WO2002032895A1

WO2002032895A1 - Chemical compounds

Info

Publication number: WO2002032895A1
Application number: PCT/GB2001/004582
Authority: WO
Inventors: Gordon John Dear; Kamlesh Gohil
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2000-10-17
Filing date: 2001-10-15
Publication date: 2002-04-25
Anticipated expiration: 2003-04-17
Also published as: AU2001295724A1; GB0025449D0

Abstract

The invention provides the compounds of formula (I) and pharmaceutically acceptable derivatives thereof in which, R1 is halogen, C1-6alkyl, C1-6alkoxy substituted by one or more fluorine atoms, or O(CH¿2?)1-4NR?4R5; R2¿ is hydroxy; R3 is C¿1-6?alkyl or NH2; and R?4 and R5¿ are independently selected from H, or C¿1-6?alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever, inflammation of a variety of conditions and diseases.

Description

CHEMICAL COMPOUNDS

This invention relates to pyrazolo[1 ,5-b]pyridazine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

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 inflammatory 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 pharmaceutically acceptable derivatives thereof in which:

R¹ is halogen, C,_₆alkyl, C^alkoxy, C^alkoxy substituted by one or more fluorine atoms, or 0(CH₂)_1.4NR⁴R⁵;

R² is hydroxy;

R³ is C^alkyl or NH₂; R⁴ and R⁵ are independently selected from H, or C,_₆alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring.

By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester, of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

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

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.

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

The term 'alky!' 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.

In one aspect, R¹ is at the 3- or 4-position of the phenyl ring, as defined in formula (I).

In another aspect, R² is at the 6-position of the pyridazine ring, as defined in formula (I).

In another aspect, R¹ is F, C^alkyl, C₁.₃alkoxy, C₁.₃alkoxy substituted by one or more fluorine atoms, or 0(CH₂)₁.₃NR⁴R⁵. In a further aspect R is F, C_1.3alkoxy or C₁.₃alkoxy substituted by one or more fluorine atoms.

In another aspect, R is methyl or NH 2-

In another aspect R⁴ and R⁵ are independently C_halky! or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring. Within the invention there is provided one group of compounds of formula (I) (group A) wherein: R¹ is F, C^alkyl, C^alkoxy, C^alkoxy substituted by one or more fluorine atoms, or 0(CH₂)₁.₃NR⁴R⁵; R² is hydroxy; R³ is methyl or NH₂; R⁴ and R⁵ are independently C₁.₃alkyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring.

Within group A, there is provided another group of compounds (group A1) wherein R¹ is F, methyl, C^alkoxy, OCHF₂, or O(CH₂)₁.₂NR⁴R⁵; R² is hydroxy; R³ is methyl or NH₂; R⁴ and R⁵ are both methyl, or together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring.

Within groups A and A1 , there are provided further groups of compounds wherein R¹ is at the 3- or 4-position of the phenyl ring and R² is at the 6-position of the pyridazine ring.

It is to be understood that the present 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 (e.g. racemic mixtures).

In one aspect the invention provides 2-(4-ethoxy-phenyl)-6-hydroxy-3-(4- methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine and pharmaceutically acceptable derivatives thereof.

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, aplastic 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 derivative 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 derivative 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 derivative.

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

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 derivative thereof.

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 pain relievers such as a 5HT, agonist (e.g. sumatriptan), and adenosine A1 agonist, an EP ligand (e.g. and EP4 antagonist), a glycine antagonist, a sodium channel inhibitor (e.g. lamotrigene), a substance P antagonist (e.g. an N^ antagonist), cannabinoids, acetaminophen or phenacetin; a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor (e.g. an iNOS or an nNOS inhibitor); an inhibitor of the release, or action, of tumour necrosis factor ; an antibody therapy (e.g. a monoclonal antibody therapy); a stimulant, including caffeine; an H₂-antagonist, such as ranitidine; a proton pump inhibitor, such as omeprazole; an antacid, such as aluminium or magnesium hydroxide; an antiflatulent, such as simethicone; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antitussive, such as 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 pharmaceutically acceptable derivative thereof in combination with one or more other therapeutic agents.

Further examples of suitable agents for adjunctive therapy include 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); an antiviral agent, such as a nucleoside inhibitor (e.g. lamivudine) or an immune system modulator (e.g. interferon); an opioid analgesic or a local anaesthetic.

The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.

Thus, in another aspect of the 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. 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 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 (I) and their pharmaceutically acceptable derivatives.

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

For transdermal administration, the pharmaceutical composition 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 (I) or a pharmaceutically acceptable derivative 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 derivative 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 0.01 mg/kg to 500mg/kg, such as 0.05mg/kg to 100mg/kg, e.g. 0.1 mg/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 pharmaceutically acceptable derivatives thereof may be prepared by any method known in the art for the preparation of compounds of analogous structure. Suitable methods for the preparation of compounds of formula (I) include, for example, those disclosed in WO99/12930, incorporated herein by reference, and in particular process (A) therein.

Thus according to a first process (A), compounds of formula (I) wherein R² is at the 6-position may be prepared by reacting a compound of formula (II)

or a protected derivative thereof with a boronic acid of formula (III)

or a suitable derivative thereof in the presence of a suitable transition metal catalyst. Suitable derivatives of formula (III) include boronic acid esters, such as those described in R. Miyaura et a/, J. Org. Chem., 1995, 60, 7508-7510. Conveniently, the reaction is carried out in a solvent, such as an ether (e.g. 1 ,2 dimethoxyethane); in the presence of a base, such as an inorganic base (e.g. sodium carbonate); and employing a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0).

According to another process (B), compounds of formula (I) may be prepared by dealkylation a compound of formula (IV)

or a protected derivative thereof under conventional conditions. Conveniently the "OAIkyl" group of formula (IV) is OMethyl and the dealkylation is demethylation. Dealkylation, such as demethylation, may conveniently be effected by treatment with an alkylborohydride, such as a lithiumtrialkylborohdride (e.g. L-Selectride^®; or Super-Hydride^®); in the presence of a solvent, such as an aromatic ether (e.g. THF) and at ambient to elevated temperature (e.g. under reflux); as for example described by G Majetich et a/,

Tetrahedron Letters, 35, 8727 (1994), incorporated herein by reference_. Dealkylation, such as demethylation, may also be conveniently effected by treatment with a Lewis acid, such as a boron trihalide (e.g. BBr₃); in the presence of a solvent, such as a haloalkane (e.g. DCM); and at reduced temperature, such as from -78°C to ambient temperature (e.g. -20 to 0°C). Dealkylation, such as demethylation, may also be conveniently effected by treatment with a pyridine salt (such as pyridine hydrochloride); in the presence of a solvent such as an alkylbenzene (e.g. xylene), or in the absence of solvent; at a high temperature (e.g. 150-200°C), as for example described by Seki et al, Chem. Pharm. Bull., 1996, 14(5), 453-461.

As will be appreciated by those skilled in the art compounds synthesised according to process (B) may be converted to compounds of formula (I) via oxidation under conventional conditions, as described in WO99/12930, incorporated herein by reference.

In a variation of process (B), compounds of formula (I) may also be prepared by dealkylation of a compound of formula (IVa), or a protected derivative thereof.

According to another process (C), compounds of formula (I) may be prepared by oxidation of a compound of formula (V)

under conventional conditions. Conveniently the oxidation is effected in a solvent, such as a halogenated alkane (e.g. dichloromethane); at ambient to elevated temperature, such as from 20°C to reflux (e.g. at about 25 °C); and in the presence of a catalyst, such as activated carbon, or a transition metal catalyst (e.g. palladium on activated carbon).

According to another process (D) compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors.

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.

Another process (E) for preparing compounds of formula (I) thus comprises deprotecting protected derivatives of compounds of formula (I).

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. Greene 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. Reference is made in particular to chapters 2 and 7, respectively relating to protection for hydroxyl and amino groups.

Compounds of formula (II) may be prepared according to Scheme 1 that follows.

Boronic acids of formula (III) are either known compounds or may be prepared by literature methods such as those described in, for example, EPA publication No. 533268.

Compounds of formula (IV) may be prepared by the methods described in W099/12930 for the preparation of corresponding compounds of formula (I).

Compounds of formula (V) may be prepared according to Scheme 2 that follows.

The acetophenones of schemes 1 and 2 are either known compounds or may be prepared by conventional chemistry. Scheme 2

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 (II) and (V) 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 Example that follows illustrates the invention but does not limit the invention in any way. Nmr spectra were recorded on a Bruker 600 spectrophotometer. Chemical shifts are given, with respect to tetramethylsilane as internal chemical shift reference, in δ ppm. The following abbreviations are used in the schemes and examples: DMF = dimethylformamide; DMFDMA = dimethylformamide dimethyl acetal; BOC = t-butoxycarbonyl; THF = tetrahydrofuran; s = singlet, d = doublet, t = triplet and q = quartet. Mass spectra were obtained on a Bruker Esquire-LC.

Example 1

2-(4-ethoxy-phenyl)-6-hydroxy-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5- bjpyridazine

O HCI

20% 6%

Title compound

MH⁺ 410 δ_H (MeCN/D₂0) 7.88 (2H, d), 7.75 (1 H, d), 7.55 (2H, d), 7.40 (2H, d), 6.90 (2H, d) 6.68 (1 H, d), 3.16 (3H, s), 4.06 (2H, q), 1.34 (3H, t).

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), 1 mM phenol, 1 mM reduced glutathione, 20mg/ml gelatin and 0.001 mM Hematin). Once diluted the enzyme solution was then sonicated for 5 seconds (Branson sonicator, setting 4, 1 cm tip) to ensure a homogeneous suspension. 155μl enzyme solution was then added to each well of a 96-well microtitre plate containing either 5μl test compound (40x required test concentration) or 5μl DMSO for controls. Plates were then mixed and incubated at room temperature for 1 hour. Following the incubation period, 40μl of 0.5μM arachidonic acid was added to each well to give a final concentration of 0.1 μM. Plates were then mixed and incubated for exactly 10 minutes (room temperature) prior to addition of 25μl 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).

The following IC₅₀ values for inhibition of COX-2 and COX-1 were obtained from the microsomal assay for compounds of the invention:

Claims

1. Compounds of formula (I)

and pharmaceutically acceptable derivatives thereof in which: R¹ is halogen, C^alkyi, C^alkoxy, C^alkoxy substituted by one or more fluorine atoms, or 0(CH₂)₁.₄NR R⁵; R² is hydroxy; R³ is C_halky! or NH₂; and

R⁴ and R⁵ are independently selected from H, or C.,.₆alkyl or, together with the nitrogen atom to which they are attached, form a 4-8 membered saturated ring.

2. Compounds as claimed in claim 1 wherein R¹ is F, C₁.₃alkyl, C.,.₃alkoxy, C.,.₃alkoxy substituted by one or more fluorine atoms, or 0(CH₂)_1.3NR R⁵; R² is hydroxy; R³ is methyl or NH₂; and R⁴ and R⁵ are independently C^alkyl or, together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring.

3. Compounds as claimed in claim 1 or 2 wherein R¹ is F, methyl, O,_.2alkoxy, OCHF₂, or O CH^NR'R⁵; R² is hydroxy; R³ is methyl or NH₂; and R⁴ and R⁵ are both methyl or, together with the nitrogen atom to which they are attached, form a 5 - 6 membered saturated ring.

4. Compounds as claimed in any one of claims 1 to 3 wherein R¹ is at the 3- or 4-position of the phenyl ring.

5. Compounds as claimed in any one of claims 1 to 4 wherein R² is at the 6- position of the pyridazine ring.

6. 2-(4-Ethoxy-phenyl)-6-hydroxy-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5- bjpyridazine; and pharmaceutically acceptable derivatives thereof. A process for the preparation of compound of formula (I) and pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 6, which comprises:

(A) where R² is at the 6-position, reaction of a compound of formula (II)

or a protected derivative thereof with a boronic acid of formula (III)

or a suitable derivative thereof in the presence of a suitable transition metal catalyst; or

(B), dealkylation of a compound of formula (IV)

or a protected derivative thereof; or in a variation of process (B), dealkylation of a compound of formula (IVa)

or a protected derivative thereof; or (C), oxidation of a compound of formula (V)

or a protected derivative thereof; or

(D), interconversion of a compound of formula (I) into another compound of formula (I); or

(E), deprotecting a protected derivative of compound of formula (I);

and optionally converting compounds of formula (I) prepared by any one of processes (A) to (E) into pharmaceutically acceptable derivatives thereof.

8. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 6 in admixture with one or more physiologically acceptable carriers or excipients.

9. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 6 for use in human or veterinary medicine.

10. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 6 for use in the treatment of a condition which is mediated by COX-2.

11. 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 derivative as defined in any one of Claims 1 to 6.

12. The use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 6 for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by COX-2, such as an inflammatory disorder.