MXPA01007704A - Indole derivatives and their use as mcp-1 antagonists - Google Patents

Abstract

A compound of formula (I) wherein R1 is hydrogen, halo or methoxy;R2 is hydrogen, halo, methyl, ethyl or methoxy;R3 is carboxy, tetrazolyl, or -CONHSO2R4 where R4 is methyl, ethyl, phenyl, 2, 5-dimethylisoxazolyl or trifluoromethyl;T is -CH2- or -SO2-;and ring A is 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrid-5-yl;or a pharmaceutically acceptable salt or prodrug thereof, as well as pharmaceutical compositions containing them are described and claimed. These compounds and compositions are useful in the treatment of disease mediated by monocyte chemoattractant protein-1 or RANTES (Regulated Upon Activation, Normal T-cell Expressed and Secreted), such as inflammatory disease.

Description

INDOL DERIVATIVES AND THEIR USE AS MCP-I ANTAGONISTS The present invention relates to anti-inflammatory compounds that act by receptor antagonism CCR2, (also known as the MCP-1 receptor), which leads inter alia to inhibition of monocyte chemoattractant Protein-1 (MCP-1). These compounds contain an indole moiety. The invention also relates to pharmaceutical compositions containing them, to processes for their preparation, to intermediates useful in their preparation and to their use as therapeutic agents. MCP-1 is a member of the chemosin family of pro-inflammatory proteins that mediate chemotaxis and leukocyte activation. MCP-1 is a C-C chemosin which is one of the most potent and selective activators and chemoattractants of monocytes and known T cells. MCP-1 has been implicated in the pathophysiology of a large number of inflammatory diseases, including rheumatoid arthritis, glomerular nephritis, pulmonary fibrosis, restenosis (International Patent Application WO 94/09128), alveolitis (Jones et al., 1992, J. Im. unol., 149, 2147) and asthma. Other disease areas where MCP-1 is considered to play a part in its pathology are atherosclerosis (e.g. Koch et al., 1992, J. Clin. Invest., 90, 772-779), psoriasis.

(Deleuran et al., 1996, J. Dermatological Science, 13, 228-236), delayed-type skin hypersensitivity reactions, inflammatory bowel disease (Grimm et al., 1996, J. LeuJcocyte Biol., 59, 804- 812), multiple sclerosis and brain trauma (Berman et al., 1996, J. Iwmunol., 156, 3017-3023). An inhibitor of MCP-1 can also be useful for treatment of attack, reperfusion injury, ischemia, myocardial infarction and transplant rejection. MCP-1 acts through the CCR2 receptor. MCP-2 and MCP-3 can also act at least in part, through this receptor. Therefore in this specification, when reference is made to "inhibition or antagonism of MCP-1" or "effects mediated by MCP-1" this includes inhibition or antagonism of effects mediated by MCP-2 and / or MCP-3, when MCP-2 and / or MCP-3 act through the CCR2 receiver. Applicants have found a class of compounds containing an indole moiety, which have useful inhibitory activity against MCP-1. Co-pending application UK 9716657.3 describes a class of indoles with inhibitory activity of MCP-1. This application is based on the surprising discovery that particular substituted 5-hydroxy indoles are inhibitors of MCP-1 which possess unexpected and beneficial properties with respect to potency and / or blood levels and / or bioavailability and / or solubility. Accordingly, the present invention provides a compound of the formula (I): (l) wherein: R1 is hydrogen, halo or methoxy; R2 is hydrogen, halo, methyl, ethyl or methoxy; R3 is carboxy, tetrazolyl or -CONHS02R4 wherein R4 is methyl. ethyl, phenyl, 2,5-dimethylisoxazolyl or trifluoromethyl; T is -CH2- or -S02-; and ring A is 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl. 3 - . 3-Fluoro-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrid-5-yl; or its pharmaceutically acceptable salt or prodrug. In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific only to the straight chain version. The term "halo" refers to fluorine, chlorine, bromine and iodine. Particular novel compounds of the invention include, for example, compounds of the formula (I), or their pharmaceutically-acceptable salts or prodrugs, wherein, unless otherwise stated: a) R1 has any of the values defined in i) - iii) below or a combination of two of these values; b) R2 has any of the values defined in iv) - viii) below or a combination of two of these values; c) R3 has any of the values defined in ix) - xi) below or a combination of two of these values; e) T has any of the values defined in xii) - xiii) below; f) ring A has any of the values defined in xiv) - xxi) below or a combination of two or more of these values; i) R1 is hydrogen; ii) R1 is halo; iii) R1 is methoxy; iv) R2 is hydrogen; v) R2 is halo; vi) R2 is methyl; vii) R2 is ethyl; viii) R2 is methoxy; ix) R3 is carboxy; x) R3 is tetrazolyl; xi) R3 is -CONHS02R4 wherein R4 is methyl, ethyl, phenyl, 2,5-dimethylisoxazolyl or trifluoromethyl; xii) T is -CH2-; xiii) T is -S02-; xiv) Ring A is 3-chlorophenyl; xv) Ring A is 4-chlorophenyl; xvi) Ring A is 3-trifluoromethylphenyl; xvii) Ring A is 3,4-dichlorophenyl; xviii) Ring A is 3,4-difluorophenyl; xix) Ring A is 3-fluoro-4-chlorophenyl; xx) Ring A is 3-chloro-4-fluorophenyl; and xxi) Ring A is 2,3-dichloropyrid-5-yl. Preferably R1 'is hydrogen. Preferably R2 is hydrogen. Preferably R3 is carboxy. Preferably T is -CH2-. Preferably ring A is 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl or 3-chloro-4-fluorophenyl. More preferably Ring A is 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl or 3-chloro-4-fluorophenyl. For example, Ring A is 3,4-dichlorophenyl or 3-chloro-4-fluorophenyl. In another aspect of the invention preferably Ring A is 3,4-dichlorophenyl, 2,3-dichloropyrid-5-yl or 3-chloro-4-fluorophenyl.

Therefore, in a preferred aspect of the invention there is provided a compound of the formula (I) as illustrated above, wherein: R 1 is hydrogen; R2 is hydrogen; R3 is carboxy; T is -CH2-; and Ring A is 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl or 3-chloro-4-fluorophenyl, in particular 3,4-dichlorophenyl or 3-chloro-4-fluorophenyl; or its pharmaceutically acceptable salt or prodrug. Preferred compounds of the invention include any of the Examples. More preferred compounds of the invention are Examples 1, 3 and 4, for example, Examples 1 and 3. The invention furthermore relates to all tautomeric forms of the compounds of the formula (I). It will also be understood that certain compounds of the formula (I) can exist in solvated as well as non-solvated forms such as for example hydrated forms. It will be understood that the invention encompasses all these solvated forms. The compounds of the formula (I) are inhibitors of monocyte chemoattractant protein-1. In addition, it seems to inhibit RANTES-induced chemotaxis. RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted = Regulated before Activation, Expressed and Secreted of Normal T Cell) is another chemosin from the same family as MCP-1, with a similar biological profile, but acting through the CCRl receiver. As a result, these compounds can be used to treat disease mediated by these agents, in particular inflammatory disease. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include base salts such as an alkali metal salt eg sodium, an alkaline earth metal salt, for example calcium or magnesium, an organic amine salt eg triethylamine, morpholine , N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, I., _. Dibenzylethylamine or amino acids for example lysine. In another aspect, wherein the compound is sufficiently basic, suitable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. There may be more than one cation or anion depending on the number of charged functions and the valence of the cations or anions. A preferred pharmaceutically acceptable salt is a sodium salt. Several forms of prodigies are known in the specialty. For examples of these prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al., (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.

Bundgaard, Chapter 5"Design and Application of Prodrugs" (Design and Application of Prodrogas), by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8., 1-38 (1992); d) H. Bundgaard, et al. , Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al. , Chem Pharm Bull, 32, 692 (1984). Examples of these prodrugs are in vivo cleavable esters of a compound of the invention. An in vivo cleavable ester of a compound of the invention containing a carboxy group, for example is a pharmaceutically-acceptable ester that is cleaved in the human or animal body to produce the main acid. Suitable pharmaceutically-acceptable esters for carboxy include alkyl having 1 to 6 carbon atoms-esters, for example methyl or ethyl; C 1 -C 6 -alkoxy methyl esters, for example methoxymethyl; C 1 -C 6 -alkanoyloxy-methyl esters, for example pivaloi loxymethyl; phthalidyl esters; cycloalkoxycarbonyloxy with 3 to 8 carbon atoms-alkyl having 1 to 6 carbon atoms, for example 1-cyclohexylcarbonyloxyethyl; 1, 3-dioxolan-2-ylmethyl esters, for example 5-methyl-l, 3-dioxolan-2-ylmethyl; C 1 -C 6 alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl; aminocarbonylmethyl esters and their mono- or di- N- (C1-C6 alkyl) versions thereof, for example N, N-dimethylaminocarbonylmethyl esters and N-ethylaminocarbonylmethyl esters; and can be formed in any carboxy group in the compounds of this invention. An in vivo cleavable ester of a compound of the invention containing a hydroxy group, for example, is a pharmaceutically-acceptable ester that is cleaved in the human or animal body to produce the major hydroxy group. Suitable pharmaceutically acceptable esters for hydroxy include alkanoyl with 1 to 6 carbon atoms-esters, for example acetyl esters; and benzoyl esters wherein the phenyl group may be substituted with aminomethyl or mono- or di-alkyl having 1 to 6 carbon atoms, N-substituted, for example 4-aminomethylbenzoyl esters and 4-N, N-dimethylaminomethylbenzoyl esters. Additional examples of these prodrugs are cleavable amides in vivo of a compound of the invention. Examples of these cleavable amides in vivo include N-alkylamide with 1 to 6 carbon atoms and N, N-di- (C1-C6 alkyl) such as N-methyl, N-ethyl, N-propyl, N , N-dimethyl, N-ethyl-N-methyl or N, N-diethylamide. Another aspect of the present invention provides a process for the preparation of the compound of formula (I) or its pharmaceutically acceptable salt or prodrug, this process (wherein R1, R2, R3, T and Ring A are as defined for Formula (I) unless otherwise stated) comprises: a) reacting compounds of formula (II): (ll) wherein Ra is R3 or R3 protected and R is hydrogen or a suitable hydroxy protecting group with compound of the formula (III): Tdi ") wherein L is a displaceable group, and subsequently, if necessary: i) converting a compound of the formula (I) to another compound of the formula (I), ii) removing any protective groups, or iii) forming its pharmaceutically acceptable salt or prodrug Suitable values for L are for example a halogen or sulfonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group Specific reaction conditions for the above reactions are as follows: a) Compounds of the formula (II) and (III) can be reacted together in an inert solvent and a base such as N, N-dimethylformamide / sodium hydride or dichloromethane / sodium hydroxide or potassium acetonitrile-carbonate, or in the presence of a phase transfer catalyst such as tetra-n-butylammonium hydrogen sulfate The reaction is conveniently carried out for 1 to 6 hours preferably 1-3 hours, at a temperature of 15-30 ° C preferably 20- 25 ° C for give a compound of the formula (I). Compounds of the formula (II) may be commercially available, or they may be made by modification using known processes of commercially available compounds of the formula (II), or they may be prepared by the following procedures: Processes i) Reaction a compound of the formula (IV) wherein Rb is as defined above with a compound of the formula (V) (V) wherein Rc is alkyl with 1 to 4 carbon atoms. Compounds of formula (IV) and (V) are reacted together under Reissert reaction conditions such as in an inert solvent (such as tetrahydrofuran), in the presence of a base (such as potassium ethoxide) at a temperature range of 15-30 ° C preferably 20-25 ° C, for 10-20 hours preferably 15-17 hours. The resulting compound is isolated and dissolved in an alcohol such as ethanol and an organic acid (such as acetic acid) and a transition metal catalyst (such as 10% Pd / C) and cyclohexene is added. The mixture is heated to a temperature of 60-120 ° C, preferably 70-90 ° C for 15-25 hours, preferably 16-20 hours, to give a compound of the formula (II) wherein Ra is -C02-alkyl with 1 to 4 carbon atoms. Process (ii) React a compound of the formula (VI): wherein Rb is as defined above, with a compound of the formula (VII): (Vile) wherein Rd is alkyl with 1 to 4 carbon atoms. Compounds of the formula (VI) and (VII) are reacted together under Fischer conditions such as with an organic acid (such as acetic acid), in an alcohol (such as ethanol), at a temperature of 60-90 ° C, preferably 75-85 ° C, for 1-5 hours, preferably 1-3 hours. The resulting compound is mixed with a strong acid (such as polyphosphoric acid) and heated at 90-150 ° C, preferably 100-120 ° C, for 0.5-4 hours, preferably 0.5-2 hours to give a compound of the Formula (II) wherein R2 is hydrogen. Then, if desired, R2 can be optionally converted to another value of R2 as defined in formula (I) using techniques known in the art such as those described below. Process (iii) Cyclization of a compound of the formula (VIII) (VIII) wherein R1, Ra, R and R2 are as defined above. Cyclization can be effected upon refluxing the compound in an inert solvent such as xylene. Compounds of the formula (VIII) are conveniently prepared by reacting a compound of the formula (IX) wherein R1, R2 and Rb are as defined above, with a compound of the formula (X) I 3 Ra (X) where Ra is as defined above. The reaction is conveniently carried out in an organic solvent such as an alcohol, in particular methanol, in the presence of a base such as an alkali metal alkoxide, in particular sodium methoxide. Moderate temperatures of -30 to 20 ° C are conveniently used. Process (iv) Still in a further modification, the compounds of the formula (II) are prepared by cyclization of a compound of the formula (XI) (XI) wherein R1 and Rb are as defined above, R7 is alkyl, such as methyl, and R8 is a carboxy protective group such as alkyl, in particular methyl.

The cyclization is conveniently carried out under Japp Klingemann conditions, by heating a solution of the compound in an organic solvent such as toluene and a convenient acid, such as p-toluene sulphonic acid. Compounds of the formula (XI) are conveniently prepared by reacting a compound of the formula (XII) (XII) wherein R1, Rb, R5 and R6 are as defined above, with a compound of the formula (XIII) (XIII) wherein R7 and R8 are as defined in relation to formula (XI). The compound of the formula (XII) is conveniently dissolved in a dilute acid such as 1.5N HCl in the presence of a nitrite such as sodium nitrite at moderately low temperatures of -30 to 0 ° C, preferably -5 ° C.

This solution is then mixed with a solution of a compound of the formula (XIII) in an organic solvent such as ethanol, in the presence of a solution of a base such as alkali metal hydroxide, for example aqueous sodium hydroxide solution. Compounds of the formulas (III), (IV), (V), (VI), (VII), (VIII), (X), (XII) and (XIII) are known or commercially available or prepared by methods known in the art by standard handling of known or commercially available materials. R ° and R are alkyl with 1 to 4 carbon atoms. Preferably Rc and Rd are methyl or ethyl. It will also be appreciated that in some of the reactions mentioned herein, it may be necessary / convenient to protect any sensitive groups in the compounds. Cases where protection is necessary or convenient and methods suitable for protection are known to those skilled in the art. Thus, if the reactants include groups such as carboxy or hydroxy, it may be convenient to protect the group in any of the reactions mentioned herein. A suitable protecting group for a hydroxy group for example is an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the selection of the protecting group. In this way, for example an acyl group such as an alkanoyl or aroyl group can be removed, for example by hydrolysis with a convenient base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group can be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group, for example, is an esterifying group, for example a methyl or ethyl group which can be removed, for example by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which it can be removed for example by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which can be removed for example by hydrogenation on a catalyst such as palladium-on-carbon. The protecting groups can be removed at any convenient stage in the synthesis, using conventional techniques well known in the chemical art. Some of the intermediates described herein may be novel, for example intermediates of the formula (II), and as such are provided as a further feature of the invention.

When a pharmaceutically-acceptable salt of a compound of the formula (I) is required, it can be obtained for example, by reaction of a compound with the appropriate acid (which produces a physiologically acceptable anion) or with the appropriate base (which produces a cation). physiologically acceptable) or by any other conventional salt formation process. According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) as previously defined or its pharmaceutically acceptable salt or prodrug, in association with a pharmaceutically acceptable carrier or excipient. The compositions of the invention may be in a form suitable for oral use (for example as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, powders or dispersible granules, syrups or elixirs), for topical use (for example as creams, ointments, gels or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration ( for example as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate, granulating and disintegrating agents such as corn starch, or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p_-hydroxybenzoate, and anti-oxidants such as ascorbic acid. Tablet formulations can be uncoated or coated either to modify their disintegration and the absorption subsequence of the active ingredient within the gastrointestinal tract or to improve their stability and / or appearance, in any case using conventional coating agents and well-known procedures in the specialty. Compositions for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin or as soft gelatin capsules wherein the active ingredient is mix with water or an oil such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions generally contain the active ingredient in finely pulverulent form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethylene oxyketanol or condensation products, ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxyketanol or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate), anti-oxidants (such as ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (such as sucrose, saccharin or aspartame) . Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). Oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those established above and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water, generally contain the active ingredient together with a wetting or dispersing agent, suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-petticoat emulsions. The oily phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Convenient emulsifying agents, for example may be gums of natural origin such as acacia gum or tragacanth gum, phosphatides of natural origin such as soybean, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides (eg sorbitan monooleate ) and condensation products of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulgent, preservative, flavoring and / or coloring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension which can be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been previously mentioned. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions can generally be obtained by formulating an active ingredient with a conventional, topically acceptable vehicle or diluent, using a method well known in the art.

Compositions for administration by insufflation may be in the form of particles containing finely divided powder with average diameter for example of 30 μ or much less, the powder itself already comprises an active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose . The powder for insufflation is then conveniently retained in a capsule containing for example 1 to 50 mg of active ingredient for use with a turbo-inhaler device such as is used to insufflate the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to deliver the active ingredient either as an aerosol containing liquid droplets or finely divided solids. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be employed and an aerosol device is conveniently arranged to deliver a metered amount of active ingredient. For more information regarding formulation the reader is referred to chapter 25.2 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch: Chairman of the Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 mg to 2 g of active agent, formulated with an appropriate and convenient amount of excipients which may vary from about 5 to about 98% by weight of the total composition. Unit dosage forms will generally contain about 1 mg to about 500 mg of active ingredient. For more information regarding Administration Routes and Dosage Regimens, refers to the reader to Chapter 25.3 in Volume 5 of (Broad Medicinal Chemistry) (Corwin Hansch: Chairman of the Editorial Board), Pergamon Press 1990. The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will vary naturally according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, in accordance with well-known medicine principles. As mentioned above, compounds of formula I are useful for treating diseases or medical conditions that are due only or in part to the effects of farnesylation of rats. When using a compound of the formula I for therapeutic or prophylactic purposes, it will generally be administered in such a way that a daily dose in the range, for example, 0.5 mg to 75 mg, per kg of body weight, is received if required. divided doses. In general, lower doses will be administered when a parenteral route is used. Thus, for example for intravenous administration, a dose in the range of, for example, 0.5 mg to 30 mg per kg of body weight will generally be employed. Similarly for administration by inhalation, a dose in the range of, for example, 0.5 mg to 25 mg per kg of body weight will be employed. However, oral administration is preferred. According to a further aspect of the present invention, there is provided a compound of the formula (I) or its pharmaceutically acceptable salt or prodrug, as previously defined for use in a method for the treatment of the human or animal body by therapy. Conveniently, the invention provides a method for treating inflammatory disease by administering a compound of formula (I) or its pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition thereof as described above. A further feature of the present invention is a compound of the formula (I) and or its pharmaceutically acceptable salt or prodrug, for use for use as a medicament. Conveniently this is a compound of the formula (I), or its pharmaceutically acceptable salt or prodrug, to be used as a medicament for antagonizing an effect mediated by MCP-1 in a warm-blooded animal such as a human. Thus in accordance with a further as of the invention, there is provided the use of a compound of the formula (I), or its pharmaceutically acceptable salt or prodrug, in the production of a medicament for use in antagonizing an effect mediated by MCP. -1 in a warm-blooded animal such as a human being. According to a further as of the invention there is provided a method for antagonizing an effect mediated by MCP-1 in a warm-blooded animal such as a human being requiring such treatment, which comprises administering to said animal an effective amount of a compound of the formula (I), or its pharmaceutically acceptable salt or prodrug, as previously defined. Biological Tests The following methods of biological tests, data and Examples serve to illustrate the present invention. ATCC American Type Culture Collection, American Type Culture Collection, Rockville, USA. BCA Bicinchronic acid (used with copper sulfate for protein assay) BSA Bovine serum albumin DMEM Dulbecco-modified Eagle medium EGTA Ethylenebis (oxyethylenetrnitrile) tetraacetic acid FCS Fetal calf serum HEPES Acid (N- [2-Hydroxy et il] pipera zi na -N '- [2-ethanesulfonic acid] HBSS Hank balanced salt solution hMCP-1 Protein 1 human monocyte chemoattractant PBS Phosphate buffer phosphate PCR AMPLITAQ ™ polymerase chain reaction, available from Perkin-Elmer Cetus. it is used as the source of thermo-stable DNA polymerase. Binding buffer or binder is 50 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.5% fetal bovine serum adjusted to pH 7.2 with 1 M NaOH. Amino Non-essential acids (100X concentrate) is: L-Alanine, 890 mg / 1; L-Asparagine, 1320 mg / 1; L-Aspartic acid, 1330 mg / 1; L-Glutamic acid, 1470 mg / 1; Glycine, 750 mg / 1; L-Proline, 1150 mg / 1 and; L-Serine, 1050 mg / 1. Thymidine and hypoxanthine supplement (50x concentrate) is: hypoxanthine, 680 mg / 1 and; thymidine, 194 mg / 1. Penicillin-streptomycin is: Penicillin G (sodium salt); 5000 units / ml; streptomycin sulfate, 5000 μg / ml. Human monocytic cell line THP-1 cells available from ATCC, access number TIB-202. Hank's balanced salt solution (HBSS) is obtained from Gibco; see Proc. Soc. Exp. Biol. Med., 1949, 71, 196. Synthetic cell culture medium, RPMI 1640 is obtained from Gibco; contains inorganic salts [Ca (N03) 2.4H20100 mg / 1; KCl 400 mg / 1; MgSO4.7H20 100 mg / 1; NaCl 6000 mg / 1; NaHCO3 2000 mg / 1 & Na2HP04 (anhyd) 800 mg / 1]. D-Glucose 2000 mg / 1, reduced glutathione mg / 1, amino acids and vitamins.

FURA-2 / AM is l- [2- (5-carboxyoxazol-2-yl) -6-aminobenzofuran-5-oxyl-2- (2'-amino-5 '-methylphenoxy) -ethane-N-pentaacetoxymethyl ester , N, N ', N' -tetraacetic and is obtained from Molecular Probes, Eugene, Oregon, USA. Blood sedimentation buffer contains 8. 5g / l NaCl and 10g / l of hydroxyethyl cellulose. Lysis buffer is 0.15M NH4C1. "LOmM KHC03, lmM EDTA. Binding buffer or whole cell binder is 50 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.5% BSA, 0.01% NaN3, adjusted to pH 7.2 with 1M. NaOH Wash buffer is 50mM HEPES, lmM CaCl3, 5mM MgCl2, thermo-inactivated FCS, 0.5% 0.5-MNaCl adjusted to pH7.2 with 1M NaOH General molecular biology procedures can be followed by any of the methods described in "Molecular Cloning - A Laboratory Manual "(Molecular Cloning-A Laboratory Manual) Second Edition, Sambrook, Fritsch and Maniatis [Cold Spring Harbor Laboratory, 1989] i) Cloning and expression of hMCP-1 receptor The MCP-B receptor cDNA 1 (CCR2B) is cloned by PCR from THP-l cell RNA using convenient oligonucleotide primers based on the published MCP-1 receptor sequences (Charo et al., 1994, Proc.

Nati Acad. Sci. USES. 91, 2752). The resulting PCR products were cloned into the PCR-II ™ vector (Invitrogen, San Diego, CA.). CDNA free CCR2B error was sub-cloned as a fragment III-Not I in the eucaryotic expression vector pCDNA3 (Invitrogen) to generate pCDNA3 / CC-CKR2A and pCDNA3 / CCR2B, respectively. Linearized pCDNA3 / CCR2B DNA is transfected into CHO-K1 cells by calcium phosphate precipitation (Wigler et al., 1979, Cell (Cell), 16, 777). The transfected cells were selected by the addition of Geneticin sulfate (G418, Gibco BRL) at 1 mg / ml, 24 hours after the cells were transfected. Preparation of RNA and staining Northern are carried out as previously described (Needham et al., 1995, Prot. Express. Purific., 6, 134). Clone 7 CHO-Kl (CHO-CCR2B) is identified as the highest MCP-1 receptor B expressor. ii) Preparation of membrane fragments CHO-CCR2B cells were developed in DMEM supplemented with 10% fetal calf serum, 2 mM glutamine, non-essential amino acids 1 x, thymidine supplement and hypoxanthine 1 x and Penicillin-streptomycin (at 50 μg of streptomycin / ml, Gibco BRL). Membrane fragments were prepared using differential centrifugation / cell lysis methods as previously described (Sicilian and collaborators, 1990, "Biol. Chem., 265, 19658).

The protein concentration is estimated by BCA protein assay (Pierce, Rockford, Illinois) according to the manufacturer's instructions. iii) Assay MCP-1 125I is prepared using the conjugation of Bolton and Hunter (Bolton et al., 1973. Biochem. J., 133, 529; Amersham International foot]. Equilibrium binding assays were carried out using the method of Ernst et al., 1994, J. Immunol, 152, 3541. Briefly, various amounts of 125 I-labeled MCP-1 were added to 7 μg of CH0-CCR2B cell membranes. purified in 100 μl of link buffer. After 1 hour of incubation at room temperature, the binding reaction mixtures were filtered and washed 5 times through a plate washer (Brandel MLR-96T cell harvester) using ice-cooled binding buffer. Filter mats (Brandel GF / B) were pre-impregnated for 60 minutes in 0.3% polyethyleneimine before use. After filtration, individual filters were separated in 3.5 ml tubes (Sarstedt No. 55,484) and MCP-1 labeled with 125 I ligated is determined (LKB 1277 Gammamaster). Cold competition studies were conducted as before using MCP-1 labeled with 100 pM 125 I in the presence of varying concentrations of unlabelled MCP-1.

Non-specific binding is determined by the inclusion of a 200-fold molar excess of MCP-1 not labeled in the reaction. Ligand binding studies with membrane fragments prepared from CHO-CCR2B cells showed that the CCR2B receptor was present at a concentration of 0.2 pmoles / mg membrane protein and selectively bound MCP-1 with high affinity (IC50 = 110 pM, Ka = 120 pM). The binding to these membranes was completely reversible and reached equilibrium after 45 minutes at room temperature, and there was a linear relationship between MCP-1 binding and cell membrane concentration CHO-CCR2B when using MCP-1 at concentrations between 100 pM and 500 pM. Test compounds dissolved in DMSO (5 μl) were tested in competition with MCP-1 labeled with 100 pM over a range of concentrations (0.01-50 μM) in duplicate using eight-point dose response curves and IC50 concentrations were calculated . The tested compounds of the present invention had IC 50 values of 50 μM or less in the hMCP-1 receptor binding assay described herein. For example, compound 81 had an IC50 of 6.86μM. b) Calcium flow mediated by MCP-1 in THP-1 cells The THP-1 of human monocytic cell line is developed in a synthetic cell culture medium RPMI 1640 supplemented with 10% fetal bovine serum. 6mM glutamine and Penicillin-Streptomycin (at 50 μg streptomycin / ml.

Gibco BRL). THP-1 cells were washed with HBSS (lacking Ca 2+ and Mg 2+) + 1 mg / ml BSA and resuspended in the same buffer at a density of 3 x 10 6 cells / ml. The cells were then loaded with 1 mM FURA-2 / AM for 30 minutes at 37 ° C, washed twice in HBSS, and resuspended at lx106 cells / ml. The THP-I cell suspension (0.9 ml) is added to a 5 ml disposable cuvette containing a magnetic stir bar and 2.1 ml of pre-heated HBSS (37 ° C) containing 1 mg / ml BSA. 1 mM MgCl 2 and 2 mM CaCl 2. The cuvette was placed in a fluorescence spectrophotometer (Perkin Elmer, Norwalk, CT) and preincubated for 4 minutes at 37 ° C with shaking. Fluorescence was recorded over 70 seconds and cells were stimulated by addition of hMCP-1 to the cuvette after 10 seconds [Ca2 +] i was measured by excitation at 340 nm and 380 nm alternately and subsequently the intensity of the emission is measured of fluorescence at 510 nm. The ratio of intensities of the fluorescent light emitted after excitation at 340 nm and 380 nm, (R), is calculated and displayed to give and estimate [Ca2 +] cytoplasmic according to the equation: [Ca +] i (R-Rmin) (Sf2 / Sb2) (Rmax-R) where the i for the FURA-2 Ca2 + complex at 37 ° C is taken as 224nm. R, ^ is the maximum fluorescence ratio determined after the addition of 10 mM of ionomycin, Rm? N is the minimum ratio determined by the subsequent addition of a free Ca2 + solution containing 5 mM EGTA, and Sf2 / Sb2 is the ratio of fluorescence values at excitation 380 nm determined to R ^ - and Rmax, respectively. The stimulation of THP-1 cells with hMCP-1 induces a rapid transient increase in [Ca +] i in a specific and dose-dependent manner. Dose response curves indicate an EC50 of approximately 2 nm. Test compounds dissolved in MSO (10 μl) were assayed for inhibition of calcium release by adding it to the cell suspension 10 seconds before ligand addition and measuring the reduction of the transient increase in [Ca +] i. Test compounds were also checked for the lack of agonist activity by addition instead of hMCP-1. c) Quaniothoxia mediated by RANTES and hMCP-1 In vitro chemotaxis assays were performed using the human monocytic cell line THP-1. Cell migration through polycarbonate membranes was measured by enumerating those that pass through either directly by Coulter counting or indirectly by the use of a colorimetric viability assay that measures the cleavage of a tetrazolium salt by mitochondrial respiratory chain (Scudiero DA and collaborators, 1988, Cancer Res., 48, 4827-4833). Chemoattractants were introduced into a 96-well microtiter plate that forms the lower well of a chemotaxis chamber adapted with a filter membrane framed with polycarbonate adhesive with pore size 5 μm free of PVP (NeuroProbe NB series, Cabin John, MD 20818 USA) according to the manufacturer's instructions. The chemoattractant is diluted as appropriate in synthetic cell culture medium, RPMI 1640 (Gibco) or supplemented with 2 mM glutamine and 0.5% BSA, or alternatively with HBSS with Ca 2+ and Mg 2+ without phenol red (Gibco) plus 0.1% BSA. Each dilution was degassed under vacuum for 30 minutes and placed (400 μl) in the lower wells of the chamber and THP-l cells (5 x 105 in 100 μl RPMI 1640 + 0.5% BSA) were incubated in each well of the chamber higher. For inhibition of chemotaxis, the chemoattractant is maintained at a previously determined constant sub-maximal concentration (InM MCP-1) and added to the lower well together with the test compounds dissolved in DMSO (final DMSO concentration <0.05% v / v) at varying concentrations. The chamber is incubated for 2 h at 37 ° C under 5% C02. The medium is removed from the upper wells which were then washed by 200 μl physiological saline before opening the chamber, dry clean the membrane surface and centrifuge the 96-well plate at 600 g for 5 minutes to harvest the cells. Supernatant (150 μl) is aspirated and 10 μl of cell proliferation reagent, WST-1,. { 4- [3- (4-iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazolium] -1,3-phenyl disulfonate} plus an electron coupling reagent (Boehringer Mannheim, Cat. No. 1644 807) are added back to the wells. The plate is incubated at 37 ° C for 3 hours and the absorbance of the soluble formazan product is read on a microtiter plate reader at 450 nm. The data are fed into a spreadsheet, corrected for any random migration in the absence of chemoattractant and the average absorbance values, standard error of the mean and significance tests were calculated. Cell migration dependent on the induced concentration of hMCP-1 with a characteristic biphasic response, maximum at 0.5-1.0 nm. In an alternate form of the above assay, fluorescently labeled cells may be employed in order to aid in endpoint detection. In this case, the THP-l cells used are fluorescently labeled by incubation in the presence of 5mM Calcein AM (Glycine, NN '- [[3', 6'-bis (acetyloxy) -3-oxospiro [isobenzofuran-1 (3H ), 9 '- [9H] xanthene] -2', 7'-diyl] bis (methylene)] bis [N- [2 - [(acetyloxy) methoxy] -2-oxoethyl]] - bis [(acetyloxy) methyl ] ester; Molecular Probes) for 45 minutes in the dark. The cells are harvested by centrifugation and resuspended in HBSS (without phenol red) with Ca2 +, Mg2 + and 0.1% BSA.50 μl (2xl05 cells) of the cell suspension are placed in the filter on each well and as before, the unit is incubates at 37 ° C for 2 hours under 5% C02. At the end of the incubation, the cells are washed by dragging the upper face of the filter with phosphate buffered saline, the filter is removed from the plate and the number of cells attracted to either the lower side of the filter or the lower well are estimated. by fluorescence reading at excitation wavelengths of 485 nm, emission of 538 nm (max, Molecular Devices). Data are fed into a spreadsheet, corrected for any random migration in the absence of chemoattractant, and average fluorescence values, standard error of the mean, inhibition in percent, and IC50 of compounds under test and significant tests can be calculated. In addition to chemotherapy induced by MCP-1, this alternative form of the assay is also used to measure inhibition of chemotaxis induced by RANTES (2nM). d) Union to human peripheral mononuclear cells (PBMCs) i) Preparation of human PBMCs Fresh human blood (200 ml) is obtained from voluntary donors, collected in a sodium citrate anticoagulant to give a final concentration of 0.38%. The blood is mixed with settling buffer and incubated at 37 ° C for 20 minutes. The supernatant is collected and centrifuged at 1700 rpm for 5 minutes (Sorvall RT6000D). The obtained nodule was resuspended in 20 ml RPMI / BSA (lmg / ml) and 4 x 5 ml of cells were layered, carefully over 4 x 5 ml of Lymphoprepa (Nycomed) in 15 ml centrifuge tubes. The tubes were centrifuged at 1700 rpm for 30 minutes (Sorvall RT6000D) and the resulting cell layer was removed and transferred to 50 ml Falcon tubes. The cells were washed twice in Lysis buffer to remove any remaining red blood cells followed by 2 washes in RPMI / BSA. The cells were resuspended in 5 mis of binding buffer. The number of cells is measured in a Coulter counter and additional binding buffer is added to give a final concentration of 1.25 x 10 7 PBMCs / ml. ii) Assay [125I] MCP-1 is prepared using the conjugation of Bolton and Hunter (Bolton et al., 1973, Biochem. J., 133, 529, Amersham International foot.] Equilibrium binding assays are carried out using the method of Ernst et al., 1994, J. Immunol., 152, 3541. Briefly, 50 μl of 125 I-labeled MCP-1 (final concentration lOOpM) are added to 40 μl (5 x 10 5 cells) of cell suspension in a 96-well plate Compounds, diluted in integral cell-binding buffer of a material solution of 10 mM in DMSO, are added in a final volume of 5 μl to maintain a constant DMSO concentration in the assay of 5%. Total binding is determined in the absence of compounds.Non-specific binding or binding is defined by the addition of 5 μl cold MCP-1, to give a final assay concentration of 100nM.Test wells were constituted at a final volume of 100 μl with whole cell binding buffer and the plates were sealed.After incubation at 37 ° C for 60 minutes the binding reaction mixtures were filtered and washed for 10 seconds using ice-cooled washing buffer, using a plate washer (Brandel cell harvester MLR-96T). Filter mats (Brandel GF / B) were pre-impregnated for 60 minutes in 0.3% polyethyleneimine plus 0.2% BSA before use. After filtration, the individual filters were separated in 3.5 ml tubes (Sarstedt No. 55,484 and MCP-1 labeled with 125 I ligated is determined (LKB 1277 Gammamaster). The power of test compound was doubled using response curves of 6-point dose and IC 50 concentrations were determined.No physiologically unacceptable toxicity was observed at the effective dose for the tested compounds of the present invention., but is not limited by the following examples where the following general pdures were employed unless otherwise stated. i) N, N-Dimethylformamide (DMF) was dried over 4Á molecular sieves. Anhydrous tetrahydrofuran (THF) was obtained from Aldrich SURESEALHR bottles. Other reagents and commercially available solvents were used without further purification unless otherwise stated. Extracts of organic solvents were dried on anhydrous MgSO4, ii) XH NMR, 13C and 19F were recorded on Bruker instruments WM200, WM250, WM300 or WM400 using DMSO-d6 with Me4Si or CC13F as internal standard as appropriate, unless otherwise form is established. Chemical shifts are quoted in d (ppm) and peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt. doublet of triplets; q, quartet; m, multiplet; br, broad, iii) Mass spectra were recorded on spectrometers VG 12-12 quadrupole, VG 70-250 SE. VG ZAB 2-SE or an AEl / Kratos MS9 VG modified. iv) For TLC analysis, Merck pre-coated TLC plates (silica gel 60 F254, d = 0.25 mm) were used. v) Instant chromatography is carried out on silica (Merck Kieselgel: Art.9385). Example 1 N- (3,4-Dichlorobenzyl) -5-hydroxyindole-2-carboxylic acid Sodium hydroxide (2M, 3 ml) is added to a stirred solution of ethyl N- (3,4-dichlorobenzyl) -5-hydroxyindole - 2-carboxylate (0.1 g) in THF (3 ml) and methanol (1.5 ml). The reaction is stirred at room temperature for 4 hours. The reaction is concentrated in vacuo and the residue is dissolved in water (5 ml). The solution is acidified by the addition of aqueous hydrochloric acid (2M, 4 ml) to precipitate the product as a white solid. The product is filtered, washed with water and dried in vacuo to give the title compound (82 mg, 89%). NMR: d 5.77 (s, 2H), 6.81 (dd, 1H), 6.89 (dd, 1H), 6.95 (d, 1H), 7.13 (s, 1H) 7.26 (d, 1H), 7.34 (d, 1H) , 7.52 (d, 1H), 9.01 (s, 1H), 12.85 (s, 1H); m / z 334 (M-H +). The procedure described in the previous Example is repeated using appropriate ethyl indole -2-starting carboxylates. In this manner, the compounds described below were obtained. Example 2 N- T (2,3-Dichloropyrido-5-yl) methyl 1 -5-hydroxyindole -2 -carboxylic acid 36% yield. NMR (CD3SOCD3) d 5.80 (s, 2H), 6.84 (dd, 1H), 6.96 (d, 1H), 7.14 (s, 1H), 7.23 (d, 1H), 7.73 (d, 1H), 8.06 (d , 1?); m / z 339 (M-H +) 337, 335. EXAMPLE 3 N- (3-Chloro-4-fluorobenzyl) -5-hydroxyindole-2-carboxylic acid 68% yield. NMR (CD3SOCD3) d 5.75 (s, 2H), 6.82 (dd, 1H), 6.95 (m, 2H), 7.12 (s, 1H), 7.2-7.4 (m, 3H); m / z 320 (M-H +), 318. Example 4 N- (4-Chloro-3-fluorobenzyl) -5-hydroxyindole-2-carboxylic acid 94% yield. NMR (CD3SOCD3) d 5.78 (s, 2H), 6.78 (dd, IH). 6.80 (dd, 1H), 6.96 (d, 1H), 7.03 (dd, 1H), 7.12 (s, 1H), 7.31 (d, 1H), 7.43 (t, 1H); m / z 318 (M-H +).

Example 5 N- (3-Chlorobenzyl) -5-hydroxyindole-2-carboxylic acid 75% yield, m / z 300 (M-H +). Example 6 N- (3-Trifluromethylbenzyl) -5-hydroxyindole-2-carboxylic acid 81% yield, m / z 334 (M-H +). Example 7 N- (4-Chlorobenzyl) -5-hydroxyindole-2-carboxylic acid 82% yield, m / z 300 (M-H +). Example 8 3-Bromo-N- (3,4-Dichlorobenzyl) -5-hydroxyindole-2-carboxylic acid 95% yield, m / z 414 (M-H +). Example 9 4-Bromo-i.- (3,4-dichlorobenzyl) -5-hydroxyindole-2-carboxylic acid 96% yield. NMR (CD3SOCD3) d 5.78 (s, 2H), 6.86 (dd, 1H), 7.01 (d, 1H), 7.04 (s, 1H), 7.33 (s, 1H), 7.40 (d, 1H), 7.52 (d , 1H), 9.78 (s, 1H), 13.10 (bs, 1H): m / z 414 (M-H +). Example 10 N- (3,4-Dichlorobenzyl) -5-hydroxy-3-methylinindole-2-carboxylic acid 73% yield. NMR (CD33SOCD33) d 2.44 (s, 3H) .5.69 (s, 2H), 6.83 (m, 2H), 6.92 (d, 1H), 7.25 (d, 1H), 7.30 (d, 1H), 7.50 (d , 1H), 9.00 (s, 1H), 12.90 (bs, 1H); m / z 350 (M-H +). Example 11 N- (3,4-dichlorobenzyl) -4-fluoro-5-hydroxyindole-2-carboxylic acid 68% yield. NMR (CD3SOCD3) d 5.80 (s, 2H), 6.88 (m, 1H), 7.00 (t, 1H), 7.20 (m, 2H), 7.32 (m, lH), 7.50 (m, 1H), 9.25 (s) , IH), 13.10 (s, 1H); M / z (M-H +) 351.9 Example 12 N- (3,4-Dichlorobenzyl) 3-methoxy-5-hydroxy-2-carboxylic acid 73% yield. NMR (CD3SOCD3) d 4.3 (s, 3H), 5.7 (s, 2H), 6.9 (m, 2H), 7.1-7.4 (m, 4H); m / z 364, 366 (M-H +) Example 13 N- (3,4-Dichlorobenzyl) -3-chloro-5-hydroxyindole-2-carboxylic acid 97% yield. NMR (CD3SOCD3) d 5.75 (s, 2H), 6.9 (m, 3H), 7.3 (s, 1H). 7.45 (d, 1H), 7.5 (d, 1H), 9.35 (s.1H): m / z 368 (M-H +). Example 14 N- (3,4-dichlorobenzyl) -4-chloro-5-hydroxyindole-2-carboxylic acid 83% yield. NMR (CD3SOCD3) d 5.79 (s, 2H), 6.88 (dd, 1H), 7.01 (d, 1H). 7.11 (s, 1H), 7.3 (d, lH), 7.38 (d, 1H). 7.51 (d, 1H..9.67 (bs.1H); m / z 368.2 (M-H +) Preparation of Starting Materials The starting materials for the above Examples are either commercially available or are easily prepared by standard methods from of known materials For example, the following reactions (Methods AJ) are illustrations but not limitations of the preparation of the starting materials used in the above reactions Method A 3-Chloro-4-fluorobenzyl bromide A solution of 3-chloro -4-Fluorobenzaldehyde (3 g) in THF (40 ml) is added over 2 minutes to a stirred suspension of sodium borohydride (1.07 g) in methanol (40 ml) at 0 ° C. The mixture is allowed to warm to room temperature The resulting suspension is partitioned between water and diethyl ether and the combined organic extracts are dried and concentrated in vacuo.The residue is dissolved in dichloromethane (90 ml) and triphenylphosphine (4.62 g) and tetrabromomethane (6.64 g). g) a Gregaron at 0 ° C. The mixture is allowed to warm to room temperature overnight then concentrated in vacuo and the residue is purified by column chromatography using iso-hexane as eluent to give the desired product (3.57 g, 85%). NMR: d 4.7 (s, 2H), 7.4 (m, 2H), '7.7 (m, 1H). In a similar form but starting from 3-fluoro-4-chlorobenzaldehyde, prepare: 3-Fluor-4-chlorobenzyl bromide 74% yield. NMR: d 4.5 (s, 2H), 7.1 (t, 1H), 7.25 (m, lH), 7.45 (dd, 1H). Method B 2, 3-Dichloro-5- (hydroxymethyl) pyridine Complex Borane-tetrahydrofuran (1M solution in tetrahydrofuran, 52 ml) is added to a stirred solution of 5,6-dichloronicotinic acid (2 g) in tetrahydrofuran (60 ml) for 20 minutes at 0 ° C. The reaction mixture is allowed to warm to room temperature for 90 minutes and then cooled to 0 ° C and neutralized with water (100 ml). The solution is saturated with solid sodium chloride and extracted with ethyl acetate and the combined organic extracts are dried and concentrated in vacuo. The residue is triturated with 50% dichloromethane-ethyl acetate and the solid by-product is removed by filtration. The filtrate is concentrated in vacuo and purified by column chromatography using isohexane / ethyl acetate (1: 1 v / v) as eluent to give the product as a white solid (820 mg, 45%). NMR: d 4.55 (d, 2H), 5.5 (t, 1H), 8.0 (m, 1H), 8.3 (m, 1H); m / z 178.1 (M + H +).

Method C 2, 3 -Dichloro-5- (bromomethyl) pyridine 2,3 -Dichloro-5- (hydroxymethyl) pyridine (275 mg) is dissolved in dichloromethane (10 ml) and stirred in the presence of triphenylphosphine (444 mg) and tetrabromomethane (641 mg) overnight. The solution is concentrated in vacuo and the residue is purified by column chromatography using isohexane: 2.5% ethyl acetate as eluent to give the product as a white solid (270 mg, 73%). NMR: d 4.75 (s, 2H), 8.25 (m, 1H), 8.5 (m, 1H); m / z 242 (M + H +). Method D Ethyl 5-acetoxy-N- (3,4-dichlorobenzyl) indole -2-carboxylate i) Ethyl 5-hydroxyindole-2-carboxylate Boron Tribromide (64.58 g) is added dropwise to a stirred solution of ethyl 5- methoxyindole-2-carboxylate (20 g) in dichloromethane (1000 ml) at -78 ° C under an argon atmosphere. The reaction is allowed to warm to room temperature and stir for 2 more hours. The reaction is poured into saturated aqueous sodium hydrogen carbonate / ice solution with stirring and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution, water, saturated aqueous sodium chloride solution and dried. The solution is concentrated in vacuo and the residue is purified by column chromatography using 0-60% diethyl ether: iso-hexane as eluent to give product as a white solid (9.02 g, 48%). NMR: d 1.31 (t, 3H), 4.29 (q, 2H), 6.79 (dd, IH), 6.90 (dd, 1H), 7.22 (d, 1H), 8.84 (s, 1H), 11.52 (brs, 1H) ); m / z 206 (M + H +). ii) Ethyl 5-acetoxyindole-2-carboxylate A stirred solution of ethyl 5-hydroxyindole-2-carboxylate (7.79 g) and 4-dimethylaminopyridine (20 mg) in acetic anhydride (80 ml) is heated at 80 ° C for 4 hours. The reaction is concentrated in vacuo and the residue is dissolved in ethyl acetate. Combined organic extracts were washed with hydrochloric acid (2 M), aqueous sodium hydrogen carbonate solution, water, saturated aqueous sodium chloride solution and dried. The solution is concentrated in vacuo to give the product as a yellow solid (9.39 g, 100%). NMR: d 1.20 (t, 3H), 2.10 (s, 3H), 4.19 (q, 2H), 6.86 (dd, 1H), 6.97 (d, 1H), 7.20 (s, 1H), 7.29 (d, 1H) ), m / z 248 (M + H +). iii) Ethyl 5-acetoxy-iV- (3,4-dichlorobenzyl) indole-2-carboxylate 3,4-Dichlorobenzyl bromide (5.96 g) is added to a stirred solution of ethyl 5-acetoxyindole-2-carboxylate (5.4 g) ) and potassium carbonate (6.94 g) in acetonitrile (500 ml) under an argon atmosphere. The reaction is heated at 80 ° C for 16 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water. Combined organic extracts were washed with water, saturated aqueous sodium chloride and dried.

The solvent is removed in vacuo and the residue triturated with iso-hexane to give the product as a cream solid (5.55 g, 63%). NMR: d 1.27 (t, 3H), 2.27 (s, 3H), 4.28 (q, 2H), 5.82 (s, 2H), 6.90 (d, 1H), 7.09 (dd, 1H), 7.33 - 7.40 (m , 2H), 7.46 (d, 1H) 7.52 (d, 1H), 7.60 (d, 1H). The procedures described in method D i) - iii) are repeated using the appropriate benzyl halide or using the alkyl indole-2-carboxylates as prepared by the F & G method, with the appropriate benzyl halide. In this manner, the compounds described below were obtained. DI method. Ethyl 5-acetoxy-_.- [(2,3-dichloropyrido-5-yl) methyl] indole-2-carboxylate 90% yield. NMR: d 1.27 (t, 3H), 2.26 (s, 3H), 4.28 (9, 2H), 5.85 (s, 2H), 7.12 (dd, 1H), 7.38 (s, 1H), 7.47 (d, 1H) ), 7.68 (d, 1H), 7.78 (d, IH), 8.10 (d, IH); m / z 409 (M + H +), 407. Method D2. Ethyl 5-acetoxy-2- (3-chloro-4-fluorobenzyl) indole -2-carboxylate 57% yield. NMR (CDC13): d 1.37 (t, 3 H), 2.33 (S, 3 H) 4.35 (q, 2H), 5.74 (s, 2H), 6.90 (m, 1H), 7.00 (d, 1H), 7.05 (dd, 1H), 7.13 (dd, 1H), 7.26 (d, IH, 7.36 (s, 1H), 7.22 (d, 1H), Ethyl 5-acetoxy-i.- (4-chloro) -3-fluorobenzyl) indole-2-carboxylate 73% yield, m / z 390 (MH +). Ethyl 5-acetoxy-i.- (3-chlorobenzyl) indole-2-carboxylate 93% yield, m / z 372 (MH + Ethyl 5-acetoxy-NT- (3-trifluoromethylbenzyl) indole-2-carboxylate 91% yield, m / z 406 (MH +). Ethyl 5-acetoxy-i.- (4-chlorobenzyl) indole-2-carboxylate 70% yield, m / z 372 (MH +). Ethyl 5-acetoxy-3-bromo-N- (3,4-dichlorobenzyl) indole -2-carboxylate 86% yield, m / z 486 (MH +). acetoxy-4-bromo-N- (3,4-dichlorobenzyl) indole-2-carboxylate 62% yield: 1.40 (t, 3H) NMR, 2.39 (s, 3H), 4. 38 (q, 2H), 5.77 (s, 2H), 6.82 (dd, 1H), 7.08 (d, 1H), 7.18 (s, 1 H), 7.22 (d, 1 H), 7.32 (d, 1 H) ), 7.42 (s, 1H); m / z 486 (MH +). Ethyl 5 -acetoxy -A.- (3,4-dichlorobenzyl) -3-methyl indole -2-carboxylate 79% yield. NMR d 1.40 (t, 3H), 2.36 (s, 3H), 2.40 (s, 3H), 4.35 (q, 2H), 5.76 (s, 2H), 6.83 (dd, 1H), 7.00 (d, 1H), 7.10 (d, 1H), 7.19 (s, 1H), 7.30 (d.1H), 7.40 (s, 1 HOUR); m / z 421 (M + H +). Et il S-acetoxy-N- (3,4-dichlorobenzyl) -3-chloro indol-2-carboxylate 83% yield. NMR d 1.25 (t, 3H), 2.25 (s, 3H), 4.3 (q, 2H), 5.8 (s, 2H), 6.9 (d, 1H), 7.2 (m, 1H), 7.4 (m, 2H) , 7.5 (d, 1H), 7.7 (d, 1H); m / z 441.8 (M + H +). Method E Ethyl N- (3,4-dichlorobenzyl) -5-hydroxyindole-2-carboxylate Sodium ethoxide (1.86 g) is added to a stirred solution of ethyl 5-acetoxy-i'- (3,4-dichlorobenzyl) indole -2-carboxylate (5.55 g) in ethanol (50 ml) under an argon atmosphere. The reaction is stirred at room temperature for two hours, then concentrated in vacuo and the residue is acidified with aqueous hydrochloric acid (2M) and extracted with dichloromethane. Combined organic extracts were washed with water, saturated aqueous sodium chloride solution and dried. The solvent is removed in vacuo and the residue triturated with hexane / diethyl ether to give the product as a white solid (3.17 g, 92%). NMR: d 1.26 (t, 3H), 4.25 (q, 2H), 5.75 (s, 2H), 6.81-6.91 (m, 2H), 6.98 (d, 1H), 7.19 (s, 1H), 7.29 (d , 1H), 7.38 (d, 1H) 7.50 (d, 1H), 9.06 (s, 1H); m / z 364 (M + H +). Method F: Ethyl 5-acetoxy-3-bromoindol-2-carboxylate iV-Bromosuccinimide (0.14 g) is added to a stirred solution of ethyl 5-acetoxyindole -2-carboxylate (0.2 g) in DMF (3.0 ml). The reaction is stirred for 4 hours, then emptied in water. The resulting precipitate is filtered and dried in vacuo to give the title compound as a white powder (0.23 g, 87%). NMR d 1.38 (t, 3H), 2.23 (s, 3H), 4.38 (q, 2H), 7.10 (dd, 1H), 7.23 (d, 1H), 7.50 (d, 1H), 12.28 (bs, 1 H) ); m / z 326 (M +). Method Fl Ethyl 5-acetoxy-3-chloroindol-2-carboxylate A solution of ethyl 5-acetoxyindole-2-carboxylate (500 mg) in dichloromethane (10 ml) is stirred at room temperature in the presence of N-chlorosuccinimide (297mg) and potassium carbonate (279 mg) overnight. The resulting precipitate is collected by filtration, washed with cold dichloromethane followed by water and dried in vacuo overnight to give the desired product as a white powder (425 mg, 75%). NMR: d 1.35 (t, 3H), 2.25 (s, 3H), 4.4 (q, 2H), 7.1 (d, lH), 7.3 (s, 1H), 7.5 (d, 1H), 12.2 (s, l H); m / z 281.9 (M + H +). Method G Ethyl 5-acetoxy-3-methylindole-2-carboxylate (i) Ethyl 5-methoxy-3-methylindole-2-carboxylate Concentrated sulfuric acid (1 ml) is added to a solution of 4-methoxyphenylhydrazine hydrochloride (11.2 g) ) and 2-oxobutyric acid (8.72 g) in ethanol (250 ml), and the solution is heated at reflux for 16 hours. The reaction is cooled, concentrated in vacuo and the residue triturated with ethanol to give the title compound as a white solid (8.8 g, 59%). NMR d 1.36 (t, 3H), 3.76 (s 3H), 4.30 (q, 2H), 6.88 (dd, 1H), 7.03 (d, 1H), 7.28 (d, 1H), 11.28 (bs.1H); m / z 232 (M-H +). (ii) Ethyl 5-acetoxy-3-methylindole-2-carboxylate Boron tribromide (25 g) is added dropwise to a stirred solution of ethyl 5-methoxy-3-methylindole-2-carboxylate (2.0 g) in dry dichloromethane (250 ml) at -78 ° C under an argon atmosphere. The reaction is allowed to warm to room temperature and stir for a further 2 hours. The reaction is poured into saturated aqueous sodium hydrogen carbonate / ice solution with stirring and extracted with ethyl acetate.

Combined organic extracts were washed with saturated aqueous sodium carbonate hydrogen solution, water, saturated aqueous sodium chloride solution and dried (MgSO4). The solution is concentrated in vacuo and the residue is dissolved in ethyl acetate. DMAP (20 mg) and acetic anhydride (0.5 ml) were added and the solution heated to reflux for 5 minutes. The reaction is cooled, concentrated in vacuo and the residue triturated with ether to give the title compound as a white powder (0.4 g, 18%). NMR d 1.37 (t, 3H), 2.25 (s, 3H), 2.50 (s, 3H), 4.34 (q, 2H), 7.00 (dd, 1H), 7.37 (d, 1H), 7.40 (d, 1H) , 11.52 (bs, 1H); m / z 260 (M-H +). In a similar manner but starting with ethyl 4-bromo-5-methoxyindole -2-carboxylate, it is prepared: Ethyl 5-acetoxy-4-bromoindol-2-carboxylate NMR d 1.42 (t, 3H), 2.39 (s, 3H), 4.42 (q, 2H), 7.02 (d, 1H), 7.23 (s, lH), 7.35 (d, 1H), 9.22 (bs, 1H): m / z 324.326 (M-H +). Method H Methyl-N- (3,4-dichlorobenzyl) -4-fluoro-5-hydroxyindole-2-carboxylate (i) 2-Fluor-3-benzyloxy benzaldehyde 2-Fluor-3-hydroxybenzaldehyde (16.49 g) are dissolved in dimethylformamide (200ml) and stir under an argon atmosphere. Sodium hydride (60% in mineral oil 5.18g) is added and the mixture is stirred for 30 minutes. Benzyl bromide (16.8 ml) is added and the mixture is stirred overnight. The reaction mixture is concentrated in vacuo and the resulting residue is partitioned between diethyl ether (200 ml) and water (200 ml). The combined organic extracts were washed with water (400 ml), dried (MgSO 4) and concentrated in vacuo. The residue is purified by flash column chromatography, using a gradient of 0-10% ethyl acetate / iso-hexane as eluent to give the product as a yellow solid (18.41 g) NMR: H (DMSO-d6) d 5.20 (s) , 2H), 7.2-7.6 (m, 8H), 10.21 (s, 1H). (ii) Methyl-2-azido-3- (2-fluoro-3-benzyloxyphenyl) propenoate A mixture of methylazidoacetate (36.64 g) and 2-Fluoro-3-benzyloxy benzaldehyde (18.32 g) in methanol (250 ml) is added per drops, with stirring for 1 hour to a mixture of sodium methoxide (17.20 g) in methanol (100 ml) at -25 ° C under a stream of argon. The mixture is allowed to stir for 20 minutes, let it warm at 5 ° C and shake overnight. The resulting precipitate is filtered, then washed sequentially with cold methanol, diluted acetic acid solution in water and water. The resulting solid is dried in vacuo to give the product as a pale brown solid (16.70 g) which is used without purification. (iii) Methyl-4-fluoro-5-benzyloxyindole-2-carboxylate A solution of methyl-2-azido-3- (2-fluoro-3-benzyloxyphenyl) propenoate (16.7 g) in xylene (600 ml) is added by drops with stirring to xylene under reflux (2.4 L) for 1 hour and then stirred for 20 more minutes. The reaction mixture is concentrated in vacuo and purified by flash column chromatography using a gradient of 0-100% ethyl acetate / iso-hexane as eluent to give the product as a yellow solid (12.93g) * NMR * (DMSO-d6 ) d 3.85 (s, 3H) 5.15 (s, 2H), 7.05-7.45 (m.8H), 12.06 (s1H); M / z (+) 300.4 (MH +). (iv) Methyl-N- (3,4-dichlorobenzyl) -4-fluoro-5-benzyloxyindole-2-carboxylate Sodium hydride (60% in mineral oil, 589 mg) is added to a solution of methyl-4-fluorine -5-benzyloxyindole-2-carboxylate (4 g) in dimethylformamide (100 ml) and the mixture is stirred under an argon atmosphere for 30 minutes. 3,4-Dichlorobenzyl chloride (2.22 ml) is added and the mixture is stirred overnight. The reaction mixture is concentrated in vacuo and the residue is partitioned between diethyl ether (100 ml) and water (100 ml). Organic extracts were washed with water (100 ml), dried (MgSO 4), concentrated in vacuo and purified by flash column chromatography using iso-hexane followed by ethyl 5% acetate / iso-hexane as eluent, to give the product as a solid. crystalline yellow (4.61 g) NMR * H (DMSO-d6) d 3.80 (s, 3H), 5.15 (s, 2H), 5.80 (s, 2H), 6.85 (m, 1H), 7.25-7.52 (m, 10H) ); M / z (+) 458.2 (MH +). (v) Methyl-jy.- (3,4-dichlorobenzyl) -4-fluoro-5-hydroxyindole-2-carboxylate A mixture of methyl-N- (3, -dichlorobenzyl) -4-fluoro-5-benzyloxyindole-2-carboxylate (8.22 g) and 5% Pd / C (200 mg) in ethyl acetate (250 ml) is stirred under an atmosphere of hydrogen overnight, filtered through celite, concentrated in vacuo and purified by flash column chromatography using a gradient of 0-50% ethyl acetate / iso-hexane as eluent to give the product as a brown solid (6.18 g) XH NMR (DMSO-d6) d 3.80 (s, 3H), 5.75 (s, 2H), 6.85 (m, 1H), 7.00 (t, 1H), 7.22 (m, 2H), 7.30 (m, 1H), 7.50 (m, lH), 9.33 (s, 1H); M / z (-) 366.2 (MH "). Method I Et il-N- (3,4-di c-lorobenzyl) 3-methoxy-5-hydroxy-indol-2-carboxylate (i) Ethyl 5-benzyloxy diazoindole -2-carboxylate Sodium nitrite (6 g) is added in portions to a solution of ethyl 5-benzyloxyindole-2-carboxylate in ethyl acetate (40 ml) and acetic acid (20 ml). The mixture is stirred for 18 hours and then divided between ethyl acetate and water. The organic extracts are washed with water, saturated aqueous sodium carbonate hydrogen and dried. The solvent is removed in vacuo and the resulting gum is triturated with diethyl ether to give the product as an orange powder (1.8 g) NMR: d 1.45 (t, 3H), 4.5 (q, 2H), 5.1 (s, 2H) 7.05 (m, 2H), 7 3 (m, SH), 7.9 (d.1H); m / z 322 (M + H +). (ii) Ethyl 3-methoxy-5-benzyloxy indol-2-carboxylate Rhodium octanoate (300 mg) is added to a stirred solution of ethyl 5-benzyloxy diazoindole-2-carboxylate (2.0 g) in toluene (100 ml) and methanol (10 ml). The mixture is refluxed under an inert atmosphere for 2.5 hours. The solution is concentrated in vacuo and the residue is purified by column chromatography using 30-50% diethyl ether / iso-hexane to give an orange solid (1.41 g). NMR: d 1.4 (t, 3H), 4.05 (s, 3H), 4.4 (q, 2H), 5.1 (s, 2H), 7.1 (dd, 1H), 7.2-7.5 (m, 8H); m / z 326 (MH +). (iii) Ethyl-N- (3,4-dichlorobenzyl) 3-methoxy-5-benzyl / oxy indol-2-carboxylate 3,4-dichlorobenzyl chloride (0.72 ml) is added to a stirred solution of ethyl 3-methoxy-5- benzyloxyindole-2-carboxylate (1.40 g), potassium carbonate (0.90 g) and potassium iodide (Ol g) in DMF (50 ml) under an inert atmosphere. The reaction mixture is heated at 50 ° C for 6 hours, then divided between ethyl acetate and water. The combined organic extracts were washed with water, then 3 times with saturated aqueous sodium chloride solution and dried. The solvent is removed in vacuo and the residue is purified by column chromatography using 10-30% ethyl acetate / iso-hexane to give a yellow oil (0.9 g). NMR: dl.4 (t, 3H), 4.0 (s, 3H), 4.4 (q, 2H), 5.1 (s, 2H), 5.6 (s, 2H), 6.9 (dd, 1 H), 7.0-7.5 (m, 9H); m / z 484 (MH +) (iv) Ethyl-N- (3,4-dichlorobenzyl) 3-methoxy-5-hydroxyindole-2-carboxylate 5% Pd / C (100 mg) is added to a stirred solution of ethyl- N- (3,4-dichlorobenzyl) 3-methoxy-5-benzyloxyindole-2-carboxylate (0.9 g) in ethyl acetate (50 ml) and the mixture is hydrogenated for 12 hours. The catalyst is separated by filtration and the filtrate is evaporated to give a brown oil (0.61 g) which is used without further purification. NMR: d 1.4 (t, 3H), 4.0 (s, 3H), 4.4 (q, 2H), 5.6 (s, 2H), 6.8 (dd, 1H), 6.9 (dd, 1H), 7.1 (m, 3H) ), 7.3 (d, 1H); m / z 394 (MH +). Method J Ethyl N- (3,4-dichloro) benzyl) -4-chloro-5-methoxy indole -2-carboxylate (i) Ethyl-2-azido-3- (2-chloro-3-methoxyphenyl) propenoate A solution of ethyl azidoacetate (9.9 g) and 2-chloro-3-methoxybenzaldehyde (3 g) in ethanol (20 ml) is added dropwise to a solution of sodium ethoxide (4.7 g) in ethanol (10 ml) at 0 ° C. The reaction is allowed to warm to room temperature for 18 hours then divided between 2N HCl (50 ml) and dichloromethane (250 ml). The organic phase is dried (MgSO4) concentrated in vacuo and the residue purified by column chromatography using isohexane-12% ethyl acetate / isohexane as eluent to give the product as a pale yellow crystalline solid (2.2 g, 44%). This is used without further purification. (ii) Ethyl-4-chloro-5-methoxyindole-2-carboxylate A solution of ethyl-2-azido-3- (2-chloro-3-methoxyphenyl) propenoate (2.22 g) in xylene (100 ml) is heated to reflux for 30 minutes, concentrate in vacuo and the residue is purified by column chromatography using iso / hexane-50% ethyl acetate as eluent to give the product as a pale yellow solid (1.34 g, 67%), d-NMR (CDC13) 1.31 (t, 3H), 3.84 (s, 3H) 4.32 (q, 2H), 7.0 (d, 1H), 7.22 (d, 1H), 7.39 (d, 1H), 12.2 (bs.1H); (iii) Ethyl-N- (3,4-dichlorobenzyl) -4-chloro-5-methoxyindole -2-carboxylate Sodium hydride (60 mg) is added to a solution of ethyl-4-chloro-5-methoxyindole-2-carboxylate (250 mg), 3,4-dichlorobenzyl chloride (0.21 ml) and tetrabutylammonium iodide (3 mg) in DMF at room temperature under an inert atmosphere. The reaction is stirred at room temperature for 18 hours then divided between ethyl acetate (30 ml) and water (30 ml). The organic phase is dried (MgSO4), concentrate in vacuo and the residue purified by column chromatography using isohexane-15% ethyl acetate as eluent to give the product as a white solid (196 mg, 48%). NMR: d (CDC13) 1.39 (t, 3H), 3.93 ( s, 3H), 4.32 (q, 2H), 5.73 (s, 2H), 6.84 (dd, 1H), 7.06-7.16 (m, 3H), 7.31 (d, 1H), 7.42 (s, 1H). (iv) Ethyl N- (3,4-dichlorobenzyl) -4-chloro-5-hydroxyindole-2-carboxylate Trimethylsilyl iodide (0.6 ml) is added to a solution of ethyl-N- (3,4-dichlorobenzyl) -4- Chloro-5-methoxyindole-2-carboxylate (190 mg) in chloroform (20 ml). The mixture is heated at 50 ° C for 18 hours then emptied into methanol (50 ml) and concentrated in vacuo. The residue is purified by column chromatography using isohexane 20% ethyl acetate / isohexane as eluent to give the product as a yellow solid (100mg, 71%) NMR: d (CDC13) 1.39 (t, 3H), 4.35 (q.2H) ), 5.72 (s.2H), 6.84 (dd.1H), 7.05-7.13 (m.3H) 7.3 (d, 1H) 7.35 (s, 1H); m / z396.2 / 398.2 (M-H +). EXAMPLE 15 N- (3,4-Dichlorobenzyl) -2-t rif luromet ilsul phonamido-5-hydroxyindole Sodium methoxide (21 mg) is added to a stirred solution of N- (3,4-dichlorobenzyl) -2-trifluoromethylsulfonamido -5-acetoxyindole (90 mg) in methanol (10 ml). The reaction is stirred at room temperature for 1.5 hours then concentrated and acidified by the addition of aqueous hydrochloric acid (2M, 5 ml), extracted with dichloromethane and concentrated in vacuo to give brown oil. (50 mg). NMR: d 5.8 (s, 2H), 6.7 (dd, 1H), 6.9 (m, 1H), 7.0 (dd, 1H), 7.2 (dd, 1H), 7.3 (m, lH), 7.5 (d, IH ); m / z 465, 467 (M-H +). The starting material for the above is prepared by: (i) N- (3,4-dichlorobenzyl) -5-acetoxyindol-2-carboxylic acid Dimethylaminopyridine (100 mg) and acetic anhydride (1.12 ml) are added to a solution of N- (3,4-Dichlorobenzyl) -5-hydroxyindole-2-carboxylic acid in ethyl acetate (50 ml) and stirred at room temperature for 1 hour. Ethanol (10 ml) is added and the reaction is stirred for 30 minutes. Partially evaporated solvent and isohexane is added to give a precipitate which is filtered off and dried to give the product as a white solid (1.12 g). NMR: d 2.25 (s, 3H), . 85 (s, 2H), 6.9 (dd, 1H), 7.3-7.6 (m, 5H); m / z 376, 378 (M-H +). (ii) N- (3,4-Dichlorobenzyl) -2-trifluoryl-sulphonyl-5-acetoxyindole To a stirred solution of N- (3,4-dichlorobenzyl) -5-acetoxyindole-2-carboxylic acid in DMF (5 ml ), under an inert atmosphere is added to HATU (0.27 g), DIPEA (0.12 ml) and trifluromethylsufonamide (97 mg). The reaction is stirred at room temperature for 18 hours. The mixture is drained in saturated sodium bicarbonate solution and the resulting precipitate is filtered off and dried to give the product (90 mg). NMR: d 2.25 (s, 3H), 5.9 (s, 2H), 6.9 (dd, 1H), 7.0 (dd, lH). 7.1 (s, lH), 7.35 (m, 1H); m / z 506, 508 (MH ") Example 16 N- (3,4-Dichloroberlzyl) -5-hydroxyindole-2-tetrazole Ammonium chloride (54 mg) and sodium azide (65 mg) are added to a stirred solution of N- (3,4-Dichlorobenzyl) -5-acetoxyindole-2-nitrile in DMF (5 ml) The reaction mixture is heated at 100 ° C for 10 hours, an additional amount of ammonium chlorofide (35 mg) and Sodium azide (42 mg) is added and the reaction is heated at 100 ° C for 18 hours.The reaction mixture is acidified by the addition of aqueous hydrochloric acid (2M, 10 ml) and extracted with ethyl acetate, dried, concentrated in vacuo. and purify by column chromatography using 20% ethyl acetate in iso-hexane, increasing to 5% methanol in ethyl acetate to give the product as a brown oil (40 mg) which solidifies upon standing NMR: d 5.9 (s, 2H ), 6.75 (dd, 1H), 6.9 (dd, 1H), 7.1 (s, lH), 7.1-7.3 (m, 2H), 7.5 (d, 1H), 9.0 (s, lH), m / z 360 / 362 (MH +) The starting material is prepared by: Methansulfonyl chloride (0.5 ml) is added to a to a cooled solution (0 ° C) of N- (3,4-dichlorobenzyl) -5-acetoxyindole-2-carboxylic acid (1.12 g) in pyridine (30 ml) and stir at 0 ° C for 1.5 hours. Gaseous ammonia is bubbled through the reaction mixture for 15 minutes, then the excess ammonia is removed in vacuo. The reaction mixture cooled to 0 ° C and methyl sulfonyl chloride (2.5 ml) are added to the stirred solution and allowed to reach room temperature for 18 hours. Methansulfonyl chloride (2ml) is added and the reaction mixture is allowed to sit for 60 hours. The solvent is removed in vacuo, re-dissolved in dichloromethane and washed 3 times with a 1: 1 mixture of aqueous hydrochloric acid (1M) and saturated ammonium chloride solution. The organic extracts were dried, concentrated in vacuo, and the residue was purified by column chromatography using 10-25% ethyl acetate / isohexane to give the desired product (300 mg). NMR: d 2.25 (s, 3H), 5.6 (s, 2H). 7.0 (dd, 1H), 7.45-7.65 (m, 4H), 7.7 (d, 1H). Example 17 N- (3,4-Dichlorophenylsulfonyl) -5-hydroxyindole-2-carboxylic acid A solution of anhydrous lithium iodide (870 mg) and methyl N- (3,4-dichlorophenylsulfonyl) -5-hydroxyindole-2-carboxylate (260 mg) in pyridine (15 ml) is stirred at reflux for 4 hours.

The reaction is cooled and concentrated in vacuo. The residue is dissolved in water (20 ml) and acidified with acetic acid. The product is extracted with ethyl acetate and the combined extracts are dried, concentrated in vacuo and the residue is purified by column chromatography using dichloromethane-50% ethyl acetate containing 1% acetic acid as eluent to give the desired product as glass ( 72 mg, 29%). NMR: d 6.9 (m, 2H), 7.25 (s, 1H), 7.85 (d, 1H), 7.9 (m, 2H), 8.15 (s, 1H), 9.5 (s, 1H); m / z 385.8 (M-H ") The starting material is prepared by: (i) Methyl N- (3,4-dichlorophenylsulfonyl) -5-benzyloxyindole-2-carboxylate Sodium hydride (60% dispersion), 444 mg) is added to a stirred solution of methyl 5-benzyloxyindole-2-carboxylate (2.08 g) in DMF (50 ml) at room temperature. After 1 hour, 3,4-dichlorobenzenesulfonyl chloride (2.72 g) is added. Stirring is continued for 2 hours after which the reaction mixture is divided between water and ethyl acetate. The combined organic extracts were dried and concentrated in vacuo and the residue was purified by column chromatography using isohexane-20% ethyl acetate as eluent to give the desired product as a white solid (2.02 g, 56%). NMR: d 3.85 (s, 3H), 5.1 (s, 2H), 7.2 (, 1H), 7.4 (m, 7H), 7.9 (s, 2H), 8.0 (d, 1H), 8.2 (s, 1H); m / z 489.8 (MH +). (ii) Methyl N- (3,4-dichlorophenylsulfonyl) -5-hydroxyindole-2-carboxylate A suspension of palladium on charcoal 5% in ethyl acetate (450 ml) and methyl N- (3,4-dichlorophenylsulfonyl) -5 -benzyloxyindole -2-carboxylate (2.01 g) is stirred at 60 ° C under hydrogen at atmospheric pressure for 48 hours. The catalyst is removed by filtration and the filtrate is concentrated in vacuo.

The residue is purified by column chromatography using 20% ethyl acetate / isohexane as eluent to give the desired product as a gum (270 mg, 16%). NMR: d 3.85 (s, 3H), 7.0 (m, 2H), 7.35 (s, 1H), 7.9 (, 3H), 8.1 (s.lll), 9.6 (s, 1H); m / z401.9 (MH +). Example 18 N- (3,4-Dichlorobenzyl) -5-acetoxyindole-2-carboxylic acid To a solution of N- (3,4 -Dichlorobenzyl) -5-hydroxyindole-2-carboxylic acid (10 g) in hot ethyl acetate (250 ml) 4-dimethylaminopyridine (100 mg) and acetic anhydride 5.0 ml are added and the resulting mixture is stirred for two hours. The organic portions were washed with IN HCl and dried. Hexane was added to cause crystallization of the product. The solid was filtered and washed with hexane to give the desired product (5 g, 44%). X H NMR (DMSO-d 6) d 2.25 (s, 3 H), 5.85 (s, 2 H), 6.9 (dd, 1 H), 7.05 (dd, 1 H), 7.3-7.6 (m, 5 H); m / z 378.380 (MH +).

Example 19 PHARMACEUTICAL COMPOSITIONS This Example illustrates, but is not intended to limit representative pharmaceutical dosage forms of the invention as defined herein (the active ingredient is referred to as "Compound X"), for therapeutic or prophylactic use in humans. Example A (a) (b) (c) (d) (and) (F) (g) (h) (i) (j) (k) (1) Note: Compound X in the above formulations may comprise a compound as illustrated in Examples 1 to 3 present. The above formulations can be obtained by conventional procedures well known in the pharmaceutical art. Tablets (a) - (c) can be enteric coated by conventional means, for example to provide a cellulose acetate phthalate coating. The aerosol formulations (h) - (k) can be used in conjunction with standard metered dose aerosol dispensers, and the suspending agents trioleate sorbitan and soy lecithin can be replaced by an alternate suspending agent such as sorbitan monooleate, sorbitan sesquileate , polysorbate 80, polyglycerol oleate or oleic acid.

Claims (10)

1. A compound of the formula (I) (i) wherein R1 is hydrogen, halo or methoxy; R2 is hydrogen, halo, methyl, ethyl or methoxy; R3 is carboxy, tetrazolyl or -CONHS02R4 wherein R4 is methyl, ethyl, phenyl, 2,5-dimethylisoxazolyl or trifluoromethyl; T is -CH2- or -S02-; and ring A is 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-difluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrido- 5-ilo; or its pharmaceutically acceptable salt or prodrug.

2. A compound in accordance with the claim 1, characterized in that ring A is 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl or 3-chloro-4-fluorophenyl.

3. A compound in accordance with the claim 2, characterized in that ring A is 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl or 3-chloro-4-fluorophenyl.

4. A compound in accordance with the claim 1, characterized in that ring A is 3,4-dichlorophenyl, 2,3-dichloropyrido-5-yl or 3-chloro-4-fluorophenyl.

5. A compound according to any of the preceding claims, characterized in that T is -CH2-.

6. A compound according to any of the preceding claims, characterized in that R3 is carboxy.

7. A compound according to claim 1, characterized in that in the compound of the formula (I), R1 is hydrogen; R2 is hydrogen; R3 is carboxy; T is -CH2-; and ring A is 3,4-dichlorophenyl or 3-chloro-4-fluorophenyl; or its pharmaceutically acceptable salt or prodrug.

8. A process for preparing a compound according to claim 1, characterized in that it comprises: a) reacting compounds of the formula (II): wherein Ra is a group R3 as defined in claim 1, or the protected form of a group R3, Rb is hydrogen or a hydroxy protecting group, and R1 and R2 are as defined in claim 1, with a compound of Formula III: wherein T and ring A are as defined in claim 1, and L is a displaceable group; and subsequently if necessary: i) converting a compound of the formula (I) to another compound of the formula (I); ii) remove any protective groups; or iii) forming its pharmaceutically acceptable salt or prodrug.

9. A pharmaceutical composition comprising a compound according to any of claims 1 to 7, in combination with a pharmaceutically acceptable carrier.

10. Compound according to any one of claims 1 to 7, for use in the preparation of a medicament for use in the treatment of RANTES-mediated disease or monocyte chemoattractant protein such as inflammatory disease (Regulated upon Activation, Normal T-cell Expressed and Secreted = Regulated before Activation, Expressed and Secreted of Normal T Cell).