MXPA97007379A - Derivatives of imidazo [1,2-a] pirid - Google Patents

Abstract

The present invention provides compounds of the formula (I), and pharmaceutically acceptable derivatives thereof in which: R0 represents halogen, R1 and R2 are independently selected from H, halogen, C1-4alkyl, C1-4alkyl substituted by one or more atoms fluorine, C1-4alkoxy, C1-4hydroxyalkyl, SC1-4alkyl, C (O) H or C (O) C1-4alkyl: and R3 represents C1-4alkyl. The compounds of formula (I) are selective and potent COX-2 inhibitors and are of use in the treatment of pain, fever, inflammation of a variety of conditions and disease

Description

"DERIVADOS DE IMIDAZO [lr2-Aj PIRIDINA" This invention relates to imidazo [1, 2-a] pyridine derivatives, and to processes - for their preparation, to pharmaceutical compositions containing them and to their use in medicine. It has recently been discovered that the enzyme cyclooxygenase (COX) exists in two isoforms, COX-1 and COX-2. COX-1 corresponds to the constitutive enzyme originally identified, whereas COX-2 is rapidly and easily inducible by a number of agents including itogens, endotoxin, hormones, cytokines and growth factors. The rostaglandins generated by the action of COX have both pathological and physiological roles. It is generally believed that COX-1 is responsible for important physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, the inducible form, COX-2, is thought to be responsible for the pathological effects of prostaglandins where the rapid induction of the enzyme occurs in response to such agents as inflammatory agents, hormones, growth factors and cytokines. Therefore, a selective COX-2 inhibitor would have anti-inflammatory, anti- REF: 025678 pyretic and analgesic, without the side effects, potentials associated with the inhibition of COX-1. Now we have found a new group of compounds that are both selective and potent inhibitors of COX-2. The invention thus provides the compounds of the formula (I) and pharmaceutically acceptable derivatives thereof in which: R ° represents halogen; R1 and R2 are independently selected from H, halogen, C? -4alkyl, C? _alkyl substituted by one or more fluorine atoms, C1.alkoxy, C? _4hydroxyalkyl, SC? -4a-alkyl, C (0) H or C (0) C- ^ alkyl; and R3 represents C? -4alkyl. By "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of this ester, of the compounds of the formula (I), or any other compound which on administration to the recipient is capable of providing ( directly or indirectly) a compound of formula (I) or an active metabolite or the residue thereof. It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example, in the preparation of compounds of the formula (I) and the physiologically acceptable salts thereof. . Suitable pharmaceutically acceptable salts of the compounds of the formula (I) include * the acid addition salts formed with organic or inorganic acids, preferably, inorganic acids, for example, hydrochlorides, hydrobromides and sulfates. The term halogen is used to represent fluorine, chlorine, bromine or iodine. The term 'alkyl' as a group or part of a group means a branched or straight chain alkyl group, for example, a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t- group butyl. The substituents R1 and R2 may be at positions 5, 6, 7 or 8 of the pyridine ring of the formula (I), as defined hereinafter: Preferably, R1 is in position 8; Y R2 is in position 7 or, when R1 is different from H, position 5, 6 or 7. More preferably, R1 is in position 8; and R2 is in the 7-position or, when R1 is C? -4alkyl (e.g., methyl), the 5 or 7 position. Preferably, R ° represents fluorine. Preferably, R1 represents H, chloro, bromo, d-4alkyl (e.g., methyl), methyl substituted by one to three fluorine atoms (e.g., CH2F or CF3), C4-4 hydroxyalkyl (e.g. CH2OH or CH (OH) CH3), SC? -4alkyl (eg, SCH3), C (0) H or C (0) C? -4alkyl (eg, C (0) CH3). More preferably, R1 represents H, chloro, bromo, methyl, CH2F, 'GF3, SCH3, C (0) H or C (0) CH3. More preferably, R1 represents C (0) CH3. Preferably, R 2 represents H, chloro, bromo, or C 4 -alkyl (for example, methyl). More preferably, R 2 represents H, bromo or methyl. Preferably, R3 represents methyl. Within the invention there is provided a group of compounds of the formula (I) (group A) wherein: R ° represents fluorine; R1 represents H, chloro, bromo, C? Alkyl (e.g., methyl), methyl substituted by one to three fluorine atoms (e.g., CH2F or CF3), C? -4-hydroxyalkyl (e.g., CH2OH or CH (OH CH3), SCi-4alkyl (for example, SCH3), C (0) H or C (0) C? -alkyl (for example, C (0) CH3); R2 represents H, chloro, bromo, or C? -4alkyl (e.g., methyl); and R3 represents methyl. Within group A, the subgroup of compounds is provided where: R ° represents fluorine; R1 represents H, chloro, bromo, methyl, CH2F, CF3, SCH3, C (0) H or C (0) CH3; R 2 represents H, bromo or methyl; and R3 represents methyl. Within the invention there is provided a group of compounds of the formula (I) (group B) wherein: R ° represents fluorine; R1 is in the 8-position and represents H, chloro, bromo, C? -4alkyl (for example, methyl), methyl substituted by one to three fluorine atoms (for example, CHF or CF3), C? -4-hydroxyalkyl (for example , CH20H or CH (0H) CH3), SC? -4alkyl (eg, SCH3), C (0) H or C (0) C? -4alkyl (eg, C (0) CH3); R2 is in the 7-position or when R1 is different from H, the 5, 6 or 7 position, and represents H, chloro, bromo, or Ci-4alkyl (e.g., methyl); and R3 represents methyl.

Within group B the sub-group of compounds is provided where: R ° represents fluorine; R1 is in position 8 and represents H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C (0) H or C (0) CH3; R2 is in the 7-position or when R1 is methyl, the 5 or 1 position, and represents H, bromo or methyl; and R3 represents methyl. Within the invention there is provided an additional group of compounds of the formula (I) (group C) wherein R ° represents fluorine; R1 is in the 8-position and represents H, chloro, bromo, C? -alkyl (eg, * methyl), methyl substituted by one to three fluorine atoms (eg, CH2F or CF3), C? -4-hydroxyalkyl (eg example, CH20H or CH (0H) CH3), C? -4alkyl (eg, SCH3), C (0) H or C (0) C? -alkyl (eg, C (0) CH3); R2 represents H; and R3 represents methyl. Within group C the sub-group of compounds is provided where: R ° represents fluorine; R1 is in position 8 and represents H, chlorine, bromine, methyl, CH2F, CF3, CH (0H) CH3 SCH3, C (0) H or C (0) CH3; R2 represents H ,, and R3 represents methyl. Within the above groups (and preferred groups) of compounds, especially preferred groups of compounds are those wherein R 1 represents C (0) CH 3. It is understood that the present invention comprises all isomers of the compounds of the formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures). The preferred compounds of the invention are: 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine; 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-methyl-imidazo [1,2-a] pyridine; 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-trifluoromethyl-imidazo [1,2-a] pyridine; 3 (4-fluoro-phenyl) -2- (4-methanesulfonyl) -7-methyl-imidazo [1,2-a] pyridine; 8-chloro-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine; 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-methanesulfanyl-imidazo [1,2-a] pyridine; 8-bromo-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine; 8-fluoromethyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine; 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -7,8-dimethyl-imidazo [1,2-a] pyridine; 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine-8-carbaldehyde 5-bromo-3- (4-fluoro-phenyl) -2- ( 4-methanesulfonyl-phenyl) -8-methyl-imidazo [1,2-a] pyridine; β-bromo-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-methyl-imidazo [1,2-a] pyridine; [3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2- a] pyridin-8-yl] -methanol; (±) 1- [3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2- a] pyridin-8-yl] -ethan-1-ol; and pharmaceutically acceptable derivatives thereof. A particularly preferred compound of the invention is: 8-acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine; and pharmaceutically acceptable derivatives thereof. The compounds of the invention are selective and potent inhibitors of C0X-2. This activity is illustrated by its ability to selectively inhibit C0X-2 on C0X-1. In view of their inhibitory, selective, C0X-2 activity, the compounds of the present invention are of interest for use in veterinary and human medicine, particularly in the treatment of pain, fever and inflammation of a variety of conditions and diseases. Such diseases and conditions are well known in the art and include rheumatic fever; symptoms associated with influenza or other viral infections, such as common cold; pain in the neck and lower back; headache; toothache; strains and fatigue; myositis; neuralgia; synovitis; arthritis, including rheumatic arthritis; degenerative diseases of the joints, including osteoarthritis; gout and ankylosing spondylitis; tendonitis; bursitis; conditions related to the skin, such as psoriasis, eczema, burns and dermatitis; damages, such as'. sports injuries and those from dental and surgical procedures. The compounds of the invention may also be useful for the treatment of other conditions mediated by the selective inhibition of C0X-2. For example, the compounds of the invention can inhibit neoplastic and cellular transformation and the growth of metastatic tumors and therefore be useful in the treatment of certain cancerous diseases, t.al as colon cancer. The compounds of the invention can also prevent neuronal damage by inhibiting the generation of neuronal free radicals (and therefore oxidative stress) and therefore can be of use in the treatment of strokes; epilepsy; and epileptic seizures (which include partial seizures and ioclonic epilepsy, mal seizures and seizures). The compounds of the invention also inhibit the contraction of smooth muscle induced by prostanoid and therefore may be of use in the treatment of dysmenorrhea and premature labor. The compounds of the invention inhibit inflammatory processes and therefore may be of use in the treatment of asthma, allergic rhinitis and respiratory distress syndrome; gastrointestinal conditions such as inflammatory bowel disease, Chron's disease, gastritis, irritable bowel syndrome and ulcerative colitis; and inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodg in disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet syndrome, polio, gingivitis, conjunctivitis and myocardial ischemia. The compounds of the invention may also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and acute damage to eye tissue. The compounds of the invention may also be useful for the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease and Creutzfeldt-Jakob disease). , and vascular dementia (including multi-infarct dementia), as well as dementia associated with lesions that occupy intracranial space, trauma, infections and related conditions (including HIV infection), metabolism, toxins, anoxia, and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Deterioration of Memory Associated with Age. According to a further aspect of the invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable derivative thereof for use in veterinary or human medicine. According to another aspect of the invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition that is mediated by the selective inhibition of C0X-2. According to a further aspect of the invention, it provides a method of treating a human or animal subject suffering from a condition that is mediated by the selective inhibition of COX-2 which comprises administering to the subject an effective amount of a compound of the invention. Formula (I) or a pharmaceutically acceptable derivative. According to another aspect of the invention, there is provided the use of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a therapeutic agent for the treatment of inflammatory disorders. According to a further aspect of the invention, there is provided a method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to the subject an effective amount of a compound of the formula (I) or a derivative pharmaceutically acceptable thereof. It is understood that the reference to treatment includes both the treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise. It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more other therapeutic agents. Examples of agents suitable for adjunctive therapy include pain relievers such as glycine antagonist, a sodium channel inhibitor (e.g., lamotrigine), a substance P antagonist (e.g., an NKi antagonist), acetaminophen or phenacetin; a metalloproteinase matrix inhibitor; an inhibitor of nitric oxide synthase (NOS) (for example, an inhibitor of iNOS or an nNOS); an inhibitor of relief, or action, of tumor necrosis factor a; an antibody therapy (e.g., a therapy of monoclonal antibodies); a stimulant, which includes caffeine; an H2-antagonist, such as ranitidine; an antacid, such as aluminum or magnesium hydroxide; an antiflatulent, such as simethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-deoxyeedrine; an antitussive, such as codeine, hydrocodone, carmifen, carbetapentana, or dextrametorfan; a diuretic; or a sedative or non-sedating antihistamine. It is understood that the present invention covers the use of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents.

The compounds of the formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in veterinary or human medicine. These compositions may conveniently be present for use in the conventional manner in admixture with one or more physiologically acceptable carriers or excipients. The compounds of the formula (I) and their pharmaceutically acceptable derivatives can be formulated for administration in any suitable manner. They can, for example, be formulated for topical administration or administration by inhalation or, more preferably, by oral, transdermal or parenteral administration. The pharmaceutical composition can be in such a form that it can effect the controlled release of the compounds of the formula (I) and their pharmaceutically acceptable derivatives. For oral administration, the pharmaceutical composition may take the form of, for example, tablets (including sub-lingual tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients. For transdermal administration, the pharmaceutical composition can be in the form of a transdermal patch, such as a transdermal iontophoretic patch. For parenteral administration, the pharmaceutical composition can be given as a continuous infusion or injection (eg, intravenously, intravascularly or subcutaneously). The compositions may take such forms as suspensions, solutions or emulsions in aqueous or oily vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. For administration by injection, they may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative. Alternatively, by parenteral administration the active ingredient may be in the powder formed for reconstitution with a suitable vehicle. The compounds of the invention can also be formulated as a warehouse preparation. These long acting formulations can be administered by implantation (eg, subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly salt soluble. As discussed above, the compounds of the invention can also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the formula (I) or a pharmaceutically acceptable derivative thereof together with an additional therapeutic agent. The combinations referred to above may conveniently be present for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations can be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. When a compound of the formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease, it is stated that the dose of each compound may differ from that when the compound is used alone. The appropriate doses will be readily appreciated by those skilled in the art. A proposed daily dose of a compound of the formula (I) for the treatment of man is 0.01 mg / kg to 500 mg / kg, such as 0.05 mg / kg to 100 mg / kg, for example, 0.1 mg / kg to 50 mg / kg, which can be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and the route of administration. Thus, for example, a daily dose of 0.25 mg / kg to 10 mg / kg may be suitable for systemic administration. The compounds of the formula (I) and the pharmaceutically acceptable derivatives thereof can be prepared by any method known in the art for the preparation of compounds of analogous structure. Suitable methods for the preparation of the compounds of the formula (I) and the pharmaceutically acceptable derivatives thereof are described below. In the formulas following R ° to R3 are as defined in formula (I) above unless otherwise stated and that Lg represents a leaving group, such as a sulfonate (eg, methanesulfonate) or a halogen ( for example, bromine). Thus, according to a first process (A), the compounds of the formula (I) can be prepared by reacting a compound of the formula (II) or a protected derivative thereof with a compound of the formula (III) or a protected derivative thereof. The reaction is conveniently carried out in a solvent, such as a polar solvent (eg, acetonitrile or isopropanol); at high temperature, for example, reflux; and optionally in the presence of a base, such as an alkali metal bicarbonate or carbonate (for example, potassium carbonate). Appropriate leaving groups or atoms with respect to Lg in formula (II) are described in many standard texts in organic chemistry, for example, in Table 10.10 on page 357 of "Organic Chemistry.

Advanced "by Jerry March, fourth edition (Wiley, 1992).

It will be appreciated by a person skilled in the art that the choice of a particular leaving group in the above reaction may depend on the meanings of R ° to R3 (and therefore the compound of the formula (I) desired) and the reaction conditions used. According to another process (B), the compounds of the formula (I) can be prepared by reacting a compound of the formula (IV) or a protected derivative thereof with an oxidizing agent. Conveniently, the oxidation is effected using a monopersulfate compound, such as potassium peroxymonosulfate (known as Oxone ™) and the reaction is carried out in a solvent, such as an aqueous alcohol, (eg, aqueous methanol), and in between. 78 ° C and room temperature. According to another process, the compounds of the formula (I) can be prepared by interconversion, using other compounds of the formula (I) as precursors. Thus, for example, the compounds of the formula (I) wherein R 1 or R 2 represent chloro, bromo or iodo can be prepared from the corresponding compound of the '. formula (I) wherein R 1 or R 2 represent H, by treatment with an appropriate halogenating agent (e.g., chlorine-, bromate- or iodidation agent). Suitable agents include the corresponding N-halosuccinimides. Conveniently, the reaction is carried out in the presence of a solvent, such as a halogenated hydrocarbon (eg, chloroform) and at room temperature. The compounds of the formula (I) wherein R 1 or R 2 represents C 4 -4 alkyl substituted by one or more fluorine atoms, can be prepared from the compound of the formula (I) wherein R 1 or R 2 represents the corresponding C 4 -hydroxyakyl by treatment with an adequate source of fluoride. Suitable sources of fluorine include, for example, diethylaminosulfur trifluoride. Conveniently, the reaction is carried out in the presence of a solvent, such as a halogenated hydrocarbon (for example, dichloromethane). and at reduced temperature, such as -78 ° C. • The compounds of the formula (I) wherein R 1 or R2 represent C (0) H can be prepared from the corresponding compound of the formula (I) wherein R1 or R2 represent CH20H by oxidation. Suitable oxidizing agents include, for example, manganese (IV) oxide. Conveniently, the oxidation is effected in the. presence of a solvent, such as a halogenated hydrocarbon (eg, chloroform), and at elevated temperature (e.g., reflux). The compounds of the formula (I) wherein R 1 or R 2 represent C 4 -hydroxyakyl, and wherein the hydroxy group is attached to the carbon atom bonded to the pyridine ring, can be prepared by reduction of the compound of the formula (I) wherein R1 or R2 represent the corresponding aldehyde or ketone. Suitable reducing agents include hydride reducing agents, such as diisobutylaluminum hydride. Conveniently, the reduction is effected in the presence of a solvent, such as a halogenated hydrocarbon (for example, dichloromethane), and at a reduced temperature, such as -78 ° C.

As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the processes described above to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Another process (D) for preparing the compounds of the formula (I) thus comprises deprotecting the protected derivatives of the compounds of the formula (I). The protecting groups used in the preparation of the compounds of the formula (I) can be used in the conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W. Green, second edition, (John Wiley and Sons, 1991), which also describes methods for the removal of such groups. The compounds of the formula (II) can be prepared from the compounds of the formula (V) by conventional means Thus, the compounds of the formula (II) wherein Lg represents a halogen can be prepared from the compounds of the formula (V) by treatment with a halogenating agent, at reduced temperature and in a solvent, such as a chlorinated hydrocarbon. For example, where Lg represents bromine, the reaction is conveniently carried out with a brominating agent, such as bromine in the presence of a strong acid (for example, hydrobromic acid in acetic acid). Compounds of the formula (II) wherein Lg represents a sulfonate can be prepared from the compounds of formula (V) first by oxidation to the corresponding α-hydroxy ketone, followed by treatment with a sulfonation agent. Suitable oxidizing agents include, for example, Pb (0Ac), dimethyldioxirane and those descr in F A Davis, J. Org. Chem., 1984, 49 (17), 3284. Suitable sulfonating agents include sulfonylhalons, such as sulfonylchlorides (for example, methanesulfonylchloride). Sulfonylation is conveniently effected in the presence of a base, such as an amine (e.g., triethylamine); and in a solvent, such as a halogenated hydrocarbon. The compounds of the formula (V) can be prepared from the compounds of the formula (VI) by treatment with an alkaline sulfinate, such as sodium sulfinate. Conveniently, the reaction is carried out in polar solvent, such as dimethyl sulfoxide, and at elevated temperature. The compounds of the formula (III) are either known compounds or can be prepared by methods of the literature such as those descr in, for example, J A Turner, J. Org. Chem., 1983, 48 3401., M Malinowski, Bull. Soc. Chim. Belg. , 1988, 97, 51; W O Siegl, J. Het. Chem., 1981, 18 1613-18; or F.Trecourt et al, J. Chem. Soc., Perkin Trans.1 1990, 9, 2409-2415. The compounds of the formula (VI) are either known compounds or can be prepared by methods such as those descr in the literature, for example, N Seko et al, Chem. Pharm. Bull., 1991, 39 (3), 651-7, or I Lalazori et al, J. Med. Chem. 1971, 14 1138-40 The compounds of the formula (IV) or the protected derivatives thereof can be prepared using conventional chemistry, for example , chemistry analogous to that descr herein for the preparation of the compounds of the formula (I). Certain intermediate compounds descr above are novel compounds, and it should be understood that all of the new intermediates herein form additional aspects of the present invention. The compounds of the formula (II) and (IV) are key intermediates and represent particular aspects of the present invention. Conveniently, the compounds of the invention are isolated following the preparation in the form of the free base. The pharmaceutically acceptable acid addition salts of the compounds of the invention can be prepared using conventional means. Solvates (eg, hydrates) of a compound of the invention can be formed during the process of making one of the above-mentioned process steps. The following Examples illustrate the invention but do not limit the invention in any way. All temperatures are in ° C. Flash chromatography was performed using Merck 9385 silica. Thin layer chromatography (TLC) was carried out on silica plates. The NMR was performed on a Brucker 300 MHz spectrometer, using CDC13 as a solvent. The chemical changes are given in ppm with respect to tetramethylsilane as a reference for internal chemical change. The following abbreviations are used: Et = ethyl, s = singlet, d = doublet, t = triplet and m = multiplet.

Intermediate 1 2- (4-Fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone.

A mixture of 2- (4-fluoro-phenyl) -1- (4-fluoro-phenyl) -ethanone (3 g) and sodium methansulfinate (1.58 g) in dry dimethyl sulfoxide (10 ml) was heated to 105-110. ° under nitrogen for 18h. The cooled reaction mixture was poured into water (500 ml) and the mixture was extracted with ethyl acetate. The combined organic extracts were absorbed in silica and purified by flash chromatography eluting with ethyl acetate: hexane (1: 1) to give the title compound as a white solid (2.1 g). p.f. 115-116 ° ^ ef: I Lalazori et al, J. Med. Chem. 1971, 14, 1138-40.

Intermediate 2 2-Bromo-2- (-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone A solution of 2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (1.6 g) in dichloromethane (30 ml) and glacial acetic acid (15 ml) was cooled to 0 ° and treated with 48% hydrobromic acid (3 drops). A solution of bromine (875 mg) in acetic acid (2 ml) was added and stirring was continued for 4 hours. The mixture was diluted with dichloromethane (35 ml) and the solution was washed with water, dried, and concentrated to give the title compound as a yellow solid. (2.0 g). p.f. 124-1 26 ° Intermediate 3 3-Trifluoromethyl-pyridin-2-ylamine A * mixture of 2-chloro-3-trifluoromethyl-pyridine (5 g), copper iodide (1) (5 g) and liquid ammonia (50 ml) was heated in an autoclave at 80 ° C. (internal temperature) for 28 hours. The cooled reaction mixture was converted to a slurry with methanol / chloroform (1 / 1-250 ml) and filtered. The filtrate was absorbed on silica and purified by flash chromatography eluting with ethyl acetate / hexane (1/1) to yield the title compound as a white solid (1.4 g). p.f. 71-72 ° MH '= 163 Tic Si02, Rf 0.50 (ethyl acetate / hexane (1/1)) UV / KMn04 detection Intermediate 4 2- (4-Fluoro-phenyl) -1- (4-methanesulfanyl-phenyl) -ethanone A mixture of 2- (4-fluoro-phenyl) -1- (4-fluorophenyl) -ethanone (10.0 g), sodium metantiolate (3.0 g) and dimethyl sulfoxide (10 ml) was heated to ca. 100 ° for 8h under nitrogen. The cooled mixture was added to water (250 ml), stirred for 10 min and filtered. The resulting solid was crystallized from isopropanol (100 ml) twice to give the title compound as a white solid (5.0 g). p.f.143-144 ° Intermediate 5 2-Bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfanyl-phenyl) -ethanone A solution of 2- (4-fluoro-phenyl) -1- (4-methanesulfanyl-phenyl) -ethanone (4.8 g) in dichloromethane (75 ml) and acetic acid (30 ml) at 0 ° containing 48% HBr (15 drops) was treated dropwise with bromine (2.6 g) in acetic acid (6 ml). The solution was stirred at 0 ° for 10 min and at room temperature for 3 h, it was diluted. with dichloromethane (100 ml) and washed with water (2 x 100 ml). The dried organic phase (MgSO4) was evaporated and the residue was triturated with diethyl ether (30 ml) to give the title compound as a white solid (4.5 g). p.f. 117-119 °. Tic Si02 (Et20: hexane 1: 1) Rf 0.6 det u.v. KMn0. isopropanol Intermediate 6 3- (4-Fluoro-f > enyl) -2- (4-methanesulfanyl-phenyl) -imidazo [1,2-a] pyridine A solution of 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfanyl-phenyl) -ethanone (4.0 g) and 2-aminopyridine (1.2 g) in acetonitrile (25 ml) was refluxed under nitrogen for 2 h and left at room temperature for 16 h. The solution was evaporated and the residue was purified by flash column chromatography eluting with diethyl ether (applied in CH2C12) to give the title compound as a white solid (1.6 g) • m.p. 115-118 ° Tic Si02 (Et20) Rf 0.5 det u.v., isopropanol.

Intermediate 7 8-Chloro-3- (4-fluoro-phenyl) -2- (4-methanesulfanyl-phenyl) -imidazo [1,2-a] pyridine n-Butyllithium in hexane (1.6 m, 0.35 ml) was added dropwise to a solution of 3- (4-fluorophenyl) -2- (4-methansulphane-phenyl) -imidazo [1,2-a] pyridine (167 mg) in tetrahydrofuran (2 ml) at -78 ° under nitrogen. The solution was stirred at -78 ° per lh and treated with hexachloroethane (142 mg) in tetrahydrofuran (0.25 ml). The solution was allowed to warm to room temperature for 30 min and water (2 ml) was added. The mixture was extracted with ethyl acetate (2 x 5 ml) and the dried extract (MgSO) was evaporated to give the title compound as a cream solid (180 mg). p.f. 148-149 ° MH * = 369 Intermediate 8 3-Methylsulfanyl-pyridin-2-ylamine A solution of 2,2-dimethyl-N-pyridin-2-yl-propionamide2 (890 mg) in dry tetrahydrofuran (30 ml) was cooled to -78 ° and treated with a solution of n-butyllithium (6.25 ml, 1.6 M) This solution was stirred at '. 0 ° for 4 hours and a solution of dimethyldisulfide (235 mg) in tetrahydrofuran (5 ml) was added and stirring continuously at room temperature for 30 minutes. 2N hydrochloric acid (1 ml) was added and the solution was concentrated in vacuo. A mixture of the residue and 2N hydrochloric acid (15 ml) was heated to reflux for 4 hours. The cooled reaction mixture was made basic by the addition of solid potassium carbonate. The basic mixture was extracted with ethyl acetate (15 ml), the organic extract was dried (Na2SO4) and absorbed on silica. The title compound was obtained by flash chromatography eluting with ethyl acetate / cyclohexane (1/1) as a colorless oil (490 mg). MH + = 141 Tic, SiO2, Rf 0.48, (ethyl acetate / cyclohexane (1/1)) u.v. detection, KMn0 2Ref: J A Turner J. Org. Chem. 1983,48,3401 Intermediate 9 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine-8-carboxylic acid methyl ester A solution of 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (700 mg), and 2-amino-nicotinic acid methyl ester (287 mg) in dry acetonitrile it was heated at reflux overnight. The reaction mixture was concentrated on silica and the title compound was obtained by flash chromatography eluting with ethyl acetate: cyclohexane 5: 1 as a yellow solid (176 mg). MHT = 425 Tic, Si02 Rf 0.21 (ethyl acetate: cyclohexane 5: 1) uv detection Intermediate 10 8-Acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfanyl-phenyl) -imidazo [1 , 2-a] pyridine n-Butyllithium in hexane (1.6 m, 0.5 ml) was added dropwise to a solution of 3- (4-fluoro-phenyl) -2- (4-methansulfaphyl-phenyl) -imidazo. [1, 2-a] pyric (250 mg) in tetrahydrofuran (3 ml) at -78 ° under nitrogen. The solution was stirred at -78 ° per lh and treated with N-methyl, N-methoxyacetamide (90 mg) in tetrahydrofuran (0.25 ml). The solution was allowed to warm to room temperature for 60 min and water (10 ml) was added. The mixture was extracted with ethyl acetate (2 x 5 ml) and the dried extract (MgSO) was evaporated. The residue was purified on a silica column, eluting with hexane: diethylether (3: 1) to give the title compound as a cream solid (130 mg). MH + = 377 Tic SiO2 (Et2Q) Rf 0.9 det uv Example 1 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine.

A solution of 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (233 mg) and 2-aminopyridine (59 mg) in dry acetonitrile was heated to reflux during the night. The reaction mixture was adsorbed in silica and purified by flash chromatography eluting with ethyl acetate to give the title compound as a cream solid (100 mg). MH + = 367.2. p.f. 198-200 ° Example 2 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-methyl-imidazo [1,2-a] pyridine A solution of 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (233 mg) and 2-amino-3-ethylpyridine (68 mg) in dry acetonitrile ( 10 ml) was heated to reflux overnight. The reaction mixture was adsorbed in silica and purified by flash chromatography eluting with dichloromethane / methanol (19: 1) to give the title compound as a pale brown solid (61 mg). MH * -381 p.f. 180-182 ° Example 3 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-trifluoromethyl-imidazo [1,2-a] pyridine A solution of 2-bromo-2- (4-fluoro-phenyl) -1- ' (4-methanesulfonyl-phenyl) -ethanone (742 mg), and 3-trifluoromethyl-pyridin-2-ylamine (324 mg,) in dry acetonitrile containing potassium carbonate (276 mg) was heated to reflux overnight. The reaction mixture was concentrated in silica and purified by flash chromatography eluting with ethyl acetate to give a yellow solid. Further purification by recrystallization from propan-2-ol afforded the title compound as yellow crystals (21.0 mg). p.f. 260-261 ° Analysis: Found: C, 57.7; H, 3.0; N, 6.2; S, 7.3 C2? H? 4F4N202S Requires: C, 58.1; H, 3.25; N, 6.45; S, 7.4% MH + = 435 Tic, Si02, Rf 0.25, (ethyl acetate) uv detection.

Example 4 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl) -7-methyl-imidazo [1,2-a] pyridine A solution of 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (233 mg) and 2-amino-4-methylpyridine (68 mg) in acetonitrile (10 ml) ) was heated to reflux for 18 hours. The cooled reaction mixture was absorbed in silica and the title compound was obtained by flash chromatography eluting with ethyl acetate / hexane (1/1), as a buff solid (105 mg). p.f. 194-196 ° MH + = 381 Tic, Si02 Rf 0.26, (ethyl acetate / hexane (2/1)) u.v.

Example 5 8-Chloro-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine A suspension of 8-chloro-3- (4-fluoro-phenyl) -2- (4-methansulphane-phenyl) -imidazo [1, 2-a] pyridine (150 mg) in methanol (8 ml) and water (2 ml) was treated with Oxone ™ (561 mg) and stirred for 2 h at room temperature. The resulting suspension was treated with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The dried extract (MgSO4) was evaporated and the resulting solid was treated with boiling isopropanol (8 ml) for (10 min), cooled and filtered to give the title compound as a white solid (85 mg). p.f. 242-244 ° Tic Si02 (Et20) RF 0.5 det u.v., KMn04 MH + = 401 Example 6 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-methansulfañyl-imidazo [1,2-a] pyridine A solution of 3-methylsulfanyl-pyridin-2-ylamine (140 mg) and 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (371 mg) in acetonitrile (15 ml) was heated to reflux overnight. The cooled reaction mixture was absorbed in silica and the title compound was obtained by flash chromatography eluting with ethyl acetate / cyclohexane (1/1) as a white solid (179 mg). p.f. 224-226 ° M = 413 tic, Si02, Rf 0.60 (ethyl acetate / cyclohexane (1/1)) detection u.v./KMn04 Example 7 8-Bromo-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine A solution of 3-bromo-pyridin-2-ylamine (173 mg) and 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (371 mg) in acetonitrile (15 mg). ml) was heated to reflux overnight. On cooling to room temperature the title compound crystallized from the solution and was isolated by filtration as a white solid (241 mg). p.f. 266-268 ° MHT = 446 Analysis: Found: C, 53.5; H, 3.0; N, 6.2; F, 4.3; S, 7.1 - • C20H? 4BrFN2O2S Requires: C, 53.9; H, 3.2; N, 6.3: F, 4.3; S, 7.2% tic, Si02, Rf 0.61 (Ethyl acetate / cyclohexane (2/1)) uv detection, KMn04 3Ref: M. Malinowski, Bull. Soc. Chim. Belg. 1988, 97, 51 Example 8 8-Fluoromethyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine A solution of 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine-8-methanol (200 mg) in dichloromethane (10 ml) was added to a cold solution of diethylaminosulfur trifluoride (0.067 ml) in dichloromethane (4 ml) at -78 ° for 5 minutes. The solution was allowed to warm to room temperature for 30 minutes. Water (15 ml) was carefully added with stirring, the organic fa was separated, dried (Na 2 SO) and absorbed in silica. The title compound was obtained by flash chromatography eluting with ethyl acetate / cyclohexane (1/1) as a white solid which was further purified by crystallization from propan-2-ol (10 ml) to yield white crystals (85 mg). p.f. 221-222 ° MH '= 399 Analysis Found: C, 63.1; H, 3.9; N, 6.8, F, 9.4: S, 8.1 C2: H16F2N202S Requires: C, 63.3; H, 4.05; N, 7.1, F; 9.5: S, 8.05% Example 9 3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -7,8-dimethyl-imidazo [1,2-a] pyridine A solution of 3,4-dimethyl-pyridin-2-ylamine (122 mg) and 2-bromo-2- (4-fluoro-phenyl) -1- (methanesulfonyl-phenyl) -ethanone (371 mg) in acetonitrile (15 mg). ml) containing potassium carbonate (138 mg) was heated to reflux overnight. The cooled mixture was absorbed in silica and the title compound was obtained by flash chromatography eluting with ethyl acetate / cyclohexane (1/1) as a white solid. Crystallization from propan-2-ol (10 ml / produced white crystals (136 mg), mp 228-230 ° MHT = 39"5 Analysis Found: C, 66.6; H, 4.7; N, 6.9; F, 4.8; , 8.2 C22H19N2F02S Requires: C, 67.0, H, 4.85, N, 7.1, F, 4.8, S, 8.1% 4Ref: WO Siegl, J Het, Chem. 1981, 18, 1613-18 E emplo 10 3- (4- Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [l, 2-a] pyridine-8-carbaldehyde A solution of [3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridin-8-yl] -methanol (500 mg) and manganese oxide (IV ) (1.32 g) chloroform (50 ml) was heated to reflux for 16 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in silica. The title compound was obtained by flash chromatography eluting with ethyl acetate / cyclohexane (4/1) as a clear yellow solid (315 mg). MH * = 395 Analysis Found: C, 63.71; H, 3.55; N, 6.89: S, 8.07. C2? H? 5FN203S Requires: C, 63.95; H, 3.83; N, 7.10; S, 8.13%.

Example 11 5-Bromo-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-methyl-imidazo [1,2-a] pyridine A solution of 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-methyl-imidazo [1,2-a] pyridine (380 mg) in chloroform (20 ml) was treated with N solid bromosuccinimide (178 mg) in one portion at room temperature, and the resulting solution was stirred overnight. Water (50 ml) was added and the organic phase was collected, dried (Na2SO4) and absorbed in silica. The title compound was obtained by flash chromatography eluting with cyclohexane / ethyl acetate (1/1) as a white solid (106 mg). p.f. 277-279 ° (dec) MH + = 461 Tic, Si02, Rf 0.22 (Ethyl acetate / cyclohexane (1/1)) uv detection, KMn04 Example 12 8-Acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine A suspension of 8-acetyl-3- (4-fluoro-phenyl) -2- (4-methansulphane-phenyl) -imidazo [1,2-a] pyridine (130 mg) in methanol (8 ml) and water (2 ml) was treated with Oxone ™ (436 mg) and stirred for 3 h at room temperature. The resulting suspension was treated with water (50 ml) and extracted with ethyl acetate (50 ml). The dried extract (MgSO4) was evaporated and the resulting solid was treated with boiling isopropanol (3 ml) for (10 min), cooled and filtered to give the title compound as a white solid (85 mg). p.f. 236-237 ° Tic SiO? (Et0) Rf 0.5 det u.v., KMn04 MH + = 401 Example 13 6-Bromo-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -8-methyl-imidazo [1,2-a] pyridine A mixture of l-amino-4-bromo-2-methylpyridine (500 mg), 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (1.0 g) and acetonitrile (10 ml) were refluxed under nitrogen for 20 h and evaporated. The residue was triturated with diethyl ether (20 ml) for 5 min, cooled and filtered. The procedure was repeated to give the title compound as a yellowish-slow powder (580 mg). MH + = 461 Tic Si02 (Et2G) Rf 0. 6 detection u. v, KMn04 Example 14 8-Acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine A solution of 3-acetyl-2-aminopyridine5 (2.50 g) and 2-bromo-2- (4-fluorophenyl) -1- (4-ethanesulfonyl) -ethanone (6.82 g) in acetonitrile (125 ml) containing sodium bicarbonate (2.31 g) was heated to reflux for the night. The mixture was filtered hot and the filtrate was allowed to cool to ambient temperature. The title compound crystallized from solution and was isolated by distillation as a yellow solid (3.58 g). Tic Si02 Rf 0.34 (ethyl acetate / hexane, 1.3: 1) uv detection, iodine: H NMR 3.04 (3H, s, CH3S02-), 3.16 (3H, s, CH3CO-), 6.90 (1H, t, J = 7.0 Hz, H-6), 7.31 (2H, t, J = 8.8 Hz) and 7.45 (2H, dd, J = 5.2 Hz, 8.8 Hz) -C6H4F-, 7.85 (2H, d, J = 8.4 Hz) and 7.91 (2H, d, J = 8.4 Hz) -C6H4S02, 7.93 (1H, dd, J = 1.1, 7.0 Hz, H-7), 8.02 (1 H, dd, J = ll, 7.0 Hz, H-5) . 5 Ref: F. Trecourt et al, J. Chem. Soc., Perkin Trans. 1 1990, 9, 2409-2415 Example 15 [3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridin-8-yl] -methanol A solution of 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine-8-carboxylic acid methyl ester (1.85 g) in dry tetrahydrofuran (130 ml) ) was cooled to -78 ° and treated with diisobutylaluminum hydride (17.4 ml, 1.0 M solution in dichloromethane). Once the addition was complete, the mixture was allowed to warm to 25 ° and stirring was continued for 2 h. Methanol (80 ml) was added and the mixture was concentrated in silica. The title compound was obtained by flash chromatography eluting with dichloromethane / ethanol / ammonia, 100/8/1, as a white foam (1.54 g). MH + = 397 Tic (Si02) Rf 0.28 (dichloromethane / ethanol / ammonia, 100/8/1) U.V. detection Example 16 (±) 1- [3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2- a] pyridin-8-yl] -ethan-1-ol A solution of [3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2- a] pyridin-8-yl] -methanol (204 mg) in dry dichloromethane (10 ml. ) was cooled to -78 °. A solution of diisobutylaluminum hydride (1.0 M in dichloromethane 1 ml) was added dropwise and the mixture was allowed to warm to room temperature for 30 minutes. Methanol (10 ml) was added in one portion and stirring continued for an additional 30 minutes. The reaction mixture was absorbed in silica and the title compound was obtained by flash chromatography eluting with ethyl acetate as a white solid (120 mg) m.p. 201-203 ° T.l.c. Si02 Rf 0.45 (ethyl acetate) U.V. detection Example 17-Tablets a) Compound of the invention 5.0 mg Lactose 95.0 mg Microcrystalline cellulose 90.0 mg Crosslinked polyvinylpyrrolidone 8.0 mg Magnesium stearate 2.0 mg Compression weight 200.0 mg The compound of the invention, microcrystalline cellulose, lactose and crosslinked polyvinylpyrrolidone are screened through a 500 micron sieve and mixed in a suitable mixer. The magnesium stearate is screened through a 250 micron sieve and mixed with the active mixture. The mixture is compressed into tablets using suitable punches. b) Compound of the invention 5.0 mg Lactose 165.0 mg Pregelatinised starch 20.0 mg Crosslinked polyvinylpyrrolidone 8.0 mg Magnesium stearate 2.0 mg Compression weight 200.0 mg The compound of the invention, lactose and pregelatinized starch are mixed together and granulated with aq. The wet mass is dried and ground. The magnesium stearate and cross-linked polyvinylpyrrolidone are screened a. through a 250 micron sieve and mix with the granule. The resulting mixture is compressed using suitable tablet punches.

Example 18-Capsules a) Compound of the invention 5.0 mg Lactose 193.0 mg Magnesium stearate 2.0 mg Weight of filling 200.0 mg The compound of the invention and pregelatinized starch are screened through a sieve of 500 microns in size, mixed together and lubricated with magnesium stearate, (sieved through a 250 micron sieve). The mixture is filled into the hard gelatin capsules of a suitable size. b) Compound of the invention 5.0 mg Lactose 177.0 mg Polyvinylpyrrolidone 8.0 mg Crosslinked polyvinylpyrrolidone 8.0 mg Magnesium stearate 2.0 mg Weight of filling 200.0 mg The compound of the invention and lactose are mixed together and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried and ground. The magnesium stearate and the cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and mixed with the granules. The resulting mixture is filled into the hard gelatin capsules of an appropriate size.

Example 19-Syrup a) Compound of the invention 5.0 mg Hydroxypropylmethylcellulose 45.0 mg Propyl hydroxybenzoate 1.5 mg Butyl hydroxybenzoate 0.75 mg Sodium saccharine 5.0 mg Sorbitol solution 1.0 ml Suitable shock absorbers q.s. Suitable flavors q.s. Purified water up to 10. ml The hydroxypropylmethylcellulose is dispersed in a portion of warm purified water together with the hydroxybenzoates and the solution is allowed to cool to room temperature. Saccharin, sodium flavors and sorbitol solution are added to the volume solution. The compound of the invention is dissolved in a portion of the remaining water and added to the bulk solution. Suitable dampers can be added to control the pH in the region of maximum stability. The solution is made to the volume, filtered and filled into suitable containers.

Example 20-Injection formulation% w / v Compound of the invention 1.00 Water for injections B.P. up to 100.00 The sodium chloride can be added to adjust the tonicity of the solution and the pH can be adjusted to that of maximum stability and / or to facilitate the solution of the compound of the invention using diluted acid or alkali or by the addition of suitable buffer salts. Also, anti-fatiguers and metal chelating salts can be included. The solution is rinsed, made up to the final volume with water and the pH is again measured and adjusted if necessary, to provide 10 mg / ml of the compound of the formula (I). The solution can be packaged for injection, for example, by filling and sealing in ampoules, vials or syringes. The vials, vials or syringes can be aseptically filled (for example, the solution can be sterilized by filtration and filled in sterile vials under aseptic conditions) and / or terminally sterilized (for example, by heating in an autoclave using one of the acceptable cycles). The solution can be packaged under an inert nitrogen atmosphere. Preferably, the solution is filled in ampoules, sealed by melting the glass and terminally sterilized. The additional sterile formulations are. prepare in a similar manner containing 0.5, 2.0 and 5% w / v of the compound of the formula (I), to give respectively 5, 20 and 50 mg / ml of the compound of the formula (I).

Biological Data The inhibition activity against human COX-1 and COX-2 was evaluated in COS cells that have been transfected. stably with cDNA for human COX-1 and human COX-2. 24 Hours prior to experimentation, COS cells were transferred from the 175 cm2 flasks in which they grew, into 24 cavity cell culture plates using the following procedure. The incubation medium, which is Dulbecco's modified medium eagles (DMEM) to which heat-inactivated fetal calf serum (10% v / v) was added, penicillin (100 U / ml), streptomycin (100 μg / ml) ) and geneticin (600 μg / ml), was removed from a flask of confluent cells (1 flask in confluence 7 contains approximately 1 x 10 cells). 10 ml of phosphate buffered saline (PBS) was added to the flask to wash the cells. Having removed the PBS, the cells were rinsed in 10 ml of trypsin for 20 seconds, after which the trypsin was removed and the flask was placed in an incubator (37 °) for 1-2 minutes until the cells reached be detached The flask was then removed from the incubator and the cells resuspended in 10 ml of fresh incubation medium. The contents of the flask were transferred to a sterile 250 ml container and the volume of the incubation medium was consecutively brought to 100 ml. One ml of the cell suspension was pipetted into each well of the 4x24-well cell culture plates. The plates were then placed in an incubator (37 ° C, 95% air / 5% C02) overnight. If more than 1 flask was used, the cells were combined before being dispensed into the 24-well plates. After incubation overnight, the incubation medium was completely removed from the 24-well cell culture plates and replaced with 250μl fresh DMEM (37 ° C). The test compounds were constituted at 250x the required test concentration in DMSO and were added to the wells in a volume of 1 μl. The plates were then mixed gently by swirling and then placed in an incubator for 1 hour (37 ° C, 95% air / 5% C02). After the incubation period, 10 μl of arachidonic acid (750 μM) was added to each well to give a final concentration of arachidonic acid of 30 μM. The plates were then incubated for 15 minutes, after which, the incubation medium was removed from each cavity of the plates and stored at -20 ° C, prior to the determination of the levels of prostaglandin E2 (PGE2). using enzyme immunoassay. The inhibitory potency of the test compounds was expressed as an IC50 value, which is defined as the concentration of the compound required to inhibit the PGE2 release of the cells by 50%. The selectivity ratio of the inhibition of COX-1 against COX-2 was calculated by comparing the respective IC50 values. The following IC50 values for the inhibition of COX-2 and COX-1 were obtained for compounds of the invention:

Claims (19)

1. Compounds of the formula (I and pharmaceutically acceptable derivatives thereof, characterized in that R ° represents halogen; R1 and R2 are independently selected from H, halogen, C? -alkyl, C? -alkyl substituted by one or more fluorine atoms, C? -alkoxy, C? -4-hydroxyalkyl, SC? -4alkyl, C (0) H or C (0) C? -alkyl: and R3 represents C? -4alkyl.

2. Compounds according to claim 1, characterized in that R3 represents methyl.

3. Compounds according to claim 1 or 2, characterized in that R ° represents fluorine.

4. Compounds according to any of claims 1 to 3, characterized in that R1 represents H, chloro, bromo, C? _ Alkyl (e.g., methyl), methyl substituted by one to three fluorine atoms (e.g., CH2F or CF3) , C? -4-hydroxyalkyl (eg, CH2OH or CH (OH) CH3), SC? -alkyl (eg, SCH3), C (0) H or C (0) C? -4alkyl (eg C (0)) ) CH3).

5. Compounds according to any one of claims 1 to 4, characterized in that R2 represents H, chloro, bromo or C? -alkyl (for example, methyl).

6. Compounds according to any of claims 1 to 5, characterized in that R ° represents fluorine; R1 represents H, chloro, bromo, C? -alkyl (for example, methyl), methyl substituted by one to three fluorine atoms (for example, CH2F or CF3), C? -4hydroxyalkyl (for example, CH20H or CH (0H) ) CH3), SC? -4alkyl (for example, SCH3), C (0) H or C (0) C? -4alkyl 'for example, C (0) CH3): R2 represents H, chlorine, bromine, or C? -4alkyl (for example, methyl); and R3 represents methyl.

7. Compounds according to any of claims 1 to 6, characterized in that R represents fluorine; R1 represents H, chloro, bromo, methyl, CH2F, CF3, SCH3, C (0) H or C (0) CH3: R2 represents H, bromo or methyl; and R3 represents methyl.

8. Compounds according to any of claims 1 to 7, characterized in that R1 is in position 8; and R2 is in position 7 or, when R1 is different from H, position 5, 6 or 7.

9. Compounds according to any of claims 1 to 8, characterized in that R1 is in position 8; and R2 is in the 7-position or, when R1 is C? -alkyl (eg, methyl), the 5 or 7 position.

10. Compounds according to any of claims 1 to 9, characterized in that R1 represents. C (0) CH3.

11. 8-Acetyl-3- (4-fluoro-phenyl) -2- (4-methansul-fonyl-phenyl) -imidazo [1,2- a] pyridine and pharmaceutically acceptable derivatives thereof.

12. Compounds according to any of claims 1 to 11, characterized in that the compound of the formula (I) is in the form of a hydrochloride, hydrobromide or sulfate.

13. A process for the preparation of the compound of the formula (I) and pharmaceutically acceptable derivatives thereof, as defined in any of claims 1 to 12, characterized in that it comprises: (A) reacting a compound of the formula (II) or a protected derivative thereof, wherein Lg represents a leaving group, with a compound of the formula (III). or a protected derivative thereof; or (B) reacting a compound of the formula (IV) or a protected derivative thereof with an oxidizing agent; or (C) interconversion of a compound of the formula (I). in another compound of the formula (I); or (D) deprotecting a protected derivative of the compound of the formula (I); and optionally converting compounds of formula (I) prepared by any of the processes of (A) to (D) into pharmaceutically acceptable derivatives thereof.

14. A pharmaceutical composition, characterized in that it comprises a compound of the formula (I) or a pharmaceutically acceptable derivative thereof, as defined in any of claims 1 to 12 in the mixture with one or more physiologically acceptable carriers or excipients.

15. A compound of the formula (I) or a pharmaceutically acceptable derivative thereof, as defined in any of claims 1 to 12 for use in veterinary or human medicine.

16. A compound of the formula (I) or a pharmaceutically acceptable derivative thereof as defined in any of claims 1 to 12 for use in the treatment of a condition that is mediated by the selective inhibition of COX-2.

17. A method for treating an animal or human subject suffering from a condition that is mediated by the selective inhibition of COX-2, characterized in that it comprises administering to the subject an effective amount of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof. it is defined in any of claims 1 to 12.

18. The use of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof as defined in any of claims 1 to 12 for the manufacture of a therapeutic agent for the treatment of inflammatory disorders.

19. A method for treating an animal or human subject suffering from an inflammatory disorder, the method is characterized in that it comprises administering to the subject an effective amount of a compound of the formula (I) or a pharmaceutically acceptable derivative thereof as defined in any of claims 1 to 12.