MXPA06004136A - Compounds having crth2 antagonist activity - Google Patents

Abstract

Compounds of general formula (I) and their pharmaceutically acceptable salts, hydrates, solvates, complexes and prodrugs are useful in the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

Description

COMPOUNDS THAT HAVE CRTH2 ANTAGONIST ACTIVITY FIELD OF THE INVENTION The present invention relates to compounds that are useful as drugs, to methods for preparing those compounds, compositions containing them and their uses for the treatment and prevention of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis and other Inflammatory diseases mediated by prostaglandin D2 (PGD2) that acts as the CRTH2 receptor on cells including eosinophils, basophils and Th2 lymphocytes.

BACKGROUND OF THE INVENTION PGD2 is an eicosanoid, a kind of chemical mediator synthesized by cells in response to local tissue damage, normal stimuli or hormonal stimuli or by cellular activation pathways. Eicosanoids bind to specific cell surface receptors on a wide variety of tissues throughout the body and mediate various effects on those tissues. It is known that PGD2 is 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 al, (1986), N. Engl.

J. Med. 315: 800-804). The instillation of PGD2 in the airways can cause many characteristics 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 accumulation of eosinophils (Ery et al, (1989) J. Appl. Physiol. 67: 959-962). The potential of PGD2 applied exogenously to induce inflammatory responses has been confirmed by the use of transgenic mice that overexpress human PGD2 synthase which exhibit exaggerated eosinophilic pulmonary inflammation and Th2 cytokine production in response to antigen (Fujitani et al, (2002 J. Immunol. 168: 443-449). The first specific receptor for PGD2 when discovered was the DP receptor which is linked to the elevation of intracellular levels of cAMP. However, it is thought that PGD2 mediates much of its proinflammatory activity through interaction with a G-protein coupled receptor called CRTH2 (molecule homologous to the chemoattractant receptor expressed on Th2 cells) which is expressed by Th2, eosinophilic lymphocytes. 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 to be clear that the effect of PGD2 on the activation of Th2 lymphocytes and eosinophils is mediated through CRTH2 since selective CRTH2 agonists 13,14 dihydro-15-keto-PGD2 (DK-PGD2) and 15R-methyl-PGD2 can produce 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 of BW245C does not promote the migration of Th2 or eosinophil lymphocytes (Hirai et al, 2001; Gervais et al, (2001) J. Allergy Clin. Immunol., 108: 982-988). On the basis of this evidence, the antagonism of PGD2 at the CRTH2 receptor is an attractive method to treat the inflammatory component of allergic and Th2-dependent diseases such as asthma, allergic rhinitis and atopic dermatitis. EP-A-1170594 suggests that the method with which it is related can be used to identify compounds that 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 on the CRTH2 receiver. Compounds that bind to CRTH2 are taught in WO-A-03066046 and WO-A-03066047. These compounds are not novel but were described for the first time, together with similar compounds, in GB 1356834, GB 1407658 and GB 1460348, where they are said to have anti-inflammatory, analgesic and antipyretic activity. WO-A-03066046 and WO-A-03066047 teach that the compounds in which they are related are modulators of CRTH2 receptor activity and therefore are 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 the bones and joints, skin and eyes, Gl tract, central and peripheral nervous system and other tissues as well as the rejection of an allograft. The compounds described in those documents are indoles with a carboxylic acid group being in the 3-position of the system of an indole ring, a quinoline, quinazoline or benzothiazole group in the 1-position.

SUMMARY OF THE INVENTION The present invention relates to novel compounds which bind to CRTH2 and which will therefore also be useful in the treatment of diseases and conditions mediated by the activity of PGD2 at the CRTH2 receptor. In the present invention, compounds of general formula (I) are provided where R1, R2, R3 and R4 are independently hydrogen, halo, C6-C6 alkyl, -O (C6-C6 alkyl), -CON (R9) 2, -SOR9, -S02R9, -S02N (R9) 2, -N (R9) 2, -NR9COR9, -C02R9, -COR9, -SR9, -OH, -N02 or -CN; each R5 is independently hydrogen or C-Ce alkyl; R 5 and R 6 are each independently hydrogen, or C 1 -C 6 alkyl or together with the carbon atom which is attached form a C 3 -C 7 cycloalkyl group; R is hydrogen or C? -C6 alkyl is 1 or 2; X is a bond or, when n is 2, X may also be a group NR9; where R9 is as defined above; when X is a bond R8 is a C-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, biphenyl or a bicyclic or tricyclic heteroaryl group of 9-14 members; when X is a group NR9 and R8 can additionally be phenyl, naphthyl or a 5-7 membered heteroaromatic ring; and The R8 group is optionally substituted with one or more substituents selected from halo, C? -C6 alkyl, -0 (C? -C6) alkyl, aryl, -O-aryl, heteroaryl, -O-heteroaryl, -CON (R9) 2, -SOR9, -S02R9, S02N (R9) 2, -N (R9) 2, -NR9COR9, -C02R9, -COR9, -SR9, -OH, -N02-CN; where R9 is as defined above; or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof Compounds of general formula (I) are antagonists of PGD2 at the CRTH2 receptor and will therefore be useful in the treatment of conditions that are mediated by the binding of PGD2 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 and contact hypersensitivity, (including contact dermatitis) conjunctivitis, or especially allergic conjunctivitis, bronchitis eosinophilic, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other diseases mediated by PGD2, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematosus, psoriasis, acne, sclerosis multiple, graft rejection, reperfusion injury, chronic obstructive pulmonary disease, as well as rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Similarly, but not identical, the compounds are described in WO-A-9950268. These compounds differ from those of the present invention in that they do not contain a sulfone / sulfonamide moiety attached at the 3-position of the indole ring. In addition, it is not taught that they are useful in the treatment of conditions such as asthma and allergic conditions, which are mediated by PGD2. In addition, in the treatment of complications arising from diabetes mellitus. PL 65781 and JP 43-24418 are also related to indole derivatives. However, the compounds described in both of these documents differ from the compounds of the present application in that they are indole N-sulfonamides in place of 3-sulfones or 3-sulfonamides as the compounds of the present invention. The compounds described in PL 65781 and JP 43-24418 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 those documents were the compounds they describe are COX inhibitors, an activity that is very different from the compounds of the present invention. In fact, COX inhibitors are contraindicated in the treatment of many diseases and conditions, for example asthma, and inflammatory bowel disease, for which the compounds of the present invention are useful, although they can sometimes be used to treat arthritic conditions. Compounds that bind to the CRTH2 receptor are described in WO-A-03/097042 and WO-A-03/097598. These compounds are indole acetic acids but in WO-A-03/097042 the indole system is fused at positions 2-3 to a 5-7 membered carbocyclic ring. In WO-A-03/097598 there is a pyrrolidine p in the 3-position of the indole. WO-A-03/101981 and WO-A-03/101961 both relate to the CRTH2 antagonist. The compounds described in WO-A-03/101961 are similar to the structure of the compounds of the present invention in which X is a bond. They differ from the compounds of the general formula (I) because there is a p -S- linked to the 3-position of the indole instead of the SO or S02 p of the compounds of the general formula (I). In addition, the p equivalent to the p R8 in the compounds of general formula (I) is an aryl or heteroaryl p. There are no aliphatic substituents in this position, as with the compounds of general formula (I). It has surprisingly been found that although these compounds have a high intrinsic activity, they are less suitable for use as medicaments in the compounds of the present invention. This is because certain of the compounds of WO-A-03/101961 are inhibitors of cytochrome P50S and thus have implications for the metabolism of any pharmacological agent that can be co-administered with those compounds. In contrast, the inventors of the present have shown that, surprisingly, the compounds of the present invention do not inhibit cytochrome PsoS. In addition, our preliminary binding experiments have indicated that the sulfide compounds described in WO-A-03/101961 appear to bind to human eosinophils at a low speed, which could lead to an unappreciated duration of action. WO-A-03/10981 relates to compounds that are similar in structure to the compounds of the present invention, except that the substituent in the 3-position of the indole ring system is a phenyl, naphthyl or heteroaryl p without a linker. of SO, S02 or S02NR9, with the compounds of general formula (I). Clearly the inclusion of the linking p probably has a substantial effect on the activity of the compound. In addition, the substituent in the 3- position of the indole can not be an aliphatic p, as in the present invention. WO-A-2004/007451 relates to inhibitors of CRTH2 which are similar in structure to the compounds of the present invention in which X is a bond, except that the p equivalent to the p R8 of the compounds of formula general (I) is a 5-7 membered phenyl, naphthyl or heteroaromatic p. In effect, all the exemplified compounds have a substituted phenyl p in this position. This is clearly different from the compounds of the present invention where the R8 ps are a bicyclic or tricyclic heteroaromatic ring, or an alkyl, alkenyl or alkynyl p. It is particularly surprising that the compounds containing alkyl, alkenyl and alkynyl ps have proven to be active since they differ markedly in the structure of the prior art compounds. In the present specification "C? -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 cycloalkyl ps -C. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl, methylenecyclopropyl, ethylenecyclobutyl, methylenecyclobutyl and methylenecyclopentyl. "C-C alkyl" and "C-C18 alkyl" have similar meaning except that they contain more than one to four and one to eighteen carbon atoms respectively. C3-C-cycloalkyl refers to a 3 to 7 membered saturated carbocyclic ring. Examples of those ps include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The terms "C2-C6 alkenyl,!" And "C2-C6 alkynyl" refer to straight or branched hydrocarbon chains having from two to six carbon atoms containing respectively at least one carbon-carbon double bond or at least one a carbon-carbon triple bond As with alkyl groups, they may be optionally substituted with one or more halo substituents or with one or more C3-C7 cycloalkyl groups In the present specification, "halo" refers to fluorine, chlorine , bromine or iodine The terms "aromatic portion" and "aryl" in the context of the present specification refer to an aromatic ring system having from 5 to 14 carbon atoms in the ring and containing up to three rings. of aromatic moieties are benzene and naphthalene.The aryl groups may be substituted with one or more substituents selected from halo, C? -C? alkyl ?, C? -C6 alkoxy, a 5-7-membered heterocyclic ring or S02R9 where R9 is as defined above. The terms "heteroaromatic portion" and "heteroaryl" refer to an aromatic ring system in which at least one of the ring carbon atoms is replaced by a nitrogen, oxygen or sulfur atom. Examples include simple ring systems such as pyridine, pyrimidine, pyrazole, thiophene, oxazole and isoxazole. Other examples include fused ring systems such as quinoline, isoquinoline, quinazoline, benzothiazole, benzoxazole, benzimidazole and indole groups. Unless otherwise stated a heteroaromatic portion has 5 to 14 carbon atoms in the ring, but, for example, the "5- to 7-membered heteroaromatic ring" contains from 5 to 7 ring atoms. The bicyclic and tricyclic heteroaryl groups contain respectively two to three fused rings. The bicyclic heteroaryl groups can be, for example, ring systems 6,6- or 6-5- those exemplified above. As with the aryl groups, the heteroaryl groups can also be substituted with one or more substituents chosen from halo, C? -C6 alkyl, C-C6 alkoxy, a 5-7-membered heterocyclic ring or S02R9 where R9 is as It was defined earlier. The term "5- to 7-membered heterocyclic ring" refers to a non-aromatic ring system having from 5 to 7 ring atoms and where at least one of the ring carbon atoms is replaced by a nitrogen atom, oxygen or sulfur. Examples include piperidine, morpholine, imidazole, piperazine and tetrahydrofuran. Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formulas (I) and (II) include basic addition salts such as the sodium, potassium, calcium, aluminum, 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, gluco-heptane, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivolate, camphorrate, undecanoate and succinate , organic sulphonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2-naphthalene sulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric and sulphonic acids. Salts that are not pharmaceutically or veterinarily acceptable can still be valuable as intermediates. Prodrugs are any covalently linked compounds that release the active parent drug according to general formula (I) in vivo. Examples of prodrugs include the alkyl esters of the compounds of general formula (I), for example the esters of the general formula (II) below. If a chiral center or other isomeric center form is present in a compound of the present invention, all forms of that isomer or isomers, including the enantiomers and diastereomers, are intended to be covered here. The compounds of the invention which contain a chiral center can be used as a racemic mixture, a mixture enriched above, or the racemic mixture can be separated using well known techniques and an individual enantiomer can be used alone. The compounds of general formula (I), it is preferred that, independently or in any combination: R1 is halo or hydrogen; R2 is halo or hydrogen; R3 is halo or hydrogen; R4 is halo or hydrogen; In more preferred compounds, R1, R3 and R4 are hydrogen, while R2 is also halo, particularly fluorine. In preferred compounds of general formula (I), R5 and R6 are each independently hydrogen or C? -C4 alkyl. However, in more active compounds, at least one, and preferably both of R5 and R6 are hydrogen. The compounds of general formula (I) preferably have a group R7 selected from H or C? -C6 alkyl; more adequately R7 is methyl. In particularly preferred compounds of general formula (I), n is 2. When X is a bond, it is preferred that R 8 is C 1 -C 6 alkyl, biphenyl or a bicyclic heteroaryl group or any of which may be substituted by halogen, phenyl, -C02R9 CON (R9) 2 or -S02R9, where R9 is as defined above. The most preferred compounds in which X is a bond include those in which Rs is an alkyl group of C? -C, biphenyl or a bicyclic heteroaryl, any of which may be substituted with phenyl, -C02R9 CON (R9) 2 or -S02R9, where R9 is H or C? -C4 alkyl. When X is NR9, it is preferred that R9 is H or methyl and R8 is: phenyl optionally substituted with one or more halo groups, C-C6 alkyl or -O (C? -C6 alkyl) C? -C6 alkyl, optionally substituted with aryl; or heteroaryl. More preferably, when X is NR9, R8 is phenyl, benzyl or pyridyl, any of which may be optionally substituted with one or more halo, methyl or methoxy groups. Among the most preferred compounds are the following: 1. [3- (Butan-1-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid. 2. Acid 3 (biphenyl-4-sulfonyl) ) -5-fluoro-2-methyl-indol-1-yl] -acetic acid 3. (3-Carboxymethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid 4. Acid (3- Carbamoylmethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid 5. [5-Fluoro-3- (2-methanesulfonyl-ethansulfonyl) -2-methyl-indol-1-yl] -acetic acid 6. [3- (Benzothiazole-2-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid. 7. [3- (Benzothiazol-2-sulfinyl) -5-fluoro-2- acid. methyl-indole-1-yl] -acetic acid. 8. [5-Fluoro-2-methyl-3- (quinolin-2-sulfo-nyl) -indol-1-yl] -acetic acid. Acid [5-Fluoro- 2-methyl-3- (quinolin-8-yl-sulfonyl) -indol-1-yl] -acetic acid 10. (5-Fluoro-2-methyl-3-phenylmetansulfo-nyl-lH-indol-1-yl) -acetic 11. [3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid. [3- (3-Chloro-phenylsulfamoyl) -5-fluoro- 2-methyl-indol-l-il] -acé 13. Acid [3- (4-Fluoro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid. [3- (2-Chloro-phenylsulfamoyl) -5-fluoro-2 acid] -methyl-indol-1-yl] -acetic acid 15. (3-Benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid. Acid [5-Fluoro-3- (2-methoxy) phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid. [5-Fluoro-3- (4-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid. -Fluoro-2-methyl-3-phenylsulfamoyl-indol-1-yl) -acetic acid 19. [3- (3,4-Dichloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] - acid Acetic acid 20. [5-Fluoro-3- (3-methoxy-phenylsulfamoyl)] -2-methyl-indole-l-yl] -acetic acid 21. Acid (5-Fluoro-2-methyl-3-m-tolylsulfamoyl-indol-1-yl) -acetic acid. 22. Acid (5-Fluoro-2-methyl) -3-p-tolylsulfamoyl-indol-1-yl) -acetic acid 23. [3- (4-Chloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid. Acid [3] - (Benzyl-methyl-sulfamoyl) -5-fluoro-2-methyl-indole-1-yl] -acetic acid. Acid [5-Fluoro-2-methyl-3- (pyridin-3-yl-sulfamoyl) -indole -1-yl] -acetic; or the alkyl esters of C? -C6, aryl, (CH2) mOC (= 0) -alkyl of C? -C6, (CH2) mN (R11) 2, CH ((CH2) mO (C = 0) R12 2 of any of the above; where m is 1 or 2; R11 is hydrogen or methyl; R12 is C? -C? 8 alkyl. In a further aspect of the present invention, a compound of general formula (II) is provided: where R1, R2, R3, R4, R5, R6, n, X, R7 and R8 are as defined for the general formula (I); R10 is C? -C6 alkyl, aryl, (CH2) m0C (= 0) C? -C6 alkyl, CH2) mN (R >? A ??) 2, CH ((CH2) mO (C = 0) R 1 ± 2 ?,) 2; m is 1 or 2; R11 is hydrogen or methyl; R12 is C? -C? Alkyl. The compounds of general formula (II) are novel and can be used as prodrugs for compounds of general formula (I). When the compound of general formula (II) acts as a prodrug, the latter is converted to drug by the action of an esterase in the blood or tissue of the patient. Examples of particularly suitable R10 groups when the compound of general formula (II) is used as a prodrug includes: methyl, ethyl, propyl, phenyl, CH20C (= 0) tBu, CH2CH2N (Me) 2 CH2CH2NH2 or CH (CH20 (C = 0) R12) 2 where R12 is as defined above. The compounds of general formula (I) wherein R 1, R2, R3, R4, R5, R6, R7 and R8 are as defined for the general formula (I) and X is a bond, they can be prepared from compounds of the general formula (la), which is a compound of general formula (I) wherein n is 0 and X is a bond by oxidation with a suitable oxidizing agent such as potassium peroxymonosulfate, m-CPBA, hydrogen peroxide or other well-known oxidizing reagents. In addition to their use as prodrugs, the compounds of general formula (II) wherein R 10 is alkyl C1-C6 can be used in a process for the preparation of a compound of general formula (I), the process comprising reacting the compound of general formula (II) with a base such as sodium hydroxide or lithium hydroxide. The reaction can 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. The same method can be used to prepare compound of general formula (la) as defined above from the compounds of general formula (lia), which are identical to the compounds of general formula (II) except that n is 0. The compounds of general formula (II) and (lía) in which X is a bond can be prepared from the compounds of general formula (III): III wherein R1, R2, R3, R4, R7 and R8 are as defined for the general formula (I) and n is O, 1 or 2; by reaction with a compound of general formula (IV): X-CR5R6-C02R10 (IV) wherein R5 and R6 are as defined for general formula (I), R10 is as defined for general formula (II) and X is a leaving group, in particular a halo group, for example bromine. The reaction is conducted under strongly basic conditions, for example in the presence of excess sodium hydride and in a polar organic solvent such as dimethylformamide. The compounds of general formula (IV) are well known and readily available or can be prepared by methods known to those skilled in the art. The compounds of general formula (III) wherein R1, R2, R3, R4, R7 and R8 are as defined for the general formula (I) and n is 2; they can be prepared by reacting a compound of general formula (V): V where R1, R2, R3, R4, and R7 are as defined in general formula (I); with a compound of general formula (VI): R8-S02C1 (VI) wherein R8 is as defined in general formula (I).

The reaction is carried out in the presence of a Lewis acid such as indium (III) bromide. The reaction can be conducted in a polar organic solvent, particularly a chlorinated solvent such as 1,2-dichloroethane. The compounds of general formulas (V) and (VI) are well known in the art and are readily available or can be prepared by known methods. The compounds of general formula (II) in which X is NR 9 can be prepared from the compounds of general formula (VII): VII wherein R1, R2, R3, R4, R5, R6 and R7 are as defined for the general formula (I) and R10 is as defined in the general formula (II) by the reaction with a compound of the general formula (VIII ): HNR8R9 (VIII) where R8 and R9 are as defined above for the general formula (I). The reaction solvent can be a polar organic solvent such as dichloromethane. The compounds of general formula (VIII) are well known and readily available or can be prepared by methods well known to those skilled in the art. The compounds of general formula (VII) can be prepared from compounds of general formula (IX) 0 IX wherein R1, R2, R3, R4, R5, R5 and R7 are as defined for the general formula (I) and R10 is as defined for the general formula (II); by reaction with chlorosulfonic acid. The reaction preferably takes place in a non-polar organic solvent. The compounds of general formula (IX) are well known and readily available or can be prepared by methods well known to those skilled in the art. The compounds of general formula (III) wherein Ra, R2, R3, R4, R7, and R8 are as defined for the general formula (I) and n is 0 can be prepared by reacting a compound of general formula (IX) wherein R1 , R2, R3, R4, and R7, are as defined in the general formula (I) and R10 is as defined for the general formula (II); by a compound of general formula (X): R8-SH (X) wherein R8 is as defined in general formula (I). The reaction is carried out in the presence of iodine and potassium iodide. The reaction can take place in an aqueous or organic solvent or a mixture of the two. A typical solvent used for the reaction is a mixture such as ethanol and water. The compounds of the general formula (I) are antagonists of the PGD at the CRTH2 receptor and the compounds of the general formula (II) are prodrugs for the compounds of the general formula (I). The compounds of general formulas (I) and (II) are therefore useful in a method for the treatment of diseases and conditions mediated by PGD2 at the CRTH2 receptor, the method comprises administering to a patient in need of such treatment an amount of a compound of general formula (I) or (II). In a third aspect of the invention, there is provided a compound of general formula (I) or (II) for use in medicine, particularly for use in the treatment or prevention of diseases and conditions mediated by PGD2 at the CRTH2 receptor. In addition, the use of a compound of general formula (I) or (II) in the preparation of an agent for the treatment or prevention of diseases and conditions mediated by PGD2 at the CRTH2 receptor is also provided. As mentioned above, those diseases and conditions include allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis, and conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, Eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other diseases mediated by PGD2, for example, autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, as well as ratoid arthritis, psoriatic arthritis and osteoarthritis. The compounds of general formula (I) or (II) must be formulated in an appropriate form depending on the diseases or conditions that are required to be treated. Therefore, in a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of general formula (I) or (II) together with a pharmaceutical excipient or carrier. Other active materials may also be present, as may be considered appropriate or contemplated for the disease or condition being treated or prevented. The support, or, if more than one, each of the supports, must be acceptable in the sense of being compatible with other ingredients of the formulation and not be harmful to the recipient. Formulations include those suitable for oral, rectal, nasal, bronchial (inhaled), topical (including eye, buccal and sublingual drops) vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) and can be prepared by methods well known in the pharmacy technique. The route of administration will depend on the condition to be treated but the preferred compositions are formulated for oral, nasal, bronchial or topical administration. The compositions can be prepared by bringing into association the active agent defined above with the support. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid supports or both, and then if necessary forming the product. The invention extends to methods for preparing a pharmaceutical composition comprising placing a compound of general formula (I) or (II) together or in association with a pharmaceutically or veterinarily acceptable carrier or vehicle. Formulations for oral administration in the present invention can be presented as: discrete units such as capsules, sachets or tablets each of which contain a predetermined amount of the active agent; as a powder or granules; as a solution or suspension of the active agent in an aqueous liquid or a non-cumbersome liquid; or as an oil-in-water liquid emulsion or 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 carriers as common excipients e.g. binding agents, e.g., syrup, acacia, gelatin, sorbitol, tragacanth, polyvinyl pyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and supports, 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 metal stearates, glycerol stearate, stearic acid, fluid silicone, talc, waxes, oils, and colloidal silica. Fluidizing agents such as peppermint, glauteria oil, cherry flavor and the like can also be used. It may be desirable to add a coloring agent to make the dosage form easily identifiable. The tablets may also be coated by methods well known in the art. A tablet can be produced by compression or molding, optionally with one or more accessory ingredients. The compressed tablets can be prepared by compressing in a suitable machine the active agent in a free flowing form as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, conservative, surfactant or dispersing agent. The molded tablets can be produced by molding in a suitable machine a mixture of wet pulverized compound with an inert liquid diluent. The tablets may be optionally coated or labeled or they may be formulated to provide a slow or controlled release of the active agent. Other formulations suitable for oral administration include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth, lozenges comprising the active agent in an inert base, or gelatin and glycerin, or sucrose and acacia; buccal washes comprising the active agent in a suitable liquid support. For topical application to the skin, the compounds of general formula (I) or (II) can be produced in a cream, ointment, jelly, solution or suspension, etc. The cream or ointment formulations that can be used for the drug are conventional formulations well known in the art, for example, as described in standard pharmacy textbooks such as the British Pharmacopoeia. The compounds of general formula (I) or (II) can 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 Drops form a solution or suspension. Pharmaceutical compositions with powder dispersion properties usually contain, in addition, the active ingredient and with a liquid propellant with a boiling point lower than room temperature, and if desired, adjuvants, such as liquid or solid nonionic or anionic surfactants and / or diluents. The pharmaceutical compositions in which the pharmacologically active ingredient is in solution contain, in addition to this a suitable propellant and further, if necessary, an additional solvent and / or stabilizer. Instead of the propellant, compressed air can also be used, making it possible for it to be produced as required by means of a suitable compression and expansion device. Parenteral formulations will generally be sterile. Typically, the compound dose will be from about 0.01 to 100 mg / kg; to maintain the concentration of the drug in the plasma at an effective concentration to inhibit PGD2 at the CRTH2 receptor. The precise amount of the compound of general formula (I) or (II) that is therapeutically effective, and the route by which that compound is best administered, is actually determined by one skilled in the art by comparing the blood level of the agent with the concentration required to have a therapeutic effect. The compounds of general formula (I) or (II) can be used in combination with one or more active agents which are useful in the treatment of the diseases and conditions listed above, although their active agents are not necessarily inhibitors of PGD2 in the CRTH2 receiver. Therefore, the pharmaceutical compositions described above may additionally contain one or more of these active agents. Also provided is the use of a compound of general formula (I) or (II) in the preparation of an agent for the treatment of diseases and conditions mediated by PGD2 at the CRTH2 receptor, wherein the agent also comprises an additional active agent useful for the treatment of the same diseases and conditions. Those additional active agents, which may have a completely different mode of action, 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; therapies with anti-IgE antibody such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); antifungals 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 can also be combined with therapies that are in development for inflammatory indications including: Other PGD antagonists that act in other receptors as DP antagonists; Inhibitors of phosphodiesterase type 4 such as cilonilast; drugs that modulate cytokine production as inhibitors of the TNFa converting enzyme (TACE); drugs that modulate the activity of the Th2 cytokines IL-4 and IL-5 as blocking monoclonal antibodies and soluble receptors; PPAR-agonists and such as rosiglitazone; 5-lipoxygenase inhibitors such as zileuton. In a further aspect of the invention, there is provided a product comprising a compound of general formula (I) or (II) and one or more of the agents listed above as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD2 at the CRTH2 receptor.

BRIEF DESCRIPTION OF THE FIGURES The invention will now be described in greater detail with reference to the following non-limiting examples and the drawings in which: Figure 1 shows the effect of CRTH2 agonists on calcium mobilization in CHO / CRTH2 cells.

DETAILED DESCRIPTION OF THE INVENTION Example 1- Synthesis of 3-Sulfonyl indole Derivatives (Method A) 1. Synthesis of 3- (Butan-1-sulfonyl) -5-fluoro-2-methyl-1H-indole Indium bromide was added (III) (94.7 mg, 0.267 mmol) in one portion to a solution, with stirring, of 5-fluoro-2-methylindole (50 mg, 0.34 mmol) and butanesulfonyl chloride (418 mg, 2.67 mmol) in 1, 2 -dichloroethane (2 ml) at room temperature. The mixture was subjected to microwave conditions (85 ° C, 150 W) for 45 minutes, cooled to room temperature and then concentrated in vacuo to leave a brown residue. Purification by flash column chromatography on silica gel eluting with 10% ethyl acetate: hexane at 100% ethyl acetate gave the sulfone (55 mg, 15%) as a white off-white solid. 2. Synthesis of [3- (Bt-tan-1-sulfonyl) -5-fluoro-2-methyl-indol-l-yl] -acetic acid Compound 1) 3- (Butan-1-sulfonyl) -5-fluoro was added -2-methyl-lH-indole (55 mg, 0.204 mmol) in DMF (1 ml) was dripped for 1 minute into a suspension, with stirring, of sodium hydride (11 mg, 0.29 mol, 60% in mineral oil) in DMF (1 ml) at 0 ° C. The solution was stirred at 0 ° C for 45 minutes and then ethyl bromoacetate (0.032 ml, 0.29 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 18 hours. The mixture was adjusted to pH 4 with 10% citric acid and then extracted into ethyl acetate (2 x 10 ml). The combined organic extracts were dried and concentrated in vacuo to leave a residue. The residue was extracted THF (1 ml) and then lithium hydroxide monohydrate (19 mg, 0.464 mmol) in water (1 ml) was added in one portion at room temperature. The mixture was stirred at room temperature for 3 hours and then the solution was adjusted to pH 4 with 10% citric acid. The product was extracted with ethyl acetate and the combined organic extracts were dried and concentrated in vacuo to give a residue which was triturated with diethyl ether to give the carboxylic acid as a white off-white solid (5.4 mg, 8%), dH ( 400 MHz, MeOD) 7.57 (1H, dd J 9.8, 2.3 Hz, Ar), 7.43 (1H, dd J 9. 1, 4.0 Hz, Ar), 7.04 (1H, td J 9.1, 2.5 Hz, Ar), 4.79 (2H, s, CH2C02H), 3.23-3.19 (2H, m, S02CH2), 2.70 (3H, s, CCH3), 1.77-1.70 (2H, m, CH2CH2CH2CH3), 1.47-1.41 (2H, m, CH2CH2CH2CH3), 0.93 (3H, t J 7.6 Hz, CH2CH2CH2CH3); Tr = 1.38 min, m / z (ES +) (M + H) + 308.24. Tr = 1.82 min (98%), m / z (ES +) (M + H) + 328.20. Compound 2 was prepared using the same general method as for Compound 1 but with the initial materials chosen appropriately.

Compound 2 2-3- (Biphenyl-4-sulfonyl) -5- fluoro-2-methyl-indol-1-yl] -acetic acid dH (400 MHz, MeOD) 8.03 (2H, d, J 8.6 Hz Ar), 7.80 (2H, d, J 8.6 Hz, Ar), 7.77-7.74 (1H, dd, J 9.6, 2.5Hz, Ar), 7.66-7.64 (2H, dd, J 8.0, 1. 3Hz, Ar), 7.49 -7. 39 (4H, m, Ar), 7.07 (1H, td, J 9.1, 2.5Hz, Ar), 5.07 (2H, s, CH2), 2.76 (3H, s, CH3); Tr = 1.52 min, m / z (ES +) (M + H) + 424.1.

Example 2 - Synthesis of 3-Sulfonyl indole Derivatives (Method B) 1. 2-Methylsulfanyl-ethantiol A solution of methyl iodide (10 ml, 22.82 g, 0.161 mol) in acetone (50 ml) in a suspension was added dropwise. with stirring of etiethiol dithiol (11.24 ml, 12.62 g, 0.134 mol) and potassium carbonate (37.04 g, 0.268 mol) in acetone (150 ml). The resulting mixture was stirred at room temperature for 4 hours. Water (150 ml) was added and the mixture was stirred for an additional 15 minutes. The reaction mixture was extracted with dichloromethane (3 x 200 ml), the organic washes combined, dried over sodium sulphate and evaporated (maintenance pressure above 200 mbar to ensure that there is no coevaporation of the product) to give 2-methylsulfanyl- etantiol The LC / MS showed < 5% initial material and a 2: 1 mixture of mono- and bis-methylated material. The material was used in the following steps without further purification. 2. Ethyl ester of [5-Fluoro-2-methyl-3- (2-methylsulfanyl-ethylsulfanyl) -indol-1-yl] -acetic acid To a stirred solution of ethyl ester of (5-fluoro-2-methyl) acid indol-1-yl) -acetic (1.20g, 5.10 mmol) and 2-methylsulfanyl-ethantiol (1.04g, 6.12mmol) in 1: 1 EtOH: H20 (40ml) at room temperature iodine was added (1.29g, 5.10mmol) and potassium iodide (0.847g, 5.10 mmol). The mixture was heated to 100 ° C and stirred during 2 hours and then stirred at room temperature for 16 hours. The reaction mixture was quenched by the careful addition of NaHCO3 (aq), then extracted with DCM (2 x 50ml). The organic washes were combined, washed with saturated sodium thiosulfate (2 x 70ml), dried over magnesium sulfate and evaporated to give an oil. The crude oil was purified by chromatography (3 x 12 cm column, 4: 1 hexane: EtOAc as eluent) to give the ester (1.17g, 67%). dH (400 MHz, CDC13) 7.36 (1H, dd J 9.2, 2.5 Hz, Ar), 7.11 (1H, dd J 8.8, 4.1 Hz, Ar), 7.05 (1H, td J 9.2, 2.3 Hz, Ar), 4.79 (2H, s, CH2C02Et), 4.21 (2H, q J 7.2 Hz, C02CH2CH3), 2.86-2.79 (2H, m, CH2CH2), 2.59-2.55 (2H, m, CH2CH2), 2.50 (3H, s, SCH3) , 2.04 (3H, s, CCH3), 1.25 (3H, t J 7.2 Hz, C02CH2CH3). 3. Ethyl ester of [5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid. Oxone (8.43 g, 13.7 mmol) was added to a stirred solution of ethyl ester of [5-Fluoro-2-methyl-3- (2-methylsulfanyl-ethylsulfanyl) -indol-1-yl] -acetic acid (1.17g, 3.43mmol) in 4: 1, 4-dioxane: H20 at room temperature. After 30 minutes the reaction mixture was quenched by the careful addition of saturated sodium bicarbonate (50 ml, care for effervescence), then extracted with DCM (2 x 100 ml). The organic washes were combined and washed with brine (2 x lOOml). The aqueous washings were then extracted again with DCM (100 ml). All organic layers were combined, dried over magnesium sulfate and evaporated to give a pale green crystalline solid. The solid was suspended in DCM and collected via filtration to give the ester (l.Oßg, 76%). dH (400 MHz, CDCI3) 7.66 (1H, dd J 9.1, 2.5 Hz, Ar), 7.22 (1H, dd 1 9.0, 4.0 Hz, Ar), 7.08 (1H, td J 8.9, 2.5 Hz, Ar), 4.86 (2H, s, CH2C02Et), 4.26 (2H, c J 7.1 Hz, C02CH2CH3), 3.61-3.57 (2H, m, CH2CH2), 3.48-3.44 (2H,, CH2CH2), 2.99 (3H, s, SCH3), 2.71 (3H, s , CH3), 1.30 (3H, t J 7.1 Hz, C02CH2CH3). 4. Compound 5 - [[5-Fluoro-3- (2-mstansulfonyl-ethanesulfonyl) -2-? Tetyl-indol-1-yl] -acetic acid. Lithium hydroxide monohydrate (132 mg, 3.14 mmol) was added in one portion to a solution, with stirring of [5-fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid ethyl ester (1.06 g 2.61 mmol) in THF: water (with stirring). 5: 1; 15ml) and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to leave a residue which is partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and the aqueous solution extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried and concentrated in vacuo to give a matt white solid. The solid was then triturated with dichloromethane to give the carboxylic acid as a white matte solid, (438 mg, 44%), dH (400 MHz, 6-Acetone) 7.58-7.63 (2H, m, Ar) 7.09 (1H, td J 9.2, 2.6 Hz, Ar), 5.22 (2H, s, CH2C02H), 3.60-3.66 (2H, m, S02CH2CH2), 3.45 (2H, m, S02CH2CH2), 3.02 (3H, s, S02CH3), 2.75 (3H , s, CH3); Tr = 1.08 min (98%), m / z (ES +) (M + H) + 378.16. Compounds 3 and 4 were prepared by a similar route using the appropriate starting materials.

Compound 3 - (3-Carboximetanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid Tr = 1.16 min, / z (ES +) (M + H) + 330.10.

Compound 4 (3-Carbamoylmethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid Tr = 1.50 min, m / z (ES +) (M + H) + 329.17.

Example 3 - Synthesis of 3-Sulfonyl indole Derivatives (Method B2) A method similar to that set forth in step 2 of Example 2 was used to synthesize the following intermediates. However, hydrolysis to the acid occurred prior to oxidation to give the sulfone or sulfoxide derivative. [5-Fluoro-2-methyl-3- (quinolin-8-ylsulfa-nyl) -indol-1-yl] -acetic acid dH (400 MHz, MeOD) 8.95-8.94 (1H, m, Ar), 8.36 ( 1H, dd J 8.3, 1.7 Hz, Ar), 7.64-7.60 (2H, m, Ar), 7.45 (1H, dd J 8. 8.4, 2 Hz, Ar), 7.29 (1H, t J 7. 8 Hz, Ar), 7.09 (1H, dd J 9.2, 2.6 Hz, Ar), 7.00 (1H, td J 9.2, 2.6 Hz, Ar), 6.85 (1H, ap d J 7.3 Hz, Ar), 5.14 (2H, s, CH2C02H), 2.52 (3H, s, CCH3); Tr = 1.30 min, m / z (ES +) (M + H) + 367.39.

Acid [5-fluoro-2-methyl-3- (quinolin-2-ylsulphanyl) -indol-1-yl] -acetic dH (400 MHz, MeOD) 8.01 (1H, d J 8.6 Hz, Ar), 7.93 (1H, d J 7.8 Hz, Ar), 7.82 (1H, d J 8.1 Hz, Ar), 7.76 (1H, ap td J 7.1, 1.4 Hz, Ar), 7.53 (1H, ap td J 1 .0, 1.1 Hz, Ar), 7.47 (lH, dd J 9.1, 4.2 Hz, Ar), 7.16 (1H, dd J 9.0, 2.4 Hz, Ar), 7.03 (1H, td J 9.2, 2.6 Hz, Ar), 6.87 (1H , d J 8.8 Hz, Ar), 5.14 (2H, s, CH2C02H), 2.55 (3H, s, CCH3); Tr = 1.37 min, m / z (ES +) (M + H) + 367.24. [3- (Benzothiazol-2-ylsulfanyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid dH (400 MHz, MeOD) 7.81 (1H d J 8.3 Hz, Ar), 7. 71 (1H, d J 7.8 Hz, Ar), 7.50-7.43 (2H, m, Ar), 7.31-7.24 (2H, m, Ar), 7.06 (1H td J 9.0, 2.4 Hz, Ar), 5.15 (2H, s, CH2C02H), 2.60 (3H, s, CCH3); Tr = 1.49 min, m / z (ES +) (M + H) + 373.34.

Acid (3-Benzylsulfanyl-5-fluoro-2-methyl-indole-1-yl) -acetic dH (250 MHz, d6-DMSO) 7.46 (1H, dd J 8.8, 4.3 Hz, Ar), 7.21-7.18 (3H , m, Ar), 7.14 (1H, dd J 9.5, 2.5 Hz, Ar), 7.01-6.92 (3H,, Ar), 4.99 (2H, s, CH2C02H), 3.75 (2H, s, ArCH2), 2.01 ( 3H, s, CH3); Tr = 1.56 min (100%) / z (ES +) (M + H) + 330.16. These intermediates can be oxidized to give compounds of general formula (I) where n is 1 or 2 using the following method. 1. Compound 6 - [3- (Benzothiazol-2-sulphonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid and Compound 7 - [3- (Benzothiazole-2-sulfinyl) -5- acid] -fluoro-2-methyl-indol-1-yl] -acetic Potassium peroxymonosulfate (131.0 mg, 214 mmol) was added in one portion to a solution, with stirring, of [3- (benzothiazol-2-ylsulfanyl) - 5-fluoro-2-methyl-indol-1-yl] -acetic acid (20.0 mg, 53.6 mmol) in 1,4-dioxane: water (0.3 ml, 4: 1) at room temperature. The mixture was stirred at room temperature for 18 h and then a saturated solution of sodium bicarbonate (5 ml) was added. The product was extracted with ethyl acetate (3 ml) and the combined organic extracts were washed with brine and dried in vacuo to leave a residue which was purified with a preparative CLAP to give the sulfone, compound 6. (10.0 mg, 46%) as a dull white solid, dH (400 MHz, MeOD) 8.11 (2H, obs dd J 7.9, 2.8 Hz, Ar), 7.79 (1H, dd J 9. 6, 2.5 Hz, Ar), 7.65-7.57 (2H, m, Ar), 7.43 (1H, dd J 8.8, 4.3 Hz, Ar), 7.06 (lH, td J 9.1, 2.5 Hz, Ar), 4.76 (2H , s, CH2C02H), 2.85 (3H, s, CCH3); Tr = 1.44 min (100%), m / z (ES +) (M + H) + 405.21, and the sulfoxide, Compound 7 (3.2 mg, 15%) as a dull white solid, dH (400 MHz, MeOD) 8.16 (1H, ap d J 9.1 Hz, Ar), 8.01 (1H, d J 8.1 Hz, Ar), 7.62-7.54 (2H, m, Ar), 7.47 (1H, dd J 9. 1.4 .0 Hz, Ar), 7.23 (1H, dd J 9. 6.2, 5 Hz, Ar), 7.02 (1H, td J 9.1, 2.0 Hz, Ar), 5.10 (2H, s, CH2C02H), 2.78 (3H, s, CCH3); Tr = 1.34 min (100%), m / z (ES +) (M + H) + 389.09. Compounds 8 to 10 were prepared using the same general method as for compounds 6 and 7, but with the initial materials chosen appropriately.

Compound 8 - [5-Fluoro-2-methyl-3- (quino-lin-2-sulfonyl) -indol-1-yl] -acetic acid dH (400 MHz, MeOD) 8.57 (1H, d J 8.6 Hz, Ar ), 8. 20 (1H, d J 8.6 Hz, Ar), 8.13 (1H, d J 8.6 Hz, Ar), 8.02 (1H, d J 8.1 Hz, Ar), 7.89-7.82 (2H, m, Ar), 7.73 (1H , ap t J 8.1 Hz, Ar), 7.42 (1H, dd J 8.8, 4.3 Hz, Ar), 7.05 (1H, td J 9.1, 2.5 Hz, Ar), 5.08 (2H, s, CH2C02H), 2.86 (3H , s, CCH3); Tr = 1.39 min (92%), m / z (ES +) (M + H) + 399.26. Compound 9 - [5-Fluoro-2-methyl-3- (quinolin-8-ylsulfonyl) -indol-1-yl] -acetic acid dH (400 MHz, MeOD) 8.89 (1H, ap d J 4.3 Hz, Ar), 8.71 (1H, dd J 7.3 Hz, Ar), 8.34 (1H, ap d J 8.3 Hz, Ar), 8.20 (1H, ap d J 8.3 Hz, Ar), 7.80 (1H, t J 8.1 Hz, Ar), 7.58 (1H, dd J 10.1, 2.5 Hz, Ar), 7.53 (1H, dd J 8.3, 4.3 Hz, Ar), 7.34 (1H, dd J 8.8, 4.3 Hz, Ar), 6.95 (1H, td J 9.1, 2.5 Hz, Ar), 5.02 (2H, s, CH2C02H), 2.97 (3H, s, CCH3); Tr = 1.78 min (100%), m / z (ES +) (M + H) + 399.29.

Compound 10 - (5-Fluoro-2-methyl-3-phenyl-methanesulfonyl-1H-indol-1-yl) -acetic acid dH (250 MHz, d6-DMSO) 7.61 (1H, dd J.9.0, 4.5 Hz, Ar), 7.35 (1H, dd J 9.8, 2.5 Hz, Ar), 7.30-7.19 (3H, m, Ar), 7.10 (1H, td J 9.1, 2.6 Hz, Ar), 7.02 (2H, m, Ar), 5.10 (2H, s, CH2C02H), 4.51 (2H, s, ArCH2), 2.06 (3H, s, CH3); Tr = 1.30min (100%) m / z (ES +) (M + H) + 362.13.

Example 4 - Synthesis of 3-Sulfamoyl indole Derivatives (Method C) The method described below is employed for compounds of general formula (I) in which X is NR9. 1. [3- (4-chloro-phenyl-sulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ethyl ester. Chlorosulphonic acid (0.042 ml, 0.63 mmol) was added dropwise over 1 min. solution, with stirring of (5-fluoro-2-methyl-indol-1-yl) -acetic acid ethyl ester (100 mg, 0.43 mmol) in ether (1 ml) at 0 ° C. The solution was stirred at 0 ° C for 10 min and then concentrated in vacuo to leave a residue which was azeotroped with dichloromethane (2 x 2 ml). The residue was extracted with dichloromethane and then N, N-diisopropyl ethylamine (0.075 ml, 0.43 mmol) and 4-chloroaniline (53.4 mg, 0.42 mmol) were added. The resulting mixture was stirred at room temperature for 40 min. and then concentrated in vacuo to leave the residue which was partitioned between ethyl acetate (5 ml) and water (5 ml). the organic layer was then separated, washed with saturated sodium hydroxide solution (20 ml), dried and concentrated in vacuo to leave a residue which was purified by flash column chromatography (Flashmaster) on silica gel eluting with ethyl acetate at 15%: heptane to give the sulfonamide (6 mg, 3%) as a white matte solid, dH (400 MHz, CDC13) 7.63 (1H, dd J 9.5, 2.4 Hz, Ar), 7.18-7.12 (3H, m , Ar), 7.05-6.99 (1H, m, Ar), 6.96-6.90 (2H, m, Ar), 6.55 (1H, s, NH), 4.73 (2H, s, NCH2), 4.20 (2H, qJ 7.3 Hz, 0CH2CH3), 2.33 (3H, s, CCH3), 1.22 (3H, t J 7.3 Hz, OCH2CH3); Tr = 1.57 min (100%), m / z (ES +) (M + H) + 425. 2. Compound 11-Acid [3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid. Lithium hydroxide monohydrate (7.0 mg, 0.17 mmol) in water (2 ml. ) in one portion with a stirring solution of ethyl ester in [3- (4-chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid (6 mg, 0.014 mmol) in tetrahydrofuran (2 ml). The resulting mixture was stirred at room temperature for 3 h and then the pH 1 of the mixture was adjusted with 1M hydrochloric acid. The product extracted with ethyl acetate (2 x 10 ml) and the combined organic extracts were then dried and concentrated in vacuo to give the carboxylic acid (4.3 mg, 77%) as a white off-white solid, dH (400 MHz, CDCl 3). 8.74 (1H, s, NH), 7.70 (1H, dd J 9.5, 2.6 Hz, Ar), 7.13-7.06 (3H,, Ar), 6.99-6.92 (3H, m, Ar), 4.67 (2H, s, NCH2), 2.41 (3H, s, CH3); Tr = 1.84 min (91%), m / z (ES +) (M + H) + 397. Compounds 12 to 25 were prepared using the same general method but with the initial materials chosen appropriately. Compound 12-Acid [3- (3-chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic dH (400 MHz, CDC13) 7.63 (1H, dd J 9.3, 2. 6 Hz , Ar), 7.17-7.14 (1H, m, Ar), 7.10-6.98 (5H, m, Ar, NH), 6.86-6.84 (1H, m, Ar), 4.73 (2H, s, NCH2), 2.46 ( 3H, s, CH3); Tr = 1.84 min (100%), m / z (ES +) (M + H) + 397.

Compound 13-Acid [3- (4-Fluoro-phenylsulfamoyl) -5-luoro-2-methyl-indol-1-yl] -acetic dH (400 MHz, CDC13) 8.45 (1H, s, NH), 7.66 (1H , dd J 9.7, 2.3Hz, Ar), 7.11 (1H, dd J 9.4.2Hz, Ar), 6.97-6.90 (3H, m, Ar), 6.81-6.77 (2H, m, Ar), 4.64 ( 2H, s, NCH2), 2.29 (3H, s, CH3); Tr = 1.79 min (99%), m / z (ES +) (M + H) + 381. Compound 14-[3- (2-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid dH (400 MHz, CDC13) 7.69 (1H, s, NH), 7.58-7.49 (2H, m, Ar), 7.23-7.13 (3H, m, Ar), 7.03-6.93 (2H, m, Ar), 4.70 (2H, s, NCH2), 2.44 (3H, s, CH3); Tr = 1.83 (100 %), m / z (ES +) (M + H) + 397. Compound 15-Acid (3-Benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic dH (400 MHz, dg-DMSO ) 7.99 (1H, t J 6.3 Hz, Ar), 7. 58 (2H, m, Ar), 7.21 (4H, m, Ar), 7.09 (1H, td J 9.23, 2. 65 Hz, Ar), 5.11 (2H, s, CH2C02H), 3.92 (2H, d J 6.31 Hz, NCH2) 2. 56 (3H, s, CH3), Tr = 1.31min (100%), m / z (ES +) (M + H) + 377. 25 Compound 16-Acid [5-Fluoro-3- (2-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic dH (400 MHz, de-DMSO) 9.18 (1H, s, S02NH), 7.52 (1H, dd J 9.00, 4.4 Hz, Ar), 7.47 (1H, dd J 10.2, 2.6 Hz, Ar), 7.23 (1H, dd J 7.9, 1.6 Hz, Ar), 7.09-7.01 (2H, m,? r), 6.84 (1H, t J 7.7 Hz, Ar), 6.77 (1H, d J 7. 2 Hz, Ar), 5.05 (2H, s, CH2C02H), 3.24 (3H, OCH3), 2.30 (3H, s , CH3); Tr = 1.31 min (100%), m / z (ES +) (M + H) + 393.25. Compound 17-Acid [5-fluoro-3- (4-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic dH (400 MHz, de-DMSO) 9.62 (1H, s, S02NH), 7.49 (1H, dd J 10.3, 2.6 Hz, Ar), 7.36 (1H, dd J 9.0, 4.6 Hz, Ar), 6.98 (1H, dd J 9.2, 2.8 Hz, Ar), 6.93 (2H, d J 9.1 Hz, Ar), 6.74 (2H, d J 9.1 Hz, Ar), 4.45 (2H, s, CH2C02H), 3. 64 (3H, s, 0CH3), 2.36 (3H, s, CH3); Tr = 1.27 min (100%), m / z (ES +) (M + H) + 393.26. Compound 18-Acid (5-fluoro-2-methyl-3-enylsulfamido-indol-1-yl) -acetic dH (400 MHz, d6-DMS0) 10.15 (1H, s, S02NH), 7.60 (1H, dd J 10.1, 2.6 Hz, Ar), 7.53 (1H, dd J 9.1, 4.5 Hz, Ar), 7.17 (2H, m, Ar), 7.07 (1H, dd J 9. 1, 2.6 Hz, Ar ), 7.03 (2H, m, Ar), 6.96 (1H, t J 7.3 Hz, Ar), 5.03 (2H, s, CH2C02H), 2.48 (3H, s, CH3); Tr = 1.28 min (96%), m / z (ES +) (M + H) + 363.25. Compound 19-Acid [3- (3,4-dichloro-benzylsulfamoyl) -5-f-luoro-2-methyl-indol-1-yl] -acetic dH (400 MHz, de-DMSO) 7.92 (1H, broad, S02NH ), 7.47 (1H, dd J 10. 3, 2.6 Hz, Ar), 7.40 (1H, d J 8.3 Hz, Ar), 7.37 (1H, d J 1.7 Hz, Ar), 7.31 (1H, dd J 9.0, 4.6 Hz, Ar), 7.13 (1H, dd J 8.2, 2.0 Hz, Ar), 6.96 (1H, td J 9.3, 2.7 Hz, Ar), 4.32 (2H, s, CH2C02H), 3.93 (2H, s, NCH2 ), 2.49 (3H, s, CH3); Tr = 1.43 min (97%), m / z (ES +) (M + H) + 445.15. Compound 20-Acid [5-f luoro-3- (3-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic dH (400 MHz, d6-DMS0) 10.22 (1H, s, S02NH), 7.60 (1H, dd J 9.9, 2.5 Hz, Ar), 7.50 (1H, dd J 9.1, 4.1 Hz, Ar), 7.05 (2H, m, Ar), 6.61 (2H, m, Ar), 6.50 (1H, d 8.7 Hz, Ar), 4.88 (2H, s, CH2C02H), 3.60 (3H, s, OCH3), 2.54 (3H, s, CH3); Tr = 1.28 min (100%), m / z (ES +) (M + H) + 393. 28. Compound 21-Acid (5-fluoro-2-methyl-3-m-tolylsulfamoyl-indol-1-yl) -acetic dH (400 MHz, d6-DMSO) 10.11 (1H, s, S02NH), 7.61 (1H, dd J 10.1, 2.6 Hz, Ar), 7.55 (1H, dd J 9.1, 4.5 Hz, Ar), 7.08 (1H, dd J 9.2, 2.6 Hz, Ar), 7.03 (1H, d J 7.8, Ar), 6.85-6.81 (2H, m, Ar), 6.76 (1H, d J 7.6 Hz, Ar), 5.08 (2H, s, CH2C02H), 2.50 (3H, s, CH3), 2.15 (3H, s, ArCH3), Tr = 1.33 min (100%), m / z (ES +) (M + H) + 377.24. Compound 22-Acid (5-fluoro-2-methyl-3-p-tolylsulfamoyl-indol-1-yl) -acetic dH (400 MHz, d6-DMS0) 9.90 (1H, broad, S02NH), 7.55 (1H, dd J 10.2, 2.6 Hz, Ar), 7.32 (1H, dd J 9.1, 4. 6, Ar), 6.94 (5H, m, Ar), 4.31 (2H, s, CH2C02H), 2.45 (3H, s, CH3) , 2.15 (3H, s, CH3), Tr = 1.33 min (100%), / z (ES +) (M + H) + 377.25.

Compound 23-Acid [3- (4-Chloro-benzylsulfonyl) -5-f-luoro-2-methyl-indol-1-yl] -acetic dH (400 MHz, d6-DMS0) 8.04 (1H, t J 5.9 Hz , NH), 7.58-7.51 (2H,, Ar), 7.25 (2H, d J 8.6 Hz, Ar), 7.18 (2H, d J 8.6 Hz, Ar), 7.07 (1H, td J 9. 5, 2.7 Hz , Ar), . 07 (2H, s, CH2C02H), 3.93 (2H, d J 6.3 Hz, NCH2) 2.56 (3H, s, CH3); Tr = 1.38 min (91%), m / z (ES +) (M + H) + 411.07. Compound 24-Acid [3- (Benzyl-methyl-sulfamoyl) -5-f-luoro-2-methyl-indol-1-yl] -acetic dH (400 MHz, d6-DMS0) 7.52 (1H, dd J 10.0, 2.6 Hz, Ar), 7.46 (lH, dd J 8.9, 4.4 Hz, Ar), 7.39-7.28 (5H, m, Ar), 7.03 (1H, td J 9.4, 2.8 Hz, Ar), 4.46 (2H, s, CH2C02H), 4.10 (2H, s, NCH2), 2.60 (3H, s, NCH3), 2.48 (3H, s, CH3); Tr = 1.43 min (100%), m / z (ES +) (M + H) + 391.15. Compound 25-Acid [5-fluoro-2-methyl-3- (pyridin-3-ylsulfamyl) -indol-1-yl] -acetic acid dH (400 MHz, de-DMSO) 10.42 (1H, s, S02NH), 8.25 (1H, d J 2.6 Hz, Ar), 8.19 (1H, d, 3.3 Hz, Ar), 7.59-7.55 (2H, m, Ar), 7.40 (1H, d J 8.3Hz, Ar), 7.24-7.21 (2H, m, Ar), 5.10 (2H, s, CH2C02H), 2.49 (3H, s, CH3); Tr = 0.96 min (100%), m / z (ES +) (M + H) + 364.1.

Example 5 - Measurement of Activity CRTH2 Antagonists Materials and Methods Materials Calcium-3 dye was obtained from Molecular Devices (Wokingham, UK). The mono-poly resolution medium was obtained from Dainippon Pharmaceuticals (Osaka, Japan). The anti-CDl6 Macs anti microbeads were from Miltenyi biotec (Bisley, Surrey). ChemoTx plates were obtained from Neuroprobe (Gaithesburg, MD). The 96-well plates coated with poly-D-lysine were obtained from Greiner (Gloucestershire, UK). The [3H] PGD2 was from Amersham Biosciences (Buckinghamshire, UK). [3H] SQ29548 was obtained from Perkin Elmer Life Sciences (Buckinghamshire, UK). All other reagents were obtained from Sigma-Aldrich (Dorset, UK), unless otherwise indicated.

Methods Cell Culture Chinese hamster ovary cells were transfected with CRTH2 or DP receptors (CH0 / CRTH2 and CHO / DP) and were kept in culture in a humid atmosphere at 37 ° C (5% C02) in Minimum Essential Medium (MEM) ) supplemented with 10% fetal bovine serum, 2 M glutamine, and 1 mg ml "1 active G418 cells were passed every 2-3 days.For the radioligand binding assay, the cells were prepared in triple flasks layer or in 175 cm2 square flasks (for membrane preparation) For the calcium mobilization assay, the cells were grown in a 96-well plate 24 hours before the assay at a rate of 80,000 cells per well.

Preparation of cell membranes The membranes were prepared from cellular CHO / CRTH2 and CHO / DP, or from platelets (as sources of TP receptors). CHO cells that grew to confluence were washed with PBS and detached using a Versene solution (15 ml per flask). When the cells grew in 175 cm2 square flasks they were collected by detaching in PBS. The cell suspensions were centrifuged (1,700 rpm, 10 min, 4 ° C) and resuspended in 15 ml of buffer (IxHBSS, supplemented with 10 mM HEPES, pH 7.3). The cell suspensions were then homogenized using an Ultra Turrax set at 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 1 h at 4 ° C. The resulting pellet was resuspended in buffer and stored at -80 ° C in 200-500 μl aliquots. 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 centrifuged directly at 20,000 rpm for 30 minutes. 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. The tests were carried out in a final volume of 100 μl of buffer (1 × HBSS / 10 mM HEPES, pH 7.3). Cell membranes (15 μg). 15mg of cell membranes were preincubated at room temperature with varying concentrations of competent ligand for 15 min. Then [3H] PGD2 (mol, final concentration) and the incubation was continued for 1 hour more at room temperature. The reaction was terminated by the addition of 200 μl of ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF / B glass fiber filters using a Unifilter cell harvester (PerkinElmer Life Sciences) and six washes. 300 μl of ice-cooled buffer. The Unifilter plates were dried at room temperature for at least 1 h and the radioactivity retained on the filters was determined in a Beta Trilux counter (PerkinElmer Life Sciences), following the addition of 40 μl of Optiphase Hi-Safe 3 liquid flasher (Wallac). No non-specific binding was defined in the presence of 10 μ of unlabeled PGD2. The tests were carried out in duplicate. The results of the radioligand binding experiments at the CRTH2 and DP receptors are shown in Table 1. The results shown in Table 1 demonstrate that the compounds of the general formula (I) have high affinity for the CRTH2 receptor. In those cases where a comparison was made, the affinity of the compounds of the general formula of the compounds (I) is much higher than CRTH2 than for the DP receptor.

Table 1 - Radioligand binding data (Ki on the CRTH2 receptor and the DP receptor) Ki Ki binding compound of the CRTH2 nM DP junction μM 192 > 10 75 > 10 2000 ND 2300 ND 89 > 10 209 ND 54 ND 249 ND 254 > 10 10 ND 11 51 > 10 12 45 > 10 13 182 ND 14 225 ND 15 278 > 10 16 771 > 10 17 1450 > 10 18 236 > 10 19 181 > The radioligand binding of the TP receptor was carried out on membranes prepared from platelets. 15-40 μg of protein were pre-incubated with varying concentrations of competent ligand for 15 min at room temperature in assay buffer (10 mM Tris-HCl, pH 7.4, 5 M glucose, 120 mM NaCl, 10 μM indomethacin). Then [3H] SQ29548 (38 Ci / mmol, final concentration of 10 nM) was added and incubation was continued for an additional 30 min at room temperature. The reaction was terminated by the addition of 200 μl of ice-cold assay buffer to each well, followed by rapid filtration through Whatman GF / C glass fiber filters using a Unifilter cell harvester (PerkinElmer Life Sciences) followed by six washed 300 μl of ice-cooled buffer. The radioactivity was determined as described above. All the compounds studied in that assay were bound to the TP receptor with low affinity (Ki> 10 μM). The compounds of general formula (I) were bound to the CRTH2 receptor expressed in CHO cells with a variable affinity range of very high to moderate. Indeed, Ki values determined in the competition against [3 H] PGD2 ranged from 500 pM to 1 μM. The compounds of general formula (I) had no activity (or very weak activity) at the DP and TP receptors. The binding selectivity of the compounds of general formula (I) for the CRTH2 receptor was greater than 200 times for the CRTH2 receptor, compared to that of the DP and TP receptors.

Calcium mobilization assay Cells were seeded onto 96-well plates coated with poly-D-lysine at a density of 80,000 cells per well and incubated at 37 ° C overnight to allow the cells to adhere. The cells were washed twice with HBSS and incubated for 1 h at 37 ° C in 100 μl of HBSS and 100 μl of calcium-3-dye solution (Molecular Devices), supplemented with probenecid 4mM. Changes in fluorescence were verified over a 50 s time course with addition of agonist at 17 s using a Flexstation (Molecular Devices).

Effect of CRTH2 agonists on calcium mobilization of C-O-CRTH2 cells PGD2 produced a dose-dependent increase in intracellular Ca2 + mobilization in CH0 / CRTH2 cells, with an EC50 = 2.4 + 0.5nM (n = 3) (Figure 1).

Effect of the compounds of general formula (I) on the mobilization of calcium induced by PGD? The flow of Ca2 + stimulated by PGD2 was completely inhibited by the compounds of general formula (I) and the IC 50 value for each compound in the calcium assay was comparable to its Ki value in the radioligand binding. The IC 50 values of the compounds of general formula (I) ranged from 5 nM to 1 μM. The results for the different compounds of general formula (I) are shown in Table 2. The increase in the dose of the compounds of general formula (I) produced a dose-dependent and parallel deviation of the dose response curve of PGD2 in CH0 / CRTH2 cells, thus indicating that the compounds are repetitive antagonists of CRTH2. The antagonistic effect of the compounds of formula (I) appears to be selective for CRTH2 since no inhibitory effect was observed with the Ca2 + flux stimulated by ATP in CHO / CRTH2 cells.

Table 2 - Inhibition of calcium flux induced by PGD2

Claims (30)

1. NOVELTY OF THE INVENTION Having described the invention as above, property is claimed as contained in the following:
2. CLAIMS A compound of general formula (I) characterized in that R1, R2, R3 and R4 are independently hydrogen, halo, C? -C6 alkyl, -O (C? -C6 alkyl), -CON (R9) 2, -SOR9, -S02R9, -S02N (R9) ) 2, -N (R9) 2, -NR9COR9, -C02R9, -COR9, -SR9, -OH, -N02 or -CN; each R9 is independently hydrogen or C6-C6 alkyl; R5 and R6 are each independently hydrogen, or C? -C6 alkyl or together with the carbon atom which is attached form a C3-C7 cycloalkyl group;
3. R7 is hydrogen or C? -C6 alkyl is 1 or 2; X is a bond, when n is 2, X may also be a group NR9; where R9 is as defined above; when X is a bond R8 is a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 5 alkynyl, biphenyl or a bicyclic heteroaryl group or 9-14 member tricyclic; when X is a group NR9 and R8 can additionally be phenyl, naphthyl or a 5-7 membered hetero aromatic ring; and the R8 group is optionally substituted with one or more substituents selected from halo, Cx-Ce alkyl, -O (Ci-Cß) alkyl / aryl, -O-aryl, heteroaryl, -O-heteroaryl, -SOR9, - S02R9, S02N (R9) 2, -NR9COR9, -C02R9, -COR9, -SR9, -OH, -N02O-CN; where R9 is as defined above; or a salt, hydrate, solvate, complex or prodrug thereof. 2. A compound of general formula (II): characterized in that R1, R2, R3, R4, R5, R6, n, X, R7 and R8 are as defined for the general formula (I); R10 is C? -C6 alkyl, aryl, (CH2) mOC (= 0) C? -C6 alkyl, (CHZJH? R11) ^ CH ((CH2) mO (C = 0) R12) 2; m is 1 or 2; R11 is hydrogen or methyl; R12 is C? -C? Alkyl. 3. The compound according to claim 1 or claim 2, characterized in that, independently or in any combination: R1 is halo or hydrogen; R2 is halo or hydrogen; R3 is halo or hydrogen; R4 is halo or hydrogen;
4. 4. The compound according to any of claims 1 to 3, characterized in that R1, R3 and R4 are hydrogen and R2 is halo.
5. 5. The compound according to claim 4, characterized in that R2 is fluorine.
6. 6. The compound according to any of claims 1 to 5, characterized in that R5 and R6 are each independently hydrogen or C? _C alkyl.
7. 7. The compound according to claim 6, characterized in that at least one of R5 and R5 are hydrogen.
8. 8. The compound according to claim 7, characterized in that both of R5 and R6 are hydrogen.
9. 9. The compound according to any of claims 1 to 8, characterized in that R7 is H or Ci-Cß alkyl.
10. 10. The compound according to claim 9, characterized in that R7 is methyl.
11. 11. The compound according to any of claims 1 to 10, characterized in that n is 2.
12. 12. The compound according to any of claims 1 to 11, characterized in that X is a bond and R8 is C-Ce alkyl. , biphenyl or a bicyclic heteroaryl group, any of which may be substituted by halogen, phenyl, -C02R9 CON (R9) 2 or -S02R9, where R9 is as defined above.
13. 13. A compound according to claim 12, characterized in that R8 is C-C4 alkyl, biphenyl, a bicyclic heteroaryl group or a 5-7 membered heterocyclic ring, any of which may be substituted with phenyl, -C02R9 CON (R9) ) 2 or -S02R9, where R9 is H or C? -C4 alkyl. A compound according to any of claims 1 to 11, characterized in that X is NR9, R9 is H or methyl and R8 is: phenyl optionally substituted with one or more halo groups, C-Ce alkyl or -O (alkyl) of C? -C6) Ci-Ce alkyl, optionally substituted with aryl; or heteroaryl. 15. The compound according to claim 14, characterized in that R8 is phenyl, benzyl or pyridyl, any of which may be optionally substituted with one or more halo, methyl or methoxy groups. 16. [3- (Butan-1-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid. 3- (Biphenyl-4-sulfonyl) -5-fluoro-2-methyl-indole acid -1-yl] - acetic acid (3-Carboxymethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid (3-carbamoylmetanesulfonyl-5-fluoro-2-methyl-indol-1-yl) - acetic acid [5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid [3- (Benzothiazole-2-sulfonyl) -5-fluoro-2-methyl-indole -1-yl] - acetic acid [3- (Benzothiazol-2-sulfinyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid [5-fluoro-2-methyl-3- (quinoline- 2- sulfonyl) -indol-1-yl] -acetic acid [5-Fluoro-2-methyl-3- (quinolin-8-ylsulfonyl) -indol-1-yl] -acetic acid (5-fluoro-2-methyl) -3-phenylmetanesulfonyl-lH-indol-1-yl) -acetic acid [3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid [3- (3- Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid [3- (4-Fluoro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid [3- (2-Chloro-fe nilsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid (3-Benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid [5-fluoro-3- ( 2-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid [5-Fluoro-3- (4-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid (5-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid -fluoro-2-methyl-3-phenylsulfamoyl-indol-1-yl) -acetic acid [3- (3,4-Dichloro-benzylsulfamoyl) -5- fluoro-2-methyl-indol-l-yl] -acetic acid [5-fluoro-3- (3-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid (5-fluoro-2-methyl-3-m-tolylsulfamoyl-indol-1-yl) - acetic Acid (5-fluoro-2-methyl-3-p-tolylsulfamoyl-indol-1-yl) -acetic acid [3- (4-Chloro-benzylsulfamoyl) -5-fluoro-2-methyl-indole-1-yl ] -acetic acid [3- (benzyl-methyl-sulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid [5-fluoro-2-methyl-3- (pyridin-3-ylsulfamoyl)] -indol-1-il] -acetic; or the alkyl esters of C? -C6, aryl, (CH2) OC (= 0) C, -alkyl of C? -C6, (CH2) mN (R11) 2, CH ((CH2) mO (C = 0 ) R12) 2 of any of the foregoing; where m is 1 or 2; R11 is hydrogen or methyl; R12 is C? -C18 alkyl. 17. A process for the preparation of a compound of general formula (I) according to any of claims 1 to 13 or 16, wherein n is 1 or 2 and X is a bond, the process is characterized in that it comprises a compound of general formula (la), which is a compound of general formula (I) wherein n is = and X is a bond, by oxidation with a suitable oxidizing agent. 18. A process for the preparation of a compound of formula (I) according to any of claims 1 to 16, characterized in that the process comprises reacting a compound of general formula (II) according to claim 2 and wherein R10 is Ci-Cß alkyl with a base. 19. The compound according to any of claims 1 to 16 for use in medicine. The compound according to any one of claims 1 to 16 for use in the treatment of allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis , eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other diseases mediated by PGD2, for example autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematosus, psoriasis, acne , multiple sclerosis, allograft rejection, reperfusion injury and chronic obstructive pulmonary disease or rheumatoid arthritis, psoriatic arthritis and osteoarthritis. 21. The use of a compound according to any of claims 1 to 16 in the preparation of an agent for the treatment or prevention of allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including dermatitis) contact), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis and Crohn's disease, mastocytosis and also other diseases mediated by PGD2, for example, autoimmune diseases such as the syndrome hyper IgE and systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease or rheumatoid arthritis, psoriatic arthritis and osteoarthritis. 22. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1 to 16 together with a pharmaceutical excipient or carrier. 23. The composition according to claim 22, characterized in that it is formulated for oral, rectal, nasal, bronchial (inhaled), topical (including eye, buccal and sublingual drops) vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal). 24. A composition according to claim 23, characterized in that it is formulated for oral, nasal, bronchial or topical administration. 25. The composition according to any of compositions 22 to 24 characterized in that it contains one or more additional active agents useful in the treatment of diseases and conditions mediated by PGD at the CRTH2 receptor. 26. The composition according to claim 25, characterized in that the additional active agents are selected from: ß2 agonists such as salmeterol; corticosteroids such as fluticasone; antihistamines such as loratidine; leukotriene antagonists such as montelukast; therapies with anti-IgE antibody such as omalizumab; anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); antifungals such as clotrimazole (particularly for the treatment of atopic dermatitis); immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease; other PGD2 antagonists that act on other receptors as DP antagonists; phosphodiesterase type 4 inhibitors such as cilonilast; drugs that modulate the production of citone as inhibitors of the TNFa converting enzyme (TACE); drugs that modulate the activity of the Th2 cytokines IL-4 and IL-5 as blocking monoclonal antibodies and soluble receptors; PPAR-agonists and such as rosiglitazone; 5-lipoxygenase inhibitors such as zileuton. 27. A process for the preparation of a pharmaceutical composition according to any of claims 22 to 26, characterized in that it comprises binding a compound according to any of claims 1 to 16 in conjunction with an association with a support or vehicle pharmaceutically or veterinarily acceptable. 28. A product, characterized in that it comprises a compound according to any of claims 1 to 16 and one or more of the agents listed in claim 26 with a combined preparation for simultaneous, separate or sequential use in the treatment of a disease or condition mediated by the action of PGD at the CRTH2 receptor. 29. The use according to claim 21, wherein the agent also comprises the additional active agent useful for the treatment of diseases and conditions mediated by PGD2 at the CRTH2 and / or DP receptor. 30. Use in accordance with the claim 29, where the additional active agent is one of the agents listed in claim 26.