State of the art The problems deriving from the use of peptides having a high molecular weight as antagonist drugs of tachykinins have led to the search for the smallest peptide fragment still capable of exerting an antagonist action. These studies have resulted in the identification of tripeptides and dipeptides suitably derived, which are antagonists of the P substance (European patents EP 333174 and EP 394989).

Recently non-peptide antagonists have been identified, which thus do not present the drawbacks linked to the metabolic instability of peptides (patents WO 9413694, WO 9515311, and WO 9519966).

Summary of the invention In particular, the present invention regards compounds having the following general formula (I): where R, is wherein R5 is chosen from a group consisting of hydrogen or methyl,

X1 is -CONH- X2 is -NR,2CO-, wherein R,2 is hydrogen or methyl; X3 is chosen in the group consisting of -NR,2CO-, NR,2CONH-, where R,2 is as defined above; where B, C, D, and E, independently from each other, may be CH or N; R6, R7, R8 and Rg are independently hydrogen, OH or NR,3R,4, where R,3 and R,4 are chosen independently in the group consisting of hydrogen, methyl, cyclohexyl, or 4-piperidine; R2 is chosen in the group consisting of R2 is chosen in the group consisting of aryl, aryl-alkyl radicals with a maximum of 15 carbon atoms, wherein the aryl group is chosen in the group consisting of benzene, naphtalene, benzofurane and indole and is possibly substituted on the ring with one or more substituents independently chosen in the group consisting of halogen, alkyl radical containing from 1 to 6 carbon atoms, possibly substituted with a number of fluorine atoms not higher than three (e.g., trifluoromethyl group), oxyalkyl radical containing from 1 to 6 carbon atoms, possibly substituted with a number of fluorine atoms not higher than three (e.g., trifluoromethoxyl group), tetrazole radical, -NH2, -NHR10, -NH(R10)2, -OR10, -CONHR10, COR10, COOR10, R11COOR10, -OR11COOR10, -R11COR10, -CONHR10, -R11CONHR10, -NHCOR10, and - nitro radicals, where R10 is chosen in the group consisting of hydrogen or alkyl radical with linear or branched chain containing from 1 to 6 carbon atoms, and R,1 is an alkyldene radical with linear or branched chain containing from 1 to 6 carbon

atoms; considering that: - when one of the variables B, C, D, E is N, the others are CH.

Also forming part of the present invention are the corresponding pharmacologicaliy acceptabie salts and, in view of the presence of chiral centres, the possible optical isomers or mixtures of the same, also in racemic form.

The compounds of formula (I), which have a receptor tachykinin antagonist activity, prove useful in the treatment of illnesses where tachykinins play a pathogenetic role, in particular arthritis, emesis, Huntington's disease, neuritis, neuralgia, hemicrania, hypertension, urinary incontinence, urticaria, signs indicating carcinoid syndrome, influenza and common cold, illnesses of the immune system, diseases of the respiratory tract (e.g., asthma, rhinitis of various forms and obstructive chronic bronchitis), ophthalmic illnesses (e.g., conjunctivitis), cutaneous illnesses (e.g., allergic and contact dermatitis and psoriasis), intestinal illnesses (e.g., ulcerative colitis and Chron's disease), tumors wherein the cells present a functionally espressed NK-1 receptor (in particular astrocytomas and gliomas).

Detailed description of the invention It has been unexpectedly found, and this constitutes a fundamental characteristic of the present invention, that the compounds of formula (I), as previously defined, having non-peptide nature, present better characteristics of inhibition of the bond of tachykinins on the NK-1 receptor and a higher metabolic stability.

In particular, unexpectedly, if assayed in an in vivo test of inhibition of bronchospasm due to l.V. administration of agonist in guinea pigs, these compounds are active, both intravenously and orally, at doses of less than 1 nmole/kg, unlike the compounds claimed in patents WO 9515311 and WO 9519966, which, besides having a lower affinity for the NK-1 receptor, in the order of nanomoles, if assayed in vivo in the test described above, have an EDso of over 1 nmole/kg.

A preferred group of compounds of the present invention includes the compounds that may be described by the general formula (I), where

where X1 = -CONH-, X2 = -NHCO-, and X3 = -NCH3CO-; R3 = a benzyl group possibly substituted with one or more substituents chosen, independently from each other, in the group consisting of: Cl, Br, F, I, CH3, CF3, OH, OCH3, OCF3, NH2, NHOH3, N(CH3)2, COOH, COOCH3, CONY2, CONCH3, CON(CH3)2, NO2, CN; and R2, R4, R6, R7, R8, R91 R10, R11, R13, R14, B, C, D, and E are as defined above.

Preferably, according to the present invention: - the alkyl radical as defined for R3 and R10 and the alkyl-moiety of the oxyalkyl radical defined for R3 are chosen in the group consisting of methyl, ethyl, propyl, and butyl; - the aryl-alkyl radicals as defined for R3 and the alkyliden-radicals as defined for R" present an alkylidene radical chosen in the group consisting of: methylene, ethylidene and propylidene; and - the halogen radical is chosen in the group consisting of chlorine, fluorine, bromine, and iodine.

In view of the centres of asymmetry present in formula (I), the invention refers to the various diastereoisomers included in the formula itself; in particular, the carbon atom bound to the substituent R2 has R configuration.

The compounds of the present invention have shown an antagonist activity of the action of the P substance, neurokinin A, and neurokinin B.

They can therefore be used as drugs in the treatment and prevention of illnesses where the tachykinins P substance, neurokinin A and neurokinin B are implicated as neuromodulators. Just to provide a few examples, the following illnesses may be mentioned: arthritis, emesis, Huntington's disease, neuritis, neuralgia, hemicrania, hypertension, urinary incontinence, urticaria, signs indicating carcinoid

syndrome, influenza and common cold, illnesses of the immune system, diseases of the respiratory tract (e.g., asthma, rhinitis of various forms and obstructive chronic bronchitis), ophthalmic illnesses (e.g., conjunctivitis), cutaneous illnesses (e.g., allergic and contact dermatitis and psoriasis), intestinal illnesses (e.g., ulcerative colitis and Chron's disease), tumors wherein the cells present a functionally espressed NK-1 receptor (in particular astrocytomas and gliomas).

The compounds of general formula (I), as previously defined, are prepared according to the following reaction schemes and discussions, where, unless otherwise explicitly specified, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R,3, R14 and A are as previously defined. a) By condensation of the intermediate compound of formula (Ila) with the intermediate compound of formula (Illa) the said intermediate of general formula lla being prepared, for example, according to scheme 1, using a condensing agent that is well known to experts in the field or using, as species activated in the condensation reaction, an acyl halide.

The said intermediate of general formula Illa is prepared, for example, according to scheme 2.

Scheme 2 describes the preparation of an intermediate of general formula Illa, where X3 = NR,2CO and R2 and R3 are as defined previously, and the configuration of the carbon atom to which R3 is bound is preferably R, the said intermediate being prepared by reaction between the derivative of the D-amino

acid of general formula (Vl), available on the market or prepared by some other synthetic means obvious for experts in the field, and the acyl halide of general formula (VII), via prior silylation of the amino acid with bis (trimethylsilyi) acetamide. This acyl halide is prepared from the corresponding R3-COOH carboxylic acid, following conventional methods that are obvious for experts in the field. The subsequent reaction is carried out in the presence of the alkyl halide of general formula R,2-Hal, where Hal is chosen from among a group comprising chlorine, iodine or bromine, and R,2 is as previously described, in the presence of a base, chosen in the group comprising alkaline or alkaiine-earth hydrides, in an aprotic polar inert solvent, for example tetrahydrofuran or dioxane. Preferably the reaction is carried out at 0°C in tetrahydrofuran, using sodium hydride as a base and methyl iodide as alkylating agent.

The condensations described in the various schemes may be conveniently carried out according to any of the procedures described in the literature for the synthesis of peptides.

Excellent results, in terms of yield and purity of the products, have been obtained using, as condensing agent, benzotriazolyl tripyrrolidine phosphonio hexafluorophosphate (PyBop). In particular, the reaction was carried out adding PyBop slightly in excess to a solution of the carboxylic component, which was kept at a low temperature, foliowed by addition of the hydrochloride of the amine component and of a quantity of tertiary amine corresponding to three equivalents with respect to the condensing agent.

An alternative procedure involves the use, as condensing agent, of 1-ethyl-3-(3'- dimehtylaminopropyl)carbodiimide (WSC.HCI).

As regards the condensation reaction, which may be convenientiy carried out at room temperature, conventional aprotic polar organic solvents are used, chosen in the group comprising dimethylformamide, dioxane, tetrahydrofuran, methylene chloride, dichloroethane, and chloroform.

A further characteristic of the present invention are therefore the processes of synthesis of the intermediates of general formulas (II) and (III), and the said intermediates that are obtained from the said processes.

The compounds of the present invention may exist in various isomeric forms. In

fact, whilst the configuration of the carbon linked to the substituent is uniquely pre- fixed by using during the synthesis the appropriate aminoacid derivative, the other starting products may consist of mixtures of stereoisomers that are difficult to separate. Consequently, the compounds of the present invention may be obtained as mixtures of diastereoisomers. The said mixtures may be resolved by chromatography. The compounds of formula (I) may in any case be used both in the optically active form and in the form of mixtures of isomers.

For therapeutical purposes, the compounds of the present invention may be administered through the parenteral intranasal, oral or sub-lingual routes. The formuiations containing the new compounds may be prepared, according to known techniques, combining the active principle with an inert vehicle, and possibly with suitably chosen conventional additives. For oral or sub-lingual use, the compounds of the present invention may be administered in the form of tablets, capsules, drops, elixirs, etc., prepared using conventional vehicles/excipients, such as starch, sugars, water, alcohol, etc., and possibly containing flavouring agents, stabilizing agents, preserving agents, lubricants, etc.

For parenteral or intranasal use, the vehicle of choice is sterile water for injections.

Additives may be added according to the known art.

The therapeutically effective daily dosage will vary according to the subject to be treated (weight, age, degree of seriousness of the illness) and administration route. In general, however, the compounds of the invention are active when they are administered in a daily dosage of between 0.005 and 10 mg/kg. The pharmaceutical formulations of the present invention will thus contain the compounds of general formula (I) in quantities such as to guarantee an appropriate daily dosage within the range specified above, generally for administration from once to three times a day.

There follow a number of examples that are representative of the present invention, and the methods for their synthesis: Example 1 <BR> <BR> <BR> <BR> (1 R,2S)-1 -N-( 1 (H )indol-3-yl-carbonyl)-2-N(Namethyl-N(4-methyl-phenylacetyl)D - 3(2-naphthyl)alanyl)-diamino-cyclohexane and (1 s,2R)-1 -N-[(1 (H)indol-3-yl- carbonyl)-2-N (Namethyl-N(4-methyl-phenyiacetyl )D-3(2-naphthyl) alanyl)-

diaminocyclohexane 1a)0xalyl chloride (512 coil) is added to a solution of 3-indolyl carboxylic acid (0.630 g) in 10 ml of CH2CI2, and the solution is refluxed for 2 hours in nitrogen atmosphere. The solvent is eliminated by evaporation, and the solid is washed with hexane and dried under a stream of nitrogen to obtain crude acyl chloride (yield, 82%), which is passed on to the subsequent reaction without undergoing any further purification processes. A solution of the acyl chloride (0.530 g) in tetrahydrofuran (THF) is added, in nitrogen atmosphere in a period of 2 hours, to a solution of cis 1,2 diaminocyclohexane (1.15 ml) and diisopropyiethylamine (DIEA) (0.61 ml) in 50 ml of THF. At the end of the addition, the solution is filtered, the filtrate is concentrated under reduced pressure, and the residue distributed between ethyl acetate (EtOAc) and HCI 1N in water. The aqueous phase is brought to pH 11 using NaOH and extracted with EtOAc. The organic extracts are re-united, washed with a saturated NaCI solution, de-hydrated on Na2SO4, and dried. The crude residue is triturated with CH3CN, filtered and dried to yield 473 mg of cis-N-{( 1 (H )indol-3-ylcarbonyl)- 1 2-diaminocyclohexane.

TLC[chloroform/methanol/acetic acid 85/10/5 v/v (CMA)] R, = 0.12 For high-pressure liquid chromatography (HPLC), a column Phase Sep.

Spherisorb ODS.2 5m 46 x 250 mm was used, and as eluents the following: A = 0.1 trifluoroacetic acid in acetonitrile; B = 0.1 trifluoroacetic acid in water; linear gradient from 20% of A to 80% of A in 25 min; isocratic 80% of A for 10 min; flow 1 ml/min; UV detection at 230 nm.

HPLC analysis revealed a single peak at TR = 14.44 min.

1 b) Oxalyl chloride (462 ,xLI) is added to a solution of para-tolylacetic acid (0.530 g) in 10 ml of CH2CI2 (DCM), and the solution is refluxed for 1 hour in nitrogen atmosphere. The solvent and the excess oxalyl chloride are eliminated to obtain the crude acyl chloride (0.595 g), which is passed on to the subsequent reaction without undergoing any further purification processes. Bis(trimethylsilyl)acetamide (1.96 ml) is added to a suspension of D-3-(2-naphthyl)alanine (0.775 g) in 12 ml of THF. The suspension is kept stirred at room temperature until complete dissolution (approx. 1 hour), cooled down to 0°C, and a solution of the chloride of the para-tolylacetic acid (0.595 g) is added under stirring. The product is kept

stirred for 16 hours at room temperature. To this, 5 ml of water are added, and the solution is kept stirred for half an hour. The solvent is eliminated by evaporation under reduced pressure, and the residue is distributed between EtOAc and water.

The organic phase is extracted with an aqueous solution and an NaCI saturated aqueous solution. The organic phase is dried. The crude product is crystallized using EtOAc to yield 0.953 g of Nx (4-methylphenylacetyl)-D-3(2-naphthyl)alanine.

TLC(CMA) R, = 0.60; [aD] = -65.1° (c 0.805, CH3OH) HPLC analysis revealed a single peak at TR = 20.24 min.

1c) Sodium hydride (58 mg, 80% in mineral oil) and iodomethane (0.306 ml) are added to a solution of the product of the previous step (0.213 g) in anhydrous THF (2 mi) kept at 0°C under stirring in a nitrogen atmosphere. The solution is kept stirred for 23 hours at room temperature. EtOAc is added, followed by 2 ml of water. The solvent is eliminated under reduced pressure, and the residue diluted in EtOAc and NaHCO3 5% aqueous solution. The aqueous phase is acidified to pH 2 using HCI 1N and extracted with EtOAc; the organic phase is washed with H2O, aqueous Na2S2O3, and finally with an NaCI saturated aqueous solution. The organic phase is filtered and dried. The crude product is purified by flash chromatography, eluting with acetic acid/toluene (27/63 viv) to yield 0.181 g of N" (4-methylphenylacetyl)-N<methyl-D-3(2-naphthyl)alanine.

TLC (20% acetic acid/toluene)R, = 0.23; [a]D = +54.7° (c 0.541, CH3OH) HPLC analysis revealed a single peak at TR = 22.66 min.

Id) 1 -ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCI) (0.285 g) is added in a single portion to a solution, cooled down to 0°C, of the product of step 1a (0.467 g), the product of the previous step 1 c (0.438 mg), and 7-aza-1-hydroxybenzotriazole (HOAt) (0.202 g) in 15 ml of DCM. Collidine (0.437 ml) is added, and the solution is kept at room temperature for 24 hours. After the solvent has been eliminated under reduced pressure, the residue is diluted in ethyl acetate and extracted with a 5% solution of NaHCO3, an aqueous solution of HCI 0.1N, and an NaCI saturated aqueous solution. The organic phase is dried.

The two diastereoisomers are isolated by means of reverse-phase chromatography using a Hibar Merck column with 7-m Lichrosorb RP-18 filling, eluting with a gradient of from 32% water in methanol to 12% water in methanol

over a period of two hours, flow 8 ml/min. The fractions corresponding to the two isolated diastereoisomers are concentrated to a small volume under reduced pressure and lyophilized, yielding respectively 0.267 g and 0.254 g of the two diastereoisomers (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4 methyl-phenylacetyl)D-3(2-naphthyl)alanyl)-diamino-cyclohexa ne and (1 S,2R)-1 - <BR> <BR> <BR> <BR> N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phen ylacetyl)D-3(2<BR> <BR> <BR> <BR> <BR> <BR> naphthyl)alanyl)-diaminocyclohexane.

HPLC analysis, in the conditions of example 1a, revealed for each of the two products (defined as fast and slow according to whether they are eluted by the column before or after, respectively) a single peak: HPLC (fast) (Prog. 6) TR = 27.20 min. HPLC (slow) TR = 29.21 min.

Following a similar scheme of synthesis the following were prepared: Example 2 (1 R,2S )-1 -N-[(1 (H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(phenylacetyl)D-3(2 - naphthyl)alanyl)-diaminocyclohexane and (1S,2R)-1-N-[(1(H)indol-3-yl-carbonyl)- 2-N(Nαmethyl-Nα(phenylacetyl)D-3(2-naphthyl)alanyl)-diamin ocyclohexane Example 3 (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-c hlorophenylacetyl)D 3(2-naphthyl)alanyl)-diaminocyclohexane and (I S,2R)-I -N-[(I (H)indol-3-yi- carbonyl)-2-N(Nαmethyl-Nα(4-chlorophenylacetyl)D-3(2-napht hyl)alanyl)- diaminocyclohexane Examnle 4 (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(3,4 -dimethyl- phenylacetyl)D-3(2-naphthyl)alanyl)-diaminocyclohexane and (1S,2R)-1-N- [(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(3,4-dimethyl-ph enylacetyl)D-3(2- naphthyl)alanyl)-diaminocyclohexane Example 5 (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-t rifluoromethyl phenylacetyl)D-3(2-naphthyl)alanyl)-diaminocyclohexane and (1 S ,2R)- 1-N- <BR> <BR> <BR> <BR> [(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-trifluorometh yl-phenylacetyl)D-3(2- naphthyl)alanyl )-diaminocyclohexane

Example 6 <BR> <BR> <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-b romo-phenylacetyl)D- 3(2-naphthyl)alanyl)-diaminocyclohexane and (1 S,2R)-1-N-[(1 (H)indol-3-yl- carbonyl)-2-N(Nαmethyl-Nα(4-bromo-phenylacetyl)D-3(2-napht hyl)alanyl)- diaminocyciohexane Example 7 <BR> <BR> <BR> <BR> <BR> (1S,2R)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D- 3(3,4-dichlorophenyl)alanyl)-diaminocyclohexane and (1 R,2S)-1 -N-[(1 (H)indol-3- yl-carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phenylacetyl)D-3(3,4 - dichlorophenyl)alanyl)-diaminocyclohexane Example 8 (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-t rifluoromethyl- phenylacetyl)D-3(3,4-dichlorophenyl)alanyl)-diaminocyclohexa ne and (1 S,2R)-1 - N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-trifluorome thyl-phenylacetyl)D- 3(3,4-dichlorophenyl)alanyl)-diaminocyclohexane Example 9 <BR> <BR> <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-b romo-phenylacetyl)D- 3(3,4-dichlorophenyl)alanyl)-diaminocyclohexane and (1S,2R)-1-N-[(1 (H)indol-3- <BR> <BR> <BR> <BR> <BR> yl-carbonyl)-2-N(N«methyl-N«(4-bromo-phenylacetyl)D-3(3,4- <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> dichlorophenyl)alanyl)-diaminocyclohexane Example 10 (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nα(4-methyl-phen ylacetyl)D-3(3,4- dichlorophenyl)alanyl)-diaminocyclohexane and (1 S,2R)-1 -N-[(1 (H)indol-3-yl- carbonyl)-2-N(Nα(4-methyl-phenylacetyl)D-3(3,4-dichlorophen yl)alanyl)- diaminocyclohexane Examole 11 (1 R,2S )-1 -N-[(1 (H )indol-3-yl-carbonyl)-2-N(N«methyl-N«(3,4-d imethyl- phenylacetyl)D-3(3,4-dichlorophenyl) alanyl)-diaminocyclohexane and (1S,2R)-1- <BR> <BR> <BR> <BR> <BR> N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(3,4-dimethyl- phenylacetyl)D-3(3,4- dichlorophenyl) alanyl)-diaminocyclohexane Examole 12

(I R,2S)-I -N-[(I (H )indoi-3-yl-carbonyl)-2-N(N«methyl-N«(3,4-dichloro- phenylacetyl)D-3(3,4-dichlorophenyl) alanyl)-diaminocyclohexane and (1S,2R)-1- <BR> <BR> <BR> <BR> <BR> N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(3,4-dichloro- phenylacetyl)D-3(3,4- dichlorophenyl) alanyl)-diaminocyclohexane Example 13 (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(3,4 -dichloro phenylacetyl)D-3(2-naphthyl)aianyl)-diaminocyclohexane and (1 S,2R)-1 -N- <BR> <BR> <BR> <BR> [(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(3,4-dichloro-ph enylacetyl)D-3(2-<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> naphthyl)alanyl)-diaminocyclohexane Example 14 <BR> <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D- 3(2-naphthyl)alanyl)-diamino-4-hydroxy-cyclohexane and (1 S,2R)-1 -N-[(1 (H)indol- <BR> <BR> <BR> <BR> <BR> 3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phenylacetyl)D-3(2 -naphthyl)alanyl)-<BR> <BR> <BR> <BR> <BR> <BR> <BR> diamino-4-hydroxy-cyclohexane Example 15 <BR> <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D 3(2-naphthyl)alanyl)-diamino-5-hydroxy-cyclohexane and (1S,2R)-1-N-[(1 (H )indol- 3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phenylacetyl)D-3(2 -naphthyl)alanyl)- diamino-5-hydroxy-cyclohexane Example 16 <BR> <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D- 3(2-naphthyl)alanyl)-diamino-(4,5-dihyd roxy)-cyclohexane and (1 S ,2R)-1 -N- <BR> <BR> <BR> <BR> [(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phenyl acetyl)D-3(2<BR> <BR> <BR> <BR> <BR> <BR> <BR> naphthyl)alanyl )-diamino-(4,5-dihyd roxy)-cyclohexane Example 17 <BR> <BR> <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D 3(3,4-dichlorophenyl)alanyl)-diamino-(4-hydroxy)-cyclohexane and (1 S,2R)-I -N- <BR> <BR> <BR> <BR> [(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phenyl acetyl)D-3(3,4-<BR> <BR> <BR> <BR> <BR> <BR> <BR> d ichlorophenyl )alanyl)-d iamino-(4-hyd roxy)-cyclohexane Example 18 <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D

3(3,4-dichlorophenyl)alanyl)-diamino-5-hydroxy-cyclohexane and (1 S,2R)-1 -N- [(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phenyl acetyl)D-3(3,4- dichlorophenyl)alanyl)-diamino-5-hydroxy-cyclohexane Example 19 <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D- 3(3,4-dichlorophenyl)alanyl)-diamino-(4,5-dihydroxy)-cyclohe xane and (1S,2R)-1- N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phen ylacetyl)D-3(3,4- dichlorophenyl)alanyl)-diamino-(4 ,5-dihydroxy)-cyclohexane Example 20 <BR> <BR> <BR> (2R,3S)-2-N-[(1(H)indol-3-yl-carbonyl)-3-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D- 3(2-naphthyl)alanyl-diaminopiperidine and (2S,3R)-1-N-[(1(H)indol-3-yl-carbonyl)- <BR> <BR> <BR> 2-N(Nαmethyl-Nα(4-methyl-phenylacetyl)D-3(2-naphthyl)alany l)-diaminopiperidine Example 21 <BR> <BR> <BR> (3R,4S)-3-N-[(1(H)indol-3-yl-carbonyl)-4-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D- 3(2-naphthyl)alanyl-diaminopiperidine and (3S,4R)-1-N-[(1(H)indol-3-yl-carbonyl)- <BR> <BR> <BR> 2-N(Nαmethyl-Nα(4-methyl-phenylacetyl)D-3(2-naphthyl)alany l)diaminopiperidine Example 22 <BR> <BR> <BR> (3R,4S)-3-N-[(1(H)indol-3-yl-carbonyl)-4-N(Nαmethyl-Nα(4-m ethyl-phenylacetyl)D- 3(3,4-dichlorophenyl)alanyl)-diaminopiperidine and (3S,4R)-1-N-[(1 (H)indol-3-yl- <BR> <BR> <BR> carbonyl)-2-N(Nαmethyl-Nα(4-methyl-phenylacetyl)D-3(3,4-di chlorophenyl)alanyl)- diaminopiperidine Example 23 <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα4-me thyl-phenylacetyl)D- 3(2-naphtyl)alanyl-4-amino-diamino cyclohexane and (1S,2R)-1-N-[(1(H)indol-3- yl-carbonyl)-2-N (Namethyl-Na4-methyl-phenyiacetyl)D-3(2-naphtyl)alanyl )-4-amino -diamino cyclohexane; Example 24 <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα4-me thyl-phenylacetyl)D- 3(2-naphtyl)alanyl-4-dimethylamino-diamino cyclohexane and (1 S,2R)-1-N- [(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα4-methyl-phenyla cetyl)D-3(2 naphtyl)alanyl-4-dimethylamino-diamino cyclohexane

Example 25 <BR> <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα4-me thyl-phenylacetyl)D- 3(2-naphtyl)alanyl)-diamino-5-amino cyclohexane and (1 S,2R)-1-N-[(1 (H)indol-3- yl-carbonyl)-2-N(Namethyl-Na4-methyl-phenylacetyl )D-3(2-naphtyl )alanyl )-5-amino -diamino cyclohexane Example 26 <BR> <BR> <BR> <BR> (1R,2S)-1-N-[(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα4-me thyl-phenylacetyl)D 3(2-naphtyl)alanyl)-5-dimethylamino-diamino cyclohexane and (1 S,2R)-1 -N- [(1(H)indol-3-yl-carbonyl)-2-N(Nαmethyl-Nα4-methyl-phenyla cetyl)D-3(2- naphtyl)alanyl)-5-dimethylamino-diamino cyclohexane Evaluation of the antagonist activity on NK-1 receptors was carried out with binding and functional in vivo assays and in vivo inhibition of bronchospasm induced by the agonist via intravenous administration.

The IM9-cell [H]SP binding assay was carried out as described in patents WO 95/15311 and WO 95/19965, and affinity was measured as pKi.

A functional assay in the isolated ileum of the guinea pig was carried out as described in patents WO 95/15311 and WO 95/19966, and the corresponding pA2 values were calculated on the basis of the data thus obtained.

The antibronchospastic effect was evaluated using the method described by Perretti et al. in European Journal of Pharmacology, 273 (1995)129-135.

[Sar9, Met(O2)1'] P substance is administered by intravenous route in doses of 1 nmol./kg at 15, 30 and 45 minutes before, and at 5, 30, 60, 90, 120, 150, and 180 minutes after IV administration of the vehicle or of the compounds to be tested (dose 0.08-1 ,umol./kg).

Bronchoconstriction was evaluated in terms of increase in intra-pulmonary pressure.

The antagonist effect of the compound was determined as ED50, expressed in mol./kg, defined as the dose of antagonist necessary to decrease by 50% the bronchoconstrictive effect of the agonist for the entire duration of period of observation.

In the following TABLE the compound according to Example 1 was compared to the structurally closely related compounds described in Examples 3 and 11 of WO 95/1531 1.

TABLE Compounds pKi pA2 ED50 Ex. 1 9.6 10.3 0.04 WO 95/15311 Ex. 3 8.4 1.0 WO 95/15311 8.4 0.069 Ex. 11 SCHEME 1 SCHEME 2