WO2005000845A2

WO2005000845A2 - Bicyclic derivatives as nk-1 and nk-2 antagonists

Info

Publication number: WO2005000845A2
Application number: PCT/EP2004/051210
Authority: WO
Inventors: Giuseppe Arnaldo Maria Giardina; Stefania Gagliardi
Original assignee: Nikem Research S.R.L.
Priority date: 2003-06-25
Filing date: 2004-06-23
Publication date: 2005-01-06
Also published as: ITMI20031292A1; ITMI20031292A0; WO2005000845A3

Abstract

Novel derivatives of formula (1) endowed with antagonistic activity towards the neurokinin-1 (NK-1) and.neurokinin-2 (NK-2) receptors and the preparation procedure thereof are described. The compounds of the invention are useful in the prevention and/or treatment of diseases dependent upon the stimulation of the NK-1 and NK-2 receptors. Formula (I) or a salt and/or solvate thereof, wherein Z is N or CH; represents on the condition that when A is Z does not represent N.

Description

BICYCLIC DERIVATIVES AS NK-1 AND NK-2 ANTAGONISTS

FIELD OF THE INVENTION

The present invention relates to novel compounds, particularly to novel arylmethylazacyclic derivatives, to processes relating to the preparation thereof, to the pharmaceutical compositions containing them and to the therapeutic use thereof. The compounds of the invention bind to specific membrane receptors, particularly to neurokinin-1 (NK-1) and neurokinin-2 (NK-2) receptors.

PRIOR ART

The mammalian tachykinins, also known as neurokinins, are a family of small peptides which have the same carboxy-terminal region Phe-X-Gly-Leu-Met- NH₂ in common; the principal members are substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) (Maggio, J.E. Ann. Rev. Neurosc. 1988, 11, 13; Maggi, C.A., Patacchini, R., Rovero, P. and Giachetti, A. J. Auton. Pharmacol. 1993, 13, 23). Tachykinins are distributed differently throughout the central nervous system (CNS) and in the peripheral nervous system, where they are predominantly localised at the peripheral ends of the capsaicin-sensitive primary afferent neurons (amyelinic C fibres) which innervate numerous sites, particularly the airways, the gastrointestinal tract, the urinary tract and the skin (Holzer, P. Neurosci. 1988, 24, 739; Otsuka, M. and Yoshioka, K. Physiol. Rev. 1993, 73, 229; Maggi, C.A., Giachetti, A., Dey, R.D. and Said, S.I. Physiol. Rev. 1995, 75, 277; Maggi, CA. Pharm. Res. 1996, 33, 161). The actions of tachykinins are mediated by at least three distinct G-protein coupled receptors, defined as neurokinin-1 (NK-1), neurokinin-2 (NK-2) and neurokinin-3 (NK-3) (Maggio, J.E., Mantyh, P.W. and

Iversen, L.L. Historical perspectives of tachykinins. In: The tachykinin receptors. Buch, S.H. (Ed.). Humana Press: Totowa, NJ 1994, 1-38). The endogenous tachykinin ligands interact with all the tachykinin receptors, although there is a defined agonist rank order of potency such that SP, NKA and NKB have the highest affinities for the NK-1 , NK-2 and NK-3 receptors, respectively. In situ hybridization and in vitro autoradiography esperiments showed that the NK-1 receptors are widely distributed in the human brain area with the highest NK-1 mRNA levels localized in the locus coeruleus and ventral striatum (Caberlotto, L. Eur. J. Neurosci. 2003, 17, 1736). In the perifery the receptor is localized in the paratiroid and, mucosal glands, in the lung (Mapp, C.E. Am. J. Respir. Crit Care Med. 2000; 161, 207), genitourinary and gastrointestinal tracts (Quartara, L. Neuropeptides. 1998; 32, 1) small arteries (Kummer, W. Neurosci Lett. 1999; 259, 119) and monocytes (Germonpre, P.H. Eur Respir. J. 1999; 14, 776)

At the peripheral level, messenger RNA (mRNA) for the NK-2 receptor has been predominantly identified in the lungs, bronchia, urinary bladder, stomach, large intestine, adrenal gland, testis (Tsuchida, K., Shigemoto, R., Yokota, Y. and Nakanishi, S. Eur. J. Biochem. 1990, 193, 751) and in the brain, including the hippocampus (Hagan R.M. et al., Regul. Peptides, 1993, 46, 9). Among the different non-peptide NK-1 antagonists known, aprepitant (5-

[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)- 4-morpholinyl]methyl]-1,2-dihydro-3H-1 ,2,4-triazol-3-one) is now on the market for control of acute and delayed nausea and emesis associated with cancer chemotherapy. Phase III clinical trials are ongoing to test the compound for depression and anxiety treatment.

A number of peptide and non-peptide antagonists of the NK-2 receptor are known; particularly the derivatives SR 48,968 or saredutant ((S)-(-)-N-methyl- N-[4-(4-acetylamino-4-phenylpiperidin-1-yl)-2-(3,4-dichIorophenyl)butyl] ben- zamide), SR 144,190, UK 224671, UK 290795 and the cydopeptide derivative nepadutant have reached various levels of pre-clinical and clinical development. Such compounds however require long and laborious chemical synthesis and have an unsatisfactory pharmacological profile (see low oral bioavailability, high metabolic clearance rate, interaction with cytochrome P450 (CYP450) isozymes, etc.). WO 00/58307 describes some 2,4- disubstituted pyridines fused with an aryl nucleus as selective ligands of the

NK-3 receptor; WO 00/02859, WO 00/20003, WO 00/20389, WO 00/69438, WO 02/051807 and WO 02/12168 describe some derivatives of naphthalene- 1-carboxamide as ligands of the NK-1 receptor. SUMMARY

We have now surprisingly identified a novel chemical class of naphthalene or heteropyridine carboxamides, substituted with a methylene azacyclic group, possessing antagonistic activity towards the NK1 and NK-2 receptor. Such compounds are represented by the structural formula (I)

(l)

wherein:

R is optionally substituted C-i-β linear or branched alkyl, optionally substituted C3-8 cycloalkyl , optionally substituted aryl or cyano;

Ri is optionally substituted Cι-₆ linear or branched alkyl, optionally substituted aryl, optionally substituted C -₈ cycloalkyl, C₃-₈ cycloalkyl C-M linear or branched alkyl, or aryl d^ linear or branched alkyl which may be substituted with an optionally substituted aryl group;

R₂ is hydrogen, optionally substituted Cι-₆ linear or branched alkyl or R₂ together with Ri forms a saturated heterocyclic ring comprising up to 8 ring member atoms, optionally condensed with an aromatic or aliphatic ring;

X is carbon, nitrogen or oxygen; n is 0, 1 or 2.

R₃ is hydrogen, C1-₆ linear or branched alkyl, optionally substituted aryl, aryl CM alkyl where the aryl group is optionally substituted and the Cι-4 alkyl group is linear or branched, hydroxy, hydroxy Cι.₆ alkyl, optionally substituted C3-₈ cycloalkyl , optionally substituted saturated heterocyclic group comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen;

R₄, which may be represented by up to two groups in the ring, is H or =O;

Rs and Re are independently hydrogen, optionally substituted C-ι-₆ linear or branched alkyl, optionally substituted aryl, aryl C-_M alkyl where the aryl group is optionally substituted and the C1-4 alkyl group is linear or branched, or R₅ and R₆ together form a saturated carbocyclic or heterocyclic ring comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen optionally condensed with an aromatic or aliphatic ring;

Z is N or CH; represents

on the condition that when A is

Z does not represent N.

The present invention also provides a process for the preparation of a compound of formula (I), or a salt and/or solvate thereof, which comprises the reaction of a compound of formula (II) or an activated derivative thereof:

(ll) wherein R, R₃, R₄, R5, R_Θ, Z, A, n and X are as defined for formula (I), or a group convertible into R₃, R4, Rs and Re respectively, with a compound of formula (III):

Ri

H N

(III) wherein R and R₂ are as defined for formula (I) .

In an alternative embodiment, the process comprises the reaction of a compound of formula (VII):

(VII) wherein R, Ri, R₂ A and Z are as defined for the compounds of formula (I) and l_ι represents a leaving group, such as a halogen atom e.g. bromine, or a mesylate, with a compound of formula (V):

wherein R₃, R*, R₅, R₆, n and X are as defined for the compounds of formula (I) or a protected form or a group convertible into R₃, R₄,Rs _Θ-

Thanks to their antagonistic activity towards NK-1 and NK-2 receptors, the compounds of formula (I) have useful pharmaceutical properties. Hence the present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use as an active therapeutic substance. Particularly, the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, for the treatment or the prophylaxis of diseases dependent on the stimulation of the NK-1 and NK-2 receptors (defined herein as NK-1/NK-2 diseases): belonging to such group of diseases are lung disorders, urinary tract and gastrointestinal tract disorders, ophthalmic diseases, cutaneous diseases, adverse immunological reactions, inflammatory diseases, neurogenic inflammations and peripheral neuropathies, CNS associated diseases, particularly anxiety, depression, psychoses and schizophrenia. The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the prevention and/or treatment of the aforesaid NK-1 /NK-2 diseases. Such medicament, and a composition of this invention, may be prepared by mixing a compound of the invention with an appropriate carrier.

This invention further provides a method for the treatment or the prophylaxis of the NK-1/NK-2 diseases in mammals, particularly in humans, which comprises the administration of a pharmaceutically acceptable, non-toxic quantity of a compound of formula (I), or a salt and/ or solvate thereof, to a mammal requiring such treatment and/or prophylaxis. DETAILED DESCRIPTION OF THE INVENTION According to the present invention a compound, or a salt and/or solvate thereof, of formula (I) is provided:

0) wherein:

R is optionally substituted Cι-₆ linear or branched alkyl, optionally substituted C₃-8 cycloalkyl , optionally substituted aryl or cyano;

Ri is optionally substituted C1-6 linear or branched alkyl, optionally substituted aryl, optionally substituted C₃.₈ cycloalkyl, C₃-₈ cycloalkyl C^ linear or branched alkyl, or aryl C1-4 linear or branched alkyl which may be substituted with an optionally substituted aryl group;

R₂ is hydrogen, optionally substituted C-β linear or branched alkyl or R₂ together with Ri forms a saturated heterocyclic ring comprising up to 8 ring member atoms, optionally condensed with an aromatic or aliphatic ring;

X is carbon, nitrogen or oxygen; n is 0, 1 or 2.

R₃ is hydrogen, C1-6 linear or branched alkyl, optionally substituted aryl, aryl C1-4 alkyl where the aryl group is optionally substituted and the C₁. alkyl group is linear or branched, hydroxy, hydroxy C₁-₆ alkyl, optionally substituted C3-8 cycloalkyl , optionally substituted saturated heterocyclic group comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen;

R4, which may be represented by up to two groups in the ring, is H or =O; Rs and Re are independently hydrogen, optionally substituted C1-6 linear or branched alkyl, optionally substituted aryl, aryl C-1-4 alkyl where the aryl group is optionally substituted and the C₁-₄ alkyl group is linear or branched, or R5 and RQ together form a saturated carbocyclic or heterocyclic ring comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen optionally condensed with an aromatic or aliphatic ring;

Z is N or CH;

represents

on the condition that when A is

Z does not represent N.

The C -₆ linear or branched alkyl group comprises methyl, ethyl, isopropyl, 3- methyl-but-2-yl and 3,3-dimethyl-but-2-yl; aryl comprises phenyl and thienyl; the C₃-₈ cycloalkyl group comprises cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl; the C₃-₈ cycloalkyl C alkyl group comprises cyclohexylmethyl; substituents for optionally substituted alkyl or aryl groups are e.g. Me, Cl, F, OMe, OH, CF₃, COOH. When Ri and R₂ together form a saturated heterocyclic ring comprising up to 8 ring member atoms optionally condensed with an aromatic or aliphatic ring, preferred rings are pyrrolidine, piperidine, isoindoline, indoline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4- tetrahydroquinoline; the optionally substituted saturated heterocyclic group comprising up to 8 ring member atoms and a maximum of 2 heteroatoms is preferably piperidine, piperazine and morpholine. Preferably, R is optionally substituted C3-8 cycloalkyl, phenyl or thienyl; more preferably, R is phenyl, thienyl or cyano. Preferably, Ri is Ci-6 linear or branched alkyl, C3.8 cycloalkyl group or C3-8 cycloalkyl C_M alkyl, or benzyl; more preferably Ri is 3-methyl-but-2-yl, 3,3- dimethyl-but-2-yl, cyclohexyl, cyclohexylmethyl, or 3,5-ditrifluoromethylbenzyl; or Ri together with R₂ forms a saturated heterocyclic group, more preferably a piperidinic ring or a 1 ,2,3,4-tetrahydroisoquinolinic ring. Preferably R₂ is hydrogen or C₁-₃ alkyl.

Preferably, X is carbon or nitrogen. Preferably, n is 1. Preferably, R₃ is hydrogen, C1-6 linear or branched alkyl, hydroxy d-C₆ alkyl, piperidin-1-yl, morpholin-4-yl; more preferably, R₃ is isopropyl, piperidin-1-yl, morpholin-4-yl.

Preferably, j is H. Preferably, R₅ and R₆ are independently hydrogen, optionally substituted C₁-₆ linear or branched alkyl, aryl, or together form a saturated carbocyclic ring or a heterocyclic ring comprising 6 ring member atoms and 1 heteroatom selected from nitrogen and oxygen; more preferably R₅ and Re are independently hydrogen or d-β linear or branched alkyl.

Preferably when Z is N, the ring indicated by A is selected from:

Particular compounds of the present invention are, for example:

3-[1 ,4'] BipiperidinyI-1 '-ylmethyl-2-phenyl-[1 ,8]naphthyridine^l-carboxylic acid cyclohexylamide;

3-[1 ,4]Bipiperidinyl-1 '-ylmethyl-6-bromo-2-phenyl-[1 ,8]naphthyridine-4- carboxylic acid cyclohexylamide; 2-[1,4lBipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid cyclohexylamide;

3-[1_I4']Bipiperidinyl-1^,-ylmethyl-4-(piperidine-1-carbonyl)-naphthalene-2- carbonitrile;

2-[1 ,4 Bipiperidinyl~1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid ((S)- 1 ,2,2-trimethyl-propyl)-amide;

2-[1 ,4']Bipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1-carboxylic acid 3,5- ditrifluoromethylbenzylamide dihydrochloride; 2-[1 ,4]Bipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid (3,5- ditrifluoromethyl-benzyl)-methyl-amide ditrifluoroacetate; 3-Cyano-2-(4-isopropyl-piperazin-1 -ylmethyl)-naphthalene-1 -carboxylic acid cyclohexylamide.

It will be noted that some compounds of formula (I) may contain one or more stereogenic centres. The present invention is extended to all the optical isomers of those compounds in entirely or partially resolved forms thereof and in the form of racemic mixtures. In a further aspect, the present invention provides a process for the preparation of a compound of formula (I), or a salt and/or solvate thereof, which comprises the reaction of a compound of formula (II) or an activated derivative thereof:

(ll)

wherein R, R₃, R4, Rs, Re. A, Z, n and X are as defined for formula (I), or a group convertible into R₃, R4, Rs and Re respectively, with a compound of formula (III):

(Ill) wherein Ri and R₂ are as defined for formula (I).

It is preferable that the compound of formula (II) be present as an activated derivative. A suitable activated derivative of a compound of formula (II) is a transiently activated form of the compound of formula (II) or a derivative wherein the carboxy group of the compound of formula (II) has been substituted with a different group or atom, for example by an acyl halide, preferably an acyl chloride, or an acyl azide or a carboxylic acid anhydride. Other suitable activated derivatives comprise: a mixed anhydride formed between the carboxylic portion of the compound of formula (II) and an alkyl chloroformate; an activated ester, such as cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phthalimide ester, N-hydroxypiperidiπe ester, N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester; alternatively, the carboxylic group of the compound of formula (II) may be activated by utilising a carbodiimide or N,N'- carbonyldiimidazole.

The reaction between the compound of formula (II) or the activated derivative thereof and the compound of formula (III) is carried out under conventional conditions appropriate for the particular compounds selected. Generally, when the compound of formula (II) is present as an activated derivative, the reaction is carried using the same solvent and conditions used for the preparation of said activated derivative; preferably the activated derivative is prepared in situ prior to the formation of the compound of formula (I). For example, the reaction between an activated derivative of the compound of formula (II) and the compound of formula (III) may be carried out by :

(a) preparing an acyl chloride and adding the compound of formula (III) to said acyl chloride in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF) or methylene chloride at a temperature comprised of between -70 and 50°C (preferably between -10 and 20°C); or

(b) treating the compound of formula (II) with a compound of formula (III) in the presence of a suitable condensing agent, such as for example N,N'- carbonyldiimidazole (GDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N'-ethylcarbodiimide, preferably in the presence of N-hydroxybenzotriazole (HOBT) in order to maximise the yields and avoid racemisation processes (for reference see Synthesis, 1972, 453), or O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronio hexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example a mixture with volumetric ratio comprised of between 1:9 and 7:3 (MeCN:THF), at whatever temperature able to provide an adequate percentage of formation of the required product, such as a temperature comprised of between -70 and 50°C, preferably between -10 and 25°C, for example 0°C The preferred reaction is described in Diagram 1 reported below:

Diagram 1

wherein R, Ri, R₂, R3, R4, Rs, Re, A, Z, n and X are as defined above for the compounds of formula (I).

In the case where the corresponding alkyl ester (such as methyl or ethyl) of the compound of formula (II) is used, hydrolysis of the compound of formula (II) is required prior to conversion to the compound of formula (I) of Diagram 1. Such hydrolysis may be carried out under acidic conditions, such as in 10-

35% hydrochloric acid at a temperature comprised of between 30 and 100 °C

Alternatively, compound of formula (I) can be prepared directly from compound of formula (II) obtained as alkyl ester (methyl or ethyl ester). In this case the alkyl ester (methyl or ethyl ester) of compound of formula (II) and compound of formula (III) are mixed and heated from 150°C to 200°C, using a microwave apparatus, for a suitable period of time, for 5 to 20 minutes. The compounds of formula (III) are known and commercially available compounds or may be prepared from known compounds using known methods, or analogous methods to those used for the preparation of known compounds, for example the methods described in Liebigs Ann. der Chemie, 1936, 523, 199.

The compounds of formula (II) or corresponding alkyl (such as methyl or ethyl) esters thereof are prepared through the reaction of a compound of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester thereof:

(IV)

wherein R, A and Z are as previously defined for the compounds of formula (I) and Li represents a leaving group, such as for example a halogen atom e.g. bromine, or a mesylate group, with a compound of formula (V):

(V)

wherein R3, R4, Rs, Re, n and X are as defined for the compounds of formula (I) or are a protected form or a group convertible into R₃, R-i.Rs and Re.

Appropriately, the reaction between the compounds of formula (IV) or the corresponding alkyl (such as methyl or ethyl) ester thereof and the compounds of formula (V) is carried out under conventional amination conditions; for example, when Li is a bromine atom or a mesylate, the reaction is appropriately carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature which provides an adequate percentage of formation of the required product, usually at room temperature; preferably the reaction is carried out in the presence of triethylamine (TEA) or K₂CO₃.

The compounds of formula (V) are known commercially available compounds or may be prepared by using analogous methods to those used for the preparation of known compounds; for example the methods described in Chemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968; Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.

The compounds of formula (IV) or the corresponding alkyl (such as methyl or ethyl) esters thereof may be prepared for example through the appropriate halogenation of a compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester thereof:

(VI)

wherein R, A, Z are as defined for the compounds of formula (I).

Suitable halogenation reagents are conventional reagents which depend on the nature of the halogen atom required; for example, when Li is bromine, the preferred halogenation reagent is N-bromosuccinimide (NBS). Halogenation of the compound of formula (VI) or the corresponding alkyl (such as methyl or ethyl) ester thereof is appropriately carried out under conventional conditions, for example, bromination is carried out through treatment with NBS in an inert solvent, such as carbon tetrachloride (CCI ), or 1 ,2-dichloroethane or CH3CN, at any temperature which provides an adequate percentage of formation of the required product, appropriately at high temperature such as a temperature comprised of between 60 °C and 100 °C, for example 80 °C; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.

The compounds of formula (VI) are compounds known in the literature (WO 00/58307 and WO 00/20389) or may be prepared using methods analogous those used in order to prepare known compounds.

In another aspect, the present invention provides a process for the preparation of a compound of formula (I), a salt and/or solvate thereof, the process of which comprises the reaction of a compound of formula (VII):

(VII) wherein R, Ri, R₂ A and Z are as defined for the compounds of formula (I) and Li represents a leaving group, such as a halogen atom such as for example a bromine atom, or a mesylate, with a compound of formula (V):

(V) wherein R₃, R4, R₅, R₆, n and X are as defined for the compounds of formula (I) or a protected form or a group convertible into R₃, R4, R5, Re-

Appropriately, the reaction between the compounds of formulas (VII) and (V) is carried out under conventional amination conditions; for example, when Li is a bromine atom, the reaction is conventionally carried out in an aprotic solvent, such as tetrahydrofuran or dimethylformamide at any temperature which provides an adequate percentage of formation of the required product, usually at room temperature; preferably the reaction is carried out in the presence of triethylamine (TEA) or K2CO₃.

The compound of formula (VII) is for example prepared through the appropriate halogenation of a compound of formula (VIII):

(VIII)

wherein R, Ri, R₂, A and Z are as defined for the compounds of formula (I).

Suitable halogenation reagents are conventional reagents which depend on the nature of the halogen atom required; for example, when Li is bromine, the preferred halogenation reagent is N-bromosuccinimide (NBS).

Halogenation of the compound of formula (VIII) is carried out under conventional conditions, for example, bromination is carried out through treatment with NBS in an inert solvent, such as carbon tetrachloride (CCI4), or 1 ,2-dichloroethane or CH3CN, at any temperature which provides an adequate percentage of formation of the required product, appropriately at a high temperature such as a temperature comprised of between 60 °C and 100 °C, for example 80 °C; preferably the reaction is carried out in the presence of a catalytic amount of benzoyl peroxide.

Appropriately, the compound of formula (VIII) may be prepared through the reaction of a compound of formula (VI) as defined above or an activated derivative thereof, with a compound of formula (III) as defined above.

It is preferable that the compound of formula (VI) be present in the reaction mixture as an activated derivative, as previously described.

The reaction between the compound of formula (VI) or the activated derivative thereof and the compound of formula (III) is carried out under conventional conditions appropriate for the particular compounds selected.

Generally, when the compound of formula (VI) is present as an activated derivative, the reaction is carried using the same solvent and conditions used for the preparation of said activated derivative; preferably the activated derivative is prepared in situ prior to the formation of the compound of formula (VIII).

For example, the reaction between an activated derivative of the compound of formula (VI) and the compound of formula (III) may be carried out by:

(a) preparing an acyl chloride and adding the compound of formula (III) to said acyl chloride in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF) at a temperature comprised of between -70 and 50°C (preferably between -10 and 20°C); or

(b) treating the compound of formula (VI) with a compound of formula (III) in the presence of a suitable condensing agent, such as for example N,N'- carbonyldiimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N'-ethylcarbodiimide, preferably in the presence of N-hydroxybenzotriazole (HOBT) in order to maximise the yields and avoid racemisation processes (for reference see Synthesis, 453, 1972), or O-benzotriazol-1-yl-N,N,N',N' tetramethyluronio hexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example a mixture with volumetric ratio comprised of between 1 :9 and 7:3 (MeCN:THF), at whatever temperature able to provide an adequate percentage of formation of the required product, such as a temperature comprised of between -70 and 50°C, preferably between -10 and 25°C, for example 0°C The preferred reaction is described in Diagram 2 reported below:

Diagram 2

(VI) (III) (VIII)

In the case where the corresponding alkyl (such as methyl or ethyl) ester of the compound of formula (VI) is used, hydrolysis is required prior to conversion to the compound of formula (VIII) of diagram 2. Such hydrolysis may be carried out under acidic conditions, such as in 10-35% hydrochloric acid at a temperature comprised of between 30 and 100 °C

Thanks to their antagonistic activity towards NK1 and NK-2 receptors, the compounds of formula (I) have useful pharmaceutical properties. Hence the present invention further provides a compound of formula (I), or a pharmaceutically salt and/or solvate thereof, to be used as an active therapeutic substance.

Particularly, the present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, for the treatment or the prophylaxis of diseases dependant on the stimulation of the NK-1 and NK-2 receptors (defined herein as NK-1/NK-2 diseases). Indeed, thanks to the strategic localisation of the NK1 and NK-2 receptors and the proven efficacy of various NK-1 and NK-2 receptor antagonists in animal models of various pathologies, the compounds of the present invention are particularly useful in the treatment of lung disorders (especially useful in the treatment of bronchospastic and inflammatory components of asthma, in chronic obstructive lung diseases, coughs, hyper-reactivity of the airways and irritation of the lung); in urinary tract disorders (particularly urinary incontinence and the syndromes associated with diseases of the bladder), in cystitis associated inflammatory processes of the bladder and urethra, in kidney infections, in colics and spasms of the biliary tract; in disorders of the gastrointestinal tract (particularly in the disorders associated with neuronal bowel control such as intestinal spasms, ulcerative colitis, Crohn's disease, irritable bowel syndrome and the gastroesofageal reflux disorders); in ophthalmic diseases such as ocular inflammation, conjunctivitis, spring conjunctivitis and the like, in cutaneous ailments such as sores and burns, in itching skin disorders, such as contact dermatitis, atopical dermatitis, urticaria and other eczematoid dermatitis, itching and psoriasis; in adverse immunological reactions such as the rejection of transplanted tissues and disturbances correlated with immunological enhancement or compromise such as systemic lupus erythematosus; in inflammatory diseases such as fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain, in neurogenic inflammations and peripheral neuropathies, CNS associated diseases, particularly anxiety, depression, psychoses and schizophrenia.

The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment of the aforesaid NK-1 /NK-2 diseases. Such medicament, and a composition of this invention, may be prepared by mixing a compound of the invention with an appropriate carrier. The mixture may contain a diluent, a binder, a filler, a disintegrant, a flavouring agent, a colouring agent, a lubricant or a preservative according to conventional methods. Those conventional excipients may be used for example as for the preparation of the compositions of known agents for the treatment of the NK-1 /NK-2 diseases.

Preferably, a pharmaceutical composition of the invention is in the form of a unit dose and in a form adapted for use in the medicinal or veterinary fields. For example, such preparations may be in multiple packs endowed with written or printed instructions for use as an agent in the treatment or prophylaxis of the NK-1 /NK-2 diseases. The suitable dosage interval for the compounds of the invention depends on the compound which must be used and the conditions of the patient. It further depends, amongst others, on the relationship between strength and absorption and on the frequency and route of administration.

The compound or the composition of the invention may be formulated for administration through whichever route, and is preferably in unit dose form or in such a form whereby the patient may auto-administer a single dose. Advantageously, the composition is indicated for oral, rectal, topical, parenteral, endovenous or intramuscular administration. The preparations may be designed in order to allow the slow release of the active ingredient. The compositions may, for example, be in the form of tablets, capsules, sachets, ampoules, powders, granules, lozenges, reconstitutable powders or liquid preparations, for example solutions or suspensions, or suppositories.

The compositions, for example those adapted for oral administration, may contain conventional excipients such as binding agents, for example syrup, gum arabic, gelatine, sorbitol, tragacanth gum, or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants in tablets, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium glycolate or microcrystalline cellulose; or pharmaceutically acceptable composition agents, for example sodium lauryl sulphate. Solid compositions may be obtained through conventional mixing, filling and encapsulation methods and the like. Repeated mixing operations may be used in order to distribute the active agent in all the compositions by using ample quantities of filler. When the composition is in the form of a tablet, powder or lozenge, any suitable carrier may be used for the formulation of solid pharmaceutical compounds, for example magnesium stearate, glucose, sucrose, rice flour and gypsum. The tablets may be coated using the methods already known in normal pharmaceutical procedures. The composition may also be in the form of an ingestible capsule, for example made of gelatine containing the compound, optionally with a carrier or other excipients.

The compositions for liquid oral administration may be in the form, for example, of emulsions, syrups or elixirs, or may be presented in the form of a dry product to be reconstituted with water or other suitable carrier prior to use. Such liquid compositions may contain conventional additives such as suspension agents, for example sorbitol, syrup, methyl cellulose, gelatine, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, edible hydrogenated fats; emulsifying agents, for example lecithin, sorbitan monooleate or gum arabic; aqueous or non-aqueous vectors, which comprise edible oils, for example peanut oil, fractionated coconut oil, oily esters, for example glycerine esters, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline solution; preservatives, for example propyl or methyl p- hydroxybenzoate or sorbic acid; possibly flavouring agents or conventional colourants.

The compounds of this invention may furthermore be administered by routes other than oral. According to normal pharmaceutical procedure, the compositions may be formulated, for example, for rectal administration as suppositories. Furthermore, they may be formulated into injectable formulations in aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, for example sterile pyrogen free water or an oil acceptable for parenteral administration or a mixture of liquids. The liquid may contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes in order to make the solution isotonic with the blood, thickening agents, suspension agents or other pharmaceutically acceptable additives. Such formulations will be presented in unit dose form such as ampoules or disposable devices for injections, or in multi-dose forms such as vials from which the appropriate dose is withdrawn, or a solid form or concentrated liquid which may be used in order to prepare an injectable formulation. The compounds of this invention may furthermore be administered by inhalation, through the nasal or oral passages. Such administration may be carried out using a spray formulation comprising a compound of the invention and a suitable vector, optionally suspended, for example, in a hydrocarbon propellant.

The spray formulations comprise micronised particles of compound in association with a surfactant, solvent or dispersion agent in order to prevent the sedimentation of the suspended particles. Preferably, the dimensions of the particles of the compound should be comprised between 2 and 10 microns.

A further administration method of the compounds of the invention comprises transdermal administration by means of a patch. A transdermal formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thus allowing the compound to diffuse out of the adhesive through the skin for administration to the patient. In order to ensure a constant percentage of percutaneous absorption, already known pressure sensitive adhesives may be used such as natural or silicone rubber.

As already mentioned, the effective dose of compound depends on the particular compound used, on the conditions of the patient and on the frequency and route of administration. One dosage unit will generally contain from 20 to 1000 mg and will preferably contain from 30 to 500 mg, particularly 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may be administered one or more times per day, for example 2, 3 or 4 times per day, and the total daily dose for an adult weighing 70 kg will be comprised of between 100 and 3000 mg. Alternatively the unit dose will contain from 2 to

20 mg of active ingredient and will be administered in multiples, possibly, until reaching the previously indicated daily dose. Undesirable toxicological effects are not foreseen with the compounds of the invention if administered in accordance with the invention.

This invention further provides a method for the treatment and/or the prophylaxis of the NK-1 /NK-2 diseases in mammals, particularly in humans, which comprises the administration of a pharmaceutically acceptable, non- toxic quantity of a compound of formula (I), or a salt and/ or solvate thereof, to a mammal requiring such treatment and/or prophylaxis.

The strength of the compounds of the present invention as NK-1 and NK-2 receptor ligands, is determined by their capacity to inhibit the binding of the radiolabeled ligands [¹²⁵l]-[Sar⁹,Met(O₂)¹¹]-SP and [³H]-SR 48968 to NK-1 expressed by the human astrocytoma U-373Mg cell line and recombinant human NK-2 receptors respectively (Emonds-Alt et al. Life Sc , 1992, 15, PL101-PL106; Heulliet et al. J-.Neurochem., 1993, 60, 868-876).

The receptor binding studies used allow the determination of the concentration of compound necessary in order to reduce the specific binding of [¹²⁵l]-[Sar ,Met(O₂)¹ ]-SP and [³H]-SR 48968 to the NK-1 and NK-2 receptors respectively by 50% under equilibrium conditions (IC-so). Kj values have been determined from the IC₅₀ values according to the Cheng-Prusoff equation (Cheng and Prusoff Biochem Pharmacol, 1973, 22, 3099-3108)

For each compound tested, the receptor binding studies provide a mean Kj value on the basis of 2-5 separate experiments, carried out two or three times. Typically, the compounds of the present invention display Kj values comprised of between 0.5 and 1000 nM; the most potent compounds of the present invention display Kj values comprised of between 0.5 and 100 nM.

The NK-1 and the NK-2-antagonist activity of the compounds of the present invention is determined by their capacity to inhibit NK1 and NK-2 receptor mediated Ca²⁺ mobilisation in humans (Mochizuki et. al. J. Biol. Chem., 1994, 269, 9651-9658). Functional studies on the human receptors allow the determination of the concentration of compound necessary in order to reduce

SP and NKA agonist induced Ca** mobilisation by 50% (IC₅₀ values). In this study, the compounds of the present invention behave as antagonists. The therapeutic potential of the compounds of the present invention for the treatment of the NK-1 and NK-2 diseases may be determined by using appropriate disease models in rodents.

The following non-limiting examples illustrate the preparation of the compounds of the invention. EXPERIMENTAL PART

In the present section, the term "description" refers to the synthesis of process intermediates, and the term "example" refers to the synthesis of the final product of formula (I) according to the present invention.

Description 1. Ethyl (2-N-pivaloylaminopyridin-3-yl)glyoxalate

2,2-Dimethyl-N-pyridin-2-yl-propionamide (5.35 g, 30 mmol) was dissolved in anhydrous THF and the solution was chilled to - 78°C n-Buthyllithium (1.6 N in hexane, 50 ml, 80 mmol) was added dropwise maintaining the internal temperature below - 60°C. The reaction was stirred at -10°C for 3 h. Then the reaction was chilled to -78°C before adding a solution of diethyl oxalate (11 ml, 80 mmol) in anhydrous THF. The reaction mixture was stirred at -78°C for 15 min and then leaved at room temperature for other 15 min. The reaction was poured into iced water and extracted with Et₂O. The organic layer was washed with water, dried over Na₂SO₄, filtered and evaporated to dryness. The residue was purified by SiO₂ column chromatography (eluent hexane/EtOAc 1:1) obtaining 5.2 g of the title compound as a yellow solid, yield 60%.

MW: 278.31

Description 2. 3-Methyl-2-phenyl-[1,8]naphthyπ^'dine-4-carboxylic acid

A solution of ethyl (2-N-pivaloylaminopyridin-3~yl)glyoxalate (5.2 g, 18 mmol), prepared as in Description 1 , in water/ethanol (1:4, 75 ml) and 85% KOH (5 g, 75 mmol) was refluxed for 2 hours. Propiophenone (5 ml, 37 mmol) was added and the solution was refluxed for additional 24 hours. The organic solvent was removed under vacuum and the residue was dissolved in water and washed with CH2CI2. the aqueous phase was acidified with acetic acid and the precipitate was filtered and washed with water to give the title compound (3 g), yield 61%.

MW: 264.29 Description 3. 3-Methyl-2-phenyl-[1,8Jnaphthyridine-4-carboxylic acid methyl ester

Oxalyl chloride (7.5 ml, 85 mmol) was added dropwise to a suspension of 3- methyl-2-phenyl-[1 ,8]naphthyridine-4-carboxylic acid (4.5 g, 17 mmol), prepared as in Description 2, in CH₂CI₂ (150 ml). The reaction mixture was stirred at room temperature for 1 hour. The organic solvent was evaporated under vacuum and the residue was then suspended in CH2CI2 (100 ml) containing 10% MeOH and 10% Et,₃N. After stirring for 2 hours the organic solvent was removed under vacuum and the title compound (4.5 g) was obtained after purification by SiO₂ column chromatography; yield 94%.

MW:278.31

¹H-NMR (DMSO-de) δ: 9.07 (m, 1H); 8.72 (d br, 1H); 8.18 (dd, 1H); 7.69-7.48

(m, 6H); 3.94 (m, 1H); 2.35 (s, 3H); 2.03-1.05 (m, 10H)

Description 4. 3-Bromomethyl-2-phenyl-[1,8]naphthyridine-4-carboxylic acid methyl ester

N-Bromosuccinimide (6g, 32 mmol) and dibenzoylperoxide (0.4 g) were added to a solution of 3-methyl-2-phenyl-[1 ,8]naphthyridine-4-carboxylic acid methyl ester (4.5 g, 16 mmol), prepared as in Description 3, in CCI₄ (100 ml). The reaction mixture was refluxed for 2 hours. The organic solvent was removed under vacuum and the residue was suspended in CH2CI2. The suspension was filtered and the organic layer was washed with 10% NaHCO3, dried over Na2SO₄, filtered and evaporated to dryness. The crude residue was used for the next step without further purification.

Cι₈H₁₄BrNO₂

MW = 356.23

Description 5. 3-[1 ,4']Bipiperidinyl-1 '-ylmethyl-2-phenyl-[1,8]naphthyridine-4- carboxylic acid methyl ester.

4-Piperidinopiperidine (0.2 g, 1 mmol) and DIPEA (0.5 ml, 2.8 mmol) were added to a solution of 3-bromomethyl-2-phenyl-[1 ,8]naphthyridine-4- carboxylic acid methyl ester, prepared as in Description 4, in CH₂CI₂ e THF (1: 1, 50 ml). The reaction mixture was stirred at room temperature for 1 night. The organic solvent was evaporated to dryness and the residue was dissolved in AcOEt, washed with brine, dried over Na₂SO4, filtered and evaporated to dryness. The residue was purified by column chromatography (eluent CH₂CI₂/MeOH/NH₄OH 90:10:1 ) to yield 0.2 g of the title compound.

MW: 444.58

Description 6. 3-[1 ,4]'Bipiperidinyl-1 '-ylmethy!-2-phenyl-[1 , 8]naphthyridine-4- carboxylic acid.

3-[1 ,4lBipiperidinyl-1'-yImethyl-2-phenyl-[1 ,8]naphthyridine-4-carboxylic acid methyl ester (0.15 g, 0.33 mmol), prepared as in Description 5, was refluxed in 6N HCI (10 ml) for 2 hours. The solution was evaporated to dryness and the residue was triturated in CH₃CN to yield 0.14 g of a solid that was used in the next reaction step without purification.

MW: 430.55

Description 7. 3-[1 ,4']Bipiperidinyl-1 '-ylmethyl-6-bromo-2-phenyl-

[1,8]naphthyridine-4-carboxyIic acid methyl ester

N-Bromosuccinimide (12 g, 64 mmol) and dibenzoylperoxide (0.8 g) were added to a solution of 3-methyl-2-phenyl-[1,8]naphthyridine-4-carboxylic acid methyl ester (4.5 g, 16 mmol), prepared as in Description 3, in CCI₄ (100 ml).

The reaction mixture was refluxed for 20 hours. The solvent was evaporated to dryness and the residue was dissolved in AcOEt, washed with water, dried over Na2SO , filtered and evaporated to dryness. The crude reaction mixture was dissolved in CH₃CN and THF (1 :1 , 300 ml) and piperidinopiperidine (3.2 g, 17 mmol) and DIPEA (10 ml) were added. The reaction mixture was stirred for 1 hour at room temperature. The organic solvent was evaporated to dryness and the residue was dissolved in AcOEt, washed with brine, dried over Na₂SO , filtered and evaporated to dryness. The residue was purified by column chromatography to yield 1 g of the title compound. C₂₇H ιBrN₄O₂ MW = 523.48

Description 8. 3-[1 ,4']Bipiperidinyl-1 '-ylmethyl-6-bromo-2-phenyl-[1,8]- naphthyridine-4-carboxyiic acid.

3-[1 ,4 Bipiperidinyl-1 '-ylmethyl-6-bromo-2-phenyl-[1 ,8]naphthyridine-4- carboxylic acid methyl ester (1 g, 2 mmol), prepared as in Description 7, was refluxed in 6N HCI (30 ml) for 2 hours. The solution was evaporated to dryness and the residue was triturated in CH₃CN to yield 1 g of a solid that was used in the next reaction step without purification.

MW: 508.49

Description 9. 2-[1 ,4']Biplperidinyl-1 '-ylmethyl-3-cyano-naphthalene-1- carboxylic acid methyl ester

Λ/-Bromosuccinimide (0.79 g, 4.44 mmol) was added to a solution of 3-cyano- 2-methyl-naphthalene-1 -carboxylic acid methyl ester (500 mg, 2.22 mmol), prepared as described in J. Med. Chem., 2004, 47, 519-529 in CH₃CN (25 ml). The reaction was heated to reflux and dibenzoylperoxide (59 mg, 0.244 mmol) was added. The reaction was refluxed for 4 h. The solvent was evaporated in vacuo and the resulting solid was taken up in AcOEt and washed with water. The organic layer was dried over Na₂SO filtered and evaporated to dryness to yield 900 mg of crude 2-bromomethyl-3-cyano- naphthalene-1 -carboxylic acid methyl ester.

The crude product was dissolved in CH3CN:CH₂Cl2 (10:1 , 4 ml) and added dropwise to a suspension of 4-piperidinopiperidine (373 mg, 2.22 mmol) and K₂C0₃ (280 mg) in CH₃CN:CH₂CI₂ (10:1, 13 ml). The reaction was stirred overnight, then additional 4-piperidinopiperidine (148 mg, 0.88 mol) in CH₂CI₂ (2 ml) and Na₂CO3 (100 mg) were added. The reaction was stirred overnight at room temperature. The suspension was filtered and then evaporated to dryness. The resulting oil was purified by flash chromatography (eluent CH₂CI₂:MeOH:NH₄OH 100:4:0.5). The collected fractions yielded the title compound (559 mg) that crystallized as a yellow solid, yield 64%.

MW: 391.52

Description 10. 3-Cyano-2-methyl-naphthalene-1-carboxylic acid cyclohexylamide

3-Cyano-2-methyl-naphthalene-1 -carboxylic acid (100 mg, 0.473 mmol), was dissolved in CH₂CI₂ (4 ml) and DMF (2 ml). Λ-(3-dimethyIaminopropyl)-Λ/'- ethylcarbodiimide hydrochloride (181 mg, 0.946 mmol) and N- hydoxybenzotriazole (121.5 mg, 0.804 mmol), was added and the resulting solution was stirred at room temperature for 30 min. Cyclohexylamine (65 μl, 0.567 mmol) was added and the reaction was stirred for 4h at room temperature. Additional of cyclohexylamine (65 μl, 0.567 mmol) and Λ-methyl- morpholine (52 μl, 0.473 mmol) were added and the reaction was stirred overnight. The solvent was removed in vacuo and the resulting solid was taken up with AcOEt and washed with water, 1N HCI and then 1N NaOH. The organic phase was dried over Na₂SO₄ and evaporated in vacuo to give a yellow solid. This solid was stirred with Et₂θ and filtered off to give 3-cyano-2-methyl- naphthalene-1 -carboxylic acid cyclohexylamide (71 mg) as a white powder.

MW: 292.38

Example 1. 3-[1,4']Bipiperidinyl-1'-ylmethyl-2-phenyl-[1,8]naphthyridine-4- carboxylic acid cyclohexylamide

3-[1 ,4"]BipiperidinyI-1 '-ylmethyl-2-phenyl-[1 ,8]naphthyridine-4-carboxyIic acid (0.14 g, 0.34 mmol), prepared as in Description 6, was suspended in CH₂CI₂ (10 ml) and oxalyl chloride (0.2 ml, 2.3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. The organic solvent was evaporated to dryness and the residue dissolved in CH₂CI₂ (10 ml). This solution was added dropwise to a solution of cyclohexylamine (0.5 ml, 3 mmol) in CH2CI2. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with brine, dried over Na2SO₄, filtered and evaporated to dryness. The residue was purified by column chromatography to yield 35 mg of the title compound, mp = 250-251°C MW: 511.72

H-NMR (DMSO-d₆) δ: 9.09 (dd, 1 H); 8.59 (d br, 1 H); 8.27 (dd, 1H); 7.68 (dd, 1H); 7.60-7.43 (m, 5H); 3.90 (m, 1H); 3.56 (s, 2H); 2.57-2.31 (m, 7H); 1.98 (m, 2H); 1.80-1.06 (m, 20H).

El (source 180°C;70 V;200 uA): 345; 274; 248; 220; 167.

Example 2. 3-[1 ^Blpiperidinyl-l '-ylmethyl-6-bromo-2-phenyl-1,8]naphthyήdi- ne-4-carboxylic acid cyclohexylamide

3-[1 ,4"]BipiperidinyI-1 '-ylmethyl-6-bromo-2-phenyl-[1 ,8]naphthyridine-4- carboxylic acid (0.5 g, 1 mmol), prepared as in Description 8, was suspended in CH2CI2 (20 ml) and oxalyl chloride (0.4 ml, 5 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The organic solvent was evaporated to dryness and the residue dissolved in CH2CI2 (20 ml). This solution was added dropwise to a solution of cyclohexylamine (0.2 ml, 2 mmol) in CH2CI2. the reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with brine, dried over Na2SO , filtered and evaporated to dryness. The residue was purified by column chromatography to yield 100 mg of the title compound.

C₃₂H₄oBrN₅O MW: 590.61

El (source 180°C;70 V;200 uA): 590 (M+);

Preparation of 2-[1 ,4']Bipiperidinyl-1 '-ylmethyl-3-cyano-naphthalene-1- carboxylic acid amides. General procedure.

A mixture of 2-[1-4']bipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid methyl ester (0.153 mmol), prepared as in Description 9, and the suitable amine (0.612 mmol) was heated with a CEM Discover microwave apparatus at 180 °C for 10 min. The resulting black oil was taken up with AcOEt and washed with water. The aqueous phase was separated, basified to pH = 12 by adding 1M NaOH and extracted with AcOEt. The collected organic phases were dried over Na₂SO₄ and evaporated to dryness. The resulting oil was purified by flash chromatography (eluent CH₂CI₂:MeOH:NH₄OH 10:0.2:0.1) to yield the desired amide. Example 3-7 were prepared using this general procedure. Final compounds were sometimes isolated as salts.

Example 3. 2-[1_!4]'Bipipen^'dinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid cyclohexylamide

C₂₉H₃₈N₄O

MW: 458.65

¹H-NMR (CDCI3) δ: 8.24 (s, 1H); 8.14 (d, 1H); 7.90 (s br, 1 H); 7.86 (d, 1H); 7.68 (dd,1 H); 7.60 (dd,1 H); 4.12 (m, 1 H); 3.8 (s, 2H); 2.91 (m,2H); 2.94 (m, 3H); 2.28 (m, 2H); 2.15 (m, 2H); 1.94-1.15 (m, 20H). ESI Pos, 3.2 KV, 20 V, 300°C: 459.2 (MH+)

Example 4. 3-[1 ,4lBipiperidinyl-1 '-ylmethyI-4-(piperidine-1-carbonyl)- naphthalene-2-carbonitrile

C28H₃6N O

MW: 444.62 ¹H-NMR (CDCI3) δ: 8.22 (s, 1H); 7.88 (d, 1H); 7.81 (d, 1H); 7.65 (dd, 1H);

7.58 (dd, 1H); 4.24 (m, 2H); 3.89 (d, 1H); 3.54 (d, 1H); 3.53 (m, 1 H); 3.06 (m, 1 H); 3.01 (dd, 2H); 2.84 (m, 1H); 2.50 (m, 4H); 2.24 (dd, 1 H); 2.11 (dd, 1H); 1.88-1.22 (m, 16H). ESI Pos, 3.2 KV, 20 V, 300°C: 445.2(MH+)

Example 5. 2-[1,4']Bipiperidinyl~1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide

C₂₉H₄oN₄O MW: 460.66

[α]₂₀ ^D = 15.15 (c = 0.3%, MeOH) ¹H-NMR (CDCI₃) δ: 8.25 (s, 1H); 8.15 (d, 1 H); 7.99 (d br, 1H); 7.87 (d, 1H);

7.67 (dd, 1 H); 7.60 (dd, 1H); 4.33 (dq, 1 H); 3.90 (d, 1 H); 3.73 (d, 1H); 3.08 (m, 1H); 2.70 (m, 1 H); 2.52-2.19 (m, 7H); 1.86-1.78 (m, 10H); 1.30 (d, 3H); 1.01 (s, 9H). ESI Pos, 3.2 KV, 20 V, 300°C: 461.2 (MH+)

Example 6. 2-[1,4]'Bipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid 3,5-ditrifiuoromethylbenzylamide dihydrochloride

MW: 675.55 (salt), 602.62 (free base)

¹H-NMR (CDCI₃, detected as free base-333 K)δ: 9.84 (s br, 1H); 8.29 (s, 1 H); 8.24 (d, 1 H); 7.96-7.80 (m, 4H); 7.67 (m, 2H); 4.83 (d, 2H); 3.77 (s, 2H); 2.67 (m, 2H); 2.41-2.11 (m, 7H); 1.77 (m, 2H); 1.67-1.00 (m, 8H).

ESI Pos, 3.2 KV, 20 V, 300°C: 603.2 (MH+)

Example 7. 2-[1 ,4']Bipiperidinyi-1 '-ylmethyl-3-cyano-naphthalene-1-carboxylic acid (3, 5-ditrifIuoromethyl-benzyl)-methylamide ditrifluoroacetate

C₃₃H₃₄FeN₄O. 2C₂HF₃θ₂ MW: 844.7 (salt), 616.65 (free base)

¹H-NMR (CDCI₃, detected as free base-333 K) δ: 8.24 (s, 1H); 8.02 (s br,

2H). 7.90 (s, 1 H); 7.68-7.55 (m, 4H); 5.11 (d, 1H); 4.84 (d, 1H); 3.93 (d, 1H);

3.55 (d, 1 H); 2.93 (m, 1H); 2.79 (m, 1H); 2.70 (s, 3H); 2.54-2.41 (m, 3H);

2.26-1.04 (m, 4H); 1.77-1.20 (m, 10H). ESI Pos, 3.2 KV, 20 V, 300°C: 617.2 (MH+).

Example 8. 3-Cyano-2-(4-isopropyl-piperazin-1-ylmethyl)-naphthalene-1- carboxylic acid cyclohexylamide

3-Cyaπo-2-methyl-naphthalene-1 -carboxylic acid cyclohexylamide (71 mg, 0.243 mmol), prepared as in Description 10, was suspended in CCI (2 ml) and CH₃CN was added to ensure complete dissolution of the solid. N-

Bromosuccinimide (90.8 mg, 0.510 mmol) was added and the reaction mixture was heated to reflux before adding dibenzoylperoxide (6 mg, 0.024 mmol). The reaction was refluxed for 72 hours and, during this period, additional A/-bromosuccinimide (96 mg, 0.486 mmol) and dibenzoylperoxide (12 mg, 0.048 mmol) were added. The solvent was evaporated and 67 μl

(0.484 mmol) of triethylamine and 31 mg (0.242 mmol) of Λ/-isopropyl- piperazine were added to the crude solid dissolved in CH₂CI₂. The solution was stirred overnight at room temperature. The solvent was evaporated to dryness and the resulting oil was purified by flash chromatography (Eluent CH₂CI₂:MeOH:NH₃ 10:0.2:0.1) to yield 14 mg of the title compound that crystallized as a yellow solid. C₂₆H₃₄N₄O MW: 418.52

¹H-NMR (CDCI₃) δ: 8.24 (s, 1 H); 8.12 (d, 1 H); 7.86 (d, 1H); 7.66 (dd, 1H); 7.63 (d br, 1 H); 7.59 (dd, 1 H); 4.11 (m, 1 H); 3.83 (s, 2H); 2.76-2.41 (m, 7H); 2.16 (m, 2H); 1.81 (m, 2H); 1.72 (m, 1H); 1.62-1.39 (m, 3H); 1.37-1.15 (m, 4H);

1.03 (d br, 6H). ESI Pos, 3.2 KV, 20 V, 300°C: 419.2 (MH+)

The compounds of the invention when subjected to receptor binding tests according to the method described by Emonds-Alt et al. Life Sci., 1992, 15, PL101-PL106, have shown high binding affinity for the human NK-1 and NK-2 receptors.

Claims

1. A compound of formula (I):

(I) or a salt and/or solvate thereof,

wherein:

R is optionally substituted C₁-₆ linear or branched alkyl, optionally substituted C₃-₈ cycloalkyl , optionally substituted aryl or cyano;

Ri is optionally substituted C₁-₆ linear or branched alkyl, optionally substituted aryl, optionally substituted C3-8 cycloalkyl, C3-8 cycloalkyl CM linear or branched alkyl, or aryl C linear or branched alkyl which may be substituted with an optionally substituted aryl group;

R₂ is hydrogen, optionally substituted C1-₆ linear or branched alkyl or together with Ri forms a saturated heterocyclic ring comprising up to 8 ring member atoms, optionally condensed with an aromatic or aliphatic ring;

X is carbon, nitrogen or oxygen; n is 0, 1 or 2.

R3 is hydrogen, C₁-₆ linear or branched alkyl, optionally substituted aryl, aryl C alkyl where the aryl group is optionally substituted and the C1-4 alkyl group is linear or branched, hydroxy, hydroxy C1-₆ alkyl, an optionally substituted C₃-₈ cycloalkyl group, an optionally substituted saturated heterocyclic group comprising up to 8 ring member atoms and a maximum of

2 heteroatoms selected from nitrogen and oxygen; R4, which may be represented by up to two groups in the ring, is H or =O;

Rs and Re are independently hydrogen, optionally substituted C1-₆ linear or branched alkyl, optionally substituted aryl, aryl CM alkyl where the aryl group is optionally substituted and the C1-₄ alkyl group is linear or branched, or R5 and R₆ together form a saturated carbocyclic or heterocyclic ring comprising up to 8 ring member atoms and a maximum of 2 heteroatoms selected from nitrogen and oxygen optionally condensed with an aromatic or aliphatic ring;

Z is N or CH;

represents

on the condition that when A is

Z does not represent N.

2. A compound according to claim 1 wherein R is selected from cyano or an optionally substituted C₃-₈ cycloalkyl, phenyl or thienyl group.

3. A compound according to claims 1-2 wherein Ri is selected from C₁-₆ linear or branched alkyl, a C₃-₈ cycloalkyl group or a C₃-₈ cycloalkyl C₁--1 alkyl group, or benzyl.

4. A compound according to claims 1 -3, wherein Ri is selected from 3-methyl- but-2-yl, 3,3-dimethyl-but-2-yl, cyclohexyl, cyclohexylmethyl, 3,5- ditrifluoromethylbenzyl, or Ri together with R₂ forms a piperidinic or 1,2,3,4- tetrahydroisoquinolinic ring.

5. A compound according to claims 1-4, wherein R₂ is hydrogen or C1-₃ alkyl.

6. A compound according to claims 1-5, wherein X is selected from carbon or nitrogen, and n is 1.

7. A compound according to claims 1-6, wherein R₃ is selected from hydrogen, C1-6 linear or branched alkyl, hydroxy C1-C6 alkyl, piperidin-1-yl, morpholin-4-yI.

8. A compound according to claims 1-7, wherein R₄ is H.

9. A compound according to claims 1-8, wherein R₅ and Re are selected independently from hydrogen, C1-6 linear or branched alkyl, or together form a heterocyclic ring comprising 6 ring member atoms and 1 heteroatom selected from nitrogen and oxygen.

10. A compound according to claims 1-9, wherein Z is N, and the ring indicated by A is selected from

11. A compound according to claim 1 , selected from:

3-[1 ,4']Bipiperidinyl-1 '-ylmethyl-2-phenyl-[1 ,8]naphthyridine-4-carboxylic acid cyclohexylamide;

carboxylic acid cyclohexylamide;

2-[1 ,4^Bipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid cyclo- hexylamide;

3-[1 ,4"]Bipiperidinyl-1 '-ylmethyl-4-(piperidine-1 -carbonyl)-naphthalene-2- carbonitrile;

2-[1 ,4']Bipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid ((S)-

1 ,2,2-trimethyl-propyl)-amide; 2-[1 ,4']Bipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid 3,5- ditrifluoromethylbenzylamide dihydrochloride;

2-[1 ,4']Bipiperidinyl-1'-ylmethyl-3-cyano-naphthalene-1 -carboxylic acid (3,5- ditrifluoromethyl-benzyl)-methylamide ditrifluoroacetate;

3-Cyano-2-(4-isopropyl-piperazin-1-ylmethyl)-naphthalene-1-carboxylic acid cyclohexylamide.

12. A process for the preparation of a compound of formula (I), as described in claim 1 , which comprises the reaction of a compound of formula (II) or an activated derivative thereof:

(ll)

wherein R, R₃, R₄, R₅, R₆, Z, A, n and X are as defined for formula (I), or a group convertible into R3, R₄, R5 and Re respectively,

with a compound of formula (III):

Ri / -N \ R₂

(III)

wherein Ri and R₂ are as defined for formula (I), thus obtaining the compound of formula (I).

13. The process according to claim 12, wherein the activated derivative of formula (II) is an acyl halide, an acyl azide or an anhydride of the COOH group shown in formula (II), or a mixed anhydride formed between the aforesaid COOH and an alkyl chloroformate, or an activated ester of the aforesaid COOH, such as cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorohenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phthalimide ester, N- hydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester, or a carbodiimide of N,N'-carbonyldiimidazole of the aforesaid COOH.

14.The process according to claims 12-13, wherein the reaction between the activated derivative (II) and the compound (III) is carried out using the same solvent and conditions used for the preparation of the activated derivative (II).

15. A process for the preparation of a compound of formula (I), as described in claim 1, comprising the reaction of a compound of formula (VII):

(VII) wherein R, Ri, R₂, A and Z are as defined for the compounds of formula (I) and Li represents a leaving group, with a compound of formula (V):

(V) wherein R₃, R₄, R₅ Re, n and X are as defined for the compounds of formula (I) or a protected form or a group convertible into R₃, Rj.Rs Re, thus obtaining the compound of formula (I).

16. A compound of formula (I), as described in claim 1 , for use in therapy.

17. A pharmaceutical composition comprising a compound of formula (I) as described in claim 1 , in association with pharmaceutically acceptable excipients.

18. The pharmaceutical composition according to claim 17, in unit dose form containing from 20 to 1000 mg of active ingredient.

19. The pharmaceutical composition according to claims 17-18, in a form adapted to oral, rectal, topical, parenteral, endovenous, intramuscular, inhalative and transdermal administration.

20. The pharmaceutical composition according to claims 17-19, in the form of tablets, capsules, sachets, ampoules, powders, granules, lozenges, reconstitutable powders, solutions, suspensions, syrups, elixirs, suppositories, emulsions and transdermal patches.

21. The use of a compound of formula (I) as described in claim 1, in the preparation of a medicament useful for the prevention and/or treatment of diseases dependent on the stimulation of the NK-1 and NK-2 receptor.

22. The use according to claim 21, wherein said medicament is useful for the prevention and/or treatment of lung disorders, urinary tract and gastrointestinal tract disorders, ophthalmic diseases, cutaneous diseases, adverse immunological reactions, inflammatory diseases, neurogenic inflammations, peripheral neuropathies and CNS associated diseases.

23. The use according to claim 22, wherein said medicament is useful for the prevention and/or treatment of the bronchospastic and inflammatory components of asthma, chronic obstructive lung diseases, coughs, hyperactivity of the airways and irritation of the lung, urinary incontinence, syndromes associated with bladder diseases, cystitis associated inflammatory processes of the bladder and urethra, kidney infections, biliary tract colics and spasms, ulcerative colitis, Crohn's disease, irritable bowel syndrome, gastroesofageal reflux disease, ocular inflammation, conjunctivitis, sores and burns, itching skin disorders, contact dermatitis, atopical dermatitis, urticaria and other eczematoid dermatitis, itching and psoriasis, transplant tissue rejection, systemic lupus erythematosus, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain, neurogenic inflammations and peripheral neuropathies, anxiety, depression, psychosis and schizophrenia.