GB2359080A - Pharmaceutically active thiazolopyrimidines - Google Patents

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: <EMI ID=1.1 HE=43 WI=43 LX=312 LY=640 TI=CF> <PC>in which:<BR> A is a group of formula (a) or (b): <EMI ID=1.2 HE=61 WI=24 LX=315 LY=1304 TI=CF> <PC>wherein R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP> and R are as defined in the specification, are useful for treating chemokine mediated diseases, eg. inflammatory diseases such as psoriasis. Compounds as defined above wherein A is a group of formula (b) and R is a leaving group are novel intermediates.

Description

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

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. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.

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 such as 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 1 a and 1#3 (MIP-la and MIP-1#3).

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. 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:

in which: A is a group of formula (a) or (b):

wherein R represents a hydrogen atom, or a group NR4R5; R4 and R5 each independently represent a hydrogen atom, or a 4-piperidinyl, C3-C6 cycloalkyl or C1-C8 alkyl group, which latter two groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms and -NR6R7, - CONR6R7, -OR8, -COOR8, -NR9COR10, -SR11, -SO2R11, -SO2NR6R7, -NR9SO2R10, morpholinyl, C1-C4 alkyl, C3-C6 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, -NR6R7, -CONR6R7, -OR8, -NR9COR10, -SO2NR6R7, -NR9SO2R10, C,-C6 alkyl and trifluoromethyl groups, or R4 and RS 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

-NWR7, -CONR6R7, -ORB, -COORS, -NR9COR10, and C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen atoms and -NR11R12 and -ORS groups, R1 represents a C3-C7 carbocyclic, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, -NR6R7, -CONR6R7, -ORB; -COORS, - NR9COR10, -SR11, -SO2R11, -SO2NR6R7, -NR9SO2R10or an aryl or heteroaryl group each of which can be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, -NR6R7, -CONR6R7, -ORB, -COORS, -NR9COR10, - SR11, -SO2R11, -SO2NR6R7, -NR9SO2R10, C,-C6 alkyl or trifluoromethyl groups.

Wand R3 each independently represent a hydrogen atom, or a C3-C7 carbocyclic, C1-C8 alkyl, C2 C6 alkenyl or C2-C6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from: halogen atoms, -NR6R7, -CONR6R7, -ORB, -COORS, -NR9COR10, -SR11, -SO2R11, - SO2NR6R7, -NR9SO2R10 or a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR9 and itself optionally substituted by C1-3-alkyl, halogen, RS represents hydrogen, C1-C6 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, -0R14 and -NR15R16, -CONR15R16, -NR15COR16, -SO2NR15R16, NR15SO2R16 Wand R7 independently represent a hydrogen atom or a C1-C6 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, -0R'4 and -NR15R16, -CONR15R16, -NR15COR16, -SO2NR15R16, NR15SO2R16 or Wand R' 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, -0R'4, -COOR'4, -NR15R16, -CONR15R16, -NR15COR16, -SO2NR15R16, NR15SO2R16 or C1-C6 alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and -NR15R16 and -OR17 groups, R11 represents a hydrogen atom or a C1-C6, or phenyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, -OR17 and -NR15R16, and R9, R1 , R12, R13, R14 R'5, R'6, and R17 independently represent a hydrogen atom or a C1-C6, 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 S- or 6-membered aromatic ring optionally containing one or more heteroatoms selected from N, S, 0. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.

In formula (I) above, the group R preferably represents a hydrogen atom, or a group NR4R5. Particularly advantageous compounds of formula (I) are those in which R represents a group NR4R5, in particular those in which R4 and RS each independently represent a hydrogen atom, or a C1 -C6 alkyl group substituted by a -CONR6R7 or imidazolyl (e.g. 1H-imidazol-4-yl) group.

In formula (I) above, the group R1 represents a C3-C7 carbocyclic, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, -NR6R7, - CONR6R7, -ORB, -COORS, -NR9COR10, -SR11, -SO2R11, -SO2NR6R7, -NR9SO2R10 or an aryl or heteroaryl group each of which can be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, -NR6R7, -CONR6R7, -ORS, -COORS, -NR9COR10, -SR11, -SO2R11, -SO2NR6R7, -NR9SO2R10, C1-C6 alkyl or trifluoromethyl groups. Particularly advantageous compounds of formula (I) are those in which R1 represents an optionally substituted benzyl group. More preferably R' represents benzyl or benzyl substituted by one or more halogen atoms, in particular benzyl substituted by two fluoro atoms.

Suitably R2 and R3 each independently represent a hydrogen atom, or a C3-C7 carbocyclic, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from: halogen atoms, -NR 6R7, -CONR6R7, -ORB, -COORS, -NR9COR10, -SR11, -SO2R11, - SO2NR6R7, -NR9SO2R10 or a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR9 and itself optionally substituted by C1-3-alkyl, halogen.

Preferably one of R2 and R3 is hydrogen and the other is Cl-C8 alkyl substituted by hydroxy and one or more methyl or ethyl groups. More preferably one of R2 and R3 is hydrogen and the other is CH(CH3)CHZOH, CH(Et)CH2OH or C(CH3)2CH2OH Most preferably one of R2 and R3 is hydrogen and the other is CH(CH3)CH2OH.

Particularly preferred compounds of the invention include: (2R)-2-{2-Amino-5-[[(phenyl)methyl]thio]thiazolo[5,4-d]pyrimidin-7-yl}aminopropanol, 2R)-5-[[(Phenyl)methyl]thio]-7-[(2-hydroxy-l-methylethyl)amino]thiazolo[5,4- d]pyrimidin-2(1H)-one, and their pharmaceutically acceptable salts and solvates.

According to the invention there is also provided a process for the preparation of compounds of formula (I) in which A is (a) which comprises treatment of a compound of formula (II): -

where R', R2 and R3 are as defined in formula (I) and X is a leaving group with aqueous acid and optionally thereafter forming a pharmaceutically acceptable salt or solvate. Suitable leaving groups X include alkoxyl groups such as methoxyl. The reaction may be carried out in a solvent such as dioxan using hydrochloric acid at a temperature between 0 C and 100 C.

Compounds of formula (II) where R1, R2 and R3 are as defined in formula (I) and X is a leaving group such as methoxyl may be prepared from the corresponding compounds (II) where R1, R2 and R3 are as defined above and X is a halogen such as bromine by treatment with a metal alkoxide. The reaction may be carried out using potassium hydroxide in methanol at room temperature.

Compounds of formula (II) where R1, R2 and R3 are as defined in formula (I) and X is a halogen may be prepared from compounds of formula (I) where A is (b) and where R1, R2 and R3 are as defined above and R is NH2 by treatment with with a diazotizing agent such as tert-butyl nitrite and a halogenating agent such as bromoform.

Compounds of formula (I) where A is (b) and where R1, R2 and R3 are as defined in formula (I) and R is NH2 may be prepared by treating a compound of formula (III) with a reducing agent such as iron powder. The reaction may be carried out in the presence of ammonium chloride in aqueous ethanol at reflux.

Compounds of formula (III) where R1, R2 and R3 are as defined in formula (I) may be prepared by treating a compound of formula (IV) where R', Rz and R3 are as defined above and L is a leaving group such as halogen (e.g. chlorine) with a metal thiocyanate. The reaction may be carried out using potassium thiocyanate in dimethylformamide at room temperature.

Compounds of formula (IV) where R', R2.and R3 are as defined in formula (I) and L is a leaving group such as halogen (e.g. chlorine) may be prepared by treating a compound of formula (V) where R', R2, R3 and L are as defined above with an amine HNR2R3. The reaction may be carried out in the presence of a base such as diisopropylethylamine in a solvent such as tetrahydrofuran.

Compounds of formula (V) where R' is as defined in formula (I) and L is a halogen may be prepared by treating a compound of formula (V) where R' is as defined in formula (I) and L is an hydroxyl group with a halogenating agent such as phosphorus oxychloride. The reaction may be carried out in a solvent such as toluene at 100 C.

Compounds of formula (V) where R' is as defined in formula (I) and L is an hydroxyl group may be prepared by treating a compound of formula (VI) where R' is as defined in formula (1) and L is an hydroxyl group with a nitrating agent such as concentrated nitric 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 (VI) where R' is as defined in formula (I) and L is an hydroxyl group are suitably prepared by reacting a compound of formula (VII):

with a compound of formula R1X where R' is as defined above and X is a leaving group such as bromide in the presence of a base such as sodium hydroxide. The reaction may be carried out in aqueous NMP at room temperature.

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 (1) 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.

The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orp-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) such as irreversible 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) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; (6) (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; (7) cancers, especially non-small cell lung cancer (NSCLC) and squamous sarcoma; (8) diseases in which angiogenesis is associated with raised CXCR2 chemokine levels (e.g. NSCLC); and (9) cystic fibrosis, stroke, re-perfusion injury in the heart, brain, peripheral limbs and sepsis.

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.

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 CXCR2 receptor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (1), 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 (1), 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.l0 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.

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. Example 1 (2R)-2-{2-Amino-5-[ [(phenyl)methyl] thio]thiazolo [5,4-dlpyrimidin-7- yl)aminopropanol.

a) 2-[(Phenylmethyl)thio]-4,6-pyrimidinediol To a solution of 4,6-dihydroxy-2-mercaptopyrimidine (100 g) in 5M NaOH (360 ml) was added first NMP (200 ml), then benzyl bromide (90 ml) dropwise over 2 hours. The reaction was stirred at room temperature for 24 hours, then acidified to pH 2 with conc HCl (100 ml) added dropwise over 2 hours at -5 C to give a pink precipitate. This was isolated by decanting off the solution followed by trituration with diethyl ether (1 litre) to give the subtitled product as a white powder after filtration and drying (210 g).

m.p. 220-250 C (dec) MS: APCI (-ve) 233 (M-H) 1H NMR: b (DMSO) 11.76 (1 H, br s), 7.45 (2H, d), 7.26 (3 H, m), 5.18 (1 H, s), 4.38 (2H, s).

b) 5-Nitro-2-[(phenylmethyl)thio]-4,6-pyrimidinediol The product of step (a) (2 g) was added to, a mixture of glacial acetic acid (50 ml) and concentrated nitric acid (20 ml) and the reaction mixture heated to 50 C. A further 28 g of the product of step (a) was added in portions over 2 hours whilst maintaining the reaction temperature between 50 and 60 C. After stirring the reaction mixture for a further 1 hour at 50 C it was poured onto crushed ice and the subtitled product isolated by filtration as a yellow solid (l2.3 g).

1H NMR: 8 (DMSO) 7.48-7.19 (5H, m), 4.47 (2H, s).

c) 4,6-Dichloro-5-nitro-2-[(phenylmethyl)thio]-pyrimidine A suspension of the product of step (b) ( 59.2 g) in a mixture of POC13 (100 ml) and toluene (400 ml) was heated to 80 C. A solution of 1-methylimidazole (16.9 ml) in toluene (200 ml) was added dropwise over 1 hour. and the reaction mixture then heated at 100 C for 24 hours. After cooling to room temperature, the solvent was removed by evaporation and water (2 litres) cautiously added to the residue. The mixture was extracted with dichloromethane (4x500 ml) and the combined organic extracts dried over MgS04, filtered and evaporated to give a brown tar. This was purified by column chromatography, eluting with 10% dichloromethane in isohexane, to afford the subtitled product as a yellow solid (29.7 g).

MS: APCI (-ve) 315 (M-14) 1H NMR: 8 (DMSO) 7.43-7.24 (514, m), 4.40 (214, s).

d) (2R)-2-{[6-Chloro-5-nitro-2-[[(phenyl)methyl]thio]pyrimidin-4-yl]amino}propanol To a solution of the product of step (c) (6.4g) in tetrahydrofuran (60m1) and diisopropylethylamine (7.0m1) was added dropwise a solution of R-(-)-2-amino-l-propanol (1.5m1) in tetrahydrofuran (20m1) during 15 minutes. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the mixture poured into water (400m1) and extracted with ethyl acetate (three times), the combined organics dried (magmesium sulfate) and evaporated to a deep yellow gum (4.6g).

MS: APCI MW 355/357 (+14)1H NMR: 8 (DMSO) 8.01 (114, d), 7.40 (214, d), 7.28 (214, t), 7.25 (114, t), 4.44 (114,m), 4.36 (214,d), 3.71 (114,m), 3.60 (114,m), 1.89 (114,s), 1.26 (314,d).

e) (2R)-2-{[5-Nitro-2-[[(phenyl)methyl]thio]-6-thiocyanatopyrimidin-4- yl]amino}propanol.

The product of step (d) (4.6g) and potassium thiocyanate (2.0g) were stirred in dry dimethylformamide (120m1) at room temperature for 18 hours. The mixture was poured into water (600m1) and extracted with ethyl acetate (three times) and the organics combined, washed with water (three times), dried (manganese sulfate) and concentrated under reduced pressure to give a yellow solid (4.7g).

MS: APCI 376 (M-14), 378 (M+14) 1H NMR: 6 (DMSO) 9.06 (114, d), 7.44 (214, d), 7.29 (214,m), 7.25 (114. m), 5.10 (114, s), 4.53 (214,q), 3.53 (211,m), 1.20 (314,d). f) (2R)-2-{2-Amino-5-[[(phenyl)methyl]thio]thiazolo[5,4-d]pyrimidin-7- yl}aminopropanol.

The product of step (e) (4.7g), ammonium chloride (4.7g), and iron powder (1.4g) were heated to reflux in ethanol (200m1) and water (50m1) for 1 hour. The mixture was filtered hot and the filtrate concentrated under reduced pressure with the residue partitioned between ethyl acetate and water. The organic layer was collected and the aqueous layer extracted a further twice with ethyl acetate. The combined organics were shaken with water, dried (magnesium sulfate), and evaporated under reduced pressure to give the title compound as a fawn solid (4.3g).

MS: APCI MW 348 (M+H) 1H NMR: 8 (DMSO) 7.40 (4H, m), 7.28 (2H, t), 7.22 (1 H, t), 6.50 (1 H, d), 4.81 (1 H, t), 4.32 (2H,q), 4.23 (1H,s), 3.42 (2H,m), 1.14 (3H,d).

EXAMPLE 2 (2R)-5-[[(Phenyl)methyl]thio]-7-[(2-hydroxy-l-methylethyl)amino]thiazolo[5,4- d] pyrimidin-2(1H)-one.

a) (2R)-2-{2-Bromo-5-[[(phenyl)methyl]thio]thiazolo[5,4-d]pyrimidin-7- yl}aminopropanol.

To a suspension of the product of example 1 step (f) (0.54g) in bromoform (18m1) and acetonitrile (18m1) was added tert-butyl nitrite (0.23m1) for the mixture to be heated immediately at 60 C for 10 minutes. The red solution was quickly evaporated under reduced pressure to dryness in readiness to be purified by column chromatography (silica 4:1 dichloromethane/ethyl acetate) to give a solid (0.36g).

MS: APCI MW 409/411 (M-H), 411I413 (M+H).

b) (2R)-2-{2-Methoxy-5-[[(phenyl)methyl]thio]thiazolo[5,4-dlpyrimidin-7- yl}aminopropanol.

The product of step (a) (0.36g) was suspended in methanol (25m1) and treated with potassium hydroxide powder (0.16g). The mixture was stirred overnight at room temperature and then acidified with concentrated hydrochloric acid to pH7 prior to being evaporated to dryness under reduced pressure.

MW: APCI MW 363 (M+H) c) (2R)-5-[[(Phenyl)methyl]thio]-7-[(2-hydroxy-1-methylethyl)amino]thiazolo[5,4- d]pyrimidin-2(1H)-one.

The product of step (b) was suspended in dioxan (40m1) followed by addition of concentrated hydrochloric acid (0.06m1) and water (0.06m1) to be stirred at 40 C for 2 days. After evaporation to dryness under reduced pressure, the residue was purified by column chromatography (silica - 3:2 dichioromethane/ethyl acetate).

MW: APCI MW 349 (M+H) 1H NMR: b (DMSO) 7.39 (2H, d), 7.30 (2H, t), 7.23 (1 H, t), 6.81 (1 H, d), 4.86 (1 H, t), 4.32 (2H,t), 4.19 (1H,m), 3.44 (2H,t), 1.14 (3H,d).

Pharmacological Data Ligand Binding Assay [125I]IL-8 (human, recombinant) was purchased from Amersham, U.K. with a specific activity of 2,OOOCi/mmol. All other chemicals were of analytical grade. High levels of hrCXCR2 were expressed in HEK 293 cells (human embryo kidney 293 cells ECACC No. 85120602) (Lee et al. (1992) J. Biol. Chem. 267 pp16283-16291). hrCXCR2 cDNA was amplified and cloned from human neutrophil mRNA. The DNA was cloned into PCRScript (Stratagene) and clones were identified using DNA. The coding sequence was sub-cloned into the eukaryotic expression vector RcCMV (Invitrogen). Plasmid DNA was prepared using Quiagen Megaprep 2500 and transfected into HEK 293 cells using Lipofectamine reagent (Gibco BRL). Cells of the highest expressing clone were harvested in phosphate- buffered saline containing 0.2%(w/v) ethylenediaminetetraacetic acid (EDTA) and centrifuged (200g, 5min.). The cell pellet was resuspended in ice cold homogenisation buffer [lOmM HEPES (pH 7.4), 1mM dithiothreitol, 1mM EDTA and a panel of protease inhibitors (1mM phenyl methyl sulphonyl fluoride, 2ug/ml soybean trypsin inhibitor, 3mM benzamidine, 0.5[g/ml leupeptin and 100#tg/ml bacitracin)] and the cells left to swell for 10 minutes. The cell preparation was disrupted using a hand held glass mortar/PTFE pestle homogeniser and cell membranes harvested by centrifugation (45 minutes, 100,000g, 4 C). The membrane preparation was stored at -70 C in homogenisation buffer supplemented with Tyrode's salt solution (137mM NaCl, 2.7mM KCI, 0AmM NaH2P04), 0.1%(w/v) gelatin and 10%(v/v) glycerol. .

All assays were performed in a 96-well MultiScreen 0.45[tm filtration plates (Millipore, U.K.). Each assay contained -50pM [125I]IL-8 and membranes (equivalent to 200,000 cells) in assay buffer [Tyrode's salt solution supplemented with l OmM HEPES (pH 7.4), 1.8mM CaC12, 1mM MgC12, 0.125mg/ml bacitracin and 0.1%(w/v) gelatin]. In addition, a compound of formula (I) according to the Examples was pre-dissolved in DMSO and added to reach a final concentration of 1%(v/v) DMSO. The assay was initiated with the addition of membranes and after 1.5 hours at room temperature the membranes were harvested by filtration using a Millipore MultiScreen vacuum manifold and washed twice with assay buffer (without bacitracin). The backing plate was removed from the MultiScreen plate assembly, the filters dried at room temperature, punched out and then counted on a Cobra y-counter.

The compounds of formula (I) according to the Examples were found to have IC5o values of less than ( < ) l O#.M.

Intracellular Calcium Mobilisation Assay Human neutrophils were prepared from EDTA-treated peripheral blood, *as previously described (Baly et al. (1997) Methods in Enzymology 287 pp70-72), in storage buffer [Tyrode's salt solution (137mM NaCl, 2.7mM KCI, 04mM NaH2P04) supplemented with 5.7mM glucose and l OmM HEPES (pH 7.4)].

The chemokine GROa (human, recombinant) was purchased from R & D Systems (Abingdon, U.K.). A11 other chemicals were of analytical grade. Changes in intracellular free calcium were measured fluorometrically by loading neutrophils with the calcium sensitive fluorescent dye, fluo-3, as described previously (Merritt et al. (1990) Biochem. J. 269, pp513-519). Cells were loaded for 1 hour at 37 C in loading buffer (storage buffer with 0.1%(w/v) gelatin) containing 5#M fluo-3 AM ester, washed with loading buffer and then resuspended in Tyrode's salt solution supplemented with 5.7mM glucose, 0.1 %(w/v) bovine serum albumin (BSA), 1.8mM CaC12 and 1mM MgC12: The cells were pipetted into black walled, clear bottom, 96 well micro plates (Costar, Boston, U.S.A.) and centrifuged (200g, 5 minutes, room temperature). A compound of formula (I) according to the Examples was pre-dissolved in DMSO and added to a final concentration of 0.1 %(v/v) DMSO. Assays were initiated by the addition of an A50 concentration of GROa and the transient increase in fluo-3 fluorescence E X =490nm and #Em = 520nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).

The compounds of formula (I) according to the Examples were tested and found to be antagonists of the CXCR2 receptor in human neutrophils.

Claims (14)

1. CLAIMS 1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

   in which: A is a group of formula (a) or (b):

   wherein R represents a hydrogen atom, or. a group NR4R5; R4 and R5 each independently represent a hydrogen atom, or a 4-piperidinyl, C3-C6 cycloalkyl or C1-CB alkyl group, which latter two groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms and -NR6R7, - CONR6R7, -ORB, -COORS, -NWCOR10, -SR11, -SO2R11, -SO2NR6R7, -NR9SO2R10, morpholinyl, C1-C4 alkyl, C3-C6 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, -NR6R7, -CONR6R7, -ORS, -NR9COR10, -SO2NR6R7, -NR9SO2R10, C1-C6 alkyl and trifluoromethyl groups, or R4 and RS 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

   -NR6R7, -CONR6R7, -ORB, -COORS, -NR9COR10, and C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen atoms and -NR11R12 and -ORB groups, R1 represents a C3-C7 carbocyclic, C1-Cg alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms, -NR 6R', -CONR6R7, -ORB,8 -COORS, - NR9COR10, -SR11, -S02R11, -S02NR6R7, -NR9S02R10 or an aryl or heteroaryl group each of which can be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, -NR6R7, -CONR6R7, -ORB, -COORS, -NR9COR10, - SR11, -502R11, -S02NR6R7, -NR9S02R10, C1-C6 alkyl or trifluoromethyl groups. R2 and R3 each independently represent a hydrogen atom, or a C3-C7 carbocyclic, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from: halogen atoms, -NR 6R7, -CONR6R7, -ORB, -COORS, -NR9COR10, -SR11 , -S02R11, - S02NR6R7, -NR9S02R10 or a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR9 and itself optionally substituted by C1-3-alkyl, halogen, RS represents hydrogen, C1-C6 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, - 0R14 and -NR15R16, -CONR15R16, -NR15COR16, -S02NR15R16, NR15S02R16 Wand R' independently represent a hydrogen atom or a C1-C6 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, -0R14 and -NR15R16, -CONR15R16, -NR15COR16, -S02NR15R16, NR15S02R16 or R6 and R7 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, -OR14, -COOR14, -NR15R16, -CONR15R16, -NR15COR16, -S02NR15R16, NR15S02R16 or C1-C6 alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and -NR15RI6 and -OR17 groups, Rl1 represents a hydrogen atom or a C1-C6, or phenyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, -OR17 and -NR15R16, and R9, R1o, R12, R13, R14, R15, R l6, and R17 independently represent a hydrogen atom or a C1-C6, alkyl, or a phenyl group.
2. 2. A compound according to claim 1 in which R represents a group NR4R5
3. 3. A compound according to claim 1 or 2 wherein R' represents an optionally substituted benzylgroup.
4. 4. A compound according to any one of claims 1 to 3, wherein one of R2 and R3 is hydrogen and the other is C1-C8 alkyl substituted by hydroxy and one or more methyl or ethyl groups.
5. 5. A compound according to claim 1 selected from: (2R)-2- { 2-Amino-5-[ [(phenyl)methyl]thio]thiazolo [5,4-d]pyrimidin-7-yl } aminopropanol, 2R)-5-[[(Phenyl)methyl]thio]-7-[(2-hydroxy-l-methylethyl)amino]thiazolo[5,4- d]pyrimidin-2(1 H)-one, and their pharmaceutically acceptable salts and solvates.
6. 6. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises treatment of a compound of formula (II):

   where R1, R2 and R3 are as defined in formula (I) and X is a leaving group with aqueous acid and optionally thereafter forming a pharmaceutically acceptable salt or solvate.
7. 7. An intermediate compound of formula (II) as defined in claim 6.
8. 8. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
9. 9. A process for the preparation of a pharmaceutical composition as claimed in claim 8 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5 with a pharmaceutically acceptable adjuvant, diluent or carrier.
10. 10. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5 for use in therapy.
11. 11. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 5 in the manufacture of a medicament for use in therapy.
12. 12.A method of treating a chemokine mediated disease wherein the chemokine binds to a 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 claimed in any one of claims 1 to 5.
13. 13. A method of treating an inflammatory disease 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 claimed in any one of claims 1 to 5.
14. 14.A method according to claim 13, wherein the disease is psoriasis.