The enzyme cyclooxygenase (COX) has recently been discovered to exist in two isoforms, COX-1 and COX-2. COX-1 corresponds to the originally identified constitutive enzyme while COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors.

Prostaglandins generated by the action of COX have both physiological and pathological roles. It is generally believed that COX-1 is largely responsible for the important physiological functions such as maintenance of gastrointestinal integrity and renal blood flow. In contrast the inducible form, COX-2, is believed to be largely responsible for the pathological effects of prostaglandins where rapid induction of the enzyme occurs in response to such agents as inf ! ammatory agents, hormones, growth factors and cytokines. A selective inhibitor of COX-2 would therefore have anti-inflammatory, anti-pyretic and analgesic properties, without the potential side effects associated with inhibition of COX-1. We have now found a novel group of compounds which are both potent and selective inhibitors of COX-2.

The invention thus provides the compounds of formula (I) and pharmaceutical acceptable salts thereof, in which: R1 and R2 are independently selected from the group consisting of H, C1 6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C3-6alkenyl, C3-6alkynyl, C3- locycloalkylCo-6alkyl, C4-12bridged cycloalkyl, A (CR7R3) n and B (CR7R3) n ; R3 is selected from the group consisting of C1 6alkyl, NH2 and R10CONH ; R4 is C1 2alkyl substituted by one to five fluorine atoms;

R5 is selected from the group consisting of H, Cl-4alkyl, C1-2alkyl substituted with one to five fluorine atoms, halogen and C3-10cycloalkylC0-6alkyl, with the proviso that when R6 is H R5 is not H.

R6 is selected from the group consisting of H, C1-4alkyl, C1-2alkyl substituted with one to five fluorine atoms, halogen, CI-4alkoxy, CN, N02, C1 6alkylOCO, NH2CO, C1-6alkylNHCO, NH2, C1-6alkylNH, (C1-6alkyl)2N, (C1-6alkyl)2NCO, C1-6alkylCONH, NH2SO2, C1-6alkylNHSO2, (C1-6alkyl)2NSO2, C1-6alkylSO2NH, ArSO2NH, C1- 6alkylSO2, ArSO2, C3-10cycloalylC0-6alyl, C3-6alkenyl and C3-6alkynyl, with the proviso that when R5 is H R6 is not H.

R7 and R3 are independently selected from H or C1-6alkyl ; A is an unsubstituted 5-or 6-membered heteroaryl or an unsubstituted 6- membered aryl, or a 5-or 6-membered heteroaryl or a 6-membered aryl substituted by one or more R9 ; R9 is selected from the group consisting of hydroxy, halogen, C1-6alkyl, C1-6alkyl substituted by one more fluorine atoms, C1-6alkoxy, C1-6alkoxy, substituted by one or more F, NH2SO2 and C1-6alkylSO2 ; R10 is selected from the group consisting of H, Cl-6alkyl, CI-6alkoxy, Cl-6alkylOCl- 6alkyl, phenyl, HO2CC16alkyl, C1-6alkylOCOC1-6alkyl, C1-6alkylOCO, H2NC1- 6alkyl, C1-6alkylOCONHC1-6alkyl and C1-6alkylCONHC1-6alkyl ; B is selected from the group consisting of 0 * * o * and where ) defines the point of attachment of the ring; and n is 0 t4o 4.

Suitable pharmaceutically acceptable salts include acid addition salts formed with the amine functionality NR1R2. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977,66,1- 19. Such salts may be formed from inorganic and organic acids.

Representative examples thereof include maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicyclic, methanesulfonic, p-toluenesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicyclic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, taurocholic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.

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

The term'alkyl'as a group or part of a group means a straight or branched chain alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.

The term 5-membered heteroaryl means a heteroaryl selected from the following : The term 6-membered heteroaryl means a heteroaryl selected from:

The term 6-membered aryl means: It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutical acceptable salts, including all geometric, tautomeric and optical forms, and mixtures thereof (e. g. racemic

mixtures). In particular when the ring B lacks a plane of symmetry the compounds of formula (I) contain a chiral centre as indicated therein by the asterisk *. Furthermore, it will be appreciated by those skilled in the art that when R4 and R5 in formula (I) are different the corresponding compounds contain at least one chiral centre, by virtue of the asymmetric carbon atom defined thereby, and that such compounds exist in the form of a pair of optical isomers (i. e. enantiomers).

In one aspect the invention provides compounds of formula (I) and pharmaceutical acceptable salts thereof, in which: R'and R2 are independently selected from the group consisting of H, C1-6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C3-6alkenyl, C3-6alkynyl, C3- 10/cycloalkylC0-6alkyl, C4-12 bridged cycloalkyl, A (CR7R8)n and B (CR7R8) n ; R3 is selected from the group consisting of C1-6alkyl, NH2 and R10CONH ; R4 is C1-2alkyl substituted by one to five fluorine atoms; R 5 is selected from the group consisting of H, C1-4alkyl, C1-2alkyl substituted with one to five fluorine atoms, and C310cycloalkylCo6alkyl, with the proviso that when R6 is H R5 is not H.

R6 is selected from the group consisting of H, C1-4alkyl, C1-2alkyl substituted with one to five fluorine atoms, halogen and C1Xalkoxy, with the proviso that when R6 is H R5 is not H.

R and R8 are independently selected from H or C1 6alkyl ; A is an unsubstituted 5-or 6-membered heteroaryl or an unsubstituted 6- membered aryl, or a 5-or 6-membered heteroaryl or a 6-membered aryl substituted by one or more R9 ; R9 is selected from the group consisting of halogen, C1-6alkyl, C1-6alkyl substituted by one or more fluorine atoms, C1-6alkoxy, C1-6alkoxy substituted by one or more F, NH2 S02 and C1 6alkyl SO2 ; R10 is selected from the group consisting of H, Cl-6alkyl, Cl-6alkoxy, Cl-6alkylOCl- 6alkyl, phgenyl, HO2CC1-6alkyl, C1-6alkylOCOC1-6alkyl, C1-6alkylOCO, H2NC1- 6alkyl, C1-6alkylOCONHC1-6alkyl and C1-6alkylCONHC1-6alkyl ; B is selected from the group consisting of O O o O * * 0 * * 7 and where ) defines the point of attachment of the ring; and

n is 0 to 4.

In another aspect of the invention R'is H, In another aspect of the invention R2 is selected from the group consisting of Ci- 6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C3-6alkenyl, C3-6alkynyl, C3-10cycloalkylC0-6alkyl, C4-12bridged cycloalkyl and A (CR7R8)n.

In another aspect of the invention R2 is selected from the group consisting of Ci- 6alkyl, C3-10cycloalkylC0-6alkyl (such as C3 10cycloalkyl or C3-7cycloalkylmethyl), A (CR7R8) n and B (CR7R3) n.

In another aspect of the invention R2 is selected from the group consisting of Ci- 6alkyl, C3-10cycloalkylC0-6alkyl (such as C3-10cycloalkyl or C37cycloalkylmethyl) and A (CR7R8)n.

Representative examples of R2 when it is C1 6alkyl include n-propyl, n-butyl and s-butyl. Representative examples of R2 when it is C3-10cycloalkylC0-6alkyl include cyclohexyl.

In another aspect of the invention R3 is C1 6alkyl, such as C1-3alkyl.

Representative examples of R3 include methyl.

In another aspect of the invention R4 is CHF2, CH2F or CF3. In another aspect R4 is CF3.

In another aspect of the invention R is H or C1-4alkyl, with the proviso that when R6 is H R5 is not H.

Representative examples of R5 include H and methyl.

In another aspect of the invention R6 is selected from the group consisting of H, C1-2alkyl (e. g. methyl), CF3 and C1 2alkoxy (e. g. methoxy), with the proviso that when R5 is H R6 is not H.

In another aspect of the invention one of R5 and R6 is H.

In another aspect of the invention R7 and R3 are independently selected from H or methyl. In another aspect R7 and R3 are both H.

In another aspect of the invention A is selected from the group consisting of

and A is unsubstituted or substituted by one or two R9.

In another aspect of the invention A is selected from the group consisting of and A is unsubstituted or substituted by one or two R9.

In another aspect of the invention R9 is selected from the group consisting of hydroxy, halogen, C1-3alkyl, C1-2alkyl substituted by one to five fluorine atoms and C1 3alkoxy.

Representative examples of R9 include methyl, methoxy, fluorine, bromine and hydroxy.

In another aspect of the invention R10 is selected from the group consisting of C 6alkyl (e. g. ethyl), phenyl and aminomethyl.

In another aspect of the invention B is In another aspect of the invention n is 1 to 4.

In another aspect of the invention n is 0 to 2 (e. g. 1).

It is to be understood that the invention covers all combinations of particular aspects of the invention as described hereinabove.

Since the compounds of the present invention, in particular compounds of formula (I), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compound of formula (I) may be used for preparing the more pure forms used in pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are available in crystalline form.

When some of the compounds of this invention are allowed to crystallise or are recrysallised from organic solvents, solvent of recrystallisation may be present in the crystalline product. This invention includes within its scope such solvates.

Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all the polymorphic forms of the compounds of formula (f).

Compounds of the invention are potent and selective inhibitors of COX-2. This activity is illustrated by their ability to selectively inhibit COX-2 over COX-1.

In view of their selective COX-2 inhibitory activity, the compounds of the present invention are of interest for use in human and veterinary medicine, particularly in the treatment of the pain (both chronic and acute), fever and inflammation of a variety of conditions and diseases mediated by selective inhibition of COX-2.

Such conditions and diseases are well known in the art and include rheumatic fever; symptoms associated with influenza or other viral infections, such as the common cold ; lower back and neck pain; headache; toothache ; sprains and strains; myositis; sympathetically maintained pain; synovitis; arthritis, including

rheumatoid arthritis; degenerative joint diseases, including osteoarthritis; gout and ankylosing spondylitis ; tendinitis; bursitis; skin related conditions, such as psoriasis, eczema, burns and dermatitis; injuries, such as sports injuries and those arising from surgical and dental procedures.

The compounds of the invention are also useful for the treatment of neuropathic pain. Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them.

Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia ; HIV-related neuropathy; neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia ; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved. The symptoms of neuropathic pain are incredibly heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain. In addition, there is pain associated with normally non-painful sensations such as"pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).

The compounds of the invention are also useful for the treatment of other conditions mediated by selective inhibition of COX-2.

For example, the compounds of the invention inhibit cellular and neoplastic transformation and metastatic tumour growth and hence are useful in the treatment of certain cancerous diseases, such as colonic cancer and prostate cancer. The compounds of the invention are also useful in reducing the number of adenomatous colorectal polyps and thus reduce the risk of developing colon cancer. The compounds of the invention are also useful in the treatment of

cancer associated with overexpression of HER-2/neu, in particular breast cancer.

Compounds of the invention also prevent neuronal injury by inhibiting the generation of neuronal free radicals (and hence oxidative stress) and therefore are of use in the treatment of stroke; epilepsy ; and epileptic seizures (including grand mal, petit mal, myoclonic epilepsy and partial seizures).

Compounds of the invention also inhibit prostanoid-induced smooth muscle contraction and hence are of use in the treatment of dysmenorrhoea and premature labour.

Compounds of the invention are also useful in the treatment of liver disease, such as inflammatory liver disease, for example chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis and liver transplant rejection.

Compounds of the invention inhibit inflammatory processes and therefore are of use in the treatment of asthma, allergic rhinitis and respiratory distress syndrome; gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis ; and the inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, plastic anaemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis, conjunctivitis and myocardial ischemia.

Compounds of the invention are also useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis and of acute injury to the eye tissue.

Compounds of the invention are also useful for 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 related conditions (including HIV infection), metabolism, toxins, anoxia and vitamin deficiency; and mild cognitive

impairment associated with ageing, particularly Age Associated Memory Impairment.

Compounds of the invention are also useful in the treatment of disorders ameliorated by a gastroprokinetic agent. Disorders ameliorated by gastroprokinetic agents include ileus, for example post-operative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD); gastroparesis, such as diabetic gastroparesis; and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP).

According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in human or veterinary medicine.

According to another aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition which is mediated by COX-2.

According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from a condition which is mediated by COX-2 which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt.

According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from an inflammatory disorder, which method comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

According to another aspect of the invention, we provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by COX-2.

According to another aspect of the invention, we provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of an inflammatory disorder.

It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.

It will be appreciated that the compounds of the invention may advantageously be used in conjunction with one or more other therapeutic agents. Examples of suitable agents for adjunctive therapy include a 5HT1 agonist, such as a triptan (e. g. sumatriptan or naratriptan); an adenosine A1 agonist; an EP ligand ; an NMDA modulator, such as a glycine antagonist; a sodium channel blocker (e. g. lamotrigine) ; a substance P antagonist (e. g. an NK1 antagonist); a cannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; a leukotriene receptor antagonist; a DMARD (e. g. methotrexate); gabapentin and related compounds; a tricyclic antidepressant (e. g. amitryptilline) ; a neurone stabilising antiepileptic drug; a mono-aminergic uptake inhibitor (e. g. venlafaxine) ; a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOS inhibitor; an inhibitor of the release, or action, of tumour necrosis factor a ; an antibody therapy, such as a monoclonal antibody therapy; an antiviral agent, such as a nucleoside inhibitor (e. g. lamivudine) or an immune system modulator (e. g. interferon); an opioid analgesic; a local anaesthetic; a stimulant, including caffeine ; an H2-antagonist (e. g. ranitidine); a proton pump inhibitor (e. g. omeprazole) ; an antacid (e. g. aluminium or magnesium hydroxide; an antiflatulent (e. g. simethicone); a decongestant (e. g. phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine) ; an antitussive (e. g. codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan); a diuretic; or a sedating or non-sedating antihistamine. It is to be understood that the present invention covers the use of a compound of formula (I) or a pharmaceutical acceptable salt thereof in combination with one or more other therapeutic agents.

The compounds of formula (I) and their pharmaceutical acceptable salts are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutical acceptable salt thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.

The compounds of formula (I) and their pharmaceutical acceptable salts may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration. The pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (1) and their pharmaceutical acceptable salts.

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

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

For parenteral administration, the pharmaceutical composition may be given as an injection or a continuous infusion (e. g. intravenously, intravascularly or subcutaneously). The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. For administration by injection these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.

Alternatively for parenteral administration the active ingredient may be in powder form for reconstitution with a suitable vehicle.

The compounds of the invention may also be formulated as a depot preparation.

Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

As stated above, the compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (1) or a

pharmaceutical acceptable salt thereof together with a further therapeutic agent.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

A proposed daily dosage of a compound of formula (I) for the treatment of man is 0. 01mg/kg to 500mg/kg, such as 0.05mg/kg to 100mg/kg, e. g. 0. 1mg/kg to 50mg/kg, which may be conveniently administered in 1 to 4 doses. The precise dose employed will depend on the age and condition of the patient and on the route of administration. Thus, for example, a daily dose of 0. 25mg/kg to 10mg/kg may be suitable for systemic administration.

Compounds of formula (I) and pharmaceutical acceptable salts thereof may be prepared by any method known in the art for the preparation of compounds of analogous structure.

Compounds of formula (I) and pharmaceutical acceptable salts thereof may be prepared by a process which comprises : reacting an amine R'R2NH of formula (II) or a protected derivative thereof with a compound of formula (III)

and thereafter and if necessary, interconverting a compound of formula (I) into another compound of formula (I) ; and/or deprotecting a protected derivative of compound of formula (I) The overall synthesis of a compound of formula (I) is shown in Schemes 1 to 3 below.

In Scheme 1, R1, R2, R4, R5 and R6 are as defined in formula (I) above, R3 is Ci- 6alkyl ; alkyl is a straight or branched chain alkyl group, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.

Scheme 1 0 y R 4 R6 (Vlll) Rs O N Rs O O 0 R R3S AICI3 R3S R5 (Vll) R3S (Vl) Kb Kb t CH3CO2H y CHC0, H alkyl-S heat zu R4 R4 s Oxidation, e. g. RsR N Oxone/CH30H R6F s tm N 'SO2alkyl \ N S-alkyl 3 I I R OzS (111) R1R2NH(11) 1 R4 R' N---N R5 \N I I R302S z

In Scheme 2, R1, R2, R4 and R6 are as defined in formula (I) above, R3 is Ci- 6alkyl, and R5 is C1-4alkyl or C3-10cucloalkylC0-6alkyl ; alkyl is a straight or branched chain alkyl group, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group.

Scheme 2 oqzR4 Ru R5CH, Mg r N R, 3 1 ! 5- FR R rY RSCHMg, . - f'Y R3S R3S R5 (Vll) R3S (Vl) R Mb Rb H, NNH CH, CO, Na CH3CO2H alkyl-S heat ra rua 5 5 R6R' N "N R RIR2NH oxidation ' NI _S-alkyl R as for Scheme 1 R'SO2 R'S

In Scheme 3, R1, R2, R4 and R5 are as defined in formula (I) above, R3 is Ci- 6alkyl, and R6 is halogen or C1 4alkoxy ; alkyl is a straight or branched chain alkyl group, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl or t-butyl group; X is a suitable leaving group such as halogen ; and CDI is 1,1'- carbonyldiimidazole.

Scheme 3 6 0 R6 0 1. CDI OH RSX 2. Mg (OCOCH2CO2tBu) 2 0T R4 O\/R4 0 (Vil) N N R 0 0 R6 O O R6 p 1. Base, R5X R4 2. acid I 2. acid Ru nez H3NNH CH, CO, Na 1 CH3CO2H alkyl-S heat R4 R4 R'R' R 6 RS (I I) RS R N F2s N 9 oxidation R1R2NH \ w N as for Scheme 1 N I 1 12 R3s R02s., JV R (IV) (I)

Referring to Schemes 1,2 and 3, the treatment of compounds of formula (III) with an amine of formula (II) is conveniently carried out in a solvent, such as nitrile (e. g. methyinitrile) and at elevated temperature (e. g. from about 50°C to

reflux). An excess of the amine may be used in place of the solvent.

Alternatively, the treatment of compounds of formula (III) with an amine of formula (II) is conveniently carried out in a solvent, such as a tertiary amine (e. g. NMP), and at between ambient and elevated temperature (e. g. ambient temperature). Use of, for example, NMP as solvent has the advantage that after completion of the reaction the desired compound of formula (I) may be precipitated from the reaction mixture by the addition of water, allowing for easier isolation and purification.

Conveniently the oxidation shown in Schemes 1,2 and 3 is effected using a monopersulfate compound, such as potassium peroxymonosulfate (known as Oxone) and the reaction is carried out in a solvent, such as an aqueous alcohol, (e. g. aqueous methanol), and at between-78°C and ambient temperature.

Alternatively, the oxidation shown in Schemes 1,2 and 3 may be effected using hydrogen peroxide in the presence of catalytic sodium tungstate dihydrate. The reaction may be carried out in a solvent such as acetic acid and at between ambient temperature and reflux (e. g. 50°C).

Referring to Schemes 1, 2 and 3, the cyclisation of diones of formula (VI) to give the corresponding pyrimidines of formula (IV) is conveniently carried out employing a thioronium salt such as a 2-methyl-2-thiopseudourea sulfate and under reflux.

Referring to Scheme 1, acid chlorides of formula (VIII) are either known compounds or may be prepared by conventional chemistry.

Compounds of formula (VII) in Schemes 1, 2 and 3 are either known compounds or may be prepared by conventional chemistry.

It will be appreciated by those skilled in the art that certain of the procedures described in Schemes 1,2 and 3 for the preparation of compounds of formula (I) or intermediates thereto may not be applicable to some of the possible substituents.

It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the transformations described in Schemes 1,2 and 3 in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I).

In one variation of Schemes 1,2 and 3, compounds of formula (111) wherein R3 is C1 6alkyl or NH2 may be prepared by oxidising a compound of formula (IV) A:

under oxidation conditions described hereinabove. Compounds of formula (IV) A may be prepared according to the general procedures of Schemes 1,2 and 3 by employing sulphonyl derivatives in place of the corresponding sulfide compounds.

It will be appreciated by those skilled in the art that compounds of formula ( !) may be prepared by interconversion, utilising other compounds of formula (I) as precursors. Suitable interconversions, such as alkylations, are well known to those skilled in the art and are described in many standard organic chemistry texts, such as'Advanced Organic Chemistry'by Jerry March, fourth edition (Wiley, 1992), incorporated herein by reference. For example, compounds of formula (I) wherein R1 is C1-6alkyl, C1-2alkyl substituted by one to five fluorine atoms, C3-6alkenyl, C3-6alkynyl, C3-ocycloalkylCo-6alkyl, C4-12bridged cycloalkane, (CR4R5) nA (with the proviso that n is not zero) and (CR4R5) nB may be prepared by alkylating the corresponding compound of formula (I) wherein R, is H.

Acylation of compounds of formula (I) wherein R3 is NH2, to provide corresponding acylated benzenesulphonamide derivatives, may be carried out by conventional means, for example by employing conventional acylating agents such as those described in'Advanced Organic Chemistry', pp 417-424, incorporated herein by reference.

As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions.

The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis'by Theodora W Green and Peter G M Wuts, second edition, (John Wiley and Sons, 1991), incorporated herein by reference, which also describes methods for the removal of such groups.

Amines of formula (it) are either known compounds or may be prepared by literature methods, such as those described in'Comprehensive Organic Transformations: a guide to functional group preparations'by Richard Larock (VCH, 1989), incorporated herein by reference.

Thioronium salts of formula (V) are either known compounds or may be prepared by literature methods, such as those described in A H Owens et al, Eur J Med Chem, 1988, 23 (3), 295-300, incorporated herein by reference.

Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention. Compounds of formulae (III) and (IV) are key intermediates and represent a particular aspect of the present invention.

Conveniently, compounds of the invention are isolated following work-up in the form of the free base. Pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared using conventional means.

Solvates (e. g. hydrates) of a compound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.

The Intermediates and Examples which follow illustrate the invention but do not limit the invention in any way. All temperatures are in °C.

Intermediate 1 1-94-(MethYlthio) phenyl] propan-1-one A solution of 4- (methylthio) benzonitrile (7.46 g, 50 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise (over a period of 0.5 hours) to a solution of ethyl magnesium bromide (100 mL, 1.0 M solution in tetrahydrofuran) with stirring, under a nitrogen atmosphere. The resultant reaction mixture was stirred for 2 hours, before being heated to reflux for a period of 5 hours. The reaction mixture was then stirred overnight at ambient room temperature.

The reaction mixture was cooled in an ice-bath to a temperature of 0 °C before 2M sulphuric acid (15 mL) was added dropwise (the temperature being maintained below 20 °C). The resultant thick yellow suspension was filtered under vacuo and the resultant filter cake was washed generously with ethyl acetate. The filtrate containing the product was then washed with 2M sulphuric acid, followed by saturated sodium hydrogen carbonate and then finally with water. The organic phase was separated and dried over anhydrous magnesium.

The magnesium sulphate was filtered off under suction and the filtrate was evaporated under vacuo to yield the desired product as a solid (8.3g, 92%).

C10H12SO (Calculated 180.2). Found MH+ 181.

Intermediate 2 4, 4, 4-Trifluoro-2-methil-1-f4- (meth I) phenyllbutane-1, 3-dione A solution of 1- [4- (methylthio) phenyl] propan-1-one (4.0 g, 22 mmol) in anhydrous tetrahydrofuran (50 mL) was cooled to a temperature of-78 °C under a nitrogen atmosphere. To this solution was added gradually a solution of sodium bis (trimethylsilylamide) (24 mL, 24 mmol, 1.0M solution in tetrahydrofuran) whilst maintaining the temperature at-78 °C. On completion of the addition of the sodium bis (trimethylsilylamide) the resultant reaction mixture was stirred for a further 45 minutes at a temperature of-78 °C, before the reaction mixture was allowed to warm to a temperature of-20 °C (briefly). The reaction mixture was then cooled to a temperature of-78 °C. To the resultant sodio-salt of 1- [4- (methylthio) phenyl] propan-1-one was added a solution of 1- (trifluoroacetyl) imidazole (2.8 mL, 25 mmol) in anhydrous tetrahydrofuran (10 mL). On completion of the addition of the solution of 1-(trifluoroacetyl) imidazole, the reaction mixture was stirred for a further 5 minutes, before the reaction mixture was allowed to warm to ambient room temperature. The reaction mixture was then stirred overnight at ambient room

temperature. The reaction mixture was carefully quenched with water and acidified with 1 M hydrochloric acid. The reaction mixture was then extracted into ethyl acetate. The organic phase was separated and combined before being washed with 1 M hydrochloric acid, followed by water. The organic phase was separated and dried over anhydrous magnesium sulphate. The magnesium sulphate was then filtered off under suction and the filtrate evaporated to yield the crude product as an oil. The crude product was purified via silica gel chromatography eluting with ethyl acetate: cyclohexane (1: 19). This gave the desired product as a colourless solid (2.3 g, 38%).

C12H1102F3S (Calculated 276.3). Found MH+ 277.

Intermediate 3 5-Methvl-2- (methylthio)-4- [4-(methvlthio) phenyll-6- (trifluoromethyl) pvrimidine A mixture of 4,4,4-trifluoro-2-methyl-1- [4- (methylthio) phenyl] butane-1,3-dione (2.2 g, 8.0 mmol), 2-methyl-2-thiopseudourea sulphate (2.7 g, 9.6 mmol) and anhydrous sodium acetate (1.3 g, 16 mmol) in glacial acetic acid (10 mL) was heated to reflux, overnight, under a nitrogen atmosphere. The reaction mixture was diluted with water and the product was extracted into ethyl acetate. The organic phase was separated and dried over anhydrous magnesium sulphate.

The magnesium sulphate was filtered off under suction and the filtrate was then evaporated under vacuo to give the crude product. The product was purified via silica gel chromatography, eluting with cyclohexane. The desired product was obtained as a colourless solid (2.2 g, 83%).

C14H13N2F3S2 (Calculated 330.4). Found MH+ 331.

Intermediate 4 5-Methyl-2-(methvlsulfonyl)-4-r4-(methvlsulphonyl) phenyl1-6- (trifluoromethyl)pyrimidine To a solution of 5-methyl-2- (methylthio)-4- [4- (methylthio) phenyl]-6- (trifluoromethyl) pyrimidine (2.2 g, 6.6 mmol) in methanol (150 mL) was added potassium peroxymonosulphate (OXONE) (18 g, 29 mmol) followed by water (30 mL). The resultant reaction mixture was stirred overnight (under a nitrogen atmosphere) at ambient room temperature. The reaction mixture was filtered under suction to remove suspended colourless solid and the filtrate was then evaporated under vacuo to give the product. The product was dissolved in dichloromethane and dried by passing the dichloromethane solution through a

hydrophobic frit. The dichloromethane was removed by evaporation under vacuo to yield the desired product as a crystalline colourless solid (2.6 g, 100%).

C14H13F3N204S2 (Calculated 394.4). Found MH+ 395 (MNH4+ 412).

Example 1 N-benzyl-5-methyl-4-4-meth lsulfonyl) phenyll-6- (trifluoromethyl) pvrimidin-2- amine.

To a solution of 5-methyl-2- (methylsulfonyl)-4- [4- (methylsulphonyl) phenyl]-6- (trifluoromethyl) pyrimidine (20 mg, 0.051 mmol) in 1-methyl-2-pyrrolidinone (2.0 mL) was added benzylamine (28, uL, 0.25 mmol). The resultant solution was stirred overnight at ambient room temperature. The reaction mixture was diluted with water (5 mL) before being applied to a reverse phase column (SPE cartridge C 18 Octadecyl, 10g, 60 mL) eluting with water (initially) to remove 1-methyl-2-pyrrolidinone, followed by acetonitrile to elute the crude product. The product was purified by silica gel chromatography eluting with dichloromethane, followed by ethyl acetate: cyclohexane (1: 1 v/v). This afforded the title compound as a colourless oil that solidified to a colourless solid on standing (12.8 mg, 59.9%).

C20H18F3N302S (Calculated 421.4). Found MH+ = 422.

Example 2 <BR> <BR> <BR> N-isobutyl-5-methyl-4-f4-(methylsulfonyl) phenyll-6-(trifluoromethyl) pyrimidin-2- amine.

To a solution of 5-methyl-2- (methylsulfonyl)-4- [4- (methylsulphonyl) phenyl]-6- (trifluoromethyl) pyrimidine (20 mg, 0.051 mmol) in acetonitrile (5.0 mL) was added isobutylamine (25 L, 0.25 mmol). The resultant solution was heated overnight at a temperature of 80 °C. The reaction mixture was allowed to cool before the solvent was removed by evaporation under vacuo. The resultant oil was purified by silica gel chromatography (SPE cartridge SiO2, 10g, 60 mL) eluting with dichloromethane, followed by ethyl acetate: cyclohexane (1: 1 v/v).

This afforded the title compound as a colourless solid (15.6 mg, 79 %).

C17H20F3N302S (Calculated 387.4). Found MH+ = 388.

Examples 3 to 15 as shown in Table 1 that follows, were prepared in the manner described for Examples 1 and 2. an open bracket, (, is used to mark the bond between the substituent and the nitrogen atom to which it is attached.

Table 1

Ex-Ra,, R5 R6 MH _ X 0,. ; < (MH3 ;- 3 H 2-hydroxybenzyl CH3 CF3 CH3 H 438 4 H < CH3 CF3 CH3 H 428 5 H 4-methylbenzyl CH3 CF3 CH3 H 436 6 H cyclohexyl CH3 CF3 CH3 H 414 7 H CH3 CF3 CH3 H 430 W° 8 H n-propyl CH3 CF3 CH3 H 374 9 H N CH3 CF3 CH3 H 423 i 10 H CH3 CF3 CH3 H 437 N 11 H n-butyl CH3 CF3 CH3 H 388 12 H \ ° CH3 CF3 CH3 H 426 13 H < CH3 CF3 CH3 H 412 14 H 4-methoxybenzyl C H3 C F3 C H3 H 452 15 H 4-fluorobenzyl CH3 CF3 CH3 H 440 Biological Data Inhibitory activity against microsomal h-COX2 was assessed against a microsomal preparation from baculovirus infected SF9 cells. An aliquot of microsomal preparation was thawed slowly on ice and a 1/40,000 dilution

prepared from it into the assay buffer (sterile water, degassed with argon containing 100mM HEPES (pH 7.4), 10mM EDTA (pH7.4), 1mM phenol, 1mM reduced glutathione, 20mg/ml gelatin and 0. 001mM Hematin). Once diluted the enzyme solution was then sonicated for 5 seconds (Branson sonicator, setting 4, 1cm tip) to ensure a homogeneous suspension. 155Ll enzyme solution was then added to each well of a 96-well microtitre plate containing either 5l test compound (40x required test concentration) or 5p1 DMSO for controls. Plates were then mixed and incubated at room temperature for 1 hour. Following the incubation period, 40, u1 of 0. 5µM arachidonic acid was added to each well to give a final concentration of 0. 1µM. Plkatesd were then mixed and incubated for exactly 10 minutes (room temperature) prior to addition of 25w1 1 M HCI (hydrochloric acid) to each well to stop the reaction. 25µl of 1M NaOH (sodium hydroxide) was then added to each well to neutralise the solution prior to determination of PGE2 levels by enzyme immunoassay (EIA). Results are expressed as % inhibition of PGE2 release by the compound compared to solvent control at 10 micromolar concentration. ExampfeNo COX-2 % inhibition COX-2 IC50 (µM 1 61 1.3 2 6.6 3 2. 5 4 0. 56 5 15. 3 6 2. 3 7 >100 8 26. 7 9 >98. 6 10 71. 2 11 43 6. 3 12 11 13 43 14 23 15 35