ZA200103344B - Pyrazolopyridine derivatives as selective COX-2 inhibitors. - Google Patents

Description

CC woo0r6216 PCT/EP99/08186 ~ PYRAZOLOPYRIDINE DERIVATIVES AS SELECTIVE COX-2 INHIBITORS

This invention relates to pyrazolo[1,5-a]pyridine 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 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 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. "20 _ The invention thus provides the compounds of formula (1)

ROS ) R?

BD A

</ 0

R® N

RY 4 3 2 3 and pharmaceutically acceptable derivatives thereof in which:

R® and R' are independently selected from H, halogen, Cisalkyl, C1.salkoxy, or

Ci-salkoxy substituted by one or more fluorine atoms;

R? is H, Cq.salkyl, Cygalkyl substituted by one or more fluorine atoms, Cisalkoxy,

Cs.ghydroxyalkyl, SCq.salkyl, C(O)H, C(O)C.salkyl, Cyalkylsulphonyl, Cisalkoxy substituted by one or more fluorine atoms; and

R® is Cy.salkyl or NH.

By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, 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 by those skilled in the art that the compounds of formula ()} may be modified to provide pharmaceutically acceptable derivatives thereof at any of the functional groups in the compounds. Of particular interest as such derivatives are compounds modified at the benzenesulphonamide function to provide metabolically labile benzenesulphonamides. 16 Acylated benzenesulphonamide derivatives are of especial interest. Examples of such benzenesulphonamide derivatives include:

N-alkylcarbonylbenzenesulphonamides;

N-alkoxyalkylcarbonylbenzenesulphonamides;

N-alkoxycarbonylbenzenesulphonamides; :

N-arylcarbonylbenzenesulphonamides; ' —N-alkoxycarbonylalkylcarbonylbenzenesulphonamides

N-carboxylalkylcarbonylbenzenesulphonamides

N-alkylcarbonyloxyalkylcarbonylbenzenesulphonamides; . ] ~~ N-alkylaminoalkylcarbonylbenzenesulphonamides: and oo

N-dialkylaminoalkylcarbonylbenzenesulphonamides.

With reference to such benzenesulphonamide derivatives, and by way of example only, alkyl may be Cysalkyl or Ciealkyl substituted by one or more halogen (e.g. chlorine) atoms; alkoxy may be Cisalkoxy or Ci.salkoxy substituted by one or more halogen (e.g. chlorine) atoms; and aryl may be phenyl or substituted phenyl.

BR : | WO 00/26216 PCT/EP99/08186

It will be appreciated by those skilled in the art that the pharmaceutically acceptable derivatives of the compounds of formula (I) may be derivatised at more than one position. it will be further appreciated by those skilled in the art that benzenesulphonamide derivatives of formula (I) may be useful as intermediates in the preparation of compounds of formula (I), or as pharmaceutically acceptable derivatives of formula (1), or both.

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 include: acid addition salts formed : with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides,

Ee hydrobromides and sulphates; and alkali metal salts, formed from addition of alkali metal bases, such as alkali metal hydroxides, e.g. sodium salts.

The term halogen is used to represent fluorine, chlorine, bromine or iodine. oT The term 'alky!l' 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-buty! or . t-butyl group.

In one aspect of the invention R® is at the 3- or 4- position of the phenyl ring, as defined in formula (1).

In another aspect of the invention R? is at the 6- position of the pyrazolopyridine ring, as defined in formula (1).

In another aspect of the invention R® and R' are independently H, halogen,

Cisealkyl, or Cyealkoxy.

In another aspect of the invention R? is Cisalkyl substituted by one or more fluorine atoms.

In another aspect of the invention R* is Cy.salkyl or NH,.

Within the invention there is provided one group of compounds of formula (1) (group A) wherein: R® and R' are independently H, halogen, Cisalkyl, or

Cisalkoxy; R? is Cy.aalkyl substituted by one or more fluorine atoms; and R3 is

Ciaalkyl or NH,.

Within group A, there is provided a further group of compounds (group A1) wherein: R® and R' are independently H, F, CI, Cy.;alkyl (e.g. methyl), or

Ci.3alkoxy (e.g. ethoxy); R? is C;.salkyl substituted by one or more fluorine atoms (e.g. trifluoromethyl); and R* is methyl or NH.

Within group A1, there is provided a further group of compounds (group A2) wherein: R® is F, Cl, or Cy.salkyl (e.g. methyl) or C.;alkoxy (e.g. ethoxy); R'is H:

R? is Cysalkyl substituted by one or more fluorine atoms (e.g. trifluoromethyl); and R%is methyl or NH,.

Within groups A, A1 and A2 there are provided further groups of compounds wherein R® is at the 3- or 4- position of the phenyl ring, and R? is at the 8- position of the pyrazolopyridine ring, as defined in formula (1).

Within the invention there is provided another group of compounds of formula (I) (group B) wherein: R® and R' are independently H, halogen, Cisalkyl, or :

Ci.galkoxy; R? is Cy.3alkyl; and R® is Cy.alkyl or NH,.

Within group B, there is provided a further group of compounds (group B1) “wherein: R® and R' are independently H, F, or C;.alkoxy (e.g. ethoxy); R? is

Cisalkyl (e.g. methyl); and R® is methyl or NH,. ~~ Within group B1, there is provided a further group of compounds (group B2) wherein: R® is H, F, or Cysalkoxy (e.g. ethoxy): R'is H: R? is Cs.aalkyl (e.g. methyl); and R® is methyl or NH,.

Within groups B, B1 and B2 there are provided further groups of compounds wherein R° is at the 3- or 4- position of the phenyl ring, and R? is at the 6- position of the pyrazolopyridine ring, as defined in formula M.

It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives,

So. WO 00126216 PCT/EP99/08186 including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).

In one aspect the invention provides the following compounds: 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1 ,5-alpyridin-3-yl]- 5 benzenesulfonamide; - 2~(3-fluoro-phenyl)-3-(4-methanesulfonyi-phenyl)-6-triflucromethyl-pyrazolo[ 1,5- alpyridine; 4-[2-(4-ethoxy-phenyl)-6-trifluoromethyl-pyrazolo[1 .5-a]pyridin-3-yl}- benzenesulfonamide; 4-[2-(4-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1 ,9-a]pyridin-3-yl}- benzenesulfonamide; 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-pheny!)-6-trifl uoromethyl-pyrazolo[1,5- ajpyridine; 4-(2-phenyl-6-trifiuoromethyl-pyrazolo[1 ,5-a)pyridin-3-yl)-benzenesulfonamide: 3-(4-methanesulfonyl-phenyl)-2-phenyl-6-trifluoromethyl-pyrazolo[1 ,9-a]pyridine; 4-[2-(4-methyl-phenyl)-6-trifluoromethyl-pyrazolo[1 ,9-a)pyridin-3-yl}- benzenesulfonamide; and pharmaceutically acceptable derivatives thereof. . In another aspect the invention provides the following compounds:

N-acetyl-4-[2-(3-fluorophenyl)-6-(trifiuoromethyl)pyrazolo[1 ,5-a]pyridin-3- } yllbenzenesulfonamide; ~N-acetyl-4-[2-(4-ethoxyphenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3- yllbenzenesulfonamide;

N-acetyl-4-{2-phenyl-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3- yllbenzenesulfonamide; sodium salt of N-acetyl-4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5- a)pyridin-3-yljbenzenesulfonamide; 4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,9-a]pyridin-3-yl}-N-(2- methoxyacetyl)benzenesulfonamide; 4-[2-(3-fluorophenyi)-6-(trifluoromethyl)pyrazolo[1 ,9-a]pyridin-3-yl}-N- propionylbenzenesulfonamide; 4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[ 1 ,0-a)pyridin-3-yi}-N- isobutyrylbenzenesulfonamide:

N-benzoyl-4-[2-(3-fluorophenyl)-6-(trifi uoromethyl)pyrazolo[1,5-a]pyridin-3- yllbenzenesulfonamide; methyl 4-[({4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[ 1 ,5-a)pyridin-3- yllphenyl}sulfonyl)amino]-4-oxobutanoate; 4-{({4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3- yllphenyl}sulfonyt)amino}-4-oxobutanoic acid: 4-{2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-3-yl]-N- pentanoyibenzenesulfonamide; 2-[({4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a}pyridin-3- yllphenyl}sulfonyl)amino]-2-oxoethyl acetate:

N-acetyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5-a)pyridin-3- yllbenzenesulfonamide;

N-(2-chloroacetyl)-4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazoto[1 ,5-alpyridin- 3-yllbenzenesulfonamide;

N-{2-(diethylamino)acetyl}-4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,5- ajpyridin-3-yllbenzenesulfonamide; methyl {4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1 ,9-a)pyridin-3- yllphenyl}sulfonylcarbamate; and tert-butyl {4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo|1 ,9-a)pyridin-3- yllphenyl}sulfonylcarbamate.

In a further aspect the invention provides the following compounds: . _4-[6-chloro-2-(3-ethoxyphenyl)pyrazolo[1 ,5-a]pyridin-3-yllbenzenesulfonamide; 6-chloro-2-(3-ethoxyp henyl)-3-[4-(methylsulfonyl)phenyl]pyrazolo[1 ,9-a)pyridine; 4-[6-methyl-2-phenyl-pyrazolo[1 ,9-a]pyridin-3-yllbenzenesulfonamide; 4-[2-(3-fluorophenyt)-6-methyl-pyrazolo[1 ,9-a]pyridin-3-yl]benzenesulfonamide; 4-[2-(3-ethoxyphenyl)-6-methyl-pyrazolo[ 1 ,9-a]pyridin-3-yilbenzenesulfonamide; 4-[2-(4-ethoxypheny!)-6-methyl-pyrazolo[1 ,5-a]pyridin-3-yllbenzenesulfonamide; 6-methyl-2-phenyl -3-[4-(methylsulfonyl)phenyl]pyrazolo[1 ,5-ajpyridine; 2-(3-fluorophenyl)-6-methyl-3-[4-(methylsulfonyl)phenyl]pyrazolo[1 ,9-a)pyridine; 2-(3-ethoxypheny!)-6-methyl-3-[4-(methylsulfonyl)phenyl]pyrazolo[ 1 ,5-a)pyridine; 2-(4-ethoxyphenyl)-6-methyl-3-[4-(methylsulfonyl)phenyl]pyrazolo[1 ,5-a)pyridine; 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.

C. WO 0026216 PCT/EP99/08186 . $ -

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; neuropathic pain (e.g. neuralgia, such as post herpetic neuralgia, trigeminal neuralgia and 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 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.

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 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,

Chron’s disease, gastritis, irritable bowel syndrome and ulcerative colitis; and the inflammation in such diseases as vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type 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 ophthatmic 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. 16 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 . ~ 20 _ treatment of a condition which is mediated by selective inhibition of COX-2.

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

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 (1) or a pharmaceutically acceptable derivative thereof.

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 selective inhibition of COX-2.

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 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 pain relievers such as a glycine : antagonist, a sodium channel inhibitor (e.g. lamotrigine), a substance P antagonist (e.g. an NK; antagonist), 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 H,-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, —_phenylipropanolamine, 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.

The compounds of formula (1) and their pharmaceutically acceptable derivatives 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 (I) or a pharmaceutically acceptable derivative 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 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.

©. WO 00126216 PCT/EP99/08186

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 0.01mg/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 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) and pharmaceutically acceptable derivatives thereof are described below. In the discussion and formulae that follow R% to R® are as defined in formula (1) above unless otherwise stated; Hal is a halogen, such as Bror I: X is a counterion, such as l NBS is N-bromosuccinimide; NCS is N-chlorosuccinimide; DMF is

N,N-dimethylformamide; and alkyl and halogen are as previously defined.

Thus according to a first process (A), compounds of formula (I) may be prepared by reacting a compound of formuta (Il)

R?

Hal — 0 N4

R N

R! with a boronic acid of formula (lil)

R°0,S —~ MH B(OH), (im or a suitable derivative thereof in the presence of a suitable transition metal catalyst. Suitable derivatives of formula (IN) include boronic acid esters, such as those described in R. Miyaura et al, 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 a another process (B), compounds of formula (I) wherein R® is ~ Ci.salkyl may be prepared by oxidising a compound of formula (IV)

RS R? ® A

AN (Iv)

RC N

=3 under conventional conditions. Conveniently the oxidation is effected using a monopersulfate compound, such as potassium peroxymonosulfate (known as

Oxone™) and the reaction is carried out in a solvent, such as an aqueous alcohol, (e.g. aqueous methanol), and at between -78°C and ambient temperature. :

According to a another process (C), compounds of formula (I) wherein R? is

C.salkylsulphonyl may be prepared by oxidising a compound of formula (V)

R%0,S SC, alkyl =\_ J

N

~~. / : R2 a N

R!

NN Vv) under conventional conditions. Conveniently the oxidation is effected in the manner described just above for process (B).

According to a another process (D), compounds of formula (I) wherein R? is

Ciealkoxy substituted by one or more fluorine atoms may be prepared by reacting a phenol of formula (VI)

R%0,S ® OH =\

N

~~. /

RY N

. 1

R (v1) ~ 10 _with a halofluoroalkane under conventional conditions. Conveniently the reaction is effected in a solvent, such as a polar solvent (e.g. DMF), in the presence of a strong base, such as an inorganic hydride (e.g. sodium hydride), at about ambient temperature and using the appropriate bromofluoroalkane to give the desired compound of formula (1).

According to a another process (E), compounds of formula (I) wherein R® is NH, may be prepared by reacting a compound of formula (X)

Hal0,S R? ~ =\. J </ (X) =O

R!

with a source of ammonia under conventional conditions. Conveniently the reaction is carried out in a solvent, such as an ester (e.g. ethyl acetate); at . ambient or elevated temperature (e.g. ambient temperature); employing . ammonium hydroxide as the source of ammonia and using a compound of formula (X) where Hal is Ci.

According to another process (F) compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors. The following procedures are illustrative of suitable interconversions.

Compounds of formula (1) wherein R? represents Ci.salkyl substituted by one or more fluorine atoms may be prepared from the appropriate compound of formula (1) wherein R? is Cishydroxyalkyl, C(O)H or C(O)C,.salkyl, by treatment with a suitable source of fluorine. Suitable sources of fluorine include, for example, (diethylamino)sulphur trifluoride. Conveniently the reaction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. dichloromethane), and at reduced temperature, such as -78°C.

Compounds of formula (I) wherein R? represents C(O)H may be prepared from the corresponding compound of formula (I) wherein R? represents CH,OH by oxidation. Suitable oxidising agents include, for example, manganese (IV) oxide.

Conveniently the oxidation is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. chloroform), and at elevated temperature (e.g. : : -under reflux).

Compounds of formula (I) wherein R? represents Cishydroxyalkyl, and wherein - - the hydroxy group is attached to the carbon linked to the pyridine ring, may be prepared by reduction of the compound of formula (I) wherein R® represents the corresponding aldehyde or ketone. Suitable reducing agents include hydride reducing agents, such as diisobutylaluminium hydride. Conveniently the reduction is effected in the presence of a solvent, such as a halogenated hydrocarbon (e.g. dichloromethane), and at reduced temperature, such as -78°C.

As will be appreciated by those skilled in the art it may be necessary or desirable at any stage in the synthesis of compounds of formula (1) to protect one or more sensitive groups in the molecule so as to prevent undesirable side reactions.

Lo « WO 0026216 PCT/EP99/08186

Another process (G) for preparing compounds of formula (I) thus comprises deprotecting protected derivatives of compounds of formula (1).

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, 1891), incorporated herein by reference, which also describes methods for the removal of such groups.

Acylation of compounds of formula (I) wherein R® is NH, 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’ by J March, fourth edition, (John Wiley and Sons, 1992), pp 417-424, incorporated herein by reference. ‘Compounds of formula (ll) may be prepared by halogenating compounds of formula (VII)

R? = y J

R® XN (VI) . R! by conventional means.

Thus esters of formula (VII) are first hydrolysed to their corresponding acids, for example by treatment with a strong base (e.g. sodium hydroxide), in the present of a solvent (e.g. ethanol) and at elevated temperature. The corresponding acid is then treated with a halogenating agent, conveniently at ambient temperature and in a solvent (e.g. chlorinated hydrocarbon), under which conditions the acid undergoes both halogenation and decarboxylation. Conveniently, the halogenating agent is a brominating agent, such as bromine in the presence of a strong acid (e.g. hydrobromic acid in acetic acid) or NBS, to yield the corresponding compound of formula (lf) wherein Hal is bromine.

Esters of formula (Vil) may be prepared by reacting a compound of formula (vi

CO, alkyl

ZZ

R2

R (Villy with an aminopyridinium complex of formula (1X)

R?

NS xX

NH, under conventional conditions. Conveniently the reaction is effected in the presence of a base, such as potassium carbonate, a solvent, such as DMF and at ambient temperature.

Compounds of formula (Il) may also be prepared by halogenating a compound of formula (XI)

R? =N\, /

N

RY N (Xt _ o _ - by conventional means. Conveniently the -halogenation is effected using a brominating agent (e.g. NBS), at ambient temperature and in a solvent (e.g. chlorinated hydrocarbon), to yield the corresponding compound of formula (Il) wherein Hal is bromine.

Compounds of formula (X1) may be prepared from an azirine of formula (Xt

R?

RY N

R} \ \_7 (Xi)

KE WO 00/26216 PCT/EP99/08186 by conventional means. Conveniently the reaction is effected in a solvent, such as an aromatic hydrocarbon (e.g. 1,2,4-trichlorobenzene) and at elevated temperature (e.g. under reflux).

Compounds of formula (XI) may be prepared from an oxime of formula (XI)

R?

R! \ \_7/ \ $ (Xt

HO by conventional means. Conveniently the oxime is dissolved in a solvent such as a haloalkane (e.g. dichloromethane), treated a with a base, such as an amine (e.g. triethylamine), the mixture cooled to about 0°C and treated with an ’ anhydride (e.g. trifluoroacetic anhydride), and the mixture then allowed to warm to ambient temperature.

Compounds of formula (XII) may be prepared from a ketone of formula (XIV)

R?

R! \ \_/ : — 0 (XIV) by conventional means. Conveviently the reaction is effected with hydroxylamine or a salt thereof (e.g. hydroxylamine hydrochloride), in a solvent such as an alcohol (e.g. methanol) and at ambient temperature.

Compounds of formula (XIV) may be prepared by reacting a compound of formula (XV) 0 ~ CH, (XV)

with a compound of formula (XVI)

R2 7 ow under conventional conditions. Conveviently the compound of formula (XV) is a chloro derivative and the reaction is effected in the presence of a strong base, such as an inorganic hydride (e.g. sodium hydride) and at about ambient temperature.

Boronic acids of formula (Ill) 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 (X) may be prepared by sulphonylating a compound of formula (XVII)

R? _ =\. J

AN (XVII) =

Rr! . —under conventional conditions. Conveniently the sulphonylation is effected using sulphonic acid or a derivative thereof, such as a halosulphonic acid (e.g. 16 chlorosulphonic acid); in the presence of a solvent, such as a halogenated ~~ alkane (e.g. dichloromethane); and at between -78°C and ambient temperature (e.g. -70°C).

Compounds of formulae (IV), (V) and (VI) and (XVI) may be prepared by methods analogous to those described for the preparation of the corresponding compounds of formula (1).

Compounds of formulae (VIll), (IX), (XV), (XVI) are either known compounds or may be prepared by literature methods such as those described in, for example:

D H Wadsworth et al, J Org Chem, (1987), 52(16), 3662-8:

J Morris and D G Wishka, Synthesis, (1994), (1), 43-6;

+ WO 0026216 PCT/EP99/08186

Y Kobayashi et al, Chem Pharm Bull, (1971), 19(10), 2106-15;

K Novitskii et al, Khim Geterotskil Soedin, (1970) 2, 57-62; and

T Tsuchiya, J Kurita and K Takayama, Chem Pharm Bull, (1980), 28(9) 2676-81; all 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 (I), (IV), (X) and (XVI) 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 following Examples illustrate the invention but do not limit the invention in any way. All temperatures are in °C. Flash column chromatography was carried out using Merck 9385 silica. Solid Phase Extraction (SPE) chromatography was carried out using Varian Mega Bond Elut (Si) cartridges (Anachem) under 15mmHg vacuum with stepped gradient elution. Thin layer chromatography (Tlc) was carried out on silica plates. NMR was carried out on a Brucker - 20 400MHz spectrometer. Chemical shifts are given, with respect to tetramethylsilane as internal chemical shift reference, in & ppm. In addition to those already defined, the following abbreviations are used: Me, methyl;

DMSO, dimethylsulphoxide; TFA, trifluoroacetic acid: DME, dimethoxyethane;

THF, tetrahydrofuran; DCM, dichloromethane; M, molar: s, singlet; d, doublet; t, triplet; m, multiplet; and br, broad.

Example 1 4-[2-( 3-Fluoro-phenyl)-6-trifluoromethyl-pyrazolo] 1,5-a]pyridin-3-yl]- benzenesulfonamide i) 3-Trifluoromethyl-pyridin-1-ylideneamine 2,4,6-trimethylphenylsulphonate

Solid t-butoxycarbonyl-O-mesitylenesulfonylhydroxylamine (13.44g, 42. 5mmol)’ was added portionwise with stirring to TFA (40ml) over 10 minutes then stirred for a further 30 minutes. The solution was poured onto ice (~250ml) and left until the ice melted. The resulting white solid was filtered off, washed with water, and dissolved in DME (200ml). The solution was dried over 4 A mol. sieves for 1.5 hours, filtered, then 3-trifluoromethylpyridine (5g, 34mmol) added and the reaction stirred at ambient temperature for 20h. The intermediate salt was isolated by filtration, washed with DME to give the title compound as a white solid (6.63g, 54%). 1H NMR 5 (DMSO) 9.34 (1H, s); 9.0 (1H, d, J 6Hz); 8.8(2H, brs); 8.68 (1H, d, J 8Hz); 8.22 (1H, t, J 7Hz); 6.75 (2H, s); 2.17 (3H, s)

Ref 1 Josef G Krause, Synthesis, 1972, 140 if) 1-(2,2-Dibromo-vinyl)-3-fluoro-benzene

To a stirred, cooled (ice/salt, 0°) solution of carbon tetrabromide (48.829) in anhydrous DCM (200ml) was added, portionwise over 3 minutes, triphenylphosphine (77.1g), maintaining the temperature below 10°. The resulting orange suspension was stirred at 0° for 1 hour before adding to it 3- fluorobenzaldehyde (7.8ml). After the addition was complete, the suspension was stirred at 0° for 1 hour then quenched by the addition of water (75ml). The organic phase was separated and washed with brine (75ml), dried (Nap;S0,4) and evaporated to dryness. The residue was poured into cyclohexane (1L) and stirred for 30 minutes. The organic phase was decanted and the residue taken up into DCM and poured into cyclohexane (1L). This procedure was repeated : twice more and the combined organic phases concentrated to ~100ml and passed through silica gel. The filtrate was concentrated to give the title compound as a mobile yellow oil (24g, 100%). MH+ 280, MH- 279

NMR (CDCl) 6 7.05 (1H, tm, J= 9Hz) 7.3 (3H, m) 7.45 (1H, s) iii) (3-Fiuoro-phenyl)-propynoic acid methyl ester :

To a stirred solution of 1-(2,2-dibromo-vinyl)-3-fluoro-benzene (23.8g) in anhydrous THF (350ml) cooled to -78° was added dropwise over 30 minutes, n- butyllithium (2.2eq, 1.6M in hexanes). The mixture was stirred for a further 30 minutes at -78° before methyl chloroformate (11.6g, 9.5ml) was added and the resultant mixture allowed to warm to 0° for 1hour before being diluted with 1:1 saturated aqueous sodium bicarbonate:ammonium chloride (100ml) and extracted into ether (2x 100ml). The combined organic extract was washed with brine (256ml), dried (Na,SO4) and evaporated to dryness to give the title compound as a brown oil (16.7g, 100%). MH- 173

NMR (CDCI3) & 7.4-7.1 (4H, m) 3.85 (3H, s, CO,Me)

Claims (23)

© WO 00126216 PCT/EP99/08186 Claims

1. Compounds of formula (I) R’0,S R? 8 = ~/ 0) RZ N = and pharmaceutically acceptable derivatives thereof in which: R® and R' are independently selected from H, halogen, C1.salkyl, Cq.salkoxy, or Ci.salkoxy substituted by one or more fluorine atoms; R? is H, Cisalkyl, Cisalkyl substituted by one or more fluorine atoms, Cisalkoxy, .Cyshydroxyalkyl, SCisalkyl, C(O)H, C(O)C1-salkyl,

Ci.salkylsulphonyl, Csealkoxy substituted by one or more fluorine atoms: and R? is Cisalkyl or NH,.

2. Compounds as claimed in claim 1 wherein R® and R' are independently H, halogen, Ci.galkyl, or Cysalkoxy; R? is Ci-.aalkyl substituted by one or more fluorine atoms; and R® is C.3alkyl or NH,.

3. Compounds as claimed in claim 1 or 2 wherein R® and R' are independently H, F, Cl, Cysalkyl (e.g. methyl), or Cysalkoxy (e.g. ethoxy); R? is Cy.salky! substituted by one or more fluorine atoms (e.g. trifluoromethyl); and R3 is methyl or NH.

4. Compounds as claimed in any one of claims 1 to 3 wherein R® is F, Cl, or : Ciaalkyl (e.g. methyl) or Cisalkoxy (e.g. ethoxy); R'is H; R? is Cysalkyl substituted by one or more fluorine atoms (e.g. trifluoromethyl); and R® is methyl or NH..

5. Compounds as claimed in any one of claims 1 to 4 wherein R? is at the 3- or 4- position of the phenyl ring; and R? is at the 6- position of the pyridine ring.

ot #3 WO 0026216 PCT/EP99/08186 . po -

6. 4-[2-(3-fluoro-phenyl)-6-trifluoromethyi-pyrazolo[1,5-a)pyridin-3-yl}- benzenesulfonamide; 2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-trifluoromethyl- pyrazolo[1,5-a]pyridine; 4-[2-(4-ethoxy-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a)pyridin-3-yl}- benzenesulfonamide; 4-[2-(4-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl}- benzenesulfonamide; 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-trifluoromethy!- pyrazolo[1,5-a]pyridine; 4-(2-phenyl-6-trifluoromethyl-pyrazolo[1,5-ajpyridin-3-yl)- benzenesulfonamide; 3-(4-methanesulfonyl-phenyl)-2-phenyl-6-trifluoromethyl-pyrazolo[1,5- ajpyridine; 16 4-[2-(4-methyl-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]- benzenesulfonamide; and pharmaceutically acceptable derivatives thereof.

7. N-acetyl-4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-alpyridin-3-

. 20 yllbenzenesulfonamide; N-acetyl-4-[2-(4-ethoxyphenyl)-6-(trifluoromethyl)pyrazolo[1,5-a}pyridin-3- yllbenzenesuifonamide; : — N-acetyl-4-[2-phenyl-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3- yllbenzenesulfonamide; sodium salt of N-acetyl-4-[2-(3-fluorophenyl)-6-(triftuoromethyl)pyrazolo[1,5- a)pyridin-3-yllbenzenesulfonamide; 4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl}-N-(2- methoxyacetyl)benzenesulfonamide; 4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-N- propionylbenzenesulfonamide; 4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-N- isobutyrylbenzenesulfonamide; N-benzoyl-4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3- yllbenzenesulfonamide; methyl 4-[({4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3- yllphenyl}sulfonyl)amino]-4-oxobutanoate:

. 4-[({4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazoio[1,5-a]pyridin-3- yljphenyl}sulfonyl)amino}-4-oxobutanoic acid; 4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yi}-N- pentanoylbenzenesuifonamide; 2-[({4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a)pyridin-3- yllphenyl}sulfonyl)amino]-2-oxoethyl acetate; N-acetyl-4-[2-(4-fluorophenyi)-6-(trifluoromethyl)pyrazolo[1,5-a}pyridin-3- yllbenzenesulfonamide; N-(2-chloroacetyl)-4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5- a)pyridin-3-yllbenzenesulfonamide; N-[2-(diethylamino)acetyl]-4-[2-(3-fluorophenyl)-6- (trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]lbenzenesulfonamide: methyl {4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3- yllphenyl}sulfonylcarbamate; and tert-butyl {4-[2-(3-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a}pyridin-3- yllphenyl}sulfonylcarbamate.

8. 4-[6-chloro-2-(3-ethoxyphenyl)pyrazolo[1,5-a]pyridin-3- yllbenzenesulfonamide; 6-chloro-2-(3-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]pyrazolof1,5-a]pyridine; 4-[6-methyl-2-phenyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide; 4-[2-(3-fluorophenyl)-6-methyl-pyrazolo[1 ,5-a]pyridin-3- : : — yllbenzenesulfonamide; 4-[2-(3-ethoxyphenyl)-6-methyl-pyrazolo[1,5-a]pyridin-3- yllbenzenesulfonamide; CT 4-[2-(4-ethoxyphenyl)-6-methyl-pyrazolo[1,5-ajpyridin-3- ) : yllbenzenesulfonamide; 8-methyl-2-phenyl -3-[4-(methylsulfonyl)phenyllpyrazolof1,5-a]pyridine; 2-(3-fluorophenyl)-6-methyl-3-[4-(methylsulfonyl)phenyi]pyrazolo[ 1,5-a]pyridine; 2-(3-ethoxyphenyl)-6-methyl-3-[4-(methylsulfonyl)phenyllpyrazolo[1,5-a]pyridine; 2-(4-ethoxyphenyl)-6-methyl-3-[4-(methylsulfonyl)phenyl]pyrazolo[1,5- ajpyridine; and pharmaceutically acceptable derivatives thereof.

> WO 0026216 PCT/EP99/08186

9. A process for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 8, which comprises: (A) reacting a compound of formula (ll) R? Hal =\ J NS N RY N R} (n : or a protected derivative thereof, with a compound of formula (li) R°0,S — )- B(OH), a) or a protected derivative thereof; or (B) where R® represents C_alkyl, reacting a compound of formula (IV) RS R? ® _ / < (Iv) . PR RC N = or a protected derivative thereof with an oxidising agent; or (C) where R?is Ci.salkylsulphonyl, oxidising a compound of formula (V) R%0,S SC, 4atkyl _ =\_ J

N

~. / R® N R 3 (Vv) or a protected derivative; or

) (D) where R? is Cygalkoxy substituted by one or more fluorine atoms, reacting a alcohol of formula (VI) R%0,S ® OH =\ N — 4 R? N 1 = w or a protected derivative thereof with a halofluoroalkane; or (E) where R® is NH,, reacting a compound of formula (X) HalO,S R? » A J ~ (X) RY N =4 with a source of ammonia under conventional conditions; or } (F) interconversion of a compound of formula (I) into another compound of formula (1); or : (G) deprotecting a protected derivative of compound of formula (1); and optionally converting. compounds of formula (1). prepared.by any one.of _ processes (A) to (G) into pharmaceutically acceptable derivatives thereof.

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

11. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 8 for use in human or veterinary medicine.

-

12. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 8 for use in the treatment of a condition which is mediated by selective inhibition of COX-2.

13. A substance or composition for use in a method of treating a human or animal subject suffering from a condition which is mediated by selective inhibition of COX-2, said substance or composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative as defined in any one of claims 1 to 8, and said method comprising administering to said subject an effective amount of said substance or composition.

14. A substance or composition for use in a method of treating a human or animal subject suffering from an inflammatory disorder, said substance or composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 8, and said method comprising administering to said subject an effective amount of said substance or composition.

15. The use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 8 for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by selective inhibition of COX-2.

16. The use of a compound of formula (lI) or a pharmaceutically acceptable derivative thereof as defined in any one of claims 1 to 8 for the manufacture of a therapeutic agent for the treatment of an inflammatory disorder.

17. A compound according to any one of claims 1, 6, 7 and 8, substantially as herein described and illustrated. AMENDED SHEET

Co #

18. A process according to claim 9, substantially as herein described and illustrated.

19. A composition according to claim 10, substantially as herein described and illustrated.

20. A compound for use in a method of treatment, substantially as herein described and illustrated.

21. A substance or composition for use in a method of treatment according to claim 13 or claim 14, substantially as herein described and illustrated.

22. A use according to claim 15 or claim 16, substantially as herein described and illustrated.

23. A new compound, a new process for the preparation of compounds, a new composition, a compound for a new use in a method of treatment, a substance or composition for a new use in a method of treatment, or a new use of a compound as claimed in any one of claims 1 to 8, substantially as herein described. AMENDED SHEET