WO2003006451A1

WO2003006451A1 - 4-phenylpyran-2-one derivatives

Info

Publication number: WO2003006451A1
Application number: PCT/EP2002/007429
Authority: WO
Inventors: Maria Isabel Crespo Crespo; Juan Miguel Jimenez Mayorga; Lidia Soca Pueyo
Original assignee: Almirall Prodesfarma SA
Current assignee: Almirall SA
Priority date: 2001-07-10
Filing date: 2002-07-04
Publication date: 2003-01-23
Anticipated expiration: 2004-01-10
Also published as: AR034744A1

Abstract

The invention relates to 4-phenylpyran-2-one derivatives of formula (I) or pharmaceutically acceptable salts thereof, which are inhibitors of cyclooxygenase-2; to processes and intermediates for their preparation; to pharmaceutical compositions containing them; and to their use in the treatment or prevention of pathological conditions mediated by cyclooxygenase-2.

Description

4-PHENYLPTRAN-2-ONE DERIVATIVES

This invention relates to new therapeutically useful 4- phenylpyran-2-one derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

It is known that non-selective inhibition of the enzyme cyclooxygenase (COX) prevents the overproduction of prostaglandins associated with inflammation, which are mediated by cyclooxygenase-2 (COX-2) but, at the same time, deprives tissues of basal levels of prostaglandins necessary for the health of certain tissues mediated largely by cyclooxygenase-1 (COX-1) . Non steroidal anti-inflammatory drugs are non- selective inhibitors of COX and for that reason, have side effects of decreased renal blood flow, decreased platelet function, dyspepsia and gastric ulceration.

We have now found that certain 4-phenylpyran-2-one derivatives selectively inhibit COX-2 in preference to COX-1 and are useful in the treatment, prevention or amelioration of COX-2 mediated diseases, such as inflammation, pain, fever, and asthma with fewer side effects.

Accordingly the present invention provides a 4- phenylpyran-2-one compound of formula (I) :

wherein:

R¹ represents an alkyl or -NR⁴R⁵ group, wherein R⁴ and R^s each independently represents a hydrogen atom or an alkyl group;

X represents a single bond, an oxygen atom or a sulfur atom; R² represents an alkyl, C₃-C₇ cycloalkyl, pyridyl, thienyl, furyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, methylsulfonyl, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups, with the proviso that when R² is an alkyl or C₃-C₇ cycloalkyl, X is an oxygen atom or a sulfur atom; and

R³ represents a hydrogen atom, methyl, hydroxymethyl, alkoxymethyl, C₃-C₇ cycloalkoxymethyl, benzyloxy ethyl, phenyl, hydroxycarbonyl, nitrile, trifluoromethyl or difluoromethyl group or a CH₂-R⁶ group wherein R⁶ represents an alkyl group; or a pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are compounds of formula (I) :

wherein:

R¹ represents an alkyl or -NRR⁵ group, wherein R⁴ and R^s each independently represents a hydrogen atom or an alkyl group;

X represents a single bond, an oxygen atom or a sulfur atom;

R² represents an alkyl, C₃-C₇ cycloalkyl, pyridyl, thienyl, furyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups, with the proviso that when R² is an alkyl or C₃-C₇ cycloalkyl, X is an oxygen atom or a sulfur atom; and

R³ represents a hydrogen atom, methyl, hydroxymethyl, alkoxymethyl, C -C_η cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile, trifluoromethyl or difluoromethyl group or a CH₂-R^S group wherein R⁶ represents an alkyl group; and pharmaceutically acceptable salts thereof.

The alkyl groups and moieties such as those present in the alkoxy, hydroxyalkyl, mono- or di-alkylamino groups, mentioned in relation to the groups R¹ to R^s are preferably "lower" alkyl that is containing from 1 to 6 particularly from 1 to 4 carbon atoms, the hydrocarbon chain being branched or straight. Preferred alkyl groups, and where relevant alkyl moieties, include methyl, ethyl, propyl including i-propyl, and butyl including n-butyl, t-butyl, i-butyl and sec-butyl. It will be understood that in the compounds of formula (I) wherein R² is a pyridyl, thienyl, furyl, naphthyl, tetrahydronaphthyl or indanyl group, said group may be attached to the pyranone ring, via moiety X, at any of its available substitutable positions. For example: when R² is indicated as being a furyl group this includes compounds wherein R² is 2- furyl and 3-furyl; when R² is indicated as being a pyridyl group this includes compounds wherein R² is 2-pyridyl, 3- pyridyl and 4-pyridyl; when R² is indicated as being a naphthyl group this includes compounds wherein R² is 1-naphthyl and 2- naphthyl; and similarly for thienyl, tetrahydronaphthyl or indanyl group.

In compounds of formula (I) wherein R² represents a phenyl group substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, methylsulfonyl, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups, it will be understood that the substituents listed can be selected independently of one another; the expression one or more means from 1 to 5, preferably from 1 to 3 and most preferably 1 or 2; and each substituent may in turn be located at any available substitutable position on the phenyl group. In compounds of formula (I) R¹ preferably represents a methyl, ethyl, propyl including i-propyl, or butyl including n- butyl, t-butyl, i-butyl and sec-butyl group, or an -NRR^S group, wherein R⁴ and R⁵ each independently represents a hydrogen atom or a methyl, ethyl, propyl including i-propyl, or butyl including n-butyl, t-butyl, i-butyl and sec-butyl groups. More preferably, R¹ represents a -NR⁴R^S group. Most preferred are compounds wherein R¹ represents an NH₂ group.

In compounds of formula (I) X preferably represents a single bond or an oxygen atom.

In compounds of formula (I) R² preferably represents a pyridyl, thienyl, furyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups. More preferably R² represents a pyridyl, thienyl, furyl or naphthyl, group, or a phenyl group which may be unsubstituted or substituted by one or two halogen atoms or alkyl, trifluoromethyl, amino, mono- or dialkylamino or alkoxy groups.

In compounds of formula (I) R³ preferably represents a hydrogen atom or a methyl, ethyl, propyl, hydroxymethyl, methoxymethyl, trifluoromethyl or difluoromethyl group. More preferably, R³ represents methyl, hydroxymethyl or difluoromethyl.

Preferred compounds of formula (I) are those wherein R² represents a pyridyl, thienyl, furyl or naphthyl group, or a phenyl group which may be unsubstituted or substituted by one or two halogen atoms or alkyl, trifluoromethyl or alkoxy groups More preferred compounds are those wherein R² represents a pyridyl, thienyl, furyl or naphthyl group, or a phenyl group which may be unsubstituted or substituted by one or two halogen atoms or methyl, ethyl, trifluoromethyl or methoxy groups.

Thus, in the preferred embodiments of the invention R² represents a pyridyl, thienyl, furyl or naphthyl group, or a phenyl group which may be unsubstituted or substituted with a fluorine, chlorine, or bromine atom, or a trifluoromethyl, methyl, ethyl or methoxy group, or disubstituted with any two groups which may be the same or different and are selected from fluoro-, chloro- and methyl, most preferably the phenyl group has a substituent at the 4-position.

Particular examples of these preferred R² substituents are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 2-furyl, 1- naphthyl, 2-naphthyl, unsubstituted phenyl 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-ethylphenyl, 4-trifluoromethylphenyl, 4- bromophenyl, 2, 4-dimethylphenyl, 2, 4-difluorophenyl, 3,4- difluorophenyl, 2, 4-dichlorophenyl, 3, 4-dichlorophenyl, 3,5- dichlorophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4- methylphenyl, 4-chloro-3-methylphenyl, 4-chloro-3-fluorophenyl or 3-chloro-4-methylphenyl group.

In the most preferred embodiments of the invention R² represents a 2-pyridyl, 3-pyridyl, 4-pyridyl or 2-furyl group or a phenyl group which is unsubstituted or substituted in the 3- and/or 4- position (s) with a fluorine or chlorine atom or a methyl or trifluoromethyl group.

In one preferred embodiment of the invention, when R¹ is a methyl group, R² is not a phenyl, fluorophenyl, pyridyl or iso-propyl group. For example, when R¹ is a methyl group, R² is typically a thienyl, furyl, naphthyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, methylphenyl, ethylphenyl or methoxyphenyl group, or a phenyl group which is disubstituted with any two groups which may be the same or different and are selected from fluoro-, chloro- and methyl.

More preferably, when R¹ is a methyl group, R² is 2- thienyl, 2-furyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl,

4-methylphenyl, 4-methoxyphenyl, 4-ethylphenyl, 4- trifluoromethylphenyl, 4-bromophenyl, 2, 4-dimethylphenyl, 2,4- difluorophenyl, 3, 4-difluorophenyl, 2, 4-dichlorophenyl, 3,4- dichlorophenyl, 3, 5-dichlorophenyl, 3-chloro-4-fluorophenyl, 3- fluoro-4-methylphenyl, 4-chloro-3-methylphenyl, 4-chloro-3- fluorophenyl or 3-chloro-4-methylphenyl group. Most preferably, when R¹ is a methyl group, R² is a 2- furyl group or a phenyl group which is substituted in the 3- or

4- position with a chlorine atom or a methyl or trifluoromethyl group or which is disubstituted in the 3- and 4- positions with two groups selected from fluorine and chlorine atoms and methyl and trifluoromethyl groups.

Alternatively or additionally, when R¹ is a methyl group,

R³ is preferably not hydrogen, methyl, trifluoromethyl or difluoromethyl. For example, when R¹ is a methyl group, R³ is typically ethyl, propyl, hydroxymethyl, methoxymethyl or phenyl. More preferably, when R¹ is a methyl group, R³ is hydroxymethyl .

In this embodiment, it is most preferred that R¹ is not a methyl group.

Of outstanding interest are: 4- (4-methanesulfonylphenyl) -β-methyl-3-phenylpyran-2-one,

3- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -β-methylpyran-

2-one,

3- ( 4 -f luorophenyl ) -4 - ( 4-methanesulfonylphenyl ) -β-methylpyran-

2-one , 4 - ( 4 -methanesulfonylphenyl ) - β-methyl-3 - ( 4 -trif luoromethyl- phenyl ) pyran-2-one,

4- (4-methanesulfonylphenyl) -β-methyl-3- (4-methylphenyl) pyran-2- one,

3- ( furan-2-yl) -4- ( 4-methanesulfonylphenyl) -6-methylpyran-2-one, 4- ( 4-methanesulfonylphenyl ) -β-methyl-3- (pyrfdin-2-yl ) pyran-2- one,

4- ( 4 -methanesulfonylphenyl ) -6-methyl-3- (pyridin-3-yl ) pyran-2- one ,

3- (4-fluorophenoxy) -4- (4-methanesulfonylphenyl) -β-methylpyran- 2-one, 3- ( 4-chlorophenoxy) -4- ( 4-methanesulfonylphenyl ) -β-methylpyran-

2-one,

4- ( 4-methanesulfonylphenyl ) -β-methyl-3- ( 4-methylphenoxy) pyran-

2-one, 3- ( 3 , 4-dif luorophenoxy) -4 - ( 4-methanesulfonylphenyl ) -β-methyl- pyran-2-one,

3- (3, 4-dichlorophenoxy) -4- (4-methanesulfonylphenyl) -β-methyl- pyran-2-one,

4- (4-methanesulfonylphenyl) -6-methyl-3- (pyridin-2-yloxy) pyran- 2-one,

4- [ β-methyl-2-oxo-3- ( 4-trifluoromethylphenyl) -2H-pyran-4- yl]benzenesulfonamide,

4- [3- ( 4-fluorophenoxy) -β-methyl-2-oxo-2H-pyran-4-yl]benzene- sulfonamide, 4- [3- (4-chlororophenoxy) -β-methyl-2-oxo-2H-pyran-2-yl]benzene- sulfonamide,

4- [6-methyl-2-oxo-3- ( 4-trifluoromethylphenoxy) -2H-pyran-2- yl] benzenesulfonamide,

4- [β-methyl-2-oxo-3- (pyridin-4-yloxy) -2H-pyran-2-yl] benzene- sulfonamide, and pharmaceutically acceptable salts thereof.

The present invention also provides processes for preparing a compound of formula (I) which depend on the definition of R³. When R³ is a hydrogen atom or a methyl group, compounds of formula (I) are prepared according to the definition of R¹ and X. Thus, compounds of formula (I) in which

R³ is a hydrogen atom or a methyl group, R¹ is an alkyl or -NR⁴R^S group in which R⁴ and R⁵ are alkyl groups, and X is a bond, viz. a 4-phenylpyran-2-one of formula (II) :

wherein R^la is an alkyl or NR^4aR^5a group in which R^4a and R^5a each independently represents an alkyl group, R^3a is a hydrogen atom or a methyl group, X^a is a bond, and R² is as defined above, which comprises reacting a derivative of formula (III) :

(III)

wherein R^la and R^3a are as defined above and Z is a leaving group, preferably bromine, with a boronic acid of formula (IV) :

R²-B(OH)₂ (IV)

wherein R² is as defined above, or with an organotin derivative of formula (V) :

R²-Sn(R⁷) (V) wherein R² is as defined above and R⁷ is an alkyl group.

The reaction between the derivative of formula (III) and the boronic acid of formula (IV) or the organotin derivative of formula (V) may be carried out in an organic solvent such as methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran, dimethoxyethane, benzene or toluene, optionally in the presence of water, at a temperature between βO°C and 120°C, with a base such as sodium or potassium carbonate and a palladium(O) catalyst such as tetrakis (triphenylphosphine) -palladium (0) .

The derivative of formula (III) wherein Z is bromine may be obtained by reacting a pyran-2-one of formula (VI) :

(VI)

wherein R^la and R^3a are as defined above, with bromine in a solvent such as methanol, methylene chloride, chloroform or acetic acid, at a temperature between 15°C and 35°C.

The pyran-2-one of formula (VI) may be prepared by reacting a pyran-2-one of formula (VII) :

(VII)

wherein R^3a is as defined above and Y represents a chlorine atom, a bromine atom, or a trifluoromethylsulfonate group, with a boronic acid of formula (VIII) :

wherein R^l is as defined above.

The Suzuki reaction of the pyran-2-one of formula (VII) and the boronic acid of formula (VIII) is preferably carried out in an organic solvent such as methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran, dimethoxyethane, benzene or toluene, optionally in the presence of water, at a temperature between 60°C and 120°C, with a base such as sodium or potassium carbonate and a palladium(O) catalyst such as tetrakis (triphenylphosphine) palladium(O) .

The pyran-2-one of formula (VI) , in which R^la is an alkyl group may also be prepared by reacting a mercapto derivative of formula (IX) :

(IX)

wherein R^lb is an alkyl group and R^3a is as defined above, with an oxidizing agent, preferably with oxone, magnesium monoperoxyphtalate or 3-chloroperoxybenzoic acid. The reaction may be accomplished in an organic solvent such as a mixture of methylene chloride or chloroform and methanol or ethanol, optionally in the presence of water, at a temperature between 10°C and 40°C. The intermediate compound of formula (IX) may be obtained by the same Suzuki process disclosed for the preparation of compound of formula (VI), utilising appropriate starting materials .

The pyran-2-ones of formula (VII) and the boronic acids of formula (VIII) are prepared by methods well known in the literature (R.W. Friesen et al . Biorg. Med. Chem. Lett . 8., 2777 (1998); F. Effenberger et al . Chem.Ber. 118,741 (1985), M. Cervera et al . Tetrahedron, 46(23), 7885 (1990), J.P.Schirman et al . Bull. Soc. Chi .Fr. 10, 3896 (1967), J.V.N. Vara Prasad et al. J. Med. Chem. 1995, 38, 898, F. Effenberger et al. Chem. Ber. 119, 3394 (1986) ) or are commercially available.

The present invention also provides a process for the preparation of a compound of formula (I) wherein R³ is a hydrogen atom or a methyl group, X is a bond and R¹ is an alkyl group, viz. a 4-phenylpyran-2-one derivative of formula (X):

(X)

wherein R^l , R², R^3a and X^a are as defined above, which comprises reacting a mercapto derivative of formula (XI) :

(Xi: wherein R^lb, R², R^3a and X^a are as defined above with an oxidizing agent, preferably with oxone, magnesium monoperoxyphthalate or 3-chloroperoxybenzoic acid, in an organic solvent such as a mixture of methylene chloride or chloroform and methanol or ethanol, optionally in the presence of water, at a temperature between 10°C and 40°C.

The mercapto derivative of formula (XI) may be obtained by reaction of a derivative of formula (XII) :

(XIi;

wherein R^lb, R^3a and Z are as defined above and Z is preferably bromine, with a boronic acid of formula (IV) or a organotin compound of formula (V) . The reaction is preferably carried out as previously disclosed for the compound of formula (III) . The derivative of formula (XII) wherein Z is bromine may be obtained by the process disclosed for the intermediate compound (III), utilising appropriate starting materials.

The present invention additionally provides a process for the preparation of a compound of formula (I) in which R³ is a hydrogen atom or a methyl group, R¹ is an alkyl or -NR⁴R⁵ group in which R⁴ and R⁵ are alkyl groups, and X is an oxygen atom or a sulfur atom, viz. a 4-phenylpyran-2-one of formula (XIII):

(XI I I )

wherein R^la, R² and R^3a are as defined above and X^b is an oxygen atom or a sulfur atom, by reacting the derivative of formula (III) with a hydroxy or mercapto derivative of formula (XIV) :

R²-X^bH (XIV)

wherein R² and X^b are as defined above. The reaction between the derivative of formula (III) and the intermediate compound (XIV) is generally carried out in the presence of a base such as sodium or potassium hydroxide, sodium hydride, sodium alkoxide or potassium or caesium carbonate, in an organic solvent such as N,N-dimethylformamide, dioxane, tetrahydrofuran, methyl isobutyl ketone or dimethylsulfoxide at a temperature between 25°C and 120°C.

The present invention also provides a process for the preparation of a compound of formula (I) in which R³ is a hydrogen atom or a methyl group, R¹ is an alkyl group, and X is an oxygen atom, viz. a 4-phenylpyran-2-one of formula (XV):

( XV)

wherein R^l , R² and R^3a are as defined above and X^c is an oxygen atom, which comprises reacting a mercapto derivative of formula (XVI) :

(XVI)

wherein R^l , R², R^3a and X^c are as defined above, with an oxidizing agent, preferably with oxone, magnesium monoperoxyphtalate or 3-chloroperoxybenzoic acid. The reaction may be carried out, as previously disclosed for the mercapto derivative of formula (IX), in an organic solvent such as a mixture of methylene chloride or chloroform and methanol or ethanol, optionally in the presence of water, at a temperature between 10°C and 40°C.

The mercapto derivative of formula (XVI) is preferably prepared by reacting. the derivative (XII) with a hydroxyderivative of formula (XVII) :

R²-X^CH (XVII) wherein R² and X^c are as defined above. The reaction may be accomplished, as previously disclosed for the compound of formula (XIII), in an organic solvent such as N,N- dimethylformamide, dioxane, tetrahydrofuran, methyl isobutyl ketone or dimethylsulfoxide at a temperature between 25°C and 120°C, in the presence of a base such as sodium or potassium hydroxide, sodium hydride, sodium alkoxide or potassium or caesium carbonate.

The present invention further provides a process for the preparation of a compound of formula (I) wherein R³ is a hydrogen atom or a methyl group and R¹ is a NR⁴R⁵ group in which

R⁴ and R⁵ are hydrogen atoms, viz. the 4-phenylpyran-2-one derivative of formula (XVIII) :

(XVIII)

wherein R²,R^3a and X are as defined above, which comprises the deprotection of the sulfonamido derivative of formula (XIX) :

(XIX)

wherein R² and R^3a are as defined above and R³ is a hydrogen atom when R⁹ is a tert-butyl group or both represent a benzyl group.

The deprotection process is preferably carried out with an excess of trifluoroacetic, sulfuric or methanesulfonic acid at IS a temperature between 0°C and 120°C. The N-protected compound of formula (XIX) is embraced by general formula (I) as defined above and can be produced by one of the above-described processes .

The compound of formula (XVIII) where X is a bond, viz a 4-phenylpyran-2-one derivatives of formula (XX) :

(XX)

wherein X^a, R² and R^3a are as defined above, may be obtained by reaction of a derivative of formula (XXI) :

(XXI)

wherein R^3a is as defined above and Z is a leaving group, preferably bromine, with a boronic acid of formula (IV) or an organotin derivative of formula (V) . The reaction is preferably carried out as previously described for the compound of formula (III) .

The derivative of formula (XXI) may^" be obtained by deprotection of the sulfonamido derivative of formula (XXII) :

( XXI i ;

wherein R^3a and Z are as defined above and R⁸ and R⁹ is a hydrogen atom when R⁹ is a tert-butyl group or both represent a benzyl group. The deprotection process may be carried out as previously described for the compound of formula (XIX) . The N- protected derivative of formula (XXII) is embraced by general formula (III) as defined above and can be produced by the above described processes. The present invention also provides a process for the preparation of compound of formula (XVIII) in which X is an oxygen atom or a sulfur atom, viz. 4-phenylpyran-2-ones of formula (XXIII) :

(XXIII)

wherein R² and R^3a are as define above and X^b is an oxygen atom or a sulfur atom, by reacting the derivative of formula (XXI) with a hydroxy or mercapto derivative of formula (XIV) . The reaction is generally carried out as previously described for the compound of general formula (XIII) .

The 4-phenylpyran-2-one derivatives of formula (I) wherein R³ is other than a hydrogen atom or a methyl group, can be prepared by processes represented in scheme 1.

SCHEME 1

The 4-phenylpyran-2-one derivatives of formula (I) wherein R³ is other than a hydrogen atom or a methyl group, viz. compounds of formula (XXV), (XXVI), (XXVII), (XXVIII), (XXX), (XXXI), (XXXII) and (XXXIII), are prepared from compounds of formula (I) in which R³ is a methyl group, viz. compound of formula (XXIV) , which processes of preparation have been disclosed above. In the first step, compounds of formula (XXV) are treated with an oxidizing agent such as selenium dioxide in an organic solvent such as tetrahydrofuran or dioxane, in a pressure vessel and at a temperature between 100°C and 190°C. The corresponding aldehyde of formula (XXV) is obtained, which is used as starting material to obtain the compounds of formula (I) where R³ is not a hydrogen atom or a methyl group.

The compounds of formula (I) wherein R³ is a hydroxycarbonyl group, viz. compound of formula (XXVI), are prepared from the corresponding aldehyde (XXV) by reaction with an oxidizing agent as pyridinium dichromate or manganese dioxide in an organic solvent as N,N-dimethylformamide or ethanol at a temperature between -5°C and 35°C. The compounds (XXVI) are used as starting materials to obtain compounds of formula (I) wherein R³ is a trifluoromethyl group, viz. compound of formula (XXVII) . The process is carried out by reaction of compounds (XXVI) with a mixture of sulphur tetrafluoride and hydrogen fluoride, optionally in the presence of an organic solvent such as methylene chloride, in a pressure vessel, and at a temperature between 20°C and 140°C.

The compounds of formula (I) wherein R³ represents a hydroxymethyl group viz. compounds of formula (XXVIII) are prepared by reduction of compounds (XXV) with a boron or aluminium hydride, preferably sodium borohydride in a solvent such as methanol or ethanol and at a temperature between 10°C and 40°C. Further reaction of compounds (XXVIII) with an appropriate halide of formula (XXIX) :

Hal - R¹⁰ (XXIX) wherein Hal represents a chlorine, bromine or iodine atom and R¹⁰ represents an alkyl, C₃-C₇ cycloalkyl or benzyl group, provide the compounds of formula (I) wherein R³ is an alkoxymethyl, C₃-C₇ cycloalkoxy ethyl or benzyloxymethyl group viz. compounds of formula (XXX) . The reaction is carried out in an organic solvent such as acetone, N, N-dimethylformamide or tetrahydrofuran in the presence of sodium or potassium hydride or amide, and at a temperature between 20°C and 120°C.

Also aldehydes of formula (XXV) are used to obtain compounds of formula (I) wherein R³ is a nitrile group, viz. compounds of formula (XXXI) . The reaction is carried out by first treating aldehydes of formula (XXV) with hydroxylamine hydrochloride and formic acid at a temperature between 80°C and 120°C. The resulting oxime derivative is isolated and heated with an excess of acetic anhydride at a temperature between 100°C and 180°C.

The compounds of formula (I) wherein R³ represents a difluoromethyl group, viz. compounds of formula (XXXII), are prepared from aldehydes of formula (XXV) by reaction with a fluorinated reagent as diethylaminosulfur trifluoride or a mixture of sulfur tetrafluoride-hydrogen fluoride, optionally in the presence of an organic solvent as methylene chloride, benzene or toluene and at a temperature between 0°C and 130°C.

The 4-phenylpyran-2-one derivatives of formula (I) in which R³ is a CH₂-R⁶ group, viz. compounds of formula (XXXIII), are also prepared from aldehydes of formula (XXV) in a two stages process. In the first stage, aldehydes (XXV) react with a triphenylphosphine derivative (XXXIV) in the presence of a solvent as dioxane, dimethoxyethane or tetrahydrofuran at a temperature between 15°C and the boiling point of the solvent. The resulting compound is hydrogenated in the second stage of the process in the presence of a catalyst such as palladium on activated carbon, and the reaction is carried out in the presence of a solvent as methanol, ethanol or ethyl acetate at a temperature between 15°C and 40°C. The 4-phenylpyran-2-one derivatives of formula (I) in which there is the presence of a basic group, can be converted by methods known per se into pharmaceutically acceptable salts, preferably acid addition salts by treatment with organic or inorganic acids such as fumaric, tartaric, succinic or hydrochloric acid. Also, 4-phenylpyran-2-one derivatives of formula (I) in which R³ represents an hydroxycarbonyl group, may be converted into pharmacologically acceptable salts with, for instance, alkali metals such as sodium or potassium by reaction with an alkali metal hydroxide, or by reaction with organic bases.

COX-1 and COX-2 activities in human whole blood

Fresh blood from healthy volunteers who had not taken any non-steroidal anti-inflammatory drugs for at least 7 days prior to blood extraction was collected in heparinized tubes (20 units of heparin per ml) . For the COX-1 activity determination, 500 μl aliquots of blood were incubated with either 5 μl vehicle (dimethylsulfoxide) or 5 μl of a test compound for lh at 37°C. Calcium ionophore A23187 (25 μM) was added 20 min before stopping the incubation. Plasma was separated by centrifugation (10 min at 13000 rpm) and kept at -30°C until TXB₂ levels were measured using an enzyme immunoassay kit (ELISA) . The effect of the compounds were evaluated by incubating each compound at five to six different concentrations with triplicate determinations. IC₅₀ values were obtained by non-linear regression using InPlot, GraphPad software on an IBM computer.

For the COX-2 activity determination, 500 μl aliquots of blood were incubated in the presence of LPS (10 μg/ml) for 24 h at 37°C in order to induce the COX-2 expression (P. Patriagnani et al . J. Pharm. Exper. Ther . 271; 1705 (1994)). Plasma was separated by centrifugation (10 min at 13000 rpm) and kept at -30°C until PGE₂ levels were measured using an enzyme immunoassay kit (ELISA) . The effects of inhibitors were studied by incubating each compound (5 μl aliquots) at five to six different concentrations with triplicate determinations in the presence of LPS for 24 hours. IC_S0 values were obtained by non-linear regression using InPlot, GraphPad software on an IBM computer.

The results obtained from the biological assays are shown in Table 1.

TABLE 1

Compound (*) COX-1, IC_S0 (μ ) COX-2, IC_S0 (uM) Ratio COX-l/COX-2

Indomet acin 0.19 0.22 0.86

1 14.0 0.34 41

3 27.6 0.24 115

6 12.3 0.8 15

7 >100 1 >100

10 15.1 0.38 40

24 >100 0.16 >625

25 >100 1.17 >85

26 21 0.96 25

34 13.7 0.31 44

36 23.8 0.18 132

40 21 0.23 >91

44 104 0.24 433

45 72 0.22 327

51 30.4 0.22 >138

61 22.5 0.92 25

72 18.6 0.56 33

74 14.5 0.46 32

75 78.5 0.87 90

81 >100 1.05 >95

(*) See structures in Table 2.

Indomethacin is 1- (4-chlorobenzoyl) -5-methoxy-2-methylindole-3- acetic acid.

As shown in Table 1, the 4-phenylpyran-2-one derivatives of formula (I) are potent and selective COX-2 inhibitors whereas the reference compound indomethacin is equipotent as a COX-2 and COX-1 inhibitor. Due to their low COX-1 inhibitory activity, the compounds of formula (I) present the benefit of significantly less harmful side effects than the non-steroidal anti-inflammatory drugs commonly used (e.g. gastrointestinal toxicity, renal side-effects, reduced effect on bleeding times and asthma induction in aspirin-sensitive subjects) .

Thus the compounds of the invention are preferably selective inhibitors of mammalian COX-2, for example human COX- 2. The compounds of the invention also preferably have low inhibitory activity toward mammalian COX-1, for example human COX-1. Inhibitory activity can typically be measured by in vitro assays, for example as described above.

Preferred compounds of the invention have an IC_S0 value for COX-2 of less than 5 μM, preferably less than 1 more preferably less than 0.5 μM. Preferred compounds of the invention also have an IC₅₀ value for COX-1 of greater than 10 μM, preferably greater than 20 μM. As an indicator of selectivity for inhibition of COX-2 over COX-1, the ratio of COX-l/COX-2 IC₅₀ values is preferably greater than 10, 20, 30 or 50, more preferably greater than 80, 90 or 100.

The present invention further provides a compound of formula (I) for use in the treatment or prevention of a pathological condition or disease susceptible to amelioration by inhibition of cyclooxygenase-2, in particular for the treatment of pain, fever or inflammation, to inhibit prostanoid-induced smooth muscle contraction or for the treatment and prevention of colorectal cancer.

The present invention further provides the use of a compound of formula (I) in the manufacture of a medicament for the the treatment or prevention of a pathological condition or disease susceptible to amelioration by inhibition of cyclooxygenase-2, in particular for the treatment of pain, fever or inflammation, to inhibit prostanoid-induced smooth muscle contraction or for the treatment and prevention of colorectal cancer. The compounds of formula (I) are useful for relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhoea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, bursitis, tendinitis, injuries, following surgical and dental procedures and arthritis including rheumatoid arthritis, osteoarthritis, gouty arthritis, spondyloarthopathies, systemic lupus erythematosus and juvenile arthritis. They may also be used in the treatment of skin inflammation disorders such as psoriasis, eczema, burning and dermatitis. In addition, such compounds may be used for the treatment and prevention of colorectal cancer.

The compounds of formula (I) will also inhibit prostanoid- induced smooth muscle contraction and therefore may be used in the treatment of dysmenorrhoea, premature labour, asthma and bronchitis .

The compounds of formula (I) can be used as alternative to conventional non-steroidal anti-inflammatory drugs, particularly where such non-steroidal anti-inflammatory drugs may be contraindicated such as the treatment of patients with gastrointestinal disorders including peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, Crohn' s disease, inflammatory bowel syndrome and irritable bowl syndrome, gastrointestinal bleeding and coagulation disorders, kidney disease (e.g. impaired renal function), those prior to surgery or taking anticoagulants, and those susceptible to non- steroidal anti-inflammatory drugs induced asthma.

The compounds can further be used to treat inflammation in diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin' s disease, scleroderma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, hypersensitivity, conjunctivitis, gingivitis and myocardial ischaemia. Compounds of the present invention are inhibitors of cyclooxygenase-2 enzyme and are thereby useful to treat the cyclooxygenase-2 mediated diseases enumerated above.

Accordingly, the 4-phenylpyran-2-one derivatives of formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and/or salts thereof, may be used in a method of treatment or prevention of a pathological condition or disease susceptible to amelioration by inhibition of cyclooxygenase-2, which comprises administering to a patient requiring such treatment an effective amount of a 4-phenylpyran-2-one derivative of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of the invention may be used alone or in combination with other compounds known to be useful for the treatment, prevention or symptomatic relief of the pathological conditions mediated by cyclooxygenase-2. Both classes of compounds can be administered in the same or different pharmaceutical composition for simultaneous, separate or sequential use. The present invention also provides pharmaceutical compositions which comprise, as an active ingredient, at least a 4-phenylpyran-2-one derivative of formula (I) or a pharmacologically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001% to 99% by weight, preferably 0.01% to 90% by weight of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.

Preferably the compositions are made up in a form suitable for oral, topical, nasal, inhalation, rectal, percutaneous or injectable administration.

The pharmaceutically acceptable excipients which are admixed with the active compound, or salts of such compound, to form the compositions of this invention are well-known per se and the actual excipients used depend inter alia on the intended method of administering the compositions.

Compositions of this invention are preferably adapted for injectable and oral administration. In this case, the compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.

The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or capsules may conveniently contain between 0.2 and 500 mg of active ingredient or the equivalent amount of a salt thereof. The liquid composition adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.

Compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in pyrogen free aqueous media or other appropriate parenteral injection fluid.

Effective doses are normally in the range of 1-600 mg of active ingredient per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.

The invention is illustrated by the following Examples, which do not limit the scope of the invention in any way.

EXAMPLE 1 a) To a solution of 4-hydroxy-β-methylpyran-2-one (5.0 g, 39.6 mmol) and N, W-diisopropylethylamine (5.6 g, 43.3 mmol) in methylene chloride (150 ml) was slowly added at -70°C a solution of trifluoromethanesulfonic anhydride (12.2 g, 43.3 mmol) in methylene chloride (40 ml) . The mixture was stirred at 0°C for 1 hour and at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude was purified by column chromatography with silica gel and n- hexane/ethyl acetate (2:1) as eluent. 4-Hydroxy-6-methylpyran- 2-one trifluoromethanesulfonate (9.60 g) was obtained, m.p. 9- 11°C. b) To a solution of 4-hydroxy-6-methylpyran-2-one trifluoromethanesulfonate (4.0 g, 15.5 mmol) and 4- methylsulfanylphenylboronic acid (2.86 g, 17.0 mmol) in toluene

(115 ml) were added potassium carbonate (2.35 g, 17.0 mmol), lithium chloride (1.32 g, 31.0 mmol) and tetrakis-

(triphenylphosphine) palladium (0.32 g, 0.28 mmol). The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into water (100 ml) and diluted with ethyl acetate (100 ml) . The organic solution was washed with water (2 x 50 ml) and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the resulting solid was washed with ethyl ether. β-Methyl-4- (4-methylsulfanylphenyl) pyran-2-one (3.38 g) was obtained, m.p. 131-132°C. c) To a solution of 6-methyl-4- ( 4-methylsulfanylphenyl) - pyran-2-one (3.12 g, 13.4 mmol) in methylene chloride (75 ml) was added dropwise a solution of bromine (0.77 ml, 14.9 mmol) in methylene chloride (10 ml), meanwhile the evolved HBr was displaced by nitrogen. After being stirred at room temperature for 2 h, the mixture was washed with water (2 x 50 ml), dried (Na₂S0₄) , and the solvent removed under reduced pressure. The resulting solid was washed with ethyl ether. 3-Bromo-β- methyl-4- (4-methylsulfanylphenyl) pyran-2-one (3.37 g) was obtained, m.p. 121-123°C. d) To a solution of 3-bromo-^β-methyl-4- (4- methylsulfanylphenyl) pyran-2-one (1.5 g, 4.8 mmol) and 2-fluorophenylboronic acid (0.87 g, 6.3 mmol) in dioxane (75 ml) were added tetrakis (triphenylphosphine) palladium (80 mg, 77 umol) and a solution of potassium carbonate (0.66 g , 4.8 mmol) in water (7.5 ml). The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into a potassium carbonate saturated solution (100 ml) and extracted with ethyl acetate (2 x 50 ml) . The organic solution was washed with potassium carbonate saturated solution (2 x 50 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. 3- (2-Fluorophenyl) -β-methyl-4- ( 4-methylsulf anyl- phenyl) pyran-2-one (1.56 g) was obtained as an oil, which was used in the next step without further purification. e) To a solution of 3- (2-fluorophenyl) -6-methyl-4- (4- methylsulfanylphenyl)pyran-2-one (1.56 g) in methylene chloride (25 ml) and methanol (5 ml) was slowly added magnesium monoperoxyphtalate hexahydrate (2.96 g, 4.8 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with methylene chloride

(50 ml) , washed with saturated sodium bicarbonate solution (2 x 50 ml) , and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the residue purified by column chromatography with silica gel and chloroform as eluent.

3- (2-Fluorophenyl) -4- (4-methanesulfonylphenyl) - 6- methylpyran-2-one (0.47 g) was obtained, m.p. 143°C (Compound 2 in Table 2) .

EXAMPLE 2 a) To a solution of 3-bromo-6-methyl-4- (4- methylsulfanylphenyl) pyran-2-one (3.37 g, 10.9 mmol) in methylene chloride (30 ml) and isopropanol (30 ml) was slowly added at 0°C a solution of Oxone (12.31 g, 20 mmol) in water (85 ml) . After stirring at room temperature for 16 hours, the reaction mixture was diluted with methylene chloride (50 ml) , washed with water (2 x 50 ml), and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the resulting solid was washed with ethyl ether. 3-Bromo-4- (4-methanesulfonylphenyl) -6-methylpyran-2-one (2.80 g) was obtained, m.p. 181-182 °C. b) To a solution of 3-bromo-4- (4-methanesulfonylphenyl) -6-methylpyran-2-one (0.5 g, 1.46 mmol) and 4-methoxyphenyl boronic acid (0.29 g, 1.90 mmol) in dioxane (20 ml) were added a solution of potassium carbonate (0.20 g , 1.46 mmol) in water (2 ml) and tetrakis (triphenylphosphine) palladium (29 mg, 26 μmol) . The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into a potassium carbonate saturated solution (40 ml) and extracted with ethyl acetate (2 x 25 ml) . The organic solution was washed with potassium carbonate saturated solution (2 x 25 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and n-hexane/ethyl acetate (2:1) as eluent. 4- (4-Methane- sulfonylphenyl) -6-methyl-3- (4-methoxyphenyl) pyran-2-one (0.17 g) was obtained, m.p. 146°C (Compound 12 in Table 2) .

EXAMPLE 3 To a solution of 3-bromo-4- (4-methanesulfonylphenyl) -6- methylpyran-2-one (0.7 g, 2.0 mmol) and 3- (trimethylstannyl) - pyridine (J.J.Li et al . J. Med. Chem. 39, 1846, (1996)) (0.97 g,

4.0 mmol) in toluene (25 ml) was added tetrakis-

(triphenylphosphine) palladium (0.39 g, 0.34 mmol), and the mixture was boiled under reflux for 16 hours. After cooling, the reaction was washed with water (2 x 25 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and n-hexane/ethyl acetate (1:3) as eluent. 4- (4-Methane- sulfonylphenyl) -6-methyl-3- (pyridin-3-yl) pyran-2-one (0.50 g) was obtained, m.p. 103°C (Compound 26 in Table 2) .

EXAMPLE 4 a) To a solution of 3- (4-chlorophenyl) -4- (4-methane- sulfonylphenyl) -6-methylpyran-2-one (1.5 g, 3.92 mmoles) in dioxane (30 ml), selenium dioxide (4.35 g, 39.2 moles) was added and refluxed for 64 hours. After cooling, the raw material was filtered through Celite, washed with ethyl acetate (2 x 30 ml) and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (60 ml), washed with water (2 x 30 ml), dried (Na₂S0₄) , and the solvent was evaporated in vacuo . The resulting solid was washed with ethyl ether. 5- (4-Chlorophenyl) -4- (4-methanesulfonyl-phenyl) -6-oxo- 6ϋ-pyran-2-carbaldehyde (1.18 g) was obtained. b) To a solution of 5- (4-chlorophenyl) -4- (4-methanesulfonylphenyl) -6-oxo-6fl-pyran-2-carbaldehyde (0.5 g, 1.3 mmoles) in methanol (10 ml), sodium borohydride (0.073 g, 1.9 mmoles) was slowly added at 0°C. The resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated and the residue was solved in ethyl acetate. The organic layer was washed with water, dried (Na₂S0₄), and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography with silica gel and methylene chloride/ethyl acetate/acetic acid (78:10:1) as eluent. 4- (4-Chlorophenyl) -6-hydroxymethyl-3- ( 4-methanesulfonylphenyl) pyran-2-one (0.24 g) was obtained, m.p. 101°C (Compound 29 in Table 2).

EXAMPLE 5 To a solution of 5- (4-chlorophenyl) -4- (4-methanesulfonylphenyl) -6-oxo-6H-pyran-2-carbaldehyde (0.53 g, 1.36 mmoles) in methylene chloride (10 ml), diethylaminosulfide DAST (0.22 ml, 1.64 mmoles) was slowly added at 0°C. The reaction mixture was stirred at this temperature for 1 hour and at room temperature for 16 hours. The mixture was diluted with methylene chloride (10 ml) .' The organic phase was washed with water, dried (Na,S0₄) , and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography with silica gel and ethyl acetate/n-hexane (2:3) as eluent. 3- ( 4-Chlorophenyl) -6-difluoromethyl-4- ( 4- methanesulfonylphenyl) pyran-2-one (0.28 g) was obtained, m.p. 201°C (Compound 30 in Table 2) .

EXAMPLE 6 a) To a solution of 3-bromo-6-methyl-4- (4-methylsulfanylphenyl) pyran-2-one (1.2 g, 3.85 mmol) in anhydrous dimethylformamide (25 ml) were added 3-fluorophenol (1.29 g, 11.6 mmol) and cesium carbonate (3.76 g , 11.6 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (2 x 50 ml) . The organic solution was washed with potassium carbonate saturated solution (2 x 50 ml) and water (2 x 50 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. 3- (3-Fluorophenoxy) -6-methyl-4- (4- methylsulfanylphenyl) pyran-2-one (1.35 g) was obtained as an oil, which was used in the next step without further purification. b) To a solution of 3- (3-fluorophenoxy) -6-methyl-4- (4- methylsulfanylphenyl) pyran-2-one (1.35 g) in methylene chloride (20 ml) and methanol (4 ml) was slowly added magnesium monoperoxyphtalate hexahydrate (2.38 g, 3.85 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours . The reaction mixture was diluted with methylene chloride

(50 ml), washed with saturated sodium bicarbonate solution (2 x 50 ml) , and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the residue purified by column chromatography with silica gel and chloroform/ethyl acetate (95:5) as eluent. 3- (3-Fluorophenoxy) -4- (4-methanesulfonylphenyl) -β-methylpyran-2-one (0.48 g) was obtained, m.p. 152°C (Compound 33 in Table 2) . ^"

EXAMPLE 7 a) To a solution of 4-hydroxy-β-methylpyran-2-one trifluoromethanesulfonate (0.26 g, 1.06 mmol) and W-tert- butylsulfamoylphenylboronic acid (R.W. Friesen et al . Biorg. Med. Chem. Lett. 8, 2777 (1998)) (0.30 g, 1.16 mmol) in toluene (25 ml) were added potassium carbonate (0.16 g, 1.16 mmol), lithium chloride (90 mg, 2.12 mmol) and tetrakis-

(triphenylphosphine) palladium (22 mg, 19 μmol) . The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into water (25 ml) and diluted with ethyl acetate

(25 ml) . The organic solution was washed with water (2 x 25 ml) and with saturated sodium bicarbonate solution (2 x 25 ml) , and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the residue purified by column chromatography with silica gel and chloroform/ethyl acetate (9:1) as eluent. N- tert-Butyl-4- ( 6-methyl-2-oxo-2#-pyran-4-yl) benzenesulfonamide (0.12 g) was obtained, m.p. 154-156°C. b) To a solution of W-tert-butyl-4- ( 6-methyl-2-oxo-2f.- pyran-4-yl) benzenesulfonamide (0.6 g, 1.87 mmol) in methylene chloride (20 ml) was added dropwise a solution of bromine (0.10 ml, 2.06 mmol) in methylene chloride (2 ml), meanwhile the evolved HBr was displaced by nitrogen. After being stirred at room temperature for 2 h, the mixture was washed with water (2 x 20 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and n-hexane/ethyl acetate (3:2) as eluent. 4- (3-Bromo-6-methyl-2-oxo-2H-pyran-4-yl)-Λ?-tert- butylbenzenesulfonamide (0.20 g) was obtained, m.p. 192-194°C. c) To a solution of 4- (3-bromo-β-methyl-2-oxo-2#-pyran-4- yl) -W-tert-butylbenzenesulfonamide (0.2 g, 0.50 mmol) and phenylboronic acid (80 mg, 0.65 mmol) in dioxane (10 ml) were added tetrakis (triphenylphosphine) palladium (10 mg, 9.6 μmol) and a solution of potassium carbonate (69 mg , 0.50 mmol) in water (0.6 ml). The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into a potassium carbonate saturated solution (10 ml) and extracted with ethyl acetate (2 x 5 ml) . The organic solution was washed with potassium carbonate saturated solution (2 x 5 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and n-hexane/ethyl acetate (1:1) as eluent. W-tert-Butyl-4- (6- methyl-2-oxo-3-phenyl-2u-pyran-4-yl) benzenesulfonamide (60 mg) was obtained. d) A solution of N- tert-butyl-4- ( 6-methyl-2-oxo-3-phenyl- 2fl-pyran-4-yl) benzenesulfonamide (60 mg, 0.15 mmol) in trifluoroacetic acid (2 ml) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue purified by column chromatography with silica gel and n-hexane/ethyl acetate (1:1) as eluent. 4- (6-Methyl-2-oxo-3- phenyl-2f.-pyran-4-yl) benzenesulfonamide (25 mg) was obtained, m.p. 215°C (Compound 55 in Table 2) .

EXAMPLE 8 a) To a solution of A7,W-dibenzyl-4-bromobenzene sulfonamide (3.74 g, 9.0 mmol) and triisopropyl borate (6.77 g, 36.0 mmol) was slowly added at -70°C a solution of 2.5 M butyllithium (14.4 ml, 36.0 mmol) in n-hexane. The mixture was stirred at - 70°C for 2 hours and at room temperature for 16 hours. To the reaction was added water (13 ml) and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (150 ml) . The organic solution was washed with water (3 x 50 ml) , dried (Na₂S0₄) , and the solvent evaporated in vacuo. Crude W, N-dibenzylsulfamoylphenylboronic acid (4.08 g) was obtained as a solid, which was used in the next step without further purification. b) To a solution of 4-hydroxy-6-methylpyran-2-one trifluoromethanesulfonate (1.84 g, 7.1 mmol) and crude N, N- dibenzylsulfamoylphenylboronic acid (4.08 g) in toluene (50 ml) were added potassium carbonate (1.10 g, 8.0 mmol), lithium chloride (0.60 g, 14.1 mmol) and tetrakis (triphenylphosphine) palladium (150 mg, 0.13 mmol) . The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into water (50 ml) and diluted with ethyl acetate (50 ml) . The organic solution was washed with saturated sodium bicarbonate solution (2 x 50 ml) and water (2 x 50 ml), and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the resulting solid was washed with ethyl ether. N,N- Dibenzyl-4- ( 6-methyl-2-oxo-2#-pyran-4-yl) benzene-sulfonamide (2.92 g) was obtained, m.p. 159°C. c) To a solution of N,W-dibenzyl-4- (6-methyl-2-oxo-2fl- pyran-4-yl) benzenesulfonamide (4.0 g, 9.0 mmol) in methylene chloride (4 ml) was added dropwise a solution of bromine (0.51 ml, 9.8 mmol) in methylene chloride (10 ml), meanwhile the evolved HBr was displaced by nitrogen. After being stirred at room temperature for 2.5 hours, the mixture was washed with saturated sodium bicarbonate solution (2 x 50 ml) and water (2 x 50 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. The resulting solid was washed with ethyl ether. N, N- Dibenzyl-4- (3-bromo-6-methyl-2-oxo-2H-pyran-4-yl) benzene- sulfonamide (3.90 g) was obtained, m.p. 165°C. d) To a solution of N,W-dibenzyl-4- (3-bromo-6-methyl-2-oxo- 2fl-pyran-4-yl) benzenesulfonamide (1.0 g, 1.90 mmol) and 4- chlorophenylboronic acid (0.39 mg, 2.47 mmol) in dioxane (30 ml) were added tetrakis (triphenylphosphine) palladium (35 mg, 30.4 μmol) and a solution of potassium carbonate (0.26 g, 1.2 mmol) in water (3 ml) . The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into a potassium carbonate saturated solution (30 ml) and extracted with ethyl acetate (2 x 30 ml) . The organic solution was washed with potassium carbonate saturated solution (2 x 30 ml) and water (2 x 30 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. The residue was dissolved in sulfuric acid (8 ml) and the mixture was stirred at room temperature for 1 hour. The reaction was poured into ice/water (25 ml) and extracted with ethyl acetate (25 ml) . The organic solution was washed with water (2 x 25 ml) , dried (Na₂S0₄) , and the solvent was evaporated in vacua. The residue was purified by column chromatography with silica gel and methylene chloride/ethyl acetate/acetic acid (78:10:1) as eluent. 4- [3- (4-Chloro- phenyl) -6-methyl-2-oxo-2#-pyran-4-yl] benzenesulfonamide (0.26 g) was obtained, m.p. 104°C (Compound 60 in Table 2) .

EXAMPLE 9 a) A mixture of N, W-dibenzyl-4- (3-bromo-6-methyl-2-oxo-2i2- pyran-4-yl) benzenesulfonamide (4.7 g, 9.0 mmol) in sulfuric acid (30 ml) was stirred at room temperature for 1 hour. The reaction was poured into ice/water (50 ml) and extracted with methylene chloride/methanol (6:1) (4 x 250 ml). The organic solution was washed with water (2 x 250 ml) , dried (Na₂S0₄) , and the solvent was evaporated in vacuo . 4- (3-Bromo-6-methyl-2-oxo- 2#-pyran-4-yl) benzenesulfonamide (2.34 g) was obtained, m.p. 216°C. b) To a solution of 4- (3-bromo-6-methyl-2-oxo-2fl-pyran-4- yl) benzenesulfonamide (1.0 g, 2.9 mmol) and 2-(tributyl- stannyl) thiophene (1.0 ml, 3.2 mmol) in dry toluene (20 ml) were added 2, 6-di-tert-butyl-4-methylphenol (20 mg, 91 μg) and tetrakis (triphenylphosphine) palladium (0.2 g, 0.17 mmol) and the mixture was refluxed for 16 hours. After cooling, the reaction was diluted with toluene (20 ml) , washed with water (2 x 20 ml), dried (Na₂S0₄) , and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and n-hexane/ethyl acetate (1:4) as eluent. 4- [6-Methyl-2-oxo-3- (thiophen-2-yl) -2iϊ-pyran-4-yl] - benzenesulfonamide (0.32 g) was obtained, m.p. 164 °C (Compound 65 in Table 2) .

EXAMPLE 10

To a solution of 4- ('3-bromo-6-methyl-2-oxo-2iϊ-pyran-4- yl) benzenesulfonamide (0.6 g, 1.74 mmol) and 2-furanboronic acid (0.52 g, 4.64 mmol) in dioxane (30 ml) were added tetrakis (triphenylphosphine) palladium (32 mg, 27.6 μmol) and a solution of potassium carbonate (0.24 g, 1.74 mmol) in water (3 ml). The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into a potassium carbonate saturated solution (30 ml) and extracted with ethyl acetate (2 x 30 ml) . The organic solution was washed with potassium carbonate saturated solution (2 x 30 ml) and water (2 x 30 ml), dried (Na₂S0₄) , and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and ethyl acetate/n-hexane (1:1) as eluent. 4- [3- (Furan-2- yl) -6-methyl-2-oxo-2ϋ.-pyran-4-yl]benzenesulfonamide (67 mg) was obtained, m.p. 165°C (Compound 66 in Table 2) .

EXAMPLE 11

To a solution of 4- (3-bromo-6-methyl-2-oxo-2fl-pyran-4- yl) benzenesulfonamide (2.5 g, 7.26 mmol) in anhydrous dimethylformamide (250 ml) were added 4-fluorophenol (2.43 g, 21.8 mmol) and cesium carbonate (7.08 g , 21.8 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (250 ml) and extracted with ethyl acetate (2 x 150 ml) . The organic solution was washed with potassium carbonate saturated solution (2 x 150 ml) and water (2 x 150 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. The resulting oil was purified by column chromatography with silica gel and methylene chloride/ethyl acetate (8:1) as eluent. 4- [3- (4-Fluoro- phenoxy) -6-methyl-2-oxo-2i2-pyran-4-yl] benzenesulfonamide (1.28 g) was obtained, m.p. 162°C. (Compound 72 in Table 2) .

EXAMPLE 12 a) A solution of sodium (0.288 g, 12.53 mmol) in isopropanol (10 ml) was heated at reflux during 45 min. Solvent was evaporated and the solid residue was dissolved in dimethylformamide (6 ml) and added to a solution of 3-bromo-β-methyl-4- (4-methyl-sulfanylphenyl) pyran-2-one (2.0 g, 6.43 mmol), prepared as mentioned in example lc, in dimethylformamide (15 ml) . This mixture was stirred at room temperature during 1 hour. Water (40 ml) and brine (20 ml) were added keeping the temperature below 20 °C and this mixture was extracted with ethyl acetate (120 ml) . The organic phase was washed with water (3 x 60 ml) and brine (40 ml) , dried (Na₂S0₄) and concentrated in vacuo to give a residue that was purified by column chromatography with silica gel and a mixture of hexane/ethyl acetate (8:2) as eluent. 3-Isopropoxy-6-methyl-4- (4-methyl-sulfanylphenyl) pyran-2-one (0.052 g) was obtained as a yellow oil, m/z 290 (M⁺) . b) To a solution of 3-isopropoxy-6-methyl-4- (4-methylsulfanylphenyl) pyran-2-one (0.09 g, 0.31 mmol) in dry dichloromethane (2.5 ml) and methanol (0.5 ml) was added solid magnesium monoperoxyphtalate hexahydrate (0.201 g, 0.326 mmol) at 0°C. The resulting suspension was stirred at room temperature during 1.5 hours. Then, the reaction was poured slowly into 4M sodium bicarbonate (3.8 ml) keeping the temperature below 20 °C. The organic phase was washed successively with 4M sodium bicarbonate (1 ml), water (3 x 1 ml) and brine (1 ml) , dried (Na₂S0₄) and concentrated to give 3-isopropoxy-4- (4-methanesulfonyl-phenyl) -6-methyl-pyran-2-one (0.05 g) , m.p. 119°C (Compound 84 in Table 2).

EXAMPLE 13 a) To a solution of 4-hydroxy-6-phenylpyran-2-one (2.1 g, 11.16 mmol) and N, W-diisopropylethylamine (1.59 g, 12.28 mmol) in methylene chloride (70 ml) was slowly added at -70°C trifluoromethanesulfonic anhydride (3.46 g, 12.8 mmol). The mixture was stirred at 0°C for 1 hour and at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude was extracted several times with a mixture of hexane/ethyl acetate (4:1) to give 4-hydroxy-6-phenylpyran-2- one trifluoromethanesulfonate (3.25 g) , which was used in the next step without further purification. b) To a solution of 4-hydroxy-6-phenylpyran-2-one trifluoromethanesulfonate (3.2 g, 10.0 mmol) and 4- methylsulfanylphenylboronic acid (1.85 g, 11.0 mmol) in toluene (100 ml) were added potassium carbonate (1.52 g, 11.0 mmol), lithium chloride (0.99 g, 20.0 mmol) and tetrakis- (triphenylphosphine) palladium (0.21 g, 0.18 mmol). The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into 4% sodium bicarbonate solution (30 ml) and diluted with ethyl acetate (30 ml) . The organic solution was washed with 4% sodium bicarbonate (2 x 50 ml) , water (2 x 50 ml) and dried (Na₂S0₄) . The solvent was concentrated under reduced pressure until a solid appeared. The solid was filtered and washed with ethyl ether. 4- (4-Methylsulfanylphenyl) - 6-phenylpyran-2-one (1.2 g) was obtained, which was used in the next step without further purification. c) To a solution of 4- (4-methylsulfanylphenyl) -6-phenyl pyran-2-one (8.5 g, 28.87 mmol) in methylene chloride (225 ml) at 0°C was added dropwise a solution of bromine (5.17 g, 32.33 mmol) in methylene chloride (10 ml), meanwhile the evolved HBr was displaced by nitrogen. After being stirred at room temperature for 4.5 hours, the mixture was washed with 4% sodium bicarbonate solution (80 ml) , water (2 x 95 ml) , dried

(Na₂S0₄) , and the solvent removed under reduced pressure. The resulting solid was washed with diethyl ether. 3-Bromo-4- (4- methylsulfanylphenyl) -6-phenylpyran-2-one (10.4 g) was obtained, m.p. 170°C. d) To a solution of 3-bromo-4- (4-methylsulfanylphenyl) -6- phenylpyran-2-one (1 g, 2.68 mmol) and 3-fluorophenylboronic acid (0.49 g, 3.48 mmol) in dioxane (55 ml) were added tetrakis (triphenylphosphine) palladium (50 mg, 43 μmol) and a solution of potassium carbonate (0.38 g , 2.68 mmol) in water (5.5 ml). The mixture was boiled under reflux for 18 hours. After cooling, the reaction was poured into a potassium carbonate saturated solution (75 ml) and extracted with ethyl acetate (2 x 50 ml) . The organic solution was washed with water (2 x 50 ml), brine (50 ml) and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the residue purified by column chromatography with silica gel and hexane/ethyl acetate (8:2) as eluent. 3- (3-Fluoroρhenyl) -4- (4-methylsulfanylphenyl) - 6-phenylpyran-2-one (0.16 g) was obtained, m/z 388 (M⁺) . e) To a solution of 3- (3-fluorophenyl) -4- (4- methylsulfanylphenyl) -6-phenylpyran-2-one (0.16 g, 0.41 mmol) in methylene chloride (6 ml) and methanol (1 ml) was slowly added magnesium monoperoxyphtalate hexahydrate (0.214 g, 0.35 mmol) and the resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with methylene chloride (10 ml) , washed with saturated sodium bicarbonate solution (2 x 20 ml), and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the residue crystallized from ethanol. 3- (3-Fluorophenyl) -4- (4-methanesulfonylphenyl) -6- phenylpyran-2-one (0.069 g) was obtained, m.p. 198°C (Compound 86 in Table 2) .

EXAMPLE 14 a) A suspension of sodium (0.034 g, 1.49 mmol) in xylene (3 ml) under nitrogen was heated at reflux until sodium melted. Then, 4-fluorophenol (0.181 g, 1.49 mmol) was added, the mixture being heated at reflux during 30 min. The solvent was evaporated under reduced pressure and the resulting residue was taken up in dioxane (8 ml) . To this mixture was added 3-bromo-4- (4-methylsulfanylphenyl) -6-phenylpyran-2-one (0.5 g, 1.34 mmol) (prepared as mentioned in example 13c), copper (I) chloride (0.013 g, 0.134 mmol) and tris[2-(2- methoxyethoxy) ethyl] amine (0.043 g, 0.134 mmol). The resulting mixture was heated at reflux under nitrogen for 18 hours. After cooling, the mixture was filtered and the filtrate was concentrated in vacuo, taken up in dichloromethane (30 ml) and washed with water (2 x 20 ml)- and brine (20 ml) . The organic layer was dried (Na₂S0₄) and concentrated to give a residue that was purified by column chromatography with silica gel using a mixture of hexane/ethyl acetate (8:2) as eluent. 3-(4-Fluoro- phenoxy) -4- (4-methylsulfanylphenyl) -6-phenylpyran-2-one (0.08 g) was obtained, m/z 405 (M⁺+l) . b) To a solution of 3- (4-fluorophenoxy) -4- (4-methylsulfanylphenyl) -6-phenylpyran-2-one (1.25 g, 3.1 mmol) in dichloromethane (27 ml) and methanol (0.7 ml) was added solid magnesium monoperoxyphtalate hexahydrate (1.32 g, 2.13 mmol) at 0°C. The resulting suspension was stirred at room temperature during 2 hours. Then, the reaction was poured into 4M sodium bicarbonate keeping the temperature below 20 °C. The organic phase was washed successively with 4M sodium bicarbonate solution (40 ml) , water (2 x 30 ml) and brine (30 ml) , dried (Na₂S0₄) and concentrated to give a residue that was purified by column chromatography with silica gel using a mixture of hexane/ethyl acetate (8:2) as eluent. 3-(4-Fluoro- phenoxy) -4- (4-methanesulfonylphenyl) -6-phenylpyran-2-one (0.045 g) was obtained, m.p. 122°C (Compound 87 in Table 2) .

EXAMPLE 15 a) To a solution of 4-hydroxypyran-2-one (1.0 g, 8.92 mmol) and -Ϋ,N-diisopropylethylamine (1.27 g, 9.81 mmol) in methylene chloride (75 ml) was slowly added at -70°C trifluoro ethanesulfonic anhydride (2.77 g, 99.81 mmol). The mixture was stirred at 0°C for 1 hour and at room temperature for 16 hours. The solvent was removed under reduced pressure and the crude was purified by column chromatography with silica gel and n-hexane/ethyl acetate (2:1) as eluent. Trifluoromethanesulfonic acid 2-oxo-2H-pyran-4-yl ester (1.17 g) was obtained, which was used in the next step without further purification. b) To a solution of trifluoromethanesulfonic acid 2-oxo-2H-pyran-4-yl ester (4.45 g, 18.23 mmol) and 4- methylsulfanylphenylboronic acid (3.37 g, 20.05 mmol) in toluene (150 ml) were added potassium carbonate (2.77 g, 20.05 mmol), lithium chloride (1.80 g, 36.46 mmol) and tetrakis-

(triphenylphosphine) palladium (0.38 g, 0.33 mmol). The mixture was boiled under reflux for 24 hours. After cooling, the reaction was poured into 4% sodium bicarbonate solution (50 ml) and diluted with ethyl acetate (35 ml) . The organic solution was washed with 4% sodium bicarbonate (2 x 35 ml), water (35 ml) and dried (Na₂S0₄) . The solvent was concentrated under reduced pressure until a solid appeared. The resulting solid was filtered and washed with diethyl ether. 4- (4-Methylsulfanylphenyl) pyran-2-one (2.4 g) was obtained, m/z 218 (M⁺) . c) To a solution of 4- (4-methylsulfanylphenyl) pyran-2-one (3.20 g, 14.66 mmol) in methylene chloride (85 ml) was added dropwise a solution of bromine (2.88 g, 18.02 mmol) in methylene chloride (7 ml) , meanwhile the evolved HBr was displaced by nitrogen. After being stirred at room temperature for 17 hours, the mixture was washed with 4% sodium bicarbonate solution (40 ml), water (2 x 35 ml), dried (Na₂S0₄) , and the solvent removed under reduced pressure. The resulting solid was washed with ethyl ether. 3-Bromo-4- (4-methylsulfanylphenyl) pyran-2-one (2.3 g) was obtained, m.p. 101°C. d) To a solution of 3-bromo-4- (4-methylsulfanylphenyl) - pyran-2-one (0.4 g, 1.35 mmol) and 3-fluorophenylboronic acid

(0.25 g, 1.76 mmol) in dioxane (30 ml) were added tetrakis (triphenylphosphine) palladium (25 mg, 22 μmol) and a solution of potassium carbonate (0.19 g , 1.35 mmol) in water (3 ml) . The mixture was boiled under reflux for 16 hours. After cooling, the reaction was poured into a potassium carbonate saturated solution (15 ml) and extracted with ethyl acetate (25 ml) . The organic solution was washed with water (2 x 15 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and n-hexane/ethyl acetate (7:3) as eluent. 3- (3-Fluorophenyl) -4- (4-methylsulfanylphenyl) pyran-2-one (0.11 g) was obtained, m/z 313 (M⁺+l) . e) To a solution of 3- (3-fluorophenyl) -4- (4- methylsulfanylphenyl)pyran-2-one (0.11 g, 0.35 mmol) in methylene chloride (6 ml) and methanol (1 ml) was slowly added magnesium monoperoxyphtalate hexahydrate (0.228 g, 0.37 mmol) and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was basified with 4% sodium bicarbonate solution and the organic phase was washed with 4% sodium bicarbonate solution (4 ml), water (3 x 4 ml), and dried (Na₂S0₄) . The solvent was removed under reduced pressure and the residue purified by column chromatography with silica gel and hexane/ethyl acetate (1:1) as eluent. 3- (3-Fluorophenyl) - 4- (4-methanesulfonylphenyl) pyran-2-one (0.05 g) was obtained, m.p. 173°C (Compound 88 in Table 2) .

EXAMPLE 16 a) To a solution of 3-bromo-4 -( 4-methylsulfanylphenyl) pyran-2-one (0.05 g, 1.68 mmol) in anhydrous dimethylformamide (35 ml) were added 4-fluorophenol (0.565 g, 5.04 mmol) and cesium carbonate (1.64 g , 5.04 mmol) and the mixture was heated 2 hours at 100 °C and stirred at room temperature for 64 hours. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate (25 ml) . The organic solution was washed with 2N sodium hydroxyde (5 x 15 ml) and water (2 x 15 ml) , dried (Na₂S0₄) , and the solvent removed under reduced pressure. 3- (4-Fluorophenoxy) -4- (4- methylsulfanylphenyl) pyran-2-one (0.27 g) was obtained as an oil, m/z 328 (M⁺) . b) To a solution of 3- (4-fluorophenoxy) -6-methyl-4- (4- methylsulfanylphenyl) pyran-2-one (0.18 g, 0.548 mmol) in methylene chloride (10 ml) and methanol (1.6 ml) was slowly added magnesium monoperoxyphtalate hexahydrate (0.69 g, 1.12 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was basified with 4% sodium bicarbonate solution (7 ml) : The organic phase was washed with 4% sodium bicarbonate solution (7 ml) , water (3 x 7 ml) and dried (Na₂S0₄) . The solvent was removed under reduced pressure to give 3- (4-fluorophenoxy) -4- (4-methanesulfonylphenyl) pyran- 2-one (0.12 g) as an oil. m/z 361 (M⁺+l) (Compound 89 in Table 2 ) .

The 4-phenylpyran-2-one derivatives of general formula (I) included in Table 2 were prepared according to the processes disclosed in these Examples, but utilising appropriate starting materials .

Table 2 (cont... )

Table 2 (cont..

Examples 17 and 18 illustrate pharmaceutical compositions according to the present invention and procedure for their preparation.

EXAMPLE 17

25,000 capsules each containing 100 mg of 3- (4- fluorophenoxy) -4- (4-methanesulfonylphenyl) -6-methylpyran-2-one (active ingredient) are prepared according to the following formulation:

Active ingredient 2.5 Kg Lactose monohydrate 5 Kg Colloidal silicone dioxide 0.05 Kg Corn starch 0.5 Kg Magnesium stearate 0.1 Kg Procedure

The above ingredients are sieved through a 60 mesh sieve, and loaded into a suitable mixer and filled into 25,000 gelatine capsules.

EXAMPLE 18

100,000 Tablets each containing 50 mg of the 4- [3- (4- fluorophenoxy) -6-methyl-2-oxo-2H-pyran-2-yl] benzene- sulfonamide, (active ingredient) are prepared from the following formulation:

Active ingredient 5 Kg

Spray dried lactose 19.9 Kg

Microcrystalline cellulose 3.9 Kg Sodium stearyl fumarate 0.2 Kg

Colloidal silicon dioxide 0.2 Kg

Carboxymethyl starch 0.8 Kg

Procedure All the powders are passed through a screen with an aperture of 0.6 mm, then mixed in a suitable mixer for 20 minutes and compressed into 300 mg tablets using 9 mm disc and flat bevelled punches. The disintegration time of the tablets is about 3 minutes.

Claims

A compound of formula (I)

(I)

wherein:

R¹ represents an alkyl or -NR⁴R⁵ group, wherein R⁴ and R⁵ each independently represents a hydrogen atom or an alkyl group;

X represents a single bond, an oxygen atom or a sulfur atom;

R² represents an alkyl, C₃-C₇ cycloalkyl, pyridyl, thienyl, furyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, methylsulfonyl, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups; with the proviso that when R² is an alkyl or C₃-C₇ cycloalkyl group, X is an oxygen atom or a sulfur atom; and

R³ represents a hydrogen atom, methyl, hydroxymethyl, alkoxymethyl, C₃-C₇ cycloalkoxymethyl, benzyloxymethyl, phenyl hydroxycarbonyl, nitrile, trifluoromethyl or difluoromethyl group or a CH₂-R⁶ group wherein R^s represents- an alkyl group; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R¹ represents a -NR⁴R⁵ group.

3. A compound according to claim 2, wherein R¹ represents a -NH₂ group.

4. A compound according to any one of claims 1 to 3, wherein R² represents a pyridyl, thienyl, furyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms, alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups.

5. A compound according to claim 4 wherein R² represents a pyridyl, thienyl, furyl or naphthyl group, or a phenyl group which may be unsubstituted or substituted by one or two halogen atoms, alkyl, trifluoromethyl or alkoxy groups.

6. A compound according to claim 5, wherein R² represents a pyridyl, thienyl, furyl or naphthyl group, or a phenyl group which may be unsubstituted, substituted with a fluorine, chlorine, or bromine atom, or a trifluoromethyl, methyl, ethyl or methoxy group, or disubstituted with any two groups which may be the same or different and are selected from fluoro-, chloro- and methyl .

7. A compound according to claim 6 wherein R² represents a 2- pyridyl, 3-pyridyl, 4-pyridyl or 2-furyl group or a phenyl group which is unsubstituted or substituted in the 3- and/or 4- position(s) with a fluorine or chlorine atom or a methyl or trifluoromethyl group.

8. A compound according to any one of the preceding claims wherein R³ represents methyl, hydroxymethyl or difluoromethyl.

9. A compound according to any one of the preceding claims wherein X represents a single bond or an oxygen atom.

10. A compound according to any one of the preceding claims wherein each alkyl moiety contains from 1 to 6 carbon atoms.

11. A compound according to claim 1 which is 4- (4-methanesulfonylphenyl) -β-methyl-3-phenylpyran-2-one,

3- (3-fluorophenyl) -4- (4-methanesulfonylphenyl) -6-methyl-pyran-

2-one,

3- (4-f luorophenyl) -4- (4-methanesulfonylphenyl) -6-methyl-pyran-

2-one, 4- (4-methanesulfonylphenyl) -6-methyl-3- ( 4-trif luoromethyl- phenyl) pyran-2-one,

4- (4-methanesulfonylphenyl) -6-methyl-3- (4-methyl-phenyl) pyran-

2-one,

3- (furan-2-yl) -4- (4-methanesulfonylphenyl) -6-methylpyran-2-one, 4- (-4-methanesulfonylphenyl) -6-methyl-3- (pyridin-2-yl) -pyran-2- one,

4-4-methanesulfonylphenyl) -6-methyl-3- (pyridin-3-yl) —pyran-2- one,

3- (4-fluorophenoxy) -4- (4-methanesulfonylphenyl) -6-methyl-pyran- 2-one,

3- (4-chlorophenoxy) -4- (4-methanesulfonylphenyl) -6-methyl-pyran-

2-one,

4- (4-methanesulfonylphenyl) -6-methyl-3- (4-methyl-phenoxy) pyran-

2-one, 3- (3, 4-difluorophenoxy) -4- (4-methanesulfonylphenyl) -6- methylpyran-2-one,

3- (3, 4-dichlorophenoxy) -4- (4-methanesulfonylphenyl) -6- methylpyran-2-one,

4- (4-methanesulfonylphenyl) -6-methyl-3- (pyridin-2-yloxy) -pyran- 2-one,

4- [ 6 -methyl -2 -oxo- 3- ( 4-trif luoromethylphenyl ) -2H-pyran-4- yl] benzenesulf onamide,

4- [3- (4-fluorophenoxy) -6-methyl-2-oxo-2H-pyran-4- yl) benzenesulf onamide, 4-[3-(4-chlororophenoxy) - 6-methyl-2 -oxo-2H-pyran-2-yl ] - benzenesulfonamide,

4- [β-methyl-2-oxo-3- (4-trifluoromethylphenoxy) -2H-pyran-2- yl] benzenesulfonamide,

4- [6-methyl-2-oxo-3- (pyridin-4-yloxy) -2H-pyran-2- yl] benzenesulfonamide, or pharmaceutically acceptable salts thereof with fumaric, tartaric, succinic or hydrochloric acid or an alkali metal hydroxide .

12. A process for the preparation of a compound of formula (ID

(ID

wherein R^la is an alkyl or NR^4aR^5a group in which R^4a and R^5a each independently represent an alkyl group, R^3a is a hydrogen atom or a methyl group, X^a is a bond and R² is as defined in claim 1, which comprises reacting a derivative of formula (III) :

(III)

wherein R¹ and R³ are as defined above and Z is a leaving group, with a boronic acid of formula (IV) : R²-B ( OH ) ₂ ( IV)

R²-Sn(R⁷) (V)

wherein R² is as defined above and R⁷ is an alkyl group.

13. A process for the preparation of a compound of formula (X)

(X)

wherein R^lb is an alkyl group, R² is as defined in claim 1, R^3a is as defined in claim 12 and X^a is a single bond or an oxygen atom, which comprises reacting a mercapto derivative of formula (XI) :

wherein R¹ , R , R^3a and X^a are as defined above, with a suitable oxidizing agent.

14. A process for the preparation of a compound of formula (XIII)

(XIII)

wherein R^la# R² and R^3a are as defined in claim 12 and X^b is an oxygen atom or a sulphur atom, which comprises reacting a derivative of formula (III)

(III)

wherein R^la and R^3a are as defined above and Z is a leaving group, with a hydroxy or mercapto derivative of formula (XIV) :

R²-X^bH (XIV)

wherein R² and X° are as defined above.

15. A process for the preparation of a compound of formula (XVIII)

(XVI Ii ;

wherein R² and X are as defined in claim 1 and R^3a is as defined in claim 12, which comprises the deprotection of the sulfonamido derivative of formula (XIX) :

(XIX)

wherein R² and R^3a are as defined above and R⁸ is a hydrogen atom when R⁹ is a tert-butyl group or both represent a benzyl group.

16. A process for the preparation of a compound of formula (XX)

(XX)

wherein X^a is a bond, R² and R^3a are as defined in claim 12, which comprises reacting a derivative of formula (XXI) :

(XXI )

wherein R^3a is as defined above and Z is a leaving group, with a boronic acid of formula (IV) :

R²-B(OH)₂ (IV)

R²-Sn(R⁷) (V)

wherein R² is as defined above and R⁷ is as defined in claim 12

17. A process for the preparation of a compound of formula (XXI)

(XXI)

wherein R^3a is as defined in- claim 12 and Z is a leaving group, which comprises the deprotection of the sulfonamido derivative of formula (XXII) :

( XXI I )

wherein Z and R^3a are as defined above and R⁸ is a hydrogen atom when R⁹ is a tert-butyl group or both represent a benzyl group.

18. A process for the preparation of a compound of formula (XXIII)

(XXIII)

wherein R² and R^3a are as defined in claim 12 and X^b is an oxygen atom or a sulphur atom, which comprises reacting a derivative of formula (XXI)

(XXI : wherein R^3a is as defined above and Z is a leaving group, with a hydroxy or mercapto derivative of formula (XIV) :

R²-X^bH (XIV)

wherein R² and X^b are as defined above,

19. A process for the preparation of a compound of formula (I)

(I)

wherein R¹, R² and X are as defined in claim 1 and R³ is as defined in claim 1 with the exception of a hydrogen atom or a methyl group, which comprises reacting, in one or more steps, an aldehyde of formula (XXV)

(XXV)

wherein R¹ and R² are as defined above with one or more reagent (s) known in the art to be suitable for converting an aldehyde group into a group R³, wherein R³ is defined as above.

20. A compound of formula (III)

(III)

wherein R^l is an alkyl or NR^4aR^5a group in which R^4a and R^5a each independently represent an alkyl group, R^3a is a hydrogen atom or a methyl group and Z is a hydrogen atom or a leaving group.

21. A compound of formula (XII)

(XII)

wherein R^lb represents an alkyl group, R^3a represents a hydrogen atom or a methyl group and Z represents a hydrogen atom or a leaving group.

22. A compound according to claim 20 or 21 or a process according to any one of claims 12, 14, 16, 17 or 18 wherein Z is bromine.

23. A compound of formula (XVI)

(XVI)

wherein R^l is alkyl, R² is as defined in any one of claims 1 or 4 to 7, R^3a is a hydrogen atom or a methyl group and X^c is an oxygen atom.

24. A compound of formula (XXV)

(XXV)

wherein R¹, R² and X are as defined in any one of claims 1 to 7 or 9.

25. A compound according to any one of claims 20. to 23 wherein R^la, R^lb, R^a and R^5a represent an alkyl group containing from 1 to 6 carbon atoms.

26. Use of a compound according to any one of claims 20 to 25 as a chemical intermediate in the production of a compound as defined in any one of claims 1 to 11.

27. A . pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier or diluent.

28. A compound according to any one of claims 1 to 11 or pharmaceutically acceptable salt thereof or composition according to claim 27 for use in the treatment or prevention of a pathological condition or disease susceptible to amelioration by inhibition of cyclooxygenase-2.

29. Use of a compound according to any one of claims of 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a pathological condition or disease susceptible to amelioration by inhibition of cyclooxygenase-2.

30. Use according to claim 29, wherein the pathological condition is pain, fever, inflammation, prostanoid-induced smooth muscle contraction or colorectal cancer.

31. A method for the treatment or prevention of a pathological condition or disease susceptible to amelioration by inhibition of cyclooxygenase-2, which method comprises administering to a human or animal subject in need of treatment an effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

32. A method according to claim 31, wherein the pathological condition is pain, fever, inflammation, prostanoid induced smooth muscle contraction or colorectal cancer.