2-phenylpyran-4-one derivatives as selective COX-2 inhibitors

1. A compound of formula (I):

wherein

R 1 represents an alkyl group;

R 2 represents a group chosen from alkyl, C 3 -C 7 cycloalkyl, pyridyl, thienyl, naphthyl, tetrahydronaphthyl, indanyl, and a phenyl group; wherein the phenyl group is unsubstituted or substituted by one or more substituents independently chosen from halogen atoms, alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- and dialkylamino, hydroxyalkyl and hydroxycarbonyl groups;

R 3 and R 4 , which may be the same or different, represent, independently of each other, a group chosen from a hydrogen atom, alkyl, alkenyl and alkynyl groups, wherein the alkyl, alkenyl, and alkynyl groups are unsubstituted or substituted by one or more halogen atoms; and

X represents a single bond, an oxygen atom, or a methylene group;

, or a pharmaceutically acceptable salt thereof, in any enantiomeric form, or a mixture of any such compounds in any ratio.

2. A compound according to claim 1 wherein R 1 represents an unsubstituted alkyl group.

3. A compound according to claim 2 wherein R 1 is a methyl group.

4. A compound according to claim 1 , wherein X represents an oxygen atom.

5. A compound according to claim 1 , wherein R 3 and R 4 each represent, independently of each other, a hydrogen atom or an unsubstituted C 1-3 alkyl group.

6. A compound according to claim 5 , wherein R 3 and R 4 each represent a hydrogen atom.

7. A compound according to claim 1 , wherein R 2 is chosen from branched alkyl, C 3 -C 7 cycloalkyl, naphthyl, tetrahydronaphthyl, indanyl, an unsubstituted phenyl group, and a phenyl group substituted by one or more substituents independently chosen from halogen atoms, alkyl groups and alkoxy groups.

8. A compound according to claim 7 , wherein R 2 is an unsubstituted phenyl group or a phenyl group substituted by 1, 2 or 3 substituents independently chosen from halogen atoms, methoxy group and methyl groups.

9. A compound according to claim 8 , wherein R 2 represents a phenyl group substituted by 1 or 2 substituents independently chosen from halogen atoms and methyl groups.

10. A compound according to claim 9 , wherein R 2 represents an optionally substituted phenyl group of formula

wherein R a and R b are independently chosen from hydrogen atoms, halogen atoms, alkyl groups and alkoxy groups.

11. A compound according to claim 10 , wherein R a and R b are independently chosen from halogen atoms.

12. A compound according to claim 11 , wherein R 2 is a 2,4-difluorophenyl, a 4-chloro-2-fluorophenyl or a 4-bromo-2-fluorophenyl group.

13. A compound according to claim 1 , chosen from:

3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(4-Bromo-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(2,4-difluorophenoxy)-6-ethyl-5-methyl-2-[(4-(methylsulfinylphenyl)]-4H-pyran-4-one;

3-(4-fluoro-2-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(4-chloro-2-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(2-chloro-4-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(2-bromophenoxy)-6-methyl-2-[(4.-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(3-bromophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(4-bromo-2-fluorophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4 H-pyran-4-one;

3-(4-bromo-2-chlorophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4 H-pyran-4-one;

3-(2,4-dibromophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(2,4-difluorophenoxy)-6-methyl-2-[(4-(ethylsulfinyl)phenyl]-4 H-pyran-4-one;

6-methyl-3-(2-methylphenoxy)-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

6-methyl-3-(3-methylphenoxy)-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(2-fluoro-4-methylphenoxy)- 6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

and pharmaceutically acceptable salts thereof, in any enantiomeric form, or a mixture of any such compounds in any ratio.

14. A compound according to claim 1 , wherein the sulphur atom of the sulfinyl group has the (S) configuration.

15. A compound according to claim 1 , wherein the sulphur atom of the sulfinyl group has the (R) configuration.

16. A compound according to claim 1 , chosen from:

3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

3-(4-Bromo-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one;

wherein the compound is in the form of an enantiomer in the configuration designated 1b, 4b and 7b;

or a mixture thereof, or a pharmaceutically acceptable salt thereof.

17. A process for producing a compound as claimed in claim 1 , comprising:

reacting a mercapto derivative of formula (II):

with an oxidizing agent to produce a compound of formula (I); and

optionally converting the compound of formula (I) into a pharmaceutically acceptable salt.

18. A process according to claim 17 , wherein the oxidizing agent is chosen from:

(a) sodium metaperiodate; and

(b) a mixture of titanium tetraisopropoxide, t-butyl hydroperoxide and either the (R,R) or the (S,S) form of diethyl tartrate.

19. A process according to claim 18 , wherein the reaction takes place in at least one chlorinated solvent or in a mixture of at least one chlorinated solvent and at least one C 1 -C 4 alcohol.

20. A process according to claim 19 ; wherein the at least one chlorinated solvent is chosen from 1,2-dichloroethane, methylene chloride, chloroform and mixtures thereof.

21. A pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable carrier or diluent.

22. A method for treating pain, fever or inflammation, comprising administering to a human or animal subject in need of treatment an effective amount of a compound according to claim 1 .

23. A medicament comprising at least one compound according to claim 1 .

24. A method for treating pain, fever or inflammation, comprising administering to a human or animal subject in need of treatment an effective amount of a composition according to claim 21 .

25. A method for inhibiting prostanoid-induced smooth muscle contraction or treating colorectal cancer, comprising administering to a human or animal subject in need of treatment an effective amount of a compound according to claim 1 .

26. A method for inhibiting prostanoid-induced smooth muscle contraction or treating colorectal cancer, comprising administering to a human or animal subject in need of treatment an effective amount of a composition according to claim 21 .