GB2457040A - 1-Acetic acid indole derivatives with PGD2 activity - Google Patents

Abstract

Compounds of general formula II wherein <DL TSIZE=3 COMPACT=COMPACT> <DT>W<DD>is chloro of fluoro <DT>R1<DD>is an optionally substituted aryl <DT>R4<DD>is H or optionally substituted alkyl </DL> The compounds may be used in the treatment of asthma, allergic rhinitis and other inflammatory diseases mediated by prostaglandin D2 (PGD2) or other agonists acting on the CRTH2 receptor.

Description

Intellectual D Property Office H F -vi Appliiaflon No GBI)5O 1674 RiM Dale 17 March 2005 The following terms arc registered trademarks and should he read as such wherever they occur in this document: Abbott Grazax Synagis Brukcr Gilson Phenomenex Dainippon Chemoix Greiner Versene Arnersham Biosciences Perkin Elmer Sigma Whalman Unifilter Optiphase Hi safe Wallac UK Intellectual Property Office is an operating name of the Patent Office COMPOUNDS HAVD.JG CRTH2 ANTAGONIST ACTIVITY The present invention relates to compounds which are useful as pharmaceuticals, to methods for preparing these compounds, compositions containing them and their use in the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other inflammatory diseases mediated by prostaglandin D2 (PGD2) or other agonists acting at the CRTI-12 receptor on cells including eosinophils, basophils and Th2 lymphocytes.

PGD2 is an eicosanoid, a class of chemical mediator synthesised by cells in response to local tissue damage, normal stimuli or hormonal stimuli or via cellular activation pathways. Eicosanoids bind to specific cell surface receptors on a wide variety of tissues throughout the body and mediate various effects in these tissues. PGD2 is known to be produced by mast cells, macrophages and Th2 lymphocytes and has been detected in high concentrations in the airways of asthmatic patients challenged with antigen (Murray ci a!., (1986), N. Engi. J. Med. 315: 800-804). Instillation of PGD2 into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy ci a!., (1984) N. Engi. J. Mcd. 311: 209-213; Sampson et a!., (1997) Thorax 52: 513-518) and cosinophil accumulation (Emery ci a!., (1989) J. App!. Physiol. 67: 959-962).

The potential of exogenously applied PGD2 to induce inflammatory responses has been confirmed by the usc of transgcnic mice overexpressing human PGD2 synthase which exhibit exaggerated eosinophilic lung inflammation and Th2 cytokine production in response to antigen (Fujitani ci a!., (2002) J. Innnunol. 168: 443-449).

The first receptor specific for PGD2 to be discovered was the DP receptor which is linked to elevation of the intracellular levels of cAMP. However, PGD2 is thought to mediate much of its proiaflammatory activity through interaction with a G protein-coupled receptor termed CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) which is expressed by Th2 lymphocytes, eosinophils and basophils (I-Iirai et at., (2001) J. Exp. Med. 193: 255-261, and EP085 1030 and EP-A- 1211513 and Baucr ci at., EP-A-1 170594). It seems clear that the effect of PGD2 on the activation of Th2 lymphocytes and eosinophils is mediated through CRTII2 since the selective CRTII2 agonists 13,14 dihydro-15-keto-PGD2 (DK-PGD2) and 15R- methyl-PGD2 can elicit this response and the effects of PGD2 are blocked by an anti-CRT112 antibody (llirai ci a!., 2001; Monneret ci a!., (2003) 1. Plzarmacol. Exp.

Ther. 304: 349-355). In contrast, the selective DP agonist BW245C does not promote migration of Th2 lymphocytes or cosinophils (Hirai et al., 2001; Gervais ci al., (2001) J. Allergy Clii:. lininunol. 108: 982-988). Based on this evidence, antagonising PGD2 at the CRTH2 receptor is an attractive approach to treat the inflammatory component of Th2-dependent allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

EP-A-1 170594 suggests that the method to which it relates can be used to identify compounds which are of use in the treatment of allergic asthma, atopic dermatitis, allergic rhinitis, autoimmunc, reperfusion injury and a number of inflammatory conditions, all of which are mediated by the action of PGD2 or other agonists at the CRTH2 receptor.

Compounds which bind to CRTH2 are taught in WO-A-03066046 and WO-A-03066047. These compounds are not new but were first disclosed, along with similar compounds, in GB 1356834, GB 1407658 and GB 1460348, where they were said to have anti-inflammatory, analgesic and antipyretic activity. WO-A-03066046 and WO-A-03066047 teach that the compounds to which they relate arc modulators of CRTH2 receptor activity and are therefore of use in the treatment or prevention of obstructive airway diseases such as asthma, chronic obstructive pulmonary disease (COPD) and a number of other diseases including various conditions of bones and joints, skin and eyes, GI tract, central and peripheral nervous system and other tissues as well as allograft rejection. These compounds are all indole derivatives with an acetic acid substituent at the 3-position of the indole ring.

PL 65781 and JP 43-244 18 also relate to indole-3 acetic acid derivatives which are similar in structure to indomethacin and, like indomethacin, are said to have anti-inflammatory and antipyretic activity. Thus, although this may not have been appreciated at the time when these documents were published, the compounds they describe are COX inhibitors, an activity which is quite different from that of the compounds of the present invention. Indeed, COX inhibitors are contraindicated in the treatment of many of the diseases and conditions, for example asthma and inflammatory bowel disease for which the compounds of the present invention are useful, although they may sometimes be used to treat arthritic conditions.

There is further prior art which relates to indole-1-acetic acid compounds, although these are not described as CRTI 12 antagonists. For-example WO-A-9950268, WO-A-0032 180, WO-A-0 151849 and WO-A-0 164205 all relate to compounds which are indole-1-acetic acid derivatives but these compounds are said to be aldose reductase inhibitors useful in the treatment of diabetes mcllitus (WO-A-9950268, WO-A- 0032180 and WO-A-0164205) or hypouricemic agents (WO-A-0151849). There is no suggestion in any of these documents that the compounds would be useful for the treatment of diseases and conditions mediated by PGD2 or other CRTI-12 receptor agonists.

US 4,363,912 relates to indole-1-acetic acid derivatives which arc said to be inhibitors of thromboxane synthetase and to be useful in the treatment of conditions such as thrombosis, ischaemic heart disease and stroke.

WO-A-9603376 relates to compounds which are said to be sPLA2 inhibitors which are useful in the treatment of bronchial asthma and allergic rhinitis. These compounds all have amide or hydrazide substituents in place of the carboxylic acid derivative of the compounds of the present invention.

JP 2001247570 relates to a method of producing a 3-benzothiazolylmethyl indole acetic acid, which is said to be an aldose reductase inhibitor.

US 4,859,692 relates to compounds which are said to be leukotriene antagonists useful in the treatment of conditions such as asthma, hay fever and allergic rhinitis as well as certain inflammatory conditions such as bronchitis, atopic and cctopic eczema. Some of the compounds of this document are indole-1-acetic acids but the same authors, in J. Med. Che,n., 33, 1781-1790 (1990), teach that compounds with an acetic acid group on the indole nitrogen do not have significant peptidoleukotriene activity.

US 4,273,782 is directed to indole-1-acetic acid derivatives which are said to be useful in the treatment of conditions such as thrombosis, ischaemic heart disease, stroke, transient ischaemic attack, migraine and the vascular complications of diabetes. There is no mention in the document of conditions mediated by the action of PGD2 or other agonists at the CRTH2 receptor.

US 3,557,142 relates to 3-substitutcd-l-indole carboxylic acids and esters which arc said to be useful in the treatment of inflammatory conditions.

WO-A-03/097598 relates to compounds which are CRTH2 receptor antagonists.

They do not have an aromatic substituent at the indole-3 position.

Cross ci' al., J. Med. Chem. 29, 342-346 (1986) relates to a process for preparing indole-1-acetic acid derivatives from the corresponding esters. The compounds to which it relates are said to be inhibitors of thromboxane synthetase.

EP-A-0539 117 relates to indole-1-acetic acid derivatives which are leukotriene antagonists.

US 2003/0153751 relates to indole-1-acetic acid derivatives which are sPLA inhibitors. However, all of the exemplified compounds have bulky substituents at the 2-and 5-positions of the indole system and are therefore very different from the compounds of the present invention.

US 2004/011648 discloses indolc-1-acetic acid derivatives which arc inhibitors of PAl-1. There is no suggestion that the compounds might have CRTH2 antagonist activity.

WO 2004/058 164 relates to compounds which are said to be asthma and allergic inflammation modulators. The only compounds for which activity is demonstrated are entirely different in structure from the indole-1-acetic acid derivatives of the present invention.

Compounds which bind to the CRTH2 receptor are disclosed in WO-A-03/097042 and WO-A-03/097598. These compounds are indole acetic acids but in WO-A- 03/097042 the indole system is fused at the 2-3 positions to a 5-7 membered carbocyclic ring. In WO-A-03/097598 there is a pyrrolidine group at the indole 3-position.

WO-A-03/101981, WO-A-03/101 961 and WO-A-2004/007451 all relate to indole-1-acetic acid derivatives which are said to be CRTH2 antagonists but which differ in structure from the compounds of general formula (1) because there is no spacer or an -S-or -SO2-group attached to the indole 3-position in place of the CH2 group of the compounds of the present invention as described below.

WO-A-2005/0 19171 also describes indole-1-acetic acid derivatives which are said to be CRTH2 antagonists and which are said to be useful for the treatment of various respiratory diseases. These compounds all have a substituent which is linked to the indole-3 position by an oxygen spacer.

WO-A-2005/094816 again describes indole-1-acctic acid compounds, this time with an aliphatic substituent at the 3-position of the indole ring. The compounds are said to be CRTH2 antagonists.

WO-A-2006/034419 relates to CRTI-12 antagonist indole compounds which have a heterocyclic or heteroaromatic substituent directly linked to the 3-position of the indole ring system.

In our earlier application, WO-A-2005/044260, we describe compounds which are antagonists of PGD2 at the CRTH2 receptor. These compounds are indole-1-acetic acid derivatives substituted at the 3-position with a group wherein R' is hydrogen or alkyl and R is an aromatic moiety which may be substituted with one or more substituents. The compounds described in this document are potent antagonists in vitro of PGD2 at the CRTH2 receptor. However, we have found that when tested in vivo, the pharmacokinetic profile of some compounds is not optimal and their potency in the whole blood eosinophil shape change test, which gives an indication of the likely in vivo activity of the compounds, is often somewhat less than might have been expected from the in vitro binding results.

In another of our earlier applications, W02006/095183, the indole-I-acetic acid derivatives arc substituted at the 3-position with a l-benzenesulfonyl-1H-pyrrol-2-ylmethyl group, where the phenyl group of the benzenesulfonyl moiety may be substituted. These compounds are extremely active CRTFI2 antagonists but are rapidly metabolised as determined by incubation with human microsome preparations.

Our application PCT/GB2007/002761 also relates to CRTH2 antagonist compounds, this time to indole-1-acetic acid derivatives substituted at the 3-position with a 2-phcnylsulfonylbenzyl group. It was found that the position of the phenylsulfonyl substituent had a significant effect on both the activity of the compounds and their pharmacokinetic profile.

The present invention relate to analogues of the compounds of PCT/GB2007/00276 1 in which the 2-phenylsulfonylbenzyl group is replaced by a 2-phenyloxybenzyl group. In comparison to the compounds of W02006/095 183 the compounds of the present invention exhibit improved pharmacokinetic properties.

The present invention therefore relates to novel compounds which bind to the CRTH2 receptor and which are therefore useful in the treatment of diseases and conditions mediated by the activity of PGD2 at the CRTh2 receptor.

In the present invention there is provided a compound of general formula (I) o (1) wherein W is a chioro or fluro substituent; R' is aryl optionally substituted with one or more halo substituent, -CN, -C1 -Co alkyl, -SOR3, -SO2R', -SO2N(R2)2, -N(R2)7, -NR2C(O)R, -C02R2, -CONR2R, -NO2, -OR2, -SR2, -O(CII2)OR2, and 0(C112)pO(C112)qOR2 wherein each R2 is independently hydrogen, -Cl-Co ailcyl, -C-C cycloalkyl, aryl or heteroaryl; each R is independently, -C -C(, alkyl, -C3-C8 cycloalkyl,, aryl or heteroaryl; p and q are each independently an integer from 1 to 3; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.

The compounds of general formula (I) are antagonists at the CRTII2 receptor and are useful in the treatment of conditions which are mediated by PGD2 or other agonists binding to the CRTITI2 receptor. These include allergic diseases, asthmatic conditions and inflammatory diseases, examples of which are asthma, including allergic asthma, bronchial asthma, exacerbations of asthma and related allergic diseases caused by viral infection, particularly those exacerbations caused by rhinovirus and respiratory syncytial virus intrinsic, extrinsic, exercise-induced, drug-induced and dust-induced asthma, treatment of cough, including chronic cough associated with inflammatory and secretory conditions of the airways and iatrogenic cough, acute and chronic rhinitis, including rhinitis medicamentosa, vasomotor rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, nasal polyposis, acute viral infection including common cold, infection due to respiratory syncytial virus, influenza, coronavirus and adenovirus, atopic dermatitis, contact hypersensitivity (including contact dermatitis), eczematous dermatitis, phyto dermatitis, photo dermatitis, sebhorroeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosis et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa urticaria, angiocdema, vasculitides, toxic crythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis, panniculitis, cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; blepharitis conjunctivitis, especially allergic conjunctivitis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalmitis; bronchitis, including infectious and cosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung, hypersensitivity pneumonitis, idiopathic interstitial pneumonias, complications of lung transplantation, vasculitic and thrombotic disorders of the lung vasculature, pulmonary hypertension, food allergies, gingivitis, glossitis, periodontitis, oesophagitis including reflux, cosinophilic gastroenteritis, proctitis, pruris ani, celiac disease, food-related allergies, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other CRTI-12-mediatcd diseases, for example autoimmune diseases such as hyper IgE syndrome, 1-lashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic paschiitis, antiphospholipid syndrome and systemic lupus crythematosus, AIDS, leprosy, Sezary syndrome, paraneoplastic syndrome, mixed and undifferentiated connective tissue diseases, inflammatory myopathies including dermatomyositis and polymyositis, polymalgia rheumatica, juvenile arthritis, rheumatic fever, vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyartcritis, temporal arteritis, myasthenia gravic, acute and chronic pain, neuropathic pain syndromes, central and peripheral nervous system complications of malignant, infectious or autoimrnune processes, low back pain, familial Mediterranean Fever, Muckle-Wells syndrome, Familial 1-libernian fever, Kikuchi disease, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, as well as rheumatoid arthritis, Still's disease, ankylosing spondylitis, reactive arthritis, undifferentiated spondarthropathy, psoriatic arthritis, septic arthritis and other infection-related arthopathics and bone disorders and osteoarthritis; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, calcium paptite related tendon syndrome and synovial inflammation, Behcet's disease, primary and secondary Sjogren's syndrome systemic sclerosis and limited scicroderma; hepatitis, cirrhosis of the liver, cholecystitis, pancreatitis, nephritis, nephntic syndrome, cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvo-vaginitis, Peyronie's disease, erectile dysfunction, Alzheimer's disease and other dementing disorders; pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid, ischaemic reperfusion injuries, endocarditis, valvulitis, aortitis, phlebitis, thrombosis, treatment of common cancers and fibrotic conditions such as idiopathic pulmonary fibrosis including cryptogenic fibrosing alveolitis, keloids, excessive fibrotic scarring/adhesions post surgery, liver fibrosis including that associated with hepatitis B and C, uterine fibroids, sarcoidosis, including neurosarcoidosis, scicroderma, kidney fibrosis resulting from diabetes, fibrosis associated with RA, atherosclerosis, including cerebral atherosclerosis, vasculitis, myocardial fibrosis resulting from myocardial infarction, cystic fibrosis, restenosis, systemic sclerosis, Dupuytren's disease, fibrosis complicating anti-neoplastic therapy and chronic infection including tuberculosis and aspergillosis and other fungal infections, CNS fibrosis following stroke or the promotion of healing without fibrotic scarring.

The compounds are particularly effective when used for the treatment of allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, vernal keratoconjunctivitis and atopic keratoconjunctivitis, cosinophilic bronchitis, food allergies, cosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other PGD2-mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, rcpcrflision injury, chronic obstructive pulmonary disease, as well as rheumatoid arthritis, psoriatic arthritis, osteoarthritis and fibrotic diseases caused/exacerbated by Th2 immune responses, for example idiopathic pulmonary fibrosis and hypertrophihic scars.

In the present specification "C -C(, alkyl" refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms and optionally substituted with one or more halo substituents or with one or more C3-C cycloalkyl groups.

Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chioroethyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclobutyl and methylenecyclopentyl.

In the present specification "C--C cycloalkyl" refers to a saturated carbocyclic group having three to eight ring atoms and optionally substituted with one or more halo substituents. Examples include cyclopropyl, cyclopentyl, cyclohexyl and fluorocyclohexyl.

In the present specification, "halo" refers to fluoro, chloro, bromo or iodo.

The terms "aromatic moiety" and "aryl" in the context of the present specification refer to a ring system with aromatic character having from 5 to 14 ring carbon atoms and containing up to three rings. Where an aromatic moiety contains more than one ring, not all rings must be fully aromatic in character. Examples of aromatic moieties are benzene, naphthalene, indane and indene.

The term "heteroaromatic moiety" and "heteroaryl" in the context of the specification refer to a ring system with aromatic character having from 5 to 14 ring atoms, at least one of which is a heteroatom selected from N, 0 and S, and containing up to three rings. Where a heteroaromatic moiety contains more than one ring, not all rings must be fully aromatic in character. Examples of heteroaromatic groups include pyridine, pyriniidinc, indole, benzofuran, benzimidazole and indolene.

Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formulae (I) include basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, diethanolamine, ethanolamine, ethyl diamine, megulmine and other well known basic addition salts as summarised in J. Mcii. (hem., 50, 6665-6672 (2007) and/or known to those skilled in the art.

Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.

Prodrugs are any covalently bonded compounds which release the active parent drug according to general formula (I) in vivo. Examples of prodrugs include alkyl esters of the compounds of general formula (I), for example the esters of general formula (II) below.

In particularly suitable compounds of general formula (I), W is a fluoro substituent and the group R' is phenyl, which may be unsubstitued or substituted as set out above.

When R' is phenyl, more suitably, it is unsubstituted or substituted with one or more substituents selected from halo, C1-C4 alkyl, C -C4 alkoxy or nitrile.

Particularly suitable compounds are those in which R' is unsubstituted phenyl or phenyl substituted with one or more fluoro and chloro, methyl, ethyl, methoxy, Particularly active compounds of the present invention include: [5-fluoro-2-methyl-3-(2-phenoxybenzyl)-1 1-1-indol-I -yl]acetic acid (Compound 1); [5-fluoro-2-methyl-3-(2-(4-methoxyphenoxy)benzyl)-1 H-indol-1 -yl]acetic acid (Compound 2); [5-fluoro-2-mcthyl-3-(2-(4-mcthylphcnoxy)benzyl)-1 1-1-indol-1 -yl]acetic acid (Compound 3); [5-fluoro-2-mcthyl-3-(2-(2,4-dichlorophenoxy)benzyl)-1 11-indol-1 -yl]acetic acid (Compound 4); [5-fluoro-2-mcthyl-3-(2-(4-fluorophenoxy)benzyl)-1 Il-indol-1 -yI}acctic acid (Compound 5); [5-fluoro-2-methyl-3-(2-(3,4-difluorophcnoxy)benzyl)-1 I1-mdol-1 -yl]acctic acid (Compound 6); {5-fluoro-2-mcthyl-3 -(2-(4-cyanophenoxy)bcnzyl)-1 II-mdol-1 -yl]acetic acid (Compound 7); [5-fluoro-2-methyl-3 -(2-(4-chlorophcnoxy)benzyl)-1 I1-mdol-1 -yl]acetic acid (Compound 8); [5-fluoro-2-methyl-3-(2-(2-cyanophenoxy)benzyl)-1 II-mdol-1 -yl]acetic acid (Compound 9); or the C1-C, alkyl, aryl, (CII2)1OC(=O)Ci-Ca1ky1, ((C112)llO)I1CI12CII2X, (C1I2)111N(R'), or C11((CH7)1O(C=O)Ro)2 esters thereof; wherein mislor2; n is 1-4; X is OR5 or N(R5)2; R is hydrogen or methyl; is C1-C1 alkyl.

In a further aspect of the present invention, there is provided a compound of general formula (II):

O (II)

wherein W and R' are as defined for general formula (I); and R4 is C1-C, alkyl, Cp-C(> alkyl substituted with aryl, aryl, (CH2)fllOC(=O)CI-C(,a&yl, ((CI12),1O)CII2CII2X, (CII2)1N(R5), or CII((CI12)mO(C=O)R)2; mis 1 or2; n is 1-4; X is OR or N(R5)2; R5 is hydrogen or methyl; RisC1-C18a1kyl or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.

Compounds of general formula (II) are novel and may be used as prodrugs for compounds of general formula (I). When the compound of general formula (H) acts as a prodrug, it is later transformed to the drug by the action of an esterase in the blood or in a tissue of the patient.

Examples of particularly suitable R4 groups when the compound of general formula (II) is used as a prodrug include: methyl, ethyl, propyl, phenyl, -O(CH2)2O(CH7)2OR, O(CH2)2O(CH2)?O(CH2)2ORs, -O(CH2)2O(CH2)7NR, -O(CH2)2O(CH2)2O(CH2)2NR2, -CH2OC(=O)tBu, -CFI2CH2N(Me)2, -CH2CI-12NH2 or -CH(CH2O(C=O)R6)2 wherein R and R6 are as defmed above.

In addition to their use as prodrugs, compounds of formula (II) wherein R4 is C1-C5 alkyl or benzyl may be used in a process for the preparation of a compound of general formula (I), the process comprising reacting the compound of general formula (II) with a base such as sodium hydroxide or lithium hydroxide. The reaction may take place in an aqueous solvent or an organic solvent or a mixture of the two. A typical solvent used for the reaction is a mixture of tetrahydrofuran and water.

Compounds of general formula (II) may be prepared from compounds of general formula (III): W> (III) wherein W and R4 are as defined in general formula (11); by reaction with an aldehyde of general formula (IV):

R (IV)

wherein R' is as defined for general formula (I). The reaction may be carried out in the presence of triethylsilane in a polar organic solvent such as dichioromethane and at reduced temperature, for example - 5 to 10°C, typically 0°C.

Procedures for the preparation of compounds of general formula (III) are known to those skilled in the art and in general involve alkylation of a 5-halo-2-methylindole derivative at the I-position with an aipha-bromoacetate derivative or related alkylating agent.

A compound of general formula (IV) may be prepared by reacting a compound of general formula (V): (V) where Q is fluoro, chloro or bromo; with a compound of general formula (VI): HOR' (VI) wherein R' is as defined for general formula (I); This substitution reaction may be carried out in the presence of a weak base such as potassium carbonate, in an organic solvent such as DMSO and under an inert atmosphere such as nitrogen. The reaction mixture may also be heated, for example at about 80 to 120°C, typically 100°C.

In an alternative procedure compounds of general formula (IV) may be prepared by a Mitsunobu reaction between a compound of general formula (V) wherein Q is a hydroxyl moiety and a compound of general formula (VI) under reaction conditions known to those skilled in the art.

Compounds of general formulae (V) and (VI) are readily available or can be prepared by methods well known to those of skill in the art.

Alternatively, a compound of general formula (IV) may be prepared from a compound of general formula (VII): R1-O Hal4j (VII) where Hal is F, Cl or Br and Y and R' as defmcd in general formula (V); by treatment with n-butyl lithium in THF followed by the addition of DMF.

A compound of general formula (VII) may be prepared from a compound of general formula (VIII):

H-O Hal

(VIII) where hal is as defined above; by a Mitsunobu reaction with a compound of general formula (IX): HO-R' (IX) wherein R' as defined in general formula (I).

The reaction may be carried out under reaction conditions known to those skilled in the art.

Compounds of general formulae (VIII) and (IX) are well known and are readily available or can be prepared by methods well known to those of skill in the art.

Compounds of general formula (I) are CRTH2 receptor antagonists and compounds of general formula (II) are prodrugs for compounds of general formula (I).

Compounds of general formulae (I) and (H) arc therefore useful in a method for the treatment of diseases and conditions mediated by PGD2 or other agonists at the CRTH2 receptor, the method comprising administering to a patient in need of such treatment a suitable amount of a compound of general formula (I) or (II).

In a third aspect of the invention, there is provided a compound of general formula (I) or (II) for use in medicine, particularly for use in the treatment or prevention of diseases and conditions mediated by PGD2 or other CRTH2 receptor agonists.

Furthermore, there is also provided the use of a compound of general formula (I) or (II) in the preparation of an agent for the treatment or prevention of diseases and conditions mediated by CR1112 receptor agonists, particularly PGD2.

As mentioned above, such diseases and conditions include allergic diseases, asthmatic conditions and inflammatory diseases, examples of which are asthma, including allergic asthma, bronchial asthma, intrinsic, extrinsic, exercise-induced, drug-induced and dust-induced asthma, treatment of cough, including chronic cough associated with inflammatory and secretory conditions of the airways and iatrogcnic cough, acute and chronic rhinitis, including rhinitis medicamentosa, vasomotor rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, nasal polyposis, acute viral infection including common cold, infection due to respiratory syncytial virus, influenza, coronavirus and adenovirus, atopic dermatitis, contact hypersensitivity (including contact dermatitis), eczematous dermatitis, phyto dermatitis, photo dermatitis, sebhorroeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosis et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus crythematosus, pemphigus, pemphigoid, epidermolysis bullosa urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosmophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis, panniculitis, cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; blepharitis conjunctivitis, especially allergic conjunctivitis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalmitis; bronchitis, including infectious and eosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung, hypersensitivity pneumomtis, idiopathic interstitial pneumonias, complications of lung transplantation, vasculitic and thrombotic disorders of the lung vasculature, pulmonary hypertension, food allergies, gingivitis, glossitis, periodontitis, oesophagitis including reflux, eosinophilic gastroenteritis, proctitis, pruris ani, celiac disease, food-related allergies, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other CRTH2-mediated diseases, for example autoimmune diseases such as hyper 1gB syndrome, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, cosinophilic paschiitis, antiphospholipid syndrome and systemic lupus erythematosus, AIDS, leprosy; Sezary syndrome, paraneoplastic syndrome, mixed and undifferentiated connective tissue diseases, inflammatory myopathies including dermatomyositis and polymyositis, polymalgia rheumatica, juvenile arthritis, rheumatic fever, vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, temporal arteritis, myasthema gravic, acute and chronic pain, neuropathic pain syndromes, central and peripheral nervous system complications of malignant, infectious or autoiinmune processes, low back pain, familial Mediterranean Fever, Muckle-Wells syndrome, Familial Hibernian fever, Kikuchi disease, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, as well as rheumatoid arthritis, Still's disease, ankylosing spondylitis, reactive arthritis, undifferentiated spondarthropathy, psoriatic arthritis, septic arthritis and other infection-related arthopathies and bone disorders and osteoarthritis; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, calcium paptite related tendon syndrome and synovial inflammation, Behcet's disease, primary and secondary Sjogren's syndrome systemic sclerosis and limited scleroderma; hepatitis, cirrhosis of the liver, cholecystitis, pancreatitis, nephritis, nephritic syndrome, cystitis and Runner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvo-vaginitis, Peyronic's disease, crectile dysfunction, Alzhcimcr's disease and other dementing disorders; pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid, ischaemic reperflision injuries, endocarditis, valvulitis, aortitis, phlebitis, thrombosis, treatment of common cancers and fibrotic conditions such as idiopathic pulmonary fibrosis including cryptogenic fibrosing alveolitis, keloids, excessive fibrotic scarring/adhesions post surgery, liver fibrosis including that associated with hepatitis B and C, uterine fibroids, sarcoidosis, including neurosarcoidosis, scieroderma, kidney fibrosis resulting from diabetes, fibrosis associated with RA, atherosclerosis, including cerebral atherosclerosis, vasculitis, myocardial fibrosis resulting from myocardial infarction, cystic fibrosis, rcstcnosis, systemic sclerosis, Dupuytren's disease, fibrosis complicating anti-neoplastic therapy and chronic infection including tuberculosis and aspergillosis and other fungal infections, and CNS fibrosis following stroke. The compounds are also of use in the promotion of healing without fibrotic scarring.

The compounds of general formula (I) or (II) must be formulated in an appropriate manner depending upon the diseases or conditions they are required to treat.

Therefore, in a further aspect of the invention there is provided a pharmaceutical composition comprising a compound of general formula (I) or (II) together with a pharmaceutical cxcipicnt or carrier. Other active materials may also be present, as may be considered appropriate or advisable for the disease or condition being treated or prevented.

The carrier, or, if more than one be present, each of the carriers, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

The formulations include those suitable for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradernial) administration and may be prepared by any methods well known in the art of pharmacy.

The route of administration will depend upon the condition to be treated but preferred compositions are formulated for oral, nasal, bronchial or topical administration.

The composition may be prepared by bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of general formula (I) or (II) in conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.

Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion; or as a bolus etc. For compositions for oral administration (e.g. tablets and capsules), the term "acceptable cathcr" includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcdllulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cheriy flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

For topical application to the skin, compounds of general formula (I) or (II) may be made up into a cream, ointment, jelly, solution or suspension etc. Cream or ointment formulations that may be used for the drug arc conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.

Compounds of general formula (I) or (II) may be used for the treatment of the respiratory tract by nasal, bronchial or buccal administration of, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension. Pharmaceutical compositions with powder-dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desircd, adjuncts, such as liquid or solid non-ionic or anionic surfactants and/or diluents. Pharmaceutical compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser. Instead of the propellant, compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device.

Parenteral formulations will generally be sterile.

Typically, the dose of the compound will be about 0.01 to 100 mg/kg; so as to maintain the concentration of drug in the plasma at a concentration effective to inhibit PGD2 at the CRTII2 receptor. The precise amount of a compound of general formula (I) or (II) which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.

Compounds of general formula (I) or (II) may be used in combination with one or more active agents which are useful in the treatment of the diseases and conditions listed above, although these active agents are not necessarily inhibitors of PGD2 at the CRTII2 receptor.

Thcrefore, the pharmaceutical composition described above may additionally contain one or more of these active agents.

There is also provided the use of a compound of general formula (I) or (II) in the preparation of an agent for the treatment of diseases and conditions mediated by CRTI-12 receptor agonists, especially PGD2, wherein the agent also comprises an additional active agent useful for the treatment of the same diseases and conditions.

These additional active agents may be other CRTII2 receptor antagonists or may have a completely different mode of action. They include existing therapies for allergic and other inflammatory diseases including: Suplatast tosylate and similar compounds; 32 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol or methyixanthanines such as theophylline and aminophylline, mast cell stabilisers such as sodium cromoglycate or muscarinic receptor antagonists such as tiptropium; antihistamines, for example histamine receptor antagonists such as loratadine, cetirizine, desloratidine, levocetirizine, fexofenadine, astemizoic, azelastine and chiorpheniramine or IL receptor antagonists; a and a2 adrenoreceptor agonists such as propyihexedrine phenylephrine, phenyipropanolamine, pseudoephedrine, naphazolme hydrochloride, oxymetazoline hydrochloride, tefrahydrozoline hydrochloride, xylometazolme hydrochloride and ethylnorepmephrine hydrochloride; modulators of chemokine receptor function, for example CCRI, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR1O and CCRI 1 (for the C-C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X3-C family; Leukofriene antagonists such as montelukast and zafirlukast leukotriene biosynthesis inhibitors such as 5-lipoxygenase inhibitors or 5-lipoxygenase activating protein (FLAP) inhibitors such as zileuton, ABT-76 1, fenleuton, tepoxalin, Abbott-79 175, N-(5-substituted)-thiophene-2-alkylsolfonarnides, 2,6-di-tert-butyiphenol hydrazones, methoxytetrahydropyrans such as ZD2138, SB-210661, pyridinyl-substituted-2-cyanonaphthalene compounds such as L-739010, 2-cyanoquinoline compounds such as L-746,530, indole and quinoline compounds such as MK-591, MK-886 and BAY x 1005; Phosphdicstcrasc inhibitors, including PDE4 inhibitors such as roflumilast; anti-IgE antibody therapies such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); anti-fungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease or alternatively FK-506, rapamycin, cyclosporinc, azathioprine or methotrexate; Immunotherapy agents including allergen immunotherapy such as Grazaxand in vivo and e vivo approaches to increase the immunogenicity of patient tumour cells such as transfection with cytokines such as 1L2, 1L4 or GMCSF, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dentritic cells or approaches using cytokine-transfected tumour cell lines or anti-idiotypic antiobodies; corticostcroids such as prednisone, predniso lone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate momctasonc furoate and fluticasonc furoate drugs which promote Thi cytokine response such as interferons, TNF or GM-CSF.

CRTI-12 antagonists may also be combined with therapies that arc in development for inflammatory indications including: other antagonists of PGD2 acting at other receptors such as DP antagonists; inhibitors of phoshodiesterase type 4 such as roflumilast; drugs that modulate cytokine production such as inhibitors of TNFa converting enzyme (TACE) anti-TNF monoclonal antibodies, TNF receptor immunoglobulin molecules, inhibitors of other TNF isoforms, non-selective COX-I /COX-2 inhibitors such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindac and apazone, pyrazolones such as phenylbutazone, salicilates such as aspirin; COX-2 inhibitors such as meloxicam, celecoxib, fofecoxib, valdecoxib and etoricoxib, low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquinc, d-penicillamine, auranofm or parenteral or oral gold.

drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 such as blocking monoclonal antibodies and soluble receptors; PPAR-y agonists such as rosiglitazone; or with anti-RSV antibodies such as Synagis (palivizumab) and agents that may be used to treat rhinovirus infection in the future e.g. interferon-beta and other interferons.

In yet a further aspect of the invention, there is provided a product comprising a compound of general formula (I) or (II) and one or more of the agents listed above as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of POD2 at the CRTII2 receptor.

The invention will now be described in greater detail with reference to the following non limiting examples.

In the Examples, the NMR spectra were obtained using a Bruker Advance II spectrometer operating at 300MHz. All signals were referenced relative to residual protic solvent.

IIPLC-CAD-MS was performed on a Gilson 321 IIPLC with detection performed by a ESA Corona CAD and a Finnigan AQA mass spectrometer operating in positive-ion electrospray ionisation mode. The HPLC column was a Phenomenex Gemini Cl 8 50x4.6mm 3.t, with a mobile phase gradient between 100% 0.1% formic acid in water and 100% 0.1% formic acid in acetonitrile run over 2.5 minutes, with a total run time of 6.5 minutes.

Example I -Preparation of Compounds of General Formula (I).

The examples were all prepared following the protocol set out for Compound 1 in W02005044260 using the appropriate starting aldehyde.

[5-fluoro-2-methyl-3 -(2-phenoxybenzyl)-1 H-indol-1 -yl]acetic acid (Compound 1): H NMR (d4DMSO): 12.99 (111, br s), 7.41-7.30 (3 II, m), 7.21-7.01 (5 Ii, m), 6.95-6.80 (4 H, m), 4.91 (2 H, s), 3.95 (2 H, s) and 2.25 (3 H, s).

LCMS RT= 2.73 mi MW 390.0.

[5-fluoro-2-methyl-3-(2-(4-methoxyphenoxy)benzyl)-11 1-indol-I -yI]acetic acid (Compound 2): H NMR (d6DMSO): 13.02(1 1-1, brs), 7.34(1 1-1, dd,.J8.9 and 4.4), 7.18-7.07(3 1-1, m), 7.00-6.80 (6 H, m), 6.71 (1 H, dd, 18.1 and 1.1), 4.92 (2 H, s), 4.00 (2 H, s), 3.75 (3 H, s) and 2. 27 (3 H, s).

LCMS RT= 2.70 mm, MH 420.1 {5-fluoro-2-mcthyl-3-(2-(4-methylphcnoxy)benzyl)-1 H-indol-1 -yl]acetic acid (Compound 3) H NMR (d(,DMSO): 12.99 (1 H, br s), 7.37-7.30 (1 H, m), 7.21-7.04 (5 H, m), 7.04-6.97 (1 1-1, m), 6.89-6.77 (4 H, m), 4.92 (2 I-I, s), 3.96 (2 H, s), 2.29 (3 H, s) and 2.26 (3 H, s).

LCMS RT= 2.90 mm, MH 404.2 [5-fluoro-2-methyl-3 -(2-(2,4-dichlorophenoxy)benzyl)-I H-indol-I -yl]acetic acid (Compound 4) No acid peak H NMR (d6DMSO): 7.74 (1 H, d, 1 2.5), 7.34-7.29 (2 H, m), 7.24-7.16 (2 H, m), 7.12-7.05 (2 H, m), 6.87-6.78 (2 H, m), 6.74 (1 H, d, 18.8), 4.90 (2 H, s), 3.98 (2 1-1, s) and 2.25 (3 H, s).

LCMS RT= 3.10 mm, MH 459.7 [5-fluoro-2-methyl-3 -(2-(4-fluorophenoxy)benzyl)-1 H-indol-1 -yI]acetic acid (Compound 5) H NMR (d6DMSO): 12.97 (1 H, br s), 7.33 (1 Fl, dd, J 8.9 and 4.5), 7.23-7. 13 (4 1-1, m), 7.09-7.00 (2 H, m), 6.98-6.91 (2 H, m), 6.89-6.79 (2 11, m), 4.92 (2 H, s), 3.97 (2 I-I, s) and 2.25 (3 H, s).

LCMS RT= 2.75 mm, MR 408.2 [5-fluoro-2-methyl-3-(2-(3,4-difluorophenoxy)benzyl)-1 H-indol-1 -yl]acctic acid (Compound 6) no acid peak 11 NMR (dDMSO): 7.46-7.27 (2 H, m), 7.27-7.17 (2 1-1, m), 7.14-7.06 (1 H, m), 7.06-6.94 (2 H, m), 6.93-6.88 (1 H, m), 6.88-6.79 (1 H, m), 6.74-6.64 (1 H, m), 4.89 (2 H, s), 3.96 (2 1-1, s) and 2.23 (3 H, s).

LCMS RT= 2.78 mm, MH 426.3 [5-fluoro-2-mcthyl-3-(2-(4-cyanophcnoxy)bcnzyl)-1 H-indol-1 -yl]acetic acid (Compound 7) no acid peak 111 NMR (CDCI3): 7.44-7.37 (2 1-1, m), 7.19-7.12 (2 H, m), 7.11-7.02 (1 H, m), 6.98- 6.83 (3 H, m), 6.83-6.69 (3 H, m), 4.64 (2 H, s), 3.88 (2 1-1, s) and 2.15 (3 H, s).

LCMS RT= 2.57 mm, MI-I 415.6 [5-fluoro-2-methyl-3-(2-(4-chlorophenoxy)benzyl)-1 H-indol-I -yl]acetic acid (Compound 8) H NMR (d6DMSO): 13.0 (1 H, br s), 7.43-7.36 (2 H, m), 7.33 (1 H, dd, J 8.9 and 4.5), 7.25-7.17 (2 H, m), 7.12-7.01 (2 H, m), 6.95-6.80 (4 H, m), 4.90 (2 H, s), 3.94 (2 H, m) and2.23 (3 H,m).

LCMS RT 2.95 mm, MI-C 424.5 [5-fluoro-2-mcthyl-3-(2-(2-cyanophenoxy)bcnzyl)-1 H-indol-1 -yl]acctic acid (Compound 9) H NMR (d6DMSO): 12.96 (1 H, br s), 7.85 (1H, dd, J 7.7and 1.6), 7.52 (1 H, ddd, J 8.5, 7.5 and 1.7), 7.33-7.13 (5 II, m), 7.09-6.99 (2 H, m), 6.83 (1 H, td, J 9.2 and 2.6), 6.58 (1 H, dJ 8.2), 4.86 (2 H, s), 3.96 (2 H, s) and 2.22 (3 1-1, s).

LCMS RT= 2.51 mm, MH 415.2 Example 2-Measurement of CRTH2 Antagonist Activity Materials and Methods Materials Mono-.poly resolving medium was obtained from Dainippon Pharmaceuticals (Osaka, Japan). Macs anti-CD16 microbeads were from Miltenyi biotec (Bisley, Surrey). Chemolx plates were purchased from Neuroprobe (Gaithersburg, MD).

Poly-D-lysinc coated 96-well plates were obtained from Greiner (Gloucestershire, UK). [1-l]PGD7 was from Amersham Biosciences (Buckinghamshire, UK).

[H]SQ29548 was purchased from Perkin Elmer Life Sciences (Buckinghamshire, UK). All other reagents were obtained from Sigma- Aldrich (Dorset, UK), unless otherwise stated.

Methods 1 0 Cc'll culture Chinese Hamster Ovary cells were transfected with CRTH2 or DP receptors (CHO/CRTh2 and CI-IO/DP) and were maintained in culture in a humidified atmosphere at 37°C (5% C02) in Minimum Essential Medium (MEM) supplemented with 10% foetal bovine serum, 2 mM glutamine, and I mg ml' active G41 8. The cells were passaged every 2-3 days. For radioligand binding assay, cells were prepared in triple-layer flasks or in 175 cm2 square flasks (for membrane preparation.

Preparation o/ cell membranes Membranes were prepared either from CHO/CRTH2 and CHO/DP cells, or from platelets (as a source of TP receptors). CHO cells grown to confluency were washed with PBS and detached using a Versenc solution (15 ml per flask). When the cells were grown in 175 cm2 square flask, they were collected by scrapping in PBS. The cell suspensions were centrifuged (1,700 rpm, 10 mm, 4°C) and resuspended in 15 ml of buffer (IxHBSS, supplemented with 10 mM HEPES, pH 7.3). Cell suspensions were then homogenised using an Ultra Turrax at setting 4-6 for 20 s.

The homogenate was centrifuged at 1,700 rpm for 10 mm and the supernatant was collected and centrifuged at 20,000 rpm for lh at 4°C. The resulting pellet was resuspended in buffer and stored at -80°C in aliquots of 200-500 p.1. The protein concentration was determined by the method of Bradford (1976), using bovine serum albumin as standard. The platelets were washed by centrifugation at 600xg for 10 mm and resuspended in ice-cold assay buffer (10 mM Tris-HCI, pH 7.4, 5 mM Glucose, 120 mM NaCI, 10 jtM indomethacin) and directly centrifuged at 20,000 rpm for 30 mm at 4"C. The resulting pellet was treated as described above.

Radio1igand binding assays [H}PGD (160 Ci/mmol) binding experiments were performed on membranes prepared as described above. Assays were performed in a final volume of 100 p.1 of buffer (1XIIBSSIIIEPES 10 mM, pH 7.3). Ccli membranes (15j.ig). Cell membranes 15mg were preincubated at room temperature with varying concentration of competing ligand for 15 mm. [FIJPGD2 (mol, final concentration) was then added and the incubation continued for a further one hour at room temperature. The reaction was terminated by the addition of 200 p.! ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/B glass fibre filters using a tinifilter Cell harvester (PerkinElmer Life Sciences) and six washes of 300 p.1 of ice-cold buffer. The Unifliter plates were dried at room temperature for at least lb and the radioactivity retained on the filters was determined on a Beta Trilux counter (PerkinElmer Life Sciences), following addition of 40 p.1 of Optiphase I-li-Safe 3 (Wallac) liquid scintillation. Non specific binding was defined in the presence of 10 p.M unlabelled PGD2. Assays were performed in duplicate.

The results of the radioligand binding experiments to the CRTH2 are shown in Table 1.

Table I -Radioligand binding data (Ki on CRTH2 Receptor).

Compound Ki (nM) ___________________________________ 23 2 18 3 17 4 34 47 6 6 7 11 8 10 9 4 Example 3 -Human Whole Blood Eosinophil Shape Chance Assay Compounds I to 9 were assayed for their effect on PGD2 induced eosinophil shape change.

Methods Shape Change Assay in whole blood Compounds (lil, 200 x final concentration) were added directly to 200jil whole blood, mixed well and incubated for 15 mm, 37°C, 5% CO2. After this time, cell shape was fixed by addition of 300il Cytoflx'TM buffer (BD Biosciences), 15 mm on ice. I Omi RBC lysis buffer was added to the fixed cells, incubated 5mm, at room temperature and centrifuged, 300 x g for 5 miii. Supematant (containing lysed red cells) was removed and the lysis step was repeated. Leukocytes were resuspended in 250ji1 RPMTJ1O% FCS and shape change analysed by FACS. Eosinophils were gated out based on their autofluorescence and 2000 eosinophil events were counted per sample. Data were analysed in triplicate.

The results for the cosinophil shape change assay are shown in Table 2.

Table 2 -IC Values for the Effect of Test Compounds on 10 nM PGD2-induced Eosinophil Shape Change Compound Value (nM) 9 (0C2287) 9

Claims (19)

1. A compound of general formula (I) o (I) wherein R' is aryl optionally substituted with one or more halo substituent, -CN, -Cl-Co alkyl, -SOR, -S02R3, -SO2N(R2)2, -N(R2)7, -NR2C(O)R3, -C02R2, -CONR2R3, -NO2, -OR2, -SR2, -O(CH2)OR2, and O(CH2)pO(CH2)qOR2 wherein each R2 is independently hydrogen, -C1-C6 alkyl, -C3-C cycloalkyl, aryl or heteroaryl; each R3 is independently, -C1-C6 alkyl, -C3-C8 cycloalkyl, aryl or heteroaryl; p and q are each independently an integer from 1 to 3; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.

or a pharmaceutically acceptable salt, hydrate, solvatc, complex or prodnig thereof.

2. A compound of general formula (IL):

O

wherein W and R' are as defined for general formula (I); and R4 is CI-C(, alkyl, C1-C(, alkyl substituted with awl, aryl, (CH2),OC(=O)Ci-Ca1kyl, ((CH2)n,O)nCH2CH2X, (CH)mN(R5)2 or CH((Cfl2)11O(C=O)R6); mis I or2; n is 1-4; 5 XisOR orN(R)2; R3 is hydrogen or methyl; R' is Ci-C alkyl or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.

3. A compound as claimed in claim 1 or claim 2, wherein W is fluoro.

4. A compound as claimed in any one of claims I to 3, wherein R' is substituted

5. A compound as claimed in claim 4 wherein R' is unsubstituted phenyl or phenyl substituted with one or more substituents selected from halo, C -C4 alkyl, C -C4 alkoxy or nitrilc.

6. A compound as claimed in claim 5 wherein R' is unsubstituted phenyl or phenyl substituted with one or more substituents selected from fluoro, chioro, methyl, ethyl, methoxy, ethoxy and mtrile.

7. A compound as claimed in claim 1 selected from: [5-fluoro-2-methyl-3-(2-phenoxybenzyl)-III -indol-I -yl]acetic acid; [5-fluoro-2-methyl-3-(2-(4-methoxyphenoxy)bcnzyl)-1 Il-indol-I -yl]acetic acid; [5-fluoro-2-methyl-3 -(2-(4-methylphenoxy)benzyl)-1 H-indol-1 -yl]acetic acid; [5-fluoro-2-methyl-3-(2-(2,4-dichlorophcnoxy)benzyl)-11 l-mdol-1 -yl]acctic acid; [5-fluoro-2-methyl-3-(2-(4-fluorophenoxy)benzyl)-11 1-indol-1 -yl]acetic acid; [5-fluoro-2-mcthyl-3 -(2-(3,4-difluorophenoxy)benzyl)-1 I1-mdol-1 -yl]acetic acid; [5-fluoro-2-methyl-3 -(2-(4-cyanophenoxy)benzyl)-I H-indol-1 -yl]acetic acid; [5-fluoro-2-mcthyl-3 -(2-(4-chlorophcnoxy)benzyl)-1 Il-indol-I -yl]acetic acid; [5-fluoro-2-methyl-3 -(2-(2-cyanophenoxy)benzyl)-11 1-indol-I -yl]acetic acid; or the C-C(, alkyl, aryl, (CI12)11OC(O)Ci-CaIky1, ((CII2)1O)11CIl2CI12X, (CH2),1N(R5) or CH((CH)1O(C=O)R6) esters thereof; wherein mis I or2; n is 1-4; X is OR5 or N(R5)2; R5 is hydrogen or methyl; is CI-CIK alkyl.

8. A process for the preparation of a compound of general formula (I) as claimed in any one of claims 1 to 7, the process comprising reacting a compound of general formula (H) as defined in claim 2 and wherein R4 is Ci -Co alkyl with a base.

9. A compound as claimed in any one of claims 1 to 7 for use in medicine.

10. A compound as claimed in any one of claims 1 to 7 for usc in the treatment of asthma, including allergic asthma, bronchial asthma, exacerbations of asthma and related allergic diseases caused by viral infection, particularly those exacerbations caused by rhinovirus and respiratory syncytial virus intrinsic, extrinsic, exercise-induced, drug-induced and dust-induced asthma, treatment of cough, including chronic cough associated with inflammatory and secretory conditions of the airways and iatrogemc cough, acute and chronic rhinitis, including rhinitis medicamentosa, vasomotor rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, nasal polyposis, acute viral infection including common cold, infection due to respiratory syncytial virus, influenza, coronavirus and adenovirus, atopic dermatitis, contact hypersensitivity (including contact dermatitis), cczematous dermatitis, phyto dermatitis, photo dermatitis, sebhorroeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosis et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiformc, cellulitis, panniculitis, cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; blepharitis conjunctivitis, especially allergic conjunctivitis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalmitis; bronchitis, including infectious and cosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung, hypersensitivity pneumonitis, idiopathic interstitial pneumonias, complications of lung transplantation, vasculitic and thrombotic disorders of the lung vasculature, pulmonary hypertension, food allergies, gingivitis, glossitis, periodontitis, oesophagitis including reflux, eosinophilic gastroenteritis, proctitis, pruris ani, celiac disease, food-related allergies, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other CRTI-12-mediated diseases, for example autoimmune diseases such as hyper IgE syndrome, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic paschiitis, antiphospholipid syndrome and systemic lupus crythematosus, AIDS, leprosy, Sczary syndrome, paraneoplastic syndrome, mixed and undifferentiated connective tissue diseases, inflammatory myopathies including dermatomyositis and polymyositis, polyinalgia rheumatica, juvenile arthritis, rheumatic fever, vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, temporal arteritis, myasthenia gravic, acute and chronic pain, neuropathic pain syndromes, central and peripheral nervous system complications of malignant, infectious or autoimmune processes, low back pain, familial Mediterranean Fever, Muckle-Wells syndrome, Familial Hibemian fever, Kikuchi disease, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, as well as rheumatoid arthritis, Still's disease, ankylosing spondylitis, reactive arthritis, undifferentiated spondarthropathy, psoriatic arthritis, septic arthritis and other infection-related arthopathies and bone disorders and ostcoarthritis; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, calcium paptite related tendon syndrome and synovial inflammation, Behcet's disease, primary and secondary Sjogren's syndrome systemic sclerosis and limited scieroderma; hepatitis, cirrhosis of the liver, cholecystitis, pancreatitis, nephritis, nephritic syndrome, cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvo-vaginitis, Peyronie's disease, erectile dysfunction, Alzheimer's disease and other dementing disorders; pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid, ischaemic reperfusion injuries, endocarditis, valvulitis, aortitis, phlebitis, thrombosis, treatment of common cancers and fibrotic conditions such as idiopathic pulmonary fibrosis including cryptogenic fibrosing alveolitis, keloids, excessive fibrotic scarring/adhesions post surgery, liver fibrosis including that associated with hepatitis B and C, uterine fibroids, sarcoidosis, including neurosarcoidosis, scicroderma, kidney fibrosis resulting from diabetes, fibrosis associated with RA, atherosclerosis, including cerebral atherosclerosis, vasculitis, myocardial fibrosis resulting from myocardial infarction, cystic fibrosis, restenosis, systemic sclerosis, Dupuytren's disease, fibrosis complicating anti-neoplastic therapy and chronic infection including tuberculosis and aspergillosis and other flingal infections, CNS fibrosis following stroke or the promotion of healing without fibrotic scarring.

11. The use of a compound as claimed in any one of claims 1 to 7 in the preparation of an agent for the treatment or prevention of asthma, including allergic asthma, bronchial asthma, exacerbations of asthma and related allergic diseases caused by viral infection, particularly those exacerbations caused by rhinovirus and respiratory syncytial virus intrinsic, extrinsic, exercise-induced, drug-induced and dust-induced asthma, treatment of cough, including chronic cough associated with inflammatory and secretory conditions of the airways and iatrogcnic cough, acute and chronic rhinitis, including rhinitis medicamentosa, vasomotor rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, nasal polyposis, acute viral infection including common cold, infection due to respiratory syncytial virus, influenza, coronavirus and adenovirus, atopic dermatitis, contact hypersensitivity (including contact dermatitis), eczematous dermatitis, phyto dermatitis, photo dermatitis, sebhorroeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosis Ct atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa urticaria, angioedcma, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis, panniculitis, cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; blepharitis conjunctivitis, especially allergic conjunctivitis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalniitis; bronchitis, including infectious and cosinophilic bronchitis, emphysema, bronchiectasis, farmer's lung, hypersensitivity pneumonitis, idiopathic interstitial pneumonias, complications of lung transplantation, vasculitic and thrombotic disorders of the lung vasculature, pulmonary hypertension, food allergies, gingivitis, glossitis, periodontitis, oesophagitis including reflux, eosinophilic gastroenteritis, proctitis, pruris ani, celiac disease, food-related allergies, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other CRTH2-mediated diseases, for example autoimmune diseases such as hyper IgE syndrome, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic paschiitis, antiphospholipid syndrome and systemic lupus erythematosus, AIDS, leprosy, Sezary syndrome, paraneoplastic syndrome, mixed and undifferentiated connective tissue diseases, inflammatory myopathies including dermatomyositis and polymyositis, polymalgia rheumatica, juvenile arthritis, rheumatic fever, vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, temporal arteritis, myasthenia gravic, acute and chronic pain, neuropathic pain syndromes, central and peripheral nervous system complications of malignant, infectious or autoimmune processes, low back pain, familial Mediterranean Fever, Muckle-Wells syndrome, Familial Hibernian fever, Kikuchi disease, psoriasis, acne, multiple sclerosis, aHograft rejection, reperfusion injury, chronic obstructive pulmonary disease, as well as rheumatoid arthritis, Still's disease, ankylosing spondylitis, reactive arthritis, undifferentiated spondarthropathy, psoriatic arthritis, septic arthritis and other infection-related arthopathies and bone disorders and osteoarthritis; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, calcium paptite related tendon syndrome and synovial inflammation, Behcet's disease, primary and secondaiy Sjogren's syndrome systemic sclerosis and limited scleroderma; hepatitis, cirrhosis of the liver, cholecystitis, pancreatitis, nephritis, nephritic syndrome, cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvo-vaginitis, Peyronie' s disease, crectile dysflmction, Alzheimer's disease and other dementing disorders; pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid, ischacmic reperfusion injuries, endocarditis, valvulitis, aortitis, phlebitis, thrombosis, treatment of common cancers and fibrotic conditions such as idiopathic pulmonary fibrosis including cryptogenic fibrosing alveolitis, keloids, excessive fibrotic scarring/adhesions post surgery, liver fibrosis including that associated with hepatitis B and C, uterine fibroids, sarcoidosis, including neurosarcoidosis, scieroderma, kidney fibrosis resulting from diabetes, fibrosis associated with RA, atherosclerosis, including cerebral atherosclerosis, vasculitis, myocardial fibrosis resulting from myocardial infarction, cystic fibrosis, restenosis, systemic sclerosis, Dupuytrcn's disease, fibrosis complicating anti-neoplastic therapy and chronic infection including tuberculosis and aspergillosis and other fungal infections, CNS fibrosis following stroke or the promotion of healing without fibrotic scarring.

12. A pharmaceutical composition comprising a compound as claimed in any one of claims I to 7 together with a pharmaceutical excipient or carrier.

13. A composition as claimed in claim 12 formulated for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

14. A composition as claimed in claim 12 or claim 13 containing onc or more additional active agents useful in the treatment of diseases and conditions mediated by PGD2 or other agonists at the CRTII2 receptor.

15. A composition as claimed in claim 14, wherein the additional active agents are selected from: other CRTH2 antagonists; Suplatast tosylate and similar compounds; f32 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol or methylxanthanines such as theophylline and aminophylline, mast cell stabilisers such as sodium cromoglycate or muscarinic receptor antagonists such as tiptropium; antihistaniines, for example histamine receptor antagonists such as loratadine, cetirizinc, desloratidinc, levocetirizine, fexofenadinc, astemizole, azelastine and chiorpheniramine or IL4 receptor antagonists; a and U2 adrenoreceptor agonists such as propylhexedrine phenylephrine, phenyipropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethylnorepinephrine hydrochloride; modulators of chemokine receptor flinction, for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR1O and CCR1 1 (for the C-C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X3-C family; Leukotriene antagonists such as montelukast and zafirlukast leukotriene biosynthesis inhibitors such as 5-lipoxygenase inhibitors or 5-lipoxygenase activating protein (FLAP) inhibitors such as zilcuton, ABT-76 1, fenleuton, tepoxalin, Abbott-79 175, N-(5-substituted)-thiophene-2-alkylsolfonamides, 2,6-di-tert-butyiphenol hydrazones, methoxytetrahydropyrans such as ZD2 138, SB-2 10661, pyridinyl-substituted-2-cyanonaphthalene compounds such as L-739010, 2-cyanoqumoline compounds such as L-746,530, indole and quinoline compounds such as MK-59l, MK-886 and BAY x 1005; Phosphdiesterasc inhibitors, including PDE4 inhibitors such as roflumilast; anti-lgE antibody therapies such as omalizumab; ant i-infectives such as füsidic acid (particularly for the treatment of atopic dermatitis); anti-fungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease or alternatively FK-506, rapamycin, cyclosporine, azathioprine or methotrexate; Immunotherapy agents including allergen immunotherapy such as Grazaxand in vivo and c-vivo approaches to increase the immunogenicity of patient tumour cells such as transfection with cytokines such as 1L2, 1L4 or GMCSF, approaches to decrease T-ceII anergy, approaches using transfected immune cells such as cytokine-transfected dentritic cells or approaches using cytokine-transfected tumour cell lines or anti-idiotypic antiobodies; corticosteroids such as prednisone, prednisolonc, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate drugs which promote Thi cytokine response such as interferons, TNF or GM-CSF.

CRTH2 antagonists may also be combined with therapies that are in development for inflammatory indications including: other antagonists of PGD2 acting at other receptors such as DP antagonists; inhibitors of phoshodiesterase type 4 such as rofluniilast; drugs that modulate cytokine production such as inhibitors of TNFa converting enzyme (TACE) anti-TNF monoclonal antibodies, TNF receptor immunoglobulin molecules, inhibitors of other TNF isoforms, non-selective COX-l/COX-2 inhibitors such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindac and apazone, pyrazolones such as phenylbutazone, salicilates such as aspirin; COX-2 inhibitors such as meloxicam, celecoxib, fofecoxib, valdecoxib and etoricoxib, low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-pcnicillamine, aurano fin or parenteral or oral gold.

drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 such as blocking monoclonal antibodies and soluble receptors; PPAR-y agonists such as rosiglitazone; or with anti-RSV antibodies such as Synagis (palivizumab) and agents that may be used to treat rhinovirus infection in the future e.g. interferon-beta and other interferons.

16. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 12 to 15 comprising bringing a compound as claimed in any one of claims 1 to 7 in conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.

17. A product comprising a compound as claimed in any one of claims 1 to 7 and one or more of the agents listed in claim 15 as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD2 or other agonists at the CRTH2 receptor.

18. The use as claimed in claim 11, wherein the agent also comprises an additional active agent useful for the treatment of diseases and conditions mediated by PGD2 or other agonists at the CRTH2 and/or DP receptor.

19. The use as claimed in claim 18, wherein the additional active agent is one of the agents listed in claim 15.