JPH11501049A - Imidazo [1,2-a] pyridine derivative - Google Patents

Abstract

(57) The present invention provides compounds of formula (I) and pharmaceutically acceptable derivatives thereof, wherein R ⁰ represents halogen, and R ¹ and R ² are H, halogen, C _{1 -4} alkyl, C _1-4 alkyl substituted by one or more fluorine atoms, C _1-4 alkoxy, C _1-4 hydroxyalkyl, SC _1-4 alkyl, C (O) H or C (O) Independently selected from C _1-4 alkyl, and R ³ represents C _1-4 alkyl. The compounds of formula (I) are potent and selective inhibitors of COX-2 and are used in the treatment of pain, fever, and inflammation of various conditions and diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION                   Imidazo [1,2-a] pyridine derivatives   The present invention relates to an imidazo [1,2-a] pyridine derivative, a method for producing them, And pharmaceutical compositions containing them and their use in medicine.   The enzyme cyclooxygenase (COX) has two isoforms, COX-1 and COX-1. It was recently discovered to exist at X-2. COX-1 is a constitutive yeast originally identified. COX-2 is a mitogen, endotoxin, hormone, It is easily inducible with a number of factors, including tokines and growth factors. In general , The prostaglandins generated by the action of COX have physiological roles and pathology Have both biological roles. In general, COX-1 is associated with gastrointestinal integrity and renal blood flow. It is thought to play an important role in important physiological functions such as maintenance. versus In contrast, an inducible form of COX-2 indicates that rapid induction of this enzyme is an inflammatory factor, e. Prosta, which occurs in response to factors such as lemon, growth factors and cytokines It is thought to play an important role in the pathological effects of glandins. Accordingly Thus, a selective inhibitor of COX-2 is a potential side effect associated with inhibition of COX-1. Without action, it has anti-inflammatory, antipyretic and analgesic properties. We are now C Discover a new group of compounds that are effective and selective inhibitors of OX-2 Was.   Thus, the present invention provides compounds of formula (I) and pharmaceutically acceptable derivatives thereof I will provide a. (Where   R⁰Represents halogen,   R¹And R^TwoIs H, halogen, C_1-4Alkyl, one or more fluorine atoms C substituted by_1-4Alkyl, C_1-4Alkoxy, C_1-4Hydroxyalkyl , SC_1-4Alkyl, C (O) H or C (O) C_1-4Independently selected from alkyl And   R^ThreeIs C_1-4Represents alkyl)   Pharmaceutically acceptable derivatives are pharmaceutically acceptable salts of the compounds of formula (I), solvents Solvates or esters, or salts or solvates of such esters, or When administered to a subject, it provides a compound of formula (I) or an active metabolite or residue thereof. Means other compounds that can be provided (directly or indirectly).   For pharmaceutical use, the salts mentioned above are physiologically acceptable salts, but other salts For example, in the preparation of compounds of formula (I) and their physiologically acceptable salts. It will be appreciated that it can be used.   Suitable pharmaceutically acceptable salts of the compounds of formula (I) are inorganic or organic acids, preferably Or an addition salt formed with an inorganic acid, such as a hydrochloride, hydrobromide or sulfate Include.   The term "halogen" is used to represent fluorine, chlorine, bromine or iodine You.   The term “alkyl” refers to a straight or branched chain radical as a group or part of a group. Alkyl group, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl , S-butyl or t-butyl group.   Substituent R¹And R^TwoIs 5,6 of the pyridine ring of formula (I), as defined hereinafter. , 7 or 8 can be present:   Preferably, R¹Is in position 8 and R^TwoIs in position 7 or R¹ Is other than H, R^TwoIs at position 5, 6, or 7. More preferably, R¹ Is in position 8 and R^TwoIs in position 7 or R¹Is C_1-4Alkyl ( For example, when methyl)^TwoIs at position 5 or 7.   Preferably, R⁰Represents fluorine.   Preferably, R¹Is H, chlorine, bromine, C_1-4Alkyl (eg, methyl), 1 to Methyl substituted by three fluorine atoms (eg, CH_TwoF or CF_Three), C_1-4 Hydroxyalkyl (eg, CH_TwoOH or CH (OH) CH_Three), SC_{1 -Four} Alkyl (eg, SCH_Three), C (O) H or C (O) C_1-4Alkyl (example For example, C (O) CH_Three). More preferably, R¹Is H, chlorine, bromine or Chill, CH_TwoF, CF_Three, SCH_Three, C (O) H or C (O) CH_ThreeRepresents Than Preferably, R¹Is C (O) CH_ThreeRepresents   Preferably, R^TwoIs H, chlorine, bromine, C_1-4Represents an alkyl (eg, methyl) . More preferably, R^TwoRepresents H, bromine or methyl.   Preferably, R^ThreeRepresents methyl.   Within the scope of the present invention, one of the compounds of the formula (I) in which each group has the following meaning: A group (Group A) is provided: R⁰Represents fluorine, R¹Is H, chlorine, Bromine, C_1-4Alkyl (eg, methyl), substituted with 1 to 3 fluorine atoms Methyl (eg, CH_TwoF or CF_Three), C_1-4Hydroxyalkyl (eg, CH_TwoOH or CH (OH) CH_Three), SC_1-4Alkyl (eg, SCH_Three), C (O) H or C (O) C_1-4Alkyl (eg, C (O) CH_Three) And R^Two Is H, chlorine, bromine, or C_1-4Represents an alkyl (eg, methyl);^Three Represents methyl.   Within the scope of Group A, a subgroup of compounds wherein each group has the following meaning: Provided: R⁰Represents fluorine, R¹Is H, chlorine, bromine, methyl, CH_TwoF , CF_Three, SCH_Three, C (O) H or C (O) CH_ThreeAnd R^TwoIs H, bromine or Represents methyl, and R^ThreeRepresents methyl.   Within the scope of the present invention, other compounds of the formula (I) in which each group has the following meaning: A group (Group B) is provided: R⁰Represents fluorine, R¹Is in 8th place And H, chlorine, bromine, C_1-4Alkyl (eg, methyl), 1-3 Methyl substituted with an elemental atom (eg, CH_TwoF or CF_Three), C_1-4Hydroxy Alkyl (eg, CH_TwoOH or CH (OH) CH_Three), SC_1-4Alkyl ( For example, SCH_Three), C (O) H or C (O) C_1-4Alkyl (eg, C (O ) CH_Three) And R^TwoIs in position 7 or R¹Is other than H, 5 , 6 or 7 and is H, chlorine, bromine, or C_1-4Alkyl (for example, Represents methyl) and R^ThreeRepresents methyl.   Within the scope of group B, the compound subgroups in which each group has the following meaning: Is provided by: R⁰Represents fluorine, R¹Is in position 8, and H, chlorine, bromine , Methyl, CH_TwoF, CF_Three, SCH_Three, C (O) H or C (O) CH_ThreeRepresents R^TwoIs in position 7 or R¹Is in the 5 or 7 position when is methyl And H, bromine or methyl;^ThreeRepresents methyl.   Within the scope of the present invention, further compounds of the formula (I) in which each group has the following meaning: Group (Group C) is provided: R⁰Represents fluorine, R¹Is in 8th place And H, chlorine, bromine, C_1-4Alkyl (eg, methyl), 1-3 Methyl substituted with a nitrogen atom (eg, CH_TwoF or CF_Three), C_1-4Hydroxy Sialkyl (eg, CH_TwoOH or CH (OH) CH_Three), SC_1-4Alkyl (For example, SCH_Three), C (O) H or C (O) C_1-4Alkyl (for example, C ( O) CH_Three) And R^TwoRepresents H, and R^ThreeRepresents methyl.   Within Group C, a subgroup of compounds wherein each group has the following meaning: Provided: R⁰Represents fluorine, R¹Is in position 8, and H, chlorine, odor Elemental, methyl, CH_TwoF, CF_Three, SCH_Three, C (O) H or C (O) CH_ThreeRepresents , R^TwoRepresents H, and R^ThreeRepresents methyl.   Within the above group of compounds (and preferred groups), the compounds A particularly preferred group of is R¹Is C (O) CH_ThreeIs a group representing.   The present invention relates to all geometries of compounds of formula (I) and pharmaceutically acceptable derivatives thereof. Isomers, tautomers and optical forms, and mixtures thereof (eg, racemic It is to be understood that all isomers, including isomer mixtures, are included.   Preferred compounds of the present invention are as follows: 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-methanesulfur (Honyl-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; 6-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] -ethane-1-o Le; And pharmaceutically acceptable derivatives thereof.   Particularly preferred compounds of the invention are as follows: 8-acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl -Phenyl) -imidazo [1,2-a] pyridine and its pharmaceutically acceptable Derivatives.   The compounds of the present invention are effective and selective inhibitors of COX-2. This activity Sex is indicated by the ability to selectively inhibit COX-2 over COX-1.   The compound of the present invention has a COX-2 inhibitory activity, and And veterinary medicine, especially for the treatment of pain, fever and inflammation of various symptoms and diseases. Of importance in medical use. Such conditions and diseases are Well known in the art, including: rheumatic fever; Symptoms associated with the or other viral infections, such as cold; lower back and neck Pain; headache; toothache; sprains and contusions; myositis; neuralgia; synovitis; arthritis, for example Rheumatoid arthritis; degenerative joint diseases such as osteoarthritis; gout and ankylosing spondylitis Tendonitis; bursitis; skin-related symptoms such as psoriasis, eczema, burns and skin Flame; injury, eg, resulting from motor injury and surgical and dental procedures.   The compounds of the present invention may also be used in other conditions mediated by the selective inhibition of COX-2. May be effective for the treatment of   For example, the compounds of the present invention can be used to increase malignant transformation of cells and neoplasms and metastatic tumors. Inhibits growth and is therefore effective in the treatment of certain cancerous diseases, such as colon cancer There will be.   The compounds of the present invention also provide neuronal free radicals (and thus oxidative strikes). Res) prevents neuron damage by inhibiting the development of Seizures; epilepsy; and epileptic seizures (large seizures, small seizures, myoclonic epilepsy) (Cancer and partial seizures).   The compounds of the present invention also inhibit prostanoid-induced smooth muscle contraction and therefore It could be used in the treatment of dysmenorrhea and preterm labor.   The compounds of the invention inhibit the inflammatory process, and therefore, asthma, allergic Rhinitis and respiratory distress syndrome; gastrointestinal symptoms such as inflammatory bowel disease, Crohn's disease, Gastritis, irritable bowel syndrome and ulcerative colitis; and vascular disease, migraine, nodular Periarteritis, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, type I diabetes, severe muscle Asthenia, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's disease In the treatment of illnesses such as symptomatic groups, polymyositis, gingivitis, conjunctivitis and myocardial ischemia Could be used.   The compounds of the present invention may also be useful in treating ocular diseases such as retinitis, retinopathy, uveitis and the like. It is effective in treating acute damage to eye tissue.   The compositions of the present invention may also be useful for cognitive disorders such as dementia, especially degenerative dementia (senile Dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and And Creutzfeldt-Jakob disease), and vascular dementia (multi-infarct dementia) And lesions occupying the intracranial space, trauma, infection and related Symptoms (including HIV infection), metabolism, toxins, oxygen and vitamin deficiencies Recurrent dementia; cure of age-related mild cognitive impairment, especially age-related memory impairment It is effective in medical treatment.   According to another aspect of the present invention, there is provided a formula for use in human or veterinary medicine, A compound of I) or a pharmaceutically acceptable derivative thereof is provided.   According to another aspect of the invention, treatment of conditions mediated by selective inhibition of COX-2. Of formula (I) and pharmaceutically acceptable derivatives thereof for use in therapy Is provided.   According to another aspect of the present invention, a condition mediated by selective inhibition of COX-2 is provided. Effective amount of a compound of formula (I) in a human or animal subject and a pharmaceutically acceptable salt thereof A method of treating said subject, comprising administering the derivative to be treated. It is.   According to another aspect of the present invention, there is provided a method for producing a therapeutic agent for treating an inflammatory disease. There is provided the use of a compound of formula (I) and pharmaceutically acceptable derivatives thereof.   According to another aspect of the present invention, it is effective for human or animal subjects with an inflammatory disease. Administering an amount of a compound of formula (I) and a pharmaceutically acceptable derivative thereof. There is provided a method of treating the subject, comprising:   References to treatment, unless otherwise indicated, refer to treatment of established symptoms and prophylactic treatment. It should be understood that it encompasses both treatments.   The compounds of the present invention can be conveniently used in combination with one or more other therapeutic agents. It will be understood that Examples of suitable drugs for additional treatment are pain relief agents, e.g. For example, glycine antagonists, sodium channel inhibitors (eg, Lamotrigine), substance P antagonists (eg, NK₁Antagonis G), acetaminophen or phenacetin; matrix metalloproteiner Inhibitors; nitric oxide synthase (NOS) inhibitors (eg, iN OS or nNOS inhibitor); or the release or action of tumor necrosis factor α Inhibitors; antibody therapy (eg, monoclonal antibody therapy); caffeine Included stimulators; H_Two-Antagonists, such as ranitidine; antacids, such as Aluminum hydroxide or magnesium hydroxide; antiflatulents such as Con; decongestants such as phenylephrine, phenylpropanolamine, Pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xy Lometazoline, propylhexedrine, or levodesoxyephedrine Antitussives, such as codeine, hydrocodone, carmiphene, carbetapentane Or dextramethorphan; diuretics; or sedated or nonsedated antihistamines Agents. The present invention relates to a compound of formula (I) or a pharmaceutically acceptable derivative thereof: Should be understood to encompass the use of a combination of the drug with one or more other therapeutic agents. It is.   The compounds of formula (I) and pharmaceutically acceptable derivatives thereof are preferred in the form of a pharmaceutical composition. Administered conveniently. Thus, in another aspect of the invention, a human or veterinary medicine Compounds of formula (I) and pharmaceutically acceptable derivatives thereof for use in medicine There is provided a pharmaceutical composition comprising Such compositions are prepared in a conventional manner. For use in admixture with one or more physiologically acceptable carriers or excipients Provided for   The compound of formula (I) and pharmaceutically acceptable derivatives thereof can be prepared by any suitable method. Can be prescribed. For example, they are administered topically or by inhalation Or, more preferably, for oral, transdermal or parenteral administration Can be prescribed. The pharmaceutical composition comprises a compound of formula (I) and a pharmaceutically acceptable salt thereof. It can be in such a form as to release the derivative in a controlled manner.   For oral administration, the pharmaceutical compositions may be prepared, e.g., using conventional excipients. Tablets (including sublingual tablets), capsules, powders, solutions, It can take the form of a syrup or suspension.   For transdermal administration, the pharmaceutical composition is a transdermal patch, such as a transdermal iontophoretic patch It can be administered in the form of   For parenteral administration, the pharmaceutical compositions can be injected or continuous infused (eg, intravenously, (Intravascular or subcutaneous). The composition is oily or aqueous Can take such forms as suspensions, solutions or emulsions in Formulations such as agents, stabilizers and / or dispersants can be included. injection These are preferably unit doses or multiple doses with preservatives added. It can take the form of a dosage.   Also, for parenteral administration, the active ingredient may be in powder form for reconstitution with a suitable vehicle. It can be in the form.   The compounds of the present invention can also be formulated as a depot preparation. like this Long acting formulations can be implanted (eg, subcutaneously or intramuscularly) or injected intramuscularly Can be administered. Thus, for example, the compounds of the invention may be suitable polymers or Is a hydrophobic substance (eg, as an emulsion in an acceptable oil) or an ion-exchange tree Fats, or poorly soluble derivatives, such as poorly soluble salts, can be formulated .   As mentioned above, the compounds of the present invention may also be used in combination with other therapeutic agents. Wear. The invention thus relates, in a further aspect, to a compound of formula (I) or a drug thereof. Provides combinations comprising a chemically acceptable derivative together with a further therapeutic agent I do.   The foregoing combinations may be conveniently administered for use in the form of a pharmaceutical formulation. And therefore a combination as described above together with a pharmaceutically acceptable carrier or excipient. Pharmaceutical formulations comprising comprise a further aspect of the invention. Such unions Individual components may be used separately or in combination in a pharmaceutical formulation, either sequentially or simultaneously. Can be administered.   A compound of formula (I) or a pharmaceutically acceptable derivative thereof is treated against the same disease state When used in combination with a second therapeutically active second therapeutic agent, the dose of each compound May differ from dosage when used alone. Appropriate dosages are readily available to those skilled in the art. Will understand.   The suggested daily dose of the compound of formula (I) for human treatment is 0.01 mg / kg to 500 mg / kg, for example, 0.05 mg / kg to 100 mg / kg, for example For example, 0.1 mg / kg to 50 mg / kg, which is conveniently 1 to 4 times. Administered in dosages. The exact dosage to be used depends on the age and condition of the patient, and It will depend on the route of administration. Therefore, for example, 0.25 mg / kg to 1 A daily dose of 0 mg / kg will be suitable for systemic administration.   The compound of formula (I) or a pharmaceutically acceptable derivative thereof is a compound of similar structure It can be produced by methods known in the art for production.   A suitable process for the preparation of the compound of formula (I) or a pharmaceutically acceptable derivative thereof is described below. Describe. In the formulas below, unless otherwise specified,⁰~ R^ThreeIs in the above formula (I) And Lg is a leaving group such as a sulfonate (eg, Tansulfonate) or halogen (eg, bromine).   According to the first method (A), the compound of the formula (I) has the formula (II) Or a protected derivative thereof of formula (III) Or a protected derivative thereof, it can. The reaction is conveniently carried out in a solvent, such as a polar solvent (eg, acetonitrile). Or isopropanol) at elevated temperature, for example at reflux temperature, if necessary. Base, for example, an alkali metal bicarbonate or carbonate (eg, potassium carbonate) In the presence of   Suitable leaving atoms or groups for Lg in formula (II) are those related to organic chemistry. Many standard textbooks, such as 'Advanced Organic Chemistry', Jerry Ma rch, 4th edition (Wiley, 1992), page 10, Table 10. In the above reaction, the selection of a specific group is R⁰~ R^ThreeMeaning (therefore, the desired formula (I) One of skill in the art will understand that the .   According to another method (B), the compound of formula (I) is Or a protected derivative thereof by reacting the compound with an oxidizing agent. Can be This oxidation is conveniently carried out with monopersulfate compounds, such as Potassium xymonosulfate (Oxone^TMIs carried out using And the reaction is carried out in a solvent such as an aqueous alcohol (eg, aqueous methanol) In a temperature between −78 ° C. and ambient temperature.   According to another method (C), the compound of formula (I) is a compound of the formula (I) It can be produced by interconversion using a compound.   For example, R¹Or R^TwoA compound of formula (I) in which represents chlorine, bromine or iodine is R¹Or R^TwoFrom a corresponding compound of formula (I) wherein H represents H Ie, chlorination, bromination or iodination) it can. Suitable halogenating agents include the corresponding N-halosuccinimide. Conveniently, the reaction is carried out in a solvent such as a halogenated hydrocarbon (eg, chloropho ) At ambient temperature.   R¹Or R^TwoIn which is substituted by one or more fluorine atoms_1-4Table showing alkyl The compound of formula (I)¹Or R^TwoCorresponds to C_1-4Represents hydroxyalkyl It can be prepared from the compound of formula (I) by treatment with a suitable fluorine source. Suitable sources of fluorine include, for example, diethylamine trifluoride. Good city In some cases, the reaction is carried out in a solvent such as a halogenated hydrocarbon (eg, dichlorometha ) At low temperature, for example at -78 ° C.   R¹Or R^TwoRepresents a C (O) H, the compound of formula (I)¹Or R^TwoIs CH_Two It can be prepared by oxidation from the corresponding compound of formula (I) representing OH. Suitable oxidizing agent Includes, for example, manganese (IV) oxide. Advantageously, this oxidation is carried out with a solvent, For example, high temperatures (reduction) in the presence of halogenated hydrocarbons (eg, chloroform) Flow).   R¹Or R^TwoIs C_1-4Represents hydroxyalkyl and the hydroxy group is pyridyl The compound of formula (I) connected to the carbon atom attached to the ring is¹Or R^TwoBut Can be prepared by reduction of a compound of formula (I) which represents the corresponding aldehyde or ketone. You. Suitable reducing agents include hydride reducing agents such as diisobutylaluminum hydride. Um. Conveniently, the reduction is carried out in a solvent such as a halogenated hydrocarbon ( Performed at low temperature, for example, at -78 ° C in the presence of Is done.   As those skilled in the art will appreciate, in the above method, one or more of the Is necessary or necessary to protect the functional groups to prevent unwanted side reactions. There is something new.   Thus, another method (D) for preparing a compound of formula (I) is a compound of formula (I) Deprotecting the protected derivative of the product.   The protecting groups used in the preparation of the compounds of formula (I) can be used in a conventional manner. Wear. See, for example, 'Protective Groups in Organic Synthesis', Theodora  The protecting group described in W. Green, 2nd edition (John Wiley and Sons, 1991) It also describes a method for removing such groups.   Compounds of formula (II) are of formula (V) From the compound of formula (I) by conventional means.   The compound of the formula (II) in which Lg represents a halogen can be obtained from the compound of the formula (V) at a low temperature. By treatment with a halogenating agent in a solvent, for example, a chlorinated hydrocarbon Can be manufactured. For example, if Lg represents bromine, the reaction will be a brominating agent, such as bromine. Conveniently performed in the presence of a strong acid (eg, hydrobromic acid in acetic acid) using hydrogen Is done.   Compounds of formula (II) wherein Lg represents a sulfonate include compounds of formula (V) Oxygenate the corresponding α-hydroxyketone and then treat with a sulfonating agent Can be manufactured by Suitable oxidizing agents include, for example, Pb (OAc)_Four, Dimethyldi Oxirane and FA Davis, J. Mol. Org. Chem., 1984,49 (17)Described in 3284 Oxidizing agents. Suitable sulfonating agents are sulfonyl halides (eg, , Methanesulfonyl chloride). Sulfonation is carried out with a base, e. Solvent, for example, halogenated carbon in the presence of It is conveniently carried out in hydrogen hydride.   Compounds of formula (V) are of the formula (VI) Treating the compound with an alkali sulfinate, such as sodium sulfinate Can be manufactured. Conveniently, the reaction is carried out in a polar solvent, e.g. It is carried out at an elevated temperature in tyl sulfoxide.   Compounds of formula (III) are known compounds or are described in the literature, for example Can be prepared by the method described in the following literature: 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; Trecourt et al. Chem. So c. Perkin Trans.1 1990,9, 2409-2415.   Compounds of formula (VI) are known compounds or are described in the literature, for example, It can be produced by the method described in the following literature: N Seko et al, Chem. Pha rm. Bull., 1991,39, (3), 651-7, or I Lalazori et al., J. Am. Med. Chem. 19 71,14, 1138-40.   Compounds of formula (IV) or protected derivatives thereof may be prepared by conventional chemical techniques, for example, , A chemical method similar to that described herein for the preparation of the compounds of formula (I) It can be manufactured using the method.   Certain of the aforementioned intermediates are novel compounds, and all new Regular intermediates form another aspect of the present invention. Compounds of formulas (II) and (IV) It is a major intermediate and represents a particular aspect of the present invention.   Advantageously, the compounds of the invention are isolated after working up in the form of the free base. Pharmaceutically acceptable addition salts of the compounds of this invention may be prepared using conventional means. it can.   Solvates (e.g., hydrates) of the compounds of the invention can be prepared by one of the steps of the method described above. It can be formed during the finishing procedure.   The following examples illustrate the invention. These examples do not limit the invention. No. All temperatures are in ° C. Flash chromatography was performed on Merck (Me rck) 9385 silica. Thin layer chromatography (Tl c) was performed on a silica plate. NMR for Brucker CDCl as solvent by 300Mhz spectrophotometer_ThreeWas carried out using Conversion Chemical shift is δ ppm relative to tetramethylsilane as internal chemical shift reference Is given by The following abbreviations are used: Et = ethyl, s = singlet, d = 2 Multiplet, t = triplet and m = multiplet.   Intermediate 1 2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl)- Etanon   2- (4-Fluoro-phenyl) in dry dimethyl sulfoxide (10 ml) -1- (4-fluoro-phenyl) -ethanone¹(3 g) and methane sulfone A mixture of sodium acid (1.58 g) was added at 105-110 ° under a nitrogen atmosphere for 1 hour. Heated for 8 hours. The cooled reaction mixture was poured into water (500 ml) and the mixture Was extracted with ethyl acetate. The combined organic extracts are adsorbed on silica and Purify by chromatography and elute with ethyl acetate: hexane (1: 1) This gave the title compound as a white solid (2.1 g). 115-116 °¹ References: I Lalazori et al., J. Med. Chem. 1971.14, 1138-40.   Intermediate 2 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfonyl- Phenyl) -ethanone   2- (4-Fluoro) in dichloromethane (30 ml) and glacial acetic acid (15 ml) (Ro-phenyl) -1- (4-methanesulfonyl-phenyl) -ethanone (1.6 The solution of g) was cooled to 0 ° and treated with 48% hydrobromic acid (3 drops). Acetic acid (2m A solution of bromine (875 ml) in 1) was added and stirring was continued for 4 hours. This mixture Is diluted with dichloromethane (35 ml), the solution is washed with water, dried and concentrated This gave the title compound as a yellow solid (2.0 g). 124-126 °   Intermediate 3 3-trifluoromethyl-pyridin-2-ylamine   2-chloro-3-trifluoromethyl-pyridine (5 g), copper iodide (1) ( 5 g) and liquid ammonia (50 ml) in an autoclave at 80 ° (Internal temperature) for 28 hours. The cooled reaction mixture is Stir with rum (1 / 1-250 ml) and filter. Absorb filtrate on silica And purified by flash chromatography, ethyl acetate / hexane (1 Elution with (/ 1) afforded the title compound as a white solid (1.4 g). Melting point 71-72 ° MH⁺= 163 Tlc SO_Two, Rf 0.50 (ethyl acetate / hexane (1/1)) detection UV / KMnO_Four   Intermediate 4 2- (4-fluoro-phenyl) -1- (4-methanesulfanyl-phenyl) −Ethanone   2- (4-fluoro-phenyl) -1- (4-fluoro-phenyl) -ethano (10.0 g), sodium methanethiolate (3.0 g) and dimethyls A mixture of rufoxide (10 ml) was heated to about 100 ° for 8 hours under a nitrogen atmosphere . Cooled methylene chloride was added to water (250 ml), stirred for 10 minutes, filtered Was. The resulting solid is crystallized twice from isopropanol (100 ml) And the title compound was obtained as a white solid (5.0 g). 143-144 °   Intermediate 5 2-bromo-2- (4-fluoro-phenyl) -1- (4-methanesulfanyl -Phenyl) -ethanone   Dichloromethane (75 ml) containing 48% HBr (15 drops) and acetic acid 2- (4-fluoro-phenyl) -1- (4-methanesulfa) in (30 ml) A 0 ° solution of (nyl-phenyl) -ethanone (4.8 g) was prepared in acetic acid (6 ml). Treated dropwise with bromine (2.6 g). The solution is stirred at 0 ° for 10 minutes, Stir at room temperature for 3 hours, dilute with dichloromethane (100 ml) and add water (2 × 1 00 ml). Dry (MgSO_FourThe organic phase was evaporated and the residue Treatment with ethyl ether (30 ml) gave the title compound as a white solid. (4.5 g). 117-119 ° Tlc SO_Two(Et_TwoO: hexane 1: 1) Rf 0.6 detection u. v. KMnO_Four , Isopropanol.   Intermediate 6 3- (4-fluoro-phenyl) -2- (4-methanesulfanyl-phenyl) -Imidazo [1,2-a] pyridine   2-Bromo-2- (4-fluoro-phenyl) in acetonitrile (25 ml) ) -1- (4-Methanesulfanyl-phenyl) -ethanone (4.0 g) and A solution of 2-aminopyridine (1.2 g) was stirred under a nitrogen atmosphere for 2 hours and brought to room temperature. And left for 16 hours. The solution is evaporated and the residue is flash chromatographed. Purified by luffy, diethyl ether (CH_TwoCl_TwoEluted with This gave the title compound as a white solid (1.6 g). 115-118 ° Tlc SiO_Two(Et_TwoO) Rf 0.5 detection 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 ml; 0.35 ml) was charged in a nitrogen atmosphere. At -78 °, 3- (4-fluoro) in tetrahydrofuran (2 ml) was added. (Ro-phenyl) -2- (4-methanesulfanyl-phenyl) -imidazo [1, 2-a] pyridine (167 mg) was added dropwise. Put this solution at -78 ° And stirred for 1 hour, then add hexachloroethane in tetrahydrofuran (0.25 ml). (142 mg). The solution was allowed to warm to room temperature over 30 minutes, and water (2 ml ) Was added. The mixture was extracted with ethyl acetate (2 × 5 ml) and dried (MgSO 4). O_FourThe extract is evaporated to give the title compound as a cream colored solid. (180 mg). Melting point 148-149 ° MH⁺= 369   Intermediate 8 3-methylsulfanyl-pyridin-2-ylamine   2,2-dimethyl-N-pyridine- in dry tetrahydrofuran (30 ml) 2-yl-propionamide^Two(890 mg) was cooled to -78 ° C and n- Treated with a solution of butyllithium (6.25 ml; 1.6 M). Put this solution at 0 ° In dimethyldisulfur in tetrahydrofuran (5 ml). A solution of id (235 mg) was added and stirred at ambient temperature for 30 minutes. 2N Hydrochloric acid (1 ml) was added and the solution was concentrated in vacuo. Residue and 2N hydrochloric acid (15m The mixture with 1) was heated at reflux for 4 hours. Cool the cooled reaction mixture to solid potassium carbonate And made basic by the addition of a solution. The basic mixture was extracted with ethyl acetate (15 ml). And extract the organic extract (Na_TwoSO_Four) And absorbed on silica. flash Chromatography, eluting with ethyl acetate / cyclohexane (1/1) Afforded the title compound as a colorless oil (490 mg). MH⁺= 141 Tlc SiO_Two, Rf 0.48 (ethyl acetate / cyclohexane (1/1)) detection Out u. v. KMnO_Four.^Two References: 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   2-bromo-2- (4-fluoro-phenyl) -1- in dry acetonitrile (4-methanesulfonyl-phenyl) -ethanone (700 mg) and 2-amido A solution of non-nicotinic acid methyl ester (287 ml) was heated at reflux overnight. reaction The mixture is concentrated on silica and flash chromatographed to give ethyl acetate. Elution with cyclohexane: 5: 1 afforded the title compound as a yellow solid. (176 mg). MH⁺= 425 Tlc SiO_Two, Rf 0.21 (ethyl acetate: cyclohexane 5: 1) detection u v.   Intermediate 10 8-acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfani Ru-phenyl) -imidazo [1,2-a] pyridine   N-Butyllithium in hexane (1.6 ml; 0.35 ml) was charged in a nitrogen atmosphere. At -78 °, 3- (4-fluorine) in tetrahydrofuran (3 ml) was added. (Ro-phenyl) -2- (4-methanesulfanyl-phenyl) -imidazo [1, 2-a] pyridine (250 mg) was added dropwise. Put this solution at -78 ° And stir for 1 hour, then add N-methyl, N-methyl in tetrahydrofuran (0.25 ml). Treated with toxicacetamide (90 mg). The solution was allowed to cool to room temperature in 60 minutes. Warm and water (10 ml) was added. Extract the mixture with ethyl acetate (2 × 5 ml). Take out and dry (MgSO_Four) Was evaporated. Residue on silica column Purify and elute with hexane: diethyl ether (3: 1) to afford the title compound. Obtained as a cream solid (130 mg). MH⁺= 377 Tlc SiO_Two(Et_TwoO) Rf 0.9 detected u. v. .   Example 1 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl)- Imidazo [1,2-a] pyridine   2-bromo-2- (4-fluoro-phenyl) -1- in dry acetonitrile (4-methanesulfonyl-phenyl) -ethanone (233 mg) and 2-amido A solution of nopyridine (59 mg) was heated at reflux overnight. Absorb the reaction mixture onto silica And purified by flash chromatography, eluting with ethyl acetate The title compound was obtained as a cream solid (100 mg). MH⁺= 367.2 Melting point 198-200 °   Example 2 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl)- 8-methyl-imidazo [1,2-a] pyridine   2-Bromo-2- (4-fluoro-phen) in dry acetonitrile (10 ml) Nil) -1- (4-methanesulfonyl-phenyl) -ethanone (233 mg) And a solution of 2-amino-3-methylpyridine (68 mg) was heated at reflux overnight. The reaction mixture was adsorbed on silica and purified by flash chromatography. Elution with dichloromethane / methanol (19: 1) gave the title compound as a pale brown Obtained as a solid (61 mg). MH⁺= 381 Melting point 180-182 °   Example 3 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl)- 8-trifluoromethyl-imidazo [1,2-a] pyridine   2-Bromo- in dry acetonitrile containing potassium carbonate (276 mg) 2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl)- Ethanone (742 mg) and 3-trifluoromethyl-pyridin-2-yla A solution of the min (342 mg) was heated at reflux overnight. The reaction mixture is concentrated on silica And purified by flash chromatography, eluting with ethyl acetate, The title compound was obtained as a yellow solid. Recrystallization from propan-2-ol To give the title compound as yellow crystals (210 mg). 260-261 ° Analysis: found: C, 57.7; H, 3.0; N, 6.2; S, 7.3. C_{twenty one}H₁₄F_FourN_TwoO_TwoCalculated as S: C, 58.1; H, 3.25; N, 6. 45; S, 7.4%. MH⁺= 435 Tlc SiO_Two, Rf 0.25 (ethyl acetate) detection u. v. .   Example 4 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl) -7-methyl -Imidazo [1,2-a] pyridine   2-Bromo-2- (4-fluoro-phenyl) in acetonitrile (10 ml) ) -1- (4-Methanesulfonyl-phenyl) -ethanone (233 mg) and A solution of 2-amino-4-methylpyridine (68 mg) was heated at reflux for 18 hours. The reaction mixture was absorbed on silica and flash chromatographed Elution with ethyl / hexane (1/1) gave the title compound as a pale yellow solid. Obtained (105 mg). 194-196 ° MH⁺= 381 Tlc SiO_Two, Rf 0.26 (ethyl acetate / cyclohexane (2/1)) detection Out u. v. .   Example 5 8-chloro-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl- Phenyl) -imidazo [1,2-a] pyridine   8-Chloro-3- (4-fluoro) in methanol (8 ml) and water (2 ml) (Ro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2 -A] Oxone suspension of pyridine (150 mg)^TM(561mg) , Stirred at room temperature for 2 hours. The resulting suspension was treated with water (50 ml) and extracted with ethyl acetate. Extracted with chill (2 × 50 ml). Dry (MgSO_FourEvaporate the extract The resulting solid is treated with boiling isopropanol (8 ml) for 10 minutes and cooled. Filtration provided the title compound as a white solid (85 mg). Melting point 242-244 ° Tlc SiO_Two(Et_TwoO) Rf 0.5 detection u. v. KMnO_Four MH⁺= 401   Example 6 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl)- 8-methanesulfanyl-imidazo [1,2-a] pyridine   3-Methylsulfanyl-pyridine-2-i in acetonitrile (15 ml) Luamine (140 mg) and 2-bromo-2- (4-fluoro-phenyl)- A solution of 1- (4-methanesulfonyl-phenyl) -ethanone (371 mg) was added to Heated to reflux overnight. The cooled reaction mixture is absorbed on silica and flash chromatographed. Chromatography eluting with ethyl acetate / cyclohexane (1/1) gave the standard The title compound was obtained as a white solid (179mg). Melting point 224-226 ° MH⁺= 413 Tlc SiO_Two, Rf 0.60 (ethyl acetate / cyclohexane (1/1)) detection Out u. v. KMnO_Four.   Example 7 8-bromo-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl- Phenyl) -imidazo [1,2-a] pyridine   3-bromo-pyridin-2-ylamine in acetonitrile (15 ml)^Three( 173 mg) and 2-bromo-2- (4-fluoro-phenyl) -1- (4- A solution of methanesulfonyl-phenyl) -ethanone (371 mg) was heated at reflux overnight. did. Upon cooling to reaction temperature, the title compound crystallizes out of solution and is isolated by filtration. This gave a white solid (241 mg). Melting point 266-268 ° MH⁺= 446 Analysis: found: C, 53.5; H, 3.0; N, 6.2; F, 4.3; One. C₂₀H₁₄BrN_TwoO_TwoCalculated as S: C, 53.9; H, 3.2; N, 6.3. F, 4.3; S, 7.2%. Tlc SiO_Two, Rf 0.61 (ethyl acetate / cyclohexane (2/1)) detection Out u. v. KMnO_Four.^Three References: M. Malinowski, Bull. Soc. Chim. Bel g. 1988,97, 51.   Example 8 8-fluoromethyl-3- (4-fluoro-phenyl) -2- (4-methanesulfur (Honyl-phenyl) -imidazo [1,2-a] pyridine   3- (4-Fluoro-phenyl) -2- (4 in dichloromethane (10 ml) -Methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine-8-meta A solution of phenol (200 mg) in diethyl trifluoride in dichloromethane (4 ml) was added. Luamine sulfur (0.067 ml) in a cooled solution at -78 ° over 5 minutes Was added. The solution was allowed to warm to room temperature over 30 minutes. Be careful with water (15ml) Add with stirring, separate the organic phase and dry (Na_TwoSO_Four) Then absorb on silica I let it. Flash chromatography of the title compound, ethyl acetate / cycle Elution with hexane (1/1) gives the title compound as a white solid. This was further crystallized from propan-2-ol (10 ml) to give white crystals. (85 mg). Melting point 221-222 ° MH⁺= 399 Analysis: found: C, 63.1; H, 3.9; N, 6.8; F, 9.4; One. C_{twenty one}H₁₆F_TwoN_TwoO_TwoCalculated as S: C, 63.3; H, 4.05; N, 7. 15; F, 9.5; S, 8.02%.   Example 9 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl)- 7,8-dimethyl-imidazo [1,2-a] pyridine   3,3 in acetonitrile (15 ml) containing potassium carbonate (138 mg) 4-dimethyl-pyridin-2-ylamine^Four(122 mg) and 2-bromo- 2- (4-fluoro-phenyl) -1- (4-methanesulfonyl-phenyl)- A solution of ethanone (371 mg) was heated at reflux overnight. Absorb the reaction mixture onto silica And subjected to flash chromatography, ethyl acetate / cyclohexane ( Elution with 1/1) afforded the title compound as a white solid. Propane Recrystallization from 2-ol (10 ml) gave the title compound as white crystals. (136 mg). Melting point 228-230 ° MH⁺= 395 Analysis: found: C, 66.6; H, 4.7; N, 6.9; F, 4.8; S, 8. 2. C_{twenty two}H₁₉N_TwoFO_TwoCalculated as S: C, 67.0; H, 4.85; N, 7.1. F, 4.8; S, 8.1%.^Four References: W.O.Siegl, J.Het.Chem. 1981,18, 1613-18.   Example 10 3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl)- Imidazo [1,2-a] pyridine-8-carbaldehyde   [3- (4-Fluoro-phenyl) -2- (4) in chloroform (50 ml) -Methanesulfonyl-phenyl) -imidazo [1,2-a] pyridin-8-yl ]-Dissolution of methanol (500 mg) and manganese (IV) oxide (1.32 g) The solution was heated at reflux for 16 hours. The cooled reaction mixture was filtered and the filtrate was concentrated on silica. Shrunk. Flash chromatography, ethyl acetate / cyclohexane ( Elution with 4/1) gave the title compound as a bright yellow solid (31). 5 mg). MH⁺= 395 Analysis: Found: C, 63.71; H, 3.55; N, 6.89; S, 8.07. C_{twenty one}H_FifteenFN_TwoO_ThreeCalculated as S: 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   3- (4-Fluoro-phenyl) -2- (4-) in chloroform (20 ml) Methanesulfonyl-phenyl) -8-methyl-imidazo [1,2-a] pyridine (380 mg) in solid N-bromosuccinimide (1 (78 mg) at once and the resulting solution was stirred overnight. Add water (50ml) And the combined organic phases were dried (Na_TwoSO_Four) And absorbed on silica. flash Chromatography eluting with cyclohexane / ethyl acetate (1/1) Afforded the title compound as a white solid (106 mg). Melting point 277-279 ° (decomposition) MH⁺= 461 Tlc SiO_Two, Rf 0.22 (ethyl acetate / cyclohexane (1/1)) detection Out u. v. KMnO_Four.   Example 12 8-acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl -Phenyl) -imidazo [1,2-a] pyridine   8-Acetyl-3- (4-fur) in methanol (8 ml) and water (2 ml) Oro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1, 2-a] pyridine (130 mg) suspension in Oxone^TM(436mg) And stirred at room temperature for 3 hours. The resulting suspension is treated with water (50 ml) and vinegar Extracted with ethyl acetate (50 ml). Dry (MgSO_FourEvaporate the extract The resulting solid is treated with boiling isopropanol (3 ml) for 10 minutes and cooled Filtration provided the title compound as a white solid (85 mg). 233-237 ° Tlc SiO_Two(Et_TwoO) Rf 0.5 detection u. v. KMnO_Four MH⁺= 401   Example 13 6-bromo-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl- Phenyl) -8-methyl-imidazo [1,2-a] pyridine   1-amino-4-bromo-2-methylpyridine- (500 mg), 2-bromo -2- (4-fluorophenyl) -1- (4-methanesulfonyl-phenyl)- A mixture of ethanone (1.0 g) and acetonitrile (10 ml) was placed in a nitrogen atmosphere. Refluxed for 20 hours under reduced pressure and evaporated. The residue was taken up in diethyl ether (20 ml) Milled for 5 minutes, cooled and filtered. Repeat this procedure until the title compound is paged (580 mg) as a yellow powder. MH⁺= 461 Tlc SiO_Two(Et_TwoO) Rf 0.6 detection u. v. KMnO_Four.   Example 14 8-acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl -Phenyl) -imidazo [1,2-a] pyridine   In acetonitrile (125 ml) containing sodium bicarbonate (2.31 g) 3-acetyl-2-aminopyridine^Five(2.50 g) and 2-bromo-2- (4-Fluoro-phenyl) -1- (4-methanesulfonylphenyl) ethanone (6.82 g) was heated at reflux overnight. The mixture is filtered and the filtrate is brought to room temperature. Allowed to cool. The title compound crystallizes from solution and is isolated as a yellow solid by filtration. (3.58 g). Tlc SiO_Two, Rf 0.34 (ethyl acetate / hexane 1.3: 1) detection u. v. Iodine.¹ H NMR 3.04 (3H, s, CH_ThreeSO_Two−), 3.16 (3H, s, CH_Three CO-), 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, 8.8Hz) -C₆H_FourF-, 7.85 (2H, d, J = 8.4 Hz) and 7. 91 (2H, d, J = 8.4 Hz) -C₆H_FourSO_Two, 7.93 (1H, dd, J = 1.1, 7.0 Hz, H-7), 8.02 (1H, dd, J = 1.1, 7.0) Hz, H-5).⁸ References: F. Trecourt et al., J. Chem. Soc. Perkin. Trans. 1 1990, 9, 2409-241. Five.   Example 15 [3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -Imidazo [1,2-a] pyridin-8-yl] -methanol   3- (4-Fluoro-phenyl) in dry tetrahydrofuran (130 ml) -2- (4-Methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine Cool the solution of -8-carboxylic acid methyl ester (1.85 g) to -78 ° and add water Diisobutylaluminium hydride (17.4 ml; 1.0 M solution in dichloromethane) Liquid). Once the addition is complete, allow the mixture to warm to 25 ° And stirred for 2 hours. Methanol (80 ml) was added and the mixture was dried over silica. Concentrated. Flash chromatography, dichloromethane / ethano Elution with toluene / ammonia 100/8/1 gave the title compound as a white solid. (1.54 g). MH⁺= 397 Tlc (SiO_Two) Rf 0.28 (dichloromethane / ethanol / ammonia 1) 00/8/1) Detection U.S. V. .   Example 16 (±) 1- [3- (4-Fluoro-phenyl) -2- (4-methanesulfonyl- Phenyl) -imidazo [1,2-a] pyridin-8-yl] -ethane-1-o Le   [3- (4-Fluoro-phenyl) -2 in dry dichloromethane (10 ml) -(4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine-8 -Yl] -methanol (204 ml) was cooled to -78 °. Hydrogenated diy A solution of sobutylaluminum (1.0 M in dichloromethane, 1 ml) was added dropwise. The mixture was allowed to warm to ambient temperature over 30 minutes. Add methanol (10 ml) And stirred for an additional 30 minutes. The reaction mixture is absorbed on silica and Flash chromatography eluting with ethyl acetate gives the title compound as a white solid. Obtained as a solid (120 mg). Melting point 201-203 ° T. l. c. SiO_Two, Rf 0.45 (ethyl acetate) detected. V. .Example 17-Tablet a) Compound of the invention 5.0 mg           Lactose 95.0mg           90.0mg of microcrystalline cellulose           8.0 mg of cross-linked polyvinyl pyrrolidone           2.0 mg of magnesium stearate           Compressed weight 200.0mg   Compounds of the invention, microcrystalline cellulose, lactose and cross-linked polyvinyl pyro The lidone was sieved through a 500 micron sieve and compounded in a suitable mixer. The magnesium stearate is sieved through a 250 micron sieve and the active formulation And blended. This formulation is compressed into tablets using a suitable punch. b) 5.0 mg of compound of the invention           Lactose 165.0mg           Pre-gelatinized starch 20.0mg           8.0 mg of cross-linked polyvinyl pyrrolidone           2.0 mg of magnesium stearate           Compressed weight 200.0mg   Combining the compound of the invention, microcrystalline cellulose, lactose and pre-gelled starch And granulate with water. The wet mass is dried and comminuted. Magnesium stearate And cross-linked polyvinyl pyrrolidone through a 250 micron sieve, Mix with granules. The resulting formulation is compressed using a suitable tableting punch.   Example 18-Capsules a) Compound of the invention 5.0 mg           Lactose 193.0mg           Magnesium stearate 2.0mg           Filling weight 200.0mg   Sieve the compound of the invention and pregelatinized starch through a 500 micron sieve And blended together, magnesium stearate (passed through 250 micron sieve) Lubricate with. This formulation is filled into an appropriately sized hard gelatin capsule. You. b) 5.0 mg of compound of the invention           Lactose 177.0mg           8.0 mg of polyvinylpyrrolidone           8.0 mg of cross-linked polyvinyl pyrrolidone           Magnesium stearate 2.0mg           Filling weight 200.0mg   The compound of the present invention and lactose are blended together to dissolve polyvinylpyrrolidone. Granulate with liquid. The wet mass is dried and comminuted. Magnesium stearate and Crosslinked polyvinylpyrrolidone is sieved through a 250 micron sieve and blended with granules I do. The resulting formulation is filled into a suitably sized hard gelatin capsule.   Example 19-Syrup a) Compound of the invention 5.0 mg           Hydroxypropyl methylcellulose 45.0mg           1.5 mg of propylhydroxybenzoate           Butyl hydroxybenzoate 0.75mg           Sodium saccharin 5.0mg           Sorbitol solution 1.0ml           Appropriate buffer appropriate amount           Suitable flavoring agent Suitable amount           Purified water 10 ml   Hydroxypropyl methyl cellulose in heat purified water Hydroxybenzoate And allow the solution to cool to ambient temperature. Sodium saccharin, incense Add flavor and sorbitol solutions to the total solution. The compound of the present invention remains Dissolve in a portion of the water and add to the total solution. Add an appropriate buffer and add p H can be controlled within the maximum stability range. Bring the solution to an appropriate volume and filter. And fill into a suitable container.   Example 20-Injectable Formulation                                                   % W / v           Compound of the invention 1.00           Water for injection B. P. Amount to be 100.00   Adjust the tonicity of the solution by adding sodium chloride and dilute acid or alkali PH or by adding an appropriate buffer to maximize pH. Can be adjusted to a qualitative pH and / or facilitate dissolution of the compound of the invention. You. Antioxidants and metal chelating salts can also be included. This solution Clarify, bring to final volume with water, measure pH if necessary, adjust to 10 mg / Ml of the compound of formula (I).   The solution is filled, for example, into ampoules, vials or syringes and sealed By doing so, it can be packaged for injection. Ampoule, vial or The syringe is filled aseptically (eg, the solution is sterile filtered and sterile under sterile conditions) Can be filled in a pull) and / or can be sterilized last (For example, heating in an autoclave using one of the accepted cycles And by). This solution can be packaged under an inert atmosphere of nitrogen.   Preferably, the solution is filled into ampoules, sealed by melting the glass, and finally Sterilize.   Furthermore, it provides 5, 20, and 50 mg / ml of the compound of formula (I), respectively. Containing 0.5, 2.0 and 5% w / v of a compound of formula (I) Prepare a fungal formulation.   Biological data   Stable transfection with human COX-1 and human COX-2 cDNA Activity on human COX-1 and COX-2 in The sex was evaluated. Twenty-four hours prior to the experiment, COS cells were grown at 175 cm^Two From the flask to a 24-well cell culture plate using the following procedure. did. Heat-inactivated fetal calf serum (10% v / v), penicillin (100 U / ml) ), Streptomycin (100 μg / ml) and geneticin (600 μg / ml) ml) Dulbecco's modified Eagle's medium (DMEM) The confluent medium was removed from the confluent cell flask (Confluent To One flask is almost 1 × 10⁷Cells). 10ml phosphate buffered raw Physiological saline (PBS) was added to the flask to wash the cells. When you remove the PBS Rinse cells in 10 ml of trypsin for 20 seconds, then remove trypsin The flask is placed in an incubator (37 ° C.) until the cells are released. Put in for 2 minutes. The flask was then removed from the incubator and cells were Resuspended in 1 fresh incubation medium. Fill the contents of the flask with 2 Transfer into a 50 ml sterile container and subsequently reduce the volume of incubation medium Make up to 100 ml. 1 ml of the cell suspension was added to a 4 × 24 well cell culture plate. Pipette into each well. The plate is then placed in an incubator (37 ° C. , 95% air / 5% CO_Two) Overnight. Use more than one flask In some cases, the cells were combined and then dispersed in 24-well plates.   After overnight incubation, the incubation medium is transferred to a 24-well cell culture plate. Removed completely from the rate and replaced with 250 μl of fresh DMEM (37 ° C.) . The test compound is made up to the required test concentration of 250 × in DMSO and 1 μl of body The volume was added to the wells. The plate is then gently mixed by stirring, then Placed in an incubator for 1 hour (37 ° C, 95% air / 5% CO_Two)in Overnight. After the incubation period, 10 μl of arachidonic acid (750 μl M) was added to each well to give a final arachidonic acid concentration of 30 μM. Then press The plate is incubated for 15 minutes, then the incubation medium is added to the plate. Remove from each well and store at -20 ° C before using enzyme immunoassay. Prostaglandin E_Two(PEG2) levels were measured. Inhibition of test compound Harm IC₅₀It was expressed by. IC₅₀Inhibits PGE2 release from cells by 50% Is defined as the concentration of the compound. The relative ratio of inhibition of COX-1 / COX-2 is Each IC₅₀Calculated by comparing the values.   The following IC for inhibition of COX-2 and COX-1₅₀The values for the compounds of the invention Obtained.

[Procedure amendment] [Date of submission] October 6, 1997 [Details of amendment] Claims 1. Compounds of formula (I) and pharmaceutically acceptable derivatives thereof: (R ⁰ represents halogen, R ¹ and R ² are H, halogen, C _1-4 alkyl, one or more C _1-4 alkyl substituted by fluorine atoms, C _1-4 alkoxy, C _1- Independently selected from ₄ -hydroxyalkyl, SC _1-4 alkyl, C (O) H or C (O) C _1-4 alkyl, and R ³ represents C _1-4 alkyl). 2. R ³ represents methyl, compound of Claim 1. 3. 3. The compound according to claim 1, wherein R ⁰ represents fluorine. 4. R ¹ is H, chlorine, bromine, C _1-4 alkyl, methyl substituted by one to three fluorine atoms, C _1-4 hydroxyalkyl, SC _1-4 alkyl, C (O) H or C (O _4. ) A compound according to any one of claims 1 to 3, which represents C1-4alkyl. 5. R ² is H, chlorine, bromine or C _1-4 alkyl, A compound according to any one of claims 1 to 4. 6. R ⁰ represents fluorine, R ¹ represents H, chlorine, bromine, C _1-4 alkyl, methyl substituted with 1 to 3 fluorine atoms, C _1-4 hydroxyalkyl, SC _1-4 alkyl, C ( O) H or C (O) C _1-4 alkyl, R ² represents H, chlorine, bromine or C _1-4 alkyl, and R ³ represents methyl, one of the claims 1 to 5 one The compound according to item. 7. R ⁰ represents fluorine, R ¹ represents H, chlorine, bromine, methyl, CH ₂ F, CF ₃ , SCH ₃ , C (O) H or C (O) CH ₃ , and R ² represents H, bromine or It represents methyl and R ³ represents methyl, a compound according to any one of claims 1 to 6. 8. Present in R ¹ is 8-position, and if R ² is at the 7-position, or when R ¹ is other than H, R ² is present in 5, 6 or 7-position, any of the preceding claims A compound according to claim 1. 9. Present in R ¹ is 8-position, and when either R ² is at the 7-position, or R ¹ is C _1-4 alkyl, R ² is at the 5 or 7 position of claims 1 to 8 A compound according to any one of the preceding claims. 10. R ¹ represents C (O) CH _3, A compound according to any one of claims 1 to 9. 11. 8-Acetyl-3- (4-fluoro-phenyl) -2- (4-methanesulfonyl-phenyl) -imidazo [1,2-a] pyridine and pharmaceutically acceptable derivatives thereof. 12. 12. The compound according to any one of claims 1 to 11, wherein the compound of formula (I) is in the form of a hydrochloride, hydrobromide or sulfate. 13. (A) Formula (II) Or a protected derivative thereof, wherein Lg represents a leaving group, of the formula (II) Or a protected derivative thereof, or (B) a compound of formula (IV) Reacting a compound of formula (I) or a protected derivative thereof with an oxidizing agent, or (C) interconverting a compound of formula (I) to another compound of formula (I), or (D) Deprotecting the protected derivative of the compound, and optionally converting the compound prepared by any one of methods (A) to (D) to a pharmaceutically acceptable derivative thereof. Item 13. A method for producing the compound of the formula (I) according to any one of items 1 to 12 and a pharmaceutically acceptable derivative thereof. 14． A medicament comprising a compound of formula (I) according to any one of claims 1 to 12 and a pharmaceutically acceptable derivative thereof, and one or more physiologically acceptable carriers or excipients. Composition. 15. 15. The pharmaceutical composition according to claim 14, for use in treating conditions mediated by selective inhibition of COX-2. 16. 15. The pharmaceutical composition according to claim 14, which is used in the treatment of an inflammatory disease. 17． 13. Selective treatment of COX-2 comprising administering to a mammal, excluding a human, an effective amount of a compound of formula (I) according to any one of claims 1 to 12 and a pharmaceutically acceptable derivative thereof. Treatment of conditions mediated by inhibition. 18. 13. A method for treating an inflammatory disease comprising administering to a mammal, excluding a human, an effective amount of the compound of formula (I) and a pharmaceutically acceptable derivative thereof according to any one of claims 1 to 12. .

────────────────────────────────────────────────── ─── Continuation of front page    (31) Priority claim number 9516117.0 (32) Priority Date August 5, 1995 (33) Priority claim country United Kingdom (GB) (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, S Z, UG), UA (AM, AZ, BY, KG, KZ, MD , RU, TJ, TM), AL, AM, AT, AU, AZ , BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, I S, JP, KE, KG, KP, KR, KZ, LK, LR , LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, S D, SE, SG, SI, SK, TJ, TM, TR, TT , UA, UG, US, UZ, VN (72) Inventor Campbell, Ian Baxter             UK Hearts, Stevenage, Gun             Nels, Wood, Road, Glaxo, Lisa             , And, development, limi             Inside Ted (72) Inventor Naylor, Alan             UK Hearts, Stevenage, Gun             Nels, Wood, Road, Glaxo, Lisa             , And, development, limi             Inside Ted

Claims (1)

[Claims]   1. Compounds of formula (I) and pharmaceutically acceptable derivatives thereof: (R⁰Represents halogen,   R¹And R^TwoIs H, halogen, C_1-4Alkyl, one or more fluorine atoms C substituted by_1-4Alkyl, C_1-4Alkoxy, C_1-4Hydroxyalkyl , SC_1-4Alkyl, C (O) H or C (O) C_1-4Independently selected from alkyl And   R^ThreeIs C_1-4Represents alkyl).   2. R^ThreeThe compound of claim 1, wherein represents methyl.   3. R⁰The compound according to claim 1, wherein represents a fluorine.   4. R¹Is H, chlorine, bromine, C_1-4Alkyl (eg, methyl), 1-3 Methyl substituted by a fluorine atom (eg, CH_TwoF or CF_Three), C_1-4Hi Droxyalkyl (eg, CH_TwoOH or CH (OH) CH_Three), SC_1-4A Luquil (for example, SCH_Three), C (O) H or C (O) C_1-4Alkyl (eg , C (O) CH_ThreeThe compound according to any one of claims 1 to 3, wherein   5. R^TwoIs H, chlorine, bromine or C_1-4Represents an alkyl (eg, methyl), A compound according to any one of claims 1 to 4.   6. R⁰Represents fluorine, and R¹Is H, chlorine, bromine, C_1-4Alkyl (for example, Methyl), methyl substituted with 1 to 3 fluorine atoms (eg, CH_TwoF or CF_Three), C_1-4Hydroxyalkyl (eg, CH_TwoOH or CH (OH) C H_Three), SC_1-4Alkyl (eg, SCH_Three), C (O) H or C (O) C_1-4 Alkyl (eg, C (O) CH_Three) And R^TwoIs H, chlorine, bromine or C_1-4 Represents an alkyl (eg, methyl);^ThreeRepresents methyl. The compound according to any one of the above.   7. R⁰Represents fluorine, and R¹Is H, chlorine, bromine, methyl, CH_TwoF, CF_Three, SCH_Three, C (O) H or C (O) CH_ThreeAnd R^TwoIs H, bromine or methyl And R^ThreeRepresents methyl. 7. The compound according to claim 1, wherein Stuff.   8. R¹Is in position 8 and R^TwoIs in position 7 or R¹Is other than H , R^TwoIs present at the 5, 6 or 7 position. The compound according to the above.   9. R¹Is in position 8 and R^TwoIs in position 7 or R¹Is C_1-4A When R is alkyl (eg, methyl), R^TwoIs in the 5th or 7th position The compound according to any one of claims 1 to 8.   10. R¹Is C (O) CH_ThreeThe chemical formula according to any one of claims 1 to 9, which represents Compound.   11. 8-acetyl-3- (4-fluoro-phenyl) -2- (4-methane Sulfonyl-phenyl) -imidazo [1,2-a] pyridine and pharmaceutically acceptable salts thereof Derivatives.   12. The compound of formula (I) is in the form of a hydrochloride, hydrobromide or sulfate A compound according to any one of claims 1 to 11.   13. (A) Formula (II) Or a protected derivative thereof (wherein Lg represents a leaving group) with a compound of the formula (I II) Or a protected derivative thereof, or (B) Formula (IV) Reacting a compound of formula (I) or a protected derivative thereof with an oxidizing agent, or (C) interconverting a compound of formula (I) to another compound of formula (I), or (D) deprotecting the protected derivative of the compound of formula (I), And optionally a compound produced by any one of the methods (A) to (D) To a pharmaceutically acceptable derivative thereof. Preparation of a compound of formula (I) according to any one of the preceding claims and pharmaceutically acceptable derivatives thereof. Construction method.   14． 13. A compound of formula (I) according to any one of claims 1 to 12 and a compound thereof. A pharmaceutically acceptable derivative and one or more physiologically acceptable carriers or excipients. And a pharmaceutical composition.   15. 13. Any of claims 1 to 12 for use in human or veterinary medicine A compound of formula (I) according to any one of the preceding claims and a pharmaceutically acceptable derivative thereof.   16. Use in the treatment of conditions mediated by selective inhibition of COX-2 13. A compound of formula (I) according to any one of claims 1 to 12 and a medicament thereof. A chemically acceptable derivative.   17． Humans suffering from conditions mediated by selective inhibition of COX-2 or 13. The compound of formula (I) according to any one of claims 1 to 12, which is an effective amount for an animal subject. Administering the compound and a pharmaceutically acceptable derivative thereof. How to treat the body.   18. 13. The method according to claim 1, which is for producing a therapeutic agent for treating an inflammatory disease. Use of a compound of formula (I) according to any one of the preceding claims and a pharmaceutically acceptable derivative thereof. .   19. An effective amount for a human or animal subject suffering from an inflammatory disease. 3. A compound of formula (I) according to any one of the above 2 and pharmaceutically acceptable derivatives thereof A method of treating the subject, comprising administering to the subject.