GB2422830A

GB2422830A - Pyrrolopyridines and their use in the treatment of diseases mediated by PGD2 at the CRTH2 receptor

Info

Publication number: GB2422830A
Application number: GB0502310A
Authority: GB
Inventors: Richard Edward Armer; Edward Andrew Boyd; Frederick Arthur Brookfield
Original assignee: Oxagen Ltd
Current assignee: Oxagen Ltd
Priority date: 2005-02-04
Filing date: 2005-02-04
Publication date: 2006-08-09
Also published as: GB0502310D0

Abstract

Compounds of formula (Ia) or (Ib): <EMI ID=1.1 HE=53 WI=111 LX=542 LY=759 TI=CF> <PC>wherein R<1> R<2> and R<3> are independently hydrogen, halo, -C1-C6 alkyl, -O(C1-C6 alkyl), -C1-C6 alkyl(C3-C7 cycloalkyl), -CON(R<8>)2, -SOR<8>, -SO2R<8>, -SO2N(R<8>)2, -N(R<8>)2, -NR<8>COR<8>, -CO2R<8>, COR<8>, -SR<8>, -OH, -NO2 or -CN; ```each R<8> is independently hydrogen or C1-C6 alkyl; R<4> and R<5> are each independently hydrogen, or C1-C6 alkyl or together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R<6> is hydrogen or C1-C6 alkyl; R<7> is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, C1-C6 alkyl, -O(C1-C6)alkyl, -R<10>, -OR<10>, C(R<10>)2 -CON(R<10>)2, -SOR<10> -SO2R<10>, - SO2N(R<10>)2, -N(R<10>)2, -NR<10>COR<10>, -CO2R<10>, -COR<10>, -SR<10>, -OH, -NO2 or -CN; ```wherein each R<10> is independently hydrogen, C1-C6 alkyl, aryl or substituted aryl; X is -S- or -SO2-; or pharmaceutically acceptable salts, hydrates, solvates, complexes or prodrugs thereof are useful in the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

Description

COMPOUNDS

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) acting at the CRTH2 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 et a!, (1986), N Engi. .1. Med. 315 800-804). Instillation of PGD2 into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy et al, (1984) N Engi. J. Med. 311: 209-213, Sampson et al, (1997) Thorax 52 513-518) and eosinophil accumulation (Emery c/al, (1989)1 AppI. Physiol. 67 95 9-962) The potential of exogenously applied PGD2 to induce inflammatory responses has been confirmed by the use of transgenic mice overexpressing human PGD2 synthase which exhibit exaggerated eosinophilic lung inflammation and Th2 cytokine production in response to antigen (Fujitani et a!, (2002) .1 Immunol. 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 cAMIP. However, PGD2 is thought to mediate much of its proinflammatory 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 (Hirai c/al, (2001)1 Exp. Med. 193: 255-26 1, and EP085 1030 and EP-A- 1211513 and Bauer et al, EP-A-1 170594) It seems clear that the effect of PGD2 on the activation of Th2 lymphocytes and eosinophils is mediated through CRTH2 since the selective CRTH2 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- CRTH2 antibody (Hirai et at, 2001, Monneret et cii, (2003) .1 Pharmacol. Exp Ther.

304 349-355) In contrast, the selective DP agonist BW245C does not promote migration of Th2 lymphocytes or eosinophils (Hirai et ai, 2001; Gervais ef cii, (2001) J. Allergy (71n. Immunol. 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, autoimmune disease, reperfusion injury and a number of inflammatory conditions, all of which are mediated by the action of PGD2 at the CRTH2 receptor Compounds which bind to CRTH2 are taught in WO-A-03/066046 and WO-A- 03/066047 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-03 066046 and WO-A-03066047 teach that the compounds to which they relate are 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 WO-A-03/l0l961 and WO-A-2004/007451 also relate to compounds which are CRTH2 receptor antagonists. The compounds disclosed in both these documents are indole-1-carboxylic acid derivatives with the compounds described in WO-A- 03/101961 having an S-aryl group and the compounds of WO-A-2004/007451 having either SO-aryl or S02-aryl at the 3-position of the indole ring system.

Other compounds which are CRTH2 receptor antagonists are disclosed in our co- pending applications PCT/GB2004/004336, which relates to indole-l-acetic acid derivatives, PCT/GB2004/04337 which relates to indole-l-sulfonyl-3- acetic acid derivatives, and PCT/GB2004/004417, which relates to indole-l- acetic acid derivatives.

lndole-1-carboxylic acid derivatives are also disclosed in WO-A-99/50268, In this case, the compounds have a -alkylaryl group at the 3-position of the indole system There is no suggestion that these compounds could be useful in the treatment of conditions such as asthma and allergic conditions, which are mediated by PGD2.

Rather, they are said to be of use in the treatment of complications arising from diabetes mellitus WO-A-96/03376 relates to indole-1carboxamjdes and hydrazides with a variety of substituents at the 3position, including -alkylaryl groups These compounds are said to be sPLA2 inhibitors PL 65781 and JP 43-24418 also relate to indole 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 inflammatory bowel disease for which the compounds of the present invention are useful, although they may sometimes be used to treat arthritic conditions The present invention relates to a novel group of compounds which have been found to have activity as CRTH2 receptor antagonists.

In a first aspect of the present invention there is provided a compound of general formula (la) or (Tb): wherein R', R2 and R3 are independently hydrogen, halo, -C1-C6 alkyl, -O(C1-C6 alkyl), -C1-C6 alkyl(C3-C7 cycloalkyl), -CON(R8)2, -SOR8, -S02R8, -SO2N(R8)2, - N(R8)2, -NR8COR8, -C02R8, COR8, -SR8, -OH -NO2 or -CN; each R8 is independently hydrogen or C1-C6 alkyl; R4 and R5 are each independently hydrogen, or C1- C6 alkyl or together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group, R6 is hydrogen or C1-C6 alkyl, R7 is Cj-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, C1-C6 alkyl, -O(Ci-C6)alkyl, -R' , -OR10, C(R' )2 -CON(R' )2, -SOR' - SO2R' , SO2N(R' )2, -N(R' )2, -NR' C0R10, -C02R10, -COR' , -SR' , -OH, -NO2 or CN, wherein each R' is independently hydrogen, C1-C6 alkyl, aryl or substituted aryl, X is -S- or -SO2-; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof The compounds of general formula (Ia) and (Ib) are antagonists of PGD2 at the CRTH2 receptor and will therefore be useful in the treatment of conditions which are mediated by PGD2 binding to CRTH2 These include allergic diseases, asthmatic conditions and inflammatory diseases, examples of which are allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other PGD2mediated diseases, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfiision injury and chronic obstructive pulmonary disease, as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis In the present specification "C1-C6 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-C7 cycloalkyl groups.

Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl, methylenecyclopropyl, methyl enecyclobutyl, methylenecyclobutyl and methylenecyclopentyl "C1-C4 alkyl" and "C-C alkyl" have similar meanings except that they contain from one to four and from one to eighteen carbon atoms respectively "C2-C6 alkenyl" and "C1-C6 alkynyl" refer to straight or branched carbon chains having from one to six carbon atoms and containing respectively a carbon-carbon double bond and a carbon-carbon triple bond. The groups are optionally substituted with one or more halo substituents or with one or more C3-C7 cycloalkyl groups Examples include etheny!, ethynyl, 2- propenyl and 2-propynyl C3-C7 cycloalkyl refers to a saturated 3 to 7 membered carbocyclic ring Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present specification, "halo" refers to fluoro, chioro, bromo or iodo The terms "aromatic moiety" and "aryl" and the abbreviation "Ar" in the context of the present specification refer to an aromatic ring system having from 5 to 14 ring carbon atoms and containing up to three rings, one or more of which may be replaced by a nitrogen, oxygen or sulphur atom. Examples of aromatic moieties are benzene, pyridine, naphthalene, biphenyl, quinol i, isoquinoline, quinazoline, benzthiazole, benzoxazole, benzimidazole indole, indazole and imidazole ring systems.

References to "substituted aryl" refer to an aryl moiety substituted with halo, C1-C6 alkyl, -O(Ci-C6)alkyl, -CON(R' )2, -SOR1 -SO2R' , -SO2N(R' )2, -N(R' )2, -NR' COR' , -CO2R' , -CUR' , -SR' , -OH, -NO2 or CN, where R' is as defined above, provided that it is not substituted aryl IS In all cases where a substituent contains two or more R' groups, particularly when they are attached to the same nitrogen atom, it is preferred that at least one of the R1 groups is hydrogen or C1-C6 alkyl. More preferably, at least one of the groups is hydrogen or Ci-C4 alkyl and it is particularly preferred that at least one of the R' groups is hydrogen.

Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formulae (Ia) and (ib) include basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts as well as choline, diethanolamine, ethanolamine, ethyl diamine and other well known basic addition salts.

Where appropriate, pharmaceutically or veterinarily acceptable salts may also include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3 -phenylpropionate, picrate, pival ate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic suiphonic acids such as methanesuiphonate, ethanesulphonate, 2- hydroxyethane sulp honate, camphorsuiphonate, 2-naphthalenesu Iphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate, and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisuiphate, hemisuiphate, thiocyanate, persuiphate, phosphoric and sulphonic acids 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 (Ia) and (Ib) in vivo Examples of prodrugs include alkyl esters of the compounds of general formula (Ia) and (Ib), for example the esters of general formula (ha) and (lIb) below.

If a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.

In the compounds of general formula (ha) and (Tb), it is preferred that, independently or in any combination R' is halo or hydrogen, R2 is halo or hydrogen, R3 is halo or hydrogen, In preferred compounds of general formula (Ia) and (Ib), R4 and R5 are each independently hydrogen or C1-C4 alkyl. However, in more active compounds, at least one, and preferably both of R4 and R5 are hydrogen.

Compounds of general formula (Ia) and (Ib) preferably have an R6 group chosen from H or C1-C6 alkyl; most suitably R6 is hydrogen, methyl or ethyl.

In more active compounds of the present invention R7 is an aromatic moiety having one or two rings and substituted with one or more substituents selected from halo, -C1-C4 alkyl, -O(C1-C4 alkyl), -S02(C1-C4 alkyl), -R' and -OR' , where R' is Among the most preferred compounds are the following.

1 [3 -(4-chlorophenylsu!fanyl)2methy I-pyrro!o[3,2-b]pyridin- 1-yl] acetic acid, 2 [3-(4-chlorophenylsulfoflyl)2methylpyrrolo[3,2-b]pyridin- l-yl] acetic acid, or a C1-C4 alkyl ester of one of the above.

In a further aspect of the present invention, there is provided a compound of general formula (ha) or (JIb) ha lIb wherein R', R2, R3, R4, R5, R6 and R7 are as defined for general formula (ha) and (Ib), and R'' is C1-C6 alkyl, aryl, (CH2)rnOC(=O)CI-C6alkyl (CH2)niN(R'2) 2, CH((CH2)mO(CO)R'3)2, in is I or 2; R12 is hydrogen or methyl, R'3 is C1-C18 alkyl Compounds of general formulae (ha) and (Jib) are novel and may be used as prodrugs for compounds of general formula (ha) and (Tb). When the compound of genera! formula (ha) or (lib) 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 R groups when the compound of general formula (ha) or ([Tb) is used as a prodrug include.

methyl, ethyl, propyl, phenyl, CH2OC(=O)tBu, CH2CH2N(Me)2 CH2CH2N}12 or CH(CH2O(C=O)R)2 wherein R'3 is as defined above Other preferred substituents are as detailed for general formulae (Ia) and (Ib) above In addition to their use as prodrugs, compounds of formula (ha) and (lib) wherein R" is C1-C6 alkyl may be used in a process for the preparation of a compound of general formula (Ia) or (Tb), the process comprising reacting the compound of general formula (ha) or (lIb) 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 genera! formula (Tb) may also be prepared from compounds of general formula (Ia) by oxidation The oxidation may be achived using an oxidising agent such as a peroxyacid, for example 3- chloroperoxybenzoic acid (m-CPBA) Typically, the reaction will be conducted at room temperature in an organic solvent such as ethyl acetate A similar method can also be used for the conversion of compounds of general formula (ha) to compounds of general formula (Jib) A synthetic route to example compounds of general formulae (Ia) and (ib) is set out in Scheme 1

CI

s_cl s--j. s__ijl__cI s-1-jJ ______ ______ ______,N (L1 MeCN NaH, DPF LIOH H20 H + * BrCO2Et THF

RI N RT H H10 0 OH

OXONE

I DioxaneH2O(41 RT,2h cI

CI

? 0.5_icr 6_iZIIr mcpa N ELOAC N LiOH H20 __j)- O THF H20 (11) 1? RI, lh OH OH 0 Scheme I Compounds of general formula (ha) in which X is SO2 may be prepared from the corresponding compounds of general formula (ha) in which X is S by reaction with an oxidising agent such as potassium peroxymonosuiphate, which is sold under the trade mark Oxone Compounds of general formula (ha) in which X is S may be prepared from compounds of general formula (III) SR7 Ri N R2 R6 R3

II

wherein R', R2, R3, R6 and R7 are as defined for general formula (Ia) and (Tb) by reaction with a compound of general formula (IV) Z-C(R4R5)-CO2R" (IV) wherein R4 and R5 are as defined for general formula (Ta) and (Ib) and Z is a leaving group in particular a halo group, for example chioro or bromo The reaction is conducted under strongly basic conditions, for example using a metal hydride such as sodium hydride Suitable solvents include organic solvents such as dimethylformamide (DMF).

Compounds of general formula (IV) are well known and are readily available or can be prepared by methods known to those skilled in the art Compounds of general formula (III) may be prepared by reacting a compound of general formula (V).

R2 IxI..1IIILII-'>- R6

V

wherein R6 is as defined for general formulae (Ta) and (Tb), with a compound of general formula (VI) Y-S-R7 (VI) where R7 is as defined for general formulae (Ia) and (Tb) and Y is chloro, bromo or iodo The reaction may be conducted at room temperature in a polar organic solvent such as acetonitrile Compounds of general formula (VT) may be prepared from thiols of general formula (VII) HS-R7 (VII) where R7 is as defined for general formulae (Ia) and (Tb) by reaction with a halogenating agent such as N-bromosuccinimide or N-chlorosuccinimide. The reaction takes place at room temperature and may be conducted in a suitable organic solvent such as toluene A synthetic route to an example of a pyrrolo[3,2- b]pyridine compound of general formula (V) is illustrated in Scheme 2 below N B Propyne c11'INH RT KH, DMF THF, RI ii, NH4CI cç- Scheme 2 As illustrated in Scheme 2, compounds of general formula (V) may be prepared from an optionally protected 2-alkynyl-pyridin-3-yl amine of general formula (Viii) R7

VIII

wherein R7 is as defined for general formulae (la) and (Tb) and Q is H or a suitable protecting group such as tert-butoxycarbonyl (Boc) When Q is H, cyclisation can be achieved using potassium hydride, as set out in Example I When Q is a protecting group such as Boc, the compound of general formula (VIII) can be cyclised by heating in the presence of a copper (I) salt, for example copper (1) iodide Suitably, the reaction is carried out in an organic solvent such as dimethyl formamide (DMF).

Compounds of general formula (VIII) may be prepared by reacting 2-bromoor 2- iodo-3-aminopyridine in which the amino group is optionally protected by a suitable group such as Boc, with a compound of general formula (IX) CHEEC-R7 (IX) wherein R7 is as defined for general formulae (Ia) and (ib) The reaction is suitably carried out in the presence of a copper (I) salt, in particular copper (1) iodide.

Compounds of general formula (IX) are well known in the art and are readily available or can be prepared by known methods Optionally protected 2-bromo or 2-iodo-3-aminopyridine are also well known in the art and can be prepared by known methods.

Compounds of general formula (Ta) and (Tb) are antagonists of PGD2 at the CRTH2 receptor and compounds of general formula (ha) and (JIb) are prodrugs for compounds of general formula (Ia) and (Tb). Compounds of general formulae (Ia) and (Tb) and (ha) and (Jib) are therefore useful in a method for the treatment of diseases and conditions mediated by PGD2 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 (Ia), (Tb), (ha) or (hib).

In a third aspect of the invention, there is provided a compound of genera! formula (Ia), (ib), (ha) or (lib) for use in medicine, particularly for use in the treatment or prevention of diseases and conditions mediated by PGD2 at the CRTH2 receptor Furthermore, there is also provided the use of a compound of general formula (Ta), (Ib), (ha) or (lib) in the preparation of an agent for the treatment or prevention of diseases and conditions mediated by PGD2 at the CRTH2 receptor As mentioned above, such diseases and conditions include allergic asthma, perennial allergic rhinitis, seasonal allergic rhiniti s, atopic dermatitits, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, food allergies, eosinophilic 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, reperfusion injury and chronic obstructive pulmonary disease, as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis The compounds of general formula (Ia), (Tb), (ha) or (llb) 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 (Ta), (Tb), (ha) or (lib) together with a pharmaceutical excipient 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 intradermal) 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 (Ta), (Tb), (ha) or (JIb) 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 carrier" includes vehicles such as common excipients e g binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, 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, cherry 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 (Ta), (Ib), (ha) or (lib) may be made up into a cream, ointment, jelly, solution or suspension etc. Cream or ointment formulations that may be used for the drug are 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 (Ia), (Ib), (ha) or (lib) 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 desired, 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 CRTH2 receptor The precise amount of a compound of general formula (Ia), (Tb), (ha) or (JIb) 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 (Ia), (Tb), (ha) or (lib) may be used in combination with other active agents which are useful for the treatment of allergic and other inflammatory diseases mediated by PGD2 at the CRTH2 receptor Therefore, the pharmaceutical composition described above may contain one or more additional active agents useful in the treatment of diseases and conditions mediated by PGD2 at the CRTH2 receptor.

These additional active agents are not necessarily inhibitors of PGD2 at the CRTH2 receptor - they may have a completely different mode of action. Examples of such additional active agents include existing therapies for allergic and other inflammatory diseases including.

132 agonists such as salmeterol, corticosteroids such as fluticasone, antihistamines such as loratidine, leukotriene antagonists such as montelukast, anti-igE antibody therapies such as omalizumab, antiinfectives 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.

CRTH2 antagonists may also be combined with therapies that are indevelopment for inflammatory indications including other antagonists of PGD2 acting at other receptors such as DP antagonists, inhibitors of phoshodiesterase type 4 such as cilonilast; drugs that modulate cytokine production such as inhibitors of TNFa converting enzyme (TACE), drugs that modulate the activity of Th2 cytokines 1L-4 and IL-S such as blocking monoclonal antibodies and soluble receptors; PPAR-y agonists such as rosiglitazone, 1 5 5-lipoxygenase inhibitors such as zileuton.

In yet a further aspect of the invention, there is provided a product comprising a compound of general formula (Ia), (Ib), (ha) or (Jib) 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 PGD2 at the CRTH2 receptor.

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

Example 1 - Synthesis of F3-(4-ChIoro-phenylsuJfanyI)_2methyIpyrrolo[3,2 bi pyridin- I -vu-acetic acid (Compound 1) a. 2-Prop- l-ynyt-pyridin-3ylamine Copper (I) iodide (83 mg, 0 43 mmol) and then dichlorobis(triphenylphosphine) palladium (II) (214 mg, 0.31 mmol) were sequentially added to a stirred solution of 2-bromo-3-aminopyridine (1 07 g, 620 mmol) in triethylamine (15 ml) at room temperature in a tube under nitrogen The solution was cooled to -78 C and then propyne (-3 ml, 0.05 mol), freshly condensed into triethylamine (5 ml) at -78 C, was added to the mixture in one portion The vessel was immediately sealed and the resulting mixture was stirred at room temperature for 18 h The pressure was then released from the vessel and the mixture was diluted with water (100 ml) The product was extracted into ethyl acetate (3 x 100 ml) and the combined organic extracts were then dried and concentrated in vacuo to leave a brown residue Purification by flash column chromatography on silica gel eluting with 1 1 heptane ethyl acetate to neat ethyl acetate gave the alkyne (746 mg, 91 %) as a beige solid, Tr = 059 mm, m/z (ES) (M+H) 132.95.

b. 2-Methyl- 1H-pyrrolo 13,2-bi pyridine 2-Prop-l-ynyl-pyridin-3-ylamine (110 mg, 0.83 mmol) in anhydrous DMF (I ml) was added dropwise over 1 mm to a stirred suspension of potassium hydride (442 mg, 3 30 mmol; 30 % in mineral oil) in anhydrous tetrahydrofuran (2 ml) at room temperature. The brown mixture was stirred at room temperature for 2 h and then a saturated solution of ammonium chloride (5 ml) was added The product was extracted with ethyl acetate (3 x 30 ml) and the combined organic extracts were then dried and concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with ethyl acetate and then 10 % methanol dichloromethane to give the azaindole (66 mg, 60 %) as an off-white solid, Tr = 0.61 mm, m/z (ES) (M+H) 132 99 c. 3-(4-Chlorophenylsulfanyl)-2-methyl_ IH-pyrrolo 13,2-bi pyridine 4-Chlorobenzenesulfenylchlorjde (10 1 ml, 2.80 mmol, 0 28 M in toluene) was added dropwise over 5 miii to a stirred solution of 2-methyl-1H-pyrrolo[3, 2- b]pyridine (374 mg, 2.80 mmol) in anhydrous acetonitrile (20 ml) at room temperature. The mixture was stirred at room temperature for 2 h and then filtered to remove the white solid. The filtrate was then concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with 1 1 heptane ethyl acetate to 10 % methanol dichloromethane to give the thioether (135 mg, 17%) as a white - beige solid, Tr = 0.1 46 mm, m/z (ES) (M+H) 275.08 d. 13-(4-Chloro- phenylsulfanyl)_2_methyl_pyrrolo 13,2-b I pyridin- I -yl]-acetic acid ethyl ester Sodium hydride (11 4 mg, 0 29 mmol, 60 % in mineral oil) was added in one portion to a stirred solution of 3-(4-chloro-phenylsulfanyl)- 2-methyl.lHpyrrolo[3,2 b]pyridine (72 mg, 0.26 mmol) in anhydrous DMIF (2 ml) at room temperature. The solution was stirred at room temperature for 30 mm and then ethyl bromoacetate (29 10!xl, 0.26 mmol) was added in one portion The resulting mixture stirred at room temperature for 3 h and then concentrated in vacuo to leave a brown residue Purification by flash column chromatography on silica gel eluting with I 1 heptane ethyl acetate to neat ethyl acetate gave the ester (87 mg, 93 %) as a yellow solid, Tr = 1 28min,m/z(ES)(M+H)36l.05 e. I3-(4-Chloro-phenylsulfanyl) _2_methyIpyrroIo 13,2-bi pyridin- l-yl J-acetic acid Sodium hydride (2.8 mg, 0.07 mmol; 60 % in mineral oil) was added in one portion to a stirred solution of 3-(4-chloro-phenylsulfanyl)-2-methyl- lH- pyrrolo[3,2- b]pyridine (16 mg, 0.06 mmol) in anhydrous DMF (2 ml) at room temperature The solution was stirred at room temperature for 30 mm and then ethyl bromoacetate (6 jxl, 0.06 mmol) was added in one portion The resulting mixture was stirred at room temperature for 16 h Lithium hydroxide monohydrate (9.6 mg, 0 23 mmol) and then tetrahydrofuran water (3 ml; 2. 1) were sequentially added and the resulting mixture stirred at room temperature for 2 h The solution was then adjusted to pH 7 with I M hydrochloric acid and the solution concentrated in vacuo to dryness to leave a brown solid. The solid was then dissolved in water (5 ml) and extracted with ethyl acetate (2 x 10 ml) and then IPA: chloroform (10 ml; 1:1). The combined organic extracts were then dried and concentrated in vacuo to leave the carboxylic acid (6 mg, 3 1 %) as a beige solid, H (400 MHz, d6-DMSO) 8.28 (IH, dd 14.6, 1 2Hz, Ar), 782 (IH, dd 182, 11 Hz, Ar), 7.25 (2H, d 18.7Hz, Ar), 7 12 (1H, dd.182, 46 Hz, Ar), 7 01(21-I, d J 8 7 Hz, Ar), 4.67 (2H, s, NCH2CO2H), 2.46 (3H, s, CCH3); Tr = 1 08 mm, rn/z (ES) (M+H) 333 22.

Example 2 - Synthesis of I3-(4-Chloro-benzenesulfonyI)_2... methylpyrroio[3,..

blpyridin-1-yll-acetjc acid (Compound 2) a. 13-(4-Chloro-benzenesulfonyl)-2-methylpyrrolo 13,2-hi pyridin- 1-yl acetic acid ethyl ester Oxone (446 mg, 0.72 mmol) was added in one portion to a stirred solution of [3-(4chloro-phenylsu!fanyl)-2-methylpyrrolo[3,2-b]pyrid in-i -yl]-acetic acid ethyl ester (87 mg, 0.24 mmol) in 1,4-dioxane water (5 ml, 4:1) at room temperature The resulting mixture was stirred at room temperature for 5 h and then concentrated in vacuo to leave a white residue. The residue was partitioned between ethyl acetate and water and the organic layer separated The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried and concentrated in vacuo to leave a residue Purification by flash column chromatography on silica gel eluting with I. 1 heptane. ethyl acetate to neat ethyl acetate gave the sulfone (94 mg, 100 as a white solid, Tr = 116 mm, m/z (ES) (M+H)1 393 22 b. 13-(4-Chloro-benzenesulfonyl)_2_methyl...pyrrolo[3,2b] pyridin- l-y'Iacetic acid Lithium hydroxide monohydrate (60 mg, 1.44 mmol) was added in one portion to a stirred solution of [3 -(4-chloro-benzenesulfonyl)-2-methylpyrrolo[3,2-b] pyridin- 1- yl]-acetic acid ethyl ester (94 mg, 0.24 mmol) in tetrahydroftiran. water (6 ml, 2 1) at room temperature The resulting mixture was stirred at room temperature for 8 h The solution was adjusted to pH 7 with lM hydrochloric acid and then concentrated in vacuo to precipitate a yellow solid The solid was filtered, washed with water (5 ml) and heptane (5 ml) and finally dried under vacuum to give the carboxylic acid (20 mg, 23 %) as a white solid, oH (400 MII-Iz, d6-DMSO) 8 41 (IH, d.1 3 4 Hz, Ar), 8 12 (2H, d J 8 7 Hz, Ar), 7.84 (IH, d.17.3 Hz, Ar), 7.63 (2H, d 1 8 7 Hz, Ar), 7 19 (IH, dd 1 8.3, 4.7 Hz, Ar), 4 50 (2H, s, NCH2CO2H), 2.72 (3H, s, CCH3), Tr = 0 98 mm, m/z (ES) (M+H)365 18 Example 3 - Measurement of CRTH2 Antagonist Activity Materials and Methods Materials Calcium-3 dye was purchased from Molecular Devices (Wokingham, UK) Mono- poly resolving medium was obtained from Dainippon Pharmaceuticals (Osaka, Japan) Macs anti-CD 16 microbeads were from Miltenyi biotec (Bisley, Surrey) ChemoTx plates were purchased from Neuroprobe (Gaithesburg, MD) Poly-D- lysine coated 96-well plates were obtained from Greiner (Gloucestershire, UK) {3H]PGD2 was from Amersham Biosciences (Buckinghamshire, UK) [3H]SQ29548 was purchased from Perkin Elmer Life Sciences (Buckinghamshire, UK) All other reagents were obtained from Sigma-Aldrich (Dorset, UK), unless otherwise stated Methods Cell culture Chinese Hamster Ovary cells were transfected with CRTH2 or DP receptors (CHO/CRTH2 and CHO/DP) and were maintained in culture in a humidified atmosphere at 37 C (5% CO2) in Minimum Essential Medium (M.EM) supplemented with 10% foetal bovine serum, 2 mM glutamine, and I mg mY' active G418 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) For calcium mobilisation assay, cells were grown in a 96 well plate 24h prior to the assay at a density of 80,000 cells per well.

Preparation of 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 Versene 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 mlvi I-[EPES, 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 uI 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 NaC1, 10.tM indomethacin) and directly centrifuged at 20, 000 rpm for 30 mm at 4 C The resulting pellet was treated as described above Radioligand binding assays [3H]PGD2 (160 Ci/mmol) binding experiments were performed on membranes prepared as described above Assays were performed in a final volume of 100 tl of buffer (1XI-[BSS/HIEPES 10 mM, pH 7.3) Cell membranes (l5..tg) Cell membranes 15mg were preincubated at room temperature with varying concentration of competing ligand for 15 mm. [3H]PGD2 (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 u1 ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/B glass fibre filters using a Unifilter Cell harvester (PerkinElnier Life Sciences) and six washes of 300 tl of ice- cold buffer The Unifilter plates were dried at room temperature for at least lh and the radioactivity retained on the filters was determined on a Beta Trilux counter (PerkinElmer Life Sciences), following addition of 40.tl of Optiphase Hi- Safe 3 (Wallac) liquid scintillation Non specific binding was defined in the presence of 10 uiM unlabelled PGD2 Assays were performed in duplicate The results of the radioligand binding experiments to the CRTH2 and DP receptors are shown in Tables 1 and 2.

Table 1 - Radioligand binding data (Ki on CRTH2 Receptor).

Compounds Ki (nM) 1 143 2 736 Table 2 - Radioligand binding data (Ki on DP Receptor) Compounds Ki (nM) >10000 >10000 The results of the experiments demonstrate that for compounds of general formula (Ia) and (Ib) the affinity for the CRTH2 receptor is higher than for DP receptor Compounds of general formula (Ia) and (Ib) bound to CRTH2 receptor expressed in CHO cells with a range of affinity varying from very high to moderate. In fact the Ki values determined in competition versus [3H]PGD2 varied from 500 pM to 1 tM Compounds of general formula (Ia) and (Tb) had no activity (or very weak activity) at the DP receptors The binding selectivity of the illustrated compounds of general formula (Ia) and (Tb) for CRTH2 receptor was greater than 200 fold for CRTH2 receptor, compared to DP receptors However, the inventors have found that by varying the R8 substitutent of the compounds of general formula (Ia) and (Tb), it is possible to vary the degree of selectivity for the CRTH2 receptor Calcium mobilisation Assay Cells were seeded onto poly-D-lysine coated 96-well plates at a density of 80,000 cells per well and incubated at 37 C overnight to allow the cells to adhere Cells were washed twice with HBSS and incubated for lh at 37 C in 100il HBSS and lOOp] calcium-3- dye (Molecular Devices), supplemented with 4mM probenecid Changes in fluorescence were monitored over a SOs time course with agonist addition at 17s using a Flexstation (Molecular Devices) Effect of cRTH2 cigonisis on calcium mobilisation in CHO-C'RTH2 cells PGD2 caused a dose-dependent increase in intracellular Ca24 mobilisation in CHO/CRTH2 cells, with an EC50 2.4 0.5nM (n=3) (Figure 2).

Effect of compoundc of general formula (Ia,) and (Ib,) on the calcium mohihsation induced by PGD2 PGD2-stimulated Ca2 flux was fully inhibited by the compounds of general formula (Ia) and (Ib) and the IC50 value for each compound in the calcium assay was comparable to its Ki value in Radioligand binding 1C50 values of compounds of general formula (Ta) and (Tb) varied from 5 nM to I tM The results for several compounds of general formula (Ia) and (Tb) are shown in Table 3 Increasing doses of the compounds of general formula (Ia) and (Ib) caused a dose-dependent and parallel shift of the PGD2 dose response curve in CHO/CRTH2 cells, thereby indicating that the compounds are competitive CRTH2 antagonists The antagonistic effect of the compounds of general formula (Ia) and (Ib) appears to be CRTH2 selective, since no inhibitory effect was seen with ATP-stimulated Ca2 flux Table 3 - Inhibition of PGD2-induced calcium flux r Compounds IC50 (nM) 1 393

Claims

1 A compound of general formula (Ta) or (Tb).

X7 0 -R7 wherein R', R2 and R3 are independently hydrogen, halo, -C1-C6 alkyl, -O(C1-C6 alkyl), -C1-C6 alkyl(C3-C7 cycloalkyl), -CON(R8)2, -SOR8, -502R8, -SO2N(R8)2, - N(R8)2, -NR8COR, -C02R8, COR8, -SR8, -OH, -NO2 or -CN, each R8 is independently hydrogen or C1-C6 alkyl; R4 and R5 are each independently hydrogen, or Ci- C6 alkyl or together with thecarbon atom to which they are attached form a C3-C7 cycloalkyl group, R6 is hydrogen or Ci-C6 alkyl, R7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or an aromatic moiety, any of which may optionally be substituted with one or more substituents selected from halo, C1-C6 alkyl, -O(Ci-C6)alkyl, -R' , -OR' , C(R' )2 -CON(R10)2, -SOR' - SO2R' , - SO2N(R' )2, -N(R' )2, -NR' COR' , -CO2R' , -COR' , -SR' , -OH, -NO2 or - CN, wherein each R' is independently hydrogen, C1-C6 alkyl, aryl or substituted aryl, X is -S- or -SO2-, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof 2 A compound of general formula (Ila) or (lib) X7 0 -R7 ha hib wherein R', R2, R3, R4, R5, R6 and R7 are as defined in claim 1; and R" is C1-C6 alkyl, aryl, (CH2)mOC(=O)Ci-Coalkyl, (CH2)mN(R'2)2, CH((CH2)mO(C0)R'3)2 m is I or 2, R'2 is hydrogen or methyl, R'3 is C1-C18 alkyl.

3 A compound as claimed in claim I or claim 2 wherein, independently or in any combination R' is halo or hydrogen; R2 is halo or hydrogen, R is halo or hydrogen, 4 A compound as claimed in claim 3 wherein R', R2 and R3 are hydrogen A compound as claimed in any one of claims I to 4 wherein R4 and R5 are each independently hydrogen or C1-C4 alkyl.

6 A compound as claimed in claim 4, wherein both R4 and R5 are hydrogen.

7 A compound as claimed in any one of claims I to 6, wherein R6 is H or Cl-C(, alkyl 8. A compound as claimed in claim 7 wherein R6 is hydrogen, methyl or ethyl 9 A compound as claimed in any one of claims ito 8 wherein R7 is an aromatic moiety having one or two rings and substituted with one or more substituents selected from halo, -Ci-C4 alkyl, -O(C1-C4 alkyl), -S02(C1- C4 alkyl), -R1 and -OR' ; where R' is aryl or substituted aryl.

[3 -(4-chlorophenyisu!fanyl)-2-methyl-pyrrolo[3,2-b]pyridin- l-yl] acetic acid, [3 -(4-chlorophenylsulfonyl)-2-methyl-pyrrolo[3,2-b]pyridin- 1-yl] acetic acid, or a Ci-C4 alkyl ester of one of the above 11 A process for the preparation of a compound as claimed in claim 1, the process comprising treating a compound of general formula (ha) or (Jib) as defined in claim 2 with a base.

12. A process for the preparation of a compound of genera! formula (ib) as claimed in claim 1, the process comprising treating a compound of general formula (Ta) as claimed in claim 1 with an oxidising agent.

13 A compound as claimed in any one of claims I to 10 for use in medicine, particularly for use in the treatment or prevention of diseases and conditions mediated by PGD2 at the CRTH2 receptor 14 The use of a compound as claimed in any one of claims I to 10 in the preparation of an agent for the treatment or prevention of diseases and conditions mediated by PGD2 at the CRTH2 receptor.

A compound or the use as claimed in claim 13 or claim 14 wherein the disease or condition is allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitits, contact hypersensitivity (including contact dermatitis) conjunctivitis, especially allergic conjunctivitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis, another PGD2-mediated disease, for example autoimmu ne diseases such as hyper IgE syndrome and systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease, or rheumatoid arthritis, psoriatic arthritis and osteoarthritis 16 A pharmaceutical composition comprising a compound as claimed in any one of claims ito 10 together with a pharmaceutical excipient or carrier.

17 A pharmaceutical composition as claimed in claim 16 formulated for oral, rectal, nasal, bronchial (inhaled), topical (including eye drops, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration 18 A composition as claimed in claim 17 formulated for oral, nasal, bronchial or 1 5 topical administration 19 A composition as claimed in any one of claims 16 to 18 containing one or more additional active agents useful in the treatment of diseases and conditions mediated by PGD2 at the CRTH2 receptor.

A composition as claimed in claim 19, wherein the additional active agents are selected from J32 agonists such as salmeterol; corticosteroids such as fi uticasone, antihistamines such as loratidine, leukotriene antagonists such as montelukast; 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 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 cilonilast; drugs that modulate cytokine production such as inhibitors of TNFa converting enzyme (TACE), drugs that modulate the activity of Th2 cytokines IL-4 and IL-S such as blocking monoclonal antibodies and soluble receptors; PPAR-y agonists such as rosiglitazone; 5-lipoxygenase inhibitors such as zileuton.

21 A process for the preparation of a pharmaceutical composition as claimed in any one of claims 16 to 20 comprising bringing a compound as claimed in any one of claims 1 to 10 in conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.

22 A product comprising a compound as claimed in any one of claims I to 10 and one or more of the agents listed in claim 21 as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD2 at the CRTH2 receptor