WO2003099287A1

WO2003099287A1 - Morpholin-acetamide derivatives for the treatment of inflammatory diseases

Info

Publication number: WO2003099287A1
Application number: PCT/EP2003/005717
Authority: WO
Inventors: Caroline Mary Cook; Colin David Eldred; Lee Andrew Harrison
Original assignee: Glaxo Group Limited
Priority date: 2002-05-29
Filing date: 2003-05-27
Publication date: 2003-12-04
Also published as: GB0212355D0; AU2003232844A1

Abstract

Compounds of formula I: (I) wherein:R1 represents C3-8 cycloalkyl-Y1-, aryl-Y1-, heteroaryl-Y1-, aryl- G-Y1-, heteroaryl-G-Y1-, C1-6 alkyl-G-Y1-, J1-Y1-, NR21R22-Y1-, NR21R22-CO-Y1- or R23-CONR21-Y1-;Q represents -(CR16R19)(CR18aR19a)t-, wherein t represents an integer from 0 to 3; R2 represents hydrogen or C1-6 alkyl; X represents ethylene or a group of formula CReRf wherein Re and Rf independently represent hydrogen or C1-4 alkyl or Re and Rf may together with the carbon atom to which they are attached form a C3-8 cycloalkyl group; R3 and R4 independently represent hydrogen or C1-4 alkyl; Z represents a bond, CO, SO2, CR9R6(CH2)n, (CH2)nCR9R6, CR9R6(CH2)nO, CR9R6(CH2)nS, CR9R6(CH2)nCO, COCR9R6(CH2)n or SO2CR9R6(CH2)n; R5 represents aryl, heteroaryl or aryl-C2-6 alkenyl-; R6 represents hydrogen, C1-4 alkyl, CONR7R8 or COOC1-6 alkyl; a and b represent 1 or 2, such that a+b represents 2 or 3; G represents -S-, -SO2-, -SO2NR20, -NR20SO2 or -NR20-; n represents an integer from 0 to 4; and salts and solvates thereof are CCR3 receptor antagonists and are thus indicated to be useful in therapy.

Description

Novel Compounds

This invention relates to novel compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.

Inflammation is a primary response to tissue injury or microbial invasion and is characterised by leukocyte adhesion to the endothelium, diapedesis and activation within the tissue. Leukocyte activation can result in the generation of toxic oxygen species (such as superoxide anion), and the release of granule products (such as peroxidases and proteases). Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue. The primary function of leukocytes is to defend the host from invading organisms, such as bacteria and parasites. Once a tissue is injured or infected, a series of events occurs which causes the local recruitment of leukocytes from the circulation into the affected tissue. Leukocyte recruitment is controlled to allow for the orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, whereby recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction.

There is increasing evidence that the bronchial inflammation which is characteristic of asthma represents a specialised form of cell-mediated immunity, in which cytokine products, such as IL-4 and IL-5 released by T-helper 2 (Th2) lymphocytes, orchestrate the accumulation and activation of granulocytes, in particular eosinophils and to a lesser extent basophils. Through the release of cytotoxic basic proteins, pro-inflammatory mediators and oxygen radicals, eosinophils generate mucosal damage and initiate mechanisms that underlie bronchial hyperreactivity. Therefore, blocking the recruitment and activation of Th2 cells and eosinophils is likely to have anti-inflammatory properties in asthma. In addition, eosinophils have been implicated in other disease types such as rhinitis, eczema, irritable bowel syndrome and parasitic infections.

Chemokines are a large family of small proteins which are involved in trafficking and recruitment of leukocytes (for review see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are released by a wide variety of cells and act to attract and activate various cell types, including eosinophils, basophils, neutrophils, macrophages, T and B lymphocytes. There are two major families of chemokines, CXC- (α) and CC- (β) chemokines, classified according to the spacing of two conserved cysteine residues near to the amino terminus of the chemokine proteins. Chemokines bind to specific cell surface receptors belonging to the family of G-protein-coupled seven transmembrane-domain proteins (for review see Luster, 1998). Activation of chemokine receptors results in, amongst other responses, an increase in intracellular calcium, changes in cell shape, increased expression of cellular adhesion molecules, degranulation and promotion of cell migration (chemotaxis).

To date a number of CC chemokine receptors have been identified and of particular importance to the current invention is the CC-chemokine receptor-3 (CCR-3), which is predominantly expressed on eosinophils, and also on basophils, mast cells and Th2 cells. Chemokines that act at CCR-3, such as RANTES, MCP-3 and MCP-4, are known to recruit and activate eosinophils. Of particular interest are eotaxin and eotaxin-2, which specifically bind to CCR-3. The localization and function of CCR-3 chemokines indicate that they play a central role in the development of allergic diseases such as asthma. Thus, CCR-3 is specifically expressed on all the major cell types involved in inflammatory allergic responses. Chemokines that act at CCR-3 are generated in response to inflammatory stimuli and act to recruit these cell types to sites of inflammation, where they cause their activation (e.g. Griffiths et al., J. Exp. Med., 179, 881-887 (1994), Lloyd et al., J. Exp. Med., 191 , 265-273 (2000)). In addition, anti-CCR-3 monoclonal antibodies completely inhibit eotaxin interaction with eosinophils (Heath, H. et al., J. Clin. Invest. 99 (2), 178-184 (1997)), while an antibody for the CCR-3 specific chemokine, eotaxin, reduced both bronchial hyperreactivity and lung eosinophilia in an animal model of asthma (Gonzalo et al., J. Exp. Med., 188, 157-167 (1998). Thus, many lines of evidence indicate that antagonists at the CCR-3 receptor are very likely to be of therapeutic use for the treatment of a range of inflammatory conditions.

In addition to a key role in inflammatory disorders, chemokines and their receptors also play a role in infectious disease. Mammalian cytomegaloviruses, herpes viruses and pox viruses express chemokine receptor homologues, which can be activated by human CC chemokines such as RANTES and MCP-3 receptors (for review see Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748, 1997). In addition, human chemokine receptors, such as CXCR-4, CCR-5 and CCR-3, can act as co-receptors for the infection of mammalian cells by microbes such as human immunodeficiency viruses (HIV). Thus, chemokine receptor antagonists, including CCR-3 antagonists, may be useful in blocking infection of CCR-3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses. International Patent Application publication number WO 01/24786 (Shionogi & Co. Ltd.) discloses certain aryl and heteroaryl derivatives for treating diabetes. WO 00/69830 (Torrey Pines Institute for Molecular Studies) discloses certain diazacyclic compounds, and libraries containing them, for biological screening. WO 00/18767 (Neurogen Corporation) discloses certain piperazine derivatives as dopamine D4 receptor antagonists. United States Patent 6,031,097 and WO 99/21848 (Neurogen Corporation) discloses certain aminoisoquinoline derivatives as dopamine receptor ligands. WO 99/06384 (Recordati Industha Chimica) discloses piperazine derivatives useful for the treatment of neuromuscular dysfunction of the lower urinary tract. WO 98/56771 (Schering Aktiengesellschaft) discloses certain piperazine derivatives as anti- inflammatory agents. WO 97/47601 (Yoshitomi Pharmaceutical Industries Ltd.) discloses certain fused heterocyclic compounds as dopamine D-receptor blocking agents. WO 96/39386 (Schering Corporation) discloses certain piperidine derivatives as neurokinin antagonists. WO 96/02534 (Byk Gulden Lomberg Chemische Fabrik GmbH) discloses certain piperazine thiopyridines useful for controlling helicobacter bacteria. WO 95/32196 (Merck Sharp & Dohme Limited) discloses certain piperazine, piperidine, and tetrahydropyridine derivatives as 5-HT1 D-alpha antagonists. United States Patent 5,389,635 (E.I. Du Pont de Nemours and Company) discloses certain substituted imadazoles as angiotensin-ll antagonists. European Patent Application publication number 0 306 440 (Schering Aktiengesellschaft) discloses certain imidazole derivatives as cardiovascular agents. WO 02/26722 (Glaxo Group Limited) discloses certain morpholine amide derivatives as CCR3 antagonists. WO 02/26723 (Glaxo Group Limited) discloses certain morpholine urea derivatives as CCR3 receptor antagonists.

A novel group of compounds has now been found which are CCR-3 receptor antagonists. These compounds block the migration/chemotaxis of eosinophils and thus possess anti-inflammatory properties. These compounds are therefore of potential therapeutic benefit, especially in providing protection from eosinophil, basophil mast cell and Th2-cell-induced tissue damage in diseases where such cell types are implicated, particularly allergic diseases, including but not limited to bronchial asthma, allergic rhinitis and atopic dermatitis. Thus, according to one aspect of the invention, we provide compounds of formula I:

wherein:

R¹ represents C₃-₈ cycloalkyl-Y¹-, aryl-Y¹-, heteroaryl-Y¹-, aryl- G-Y¹-, heteroaryl-G-Y¹-, d-. alkyl-G-Y¹-, J¹-Y¹-, NR²¹R²²-Y¹-, NR ¹R²²-CO-Y¹- or R²³- CONR²¹-Y¹-;

Q represents -(CR¹⁸R¹⁹)(CR^18aR^19a)_r, wherein t represents an integer from 0 to 3;

R represents hydrogen or d-e alkyl;

X represents ethylene or a group of formula CR^eR^f wherein R^e and R^f independently represent hydrogen or d-_. alkyl or R^β and R^f may together with the carbon atom to which they are attached form a C₃^ cycloalkyl group;

R³ and R⁴ independently represent hydrogen or -₄ alkyl;

Z represents a bond, CO, S0_2l CR⁹R⁶(CH₂)_n, (CH₂)_nCR⁹R⁶, CR^aR^b(CH₂)_nO, CR .9^arR->6^D(CH₂)_nS, CR 9^arR->6°(/CH₂)_nCO, COCR -9^acR_6^D/(CH₂)_n or

S0₂CR 9^arR->6°(CH₂)_n;

R represents aryl, heteroaryl or aryl-C₂-₆ alkenyl-;

R⁶ represents hydrogen, C_H alkyl, CONR⁷R⁸ or COOd-e alkyl; a and b represent 1 or 2, such that a+b represents 2 or 3;

G represents -S-, -SO₂-, -SO₂NR²⁰, -NR²⁰SO₂ or -NR²⁰-; n represents an integer from 0 to 4;

J¹ independently represents a moiety of formula (K):

wherein X¹ represents oxygen, NR¹³ or sulphur, X² represents CH₂, oxygen, NR¹⁰ or sulphur, m¹ represents an integer from 1 to 3, m² represents an integer from 1 to 3, provided that m¹+m² is in the range from 3 to 5, also provided that when both X¹ and X² represent oxygen, NR¹³ , NR¹⁰or sulphur, m¹ and m² must both not equal less than 2, wherein K is optionally substituted by one or more (e.g. 1 or 2) -Y³-aryl, -Y³-heteroaryl, -Y³-CO-aryl, -Y³-CO-heteroaryl, -d-6 alkyl, -Y³-COOd-₆ alkyl, -Y³-COd-₆ alkyl, -Y³-W, -Y³-CO-W, -Y³-NR¹¹R¹², - Y³-CONR¹¹R¹², hydroxy, oxo, -Y³-SO₂NR ¹R¹², -Y³-S0₂C_{1 (} alkyl, -Y³-S0₂aryl, - Y³-SO₂heteroaryl, -Y³-NR¹⁴d-₆ alkyl, -Y³-NR¹⁴SO₂d-₆ alkyl, -Y³-NR¹⁴CONR¹¹R 1₂ -Y³-NR¹⁴COOR¹⁵ or -Y³-OCONR¹¹R¹²groups, and is optionally fused to a monocyclic aryl or heteroaryl ring;

R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴ and R¹⁵ independently represent hydrogen or d-

₆ alkyl;

R¹¹ and R¹² independently represent hydrogen or C₁-6 alkyl or R¹¹ and R¹² together with the nitrogen atom to which they are attached may form a morpholine, piperidine or pyrrolidine ring;

R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴ and R¹⁵ independently represent hydrogen or d-e alkyl;

R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^18a, R^19a and R²⁰, independently represent hydrogen or Ci-₆ alkyl; R²¹ and R²² independently represent hydrogen, d-β alkyl, C₃-₈ cycloalkyl or C__scycloalkylCι-₆alkyl;

R²³ represents d-e alkyl, d-β cycloalkyl, aryl or heteroaryl; W represents a saturated or unsaturated, non-aromatic 5-7 membered ring containing between 1 and 3 heteroatoms selected from nitrogen, oxygen or sulphur, optionally substituted with one or more d-₆ alkyl, halogen or hydroxy groups;

Y¹ and Y³ independently represent a bond or a group of formula - (CH₂)_pCR°R^d(CH₂)_q- wherein R^c and R^d independently represent hydrogen or d--. alkyl or R° and R^d may together with the carbon atom to which they are attached form a C₃-β cycloalkyl group, and p and q independently represent an integer from 0 to 5 wherein p + q is an integer from 0 to 5; and salts and solvates thereof.

It will be appreciated that K is a monovalent moiety wherein the point of attachment of the neighbouring moiety to the moiety of formula K may occur at any suitable point on the moiety of formula K. Thus, it will be understood that the constitutent atom or group of the ring K, i.e. X¹, or X², or the alkylene groups, at which the point of attachment occurs, will of necessity be appropriately valence-modified with respect to the definitions hereinbefore provided for X¹, X², and the alkylene groups. For example, should the moiety K represent an N- linked heterocycle, then one of X¹ or X² must be N and not NR¹¹ or NR¹² respectively.

References to 'aryl' include references to monocyclic carbocyclic aromatic rings (e.g. phenyl) and bicyclic carbocyclic aromatic rings (e.g. naphthyl) and references to 'heteroaryl' include references to mono- and bicyclic heterocyclic aromatic rings containing 1-4 hetero atoms selected from nitrogen, oxygen and sulphur. Examples of monocyclic heterocyclic aromatic rings include e.g. pyridinyl, pyrimidinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazinyl, tetrazolyl or imidazolyl, and examples of bicyclic heterocyclic aromatic rings include e.g. benzimidazolyl, quinolinyl or indolyl. Carbocyclic and heterocyclic aromatic rings may be optionally substituted, e.g. by one or more d-e alkyl, C₂-e alkenyl, halogen, d-e alkoxy, methylenedioxy, cyano, hydroxy, nitro, amino, W, -N(CH₃)₂, -NHCOd-e alkyl, -OCF_3> -CF₃, -COOd-e alkyl, -OCHF₂, -SCF_3> -S0₂NR²⁴R²⁵, -CONR²⁴R²⁵ (wherein R²⁴ and R²⁵ independently represent hydrogen or d-e alkyl), -COOH, - SO₂CH₃ or -SCH₃ groups.

Examples of group W include piperidinyl, pyrrolidinyl, morpholinyl and piperazinyl which may be optionally substituted.

Examples of group J¹ include pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (eg. morpholin-4-yl) which may be optionally substituted. References to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl. It will be appreciated that references to alkylene, alkenyl and alkoxy shall be interpreted similarly.

References to C₃-β cycloalkyl include references to all alicyclic isomers (including branched isomers) of the corresponding alkyl.

Preferably, R¹ represents aryl-Y¹-, more preferably optionally substituted phenyl, particularly phenyl substituted by one or more -OCH₃ groups.

Preferably, Y¹ represents a bond.

Preferably, Q represents -(CR¹⁸R¹⁹)(CR^18aR^19a), most preferably ethylene.

Preferably, t represents 1.

Preferably, R¹⁸, R^18a, R¹⁹ and R^19a independently represent hydrogen.

Preferably, R² represents hydrogen.

Preferably, X represents methylene. Preferably, R³ and R⁴ independently represent hydrogen.

Preferably, Z represents CR⁹R⁶(CH₂)_n, particularly CH₂.

Preferably, R⁵ represents aryl, more preferably phenyl substituted by one or more halogen (e.g. chlorine or fluorine) groups, particularly dichlorophenyl most particularly 3,4-dichlorophenyl. Preferably, R⁶ represents hydrogen.

Preferably, R⁹ represents hydrogen.

Preferably, n represents 0.

Preferably, a and b both represent 1.

Suitable salts of the compounds of formula (I) include physiologically acceptable salts and salts which may not be physiologically acceptable but may be useful in the preparation of compounds of formula (I) and physiologically acceptable salts thereof. If appropriate, acid addition salts may be derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates, maleates, 1-hydroxy-2-naphthoates, palmoates, methanesulphonates, formates or trifluoroacetates. Examples of solvates include hydrates.

When compounds of formula (I) contain chiral centres, the invention extends to mixtures of enantiomers (including racemic mixtures) and diastereoisomers as well as to individual enantiomers. Generally it is preferred to use a compound of formula (I) in the form of a single enantiomer.

The compounds of formula (I) and salts and solvates thereof may be prepared by the methodology described hereinafter, constituting a further aspect of this invention. A process according to the invention for preparing a compound of formula (I) which comprises: (a) acylation of a compound of formula (II)

wherein R², R³, R⁴, R⁵, X, Z, a and b are as described above, with a compound of formula (III)

(III)

or an activated derivative thereof, wherein R¹ and Q are as described above; or

(b) reacting a compound of formula (IV)

wherein Q, R , R , R⁴, R , Z, X, a and b are as defined above, or a protected derivative thereof, with a compound of formula R¹-Hal wherein R¹ represents aryl or heteroaryl and Hal represents a halogen atom (e.g. chlorine); or;

(c) forming a compound of formula (I) wherein R¹ represents heteroaryl-CH₂- or J¹-CH₂- (wherein heteroaryl and J¹ represent a nitrogen containing group which is linked to the CH₂ moiety via said nitrogen atom) by a process which comprises reacting a compound of formula (V)

wherein Q, R², R³, R⁴, R⁵, X, Z, a and b are as defined above and L¹ represents a suitable leaving group, or a protected derivative thereof, with a compound of formula heteroaryl-H, wherein heteroaryl represents a heteroaryl group containing a free NH group, or a compound of formula J¹-H, wherein J¹ represents a nitrogen containing group which bears a hydrogen on said nitrogen atom; or

(d) forming a compound of formula (I) wherein R¹ represents aryl-NR²⁰-CH₂-, heteroaryl-NR²⁰-CH₂- or d-e alkyl-NR²⁰-CH₂- by a process which comprises reacting a compound of formula (V) or a protected derivative thereof, with a compound of formula aryl-NR²⁰H, heteroaryl-NR²⁰H or d-e alkyl-NR^H wherein R²⁰ is as defined above; or (e) forming a compound of formula (I) wherein R¹ represents R²¹R²²N-CO- CH₂- by a process which comprises reacting a compound of formula (VI)

wherein Q, R², R³, R⁴, R⁵, X, Z, a and b are as defined above, with a compound of formula R²¹R² NH, wherein R²¹ and R²²are as defined above; or

(f) forming a compound of formula (I) wherein R¹ represents d-₆ alkyl- SO₂NR²⁰-CH₂-, aryl-SO₂NR²⁰-CH₂-, heteroaryl-SO₂NR²⁰-CH₂-, d-e alkyl-CONR²⁰- CH₂-, aryl-CONR²⁰-CH₂- or heteroaryl-CONR²⁰-CH₂- by a process which comprises reacting a compound of formula (VII)

wherein Q, R², R³, R⁴, R⁵, R²⁰, X, Z, a and b are as defined above, with a compound of formula d-e alkyl-SO₂-Hal, aryl- SO₂-Hal, heteroaryl- SO₂-Hal, d-e alkyl-CO-Hal, aryl-CO-Hal or heteroaryl-CO-Hal, respectively, wherein Hal represents a halogen atom (e.g. chlorine); or

(g) forming a compound of formula (I) wherein R¹ represents d-₆ alkyl-SO₂- CH₂-, aryl-SO₂-CH₂- or heteroaryl-S0₂-CH₂- by a process which comprises reacting a compound of formula (V) or a protected derivative thereof, with a compound of formula d-₆ alkyl-SH, aryl-SH or heteroaryl-SH, respectively, followed by a suitable oxidation step; or

(h) deprotecting a compound of formula (I) which is protected; or (i) interconversion of other compounds of formula (I);

wherein one or more of the following optional steps: (i) converting a compound of formula (I) into a further compound of formula

(i);

(ii) removing any necessary protecting group;

(iii) preparing a salt or solvate of the compound so formed; may optionally be carried out after undertaking any one of reactions (a) to (g). Process (a) may be effected simply by the reaction of a compound of formula (II) with a compound of formula (III) which may typically be achieved using a microwave oven e.g. at a power of 600W for 4 minutes. Alternatively, examples of activated derivatives of compounds of formula (III) which may be employed in this reaction include acid halides and anhydride derivatives (e.g. the acid chloride).

Process (b) may be performed in the presence of a suitable solvent, e.g. N,N-dimethylformamide and a suitable base, e.g. triethylamine and suitable catalysts e.g. dichlorobis(triphenylphosphine)palladium(ll), copper iodide and triphenylphosphine at a suitable temperature, e.g. 80-120°C. Process (c) may be performed in the presence of a suitable solvent, e.g.

N,N-dimethylformamide and a suitable base, e.g. sodium hydride at a suitable temperature, e.g. between room temperature and 100°C. Examples of suitable leaving groups for L¹ include halogen (e.g. bromine) or -OSO₂CH₃.

Process (d) may be performed in the presence of a suitable solvent, e.g. N,N-dimethylformamide and a suitable base e.g. N,N-diisopropylethylamine at a suitable temperature, e.g. between room temperature and reflux. Examples of suitable leaving groups for L¹ include halogen (e.g. bromine) or -OSO₂CH₃.

Process (e) may be performed in the presence of a suitable reagent e.g. an amide coupling agent (such as 1 ,1'-carbonyldiimidazole) in the presence of a suitable solvent, e.g. dichloromethane at a suitable temperature, e.g. room temperature.

Process (f) may be performed in the presence of a suitable solvent, e.g. dichloromethane and a suitable base e.g. N,N-diisopropylethylamine at a suitable temperature, e.g. room temperature. Process (g) may be performed in the presence of a suitable solvent, e.g. dichloromethane and a suitable base e.g. N,N-diisopropylethylamine at a suitable temperature, e.g. between room temperature and reflux. The oxidation step will typically comprise the use of a suitable oxidising agent, e.g. metachloroperbenzoic acid in the presence of a suitable solvent, e.g. dichloromethane at a suitable temperature, e.g. between 0°C and room temperature. Examples of suitable leaving groups for L¹ include halogen (e.g. bromine) or -OSO₂CH₃.

In process (h), examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991). Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate. Other suitable amine protecting groups include trifluoroacetyl (-COCF₃) which may be removed by base catalysed hydrolysis, or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group

(Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.

Process (i) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic aromatic substitution, ester hydrolysis or amide bond formation.

Compounds of formula (II) may be prepared according to the following process, or those described in WO 02/267222 and WO 02/26723:

wherein R², R³, R⁴, R⁵, X, a, b and Z are as defined above and L² represents a suitable leaving group e.g. chlorine and P¹ represents a suitable protecting group e.g. one mentioned above, such as -COCF₃. Step (i) comprises the use of a suitable solvent e.g. N,N-dimethylformamide in the presence of suitable reagents e.g. sodium iodide and potassium carbonate at a suitable temperature e.g. room temperature. Step (ii) comprises deprotection under conventional conditions appropriate for the protecting groups. When P¹ represents -COCF₃, deprotection may be achieved by the use of water and methanol in the presence of potassium carbonate at room temperature. Compounds of formula (II) wherein R² represents hydrogen, X represents methylene, a and b represent 1 and R³ and R⁴ are both attached to the morpholine ring at the 5-position may also be prepared according to the following process:

wherein R⁵ and Z are as defined above and L³ represents a suitable leaving group e.g. chlorine. Step (i) comprises heating in the absence of solvent at between 50 and 60°C. Step (ii) comprises heating with 2-(oxiran-2-ylmethyl)- 1 H-isoindole-1 ,3(2H)-dione at 80°C under nitrogen, followed by stirring with concentrated sulphuric acid at 150°C.

Compounds of formula (II) wherein R² represents H may also be prepared by solid phase synthesis according to the following process:

wherein R³, R⁴, R⁵, X, a, b and Z are as defined above and L⁴ represents a suitable leaving group e.g. chlorine. Step (i) comprises heating a compound of formula (XI; Merrifield Resin) with sodium carbonate in a suitable solvent e.g. dimethylsulphoxide at a suitable temperature e.g. 150°C. Step (ii) comprises reacting a compound of formula (XII) with a compound of formula (XIII) in the presence of a suitable solvent e.g. tetrahydrofuran at a suitable temperature e.g. room temperature. Step (iii) comprises the use of suitable solvent e.g. dimethylformamide and a suitable base e.g. diisopropylethylamine at a suitable temperature e.g. 70°C, followed by deprotection under conventional conditions appropriate for the Merrifield resin protecting group e.g. acid catalysed hydrolysis.

Compounds of formula (IV) may be prepared according to the following process:

wherein R², R³, R⁴, R⁵, X, a, b and Z are as defined above. Step (i) typically comprises the use of a microwave oven e.g. at a power of 600W for 4 minutes.

Compounds of formula (V) wherein L¹ represents bromine may be prepared according to the following process:

wherein R², R³, R⁴, R⁵, X, a, b and Z are as defined above and P² represents a suitable protecting group (e.g. t-butyldimethylsilyl). Step (i) typically comprises heating in a microwave oven e.g. at 600W for 5mins, followed by a suitable deprotection reaction (e.g. tetrabutyl ammonium fluoride). Step (ii) typically comprises the use of triphenylphosphine, carbontetrabromide and a suitable solvent, e.g. dichloromethane at a suitable temperature e.g. room temperature.

Compounds of formula (V) in which L² represents a halogen besides bromine may be prepared by an analogous process.

Compounds of formula (XVI) wherein Q represents ethylene may be prepared according to the following process:

Step (i)

COOEt

P²0^' P²0^'

(XVIII) COOEt (XX)

(XIX)

Step (ii)

wherein Q is as defined above and P represents a suitable protecting group (e.g. t-butyldimethylsilyl). Step (i) typically comprises the use of suitable reagents, e.g. nBuLi and copper iodide in the presence of a suitable solvent, e.g. tetrahydrofuran.

Step (ii) typically comprises the use of a suitable reagent, e.g. sodium hydroxide in the presence of suitable solvents, e.g. ethanol and water.

Compounds of formula (V) wherein L¹ represents a suitable sulphonate group (eg. -OSO₂CH₃) may be prepared according to the following process:

wherein R², R³, R⁴, R⁵, X, a, b and Z are as defined above. Step (i) typically comprises the use of a suitable base, e.g. N,N-diisopropylethylamine, and a suitable solvent, e.g. dichloromethane at a suitable temperature, e.g. room temperature.

Other compounds of formula (V) may be prepared by analogous processes or other conventional processes known per se.

Compounds of formula (VI) may be prepared according to the following process:

wherein R², R³, R⁴, R⁵, X, a, b and Z are as defined above and L¹ represents a suitable leaving group, e.g. bromine or -OSO₂CH₃. Step (i) typically comprises the use of a suitable reagent, e.g. sodium cyanide in the presence of a suitable solvent, e.g. dimethylsulphoxide at a suitable temperature, e.g. room temperature. Step (ii) typically comprises the use of a suitable acid, e.g. hydrochloric acid, and suitable solvents, e.g. water and ethanol, under suitable conditions, e.g. reflux.

Compounds of formula (VII) may be prepared according to the following process:

wherein R², R³, R⁴, R⁵, R²⁰, X, a, b and Z are as defined above and L¹ represents a suitable leaving group, e.g. bromine or -OSO₂CH₃. Step (i) typically comprises the use of a suitable base, e.g. N,N-diisopropylethylamine, and a suitable solvent, e.g. dichloromethane at a suitable temperature e.g. room temperature. Compounds of formula (III), (VIII), (IX), (XI), (XIII), (XV), (XVI), (XVIII) and (XIX) are either known or may be prepared in accordance with known procedures. Compounds of formula (IV), (V), (V)^a, (V)^b, (VI), (VII) and (XVII) in protected and unprotected forms are new and also form an aspect of the invention.

Compounds of the invention may be tested for in vitro and in vivo biological activity in accordance with the following assay.

CCR-3 Binding Assay

A CCR-3 competition binding SPA (scintillation proximity assay) was used to assess the affinity of novel compounds for CCR-3. Membranes prepared from K562 cells stably expressing CCR-3 (2.5μg/well) were mixed with 0.25mg/well wheat-germ agglutinin SPA beads (Amersham) and incubated in binding buffer (HEPES 50 mM, CaCI₂ 1 mM, MgCI₂ 5 mM, 0.5% BSA) at 4°C for 1.5 hr. Following incubation, 20 pM of [¹²⁵l] eotaxin (Amersham) and increasing concentrations of compound (1pM to 30μM) were added and incubated in a 96 well plate for 2 hr at 22°C then counted on a Microbeta plate counter. The total assay volume was 100 μl. Competition binding data were analysed by fitting the data with a four parameter logistic equation. Data are presented as the mean plC₅₀ values (negative logarithm of the concentration of compound which inhibits [¹²⁵l]eotaxin binding by 50%) from at least two experiments. Examples of disease states in which the compound of the invention has potentially beneficial anti-inflammatory effects include diseases of the respiratory tract such as bronchitis (including chronic bronchitis), bronchiectasis, asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD), cystic fibrosis, sinusitis and rhinitis. Other relevant disease states include diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure.

Furthermore, the compound of the invention may be used to treat nephritis, skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions and diseases of the central nervous system which have an inflammatory component (e.g. Alzheimer's disease, meningitis, multiple sclerosis) HIV and AIDS dementia.

Compounds of the present invention may also be of use in the treatment of nasal polyposis, conjunctivitis or pruritis.

Further examples of disease states in which the compound of the invention have potentially beneficial effects include cardiovascular conditions such as atherosclerosis, peripheral vascular disease and idiopathic hypereosinophilic syndrome. Other diseases for which the compound of the present invention may be beneficial are other hypereosinophilic diseases such as Churg-strauss syndrome. Additionally, eosinophilia is commonly found in parasitic diseases, especially helminth infections, and thus the compound of the present invention may be useful in treating inflammation arising from hypereosinophilic states of diseases such as hydatid cyst (Echinococcus sp.), tapeworm infections (Taenia sp.), blood flukes (schistosomiasis), and nematode (round worms) infections such as:- Hookworm (Ancylostoma sp.), Ascaris, Strongyloides, Trichinella, and particularly lymphatic filariasis including Onchocerca, Brugia, Wucheria (Elephantiasis).

The compound of the invention may be useful as an immunosuppressive agent and so have use in the treatment of auto-immune diseases such as allograft tissue rejection after transplantation, rheumatoid arthritis and diabetes. Compounds of the invention may also be useful in inhibiting metastasis. Diseases of principal interest include asthma, COPD and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis. Preferred diseases of principal interest include asthma and inflammatory diseases of the upper respiratory tract involving seasonal and perennial rhinitis. Further diseases also of principle interest include inflammatory diseases of the gastrointestinal tract such as inflammatory bowel disease.

It will be appreciated by those skilled in the art that references herein to treatment or therapy extend to prophylaxis as well as the treatment of established conditions.

As mentioned above, compounds of formula (I) are useful as therapeutic agents.

There is thus provided as a further aspect of the invention a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use as an active therapeutic agent.

There is also therefore provided a compound of formula (I), or a physiologically acceptable salt or solvate thereof, for use in the treatment of inflammatory conditions, e.g. asthma or rhinitis. According to another aspect of the invention, there is provided the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of inflammatory conditions, eg. asthma or rhinitis.

In a further or alternative aspect there is provided a method for the treatment of a human or animal subject suffering from or susceptible to an inflammatory condition e.g. asthma or rhinitis, which method comprises administering an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.

The compounds according to the invention may be formulated for administration in any convenient way. There is thus further provided a pharmaceutical composition comprising a compound of formula (I), or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers.

There is also provided a process for preparing such a pharmaceutical formulation which comprises admixing the compound of formula (I) or a physiologically acceptable salt or solvate thereof with one or more physiologically acceptable diluents or carriers.

The compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, parenteral or rectal administration, preferably for oral administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p_- hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate.

For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner. The compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

The compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multidose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.

The compounds and pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example antihistaminic agents, anticholinergic agents, anti-inflammatory agents such as corticosteroids, e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide; or non-steroidal anti-inflammatory drugs (NSAIDs) eg. sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists; or beta adrenergic agents such as salmeterol, salbutamol, formoterol, fenoterol or terbutaline and salts thereof; or antiinfective agents e.g. antibiotic agents and antiviral agents. It will be appreciated that when the compounds of the present invention are administered in combination with other therapeutic agents normally administered by the inhaled or intranasal route, that the resultant pharmaceutical composition may be administered by the inhaled or intranasal route.

Compounds of the invention may conveniently be administered in amounts of, for example, 0.001 to 500mg/kg body weight, preferably 0.01 to 500mg/kg body weight, more preferably 0.01 to 100mg/kg body weight, and at any appropriate frequency e.g. 1 to 4 times daily. The precise dosing regimen will of course depend on factors such as the therapeutic indication, the age and condition of the patient, and the particular route of administration chosen. Throughout the description and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps. The invention is illustrated by reference to, but is in no way limited by, the following Examples.

Examples

General experimental details LC/MS System This system used an 3μm ABZ+PLUS (3.3cm x 4.6mm internal diameter) column, eluting with solvents:A - 0.1%v/v formic acid + 0.077% w/v ammonium acetate in water; and B - 95:5 acetonitrile:water + 0.05%v/v formic acid, at a flow rate of 3 ml per minute. The following gradient protocol was used: 100% A for 0.7mins; A+B mixtures, gradient profile 0 - 100% B over 3.5mins; hold at 100%B for 1.1mins; return to 100% A over 0.2mins.

The LC/MS system used a micromass spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u.

Thermosprav Mass Spectra

Thermospray Mass Spectra were determined on a HP 5989A engine mass spectrometer, +ve thermospray, source temperature 250°C, probe temperatures 120°C (stem), 190°C (tip), detection mass range 100-850 a.m.u. Compounds were injected in 10μl of a mixture of solvents comprising 65% methanol and 35% 0.05M aqueous ammonium acetate, at a flow rate of 0.7ml/min.

Solid phase extraction (ion exchange)

'SCX' refers to Isolute Flash SCX-2 sulphonic acid solid phase extraction cartridges.

All LC/MS systems used a Micromass spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u.

All temperatures are in °C

Intermediates

Intermediate 1 : 2.2.2-Trifluoro-N-(morpholin-2-ylmethyl)acetamide

To a stirred solution of morpholin-2-ylmethylamine (3.1g) in methanol (70ml) under nitrogen was added an ethereal solution of ethyl-α,α,α-trifluoroacetate (5ml in 20ml ether) which had been washed with saturated aqueous sodium bicarbonate, water and brine, and dried. The mixture was stirred for 30 min at 22°C before removal of all volatiles in vacuo. The residue was dissolved in methanol (10ml) and the volatiles again removed in vacuo to give the title compound as a white crunchy foam (4.9g). Thermospray Mass Spectrum m/z 2^3 [MH⁺].

Intermediate 2: N-(r4-(3,4-Dichlorobenzyl)morpholin-2-vnmethyl)-2.2.2- trifluoroacetamide

To a stirred solution of Intermediate 1 (3.3g) in N,N-dimethylformamide (50ml) under nitrogen was added potassium carbonate (2.46g) and sodium iodide (2.12g). A solution of 3,4-dichlorobenzyl chloride (2ml) in N,N- dimethylformamide (10ml) was added dropwise to the mixture. The mixture was stirred at 22°C for 18h before the volatiles were removed in vacuo. The residue was partitioned between dichloromethane (100ml) and saturated aqueous sodium carbonate solution (50ml). The organic phase was subsequently washed with additional saturated aqueous sodium carbonate solution (2 x 50ml) and water (50ml) before drying over magnesium sulphate, filtering and evaporation of the solvent in vacuo to give a pale yellow oil. The oil was purified by Biotage flash chromatography on a 90g silica cartridge eluting with 25% ethyl acetate in cyclohexane, to give the title compound as a colourless oil (2.97g). LC/MS (System A) R, 2.63 min, Mass Spectrum m/z 371 [MH⁺].

Intermediate 3: r4-(3,4-Dichlorobenzyl)morpholin-2-yl,methylamine

To a stirred solution of Intermediate 2 (2.97g) in methanol (15ml) and water (5ml) was added potassium carbonate (5.53g). The mixture was stirred at 22°C for 18h before the methanol was removed in vacuo. Water (25ml) was added and the mixture extracted with ethyl acetate (3 x 30ml). The combined organic phases were washed with water (5ml) and saturated aqueous sodium chloride solution (10ml) before drying over sodium sulphate, filtering and evaporation of the solvent in vacuo to give a pale yellow oil. The oil was purified by Biotage flash chromatography on a 90g silica cartridge eluting with 75:8:1 dichloromethane/ethanol/0.880 ammonia solution. The required fractions were combined and the solvent evaporated in vacuo to give the title compound as a colourless oil (1.85g). LC/MS (System A) R, 1.77 min, Mass Spectrum m/z 275 [MH⁺].

Intermediate 4: N-{[4-(3.4-dichlorobenzyl)morpholin-2-yllmethyl>pent-4-vnamide To a solution of 4-pentynoic acid (0.059g, 0.6mmol) in dimethylformamide (1ml), was added diisopropylethylamine (0.21 ml, 1.2mmol), O-(7-azabenzotriazol-1-yl)- N.N.N'N'-tetramethylammonium hexafluorophosphate (0.230g, 0.6mmol), and Intermediate 3 (0.165g, 0.6mmol). The mixture was stirred at 22°C for 1hour. The solution was diluted with ethyl acetate (5ml), and saturated sodium bicarbonate was added (8ml). The biphasic mixture was stirred for 1 hour. The organic phase was separated, washed with saturated sodium bicarbonate (2x5ml), water (5ml), and brine (5ml), dried over MgSO₄. Further purification by flash chromatography using a SPE silica cartridge (5g) eluting with ethyl acetate, gave the title compound as a pale yellow gum, 0.129g. LC-MS (System A) Rt 2.30mins m/z 355 [MH⁺].

Examples Example 1 : N-(r4-(3,4-dichlorobenzyl)morpholin-2-vnmethyl)-5-(4- methoχyphenyl)pent-4-ynamide

A stream of nitrogen was passed through a solution of iodobenzene (0.010ml, 0.09mmol) in triethylamine (1.2ml) and N,N-dimethylformamide (0.7ml). The catalysts, dichlorobis(triphenylphosphine)palladium(ll) (0.005g), copper iodide (0.002g), and triphenylphosphine (0.002g) were added, and the mixture stirred for a few minutes before adding Intermediate 4 (0.03g, 0.08mmol). The mixture was stirred at 50°C for 1.5h in a sealed vial, then concentrated in vacuo. The residue was purified by application to an SCX cartridge (1g) in methanol, elution with methanol (20ml), and elution of the product with 10% ammonia in methanol solution (15ml), then concentrated in vacuo. Further purification by flash chromatography using SPE silica cartridge (1g) eluting with ethyl acetate, gave the title compound as a pale yellow gum, (0.15g). LC-MS (System A) Rt 2.88mins m/z 461 [MH⁺].

Biological Data

The compounds of the Examples were tested in the CCR-3 binding assay and the results obtained were as follows:

Claims

A compound of formula I:

wherein:

R¹ represents C₃-_ cycloalkyl-Y¹-, aryl-Y¹-, heteroaryl-Y¹-, aryl- G-Y¹-, heteroaryl-

G-Y¹-, d-e alkyl-G-Y¹-, J¹-Y¹-, NR²¹R²²-Y¹-, NR²¹R²²-CO-Y¹- or R²³-CONR² -Y¹-; Q represents -(CR¹⁸R ⁹)(CR^18aR^19a)_r, wherein t represents an integer from 0 to

3;

R² represents hydrogen or d-6 alkyl;

X represents ethylene or a group of formula CR^eR^f wherein R^e and R^f independently represent hydrogen or d^ alkyl or R^β and R^f may together with the carbon atom to which they are attached form a d-e cycloalkyl group;

R³ and R⁴ independently represent hydrogen or d^ alkyl;

Z represents a bond, CO, SO₂, CR⁹R⁶(CH₂)_n, (CH₂)_nCR⁹R⁶, CR⁹R⁶(CH₂)_nO,

CR⁹R⁶(CH₂)_nS, CR⁹R⁶(CH₂)_nCO, COCR⁹R⁶(CH₂)_n or SO₂CR⁹R⁶(CH₂)_n;

R⁵ represents aryl, heteroaryl or aryl-C₂-e alkenyl-; R⁶ represents hydrogen, d-₄ alkyl, CONR⁷R⁸ or COOd-e alkyl; a and b represent 1 or 2, such that a+b represents 2 or 3;

G represents -S-, -SO₂-, -SO.NR²⁰, -NR²⁰SO₂ or -NR²⁰-; n represents an integer from 0 to 4;

J¹ independently represents a moiety of formula (K):

wherein X¹ represents oxygen, NR¹³ or sulphur, X² represents CH₂, oxygen, NR¹⁰ or sulphur, m¹ represents an integer from 1 to 3, m² represents an integer from 1 to 3, provided that m¹+m² is in the range from 3 to 5, also provided that when both X¹ and X² represent oxygen, NR¹³ , NR¹⁰or sulphur, m¹ and m² must both not equal less than 2, wherein K is optionally substituted by one or more

(e.g. 1 or 2) -Y³-aryl, -Y³-heteroaryl, -Y³-CO-aryl, -Y³-CO-heteroaryl, -d-e alkyl, -

Y³-COOd-e alkyl, -Y³-COd-e alkyl, -Y³-W, -Y³-CO-W, -Y³-NR¹¹R¹², -Y³-

CONR¹¹R¹², hydroxy, oxo, -Y³-S0₂NR¹¹R¹², -Y³-SO₂d-₆ alkyl, -Y³-SO₂aryl, -Y³- S0₂heteroaryl, -Y³-NR¹⁴d-e alkyl, -Y³-NR¹⁴S0₂d-e alkyl, -Y³-NR¹⁴CONR¹¹R¹², -

Y³-NR¹⁴COOR¹⁵ or -Y³-OCONR¹¹R¹² groups, and is optionally fused to a monocyclic aryl or heteroaryl ring;

R¹¹ and R¹² independently represent hydrogen or d-₆ alkyl or R¹¹ and R¹² together with the nitrogen atom to which they are attached may form a morpholine, piperidine or pyrrolidine ring;

R¹⁶, R¹⁷, R¹⁸, R¹⁹, R^18a, R^19a and R²⁰, independently represent hydrogen or d-e alkyl; R²¹ and R²² independently represent hydrogen, d-e alkyl, d-β cycloalkyl or C₃- ecycloalkylCi-ealkyl;

R²³ represents d-₆ alkyl, C^ cycloalkyl, aryl or heteroaryl;

W represents a saturated or unsaturated, non-aromatic 5-7 membered ring containing between 1 and 3 heteroatoms selected from nitrogen, oxygen or sulphur, optionally substituted with one or more d-e alkyl, halogen or hydroxy groups;

Y¹ and Y³ independently represent a bond or a group of formula -

(CH₂)_pCR^cR^d(CH₂)_q- wherein R^c and R^d independently represent hydrogen or d^ alkyl or R^c and R^d may together with the carbon atom to which they are attached form a C₃-e cycloalkyl group, and p and q independently represent an integer from 0 to 5 wherein p + q is an integer from 0 to 5; and salts and solvates thereof.

2. A compound of formula (I) according to claim 1 which is N-{[4-(3,4- dichlorobenzyl)morpholin-2-yl]methyl}-5-(4-methoxyphenyl)pent-4-ynamide.

3. A process for preparing a compound of formula (I) as defined in claim 1 which comprises:

(a) acylation of a compound of formula (II)

wherein R², R³, R⁴, R⁵, X, Z, a and b are as defined in claim 1 , with a compound of formula (III)

O

HO Q- — -R I ' (III)

or an activated derivative thereof, wherein R¹ and Q are as defined in claim 1 ; or

(b) reacting a compound of formula (IV)

wherein Q, R², R³, R⁴, R⁵, Z, X, a and b are as defined in claim 1 , or a protected derivative thereof, with a compound of formula R¹-Hal wherein R¹ represents aryl or heteroaryl and Hal represents a halogen atom (e.g. chlorine); or

wherein Q, R², R³, R⁴, R⁵, X, Z, a and b are as defined in claim 1 and L¹ represents a suitable leaving group, or a protected derivative thereof, with a compound of formula heteroaryl-H, wherein heteroaryl represents a heteroaryl group containing a free NH group, or a compound of formula J¹-H, wherein J¹ represents a nitrogen containing group which bears a hydrogen on said nitrogen atom; or

(d) forming a compound of formula (I) wherein R¹ represents aryl-NR²⁰-CH₂-, heteroaryl-NR²⁰-CH₂- or d-e alkyl-NR²⁰-CH₂- by a process which comprises reacting a compound of formula (V) or a protected derivative thereof, with a compound of formula aryl-NR -20 H, heteroaryl-NR H or d-e alkyl-NR -20 H, wherein R²⁰ is as defined in claim 1 ; or

(e) forming a compound of formula (I) wherein R¹ represents R²¹R²²N-CO- CH₂- by a process which comprises reacting a compound of formula (VI)

wherein Q, R², R³, R⁴, R⁵, X, Z, a and b are as defined in claim 1 , with a compound of formula R²¹R ²NH, wherein R²¹ and R²²are as defined above; or

( ) forming a compound of formula (I) wherein R¹ represents d-e alkyl- SO₂NR²⁰-CH₂-, aryl-SO₂NR²⁰-CH₂-, heteroaryl-SO₂NR²⁰-CH₂-, d-e alkyl-CONR _'2^u0-

-20

CH₂-, aryl-CONR -CH₂- or heteroaryl-CONR -CH₂- by a process which comprises reacting a compound of formula (VII)

wherein Q, R², R³, R⁴, R⁵, R²⁰, X, Z, a and b are as defined in claim 1 , with a compound of formula d-6 alkyl-SO₂-Hal, aryl- S0₂-Hal, heteroaryl- SO₂-Hal, d-₆ alkyl-CO-Hal, aryl-CO-Hal or heteroaryl-CO-Hal, respectively, wherein Hal represents a halogen atom (e.g. chlorine); or

(g) forming a compound of formula (I) wherein R¹ represents Ci-e alkyl-SO₂- CH₂-, aryl-S0₂-CH₂- or heteroaryl-S0₂-CH₂- by a process which comprises reacting a compound of formula (V) or a protected derivative thereof, with a compound of formula d-e alkyl-SH, aryl-SH or heteroaryl-SH, respectively, followed by a suitable oxidation step; or

(h) deprotecting a compound of formula (I) which is protected; or

(i) interconversion of other compounds of formula (I).

(i);

(ii) removing any necessary protecting group; (iii) preparing a salt or solvate of the compound so formed; may optionally be carried out after undertaking any one of reactions (a) to (g).

4. A compound of formula (I) as defined in claim 1 , or a physiologically acceptable salt or solvate thereof, for use as an active therapeutic agent.

5. A compound of formula (I) as defined in claim 1 , or a physiologically acceptable salt or solvate thereof, for use in the treatment of inflammatory conditions, e.g. asthma or rhinitis.

6. Use of a compound of formula (I) as defined in claim 1 , or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammatory conditions, eg. asthma or rhinitis.

7. A method for the treatment of a human or animal subject suffering from or susceptible to an inflammatory condition e.g. asthma or rhinitis, which method comprises administering an effective amount of a compound of formula (I) as defined in claim 1 , or a physiologically acceptable salt or solvate thereof.

8. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 , or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers.

9. A compound of formula (V)

or a protected derivative thereof, wherein Q, R², R³, R⁴, R⁵, X, Z, a and b are as defined in claim 1 and L¹ represents a suitable leaving group.

10. A compound of formula (VI)

wherein Q, R², R³, R⁴, R⁵, X, Z, a and b are as defined in claim 1.

11. A compound of formula (VII)

wherein Q, R², R³, R⁴, R⁵, R²⁰, X, Z, a and b are as defined in claim 1.