MX2008007355A - Aryl acetic acid and ester derivatives and their uses as antiinflammatory - Google Patents

Abstract

There are provided according to the invention compounds of formula (I), in free or salt form, wherein R1, R2, R4, R5, R6, A, D, X, W, m and n are as described in the specification, process for preparing them, and their use as pharmaceuticals.

Description

ARILACTIC ACID AND ESTER DERIVATIVES AND THEIR USES AS ANTI-INFLAMMATORY DESCRIPTION OF THE INVENTION The present invention relates to organic compounds, their preparation and their use as pharmaceuticals. In a first aspect, the present invention provides compounds of the formula (I): in free or salt form, wherein: A is independently selected from CH and at least one nitrogen; D is independently selected from CR3 and nitrogen; R1 and R2 are independently H, halogen or alkyl of 1 to 8 carbon atoms, or R1 and R2 together with the carbon atom to which they are ated, form a carbocyclic group of 3 to 15 carbon atoms; R3 is selected from alkyl of 1 to 8 carbon atoms, halogen, cyano, hydroxyl, amino, aminoalkyl, amino (di) alkyl, a carbocyclic group of 3 to 15 carbon atoms. carbon, haloalkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms-alkyl of 1 to 8 carbon atoms, and hydroxyalkyl of 1 to 8 carbon atoms; R 4 is selected from halogen, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, a carbocyclic group of 3 to 15 carbon atoms, an aromatic carbocyclic group of 6 to 15 carbon atoms, nitro, cyano , alkylsulfonyl of 1 to 8 carbon atoms, alkylsulfinyl of 1 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, haloalkoxy of 1 to 8 carbon atoms, carboxy, carboxyalkyl of 1 to 8 carbon atoms, amino, alkylamino of 1 to 8 carbon atoms, di (aikello of 1 to 8 carbon atoms) amino, SO2NH2, (alkylamino of 1 to 8) carbon atoms) sulfonyl, di (C 1 to C 8 alkoxy) aminosulfonyl, aminocarbonyl, alkylaminocarbonyl of 1 to 8 carbon atoms, di (to 1 to 8 carbon atoms) aminocarbonyl and a heterocyclic group from 4 to 10 members; each R5 is selected from halogen, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, carbocyclic group of 3 to 15 carbon atoms, nitro, cyano, alkylsulfonyl of 1 to 8 carbon atoms, alkylcarbonyl of 1 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms carbon, alkoxy of 1 to 8 carbon atoms, haloalkoxy of 1 to 8 carbon atoms, carboxy, carboxy-alkyl of 1 to 8 carbon atoms, amino, alkylamino of 1 to 8 carbon atoms, di (alkyloxy), 1 to 8 carbon atoms) amino, aminocarbonyl, alkylaminocarbonyl of 1 to 8 carbon atoms, di (to Iq ui I or of 1 to 8 carbon atoms) aminocarbonyl and a heterocyclic group of 4 to 10 members R5a, and R5b are independently selected from H, a heterocyclic group of 4 to 14 members, a carbocyclic group of 6 to 15 aromatic carbon atoms, a carbocyclic group of 3 to 15 carbon atoms, and alkyl of 1 to 8 carbon atoms. carbon optionally substituted by a 4 to 14 membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms, or R5a and R5b together with the nitrogen atom to which they are ated form a 4 to 14 membered heterocyclic group, R5c, R5 and R5e are independently selected from H, and alkyl of 1 to 8 carbon atoms optionally substituted by a heterocyclic group of 4 to 14 members, an aromatic carbocyclic group of 6 to 15 carbon atoms, a carbocyclic group of 3 to 15 carbon atoms, or R5c together with R5d and R5e together with the nitrogen atoms to which they are ated and the carbonyl, form a 5- to 14-membered heterocyclic group; R5t is H, alkyl of 1 to 8 carbon atoms optionally substituted by a heterocyclic group of 4 to 14 members or a carbocyclic group of 3 to 15 carbon atoms; R5g is selected from H, and alkyl of 1 to 8 carbon atoms optionally substituted by a 4- to 14-membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms; R5f and R5g together with the group NSO2 to which they are ated form a heterocyclic group of 5 to 14 members; R5h and R5 'are independently selected from the group consisting of H, and alkyl of 1 to 8 carbon atoms optionally substituted by a 4- to 14-membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms, or R5h and R5 'together with the NCO group to which they are linked they form a heterocycle of 5 to 14 members; R5j and R5k are independently selected from H, and alkyl of 1 to 8 carbon atoms optionally substituted by a a 4 to 14 membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms, or R5) and R5k together with the nitrogen atom to which they are attached form a 4 to 14 membered heterocyclic group; R5 ', R5m and R5q are independently selected from H, and alkyl of 1 to 8 carbon atoms optionally substituted by a 4- to 14-membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms, or 51 together with R5m or R5q together with the nitrogen atoms of the aminosulfonamide to which they are attached form a heterocyclic group of 5 to 14 members; is selected from a 4- to 14-membered heterocyclic group, an aromatic carbocyclic group of 6 to 15 carbon atoms and a carbocyclic group of 3 to 15 carbon atoms; R6 is H, alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms; W is an aromatic carbocyclic group of 6 to 15 carbon atoms, a carbocyclic group of 3 to 15 carbon atoms, or a heterocyclic group of 4 to 14 members; X is a bond, alkylene of 2 to 8 carbon atoms optionally substituted by one or more groups selected from alkyl of 1 to 8 carbon atoms, halogen, oxo, hydroxyl, amino, aminoalkyl; and amino (dialkyl), (V -) - T- (V), a 4- to 14-membered heterocyclic group, an aromatic carbocyclic group of 6 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms; V1 is alkyl of 1 to 7 carbon atoms optionally substituted by alkyl of 1 to 8 carbon atoms, halogen, oxo, hydroxyl, amino, amino, amino-alkyl of 1 to 8 carbon atoms, or amino (di-alkyl of 1 to 8 carbon atoms); V is alkyl of 0 to 7 carbon atoms optionally substituted by alkyl of 1 to 8 carbon atoms, halogen, oxo, hydroxyl, amino, amino-alkyl of 1 to 8 carbon atoms, or amino (di-alkyl of 1 to 8 carbon atoms); T is oxygen or NR7; R7 is H or alkyl of 1 to 8 carbon atoms; wherein each carbocyclic group of 3 to 15 carbon atoms, aromatic carbocyclic group of 6 to 15 members and each heterocyclic group of 4 to 14 members, unless otherwise specified, is independently and optionally substituted by one or more selected groups of halogen, oxo, hydroxy, cyano, amino, nitro, carboxy, alkyl of 1 to 8 carbon atoms, halo-alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkylcarbonyl of 1 to 8 atoms of carbon, alkylsulfonyl of 1 to 8 carbon atoms, -SO2NH2, (alkylamino of 1 to 8 carbon atoms) - sulfonyl, di (to 1 to 8 carbon atoms) carbon) aminosulfonyl, aminocarbonyl, alkylaminocarbonyl of 1 to 8 carbon atoms and di (alkyl of 1 to 8 carbon atoms) aminocarbonyl, a carbocyclic group of 3 to 15 carbon atoms, an aromatic carbocyclic group of 6 to 15 members, a 4- to 14-membered heterocyclic group, cyano-alkyl of 1 to 8 carbon atoms, hydroxy-alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, amino-alkyl of 1 to 8 carbon atoms , amino (hydroxy) alkyl of 1 to 8 carbon atoms and alkoxy of 1 to 8 carbon atoms optionally substituted by aminocarbonyl; m and n are each, independently, an integer of 0-3; and p is an integer of 0-4. According to the formula (I) the group It is conveniently: in free or salt form According to formula (I), R1 and R2 are conveniently together H.

According to formula (I), R3 is conveniently alkyl of 1 to 8 carbon atoms, preferably methyl. According to formula (I), R4 is conveniently not present. According to formula (I), R5 is conveniently not present or represents one or two groups independently selected from halogen, for example, chloro, haloalkyl of 1 to 8 carbon atoms, for example trifluoromethyl, alkylsulfonyl of 1 to 8 carbon atoms. carbon, for example methylsulfonyl or eti Isu If on ilo. According to the formula (I), R5 is also conveniently -SO2N (R a) R5, wherein R5a and R5 are conveniently and independently selected from alkyl of 1 to 8 carbon atoms, for example, methyl and a carbocyclic group of 3 to 15 carbon atoms, example, cyclohexyl or R5a and R5b together with the nitrogen atom to which they are conveniently attached form a carbocyclic group of 4 to 14 members, for example 4-morpholinyl. More conveniently, R5a and R5b together represent methyl and cyclohexyl or together form a 4-morpholinyl group. According to formula (I), when W represents phenyl and R5 is alkylsulfonyl of 1 to 8 carbon atoms, or -SO2N (R5a) R5b, R5 is most preferably in the 4-phenyl position. W is conveniently an aromatic carbocyclic group of 6 to 15 carbon atoms, for example phenyl or a carbocyclic group of 3 to 15 carbon atoms, for example, indanyl. When W is phenyl, it is conveniently unsubstituted, 4-substituted or 2,4-substituted by R5. When W is phenyl, X is conveniently alkylene of 2 to 8 carbon atoms, for example ethylene, 1-propylene, 2-propylene or 3-propylene, or alkyleneoxy of 1 to 8 carbon atoms, for example, ethyleneoxy. When W ws indanyl (1,2 or 3 indanyl), X is conveniently a bond. A preferred embodiment of the present invention provides compounds of the formula (la): in free or salt form; wherein: W represents phenyl and X represents alkylene of 2 to 8 carbon atoms or alkylenoxy of 1 to 8 carbon atoms, or W represents indanyl and X represents a bond; R5 is not present or represents one or two groups independently selected from halogen, haloalkyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 8 carbon atoms, -SO2N (R5a) R5b, wherein R5a and R5 are independently selected from alkyl from 1 to 8 carbon atoms and a carbocyclic group of 3 to 15 carbon atoms, or R5a and R5b together with the nitrogen atom to which they are attached form a group 4 to 14 membered heterocyclic, for example, 4-morpholino. The terms used in the specification have the following meanings: "Optionally substituted" as used herein, means the group designated to be substituted in one or more positions by any or any combination of the radicals listed below. "Halogen" or "halo" can be fluorine, chlorine, bromine or iodine. "Alkyl of 1 to 8 carbon atoms" denotes straight or branched chain alkyl of 1 to 8 carbon atoms, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, fer-butyl, straight or branched chain pentyl, straight or branched chain hexyl, straight or branched chain heptyl or straight or branched chain octyl. "Carbocyclic group of 3 to 15 carbon atoms", as used herein, denotes a carbocyclic group having from 3 to 15 carbon atoms in the ring that is saturated or partially saturated, such as a cycloalkyl of 3 to 8 carbon atoms. carbon. Examples of carbocyclic groups of 3 to 15 carbon atoms include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl or a bicyclic group, such as bicyclooctyl, bicyclononyl, including indanyl and indenyl, and bicyclodecyl. "Aromatic carbocyclic group of 6 to 15 carbon atoms", as used herein, denotes an aromatic group having 6 to 15 carbon atoms in the ring. Examples of carbocyclic groups Aromatics of 6 to 15 carbon atoms include, but are not limited to, phenyl, phenylene, benzene, naphthyl, naphthylene, naphthalenyl or anthrylene. "Alkoxy of 1 to 8 carbon atoms" denotes alkoxy of 1 to 8 carbon atoms straight or branched chain which can be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy , straight or branched chain pentoxy, straight or branched chain hexyloxy, straight or branched chain heptyloxy or straight or branched chain octyloxy. Preferably, alkoxy of 1 to 8 carbon atoms is alkoxy of 1 to 4 carbon atoms. "Haloalkyl of 1 to 8 carbon atoms" and "haloalkoxy of 1 to 8 carbon atoms" denotes alkyl of 1 to 8 carbon atoms and alkoxy of 1 to 8 carbon atoms as defined above, substituted by one or more atoms of halogen, preferably one, two or three halogen atoms, preferably fluorine, bromine or chlorine atoms. Preferably, the haloalkyl of 1 to 8 carbon atoms is alkyl of 1 to 4 carbon atoms substituted by one, two or three fluorine, bromine or chlorine atoms. "Alkyl-sulfonyl of 1 to 8 carbon atoms", as used herein, denotes alkyl of 1 to 8 carbon atoms as defined above linked to -SO2-. "C 1 -C 8 -alkylsulfinyl", as used herein, denotes alkyl of 1 to 8 carbon atoms as defined above, linked to -SO-. "Aminoalkyl of 1 to 8 carbon atoms" and "aminoalkoxy of 1 to 8 carbon atoms "denote amino linked through a nitrogen atom to an alkyl of 1 to 8 carbon atoms, for example, NH2- (C1-C8) -, or alkoxy of 1 to 8 carbon atoms, for example, NH2- (C1-C8) -O-, respectively, as defined above. "Amino- (hydroxy) -alkyl of 1 to 8 carbon atoms" denotes amino bound through a nitrogen atom to alkyl of 1 to 8 carbon atoms and hydroxy linked through an oxygen atom to the same alkyl of 1 to 8 carbon atoms. "Carboxy-alkyl of 1 to 8 carbon atoms" and "carboxy-alkoxy of 1 to 8 carbon atoms" denotes carboxy attached through a carbon atom to alkyl of 1 to 8 carbon atoms or to alkoxy of 1 to 8 carbon atoms, respectively, as defined above. "Alkylcarbonyl of 1 to 8 carbon atoms", "alkoxycarbonyl of 1 to 8 carbon atoms", and "haloalkylcarbonyl of 1 to 8 carbon atoms" denote alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms. carbon or haloalkyl of 1 to 8 carbon atoms respectively, as defined above linked through a carbon atom to a carbonyl group. "Alkoxycarbonyl of 1 to 8 carbon atoms" denotes alkoxy of 1 to 8 carbon atoms as defined above, wherein the oxygen and the alkoxy group are attached to the carbonyl atom. "Alkylamino of 1 to 8 carbon atoms" and di (alkyi of 1 to 8 carbon atoms) amino "denote alkyl of 1 to 8 carbon atoms as defined above attached through an atom of carbon to an amino group. The alkyl groups of 1 to 8 carbon atoms in the amino (a to C 1 to C 8 to C 8) amino can be the same or different. "Alkylaminocarbonyl of 1 to 8 carbon atoms" and "d i (a I q u i I of 1 to 8 carbon atoms) aminocarbonyl" denote alkylamino of 1 to 8 carbon atoms and d i (alk i lo of 1 to 8 carbon atoms) amino, respectively, as defined above linked through a nitrogen atom to the carbon atom of a carbonyl group. "Di- (alkyl of 1 to 8 carbon atoms) amino-alkyl of 1 to 8 carbon atoms" and "di (at 1 to 1 to 8 carbon atoms) amino-alkoxy of 1 to 8 carbon atoms carbon "denote di (alkanoyl of 1 to 8 carbon atoms) amino as defined above attached through a nitrogen atom to the carbon atom of an alkyl group of 1 to 8 carbon atoms or an alkoxy group of 1 to 8 carbon atoms, respectively. "4 to 14 membered heterocyclic group" refers to a 4- to 14-membered heterocyclic ring containing at least one heterogeneous ring atom selected from the group consisting of nitrogen, oxygen and sulfur, which may be saturated, partially saturated or unsaturated (aromatic). Examples of 4- to 14-membered heterocyclic groups include, but are not limited to furan, azetidine, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, triazine, oxazine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1,4-dioxane, 1, 4-oxatiano, indazol, quinolina, indazol, indole or thiazol. The 4- to 14-membered heterocyclic group may be unsubstituted or substituted. Preferred substituents include halogen, cyano, oxo, hydroxy, carboxy, nitro, alkyl of 1 to 8 carbon atoms, alkylcarbonyl of 1 to 8 carbon atoms, cyanoalkyl of 1 to 8 carbon atoms, hydroxyalkyl of 1 to 8 carbon atoms. carbon, haloalkyl of 1 to 8 carbon atoms, aminoalkyl of 1 to 8 carbon atoms, amino (hydroxy) alkyl of 1 to 8 carbon atoms and alkoxy of 1 to 8 carbon atoms optionally substituted by aminocarbonyl. Especially preferred substituents include halogen, oxo, alkyl of 1 to 4 carbon atoms, alkylcarbonyl of 1 to 4 carbon atoms, hydroxyalkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, amino-alkyl of 1 to 4 carbon atoms and amino (hydroxy) alkyl of 1 to 4 carbon atoms. Through this specification and the following claims, unless the context requires otherwise, the word "comprises", or variations such as "comprises" or "comprising", shall be understood to imply the inclusion of an established integer or step or group of integers or steps, but not the exclusion of any other integer or step or groups of integers or steps. When in formula (I), m or n are 2, the two substituents may be the same or different. When m or n is 3, two or all the substituents may be the same or the three may be different. In a further aspect, the present invention provides the use of a compound in the formula (I) in any of the aforementioned embodiments, in free or salt form, for the manufacture of a medicament for the treatment of an inflammatory or allergic condition. , in particular an inflammatory or obstructive airway disease.

Salts and Isomers Many of the compounds represented by the formula (I) are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts. The pharmaceutically acceptable acid addition salts of the compound of the formula (I) include those of inorganic acids, for example, hydrohalic acids, such as hydrochloric acid or hydrobromic acid; nitric acid; sulfuric acid; phosphoric acid; and organic acids, for example, aliphatic monocarboxylic acids, such as formic acid, acetic acid, diphenylacetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoroacetic acid, hippuric acid, propionic acid and butyric acid; hydroxy aliphatic acids such as lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid or malic acid; dicarboxylic acids, such as atypical acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, masonic acid, acid sebacic or succinic acid, aromatic carboxylic acids, such as benzoic acid, p-chlorobenzoic acid or nicotinic acid, hydroxy aromatic acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid or -hydroxynaphthalene-2-carboxylic acid; and sulfonic acids such as ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, (+) - camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene acid - 1, 5-disulfonic or p-toluenesulfonic acid. These salts can be prepared from compounds of the formula (I) through known salt-forming processes. The compounds of the formula (I) which contain acidic groups, for example, carboxyl, are also capable of forming salts with bases, in particular, pharmaceutically acceptable bases, such as those well known in the art; said suitable salts include metal salts, particularly alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium, calcium or zinc salts; or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases, such as benetamine, arginine, benzathine, diethanolamine, ethanolamine, 4 (2-hydroxyethyl) morpholine, 1- (2-hydroxyethyl) pyrrolidine,? / - methyl glutamine, piperazine, triethanolamine or tromethamine. These salts can be prepared by the compounds of the formula (I) by known salt-forming processes. In those compounds where there is a carbon atom Asymmetric or an axis of chirality, the compounds exist in individual optically active isomeric forms or as mixtures thereof, for example, as racemic or diastereomeric mixtures. The present invention encompasses both individual and optically active R and S isomers, as well as mixtures, e.g., racemic or diastereomeric mixtures thereof. The specific preferred compounds of the formula (I) are described below in the Examples. The invention also provides a process for the preparation of compounds of the formula (I), in free or salt form, comprising the steps of: (i) (A) for the preparation of the compounds of the formula (I), wherein R6 is H, the cleavage of the ester group -COOR6 in a compound of the formula (I), wherein R6 is alkyl of 1 to 8 carbon atoms substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms and R1, R2, R4, R5, A, D, W , X, m, and n are as defined above; or (B) for the preparation of compounds of the formula (I), in where R6 is alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms, reacts a compound of the formula (II) wherein R6 is alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms; and R1, R2, R4, A, D and m are as defined above with a compound of the formula (III) G-X-W- (R5) n (MI) wherein G is a leaving portion, for example, a halogen atom; R5, W, X and n as defined above; and (ii) recovering the resulting compound of formula (I) in free or salt form. The variant (A) of the process can be carried out using known methods (or analogously as described below in the Examples) for the cleavage of carboxylic ester groups and it can be carried out in situ after the preparation of a compound of the formula (I), wherein R6 is alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms. For example, the compound of the formula (I), wherein R6 is alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms, which conveniently is in solution in a polar organic solvent or a mixture thereof with water, can be reacted with an aqueous inorganic base, such as NaOH to hydrolyze the ester group; where the base is NaOH, the reaction can be carried out at a temperature of -40 ° C, conveniently at room temperature. The process (B) can be carried out using known procedures or analogously as described below in the Examples. For example, the compound of the formula (II) can be reacted with an alkyl halide of the formula (III), wherein G is halogen; R5, W, X and n are as defined above, in the presence of an organic base, such as NaH; the reaction can be carried out in an organic solvent, for example, a polar aprotic solvent, such as? /,? / - dimethylformamide (DMF) and can be carried out at 10-40 ° C, conveniently at room temperature. The compounds of the formula (II) are known or can be obtained by known methods, for example, as described in the U.S. Patent. No. 3,320,268, or analogously as described hereinafter in the Examples. The compounds of the formula (III) are known or can be obtained by known methods, or analogously, as described below in the Examples. The compounds of the formula (I) in free form can be converted into the salt form and vice versa, in a conventional manner. The compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization. The compounds of formula (I) and (II) can be recovered from reaction mixtures and purified in conventional manner. Isomers, such as enantiomers, can be obtained in a conventional manner, for example, through fractional crystallization, chiral HPLC resolution or asymmetric synthesis of corresponding and asymmetrically substituted, for example, optically active starting materials.

Pharmaceutical Use and Assays The compounds of the formulas (I) and (II) and their pharmaceutically acceptable salts, hereinafter alternatively referred to as "agents of the invention", are useful as pharmaceuticals. In particular, the compounds have a good modeling activity of the CRTh2 receptor and can be tested in the following assays.

Filtration-binding assay protocol The binding of CRTh2 modulators was determined using membranes prepared from Hamster Ovary cells.

Chinese expressing human CRTh2 (CHO.K1 -CRTh2). To produce cell membranes, CHO.K1-CRTh2 cells were grown in spinner bottles and a cell dissociation pH regulator (Invitrogen) was harvested. The cells were pelleted through centrifugation (167 g, 5 minutes). The cell pellet was incubated in a hypotonic pH regulator (15 mM Tris-OH, 2 mM MgCl 2, 0.3 mM EDTA, 1 mM EGTA, 1x Complete ™ tablet) at 4 ° C for 30 minutes. At 4 ° C, the cells were homogenized using Polytron® (IKA Ultra Turrax T25) for 5 burns of 1 second. The homogenate was centrifuged (Beckman Optimum TM TL Ultracentrifuge, 48000 g, 30 minutes at 4 ° C). The supernatant was discarded and the membrane pellet was resuspended in homogenization pH regulator (75 mM Tris-OH, 12.5 mM MgCl 2, 0.3 mM EDTA, 1 mM EGTA, 250 mM Sucrose, 1x Complete ™ tablet. The membrane was aliquoted and stored at 80 ° C. The protein content was estimated using the Bradford Protein Assay Dye protein assay dye (Bio Rad) The binding of [3 H] -PGD2 (157 Ci / mmol) to CHO.K1-CRTh2 membranes were determined in the absence (total binding) and in the presence (non-specific binding) of unlabeled PGD2 (1 μM) The subtraction of cpm (counts per minute) from the binding of [3H] -PGD2 in the presence of PGD2 not marked in excess from that observed in the absence of unlabelled PGD2 in excess was defined as the specific binding. Active CRTh2 modulators are capable of competing with [3H] -PGD2 for binding to the CRTh2 receptor and are identified in a reduction in the binding number of cpm. The assay was carried out in 96-well plates with Greiner U-shaped bottom, in a final volume of 100 μl per well. CHO.K1-CRTh2 membranes were diluted in assay pH buffer (10mM HEPES-KOH (pH 7.4), 1mM EDTA and 10mM MnCl2) and 10 μg was added to each well. [3 H] -PGD2 was diluted in assay pH buffer and added to each well to a final concentration of 2.5 nM. To determine non-specific binding, the binding of [3 H] -PGD2 to the CRTh2 receptor competed with PGD2 at a final cavity concentration of 1 μM. The experiment was performed in triplicate, the agents were added to the cavities as follows: - 25 μL of assay pH regulator for total binding or - 25 μL PGD2 to determine non-specific binding - 25 μL [3H] PGD2 - 50 μL of membranes - 25 μL of the test compound in DMSO / assay pH regulator. The plates were incubated at room temperature in a shaker for 1 hour, and then harvested on GF / C plates using washing pH regulator (Tomtec Harvester 9600) (10 mM HEPES-KOH, pH 7.4) The plate was dried for 2 hours. hours, before addition of Micro-Scint 20 ™ (50 μL), and sealed with TopSeal-S ™.

The plates were then counted using a Packard Top Count counter instrument, the plates were then read on a Packard Topcount counter with the 3H Cintilation program (1 minute per cavity). Ki values (dissociation constant for inhibition) were reported for CRTh2 modulators. Ki values were determined using the Sigma Plot ™ software, using the Cheng-Prussoff equation: Ki = IC50 / 1+ [s] / Kd where S is the radioligand concentration and Kd is constantly dissociated Functional assay protocol CRTH2 cAMP This assay was conducted in CHO.K1-CRTh2 cells. CAMP was generated in the cell by stimulating the cells with 5 μM forskolin, an adenylate cyclase activator. PGD2 was added to activate the CRTh2 receptor, which resulted in the attenuation of the cAMP accumulation induced by forskolin. Potential CRTh2 antagonists were tested for their ability to inhibit PGD2 mediated attenuation of forskolin-induced cAMP accumulation in CHO.K1-CRTh2 cells. For each concentration value in the dose-response curve, test compounds were prepared in pH-regulator assay stimulation (HBSS, 5 mM HEPES, 10 μM IBMX + 0.1% human serum albumin) containing DMSO (3% vol / vol) and 5 μL / well was added to a test plate (white plate of 384 wells). CHO.K1-CRTh2 cells cultured in tissue culture flasks were washed with PBS and harvested with dissociation pH regulator. The cells were washed with PBS and resuspended in stimulation pH regulator at a concentration of 0.4 x 106 / mL and added to the assay plate (10 μL / well).

The assay plate was incubated at room temperature in a shaker for 15 minutes. A mixture of agonist (10 nM Prostaglandin D2) and μM of forskolin in pH-regulator assay and stimulation were added to the assay plate (5 μL / well). In addition, a cAMP standard was serially diluted in the pH buffer of the assay stimulation and added to separate the empty cavities in the assay plate (20 μL / well). The cAMP standard allows the quantification of cAMP generated in cells CHO.K1-CRTh2. The assay plate was incubated at room temperature on a shaker for 60 minutes. Added cell lysis pH regulator (lysis pH regulator: Milli-Q H2O, 5 mM HEPES, 0.3% Tween-20, 0.1% human serum albumin) to a bead mixture (containing anti acceptor beads) - Alphascreen ™ cAMP, 0.06 units / μL, donor beads covered with streptavidin 0.06 units / μL, biotinylated cAMP 0.06 units / μL, 10 μM IBMX) was prepared under conditions in the dark for 60 minutes before addition to the assay plate. The resulting lysis mixture was added to all the cavities of the assay plate (40 μL / well). The assay plate was sealed with Topseal-S ™ and incubated in the dark at room temperature on a shaker for 45 minutes.

The plate was then counted using a Packard instrument Fusion ™. The resulting per minute counts were converted to cAMP nM using the standard cAMP curve prepared. The IC50 values (concentration of the CRTh2 antagonist required to inhibit 50% of the PGD2 mediated attenuation of the forskolin-induced cAMP accumulation in CHO.K1-CRTh2 cells) were then determined using the Pris ™ software. The compounds of the Examples presented below generally have Ki values in the SPA binding assay below 1 μM. For example, the compound of Example 1 has a Ki value of 0.716 μM. The compounds of the Examples presented below generally have IC 50 values in the functional assay below 1 μM. For example, the compounds of Examples 1, 2, 4 and 6 have IC 50 values of 0.060, 0.083, 0.042 and 0.018 μM respectively. The compounds of the formulas (I) and (II) in free or salt form are modulators of the chemoattractant receptor coupled to the protein G CRTh2, expressed in Th2 cells, eosinophils and basophils.

PGD2 is the natural ligand for CRTh2. In this way, modulators that inhibit the binding of CRTh2 and PGD2 are useful in the treatment of allergic and anti-inflammatory conditions. The treatment according to the invention can be symptomatic or prophylactic. "Modulators" as used herein are intended to encompass antagonists, agonists, partial antagonists and / or partial agonists. Preferably, modular ones are antagonists. Accordingly, the agents of the invention are useful in the treatment of inflammatory or obstructive diseases of the respiratory tract, resulting, for example, in the reduction of tissue damage, airway inflammation, bronchial hyperreactivity, remodeling or progression. of the illness. Inflammatory or obstructive airways diseases to which the present invention is applicable, include asthma of any type or gender, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis-asthma, asthma induced by exercise, occupational asthma and asthma induced after bacterial infection. The treatment of asthma should also be understood to encompass the treatment of subjects, for example, under 4 or 5 years of age, who exhibit symptoms of panting whistles that are diagnosed or can be diagnosed as "whistling infants", a category of patient established of great medical concern and now usually identified as incipient or phase asthmatic early (For convenience, this particular asthmatic condition is referred to as "whistling infant syndrome"). The prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, for example, of asthmatic attack or bronchoconstrictor, improvement in lung function or improved hyper-reactivity of the respiratory tract. It can also be evidenced through a reduced requirement of another symptomatic therapy, that is, therapy for or that aims to restrict or address the symptomatic attack when it occurs, for example, anti-inflammatory (for example, corticosteroids) or bronchodilator. The prophylactic benefit in asthma, in particular, may be evident in subjects prone to "dripping in the morning". The "morning drip" is a recognized asthmatic syndrome, common for a substantial percentage of asthmatics and characterized by an asthma attack, for example, between 4-6 a.m., that is, at a time normal and substantially away from any previously administered symptomatic asthma therapy. Other inflammatory or obstructive airway diseases and conditions in which the present invention is applicable include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary airway or lung disease ( COPD, COAD or COLD), including chronic bronchitis or dyspnea associated with it, emphysema, as well as exacerbation of hyper-reactivity of the airways consistent with another drug therapy, in particular, another inhaled drug therapy. The mention is also applicable to the treatment of bronchitis of any type or gender including, for example, acute bronchitis, arachidic, catarrhal, chronic or phthinoid bronchitis. In addition, inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational lung disease, often accompanied by airway obstruction, either chronic or watery, and caused by inhalation). repeated powder) of any type or kind, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. With respect to their anti-inflammatory activity, in particular, in relation to the activation of eosinophil inhibition, the agents of the invention are also useful in the treatment of disorders related to eosinophils, for example eosinophilia, in particular, disorders related to eosinophils. of the respiratory tract, for example, involving morbid eosinophilic infiltration of pulmonary tissues including hypereosinophilia and affecting the respiratory tract and / or lungs, as well as, for example, eosinophilic-related disorders of the respiratory tract resulting from or concomitant with the syndrome by Lóffler; eosinophilic pneumonia; infestation of parasites, in particular metazoans, including tropical eosinophilia; bronchiopulmonary aspergillosis; polyarteritis nodosa including Churg-Strauss syndrome; eosinophilic granuloma; and eosinophil-related disorders that affect the airways caused by drug reaction. The agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitive angitis, urticaria, bullous pemphigoid, lupus erythematosus, pemfisus, epidermolysis bullosa acquired and other inflammatory or allergic conditions of the skin. The agents of the invention can also be used for the treatment of other diseases and conditions, in particular diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eyes, such as conjunctivitis, dry keratoconjunctivitis and conjunctivitis. Spring diseases that affect the nose, including allergic rhinitis; and inflammatory diseases, wherein autoimmune reactions are implied or having an autoimmune component or etiology, including autoimmune hematological disorders, for example hemolytic anemia, aplastic anemia, pure red blood cell anemia and idiopathic thrombocytopenia; systemic lupus erythematosus; polychondritis; scleroderma; Wegener's granulamatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis, Steven-Johnson syndrome; idiotic cigar; inflammatory bowel autoimmune disease, for example, ulcerative colitis and Crohn's disease; endocrine ophthalmopathy, disease Severe, sarcoidosis, alveolitis; chronic hypersensitive pneumonitis; multiple sclerosis; primary biliary cirrhosis; uveitis (anterior and posterior); dry keratoconjunctivitis and spring keratoconjunctivitis; interstitial fibrosis of the lung; psoriatic arthritis; and glomerulonephritis, with and without nephrotic syndrome, for example, including idiopathic nephrotic syndrome or inal-changing neuropathy. Other diseases or conditions that can be treated with the agents of the invention include septic shock; rheumatoid arthritis; osteoarthritis; proliferative diseases, such as cancer; mastocytosis, atherosclerosis; allograft rejection after transplantation; attacks; obesity; restenosis; diabetes, for example, type I diabetes mellitus (juvenile diabetes) and type II diabetes mellitus; diarrheal diseases; Ischemic / reperfusion damage; retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy; and conditions characterized by elevated intraocular pressure or subjection of ocular aqueous humor, such as glaucoma. Other diseases or conditions that can be treated with the agents of the invention include neuropathic pain as described in WO 05/102338. The effectiveness of an agent of the invention for inhibiting inflammatory conditions, for example, in inflammatory diseases of the respiratory tract, can be demonstrated in an animal model, for example, a mouse or rat model, conditions of inflammation of the respiratory tract or other inflammatory conditions, for example, as described by Szarka et al., J Immunol Methods, Vol. 202, p. 49-57 (1997); Renzi et al., Am Rev Respir Dis, Vol. 148, pp. 932-939 (1993); Tsuyuki et al., J Clin Invest, Vol. 96, pp. 2924-2931 (1995); Cernadas et al., Am J. Respir Cell Mol Biol, Vol. 20, pp. 1-8 (1999); and Williams and Galli, J Exp Med, Vol. 192, pp. 455-462 (2000). The agents of the invention are also useful as a co-therapeutic agent for use in combination with other drug substances, such as anti-inflammatory, bronchodilator or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases, such as those mentioned above, for example, as enhancers of therapeutic activity of such drugs or as a means to reduce the required dosage or potential side effects of said drugs. One agent of the invention can be mixed with the other drug substance in a fixed pharmaceutical composition or it can be administered separately, before, simultaneously with or after the other drug substance. Accordingly, the invention includes a combination of an agent of the invention as described hereinbefore with an anti-inflammatory drug substance, bronchodilator, antitussive antihistamine, said agent of the invention and said drug substance being the same pharmaceutical composition or a different.

Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesodine furoate or mometasone; or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60 , 67, 72, 73, 90, 99 and 101), WO 03/035668, WO 03/048181, WO 03/062259, WO 03/064445 and WO 03/07592; non-steroidal glucocorticoid agonist receptor, as described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195 and WO 04/005229; LTB4 antagonists, such as those described in the U.S. Pat. No. 5,451,700; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKine), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plow), Arofylline (Almirall Prodesfarma), PD189659 ( Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID ™ CC-10004 (Celgene), KW-4490 (Kyowa Hakko Kogyo), WO 03/104204, WO 03/104205, WO 04/000814, WO 04/000839 and WO 04/005258 (Merck), as well as those described in WO 98/18796 and WO 03/39544; A2a agonists, such as those described in EP 1052264, EP 1241176, EP 409594A2, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99 / 24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94268, WO 02/00676, WO 02/22630, WO 02/96462 and WO 03/086408; A2b antagonists, such as those described in WO 02/42298; and beta agonists (β) -2-adrenoceptor, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and its pharmaceutically acceptable salts, and compounds (in free or salt or solvate form) of the formula (I) of WO 00/75114, said document is incorporated herein by reference, preferably the compounds of their Examples, especially a compound of the formula: OH and its pharmaceutically acceptable salts, here as compounds (in free or salt or solvate form) of the formula (I) of WO 04/16601. Other ß-2-adrenoreceptor agonists include compounds such as those described in WO 99/64035, WO 01/42193, WO 01/83462, WO 02/066422, WO 02/070490, WO 02/076933, WO 2004/011416 and US 2002/0055651. Said bronchodilator drugs include anticholinergic or antimuscarinic agents, in particular, bromide ipratropium, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), but also those described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 0424021, US 5171744 and US 3714357. Said co-therapeutic antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenylhydramine and fexofenadine hydrochloride. Combinations of agents of the invention and steroids, β-2 agonists, PDE4 inhibitors or LTD 4 antagonists can be used for example in the treatment of COPD or, particularly, asthma. The combinations of the agents of the invention and anticholinergic or anti-uscarinic agents, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonist can also be used, for example, in the treatment of asthma or, particularly, COPD. Other useful combinations of agent agents of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, for example, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6. , CCR-7, CCR-8, CCR-9, CCR-10, CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5; particularly useful with CCR-3 antagonists, such as those described in WO 2002/026723, especially 4-. { 3 [(S) -4- (3,4-dichlorobenzyl) -morpholine-2-ylmethyl] -ureidomethyl} -benzamide and those described in . Also especially useful are CCR-5 antagonists, such as the Schering-Plow antagonists SC-351125, SCH-55700 and SCH-D; Takeda antagonists, such as? / - [[4 - [[[6,7-dihydro-2- (4-methylphenyl) -5H-benzo-cyclohepten-8-yl] carbonyl] amino] phenyl] -methyl chloride ] tetrahydro -? /,? / - dimethyl-2H-pyran-4-aminium (TAK-770); and antagonists of CCR-5, described in US 6166037, WO 00/66558 and WO 00/66559. The agents of the invention can be administered through any appropriate route, for example, orally, for example in the form of a tablet or capsule; parenterally, for example in an intravenous form; through inhalation, for example in the treatment of inflammatory or obstructive diseases of the respiratory tract; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor. The composition may contain a co-therapeutic people, such as an anti-inflammatory bronchodilator or antihistamine drug as described above. Said compositions can be prepared using diluents or conventional excipients and techniques known in the galenic field. In this manner, oral dosage forms may include tablets and capsules. Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g., patches. Compositions for inhalation may comprise aerosol formulations or other sprayable formulations, or dry powder formulations. When the composition comprises an aerosol formulation, it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant, such as HFA 134a or HFA227 or a mixture thereof, and may contain one or more co-solvents known in the art. the technique, such as ethanol (up to 20% by weight); and / or one or more surfactants, such as oleic acid or sorbitan trioleate; and / or one or more bulking agents, such as lactose. When the composition comprises a dry powder formulation, it preferably contains, for example, the compound of the formula (I) having a particle diameter of up to 10 microns., optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps protect against deterioration of product performance due to moisture. When the composition comprises a nebulized formulation, it preferably contains, for example, the compound of the formula (I) either dissolved or suspended, in a carrier containing water, a co-solvent such as ethanol or propylene glycol, and a stabilizer, which can be an agent surfactant. The invention includes: (a) an agent of the invention in inhalable form, for example, in an aerosol composition or other sprayable composition or in inhalable particles, for example, micronized form; (b) an inhalable medicament comprising an agent of the invention in inhalable form; (c) a pharmaceutical product comprising said agent of the invention in inhalable form in association with an inhalation device; and (d) an inhalation device containing an agent of the invention in inhalable form. The doses of the agents of the invention employed in the practice of the present invention, of course, will vary depending on for example, the particular condition to be treated, the desired effect and the mode of administration. In general, the daily doses suitable for oral administration are of the order of 0.01-100 mg / kg.

The invention is illustrated through the following Examples EXAMPLES General Conditions LCMS were recorded in an Agilent 1100 LC system with a column of Waters Xterra MS C18 4.6 x 100 5 μM, eluting with -95% of 10 mM aqueous ammonium bicarbonate in acetonitrile for 2.5 minutes, with negative ion electrospray ionization or 5-95% water + 0.1% TFA in acetonitrile with positive ion electrospray ionization. [M + H] + refers to monoisotopic molecular weights.

Abbreviations CH2CI2 dichloromethane MgSO4 magnesium sulfate aq aqueous DMF N, N-dimethylformamide EtOAc ethyl acetate HCl hydrochloric acid MeCN acetonitrile HPLC high performance liquid chromatography NaH sodium hydroxide TFA trifluoroacetic acid Et3N triethylamine MeOH methanol PS-DIEA polystyrene-diisopropylethylamine Example 1 Preparation of [2-methyl-1-phenethyl-1 H -pyrrolo [2,3-b] pyridin-3-yl) -acetic acid a) (2-methyl-1-phenethyl-1 H) methyl ester - pyrrolo [2,3-b] pyridin-3-yl) -acetic acid To a stirred solution of (2-methyl-1H-indol-3-yl) -acetic acid methyl ester (0.1, 0.49 mmol) and Nal (0.073) g, 0.49 mmoles) in 2 ml of dry DMF at room temperature, 95% NaH (0.012 g, 0.49 mmol) was added in portions. The reaction mixture was stirred at room temperature for 15 minutes.

Then, a solution of commercially available (2-bromo-ethyl) -benzene (0.91 g, 0.49 mmol) in 1 ml of dry DMF was stirred with PS-DIEA for 15 minutes and then added to the reaction mixture. The reaction mixture was stirred at 60 ° C for 2 hours. The reaction mixture was evaporated in vacuo. Purification by flash chromatography on an IST isolute ™ C18 cartridge provided a colorless oil. Another purification by flash chromatography on silica gel using 1: 1 iso-hexane: EtOAc, provided the desired product; [M + H] + 309. To a stirred solution of (2-methyl-1-phenethyl-1 H -pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (10 mg , 0.032 mmol) in 0.5 ml of MeOH at room temperature, was added 1N aqueous NaOH (0.5 ml). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated in vacuo, diluted with water and acidified to an acidic pH with aqueous 2N HCl. CH2Cl2 was added and the organic phase was separated. Evaporation in vacuo afforded the pure product as a white solid. [M + H] + 295.

Example 2 Preparation of [2-methyl-1- (3-phenyl-propyl) -1 H -pyrrolo [2,3-b] pyridin-3-yl] -acetic acid The title compound was prepared analogously to Example 1, replacing (2-bromo-ethyl) -benzene with (3-bromo-propyl) benzene to give [2-methyl-1- (3-phenyl-propyl) -1 H -pyrrolo [2,3-b] pyridine- 3-yl] -acetic; [M + H] + 309.

Example 3 Preparation of [2-methyl-1- (2-phenoxy-ethyl) -1 H -pyrrolo [2,3-b] pyridin-3-yl] -acetic acid The title compound was prepared analogously to Example 1, replacing (2-bromo-ethyl) -benzene with (2-bromo-ethoxy) -benzene to give [2-methyl-1- (2-phenoxy-ethyl) -1 H -pyrrolo [2,3-b] pyridine] -3-yl] -acetic PS. [M + H] + 311.

Example 7 Preparation of acid. { 1 - [2- (4-methanesulfonyl-phenyl) -2-oxo-ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic a) Methyl ester of the acid. { 1 - [2- (4-methanesulfonyl-phenyl) -2-oxo-ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-M} -acetic: To a stirring solution of (2-methyl-1H-indol-3-yl) -acetic acid methyl ester (1.0 g, 4.9 mmol) and Nal (0.73 g, 4.9 mmoles) in 10 ml of dry DMF at room temperature, 95% NaH (0.12 g, 4.9 mmol) was added in portions. The reaction mixture was stirred at room temperature for 15 minutes.

Then a solution of 2-bromo-1- (4-methanesulfonyl-phenyl) -ethanone (1.36 g, 4.9 mmol) in 5 ml of dry DMF was stirred with PS-DIEA for 15 minutes and then added to the reaction mixture. . The reaction mixture was stirred at 55 ° C for 2 hours. The reaction mixture was diluted with water (150 ml) and extracted with dichloromethane (2 x 60 ml). The organic extracts were combined and concentrated to dryness in vacuo. Titration from ethyl acetate followed by the addition of iso-hexane was performed to precipitate the solid impurities that were filtered. The filtrate was concentrated to dryness in vacuo and recrystallized from methanol to give the desired product as a white solid; [M + H] + 401. b) Acid methyl ester. { 1- [2-hydroxy-2- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl} -acetic: To a stirring suspension of acid methyl ester. { 1- [2-hydroxy-2- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl} -acetic (60 mg, 0.15 mmoles) in 4 ml of dry MeOH at 10 ° C was added sodium borohydride (12 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo to remove the methanol, then quenched with 10 ml of water and extracted with dichloromethane (2 x 20 ml). The organic extracts were combined and concentrated to dryness under vacuum. To give the desired product as a white foam; [M + H] + 403. c) Methyl ester of acid. { 1 - [2-Iodo-2- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-i} -acetic: To an stirring solution of triphenylphosphine (39 mg, 0.14 mmol) in 2 ml of dry dichloromethane at room temperature was added iodine (28 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 15 minutes. After this time, imidazole (11 mg, 0.16 mmol) was added followed by the addition of acid methyl ester. { 1- [2-hydroxy-2- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-1 H -pyrrolo [2,3-b] pyridin-3-yl} -acetic (40 mg, 0.10 mmol) as a solution in 1 ml of dry dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness in vacuo at room temperature, then partitioned between dichloromethane / water (20 ml: 10 ml). The organic phase was concentrated to dryness under vacuum at room temperature to give the crude product; [M + H] + 513. d) Acid methyl ester. { 1 - [2- (4-Methanesulfonyl-phenyl) -2-oxo-ethyl] -2-methyl-1 H -pyrrolo [2,3-b] pyridin-3-yl] -acetic To a stirred solution of methyl ester of the acid { 1- [2-Iodo-2- (4-methanesulfonyl-phenyl) -ethyl] -2-methyl-1 H -pyrrolo [2,3-b] pyridin-3-i} Acetic acid (52 mg, 0.10 mmol) in 2 ml of DMSO was added, at room temperature, sodium borohydride (8 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 16 minutes. hours. The reaction mixture was quenched with 20 g of water and extracted with dichloromethane (2 x 40 ml). The organic phases were combined and evaporated in vacuo. Purification by flash chromatography on an IST isolute ™ C18 cartridge using 0.1% TFA in water / MeCN provided the desired product; [M + H] + 387. e) Acid. { 1 - [2- (4-methanesulfonyl-phenyl) -2-oxo-ethyl] -2-methyl-1 H -pyrrole or [2, 3-b] pyridin-3-i} -acetic To a stirred solution of acid methyl ester. { 1- [2- (4-methanesulfonyl-phenyl) -2-oxo-ethyl] -2-methyl-1 H -pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (10 mg, 0.026 mmol) in 0.5 ml of MeOH at room temperature, aqueous 1N NaOH (0.5 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 10 ml of water and extracted with 20 ml of dichloromethane. Purification by flash chromatography on an IST isolute ™ C18 cartridge using 0.1% TFA in water / MeCN provided the desired product; [M + H] + 373. The following examples were prepared using the procedure described herein. Intermediates were prepared by methods well known to those skilled in the art. twenty

Claims (10)

1. A compound of the formula (I) free or salt, wherein: A is independently selected from CH and at least one nitrogen; D is independently selected from CR3 and nitrogen; R1 and R2 are independently H, halogen or alkyl of 1 to 8 carbon atoms, or R1 and R2 together with the carbon atom to which they are attached, form a carbocyclic group of 3 to 15 carbon atoms; R3 is selected from alkyl of 1 to 8 carbon atoms, halogen, cyano, hydroxyl, amino, aminoalkyl, amino (di) alkyl, a carbocyclic group of 3 to 15 carbon atoms, haloalkyl of 1 to 8 carbon atoms, alkoxy from 1 to 8 carbon atoms-alkyl of 1 to 8 carbon atoms, and hydroxyalkyl of 1 to 8 carbon atoms; R4 is selected from halogen, alkyl of 1 to 8 carbon atoms carbon, haloalkyl of 1 to 8 carbon atoms, a carbocyclic group of 3 to 15 carbon atoms, an aromatic carbocyclic group of 6 to 15 carbon atoms, nitro, cyano, alkylsulfonyl of 1 to 8 carbon atoms, alkylsulfinyl of 1 at 8 carbon atoms, alkoxycarbonyl 1 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, haloalkoxy of 1 to 8 carbon atoms, carboxy, carboxyalkyl of 1 to 8 carbon atoms, amino, alkylamino of 1 at 8 carbon atoms, di (some 1 to 8 carbon atoms) amino, SO 2 NH 2, (C 1 -C 8 alkylamino) sulfonyl, di (at least 1 to 8 carbon atoms) aminosulfonyl, aminocarbonyl, alkylaminocarbonyl of 1 to 8 carbon atoms, di (alkyl of 1 to 8 carbon atoms) carbon) aminocarbonyl and a heterocyclic group of 4 to 10 members; each R5 is selected from halogen, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, carbocyclic group of 3 to 15 carbon atoms, nitro, cyano, alkylsulfonyl of 1 to 8 carbon atoms, alkylcarbonyl of 1 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, haloalkoxy of 1 to 8 carbon atoms, carboxy, carboxyalkyl of 1 to 8 carbon atoms, amino, alkylamino of 1 to 8 carbon atoms, di (to Iq of 1 to 8 carbon atoms) amino, aminocarbonyl, alkylaminocarbonyl of 1 to 8 carbon atoms, d i (a Iq u i I of 1 to 8 carbon atoms) aminocarbonyl and a heterocyclic group of 4 to 10 members p5a and p5 are independently selected from H, a 4 to 14 membered heterocyclic group, a carbocyclic group of 6 to 15 aromatic carbon atoms, a carbocyclic group of 3 to 15 carbon atoms, and alkyl of 1 to 8 carbon atoms. carbon optionally substituted by a 4 to 14 membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms, wherein at least one of R 5a or R 5b is alkyl of 1 to 8 carbon atoms substituted by a heterocyclic group of 4 to 14 members or a carbocyclic group of 3 to 15 carbon atoms, or R5a and R5b together with the nitrogen atom to which they are attached form a heterocyclic group of 4 to 14 members, R5c p5d and p5e are independently linked of H, and alkyl of 1 to 8 carbon atoms optionally substituted by a heterocyclic group of 4 to 14 members, a group carbocyclic aromatic of 6 to 15 carbon atoms, a carbocyclic group of 3 to 15 carbon atoms, or R5c together with R5d and R5e together with the nitrogen atoms to which they are attached and the carbonyl, form a heterocyclic group of 5 to 14 members; R5f is H, alkyl of 1 to 8 carbon atoms optionally substituted by a heterocyclic group of 4 to 14 members or a carbocyclic group of 3 to 15 carbon atoms; R59 is selected from H, and alkyl of 1 to 8 carbon atoms optionally substituted by a 4- to 14-membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms; R5f and R59 together with the group NSO2 to which they are attached form a heterocyclic group of 5 to 14 members; R5h and R5? are independently selected from H, and alkyl of 1 to 8 carbon atoms optionally substituted by a 4- to 14-membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms, or R5h and R5 'together with the NCO group to which they are united, they form a heterocycle of 5 to 14 members; R5j and R5k are independently selected from H, and alkyl of 1 to 8 carbon atoms optionally substituted by a 4- to 14-membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms, or R5j and R5k together with the nitrogen to which they are attached, form a Heterocyclic group of 4 to 14 members; R5i R5m and R5q are independently selected from H, and alkyl of 1 to 8 carbon atoms optionally substituted by a 4- to 14-membered heterocyclic group or a carbocyclic group of 3 to 15 carbon atoms, or R51 together with R5m or R5q together with the nitrogen atoms of the aminosulfonamide to which they are attached, they form a 5- to 14-membered heterocyclic group; is selected from a 4- to 14-membered heterocyclic group, an aromatic carbocyclic group of 6 to 15 carbon atoms and a carbocyclic group of 3 to 15 carbon atoms; R6 is H or alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms; W is an aromatic carbocyclic group of 6 to 15 carbon atoms or a heterocyclic group of 4 to 14 members; X is a bond, alkylene of 2 to 8 carbon atoms optionally substituted by one or more groups selected from alkyl of 1 to 8 carbon atoms, halogen, oxo, hydroxyl, amino, aminoalkyl; and amino (dialkyl), (V -) - T- (V), A heterocyclic group of 4 to 14 members, an aromatic carbocyclic group of 6 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms; is C 1 -C 7 alkyl optionally substituted by alkyl of 1 to 8 carbon atoms, halogen, oxo, hydroxyl, amino, amino, amino-alkyl of 1 to 8 carbon atoms, amino (di-alkyl of 1) to 8 carbon atoms); V is alkyl of 0 to 7 carbon atoms optionally substituted by alkyl of 1 to 8 carbon atoms, halogen, oxo, hydroxyl, amino, amino-alkyl of 1 to 8 carbon atoms, amino (di-alkyl of 1 to 8) carbon atoms); T is oxygen or NR7; R7 is H or alkyl of 1 to 8 carbon atoms; wherein each carbocyclic group of 3 to 15 carbon atoms, aromatic carbocyclic group of 6 to 15 members and each heterocyclic group of 4 to 14 members, unless otherwise specified, is independently and optionally substituted by one or more selected groups of halogen, oxo, hydroxy, cyano, amino, nitro, carboxy, alkyl of 1 to 8 carbon atoms, halo-alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkylcarbonyl of 1 to 8 atoms carbon, alkylsulfonyl of 1 to 8 carbon atoms, -SO2NH2, (alkylamino of 1 to 8 carbon atoms) - sulfonyl, di (alkyol of 1 to 8 carbon atoms) aminosulfonyl, aminocarbonyl, alkylaminocarbonyl of 1 to 8 carbon atoms and (1 to 8 carbon atoms) aminocarbonyl, a carbocyclic group of 3 to 15 carbon atoms, an aromatic carbocyclic group of 6 to 15 members, a heterocyclic group of 4 to 14 members, cyano-alkyl of 1 to 8 carbon atoms, hydroxy-alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 8 carbon atoms, amino-alkyl of 1 to 8 carbon atoms, amino (hydroxy) alkyl of 1 to 8 carbon atoms and alkoxy of 1 to 8 carbon atoms optionally substituted by aminocarbonyl; m and n are each, independently, an integer of 0-3; and p is an integer of 0-4.

2. A compound of the formula (I) according to claim 1, in free or salt form, wherein: is R1 and R2 are H; R3 is alkyl of 1 to 8 carbon atoms; R5 is one or two groups independently selected from halogen, haloalkyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 8 carbon atoms or R5 is -SO2N (R5a) R5, wherein R5a and R5b they are independently selected from alkyl of 1 to 8 carbon atoms, and a carbocyclic group of 3 to 15 carbon atoms, or R5a and R5b together with the nitrogen atom to which they are attached form a heterocyclic group of 4 to 14 members; W is a bond, an aromatic carbocyclic group of 6 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms; and X is a bond, alkylene of 2 to 8 carbon atoms or alkylenenoxy of 1 to 8 carbon atoms; and n is 0-

3. 3. A compound of the formula (Ia) according to claim 2, wherein the compound is of the formula (Ia): in free or salt form; wherein: W is phenyl or indanyl; X is a bond, alkylene of 2 to 8 carbon atoms or alkylenoxy of 1 to 8 carbon atoms; R5 is one or two groups independently selected from halogen, haloalkyl of 1 to 8 carbon atoms, alkylsulfonyl of 1 to 8 carbon atoms, -SO2N (R5a) R5, wherein R5a and R5b are independently selected from alkyl of 1 to 8 carbon atoms carbon and a carbocyclic group of 3 to 15 carbon atoms or R5a and R5b together with the nitrogen atom to which they are attached form a heterocyclic group of 4 to 14 members; and n is 0-3.

4. A compound according to claim 1, substantially described with reference to any of the Examples.

5. A compound according to any of claims 1 to 5 for use as a pharmaceutical.

6. Pharmaceutical compositions comprising a compound according to any of claims 1 to 5. The use of a compound according to any of claims 1 to 5 in the manufacture of a medicament for the treatment of a disease mediated by the CRTh2 receiver. 8. The use of a compound according to any of claims 1 to 5 in the manufacture of a medicament for the treatment of neuropathic pain. The use of a compound according to any of claims 1 to 5 in the manufacture of a medicament for the treatment of an inflammatory or allergic condition, in particular an inflammatory or obstructive airway disease. 10. A process for the preparation of compounds of the formula (I) according to claim 1, in free or salt form, which comprises the steps of: (i) (A) for the preparation of the compounds of the formula (I), wherein R6 is H, the cleavage of the ester group -COOR6 in a compound of the formula (I), wherein R6 is alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms, and R1, R2, R4, R5, A, D , W, X, m, and n are as defined above; or (B) for the preparation of compounds of the formula (I), wherein R6 is alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms, reacting a compound of the formula (II) wherein R6 is alkyl of 1 to 8 carbon atoms optionally substituted by a carbocyclic group of 3 to 15 carbon atoms, or a carbocyclic group of 3 to 15 carbon atoms; R1, R2, R4, A, D and m are as defined above with a compound of the formula (III) G -? _ W - (R5) n (MI), wherein G is a leaving portion, and R5, W, X and n as defined above; and (ii) recovering the resulting compound of formula (I) in free or salt form.