Thiazolopyrimidines and their use as modulators of chemokine receptor activity

The present application is a national phase application under 35 U.S.C. Section 371 filed from International Patent Application PCT/SE01/00247, filed 7 Feb. 2001, which claims priority to United Kingdom patent application Serial. No. 0003025.4, filed 11 Feb. 2000. The contents of these applications are incorporated herein by reference in their entirety.

The present invention relates to certain thiazolopyrimidine compounds, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.

The compound 2,7-diamino-5-methylmercapto-thiazolo[4,5-d]pyrimidine is known from J. Amer. Chem. Soc., 73, 4226-4227 (1951).

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. At the present time, the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the C—X—C, C—C and C—X 3 —C families. The C—X—C and C—C families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues. The C—X 3 —C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the NH-proximal pair of cysteine residues.

The C—X—C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils. Examples include human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

The C—X 3 —C chemokine (also known as fractalkine) is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells.

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX 3 CR1 for the C—X 3 —C family. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

In accordance with the present invention, there is therefore provided compounds of formula (I) or a pharmaceutically acceptable salts or solvates thereof:

wherein R represents a hydrogen atom, or a group —NR 4 R 5 ;

R 4 and R 5 each independently represent a hydrogen atom, or a 4-piperidinyl, C 3 -C 6 cycloalkyl or C 1 -C 8 alkyl group, which latter two groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms and —NR 6 R 7 , —CONR 6 R 7 , —OR 8 , —COOR 8 , —NR 9 COR 10 , —SR 11 , —SO 2 R 11 , —SO 2 NR 6 R 7 , —NR 9 SO 2 R 10 , morpholinyl, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, tetrahydrofuranyl, aryl and heteroaryl groups, the aryl and heteroaryl groups being optionally substituted by one or more substituents independently selected from halogen atoms and cyano, nitro, —NR 6 R 7 , —CONR 6 R 7 , —OR 8 , —NR 9 COR 10 , —SO 2 NR 6 R 7 , —NR 9 SO 2 R 10 , C 1 —C 6 alkyl and trifluoromethyl groups, or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system, which ring system may be optionally substituted by one or more substituent groups independently selected from

—NR 6 R 7 , —CONR 6 R 7 , —OR 8 , —COOR 8 , —NR 9 COR 10 , and C 1 -C 6 alkyl optionally substituted by one or more substituents independently selected from halogen atoms and —NR 11 R 12 and —OR 8 groups,

R 1 represents a C 1 -C 6 alkyl group substituted by a five-membered heterocycle; R 2 and R 3 each independently represent a hydrogen atom, or a C 3 -C 7 carbocyclic, C 1 -C 8 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from: halogen atoms, —NR 6 R 7 , —CONR 6 R 7 , —OR 8 , —COOR 8 , —NR 9 COR 10 , —SR 11 , —SO 2 R 11 , —SO 2 NR 6 R 7 , —NR 9 SO 2 R 10 or a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR 9 and itself optionally substituted by C 1-3 -alkyl, halogen, R 8 represents hydrogen, C 1 -C 6 alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 14 and —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16 R 6 and R 7 independently represent a hydrogen atom or a C 1 -C 6 alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 14 and —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16 or R 6 and R 7 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally comprising a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR 4 , —COOR 14 , —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SO 2 NR 15 R 16 , NR 15 SO 2 R 16 or C 1 -C 6 alkly, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR 15 R 16 and —OR 17 groups, R 11 represents a hydrogen atom or a C 1 -C 6 , or phenyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 17 and —NR 15 R 16 , and R 9 , R 10 , R 12 , R 13 , R 14 R 15 , R 16 , and R 17 independently represent a hydrogen atom or a C 1 -C 6 , alkyl, or a phenyl group.

In the context of the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be linear or branched.

Aryl groups include phenyl and naphthyl. Heteroaryl is defined as a 5- or 6-membered aromatic ring optionally containing one or more heteroatoms selected from N, S, O. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan. Heterocyclic rings as defined for R 4 and R 5 means saturated heterocycles, examples of which include morpholine azetidine, pyrrolidine, piperidine and piperazine.

In formula (I) above, the group R represents a hydrogen atom, or a group —NR 4 R 5 . Particularly advantageous compounds of formula (I) are those in which R represents a group —NR 4 R 5 .

Suitably R 4 and R 5 each independently represent a hydrogen atom, or a 4-piperidinyl, C 3 -C 6 cycloalkyl or C 1 -C 8 alkyl group, which latter two groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms and —NR 6 R 7 , —CONR 6 R 7 , —OR 8 , —COOR 8 , —NR 9 COR 10 , —SR 11 , —SO 2 R 11 , —SO 2 NR 6 R 7 , —NR 9 SO 2 R 10 , morpholinyl, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, tetrahydrofuranyl, aryl and heteroaryl groups, each of which may be optionally substituted by one or more substituents independently selected from halogen atoms and cyano, nitro, —NR 6 R 7 , —CONR 6 R 7 , —OR 8 , —NR 9 COR 10 , —SO 2 NR 6 R 7 , NR 9 SO 2 R 10 , C 1 -C 6 alkyl and trifluoromethyl groups, or R 4 and R 5 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system, which ring system may be optionally substituted by one or more substituent groups independently selected from

—NR 6 R 7 , —CONR 6 R 7 , —OR 8 , —COOR 8 , —NR 9 COR 10 , and C 1 -C 6 alkyl optionally substituted by one or more substituents independently selected from halogen atoms and —NR 11 R 12 and —OR 8 groups.

Particularly advantageous compounds of formula (I) are those in which R 4 and R 5 each independently represent a hydrogen atom, or a C 1 -C 6 alkyl group substituted by a —CONR 5 R 6 or imidazolyl (e.g. 1H-imidazol-4-yl) group.

Suitably R 1 represents a methyl group substituted by furan or thiazole,.

Suitably R 2 and R 3 each independently represent a hydrogen atom, or a C 3 -C 7 carbocyclic, C 1 -C 8 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from:

halogen atoms, —NR 6 R 7 , —CONR 6 R 7 , —OR 8 , —COOR 8 , —NR 9 COR 10 , —SR 11 , —SO 2 R 11 , SO 2 NR 6 R 7 , —NR 9 SO 2 R 10 or a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR 9 and itself optionally substituted by C 1-3 -alkyl, halogen.

Preferably one of R 2 and R 3 is hydrogen and the other is C 1 -C 8 alkyl substituted by hydroxy and one or more methyl or ethyl groups. More preferably one of R 2 and R 3 is hydrogen and the other is CH(CH 3 )CH 2 OH, CH(Et)CH 2 OH, C(CH 3 ) 2 CH 2 OH or CH(CH 2 OH) 2 . When one of R 2 and R 3 is hydrogen and the other is CH(CH 3 )CH 2 OH or CH(Et)CH 2 OH the resulting compounds of formula (I) are preferably in the form of the (R) isomer. Most preferably one of R 2 and R 3 is hydrogen and the other is CH(CH 3 )CH 2 OH.

Particularly preferred compounds of the invention include:

2-[[2-Amino-5-[(1H-benzimidazol-2-ylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol 2-[[2-Amino-5-[(2-furanylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol 2-[[2-Amino-5-[[1-(2-thienyl)ethyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol (2R)-2-[[2-Amino-5-[[(2-methyl-4-thiazolyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol (2R)-2-[[2-Amino-5-[[(3,5-dimethyl-4-isoxazolyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol (2R)-2-[[2-Amino-5-[[(5-methyl-2-furanyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol N-[4-[[[2-Amino-7-[[(1R)-2-hydroxy-1-methylethyl]amino]thiazolo[4,5-d]pyrimidin-5-yl]thio]methyl]-2-thiazolyl]-acetamide, (2R)-2-[[2-Amino-5-[[(5-chloro-1,2,3-thiadiazol-4-yl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol (2R)-2-[[2-Amino-5-[(5-isoxazolylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol 2-[[2-Amino-5-[[(2-methyl-4-thiazolyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1,3-propanediol 2-[[2-Amino-5-[[(2-methyl-4-thiazolyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol (2R)-2-[[2-Amino-5-[(2-furanylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol

and their pharmaceutically acceptable salts and solvates.

According to the invention there is also provided a process for the preparation of a compound of formula (I) which comprises:

a) treatment of a compound of formula (II):

where R, R 1 , R 2 and R 3 are as defined in formula (I) or are protected derivatives thereof with a thiol R 1 SH in the presence of a base, or

(b) treatment of a compound of formula (III):

where R, R 2 and R 3 are as defined in formula (I) or are protected derivatives thereof with a compound of formula R 1 X where R 1 is as defined in formula (I) and X is a leaving group, and optionally after (a) or (b):

removing any protecting groups; forming a pharmaceutically acceptable salt or solvate.

Reaction (a) may be carried out in a solvent such as DMSO at a temperature between 0° C. and 100° C. using a base such as potassium tert-butoxide.

Reaction (b) may be carried out in NMP at room temperature. The leaving group X is preferably halogen such as bromide. Preferbly the reaction is carried out in the presence of a base such as N,N-diisopropylethylamine. The reaction may be carried out in a suitable solvent such as NMP at room temperature.

Compounds of formula (II) where R 1 , R 2 and R 3 are as defined in formula (I) may be prepared by treatment of a compound of formula (IV):

where R, R 1 , R 2 and R 3 are as defined above with an oxidizing agent such as peracetic acid. The reaction may be carried out in a solvent such as glacial acetic acid at a temperature between 0° C. and 100° C.

Compounds of formula (III) where R, R 2 and R 3 are as defined in formula (I) may be prepared by treatment of a compound of formula (IV) where R, R 1 , R 2 and R 3 are as defined in formula (I) with sodium in liquid ammonia.

Compounds of formula (IV) where R, R 1 , R 2 and R 3 are as defined in formula (I) may be prepared by treatment of a compound of formula (V) where R and R 1 is as defined above and L is a halogen such as chlorine with an amine HNR 2 R 3 . The reaction may be carried out in a solvent such as tetrahydrofuran in a sealed vessel at a temperature between 0° C. and 150° C.

Compounds of formula (V) where R and R 1 are as defined in formula (I) and L is a halogen may be prepared by treating a compound of formula (V) where R and R 1 are as defined in formula (I) and L is a hydroxyl group with a halogenating agent such as phosphorous oxychloride. The reaction may be carried out at reflux in the presence of dimethylaniline.

Compounds of formula (V) where R=NH2 and R 1 is as defined in formula (I) and L is a hydroxyl group may be formed by heating a compound of formula (VI) where R 1 is as defined above.

Compounds of formula (V) where R and R 1 is defined in formula (I) and L is a halogen can be prepared from compounds of formula (V) where R is a halogen and R 1 is defined above with an amine NR 4 R 5 . The reaction may be carried out in a solvent such as tetrahydrofuran in a sealed vessel at a temperature between 0° C. and 150° C.

Compounds of formula (V) where R is a halogen, R 1 is defined in formula (I) and L is a halogen can be prepared from compounds of formula (V) where R is NH 2 and R 1 and L are defined above with a diazotizing agent and a halogenating agent. This process is conveniently carried out in an organic solvent such as acetonitrile in the presence of a diazotizing agent such as tert-butyl nitrite and a halogenating agent such as a trimethylsilyl halide.

Compounds of formula (VI) where R 1 is as defined in formula (I) may be readily prepared by reacting a compound of general formula (VII) wherein R 1 is as defined above, with potassium thiocyanate and bromine in an inert solvent such as dimethylformamide/pyridine.

Componds of formula (V) where R=NH2 and R 1 is defined in formula (I) and L is a hydroxyl group may also be prepared from compounds od general formula (VII) without isolation of imtermediate (VI).

Compounds of formula (VII) are suitably prepared by reacting a compound of formula (VIII):

with a compound of formula R 1 X where R 1 is as defined above and X is a leaving group such as bromide in the presence of a base such as sodium hydroxide.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups. The protection and deprotection of functional groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).

Novel intermediate compounds form a further aspect of the invention. In particular compounds of formula (II) and (III) are novel and form an aspect of the invention.

The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.

The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CXCR2) activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of chemokines.

Examples of such conditions/diseases include:

(1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia; (2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis; (3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis; (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema; (5) (central and peripheral nervous system) Neurodegenerative diseases and dementia disorders, e.g. Alzheimer's disease, amyotrophic lateral sclerosis and other motor neuron diseases, Creutzfeldt-Jacob's disease and other prion diseases, HIV encephalopathy (AIDS dementia complex), Huntington's disease, frontotemporal dementia, Lewy body dementia and vascular dementia; polyneuropathies, e.g. Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, plexopathies; CNS demyelination, e.g. multiple sclerosis, acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; neuromuscular disorders, e.g. myasthenia gravis and Lambert-Eaton syndrome; spinal diorders, e.g. tropical spastic paraparesis, and stiff-man syndrome: paraneoplastic syndromes, e.g. cerebellar degeneration and encephalomyelitis; CNS trauma; migraine; and stroke. (6) (other tissues and systemic disease) atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, and idiopathic thrombocytopenia pupura; post-operative adhesions, and sepsis. (7) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; (8) Cancers, especially non-small cell lung cancer (NSCLC), malignant melanoma, prostate cancer and squamous sarcoma, and tumour metastasis; (9) Diseases in which angiogenesis is associated with raised CXCR2 chemokine levels (e.g. NSCLC, diabetic retinopathy). (10) Cystic fibrosis, re-perfusion injury in the heart, brain, peripheral limbs and other organs. (11) Burn wounds & chronic skin ulcers (12) Reproductive Diseases (e.g. Disorders of ovulation, menstruation and implantation, Pre-term labour, Endometriosis)

Thus, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

Preferably the compounds of the invention are used to treat diseases in which the chemokine receptor belongs to the CXC chemokine receptor subfamily, more preferably the target chemokine receptor is the CXCR2 receptor,

Particular conditions which can be treated with the compounds of the invention are psoriasis, diseases in which angiogenesis is associated with raised CXCR2 chemokine levels, and COPD. It is preferred that the compounds of the invention are used to treat psoriasis.

As a further aspect of the present invention, certain compounds of formula (I) may have utility as antagonists of the CX3CR1 receptor. Such compounds are expected to be particularly useful in the treatment of disorders within the central and peripheral nervous system and other conditions characterized by an activation of microglia and/or infiltration of leukocytes (e.g. stroke/ischemia and head trauma).

In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In a still further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.

In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly.

The invention still further provides a method of treating a chemokine mediated disease wherein the chemokine binds to a chemokine (especially CXCR2) receptor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.

The invention also provides a method of treating an inflammatory disease, especially psoriasis, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.

The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally. Preferably the compounds of the invention are administered orally.

The invention will now be further illustrated by reference to the following examples. In the examples the Nuclear Magnetic Resonance (NMR) spectra were measured on a Varian Unity Inova 300 or 400 MHz spectrometer and the Mass Spectrometry (MS) spectra measured on a Finnigan Mat SSQ7000 or Micromass Platform spectrometer. Where necessary, the reactions were performed under an inert atmosphere of either nitrogen or argon. Chromatography was generally performed using Matrex Silica 60® (35-70 micron) or Prolabo Silica gel 60® (35-70 micron) suitable for flash silica gel chromatography. High pressure liquid chromatography purification was performed using either a Waters Micromass LCZ with a Waters 600 pump controller, Waters 2487 detector and Gilson FC024 fraction collector or a Waters Delta Prep 4000. The abbreviations m.p. and DMSO used in the examples stand for melting point and dimethyl sulphoxide respectively.