substituted with one or two halogen atoms, indol- methyl; R5 is H or meythyl; R4 is an aryl or aryl-alkyl group with up to 15 carbon atoms wherein the aryl moiety is chosen in the group consisting of: pyridine, pyrrol, benzofurane, biphenyle, benzene, indole, naphthalene, imidazole, quinoline, furan, thiphene, indane and wherein the aromatic moiety can be possibly substituted on the ring with one or more substituents chosen among halogen, C^ alkyl possibly substituted with up to three F atoms, C^ oxyalkyl, -NHR7, -N(R7)2, -CONHR7, - COR7, -COOR7, -R8COOR7.-OR8COOR7, -R8COR7, -R8CONHR7, -NHCOR7, - NO2, wherein R7 is H or a C,^ alkyl and Re is a linear or branched C^ alkyldiene; with the proviso that - when Re is a moiety as above defined R1 is an aryl or aryl-alkyl as above defined; when R6 is an aryl or aryl-alkyl as above defined R1 is a basic moiety as above defined and the pharmaceutical acceptable salts with organic or inorganic acids chosen in the group consisting of: chloridric, sulforic, phosphoric, bromidric, acetic, trifluoroacetic, oxalyc, malonic, malic, succinic, tartaric, citric acid, as enantiomers having a purity higher than 80% or as mixture of diastereoisomers. 2. Compounds according to claim 1 wherein: R₂ is as defined in claim 1 and: R1 and R6 are: a basic moiety chosen in the group consisting of: - dimethylamina, amine-triazole, - an aliphatic heterocucle chosen in the group consisting of: piperidina, 7 morpholine, piperazine possibly substituted with methyl, aminoethyl, phenyl,

8 benzyl or piperidino; or 3-(4-methyl-piperazin-1-yl)propyl-aminocarbonyl

9 - pyridine lo - a radical indol-3-yl; l i R4 is an aryl-methyl group wherein the aryl is chosen in a group consisting of:

12 benzene, naftalene, pyridine and indole and wherein the aromatic moiety can be

13 possibly substituted on the ring with one or more substituents chosen in the group

14 consisting of: halogen, C_w alkyl possibly syubstituted with no more then three F

15 atoms, C^ oxyalkyl. Possibly substituted with no more then three F atoms, -

16 NHR7, -N(R7)2, -CONHR7, -COR7, -COOR7, -R8COOR7.-OR8COOR7, -

17 R8COR7, -R8CONHR7, -NHCOR7, -NO2, wherein R7 is hydrogen or a C^ alkyl

18 and R8 is a C^ linear or branched alkylidene ;

19 - R3, R5,m, n, p, X1 are as above defined

20 with the proviso that:

21 when R1 is a basic moiety, as above defined, R6 is indol-3-yle and vice-versa.

1 3. Compounds according to claim 2 wherein the alkyl radical containing from 1 to

2 6 carbon atoms as defined for the substituents R_{1 f} R₄, R₆ and R₇ is chosen in the

3 group consisting of methyl, ethyl, propyl, butyl; the oxyalkyl radical containing from

4 1 to 6 carbon atoms as defined for the substituents R^ R₄ and R₆ is chosen in the

5 group consisting of: methoxy, ethoxy, propyloxy; the alkyl moiety of the group aryl-

6 alkyl as defined for the substituents R_{1 t} R₆ and R₄ is methyl or ethyl; R₈ is chosen

7 in the group consisting of: methylidene, ethylidene, propylidene; halogen is:

8 chlorine, fluorine, bromine, iodine; and wherein the carbon atom linked to R₂ has

9 configuration R or S while the carbon atom linked to R₃ has configuration S.

1 4. Compounds according to claim 3, wherein:

2 n =0;

3 R₂ is as defined in claim 1 and:

4 Re is:

5 a basic moiety chosen in the group consisting of:

6 - dimethylamine, 3-amino-[1 ,2,4]triazole

7 - an aliphatic heterocycle chosen among: 1 -piperidine, 4-morpholine, piperazine, 8 3-quinuclidine, 4-quinuclidina, 4-methyl-piperazine, 4-phenyl- piperazine, 4-

9 benzylpiperazine, 4-aminoethyl-piperazine, 4-(1-piperidyl)-piperidine, 3-(4-methyl- 10 piperazin-1 -yl)propyl-aminocarbonyl; l i - pyridine

12 R₁ is indol-3-yl

13 R₃ is a group 2-naphthyl, 3,4dichlorobenzyl, 4-bromobenzyl, 3-indolyl

14 R₄ is a methylaryl wherein the aryl moiety is chosen in the group consisting of:

15 phenyl, 2-naphthyl, phenyl substituted with 4-CI, 3,4-diCI, 2,4-diCI, 4-Br, 4-1, 4-

16 CH₃, 4-CF₃, 3,5-diCF₃;

17 - R₅, m, p, X, are as above defined.

1 5. Compounds according to claim 4 as hereinafter defined:

2 i) N<x{N<*(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-L-3-

3 [(3,4-dichloro)phenyl]alanine-N-methyl-N-(4-bromobenzyl) amide

4 ii) N<x{N<*(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-3-

5 [(3,4-dichloro)phenyl]alanine-N-methyl-N-(4-bromobenzyl) amide

6 iii) N^α{N<*(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-L-

7 3-(2-naphthyl)alanine-N-methyl-N-(4-bromobenzyl) amide.

8 iv) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-3-(2-

9 naphthyl)alanine-N-methyl-N-(4-bromobenzyl) amide

10 v) (1 1500): Nα{N (1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-

11 yl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-iodobenzyl) amide

12 vi) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-3-(2-

13 naphthyl)alanine-N-methyl-N-(4-bromobenzyl) amide;

14 vii) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-L-

15 3-(2-naphthyl)alanine-N-methyl-N-(4-chlorobenzyl) amide.

16 viii) N^a{N3(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-3-

17 (2-naphthyl)alanine-N-methyl-N-(4-chlorobenzyl) amide

18 ix) N«{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-3-(2-

19 naphthyl)alanine-N-methyl-N-(4-chlorobenzyl) amide

20 x) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(1-methylpiperazin-4- yl)ethyl)]}-L-3-(2-naphthyl]alanine-N-methyl-N-(4-chlorobenzyl) amide xi) N«{N«(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-L- 3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide xii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperidin-1 -yl) ethyl)]}-L- 3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide xiii) N«{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-3- (2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide xiv) N«{N<*(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-3- (3,4-dichloro-phenyl)alanine-N-methyl-N-(4-methylbenzyl) amide xv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperazin-1 -yl) ethyl)]}-L- 3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide xvi) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-3- (2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide : xvii) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(1 -methylpiperazin-4- yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide xviii) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Asparginyl[β-N-(2(1-benzylpiperazin-4- yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide xix) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-L- 3-(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide xx) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-3- (2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide xxi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-3- (2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide xxii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperazin-1 -yl)ethyl)]}-L- 3-(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide xxiii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(1 -methylpiperazin-4- yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide xxiv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-(2(1 -methylpiperazin-4- yl)ethyl)]}-L-3-(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide xxv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-3- ((3,4-dichloro)phenyl)alanine-N-methyl-N-(benzyl) amide xxvi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}- L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide. xxvii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperidin-1-yl)ethyl)]}- L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide xxviii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Aspartil[β-(4-amminoethyl-piperazin-1 - yl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide xxix) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Aspartil[β-(4-methyl-piperazin-1 -yl)]}-L-3(2- naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide xxx) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-(α-amminoesandioil [δ-(4-methyl-piperazin- 1-yl)])}-L-3(2-naphthyl)alanine-N-methyl-N-benzyl amide xxxi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2((4-phenyl)piperazin-1 - yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide xxxii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-(piperidin-1- yl)piperidin-1-yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4- trifluoromethylbenzyl) amide xxxiii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2((4-phenyl)piperazin-1 - yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide xxxiv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2((4-benzyl)piperazin-1- yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide xxxv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L- 3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide xxxvi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L- 3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide xxxvii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperazin-1 -yl)ethyl)]}- L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide xxxviii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3-((3,4-dichloro)phenyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide. xxxix) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4- yl)ethyl)]}-L-3-((3,4-dichloro)phenyl)alanine-N-methyl-N-((2,4-dichloro)benzyl) 82 amide

83 xl) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-3-

84 ((3,4-dichloro)phenyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide

85 xli) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-L-

86 3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide.

87 xlii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piridin-2-yl)ethyl)]}-L-3(2-

88 naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide

89 xliii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-

90 3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide

91 xliv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-

92 3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide

93 xiv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-

94 3(4-bromo-phenyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide

95 xlvi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(piperazin-1 -yl)ethyl)]}-L-

96 3(2-naphthyl)alanine-N-methyl-N-((3,4-dichloro)benzyl) amide

97 xlvii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-methyl-piperazin-1-

98 yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,5-ditrifluoromethyl)benzyl) amide

99 xlviii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-benzyl-piperazin-1- loo yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide loi il) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-benzyl-piperazin-1 -

102 yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((3,5-ditrifluoromethyl)benzyl) amide

103 I) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-benzyi-piperazin-1-

104 yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-bromobenzyl) amide

105 li) Nα{Nα(1 (H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-(2(4-benzyl-piperazin-1-

106 yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide

107 lii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-(piperid-1 -yl)piperid-1 -

108 yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-benzyl amide

109 liii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2-dimethylammino-ethyl)]}- πo L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide

111 liv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-methyl-piperazin-1 -

112 yl)ethyl)]}-L-Tryptophan-N-methyl-N-((3,5-ditrifluoromethyl)benzyl) amide 113 Iv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(3-dimethylammino-

114 propyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl) amide

115 Ivi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(4-(piperid-1 -yl)piperid-1-

116 yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl) amide in ivii) Nα{Nα(1(H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(3-(4-methylpiperazin-1-

118 yl)propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl) amide

119 Iviii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(3-(1 H-[1 ,2,4]triazol-3-yl-

120 ammino)propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl) amide

121 lix) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(3-((3-(4-methyl-piperazin-

122 1 -yl)propil)amminocarbonil)propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-

123 methyl)benzyl) amide:

124 Ix) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Glutamminil[β-N-(2-(4-(piperidin-1 -

125 yl)piperidin-1 -yl)ethyl)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl)

126 amide

127 Ixi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Glutamminil[β-N-(3-(4-methylpiperazin-1-

128 yl)propil)]}-L-3(2-naphthyl)alanine-N-methyl-N-((4-methyl)benzyl) amide

129 Ixii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-L-

130 3(2-naphthyl)alanine-N-methyl-N-((3,5-bis trifluoromethyl)benzyl) amide

131 Ixiii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-

132 3(2-naphthyl)alanine-N-methyl-N-((3,5-bis trifluoromethyl)benzyl) amide

133 Ixiv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-

134 L-3(2-naphthyl)alanine-N-methyl-N-((1 -naphthyl)methyi) amide

135 Ixv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L-

136 3(2-naphthyl)alanine-N-methyl-N-((1 -naphthyl)methyl) amide

137 Ixvi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-

138 3(2-naphthyl)alanine-N-methyl-N-((1 -naphthyl)methyl) amide

139 Ixvii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-((R)quinuclidin-3-yl)]}-L-

140 3(2-naphthyl)alanine-N-methyI-N-(4-methylbenzyl) amide

141 Ixviii) Nα{Nα(1 (H)indoI-3-yl-carbonyl)-D-Asparaginyl[β-N-(2(morpholin-4-yl)ethyl)]}-

142 L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide

143 Ixix) Nα{Nα(1 (H)indol-3-yl-carbonyl)-D-Asparaginyl[β-N-((S)quinuclidin-3-yl)]}-L- 144 3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide

145 Ixx) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-3(piperidin-1 -

146 yl)propanoil))]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide: 60%

147 AN (0.1 % TFA), tR = 5.49 min; [MH]+ = 701

148 Ixxi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-4-quinuclidin-

149 carbonyl]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl)

150 Ixxii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-4-quinuclidin-

151 carbonyl]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide

152 Ixxiii) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-ornitil[Nβ-4-quinuclidin-carbonyl]}-L-3(2-

153 naphthyl)alanine-N-methyl-N-(4-trifluoromethylbenzyl) amide

154 Ixxiv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-3(1-

155 methylpiperazin-4-yl)propanoil]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-

156 methylbenzyl) amide

157 Ixxv) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-3(piperidin-1 -

158 yl)propanoil]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide

159 Ixxvi) Nα{Nα(1 (H)indol-3-yl-carbonyl)-L-(α,β)diamminopropanoil[Nβ-3(piperidin-1 -

160 yl)propanoil]}-L-tryptophan-N-methyl-N-(4-methylbenzyl) amide

161 Ixxvii Nα{Nα(1 (H)indol-3-yl-carbonyl)-D-( ,β)diamminopropanoil[Nβ-3(morpholin-4-

162 yl)propanoil]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide

163 Ixxviii) N^α{N^α(1 (H)indol-3-yl-carbonyl)-D-(α,β)diamminopropanoil[Nβ-3(piperidin-1 -

164 yl)propanoil]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide

165 Ixxix) N^α{N^α(1 (H)indol-3-yl-carbonyl)-D-(α,β)diamminopropanoil[Nβ-3(4-

166 methylpiperazin-1 -yl)propanoil))]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-

167 methylbenzyl) amide

168 Ixxx) N^α{N^α(1 (H)indol-3-yl-carbonyl)-D-(α,β)diamminopropanoil[Nβ-2(piperazin-1 -

169 yl)etanoil)]}-L-3(2-naphthyl)alanine-N-methyl-N-(4-methylbenzyl) amide no Ixxxi) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Lisin[Nβ-3(piperidin-1 -yl)propanoil]}-L-3(2-

171 naphthyl)alanine -N-methyl-N-(4-methylbenzyl) amide

172 Ixxxii) N^α{N^α(1 (H)indol-3-yl-carbonyl)-L-Lisin[Nβ-3(4-methylpiperazin-1-

173 yl)propanoil]}-L-3(2-naphthyl)alanine -N-methyl-N-(4-methylbenzyl) amide: ; [MH]⁺ 174 = 758

175 Ixxxiii) N^α{N^α(1(H)indol-3-yi-carbonyl)-L-Lisin[Nβ-3(4-(piperidin-1-yl)piperidin-1-

176 yl)propanoil]}-L-3(2-naphthyl)alanine -N-methyl-N-(4-methylbenzyl) amide.

1 6. Compounds according to claim 3, wherein:

2 R₂ is as defined in claim 1 ;

3 m = 0;

4 X, = CONH

5 R6 is indol-3-yl;

6 R1 is a basic moiety chosen in the group:

7 - dimethylamine, 3-amino-[1 ,2,4]triazole,

8 - an aliphatic heterocycle chosen in the group consisting of: 1 -piperidine, 4-

9 morpholine, piperazine, 3-quinuclidine, 4-quinuclidine, 4-methyl-piperazine, 4- lo phenyl-piperazine, 4-benzylpiperazine, 4-aminoethyl-piperazine, 4-(1-piperidyl)- li piperidine,

12 - pyridine

13 R3 is a group 2-naphthyl, 3,4-dichlorobenzyl, 4-bromobenzyl, 3-indolyl

14 R4 is a methyl-aryl group wherein the aryl is chosen in the group consisting of:

15 phenyl, 2-naphthyl or phenyl substituted with 4-CI, 3,4-di Cl, 2,4-di Cl, 4-Br, 4-1, 4-

16 CH3, 4-CF3, 3,5-di CF3;

17 - R5, n, p are as above defined.

1 7. Compounds according to claim 6 as hereinafter defined:

2 Ixxxiv) N^α{N^α[3(piperidin-1-yl)propanoyl]-L-(α,β)diaminopropanoyl[Nβ-[1 (H)indol-

3 3-yl-carbonyl]}-L-3(2-naphthyl)aianine-N-methyl-N-(4-methylbenzyl) amide

4 Ixxxv) N^α{N^α[3(piperidin-1-yl)propanoyl]-L-(α,β)diamminopropanoyl[Nβ-[1 (H)indol-

5 3-yl-carbonyl]}-L-3(2-naphthyl)alanine-N-methyl-N-(benzyl) amide.

1 8. Pharmaceutical composition comprising as active principle a pharmaceutically

2 effective amount of a compound according to claim 1 for use as tachykinins

3 antagonist.

1 9. Pharmaceutical composition comprising as active principle a pharmaceutically

2 effective amount of a compound according to claim 2 for use as tachykinins

3 antagonist.

10. Pharmaceutical composition comprising as active principle a pharmaceutically effective amount of a compound according to claim 3 for use as tachykinins antagonist 11. Pharmaceutical composition comprising as active principle a pharmaceutically effective amount of a compound according to claim 4 for use as tachykinins antagonist 12. Pharmaceutical composition comprising as active principle a pharmaceutically effective amount of a compound according to claim 5 for use as tachykinins antagonist. 13. Pharmaceutical composition comprising as active principle a pharmaceutically effective amount of a compound according to claim 6 for use as tachykinins antagonist. 14. Pharmaceutical composition comprising as active principle a pharmaceutically effective amount of a compound according to claim 7 for use as tachykinins antagonist. 15. Pharmaceutical composition comprising as active principle a pharmaceutically efetive amount of a compound according to claims 1 - 7 for use as tachykinins antagonist in the treatment of diseases of the respiratory tract, as asthma and allergic rhinitis, ophthtalmic illnesses, as conjunctivitis, cutaneous illnesses as allergic and contact dermatitis and psoriasis, intestinal illnesses, as ulcerative colitis, Crohn's disease, emesis induced by administration of anti-tumoural medicaments. The present compounds can be used also in the treatment of tumours wherein the cells present a functionally expressed NK-1 receptor (astrocytomas, gliomas). 16. Use of the compounds of formula (I) according to claims 1 , 2, 3, 4, 5, 6, 7 as active principle for the preparation of pharmaceutical compositions for use as tachykinins antagonists in the treatment of: diseases of the respiratory tract, as asthma and allergic rhinitis, ophthtalmic illnesses, as conjunctivitis, cutaneous illnesses as allergic and contact dermatitis and psoriasis, intestinal illnesses, as ulcerative colitis, Crohn's disease, emesis induced by administration of anti- tumoural medicaments. The present compounds can be used also in the treatment of tumours wherein the cells present a functionally expressed NK-1 receptor (astrocytomas, gliomas).

AMENDED CLAIMS

[received by the International Bureau on 25 February 2000 (25.02.00); original claim 1 amended; other claims unchanged (2 pages)]

1 . Compounds, containing an aliphatic or aromatic amino group, of general formula (I)

5 0) wherein: n = 0,1 ,2,3

7 p = 0,1,2,3,4 K Rl is: y a) a basic moiety chosen in the group consisting of: lo - amino possibly mono- or di-substituted by C ₃alkyl group or by an aromatic

} l heterocycle such as triazole, pyridine, pinmidine;

12 - a basic aliphatic heterocycle chosen in the group consisting of : piperidine, n piperazine, morpholine, quinuclidine, possibly substituted with C,.₃ alkyl, phenyl,

1 benzyl, C_{l l}aminoalkyl or with an aliphatic heterocycle chosen between piperidine is and morpholin, such aliphatic being possibly linked to the (CHΛ- CONH, through a lb group (CH₂)_q-X₂ wherein q is i , 2, 3, 4 and X₂ is a group -CONH- or -NHCO- ι7 - a basic, aromatic heterocycle, chosen in the group consisting of pyridine and is cninoiine possibly substituted with one or more alkyl groups containing up to 3 i9 carbon atoms

20 b) an aryl- or arylalkyl-radical wherein the aryl-moiety is chosen in a group

2ι consisting of: pirrolo, benzofuran, biphenyl, benzene, indole, naftalene, imidazole,

22 furan, thiophene, indane and wherein the aromatic moiety can be optionally

2 substituted on the

2 the ring with one or more substituents chosen among: halogen, C ₆ alkyl possibly

25 substituted with no more than three F, C,^ oxyalkyl, possibly substituted with no 33 alkylidene,

5 and X1 is -CONH- or NHCO-;

57 R3 is chosen π the group:

58 - naphthyl-methyle, benzyl substituted with one or two halogen atoms, m oism methyl,

60 R5 is H or meythyl; i R4 is an aryl or aryl-alkyl group with up to 15 carbon atoms wherein the aryl

62 moiety is chosen in the group consisting of: pyridine, pyrrol, benzofurane,

63 biphenyle, benzene, indole, naphthalene, imidazole, quinoline, furan, thiphene,

64 indane and wherein the aromatic moiety can be possibly substituted on the nng

65 with one or more substituents chosen among halogen. C^ alkyl possibly substituted with up to three F atoms, C_1-β oxyalkyl, -NHR7, -N(R7)2, -CONHR7, -

67 COR7, -COOR7, -R8COOR7,-OR8COOR7, -R8COR7, -R8CONHR7, -NHCOR7, -

68 NO2, wherein R7 is H or a C^ alkyl and Rδ is a linear or branched C,.₅ &y alkyldieπe,

7ϋ with the proviso that

71 - when 6 is a basic moiety as above defined Ri is an aryl or aryl-alkyl as above

72 defined, 3 when R6 is an aryl or aryl-alkyl as above defined Rt is a basic moiety as above

74 defined

75 and the pharmaceutical acceptable salts with organic or inorganic acids chosen in

76 the group consisting of chloridnc, sulforic, phosphoric, bromidπc, acetic,

77 trifluoroacetic, oxalyc, malonic, malic, succinic, tartaric, citric acid, as enantiomers 7S navmg a purity higher than 80% or as mixture of diastereoisomers.

1 2 Compounds according to claim 1 wherein:

2 R₂ is as defined in claim 1 and: 2 R1 and R6 are:

4 a basic moiety chosen in the group consisting of.

5 - dimethylamina, amine-tnazole,

6 - an aliphatic heterocucle chosen in the group consisting of: piperidina,