Certain 5-alkyl-2-arylaminophenylacetic acids and derivatives

1. A compound of formula I

wherein R is methyl or ethyl;

R 1 is chloro or fluoro;

R 2 is hydrogen or fluoro;

R 3 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;

R 4 is hydrogen or fluoro; and

R 5 is chloro, fluoro, trifluoromethyl or methyl;

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable prodrug ester thereof.

2. A compound according to claim 1 wherein R is methyl or ethyl; R 1 is chloro or fluoro; R 2 is hydrogen; R 3 is hydrogen, fluoro, chloro, methyl or hydroxy; R 4 is hydrogen; and R 5 is chloro, fluoro or methyl; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug ester thereof.

3. A compound according to claim 1 wherein R is methyl or ethyl; R 1 is fluoro; R 2 is hydrogen; R 3 is hydrogen, fluoro or hydroxy; R 4 is hydrogen; and R 5 is chloro; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug ester thereof.

4. A compound according to claim 1 wherein R is methyl or ethyl; R 1 is fluoro; R 2 is fluoro; R 3 is hydrogen, ethoxy or hydroxy; R 4 is fluoro; and R 5 is fluoro; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug ester thereof.

5. A compound according to claim 1 wherein R is methyl; R 1 is fluoro; R 2 is hydrogen; R 3 is hydrogen or fluoro; R 4 is hydrogen; and R 5 is chloro; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable prodrug ester thereof.

6. A compound according to claim 1 which is 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid wherein in formula I R is methyl; R 1 is fluoro; R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen; and R 5 is chloro; or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 which is 5-methyl-2-(2′, 4′-difluoro-6′-chloroanilino)phenylacetic acid wherein in formula I R is methyl; R 1 is fluoro; R 2 is hydrogen; R 3 is fluoro; R 4 is hydrogen; and R 5 is chloro; or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 which is 5-ethyl-2-(2′, 3′,5′,6′-tetrafluoroanilino)phenylacetic acid wherein in formula I R is ethyl; R 1 is fluoro; R 2 is fluoro; R 3 is hydrogen; R 4 is fluoro; and R 5 is fluoro; or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising an effective cyclooxygenase-2 inhibiting amount of a compound of claim 1 which is substantially free of cyclooxygenase-1 inhibiting activity in combination with one or more pharmaceutically acceptable carriers.

10. A pharmaceutical composition comprising an effective cyclooxygenase-2 inhibiting amount of a compound of claim 6 which is substantially free of cyclooxygenase-1 inhibiting activity in combination with one or more pharmaceutically acceptable carriers.

11. A pharmaceutical composition comprising an effective cyclooxygenase-2 inhibiting amount of a compound of claim 7 which is substantially free of cyclooxygenase-1 inhibiting activity in combination with one or more pharmaceutically acceptable carriers.

12. A pharmaceutical composition comprising an effective cyclooxygenase-2 inhibiting amount of a compound of claim 8 which is substantially free of cyclooxygenase-1 inhibiting activity in combination with one or more pharmaceutically acceptable carriers.

13. A pharmaceutical composition comprising an effective cyclooxygenase-2 inhibiting amount of a compound of claim 9 which is substantially free of cyclooxygenase-1 inhibiting activity in combination with one or more pharmaceutically acceptable carriers.

14. A method of treating cyclooxygenase-2 dependent disorders in mammals while substantially eliminating undesirable side effects associated with cyclooxygenase-1 inhibiting activity which comprises administering to a mammal in need thereof an effective cyclooxygenase-2 inhibiting amount of a compound of claim 1 which is substantially free of cyclooxygenase-1 inhibiting activity.

15. A method of selectively inhibiting cyclooxygenase-2 activity in a mammal without substantially inhibiting cycloxygenase-1 activity which comprises administering to a mammal in need thereof an effective cyclooxygenase-2 inhibiting amount of a compound of claim 1 which is substantially free of cyclooxygenase-1 inhibiting activity.

16. A method of treating rheumatoid arthritis, osteoarthritis, pain, inflammation in mammals which comprises administering to a mammal in need thereof a correspondingly effective amount of a compound of claim 1 which is substantially free of gastrointestinal ulceration.

17. A method of treating ocular inflammatory disorders, glaucoma or dry eye disease in mammals which comprises administering to a mammal in need thereof a correspondingly effective amount of a compound of claim 1 .

18. A method for the preparation of a compound of formula I according to claim 1 which comprises:

(a) coupling a compound of formula II or IIa

wherein R has meaning as defined; R a is lower alkyl; and R 6 and R 7 represent lower alkyl; or R 6 and R 7 together with the nitrogen atom represent piperidino, pyrrolidino or morpholino;

with a compound of formula III

wherein R 1 , R 2 , R 3 , R 4 and R 5 have meaning as defined in said claim 1 , in the presence of copper and cuprous iodide, to obtain a compound of formula IV or IVa

and hydrolyzing the resulting compound of formula IV or IVa to a compound of formula I; or

(b) for compounds in which R represents ethyl, condensing a compound of formula V

wherein R 1 –R 7 have meaning as defined above, with a reactive functional derivative of acetic acid, such as acetyl chloride, in a Friedel-Crafts acylation reaction to obtain a compound of the formula VI

wherein R 1 –R 7 have meaning as defined above, and which is in turn hydrogenolyzed and then hydrolyzed to obtain a compound of formula I wherein R represents ethyl; or

(c) hydrolyzing a lactam of formula VII

wherein R and R 1 –R 5 have meaning as defined, with a strong base; and

in above processes, if desired, temporarily protecting any interfering reactive groups and then isolating the resulting compound of the invention; and, if desired, converting any resulting compound into another compound of the invention; and/or if desired converting a free carboxylic acid of the invention into a pharmaceutically acceptable ester derivative thereof; and/or if desired, converting a resulting free acid into a salt or a resulting salt into the free acid or into another salt.