HRP960425A2 - Chemical compounds - Google Patents

Description

This invention relates to imidazole [1,2-a] pyridine derivatives, to processes for their preparation, to pharmaceutical preparations containing them and to their use in medicine.

Recently, it was discovered that the enzyme cyclooxygenase (COX) exists in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 can be rapidly and easily induced by a number of substances including mitogens, endotoxin, hormones, cytokines and growth factors. Prostaglandins produced by the action of COX have physiological and pathological roles. COX-i is generally believed to be responsible for important physiological functions such as gastrointestinal integrity and renal blood flow. Conversely, the inducible form of COX-2 is believed to be responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such substances as inflammatory substances, hormones, growth factors and cytotoxins. Therefore, a selective COX-2 inhibitor would have anti-inflammatory, anti-pyretic and analgesic properties, without the possible side effects associated with COX-1 inhibition. We have now found a new group of compounds that are potent and selective COX-2 inhibitors.

The present invention thus provides compounds of formula (I)

[image]

and their pharmaceutically acceptable derivatives in which:

Ro represents halogen;

R1 and R2 are independently selected from H, halogen, C1-4 alkyl, C1-4 alkyl substituted with one or more fluorine atoms, C1-4 alkoxy, C1-4 hydroxyalkyl, SC1-4 alkyl, C(O)H or C (O)C1-4 alkyl; and R 3 represents C 1-4 alkyl.

Pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, soluble substance or ester, or salt or soluble substance of such an ester, of the compounds of formula (I), or any other compound which after application is capable of providing (directly or indirectly) the compound of formula ( I) or its active metabolite or residue.

It is important that for pharmaceutical use, the salts mentioned above are physiologically acceptable salts, but other salts can also be used, for example in the preparation of compounds of formula (I) and their physiologically acceptable salts.

Suitable pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts formed with inorganic and organic acids, preferably inorganic acids, eg, hydrochlorides, hydrobromides and sulfates.

The term halogen is used to represent fluorine, chlorine, bromine and iodine.

The term "alkyl" as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, or t-butyl group.

The substituents R1 and R2 can be at the 5-, 6-, 7- and 8-position of the pyridine ring of formula (I), as defined here below:

[image]

Preferably, R1 is at position -8; and R 2 is at the –7 position or, when R 1 is other than H, at the 5-, 6-, or 7-position.

Even more preferably, R1 i at position -8; and R 2 is at the -7 position or, when R 1 is C 1-4 alkyl (eg methyl), at the 5- or 7- position.

Preferably Ro represents fluorine.

Preferably, R 1 represents H, chlorine, bromine, C 1-4 alkyl (eg, methyl), methyl substituted with one or a trifluoro atom (eg, CH 2 F or CF 3 ). C1-4 hydroxyalkyl (eg CH2OH or CH(OH)CH3), SC1-4 alkyl (eg SCH3), C(O)H or C(O)C1-4 alkyl (eg C(O)CH3). Even more preferably, R 1 represents H, chlorine, bromine, methyl, CH 2 F, CF 3 , SCH 3 , C(O)H or C(O)CH 3 . Most preferably, R 1 represents C(O)CH 3 .

Preferably, R 2 represents H, chlorine, bromine, or C 1-4 alkyl (eg methyl). More preferably, R 2 represents H, bromo or methyl.

Preferably, R 3 represents methyl.

Within this invention there is provided a group of compounds of formula (I) (group A) characterized in that: Ro represents fluorine; R1 represents H, chlorine, bromine, C1-4 alkyl (e.g. methyl), methyl substituted by one to three fluorine atoms (e.g. CH2 F or CF3), C1-4 hydroxyalkyl (e.g. CH2OH or CH(OH)CH3) , SC 1-4 alkyl (eg SCH 3 ), C(O)H or C(O)C 1-4 alkyl (eg C(O)CH 3 ); R 2 represents H, chlorine, bromine, or C 1-4 alkyl (eg methyl); and R 3 represents methyl.

Within group A, a subgroup of compounds is provided, indicated by the fact that: Ro represents fluorine; R 1 represents H, chlorine, bromine, methyl, CH 2 F, CF 3 , SCH 3 , C(O)H or C(O)CH 3 ; R 2 represents H, bromine or methyl; and R 3 represents methyl.

Provided within this invention is a second group of compounds of formula (I) (group B) characterized in that Ro represents fluorine; R1 is at position -8 and represents H, chlorine, bromine, C1-4 alkyl (e.g. methyl), methyl substituted with one to three fluorine atoms (e.g. CH2F or CF3), C1-4 hydroxyalkyl (e.g. CH2OH or CH (OH)CH 3 ), SC 1-4 alkyl (eg SCH 3 ), C(O)H or C(O)C 1-4 alkyl (eg C(O)CH 3 ); R 2 is at the -7 position or when R 1 is other than H, the 5-, 6- or 7- position, and represents H, chlorine, bromine or C 1-4 alkyl (eg methyl); and R 3 represents methyl.

Within group B, a subgroup of compounds is provided, indicated by the fact that: Ro represents fluorine; R1 is in the 8- position and represents H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(O)H or C(O)CH3; R 2 is in the 7-position or, when R 1 is methyl, the 5- or 7-position, and is H, bromo or methyl; and R 3 represents methyl.

Within this invention is provided the following group of compounds of formula (I) (group C) characterized in that R represents fluorine; R1 is in the 8-position and represents H, chlorine, bromine, C1-4 alkyl (e.g. methyl), methyl substituted with one to three fluorine atoms (e.g. CH2F or CF3), C1-4 hydroxyalkyl (e.g. CH2OH or CH (OH)CH 3 ), SC 1-4 alkyl (eg SCH 3 ), C(O)H or C(O)C 1-4 alkyl (eg C(O)CH 3 ); R 2 represents H; and R 3 represents methyl.

Within group C, a subgroup of compounds is provided, indicated by the fact that: Ro represents fluorine; R1 is in the 8-position and represents H, chlorine, bromine, methyl, CH2F, CF3, CH(OH)CH3, SCH3, C(O)H or C(O)CH3; R 2 represents H; and R 3 represents methyl.

Within the above-mentioned groups (and preferred groups) of compounds, particularly preferred groups of compounds are those characterized by the fact that R1 represents C(O)CH3.

It is important to understand that this invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (eg racemic mixtures).

Preferred compounds of this 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;

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]-ethan-1-ol;

and their pharmaceutically acceptable derivatives.

A particularly preferred compound of this invention is:

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 potent selective COX-2 inhibitors. This activity is illustrated by their ability to selectively inhibit COX-2 over COX-1.

In terms of selective COX-2 inhibitory activity, the compounds of this invention are interesting for use in human and veterinary medicine, especially in the treatment of pain, fever and inflammation of various conditions and diseases. Such conditions and diseases are well known in the art and include rheumatic fever, symptoms associated with influenza or other viral infections, such as colds, lower back pain and neck pain, headache, toothache, dislocations and sprains, myositis, neuralgia, synovitis , arthritis, including rheumatoid arthritis, degenerative connective tissue diseases, including osteoarthritis, gout and ankylosing spondylitis, tendinitis, bursitis, conditions associated with the skin, such as psoriasis, eczema, burns and dermatitis, injuries, such as sports injuries and those resulting from surgical and dental procedures.

The compounds of the present invention may also be useful in the treatment of other conditions mediated by selective inhibition of COX-2.

For example, the compounds of the present invention can inhibit cellular and neoplastic transformation and metastatic growth of tumors and thus be useful in the treatment of some cancerous diseases, such as colon cancer.

The compounds of this invention may also prevent neuronal injury by inhibiting the generation of neuronal free radicals (and thus oxidative stress) and thus may be useful in the treatment of stroke, epilepsy, and epileptic seizures (including grand mal, petit mal, myoclonic epilepsy, and partial seizures).

The compounds of the present invention also inhibit prostanoid-induced smooth muscle contractions and may therefore be useful in the treatment of dysmenorrhea and preterm labor.

The compounds of this invention inhibit inflammatory processes and therefore may be useful 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. such as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, diabetes type I, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Bechet syndrome, polymyositis, gingivitis, conjunctivitis, and myocardial ischemia. The compounds of this invention may also be useful in the treatment of eye diseases such as retinitis, retinopathy, uveitis and acute ocular tissue injury.

The compounds of this invention may also be useful in the treatment of cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease ), and vascular dementia (including multi-infarct dementia), as well as dementia associated with intracranial space-occupying lesions, trauma, infections and associated conditions (including HIV infections), metabolism, toxins, anoxia and vitamin deficiency, and mild cognitive impairment age-related, especially age-related memory loss.

In accordance with the following aspect of the present invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.

In accordance with another aspect of the present invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in the treatment of conditions mediated by selective inhibition of COX-2.

In accordance with a further aspect of the present invention, we provide a method of treating humans or animals suffering from conditions mediated by selective inhibition of COX-2 comprising administering to said patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

In accordance with another aspect of the present invention, we provide the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a therapeutic agent for the treatment of inflammatory disorders.

In accordance with a further aspect of the present invention, we provide a method of treating a human or animal suffering from an inflammatory disorder, which method comprises administering to said patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

It is important to understand that treatment includes both treatment of pre-existing symptoms and prophylactic treatment, unless explicitly stated otherwise.

It is appreciated that the compounds of the present invention can be advantageously used in combination with one or more other therapeutic agents. Examples of suitable substances for combination therapy include analgesics such as a glycine antagonist, a calcium channel inhibitor (eg, lamotrigine), a substance P antagonist (eg, an NK1 antagonist), acetaminophen, or phenacetin; matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor (eg, an iNOS or nNOS inhibitor); an inhibitor of the release, or action, of tumor necrosis factor alpha; antibody therapy (eg monoclonal antibody therapy); stimulant, including caffeine; H2-antagonist, such as ranitidine; antacid, such as aluminum or magnesium hydroxide; antiflatulence, such as simethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-deoxyephedrine; antitussive; such as codeine, hydrocodone, carmifen, carbetapentane, or dextramethorphan; diuretic; or an antihistamine with a sedative or non-sedative effect. It is important to understand that this invention covers the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in combination with one or more therapeutic agents.

The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently applied in the form of pharmaceutical preparations. Thus, in another aspect of the present invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in mixtures with one or more physiologically acceptable carriers or excipients.

The compounds of formula (I) and their pharmaceutically acceptable derivatives may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration by inhalation or, even better, by oral, transdermal or parenteral administration. The pharmaceutical preparation can be in such a form that it can release the compounds of formula (I) and their pharmaceutically acceptable derivatives in a controlled manner.

For oral administration, the pharmaceutical composition may be in the form of, for example, tablets (including sublingual tablets), capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.

For transdermal administration, the pharmaceutical composition may be in the form of a transdermal patch, such as a transdermal iontophoretic patch.

For parenteral administration, the pharmaceutical composition may be in the form of an injection or continuous infusion (eg, intravenously, intravascularly, or subcutaneously). The preparations may take the form of suspensions, solutions or emulsions in an oily or aqueous vehicle and may contain shaping substances such as suspending, stabilizing and/or dispersing substances. Injections can be presented in the form of a single dose or as a multidose, preferably with an added preservative.

Alternatively, for parenteral administration, the active substance can be in the form of a powder for reconstitution with a suitable vehicle.

The compounds of this invention may also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injections. Thus, for example, the compounds of this invention may be formulated with suitable polymeric or hydrophobic materials (for example, as emulsions in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

As stated above, the compounds of the present invention may also be used in combination with other therapeutic agents. This invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with another therapeutic agent.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and such pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise the following aspect of the present invention. Individual components of such combinations can be applied either in sequence or simultaneously in separate or combined pharmaceutical preparations.

When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with another therapeutically active substance against the same disease state, the dosage of each compound may differ from that when the compound is used alone. Appropriate dosages will be determined by those skilled in the art.

A suggested daily dose of a compound of formula (I) for the treatment of humans is 0.01 mg/kg to 500 mg/kg, as well as 0.05 mg/kg to 100 mg/kg, eg 0.1 mg/kg to 50 mg/kg., which can be conveniently administered in 1 to 4 doses. The exact dose used will depend on the age and condition of the patient and the method 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 formula (I) and their pharmaceutically acceptable derivatives may be prepared by any method known in the art for the preparation of compounds having an analogous structure.

Suitable methods for the preparation of compounds of formula (I) and their pharmaceutically acceptable derivatives are described below. In the formulas that follow, R0 and R3 are as defined in formula (I) above unless otherwise specified and Lg represents a remaining group, such as sulfonate (eg methanesulfonate) or halogen (eg bromine).

Thus, in accordance with the first process (A), compounds of formula (I) can be prepared by reaction with a compound of formula (II)

[image]

or its protected derivative with the compound of formula (III)

[image]

or its protected derivative. The reaction is conveniently carried out in a solvent, such as is a polar solvent (eg acetonitrile or isopropanol); at elevated temperature, eg reflux; and optionally in the presence of a base, such as bicarbonate or carbonate, of an alkali metal (eg potassium carbonate).

Suitable remaining atoms or groups relative to Lg of formula (II) are described in many standard organic chemistry texts, for example in Table 10.10 on page 357 in "Advanced Organic Chemistry" by Jerry March, Fourth Edition (Wiley, 1992). . Persons skilled in the art will understand that the choice of a particular remaining group in the above reactions may depend on the meanings of Ro to R3 (and thus the preferred compound of formula (I) and the reaction conditions used.

According to the second process (B), compounds of formula (I) can be prepared by reaction with a compound of formula (IV)

[image]

or its protected derivative with an oxidizing substance. Suitably the oxidation is carried out using a monopersulfate compound, such as potassium peroxymonosulfate (known as OxoneTM) and the reaction is carried out in a solvent, such as an aqueous alcohol, (eg aqueous methanol), and at between -78°C and ambient temperature.

According to another process (C), compounds of formula (I) can be prepared by means of interconversion, using other compounds of formula (I) as precursors.

Thus, for example, compounds of formula (I) where R 1 or R 2 represent chlorine, bromine or iodine can be prepared from the corresponding compounds of formula (I) where R 1 or R 2 represent H, by treatment with a suitable halogenating agent (e.g. chlorine-, bromine- or iodizing substance). Suitable substances include the corresponding N-halosuccinimides. Suitably, the reaction is carried out in the presence of a solvent, such as a halogenated hydrocarbon (eg chloroform), and at ambient temperature.

Compounds of formula (I) wherein R 1 or R 2 represents C 1-4 , alkyl substituted with one or more fluorine atoms may be prepared from compounds of formula (I) wherein R 1 or R 2 represents the corresponding C 1-4 hydroxyalkyl by treatment with a suitable source of fluorine. Suitable sources of fluorine include, for example, diethylaminosulfur trifluoride. Suitably, the reaction is carried out in the presence of a solvent, such as a halogenated hydrocarbon (eg, dichloromethane), and at a reduced temperature, such as -78°C.

Compounds of formula (I) wherein R 1 or R 2 represent C(O)H can be prepared from the corresponding compounds of formula (I) wherein R 1 or R 2 represent CH 2 OH by oxidation. Suitable oxidizing agents include, for example, manganese (IV) oxide. Suitably the oxidation is carried out in the presence of a solvent, such as a halogenated carbohydrate (eg chloroform), and at an elevated temperature (eg reflux).

Compounds of formula (I) wherein R 1 and R 2 represent C 1-4 hydroxyalkyl, and where the hydroxy group is attached to the carbon attached to the pyridine ring, may be prepared by reduction of a compound of formula (I) wherein R 1 or R 2 represents the corresponding aldehyde or ketone.

Suitable reducing agents include hydride reducing agents, such as diisobutylaluminum hydride. Suitably, the reduction is carried out in the presence of a solvent, such as a halogenated hydrocarbon (eg, dichloromethane), and at a reduced temperature, such as -78°C.

Those skilled in the art will understand that it may be necessary or desirable at any stage of the process described above to protect one or more sensitive groups in the molecule to prevent undesirable side reactions.

The following process (D) for the preparation of compounds of formula (I) thus includes deprotection of protected derivatives of compounds of formula (I).

The protecting groups used in the preparation of compounds of formula (I) can be used in the usual manner. See, for example, those described in "Protective Groups in Organic Synthesis" by Theodora W. Green, Second Edition, (John Wiley Sons, 1991), which also describes methods for removing such groups.

Compounds of formula (II) can be prepared from compounds of formula (V)

[image]

by usual means.

Thus, compounds of formula (II) where Lg represents halogen can be prepared from compounds of formula (V) by treatment with a halogenating substance at reduced temperature and in a solvent, such as a chlorinated carbohydrate. 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 (eg, hydrobromic acid in acetic acid).

Compounds of formula (II) where Lg is a sulfonate can be prepared from compounds of formula (V) first by oxidation to the corresponding alpha-hydroxy ketone, followed by treatment with a sulfonating agent. Suitable oxidizing agents include, for example, Pb(OAc) 4 dimethyldioxirane and those described in F A Davis, J. org. Chem., 1984, 49(17), 3284. Suitable sulfonating agents include sulfonyl halides, such as sulfonyl chloride (eg, methanesulfonyl chloride). Sulfonylation is conveniently carried out in the presence of a base, such as an amine (eg triethylamine); and in a solvent such as a halogenated hydrocarbon.

Compounds of formula (V) can be prepared from compounds of formula (VI)

[image]

by treatment with an alkaline sulfinate, such as sodium sulfinate. Conveniently, the reaction is carried out in a polar solvent, such as dimethyl sulfoxide, and at elevated temperature.

Compounds of formula (III) are either known compounds or can be prepared by literature methods such as those described in, for example, J A Turner, J. Org. Chem., 1983, 48, 3041; M Malinowski, Bull. Soc. Belg., 1988, 97, 51; W D Siegl, J. Het. Chem., 1981, 18, 1613-18; or F. Trecourt et al., J. Chem. Soc., Perkin Trans, 1 1990, 9, 2409-2415.

Compounds of formula (VI) are either known compounds or can be prepared using literature methods such as those described in, 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.

Compounds of formula (IV) or protected derivatives thereof may be prepared using conventional chemistry, for example chemistry analogous to that described herein for the preparation of compounds of formula (I).

Some of the intermediates described above are novel compounds, and it is important to understand that all novel intermediates herein form further aspects of the present invention. Compounds of formula (II) and (IV) are key intermediates and represent special aspects of this invention.

Suitably, the compounds of this invention are isolated following preparation in free base form. Pharmaceutically acceptable acid addition salts of the compounds of this invention can be prepared using conventional means.

Soluble substances (eg hydrates) of the compounds of this invention can be formed during the execution of one of the previously mentioned process steps.

The following examples illustrate the invention but do not limit the invention in any way. All temperatures are expressed in °C. Flash chromatography is performed using Merck 9385 silica. Thin layer chromatography (Tlc) is performed on silica plates. NMR is performed on a Bruckner 300 Mhz spectrometer, using CDCl3 as solvent. Chemical shifts are shown in delta ppm relative to tetramethylsilane as an internal chemical shift reference. The following abbreviations are used: Et = ethyl, s = single, d = double, t = triple and m = multiple.

Intermediate product 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 methane sulfinate (1.58 g) in dry dimethyl sulfoxide (10 ml) is heated to 105-110° under with nitrogen for 18 hours. The cooled reaction mixture was poured into water (500 ml) and the mixture was extracted with ethyl acetate. The combined organic extracts were adsorbed onto silica and purified by flash chromatography eluting with ethyl acetate:hexane (1:1) to afford the title compound as a white solid (2.1 g).

m.p. 115-116°

1Ref: I Lalazori et al., J. Med. Chem. 1971, 14, 1138-40.

Intermediate product 2

2-Bromo-2-(4-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). m.p. 124-126°

Intermediate product 3

3-trifluoromethyl-pyridin-2-ylamine

A mixture of 2-chloro-3-trifluoromethyl-pyridine (5 g), copper(1) iodide (5 g) and liquid ammonia (50 ml) is heated in an autoclave at 80° (internal temperature) for 28 hours. The cooled reaction mixture was slurried with methanol/chloroform (1/1-250 mL) and filtered. The filtrate was absorbed onto silica and purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to give the title compound as a white solid (1.4 g).

m.p. 71-72°

MH+ = 163

Tlc SiO2, Rf 0.50 (ethyl acetate/hexane (1/1)) detection UV/KMnO4

Intermediate product 4

2-(4-fluoro-phenyl)-1-(4-methanesulfanyl-phenyl)-ethanone

A mixture of 2-(4-fluoro-phenyl)-1-(4-fluoro-phenyl)-ethanone (10.0 g), sodium methanethiolate (3.0 g) and dimethyl sulfoxide (10 ml) was heated to -100° for 8 hours under nitrogen. The cooled mixture is 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).

m.p. 143-144°

Intermediate product 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 is stirred at 0 for 10 min at room temperature for 3 hours, diluted with dichloromethane (100 ml) and washed with water (2 x 100 ml). The dried (MgSO 4 ) organic phase was evaporated and the residue triturated with diethyl ether (30 ml) to give the title compound as a white solid (4.5 g).

m.p. 117-119°

Tlc SiO2 (Et2O:hexane 1:1) Rf 0.6 det u.v. KMnO4, isopropanal.

Intermediate product 6

3-(4-fluoro-phenyl)-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 hours and let stand at room temperature for 16 hours. The solution was evaporated and the residue was purified by flash column chromatography eluting with diethyl ether (used in CH 2 Cl 2 ) to give the title compound as a white solid (1.6 g).

m.p. 115-118°

Tlc SiO2 (Et2O) Rf 0.5 det. u.v., isopropanol.

Intermediate product 7

8-chloro-3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo [1,2-a]pyridine

n-butyllithium hexane (1.6 m; 0.35 ml) was added dropwise to a solution of 3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (167 mg) in tetrahydrofuran (2 ml) at -78° under nitrogen. The solution was stirred at -78° for 1 hour and treated with hexachloroethane (142 mg) in tetrahydrofuran (0.25 ml). The solution is allowed to warm to room temperature over 30 minutes and water (2 ml) is added. The mixture was extracted with ethyl acetate (2 x 5 ml) and the dried (MgSO 4 ) extract was evaporated to give the title compound as a cream solid (180 mg).

m.p. 148-149°

MH+ = 369

Intermediate product 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 was continued for a further 30 minutes at ambient temperature. 2 N 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 at reflux for 4 hours. The cooled reaction mixture is alkalized by the addition of solid potassium carbonate. The alkaline mixture is extracted with ethyl acetate (15 ml), the organic extract is dried (Na2SO4) and absorbed on silicic acid). The title compound was obtained by flash chromatography eluting with ethyl acetate/cyclohexane (1/1) as a colorless oil (490 mg).

MH+ = 141

Tlc, SiO2, Rf 0.48 (ethyl acetate/cyclohexane (1/1)) detection u.v., KMnO4.

2Ref: J.A. Turner J. Org. Chem. 1983, 48, 3401

Intermediate product 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 is heated at reflux overnight. The reaction mixture was concentrated on silicic acid to give the title compound by flash chromatography eluting with ethyl acetate:cyclohexane 5:1 as a yellow solid (176 mg).

MH+ = 425

Tlc, SiO2, Rf 0.21 (ethyl acetate : cyclohexane 5 : 1) detection u.v.

Intermediate product 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-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (250 mg) in tetrahydrofuran (3 ml) at -78° under nitrogen. The solution was stirred at -78° for 1 hour and treated with N-methyl, N-methoxy acetamide (90 mg) in tetrahydrofuran (0.25 ml). The solution is allowed to warm to room temperature over 60 minutes and water (10 ml) is added. The mixture was extracted with ethyl acetate (2 x 5 ml) and the dried extract (MgSO 4 ) was evaporated. The residue was purified on a silica column, eluting with hexane:diethyl ether (3:1) to give the title compound as a cream solid (130 mg).

MH+ = 377

Tlc SiO2 (Et2O) Rf 0.9 det. u.v.

Example 1

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo [1,2-a]pyridine

A solution of 2-bromo-2-(4-fluoro-phenyl9-1-(4-methanesulfonyl-phenyl)-ethanone (233 mg) and 2-aminopyridine (59 mg) in dry acetonitrile was heated at reflux overnight. absorbed on silica and purified by flash chromatography eluting with ethyl acetate to give the title compound as a cream solid (100 mg).

MH+ = 367.2

m.p. 198-200°

Example 2

3-(4-fluoro-phenyl9-2-(4-methanesulfonyl-phenyl)[1,2-a] pyridine

A solution of 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (233 mg) and 2-amino-3-methylpyridine (68 mg) in dry acetonitrile (10 ml) was heated at reflux overnight. The reaction mixture was adsorbed onto 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 m.p. 180-182°

Example 3

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-trifluoromethyl-imidazole [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) is heated at reflux overnight. The reaction mixture was concentrated on silicic acid and purified by flash chromatography eluting with ethyl acetate to give a yellow solid. Further purification by recrystallization from propan-2-ol gave the title compound as yellow crystals (210 mg).

m.p. 260-261°

Analysis: Found: C, 57.7; H, 3.0; N, 6.2; S, 7.3

C21 H14 F4 N2 O2 S requires C, 58.1; H, 3.25; N, 6.45, S, 7.4%

MH+ =435

Tlc, SiO2, Rf 0.25 (ethyl acetate) detection u.v.

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 at reflux for 18 hours. The cooled reaction mixture was absorbed on silica to give the title compound by flash chromatography, eluting with ethyl acetate/hexane (1/1), as a tan solid (105 mg).

m.p. 194-196°

MH+ = 381

Tlc, SiO2, Rf 0.26 (ethyl acetate/hexane (2/1)) detection u.v.

Example 5

8-Chloro-3-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine

A suspension of 8-chloro-3-(4-fluoro-phenyl)-2-(4-methanesulfanyl-phenyl)-imidazo[1,2-a]pyridine (150 mg) in methanol (8 ml) and water (2 ml) is treated with OxoneTM (651 mg) and stirred for 2 hours at room temperature. The resulting suspension is treated with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The dried (MgSO 4 ) extract 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).

m.p. 242-244°

Tlc SiO2 (Et2O) Rf 0.5 det. in. v., KMnO4

MH+ = 401

Example 6

3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methanesulfanyl-imidazo[1,2-a]pyridine

A solution of 3-methylsulfanyl-pyridin-2-ylamine (140 mg) and 2-bromo-2-(4-fluorophenyl)-1-(4-methanesulfonyl-phenyl)-ethanone

(37.1 mg) in acetonitrile (15 ml) was heated at reflux overnight. The cooled reaction mixture was absorbed on silica and the title compound was obtained by flash chromatography eluting with ethyl acetate/cyclohexane (1/1) as a white solid (179 mg).

m.p. 224-226°

MH+ = 413

Tlc, SiO2, Rf 0.60 (ethyl acetate/cyclohexane (1/1)) detection u.v./KMnO4

Example 7

8-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl-imidazo[1,2-a]pyridine

A solution of 3-bromo-pyridin-2-ylamine3 (173 mg) and 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (371 mg) in acetonitrile (15 ml) is heated at reflux overnight. When cooled to room temperature the title compound was crystallized from solution and isolated by filtration as a white solid (241 mg).

m.p. 266-268°

MH+ = 446

Analysis: Found: C, 53.5; H, 3.0; N, 6.2; F, 4.3; S, 7.1 C20 H14 BrFN2 O2S requires: C, 53.9; H, 3.2; N, 6.3; F, 4.3; S, 7.2% Tlc, SiO2, Rf 0.61 (ethyl acetate/cyclohexane (2/1)) detection u.v., KMnO4

3Ref; M. Malinowski, Bull. Soc. Chem. Belg. 1988, 97, 51

Example 8

B-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 cooled solution of diethylaminosulfur trifluoride (0.067 ml). in dichloromethane (4 ml) at -78° for 5 minutes. The solution is allowed to warm up to room temperature in 30 minutes. Water (15 ml) is carefully added with stirring, the organic phase is separated, dried (Na2SO4) and absorbed on silicic acid. 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 prapan-2-ol (10 ml) to give white crystals (85 mg).

m.p. 221-222°

MH+ = 399

Analysis result: C, 63.1; H, 3.9; N, 6.8; F, 9.4; S, 8.1 C21 H16 F2 N2 O2 S Required: 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-ylamine4 (122 mg) and 2-bromo-2-(4-fluoro-phenyl)-1-(4-methanesulfonyl-phenyl)-ethanone (371 mg) in acetonitrile (15 ml) containing potassium carbonate (138 mg) is heated at reflux overnight. The cooled mixture was absorbed on silica to give the title compound by flash chromatography eluting with ethyl acetate/cyclohexane (1/1) as a white solid. Crystallization from propan-2-ol (10 ml) gave white crystals (136 mg). m.p. 228-230°

MH+ = 395

Analysis result: C, 66.6; H, 4.7; N, 6.9; F, 4.8; S, 8.2 C22 H19 N2 FO2 S Requires: C, 67.0; H, 4.85; N, 7.1; F, 4.8; S, 8.1%

4Ref: 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

A solution of [3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-8-yl] methanol (500 mg) and manganese (IV) oxide (1.32 g ) in chloroform (50 ml) is heated at reflux for 16 hours. The cooled reaction mixture is filtered and the filtrate is concentrated on silicic acid. The title compound was obtained by flash chromatography eluting with ethyl acetate/cyclohexane (4/1) as a light yellow solid (315 mg).

MH+ = 395

Findings of the analysis; C, 63.71; H, 3.55; N, 6.89; S, 8.07; C21 H15 FN2 O3 S 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 5-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methyl-imidazo[1,2-a]pyridine (380 mg) in chloroform (20 ml) was treated with solid N-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 (Na 2 SO 4 ) and absorbed on silicic acid. The title compound was obtained by flash chromatography eluting with cyclohexane/ethyl acetate (1/1) as a white solid (106 mg).

m.p. 277-279° (dec)

MH+ = 461

Tlc, SiO2, Rf 0.22 (Ethyl acetate/cyclohexane (1/1)) detection u.v., KMnO4

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-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine (130 mg) in methanol (8 ml) and water (2 ml) is treated with OxoneTM (436 mg) and stirred for 3 hours at room temperature. The resulting suspension is treated with water (50 ml) and extracted with ethyl acetate (50 ml). The dried (MgSO 4 ) extracts were 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).

m.p. 236-237°

Tlc SiO2 (Et2O) Rf 0.5 det. u.v., KMnO4

MH+ = 401

Example 13

6-bromo-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-8-methyl-imidazo[1,2-a]pyridine

A mixture of 1-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) is kept at reflux under nitrogen for 20 hours and evaporated. The residue is mixed with diethyl ether (20 ml) for 5 min, cooled and filtered. The procedure was repeated to obtain the title compound as a beige powder (580 mg).

MH+ = 461

Tlc SiO2(Et2O) Rf 0.6 detection UV,

KMnO4

Example 14

8-acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine

A solution of 3-acetyl-2-aminopyridine6 (2.50 g) and 2-bromo-2-(4-fluorophenyl)-1-(4-methanesulfonylphenyl)ethanone (6.82 g) in acetonitrile (125 ml) containing potassium bicarbonate (2.31 g) is heated at reflux overnight. The mixture is filtered hot and the filtrate is allowed to cool to room temperature. The title compound crystallized from solution and was isolated by filtration as a yellow solid (3.58 g).

Tlc: SiO2 Rf 0.34 (ethyl acetate/hexane, 1:3:1) detection u.v., iodine

1H NMR 3.04 (3H, s, CH3SO2-), 3.16 (3H, s, CH3CO-), 6.90 (1H, t, J = 7.0 Hz, H-6), 7.31 (2H, t, J = 8.8 Hz) & 7.45 (2H, dd, J = 5.2 Hz, 8.8 Hz)-C6 H4 F-, 7.85 (2H, d, J = 8.4 Hz) & 7.91 (2H, d, J = 8.4 Hz) -C6 H4 SO2, 7.93 ( 1H, dd, J = 1.1, 7.0 Hz, -H-7), 8.02 (1H, dd, J = 1.1, 7.0 Hz, H-5).

5Ref: F. Trecourt et al., J. Chem. Soc., Perkin Trans. 1 1990, 9, 2409-2415

Example 15

[3-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). After the addition is complete, the mixture is heated to 25° and the mixing is continued for 2 hours. Methanol (80 ml) was added and the mixture was concentrated on silicic acid. 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

Tlc (SiO2) Rf 0.28 (dichloromethane/ethanol/ammonia, 100/8/1) detection U.V.

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) cools down to -78°. A solution of diisobutylaluminum hydride (1.0 M in dichloromethane 1 ml) is added dropwise and the mixture is allowed to warm to ambient temperature for 30 minutes. Methanol (10 ml) was added in one portion and stirring was continued for a further 30 minutes. The reaction mixture was absorbed on silica to give the title compound by flash chromatography eluting with ethyl acetate as a white solid (120 mg).

m.p. 201-203°

T.i.c. SiO2 Rf 0.45 (ethyl acetate) detection U. V.

Example 17 - tablets

a) Compound from this invention 5.0 mg

Lactose 95.0 mg

Microcrystalline cellulose 90.0 mg

Cross-linked

polyvinylpyrrolidone 8.0 mg

Magnesium stearate 2.0 mg

Compression weight 200.0 mg

The compound of this invention, microcrystalline cellulose, lactose and cross-linked polyvinyl pyrrolidone are sieved through a 500 micron sieve and mixed in a suitable mixer. Magnesium stearate is sieved through a 250 micron sieve and mixed with the active mixture. The mixture is compressed into tablets using a suitable mold.

b) Compound from this invention 5.0 mg

Lactose 165.0 mg

Pregelatinized starch 20.0 mg

Cross-linked

olivinylpyrrolidone 8.0 mg

Magnesium stearate 2.0 mg

Compression weight 200.0 mg

The compound of this invention, lactose and pregelatinized starch are mixed together and granulated with water. The wet mass is dried and ground. Magnesium stearate and cross-linked polyvinylpyrrolidone are sieved through a 250 micron sieve and mixed with the granules. The resulting mixture is compressed using a suitable mold.

Example 18 - capsules

a) Compound from this invention 5.0 mg

Lactose 193.0 mg

Magnesium stearate 2.0 mg

Filling weight 200.0 mg

The compound of this invention and the pregelatinized starch are sieved through a 500 micron mesh sieve, mixed together and lubricated with magnesium stearate (through a 250 micron sieve). This mixture is filled into hard gelatin capsules of suitable size.

b) Compound from this invention 5.0 mg

Lactose 177.0 mg

Polyvinylpyrrolidone 8.0 mg

Cross-linked polyvinyl pyrrolidone 8.0 mg

Magnesium stearate 2.0 mg

Filling weight 200.0 mg

The compound of this invention and lactose are mixed together and granulated with a solution of polyvinylpyrrolidone. The wet mass is dried and ground. Magnesium stearate and cross-linked polyvinylpyrrolidone are sieved through a 250 micron sieve and mixed with the granules. The resulting mixture is filled into hard gelatin capsules of suitable size.

Example 19-syrup

a) Compound from this invention 5.0 mg

Hydroxypropyl methylcellulose 45.0 mg

Propyl hydroxybenzoate 1.5 mg

Butyl hydroxybenzoate 0.75 mg

Saccharin sodium 5.0 mg

Sorbitol solution 1.0 ml

Suitable buffer qs

Suitable flavor enhancers qs

Purified water 10 ml

Hydroxypropyl methylcellulose is dispersed in a portion of hot purified water together with hydroxybenzoates and the solution is allowed to cool to ambient temperature. Saccharin, flavor enhancers and sorbitol solution are added to the solution. The compound of this invention is dissolved in a portion of the remaining water and added to the stock solution. Suitable buffers can be added to control the pH in the region of greatest possible stability. The volume of the solution is filled, filtered and filled in suitable containers,

Example 20 - preparations for injections

% wt

Compound of this invention 1.00

Water for injections B.P. up to 100.00

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted to the highest possible stability and/or to facilitate dissolution of the compound of this invention by the use of dilute acid or alkali or by the addition of suitable buffer salts. Antioxidants and salt-splitting metals may also be included. The solution is clarified, made up to final volume with water and the pH is again measured and adjusted if necessary to ensure 10 mg/ml of the compound of formula (I).

The solution can be packaged for injection, for example by filling and sealing in ampoules, vials and syringes. Ampoules, vials and syringes can be aseptically filled (eg, the solution can be sterilized by filtration and filled into sterile ampoules under aseptic conditions) and/or sterilized at the end (eg, 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 into ampoules, sealed with glass and finally sterilized.

Other sterile preparations are prepared in a similar way and contain 0.5, 2.0 and 5% w/v of the compound of formula (I), so that they provide 5, 20 and 50 mg/ml of the compound of formula (I).

Biological data

Inhibitory activity against human COX-1 and COX-2 was determined in COS cells transfected with cDNA for human COX-1 and human COX-2. 24 hours prior to the experiment, COS cells were transferred from the 175 cm2 flasks in which they had been grown to 24-well cell culture plates using the following procedure. Incubation medium, Dulbecco's modified eagles medium (DMEM) supplemented with heat-inactivated fetal bovine serum (10% v/v), penicillin (100U/ml), streptomycin (100 μg/ml) and gentamicin (600 μg/ml) , is removed from the flask with confluent cells (1 confluent flask contains approximately 1 x 107 cells). Add 10 ml of phosphate-buffered saline (PBS) to the flask to wash the cells. When the PBS is removed, the cells are washed with 10 ml of trypsin for 20 seconds, after which the trypsin is removed and the flask is moved to an incubator (37°) for 1-2 minutes until the cells are released. The bottle is then removed from the incubator and the cells are resuspended in 10 ml of fresh incubation medium. The contents of the bottle are transferred to a sterile container of 250 ml and the volume of the incubation medium is filled up to 100 ml. 1 ml of cell suspension is pipetted into each well of a 4 x 24 well cell culture plate. The plates are then placed in an incubator (37° C, 95% air/5% CO2) overnight. If more than 1 flask is used, cells are pooled before being distributed into 24-well plates.

After overnight incubation, the incubation medium is completely removed from the 24 well cell culture plate and replaced with 250 μl of fresh DMEM (37°C). The test compounds are filled up to 250 x the required test concentration in DMSO and added to the pools in a volume of 1 ul. The plates are then gently mixed by circular rotation and placed in an incubator for 1 hour (37° C, 95% air/5% CO2). After the incubation period, 10 µl of arachidonic acid (750 μM) was added to each well to give a final arachidonic acid concentration of 30 μM. Plates are then incubated for 15 minutes, after which the incubation medium is removed from its pool and stored at -20°C, prior to determination of prostaglandin E2 (PGE2) levels using an enzyme immunoassay.

The inhibitory power of the test compounds is expressed as an IC50 value, which is defined as the concentration of the compound that inhibits the release of PGE2 from 50% of the cells. The selectivity ratio of COX-1 to COX-2 inhibition is calculated by comparing IC50 values.

The following IC50 values for inhibition of COX-2 and COX-1 are obtained for the compounds of this invention:

[image]

Claims (19)

1. Compound of formula (I) [image] and its pharmaceutically acceptable derivatives indicated by what R° represents halogen; R1 and R2 are independently selected from H, halogen, C1-4 alkyl, C1-4 alkyl substituted with one or more fluorine atoms, C1-4 alkoxy, C1-4 hydroxyalkyl, SC1-4 alkyl, C(O)H or C (O)C1-4 alkyl; and R3 represents C1-4 alkyl, 2. Compounds as claimed in claim 1, characterized in that R 3 represents methyl. 3. Compounds as claimed in claim 1 or 2, characterized in that R° represents fluorine. 4. Compounds as claimed in any one of claims 1 to 3, characterized in that R 1 represents H, chlorine, bromine, C 1-4 alkyl (eg methyl), methyl substituted with one to three fluorine atoms (eg CH 2 F or CF3), C1-4 hydroxyalkyl (e.g. CH2OH or CH(OH)CH3), SC1-4 alkyl (e.g. SCH3), C(O)H or C(O)C1-4 alkyl (e.g. C(O) CH3). 5. Compounds as claimed in any of claims 1 to 4 wherein R 2 represents H, chlorine, bromine or C 1-4 alkyl (eg methyl). 6. Compounds as claimed in any of claims 1 to 5 wherein R° is fluorine; R1 represents H, chlorine, bromine, C1-4 alkyl (e.g. methyl), methyl substituted with one to three atoms (e.g. CH2F or CF3), C1-4 hydroxyalkyl (e.g. CH2OH or CH(OH)CH3), SC1 -4 alkyl (eg SCH 3 ), C(O)H or C(O)C 1-4 alkyl (eg C(O)CH 3 ); R 2 represents H, chlorine, bromine, or C 1-4 alkyl (eg methyl); and R 3 represents methyl. 7. Compounds as claimed in any of claims 1 to 6 wherein R° is fluorine; R1 represents H, chlorine, bromine, methyl, CH2F, CF3, SCH3, C(O)H or C(O)CH3; R 2 represents H, bromine or methyl; and R 3 represents methyl. 8. Compounds as claimed in any of claims 1 to 7, wherein R1 is in the 8-position; and R 2 is at the 7-position or, when R 1 is other than H, at the 5-, 6- or 7-position. 9. Compounds as claimed in any one of claims 1 to 8, wherein R1 is in the 8-position; and R 2 is at the 7-position or, when R 1 is C 1-4 alkyl (eg methyl), the 5- or 7-position. 10. Compounds as claimed in any one of claims 1 to 9 wherein R 1 represents C(O)CH 3 . 11. A compound characterized in that it is 8-acetyl-3-(4-fluoro-phenyl)-2-(4-methanesulfonyl-phenyl)-imidazo [1,2-a] pyridine and its pharmaceutically acceptable derivatives. 12. Compounds as claimed in any one of claims 1 to 11, characterized in that the compound of formula (I) is in the form of hydrochloride, hydrobromide or sulfate. 13. A process for preparing a compound of formula (I) and its pharmaceutically acceptable derivatives as defined in any of claims 1 to 12, characterized in that it comprises: (A) reaction of the compound of formula (II) [image] or its protected derivative, characterized in that Lg represents the remaining group, with the compound of formula (III) [image] or its protected derivative; or (B) reaction of a compound of formula (IV) [image] or its protected derivative with an oxidizing substance; or (C) interconversion of a compound of formula (I) into another compound of formula (I); or (D) deprotection of the protected derivative of the compound of formula (I); and optionally converting compounds of formula (I) prepared by any of processes (A) to (D) into pharmaceutically acceptable derivatives thereof. 14. Pharmaceutical preparation, characterized in that it contains a compound of formula (I) or its pharmaceutically acceptable derivatives as defined in any of claims 1 to 12 mixed with one or more physiologically acceptable carriers or excipients. 15. The compound of formula (I) or its pharmaceutically acceptable derivative as defined in any one of claims 1 to 12, characterized in that it is for use in human or veterinary medicine, 16. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 12, for use in the treatment of conditions mediated by selective inhibition of COX-2. 17. A method of treating humans or animals suffering from conditions mediated by selective inhibition of COX-2, characterized in that it comprises administering to said patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 until 12 18. Use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 12, characterized in that it is for the production of a therapeutic substance for the treatment of inflammatory disorders. 19. A method of treating humans or animals suffering from an inflammatory disorder, comprising administering to said patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any of claims 1 to 12.