WO2005121141A1 - Pyrrolopyridine derivatives and use thereof for treating diseases mediated by prostaglandin d2 (pgd2) - Google Patents

Abstract

Compounds of formula (Ia) or (Ib): 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

PYRROLOPYRIDINE DERIVATIVES AND USE THEREOF FOR TREATING DISEASES MEDIATED BY PROSTAGLANDIN D2 ( PGD2 )

The present invention relates to compounds which are useful as pharmaceuticals, to methods for preparing these compounds, compositions containing them and their use 5 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.

10 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 15 been detected in high concentrations in the airways of asthmatic patients challenged with antigen (Murray et al, (1986), N. Engl. J. Med. 315: 800-804). Instillation of PGD₂ into airways can provoke many features of the asthmatic response including bronchoconstriction (Hardy et al, (1984) N. Engl. J. Med. 311: 209-213; Sampson et al, (1997) Thorax 52: 513-518) and eosinophil accumulation (Emery et al, (1989) J. 20 Appl. Physiol. 67: 959-962).

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 25 production in response to antigen (Fujitani et al, (2002) J. 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 cAMP. However, PGD₂ is thought to mediate much of its proinflammatory activity through interaction with a G protein- 30 coupled receptor termed CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) which is expressed by Th2 lymphocytes, eosinophils and basophils (Hirai et al, (2001) J. Exp. Med. 193: 255-261, and EP0851030 and EP-A- 1211513 and Bauer et al, EP-A-1170594). 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 al, 2001; Monneret et al, (2003) J. Pharmacol. Exp. Ther. 304: 349-355). In contrast, the selective DP agonist BW245C does not promote migration of Th2 lymphocytes or eosinophils (Hirai et al, 2001; Gervais et al, (2001) J. Allergy Clin. 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-1170594 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-03066046 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-03/101961 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 SO₂-aryl at the 3-position of the indole ring system.

Indole-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- 1-carboxamides and hydrazides with a variety of substituents at the 3-position, 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 (lb):

la lb

wherein

R¹, R² and R³ are independently hydrogen, halo, - -C_δ alkyl, -OfCi-C_δ alkyl), - -C₆ alkyl(C₃-C₇ cycloalkyl), -CON(R⁸)₂, -SOR⁸, -SO₂R⁸, -SO₂N(R⁸)₂, -N(R⁸)₂, -NR⁸COR⁸, -CO₂R⁸, COR⁸, -SR⁸, -OH, -NO₂ or -CN; each R⁸ is independently hydrogen or -C_ό alkyl;

R⁴ and R⁵ are each independently hydrogen, or C C₆ alkyl or together with the carbon atom to which they are attached form a C₃-C cycloalkyl group;

R is hydrogen or C C₆ alkyl;

R⁷ is Ci-Cβ 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, Cι-C₆ alkyl, -O(C₁-C₆)alkyl, -R¹⁰, -OR¹⁰, C(R^l0)₂ -CON(R¹⁰)₂, -SOR¹⁰ -SO₂R¹⁰, - SO₂N(R¹⁰)₂, -N(R¹⁰)₂, -NR¹⁰COR¹⁰, -CO₂R¹⁰, -COR¹⁰, -SR¹⁰, -OH, -NO₂ or -CN; wwhheeirein each R¹⁰ is independently hydrogen, Cι-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 (la) and (lb) 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 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 and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, stroke and amyoptrophic lateral sclerosis.

In the present specification " -Ce 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, methylenecyclobutyl, methylenecyclobutyl and methylenecyclopentyl.

"Cι-C₄ alkyl" and "Ci-Ciβ alkyl" have similar meanings except that they contain from one to four and from one to eighteen carbon atoms respectively.

"C₂-C6 alkenyl" and "Cι-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-C cycloalkyl groups. Examples include ethenyl, 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, chloro, 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, quinoline, isoquinoline, quinazoline, benzthiazole, benzoxazole, benzimidazole indole, indazole and imidazole ring systems.

References to "substituted aryl" refer to an aryl moiety substituted with halo, -C_δ alkyl, -O d-Q alkyl, -CON(R¹⁰)₂, -SOR¹⁰ -SO₂R¹⁰,

-SO₂N(R¹⁰)₂, -N(R¹⁰)₂, -NR¹⁰COR¹⁰, -CO₂R¹⁰, -COR¹⁰, -SR¹⁰, -OH, -NO₂ or -CN; where R¹⁰ is as defined above, provided that it is not substituted aryl.

In all cases where a substituent contains two or more R¹⁰ groups, particularly when they are attached to the same nitrogen atom, it is preferred that at least one of the R¹⁰ groups is hydrogen or C]-C₆ alkyl. More preferably, at least one of the groups is hhyyddrrooggeenn oorr CC CC₄₄ alkyl and it is particularly preferred that at least one of the R¹⁰ groups is hydrogen.

Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formulae (la) and (lb) 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, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, 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 (la) and (lb) in vivo. Examples of prodrugs include alkyl esters of the compounds of general formula (la) and (lb), 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 (la) and (lb), it is preferred that, independently or in any combination: R¹ is halo or hydrogen; R² is halo or hydrogen; R³ is halo or hydrogen;

In preferred compounds of general formula (la) and (lb), R⁴ and R⁵ are each independently hydrogen or Cι-C₄ alkyl. However, in more active compounds, at least one, and preferably both of R⁴ and R⁵ are hydrogen. Compounds of general formula (la) and (lb) preferably have an R⁶ group chosen from H or Ci-Cβ 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, -d-C₄ alkyl, -O(C C₄ alkyl), -SO₂(Cj-C₄ alkyl), -R¹⁰ and -OR¹⁰; where R¹⁰ is preferably aryl or substituted aryl.

Among the most preferred compounds are the following: 1. [3-(4-chlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl] acetic acid;

2. [3-(4-chlorophenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl] acetic acid;

3. [3-(4-chlorophenylsulfonyl)-2-methyl-5-oxy-pyrrolo[3,2-c]pyridin-l-yl] acetic acid;

4. [4-Chloro-3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid;

5. [4-Chloro-3-(4-chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid;

6. [3-(4-Methanesulfonylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid 7. (4-Chloro-2-methyl-3-phenylsulfanyl-pyrrolo[3,2-c]pyridin-l-yl)-acetic acid

8. (4-Chloro-2-methyl-3-p-tolylsulfanyl-pyrrolo[3,2-c]pyridin-l-yl)-acetic acid

9. [4-Chloro-3-(4-fluorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid

10. [4-Chloro-3-(4-methoxyphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

11. [4-Chloro-3-(3-chlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

12. [4-Chloro-3-(4-trifluoromethylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl]-acetic acid 13. [4-Chloro-3-(3-trifluoromethylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl] -acetic acid 14. [4-Chloro-3-(2,4-dichlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

15. [4-Chloro-3-(2,5-dichlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

16. [3-(4-Bromophenylsulfanyl)-4-chloro-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

17. [3-(3-methoxyphenylsulfanyl)-4-chloro-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

18. [4-Chloro-2-methyl-3-(naphthalen-2-ylsulfanyl)-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

19. [4-Chloro-2-methyl-3-(naphthalen-l-ylsulfanyl)-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

20. [4-Chloro-3-(4-fluorophenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid

21. [4-Chloro-3-(4-trifluoromethylphenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl] -acetic acid or a -C₄ alkyl ester of one of the above.

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

Ila Mb

wherein R¹, R², R³, R⁴, R⁵ , R⁶ and R⁷ are as defined for general formula (la) and (lb); and R¹¹ is Cι-C₆ alkyl, aryl, (CH₂)_mOC(=O)C,-C₆alkyl, (CH₂)_mN(R¹²)₂, CH((CH₂)_mO(C=O)R¹³)₂; m is 1 or 2; 1 R is hydrogen or methyl; R¹³ is C1-C18 alkyl.

Compounds of general formulae (Ila) and (lib) are novel and may be used as prodrugs for compounds of general formula (la) and (lb). When the compound of general formula (JHa) or (Hb) 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 R¹¹ groups when the compound of general formula (Ha) or (lib) is used as a prodrug include: methyl, ethyl, propyl, phenyl, CH₂OC(=O)tBu, CH₂CH₂N(Me)₂ CH₂CH₂NH₂ or CH(CH₂O(C=O)R¹³)₂ wherein R¹³ is as defined above.

Other preferred substituents are as detailed for general formulae (la) and (lb) above.

In addition to their use as prodrugs, compounds of formula (Ha) and (Hb) wherein R¹¹ is Cι-C₆ alkyl may be used in a process for the preparation of a compound of general formula (la) or (lb), the process comprising reacting the compound of general formula (Ua) 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 general formula (lb) may also be prepared from compounds of general formula (la) 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 (Ila) to compounds of general formula (lib).

A synthetic route to example compounds of general formulae (la) and (lb) is set out in Scheme 1.

Scheme 1

Compounds of general formula (Ila) in which X is SO₂ may be prepared from the corresponding compounds of general formula (Ila) in which X is S by reaction with an oxidising agent such as potassium peroxymonosulphate, which is sold under the trade mark Oxone_.

Compounds of general formula (Ua) in which X is S may be prepared from compounds of general formula (III)

wherein R¹, R², R³, R⁶ and R⁷ are as defined for general formula (la) and (lb) by reaction with a compound of general formula (IV):

Z-C(R⁴R⁵)-CO₂R^π (IV) wherein R and R are as defined for general formula (la) and (lb) and Z is a leaving group in particular a halo group, for example chloro 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):

V wherein R¹, R² and R³ are as defined in general formulae (la) and (lb) and R⁶ is as defined for general formulae (la) and (lb);

with a compound of general formula (VI): Y-S-R⁷ (VI)

where R⁷ is as defined for general formulae (la) and (lb) 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 (VI) may be prepared from thiols of general formula (Vπ): HS-R⁷ (vπ)

where R⁷ is as defined for general formulae (la) and (lb) 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-c]pyridine compound of general formula (V) is illustrated in Scheme 2 below:

Scheme 2

As illustrated in Scheme 2, compounds of general formula (V) may be prepared from a protected 3-alkynyl-pyridin-4-yl amine of general formula (VIII):

VIII wherein R¹, R² and R³ are as defined in general formulae (la) and (lb) and R⁷ is as defined for general formulae (la) and (lb) and Q is a suitable protecting group such as tert-butoxycarbonyl (Boc) by heating in the presence of a copper (I) salt, for example copper (I) 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 3-iodo-4- aminopyridine in which the amino group is protected by a suitable group such as Boc, with a compound of general formula (IX):

CH≡C-R⁷ (IX)

wherein R⁷ is as defined for general formulae (la) and (lb).

The reaction is suitably carried out in the presence of a copper (I) salt, in particular copper (I) iodide and a palladium catalyst.

Compounds of general formula (IX) are well known in the art and are readily available or can be prepared by known methods.

Amine-protected 3-iodo-4-aminopyridine is also well known in the art and can be prepared by known methods, for example by protecting 4-aminopyridine with a protecting group such as Boc, then deprotonating the protected compound with n- butyllithium then reacting with iodine.

Compounds of general formula (la) and (lb) are antagonists of PGD₂ at the CRTH2 receptor and compounds of general formula (Ila) and (LTb) are prodrugs for compounds of general formula (la) and (lb). Compounds of general formulae (la) and (lb) and (Ila) and (IΙb)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 (la), (lb), (Ila) or (lib). In a third aspect of the invention, there is provided a compound of general formula (la), (lb), (Ila) or (lib) for use in medicine, particularly for use in the treatment or prevention of diseases and conditions mediated by PGD at the CRTH2 receptor.

Furthermore, there is also provided the use of a compound of general formula (la), (lb), (Ila) or (Hb) 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 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 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 and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, stroke and amyoptrophic lateral sclerosis.

The compounds of general formula (la), (lb), (Ila) or (Hb) 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 (la), (lb), (Ila) 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 (la), (lb), (Ha) or (Hb) 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, polyvinylpyrrohdone (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 (la), (lb), (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 (la), (lb), (πa) or (Hb) 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 (la), (lb), (Ha) or (lib) 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 (la), (lb), (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 PGD 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: β2 agonists such as salmeterol; corticosteroids such as fluticasone; 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 TNFα converting enzyme (TACE); drugs that modulate the activity of Th2 cytokines IL-4 and B -5 such as blocking monoclonal antibodies and soluble receptors;

PPAR-γ agonists such as rosiglitazone;

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 (la), (lb), (Ha) or (lib) 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 r3-(4-Chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2- clpyridin-1-yll-acetic acid (Compound 1) a. Pyridin-4-yl-carbamic acid tert-butyl ester

Di-tert-butyl dicarbonate (79.30 g, 0.36 mol) in dichloromethane (250 ml) was added dropwise over 45 min to a stirred suspension of 4-aminopyridine (27.05 g, 0.29 mol) and triethylamine (88 ml, 0.63 mol) in dichloromethane (250 ml) at 0 °C. The solution was stirred at room temperature for 18 h and then washed with water (2 x 250 ml). The organic layer was then dried and concentrated in vacuo to leave a residue which was slurried in ethyl acetate, filtered and dried in vacuo to give pyridin-4-yl-carbamic acid tert-butyl ester (39.62 g, 71%) as an off-white solid. δ_H (400 MHz, CDC1₃) 8.44 (2H, dd J 6.4, 1. 6 Hz), 7.31 (2H, dd / 6.4, 1.6 Hz), 6.84 (IH, br s), 1.53 (9H, s); Tr = 0.90 min, m/z (ES⁺) (M+H)⁺ 195.18.

b. (3-Iodo-pyridin-4-yl)-carbamic acid tert-butyl ester n-Butyllithium (1.6 M in hexanes; 220 ml, 0.35 mol) was slowly dropwise over 30 min to a stirred solution of pyridin-4-yl-carbamic acid tert-butyl ester (26.08 g, 0.13 mol) and /V,N,N,N-tetramethylethylenediamine (55 ml, 0.36 mol) in tetrahydrofuran (750 ml) at -78 °C. The solution was stirred at -78 °C for 15 min and 2 h at -10 °C. The mixture was cooled to -78 °C and a solution of iodine (95.11 g, 0.37 mol) in tetrahydrofuran (250 ml) was added dropwise over 30 min. The mixture was stirred for a further 2 h and then the mixture was quenched with water (250 ml) at 0 °C. A saturated solution of sodium sulfite (100 ml) was added and the organic layer separated. The aqueous layer was extracted with dichloromethane (2 x 500 ml) and then the combined organic extracts were dried and concentrated in vacuo to give a brown oil. Purification by flash column chromatography on silica gel eluting with 20 % ethyl acetate : heptane gave (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (25.00 g, 58 %) as an off-white solid, δ_H (400 MHz, CDC1₃) 8.76 (IH, s), 8.35 (IH, d J 5.7 Hz), 8.11 (IH, d J 5.7 Hz), 7.04 (IH, br s), 1.55 (9H, s); Tr = 0.99 min, m/z (ES⁺) (M+H)⁺ 321.08.

c. (3-Prop-l-ynyl-pyridin-4-yl)-carbamic acid tert-butyl ester Propyne (8 ml) was condensed into triethylamine (40 ml) at -78 °C and then added to a mixture of (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (19.59 g, 0.06 mol), copper (I) iodide (0.81 g, 4.25 rrrrnol) and palladium 6 striphenylphosphine dichloride (2.09 g, 2.98 mmol) in triethylamine (25 ml) in a pressure tube at -60 °C. The mixture was stirred at room temperature for 6 h and then diluted with ethyl acetate (1000 ml), washed with water (2 x 500 ml), dried and concentrated in vacuo to leave a residue. Purification by flash column chromatography on silica gel eluting with 40 % ethyl acetate: heptane gave (3-prop-l-ynyl-pyridin-4-yl)-carbamic acid tert-butyl ester (13.74 g, 97 %) as a yellow oil which solidified on standing, δ_H (400 MHz, CDC1₃) 8.51 (IH, s), 8.39 (IH, s), 8.07 (IH, s), 7.31 (IH, s), 2.18 (3H, s) 1.55 (9H, s); Tr = 1.00 min, m/z (ES⁺) (M+H)⁺ 233.09.

d. 2-Methyl-pyrrolo[3,2-c]pyridine-l-carboxylic acid tert-butyl ester

A stirred solution of (3-prop-l-ynyl-pyridin-4-yl)-carbamic acid tert-butyl ester (13.74 g, 0.06 mol) and copper (I) iodide (0.32 g, 1.66 mmol) in DMF (250 ml) was heated at 80 °C for 6 h. The mixture was diluted with ethyl acetate (500 ml) and washed with water (2 x 500 ml). The organic layer was then separated, dried and concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with 40 % ethyl acetate : heptane to give 2- methyl-pyrrolo[3,2-c]pyridine-l-carboxylic acid tert-butyl ester (9.73 g, 71 %) as an off-white solid, 5_H (400 MHz, CDC1₃) 8.75 (IH, s), 8.39 (IH, d J 5.8 Hz), 7.92 (IH, d J 5.8 Hz), 6.39 (IH, s), 2.62 (3H, s) 1.70 (9H, s); Tr = 1.03 min, m/z (ES⁺) (M+H)⁺ 233.22.

e. 2-Methyl-lH-pyrrolo[3,2-c]pyridine

2-Methyl-pyrrolo[3,2-c]pyridine-l-carboxylic acid tert-butyl ester (8.81 g, 0.38 mol) in 6M hydrochloric acid (75 ml) was stirred at room temperature for 18 h. The mixture was washed with dichloromethane (25 ml) and the aqueous solution adjusted to pH 13-14 with concentrated ammonia solution. The resulting mixture was extracted with ethyl acetate (5 x 150 ml) and the combined organic extracts were dried and concentrated in vacuo to give 2-methyl-lH-pyrrolo[3,2-c]pyridine (3.71 g, 74 %) as a pale yellow solid, δ_H (400 MHz, MeOD) 8.63 (IH, app s), 8.06 (IH, d / 5.8 Hz), 7.31 (IH, d J 5.8 Hz), 6.32 (IH, s), 2.48 (3H, s); Tr = 0.71 min, m/z (ES⁺) (M+H)⁺ 133.11. f. 3-(4-Chloro-phenylsulfanyl)-2-methyl-lH-pyrrolo[3,2-c]pyridine 4-Chlorobenzenethiol (3.18 g, 0.02 mol) in toluene (20 ml) was added dropwise over 2 min to a stirred solution of N-chlorosuccinimide (2.94 g, 0.02 mol) in toluene (20 ml) at 0 °C. The solution was allowed to warm to room temperature, stirred for a further 16 h and then filtered to give 4-chloro-phenylsulfenyl chloride as a 0.44 M solution in toluene. 4-Chloro-phenylsulfenyl chloride (0.44 M in toluene; 8.6 ml, 3.8 mmol) was added dropwise over 2 min to a stirred solution of 2-methyl-lH- pyrrolo[3,2-c]pyridine (0.50 g, 0.04 mol) in acetonitrile (10 ml) at room temperature. The mixture was stirred at room temperature for 2 h and then 10% citric acid (50 ml) was added. The aqueous solution was extracted with ethyl acetate (3 x 25 ml) and then the remaining aqueous layer adjusted to pH ~ 13 with 2M sodium hydroxide solution and further extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were dried and concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with 80 % ethyl acetate : heptane to 10 % methano ethyl acetate. Recrystallisation from methanol gave 3-(4- chloro-phenylsulfanyl)-2-methyl-lH-pyrrolo[3,2-c]pyridine (0.33 g, 32 %) as a white solid, δ_H (250 MHz, MeOD) 8.57 (IH, s), 8.20 (IH, d J 5.7 Hz), 7.43 (IH, d J 5.7 Hz), 7.21 (2H, d J 8.6 Hz), 7.00 (2H, d J 8.6 Hz), 2.55 (3H, s);Tr = 1.14 min, m/z (ES⁺) (M+H)⁺ 275.25.

g. [3-(4-ChIoro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid ethyl ester

3-(4-Chloro-phenylsulfanyl)-2-methyl-lH-pyrrolo[3,2-c]pyridine (100 mg, 0.36 mmol) in DMF (2 ml) was added dropwise over 1 min to a stirred suspension of sodium hydride (60 % in mineral oil; 16 mg, 0.40 mmol) in DMF (2 ml) at room temperature. The solution was stirred at room temperature for 45 min and then ethyl bromoacetate (0.04 ml, 0.36 mmol) was added dropwise over 1 min. The resulting mixture was stirred at room temperature for 1 h and then 10% citric acid (50 ml) was added. The aqueous layer was extracted with ethyl acetate (3 x 50 ml) and then the combined organic extracts were dried and concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with 20 % ethyl acetate : heptane to 50 % ethyl acetate : heptane to give [3-(4-chloro- phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid ethyl ester (80 mg, 61 %) as a white solid, δ_H (250 MHz, MeOD) 8.62 (IH, s), 8.26 (IH, d J 5.8 Hz), 7.53 (IH, d / 5.9 Hz), 7.20 (2H, d / 8.9 Hz), 7.01 (2H, d / 8.9 Hz), 5.21 (2H, s), 4.28 (2H, q / 7.1 Hz), 2.52 (3H, s), 1.31 (3H, t / 7.1 Hz); Tr = 1.35 min, m/z (ES⁺) (M+H)⁺ 361.26.

h. [3-(4-Chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid (Compound 1)

Lithium hydroxide monohydrate (9 mg, 0.2 mmol) was added in one portion to a stirred solution of [3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl]-acetic acid ethyl ester (40 mg, 0.11 mmol) in tetrahydrofuran : water (1 : 1; 1 ml) and stirred at room temperature for 1 h. The solution was adjusted to pH 4 with 10 % citric acid and then the resulting precipitate was filtered and washed with water to give [3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid (21 mg, 57 %) as a white solid, δ_H (400 MHz, DMSO) 8.62 (IH, s), 8.29 (IH, d J 6.0 Hz), 7.64 (IH, d J 5.6 Hz), 7.31 (2H, d J 9.1 Hz), 7.04 (2H, d J 8.6 Hz), 5.18 (2H, s), 2.45 (3H, s); Tr = 1.14 min, m/z (ES⁺) (M+H)⁺ 333.19.

Example 2 - Synthesis of r3-(4-Chloro-phenylsulfonyI)-2-methyl-pyrrolo[3,2- clpyridin-1-yll-acetic acid (Compound 2)

a. [3-(4-Chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid ethyl ester

Oxone™ (0.21 g, 0.33 mmol) was added in one portion to a stirred solution of [3-(4- chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid ethyl ester from step (g) of Example 1 (40 mg, 0.11 mmol) in 1,4-dioxane : water (4 : 1; 5 ml) at room temperature. The mixture was stirred for 1 h and then a saturated solution of sodium bicarbonate (50 ml) was added. The aqueous solution was extracted with ethyl acetate (3 x 25 ml) and the combined organic extracts were dried and concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with 50 % ethyl acetate : heptane to 100 % ethyl acetate to give [3-(4-chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl]-acetic acid ethyl ester (21 mg, 48 %) as a white solid, δ_H (250 MHz, MeOD) 9.21 (IH, s), 8.35 (IH, d 75.9 Hz), 7.99 (2H, d J 8.9 Hz), 7.60 (2H, d J 8.9 Hz), 7.56 (IH, d 76.0 Hz), 5.19 (2H, s), 4.24 (2H, q 77.1 Hz), 2.74 (3H, s), 1.26 (3H, t77.1 Hz); Tr = 1.17 min, m/z (ES⁺) (M+H)⁺ 393.18.

b. [3-(4-Chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid (Compound 2)

Lithium hydroxide monohydrate (5 mg, 0.1 mmol) was added in one portion to a stirred solution of [3-(4-chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl] -acetic acid ethyl ester (21 mg, 0.05 mmol) in tetrahydrofuran : water (1 : 1; 1 ml) at room temperature. The mixture was stirred for 1 h and then the solution adjusted to pH ~ 6 with 10 % citric acid. The resulting precipitate was filtered, washed sequentially with water and ether and then dried under a stream of nitrogen to give [3-(4-chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid (9 mg, 46 %) as a white solid, δ_H (250 MHz, DMSO) 9.18 (IH, s), 8.40 (IH, d 75.9 Hz), 8.04 (2H, d 78.5 Hz), 7.73 (IH, d 76.1 Hz), 7.68 (2H, d 78.7 Hz), 5.20 (2H, s), 2.69 (3H, s); Tr = 1.01 min, m/z (ES⁺) (M+H)⁺ 365.17.

Example 3 - Synthesis of r3-(4-Chloro-phenylsulfonyl)-2-methyl-5-oxy- pyrrolo[3,2-c1pyridin-l-yll-acetic acid (Compound 3)

a. [3-(4-Chloro-phenylsulfonyl)-2-methyl-5-oxy-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid ethyl ester

3-Chloroperoxybenzoic acid (70-75 % water; 116 mg, 4.61 wt. eq.) was added in two portions to a stirred solution of [3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2- c]pyridin-l-yl] -acetic acid ethyl ester from step (g) of Example 1 (25 mg, 0.07 mmol) in ethyl acetate and at room temperature. The mixture was stirred at room temperature for 16 h and then concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with 50 % ethyl acetate:heptane to 10 % methanol : ethyl acetate to give [3-(4-chloro- phenylsulfonyl)-2-methyl-5-oxy-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid ethyl ester (28 mg, 99 %) as a white solid, δ_H (250 MHz, MeOD) 9.02 (IH, app d 7 1.7 Hz), 8.22 (IH, app dd 7 7.2, 1.8 Hz), 8.00 (2H, d 7 8.9 Hz), 7.76 (IH, app d 7 7.2 Hz), 7.62 (2H, app d 7 8.9 Hz), 5.22 (2H, s), 4.25 (2H, q 77.1 Hz), 2.72 (3H, s), 1.27 (3H, t / 7.1 Hz); Tr = 1.17 min, m/z (ES⁺) (M+H)⁺ 409.21.

b. [3-(4-Chloro-phenylsulfonyl)-2-methyl-5-oxy-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 3) Lithium hydroxide monohydrate (7 mg, 0.1 mmol) was added in one portion to a stirred solution of [3-(4-chloro-phenylsulfonyl)-2-methyl-5-oxy-pyrrolo[3,2- c]pyridin-l-yl] -acetic acid ethyl ester (28 mg, 0.07 mmol) in tetrahydrofuran : water (1 : 1; 1 ml) at room temperature. The mixture was stirred at room temperature for 1 h and then the solution was adjusted to pH 4-5 with 1 M hydrochloric acid. The resulting precipitate was filtered, washed sequentially with water and ether then dried under a stream of nitrogen to give [3-(4-chloro-benzene- sulfonyl) -2-methyl-5-oxy- pyrrolo[3,2-c]pyridin-l-yl]-acetic acid (12 mg, 46 %) as a white solid, δπ (250 MHz, DMSO) 8.65 (IH, s), 8.13 (IH, d 77.2 Hz), 8.02 (2H, d 78.5 Hz), 7.77 (IH, d 77.1 Hz), 7.68 (2H, d 78.7 Hz), 5.16 (2H, s), 2.62 (3H, s); Tr = 1.03 min, m/z (ES⁺) (M+H)⁺ 381.20.

Example 4 - Synthesis of f4-Chloro-3-(4-chloro-phenylsulfanyl)-2-methyl- Pyrrolof3,2-clpyridin-l-yll-acetic acid (Compound 4)

a. (2-Chloro-3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester ⁿButyl lithium (24.5 ml, 61.3 mmol; 2.5 M in hexanes) was added dropwise over 15 min to a stirred solution of (2-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (5.60 g, 24.5 mmol) and TMEDA (9.25 ml, 61.3 mmol) in anhydrous tetrahydrofuran (105 ml) at -78 °C. The solution was stirred at -78 °C for 4 h and then iodine in anhydrous tetrahydrofuran (18 ml) was added dropwise over 15 min. The resulting dark brown solution was stirred at -78 °C for a further 2 h before being quenched with water (40 ml). The mixture was brought to room temperature and then a saturated solution of sodium bisulfite (50 ml) was added. The organic phase was separated and the aqueous solution extracted with ethyl acetate (3 x 70 ml). The combined organic extracts were washed with brine (40 ml), dried and concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with 3: 1 heptane : ethyl acetate to give a solid. The solid was finally recrystallised from heptane : ethyl acetate to give the iodopyridine (4.77 g, 55 %) as a colourless solid, Tr = 1.62 min, m/z (ES⁺) (M+H)⁺ 355.16.

b. (2-Chloro-3-prop-l-ynyl-pyridin-4-yl)-carbamic acid tert-butyl ester

This reaction was repeated in duplicate: Copper (I) iodide (99 mg, 0.52 mmol) and then dichlorobi triphenylphosphine) palladium (II) (365 mg, 0.52 mmol) were sequentially added to a stirred solution of (2-chloro-3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (1.85 g, 5.22 mmol) in tetrahydrofuran (21 ml) at room temperature in a tube under nitrogen. The solution was cooled to -78 °C and then propyne (~ 1.35 ml, 23.7 mmol), freshly condensed into triethylamine (5 ml) at -78 °C, was then added to the mixture in one portion. The vessel was immediately sealed and the resulting mixture was stirred at room temperature for 3 days. The pressure was then released from the vessel and the mixture was diluted with ethyl acetate (100 ml). The duplicate reaction was combined at this point. The organic phase was separated and washed sequentially with water (2 x 100 ml) and brine (100 ml) and then dried. The organic solvent was removed in vacuo to leave a residue which was purifed by flash column chromatography on silica gel eluting with 5 : 1 heptane : ethyl acetate gave the alkyne (1.53 g, 55 %) as a white solid, Tr = 1.57 min, m/z (ES⁺) (M+H)⁺ 267.21.

c. 4-Chloro-2-methyl-lH-pyrrolo[3,2-c]pyridine

Copper (I) iodide (33 mg, 0.17 mmol) was added in one portion to a stirred solution of (2-chloro-3-prop-l-ynyl-pyridin-4-yl)-carbamic acid tert-butyl ester (1.50 g, 5.62 mmol) in anhydrous DMF (25 ml) at room temperature. The mixture was heated to

120 °C for 24 h, cooled to room temperature and then filtered through a pad of Celite^®. The filtrate was concentrated in vacuo to leave the azaindole (936 mg, 99 %), as a dark brown solid which was used without further purification, Tr = 0.74 min, m/z (ES⁺) (M+H)⁺ 167.21.

d. 4-Chloro-3-(4-chloro-phenylsulfanyI)-2-methyl-lH pyrrolo[3,2- cjpyridine

4-Chlorobenzene sulfenyl chloride (435 mg, 2.43 mmol) in toluene (8 ml) was added dropwise over 5 min to a stirred solution of 4-chloro-2-methyl-lH-pyrrolo[3,2- cjpyridine (400 mg, 2.40 mmol) in anhydrous acetonitrile (10 ml) at room temperature. The resulting mixture was stirred at room temperature for 3 days. The soluition was concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with heptane : ethyl acetate to give the thioether (70 mg, 11 %) as a brown solid, Tr = 1.32 min, m/z (ES⁺) (M+Η)⁺ 309.19.

e. [4-Chloro-3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl] -acetic acid ethyl ester

Sodium hydride (3 mg, 0.11 mmol; 60 % in mineral oil) was added in one portion to a stirred solution of 4-chloro-3-(4-chloro-phenylsulfanyl)-2-methyl-lH pyrrolo[3,2- c]pyridine (35 mg, 0.11 mmol) in DMF (4 ml) at room temperature. The mixture was stirred at room temperature for 30 min and then ethyl bromoacetate (13 μl, 0.11 mmol) was added dropwise and the resulting mixture was stirred for a further 12. The mixture was concentrated in vacuo to leave a residue which was purified by flash column chromatography on silica gel eluting with 2: 1 ethyl acetate : heptane to 1:1 ethyl acetate : heptane to give the ester (35 mg, 81 %) as a yellow solid, Tr = 1.58 min, m/z (ES⁺) (M+Η)⁺ 395.21.

f. [4-Chloro-3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl] -acetic acid (Compound 4)

Lithium hydroxide monohydrate (8.0 mg, 0.18 mmol) was added in one portion to a stirred solution of [4-chloro-3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2 c]pyridin-l-yl]-acetic acid ethyl ester (35 mg, 0.09 mmol) in tetrahydrofuran : water (4 ml; 1:1) at room temperature. After stirring at room temperature for 12 h, water (5 ml) was added to the mixture and then the organic solvent removed in vacuo to precipitate a white solid. The suspension was washed with ethyl acetate (2 x 5 ml) and the aqueous solution adjusted to pH 7 with 1M hydrochloric acid. The resulting precipitate was filtered and dried under vacuum to give the carboxylic acid (15 mg, 46 %) as a white solid, δ_H (400 MHz, d₆-OMSO) 7.96 (IH, d 75.8 Hz, Ar), 7.49 (IH, d 75.8 Hz, Ar), 7.28 (2H, d 78.7 Hz, Ar), 6.99 (2H, d 78.7 Hz, Ar), 4.51 (2H, s, NCH₂CO₂H), 2.42 (3H, s, CCH₃); Tr = 1.34 min, m/z (ES⁺) (M+Η)⁺ 367.17.

Example 5 - Synthesis of r4-Chloro-3-(4-chIoro-phenylsulfonyl)-2-methyl- pyrrolor3,2-clpyridin-l-vπ-acetic acid (Compound 5)

a. [4-Chloro-3-(4-chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl] -acetic acid ethyl ester

Oxone^® (154 mg, 0.25 mmol) was added in one portion to a stirred solution of [4- chloro-3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid ethyl ester (33 mg, 0.083 mmol) in 1, 4-dioxane : water (5 ml; 4:1) at room temperature. The resulting mixture was stirred at room temperature for 62 h. A saturated solution of sodium bicarbonate solution (4 ml) was then added and the product extracted into ethyl acetate (3 x 10 ml). The combined organic extracts were dried and concentrated in vacuo to leave a residue. Purification by flash column chromatography on silica gel eluting with 1 : 1 heptane : ethyl acetate gave the sulfone (20 mg, 61 %) as an off-white solid, Tr = 1.42 min, m/z (ES⁺) (M+H)⁺ 427.17.

b. [4-Chloro-3-(4-chloro-phenylsulfonyl)-2-methyl-pyrroIo[3,2-c]pyridin-l- yl]-acetic acid (Compound 5)

Lithium hydroxide monohydrate (4.0 mg, 0.094 mmol) was added in one portion to a stirred solution of [4-chloro-3-(4-chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2- c]pyridin-l-yl]-acetic acid ethyl ester (20.0 mg, 0.047 mmol) in tetrahydrofuran : water (2 ml; 1:1) at room temperature. After stirring at room temperature for 2 h, water (5 ml) was added and the organic solvent removed in vacuo to precipitate a white solid. The suspension was washed with ethyl acetate (2 x 5 ml) and the aqueous solution adjusted to pH 7 with 1M hydrochloric acid. The resulting precipitate was filtered and dried under vacuum and then to give the carboxylic acid (6.6 mg, 35 %) as a white solid, δ_H (400 MHz, d₆-DMSO) 8.05 (IH, d 7 5.6 Hz, Ar), 7.85 (2H, d 7 8.5 Hz, Ar), 7.66 (2H, d 7 8.5 Hz, Ar), 7.58 (IH, d 7 5.6 Hz, Ar), 4.57 (2H, s, NCH₂CO₂H), 2.56 (3H, s, CCH₃); Tr = 1.83 min, m/z (ES⁺) (M+Η)⁺ 399.12.

Compounds 6 to 22 were prepared using a similar method to Compounds 1 and 4 but with appropriately chosen starting materials.

[3-(4-Methanesulfonylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 6) δ_H (400 MHz, rf₆-DMSO) 8.60 (IH, s, Ar), 8.29 (IH, d 7 5.6 Hz, Ar), 7.74 (2H, d 7 8.5 Hz, Ar), 7.64 (IH, d 7 5.1 Hz, Ar), 7.18 (2H, d 7 8.6 Hz, Ar), 5.17 (2H, s, CH₂CO₂H), 3.15 (3H, s, SO₂CH₃), 2.43 (3Η, s, CH₃); Tr = 1.05 min (100%), m/z (ES⁺) (M+Η)⁺ 377.05.

(4-Chloro-2-methyl-3-phenylsulfanyl-pyrrolo[3,2-c]pyridin-l-yl)-acetic acid (Compound 7) δ_H (400 MHz, d₆-DMSO) 7.93 (IH, d 7 5.6 Hz, Ar), 7.46 (IH, d 7 5.8 Hz, Ar), 7.20 (2H, t 7 7.6 Hz, Ar), 7.06 (IH, t 7 7.4 Hz), 6.96 (2H, d 7 7.2 Hz, Ar), 4.48 (2H, s, CH₂CO₂H), 2.40 (3H, s, CH₃); Tr = 1.84 min (100%), m/z (ES⁺) (M+Η)⁺ 333.16.

(4-Chloro-2-methyl-3-p-tolylsulfanyl-pyrrolo[3,2-c]pyridin-l-yl)-acetic acid (Compound 8) δ_H (400 MHZ, d₆-DMSO) 7.92 (IH, d 7 5.7 Hz, Ar), 7.44 (IH, d 7 5.7 Hz, Ar), 7.02 (2H, d 7 8.0 Hz, Ar), 6.87 (2H, d 7 8.2 Hz, Ar), 4.46 (2H, s, CH₂CO₂H), 2.40 (3H, s, CH₃), 2.20 (3Η, s, CH₃); Tr = 1.91 min (92%), m/z (ES⁺) (M+Η)⁺ 347.15.

[4-Chloro-3-(4-fluorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 9) δ_H (400 MHz, ( -DMSO) 7.93 (IH, d 75.6 Hz, Ar), 7.46 (IH, d 75.7 Hz, Ar), 7.09- 6.99 (4H, m, Ar), 4.48 (2H, s, CH₂CO₂H), 2.42 (3H, s, CH₃); Tr = 1.87 min (100%), m/z (ES⁺) (M+Η)⁺ 351.15.

[4-Chloro-3-(4-methoxyphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 10) δ_H (400 MHz, d₆-OMSO) 7.91 (IH, d 7 5.8 Hz, Ar), 7.43 (IH, d 75.6 Hz, Ar), 6.97 (2H, d 7 8.9 Hz, Ar), 6.81 (2H, d 7 8.9 Hz, Ar), 4.46 (2H, s, CH₂CO₂H), 3.67 (3H, s, OCH₃), 2.43 (3Η, s, CH₃); Tr = 1.82 min (95%), m/z (ES⁺) (M+Η)⁺ 363.14.

[4-Chloro-3-(3-chIorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 11) δ_H (400 MHz, -DMSO) 7.95 (IH, bs, Ar), 7.48 (IH, bs, Ar), 7.24 (IH, bs, Ar), 7.13 (IH, bs, Ar), 6.98 (IH, bs, Ar), 6.91 (IH, bs, Ar), 4.49 (2H, s, CH₂CO₂H), 2.40 (3H, s, CH₃); Tr = 1.96 min (100%), m/z (ES⁺) (M+Η)⁺ 367.10.

[4-Chloro-3-(4-trifluoromethylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin- l-yl]-acetic acid (Compound 12) δ_H (400 MHz, dβ-OMSO) 7.96 (IH, d 7 5.6 Hz, Ar), 7.56 (2H, d 7 8.4 Hz, Ar), 7.50 (IH, d 7 5.8 Hz, Ar), 7.14 (2H, d 7 8.3 Hz, Ar), 4.50 (2H, s, CH₂CO₂H), 2.40 (3H, s, CH₃); Tr = 2.02 min (100%), m/z (ES⁺) (M+Η)⁺ 401.12.

[4-Chloro-3-(3-trifluoromethylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin- l-yl]-acetic acid (Compound 13) δ_H (400 MHz, -DMSO) 7.96 (IH, d 7 5.8 Hz, Ar), 7.50 (IH, d 75.6 Hz, Ar), 7.43- 7.42 (2H, m, Ar), 7.39 (IH, bs, Ar), 7.14 (IH, td 7 3.9, 1.4 Hz), 4.50 (2H, s, CH₂CO₂H), 2.41 (3H, s, CH₃); Tr = 2.00 min (100%), m/z (ES⁺) (M+Η)⁺ 401.12.

[4-Chloro-3-(2,4-dichlorophenylsulfanyl)-2-methyI-pyrrolo[3,2-c]pyridin-l-yI]- acetic acid (Compound 14)

Tr = 2.08 min (100%), m/z (ES⁺) (M+H)⁺ 403.07. [4-Chloro-3-(2,5-dichlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 15) δ_H (400 MHz, d₆-DMSO) 7.99 (IH, d 7 5.8 Hz, Ar), 7.53 (IH, d 7 5.8 Hz, Ar), 7.49 (IH, d 7 8.4 Hz, Ar), 7.18 (IH, dd 7 8.5, 2.5 Hz, Ar), 6.43 (IH, d 7 2.4 Hz, Ar), 4.52 (2H, s, CH₂CO₂H), 2.39 (3H, s, CH₃); Tr = 2.02 min (100%), m/z (ES⁺) (M+Η)⁺ 403.06.

[3-(4-Bromophenylsulfanyl)-4-chloro-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 16)

Tr = 1.98 min (100%), m/z (ES⁺) (M+H)⁺ 413.03.

[3-(3-methoxyphenylsulfanyl)-4-chloro-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 17) Tr = 1.85 min (100%), m/z (ES⁺) (M+H)⁺ 363.15.

[4-Chloro-2-methyl-3-(naphthalen-2-ylsulfanyl)-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 18) δ_H (400 MHz, d₆-DMSO) 7.95 (IH, d 7 5.8 Hz, Ar), 7.81 (IH, d 77.6 Hz, Ar), 1.11 (IH, d 7 8.8 Hz, Ar), 7.67 (IH, d 7 7.8 Hz, Ar), 7.50 (IH, d 7 5.6 Hz, Ar), 7.43-7.36 (3H, m, Ar), 7.18 (IH, dd 7 8.6, 2.0 Hz, Ar), 4.52 (2H, s, CH₂CO₂H), 2.44 (3H, s, CH₃); Tr = 1.98 min (100%), m/z (ES⁺) (M+Η)⁺ 383.17.

[4-Chloro-2-methyl-3-(naphthalen-l-ylsulfanyl)-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 19) δ_H (400 MHz, ^₆-DMSO) 8.33 (IH, d 7 8.5 Hz, Ar), 8.06 (IH, d 7 5.9 Hz, Ar), 7.95 (IH, d 7 7.3 Hz, Ar), 7.72 (IH, d 75.6 Hz, Ar), 7.68-7.58 (3H, m, Ar), 7.26 (IH, t 7 7.8 Hz, Ar), 6.61 (IH, dd 7 7.3, 7.0 Hz, Ar), 5.26 (2H, s, CH₂CO₂H), 2.46 (3H, s, CH₃); Tr = 1.95 min (100%), m/z (ES⁺) (M+Η)⁺ 383.17. Oxidation and hydrolysis were carried out using the methods as described for Compounds 2, 3 and 5.

[4-Chloro-3-(4-fluorophenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid (Compound 20) δ_H (400 MHz, ck-OMSO) 8.03 (IH, d 75.8 Hz, Ar), 7.89 (2H, dd 7 8.9, 5.3 Hz, Ar), 7.58 (IH, d 7 5.6 Hz, Ar), 7.40 (2H, t 7 8.8 Hz, Ar), 4.63 (2H, s, CH₂CO₂H), 2.79 (3H, s, CH₃); Tr = 1.25 min (90%), m/z (ES⁺) (M+Η)⁺ 383.24. < [4-Chloro-3-(4-trifluoromethylphenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin- l-yl]-acetic acid (Compound 21) δ_H (400 MHz, d₆-DMSO) 8.12 (IH, d 7 5.6 Hz, Ar), 8.05 (2H, d 7 8.6 Hz, Ar), 7.97

(2H, d 7 8.3 Hz, Ar), 7.75 (IH, d 75.8 Hz, Ar), 5.18 (2H, s, CH₂CO₂H), 2.84 (3H, s,

CH₃); Tr = 1.36 min (97%), m/z (ES⁺) (M+Η)⁺ 433.27. ,

Example 6 - Measurement of CRTH2 Antagonist Activity

Materials and Methods

Materials

Calcium-3 dye was purchased from Molecular Devices (Wokingham, UK). Monopoly resolving medium was obtained from Dainippon Pharmaceuticals (Osaka, Japan). Macs anti-CD16 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 (MEM) supplemented with 10% foetal bovine serum, 2 raM glutamine, and 1 mg ml^"1 active G418. The cells were passaged every 2-3 days. For radioligand binding assay, cells were prepared in triple-layer flasks or in 175 cm 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 min, 4°C) and resuspended in 15 ml of buffer (lxHBSS, 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 min 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 μl. 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 min and resuspended in ice-cold assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM Glucose, 120 mM NaCl, 10 μM indomethacin) and directly centrifuged at 20,000 rpm for 30 min 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 μl of buffer (1XHBSS/HEPES 10 mM, pH 7.3). Cell membranes (15μg). Cell membranes 15mg were preincubated at room temperature with varying concentration of competing ligand for 15 min. [ H]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 μl ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF/B glass fibre filters using a Unifilter Cell harvester (PerkinElmer Life Sciences) and six washes of 300 μl 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 μl of Optiphase Hi-Safe 3 (Wallac) liquid scintillation. Non specific binding was defined in the presence of 10 μM 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).

The results of the experiments demonstrate that for compounds of general formula (la) and (lb) the affinity for the CRTH2 receptor is higher than for DP receptor.

Compounds of general formula (la) and (lb) 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 μM. Compounds of general formula (la) and (lb) had no activity (or very weak activity) at the DP receptors. The binding selectivity of the illustrated compounds of general formula (la) and (lb) 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 (la) and (lb), 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 lOOμl HBSS and lOOμl calcium-3-dye (Molecular Devices), supplemented with 4mM probenecid. Changes in fluorescence were monitored over a 50s time course with agonist addition at 17s using a Flexstation (Molecular Devices).

Effect ofCRTH2 agonists on calcium mobilisation in CHO-CRTH2 cells

PGD₂ caused a dose-dependent increase in vntracel ular Ca²⁺ mobilisation in CHO/CRTH2 cells, with an EC₅₀ = 2.4 ± 0.5nM (n=3) (Figure 2).

Effect of compounds of general formula (la) and (lb) on the calcium mobilisation induced by PGD2

PGD₂-stimulated Ca flux was fully inhibited by the compounds of general formula (la) and (lb) and the IC₅₀ value for each compound in the calcium assay was comparable to its Ki value in Radioligand binding. IC₅₀ values of compounds of general formula (la) and (lb) varied from 5 nM to 1 μM. The results for several compounds of general formula (la) and (lb) are shown in Table 3. Increasing doses of the compounds of general formula (la) and (lb) 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 (la) and (lb) appears to be CRTH2 selective, since no inhibitory effect was seen with ATP-stimulated Ca²⁺ flux. Table 3 - Inhibition of PGD₂-induced calcium flux

Claims

1. A compound of general formula (la) or (lb):

la lb

wherein

R¹, R² and R³ are independently hydrogen, halo, - -C_δ alkyl, -O(Ci-C₆ alkyl), -C_rC₆ alkyl(C₃-C₇ cycloalkyl), -CON(R⁸)₂, -SOR⁸, -SO₂R⁸, -SO₂N(R⁸)₂, -N(R⁸)₂, -NR⁸COR⁸, -CO₂R⁸, COR⁸, -SR⁸, -OH, -NO₂ or -CN; each R⁸ is independently hydrogen or C C_δ alkyl;

R⁴ and R⁵ are each independently hydrogen, or C Cβ alkyl or together with thecarbon atom to which they are attached form a C₃-C₇ cycloalkyl group;

R >6 : is hydrogen or d-C_ό alkyl;

R⁷ is Cι-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,

C C₆ alkyl, -O C-Q alkyl, -R , 1^,0^υ, -OR , 1'0^υ, C(R 1^ι0^υN)₂ -CON(R , 1^,0^υx)₂, -SOR , 1'0^υ -SO₂R , 1^,0^υ, - SO₂N(R¹⁰)₂, -N(R^,0)₂, -NR¹⁰COR¹⁰, -CO₂R¹⁰, -COR¹⁰, -SR¹⁰, -OH, -NO₂ or -CN; wherein each R¹⁰ is independently hydrogen, Cj-C₆ alkyl, aryl or substituted aryl;

X is -S- or -SO₂-; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof. A compound of general formula (Ha) or (lib):

Ila lib

wherein R¹, R², R³, R⁴, R⁵ , R⁶ and R⁷ are as defined in claim 1; and

R¹¹ is d-C₆ alkyl, aryl, (CH₂)_mOC(=O)C₁-C₆alkyl, (CH₂)_mN(R¹²)₂, CH((CH₂)_mO(C=O)R¹³)₂; m is 1 or 2; R , 12 is hydrogen or methyl; R¹³ is d-C₁₈ alkyl.

3. A compound as claimed in claim 1 or claim 2 wherein, independently or in any combination: R¹ is halo or hydrogen; R² is halo or hydrogen; R³ is halo or hydrogen;

A compound as claimed in claim 3 wherein R¹, R² and R³ are hydrogen.

5. A compound as claimed in any one of claims 1 to 4 wherein R and R⁵ are each independently hydrogen or Q-C₄ alkyl.

A compound as claimed in claim 4, wherein both R 4 a —nd A r R>5 are hydrogen.

7. A compound as claimed in any one of claims 1 to 6, wherein R⁶ is H or C]-C₆ 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 1 to 8 wherein R⁷ is an aromatic moiety having one or two rings and substituted with one or more substituents selected from halo, -C C₄ alkyl, -O(C C₄ alkyl), -SO₂(Cι-C₄ alkyl), -R¹⁰ and -OR¹⁰; where R¹⁰ is aryl or substituted aryl.

10. [3-(4-chlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl] acetic acid; [3-(4-chlorophenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl] acetic acid; [3-(4-chlorophenylsulfonyl)-2-methyl-5-oxy-pyrrolo[3,2-c]pyridin-l-yl] acetic acid;

[4-Chloro-3-(4-chloro-phenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid;

[4-Chloro-3-(4-chloro-phenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid; [3-(4-Methanesulfonylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid;

(4-Chloro-2-methyl-3-phenylsulfanyl-pyrrolo[3,2-c]pyridin-l-yl)-acetic acid;

(4-Chloro-2-methyl-3-p-tolylsulfanyl-pyrrolo[3,2-c]pyridin-l-yl)-acetic acid;

[4-Chloro-3-(4-fluorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid;

[4-Chloro-3-(4-methoxyphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid;

[4-Chloro-3-(3-chlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid; [4-Chloro-3-(4-trifluoromethylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid;

[4-Chloro-3-(3-trifluoromethylphenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid;

[4-Chloro-3-(2,4-dichlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid;

[4-Chloro-3-(2,5-dichlorophenylsulfanyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]- acetic acid; [3-(4-Bromophenylsulfanyl)-4-chloro-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid;

[3-(3-methoxyphenylsulfanyl)-4-chloro-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid; [4-Chloro-2-methyl-3-(naphthalen-2-ylsulfanyl)-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid;

[4-Chloro-2-methyl-3-(naphthalen-l-ylsulfanyl)-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid;

[4-Chloro-3-(4-fluorophenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l-yl]-acetic acid; [4-Chloro-3-(4-trifluoromethylphenylsulfonyl)-2-methyl-pyrrolo[3,2-c]pyridin-l- yl]-acetic acid; or a C]-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 (Hb) as defined in claim 2 with a base.

12. A process for the preparation of a compound of general formula (lb) as claimed in claim 1, the process comprising treating a compound of general formula

(la) as claimed in claim 1 with an oxidising agent.

13. A compound as claimed in any one of claims 1 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 1 to 10 in the preparation of an agent for the treatment or prevention of diseases and conditions mediated by PGD₂ at the CRTH2 receptor.

15. 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 autoimmune 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 and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, stroke and amyoptrophic lateral sclerosis.

16. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 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 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.

20. A composition as claimed in claim 19, wherein the additional active agents are selected from: β2 agonists such as salmeterol; corticosteroids such as fluticasone; 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 TNFα converting enzyme (TACE); drugs that modulate the activity of Th2 cytokines IL-4 and IL-5 such as blocking monoclonal antibodies and soluble receptors; PPAR-γ 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 1 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.