Prodrugs of diaryl-2-(5H)-furanone cyclooxygenase-2 inhibitors
View Patent ↗The invention encompasses the novel compounds of Formula (I) and Formula (II), which are prodrugs that convert in vivo to diaryl-2-(5H)-furanones useful in the treatment of cyclooxygenase-2 mediated diseases. These prodrugs are far more soluble in aqueous media than the active agents into which they convert, in vivo. As such compounds of Formula (I) and (II) are advantageous for, among other things intravenous administration. The invention also encompasses certain pharmaceutical compositions and methods for treatment of cyclooxygenase-2 mediated diseases comprising the use of compounds of Formula (I) and Formula (II).
1. A compound of Formula I or Formula II
or pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of
(a) phenyl, optionally substituted at positions 3 and 4 halogens,
(b) —O-isopropyl,
(c) —O-cyclopropyl, and
(d) —O—CH 2 -cyclopropyl;
R 2 is selected from the group consisting of:
(a) —S(O) 2 CH 3 , and
(b) —S(O) 2 NH 2 ;
R 3 is selected from the group consisting of
(a) hydrogen,
(b) methyl,
(c) ethyl,
(d) hydroxyl,
(e) F, Cl, and
(f) CF 3 ;
R 4 is selected from the group consisting of
(a) methyl, and
(b) ethyl;
X 1 is selected from the group consisting of:
(a) —OCH 2 —,
(b) —OC(R 3 )(R 4 )—,
(c) —CH 2 -linker —O—, and
(d) —C(R 3 )(R 4 )-linker-O—,
wherein the oxygen end of X 1 is attached to the carbonyl carbon of Formula I;
X 2 is selected from the group consisting of:
(a) —OCH 2 —,
(b) —OC(R 3 )(R 4 )—,
(c) —CH 2 -linker-O—, and
(d) —C(R 3 )(R 4 )-linker-O—;
wherein the carbon end of X 2 is attached to the carbon adjacent to the R 2 -phenyl explicitly shown;
-linker—is selected from the group consisting of
(a) —C(O)—(CH2) m —O—,
(b) —C(O)—(CH 2 ) m (—O—(CH 2 )n) p —O—, and
(c) —C(O)-aryl-O—,
wherein m, n and p are each independently integers ranging from 0 to 6;
Y is selected from the group consisting of
(a) hydrogen, and
(b) acyl,
wherein the acyl group is selected from the group consisting of
(a) —C(O)—C 1-6 alkyl, optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halo, hydroxyl, amino, C 1-3 alkoxy, aminoC 1-3 alkyl,
(b) —C(O)-aryl, and
(c) an amino acid;
Z is selected from the group consisting of:
(a) —OR 5 ,
(b) —NR 5 R 6 ,
wherein R 5 and R 6 are each independently selected from
(a) hydrogen,
(b) C 1-6 alkyl,
(c) phenyl, and
(d) C 1-2 -phenyl,
wherein R 5 and R 6 choices (b), (c) and (d) are optionally substituted with 1, 2, or 3 substituents selected from halo, hydroxyl, amino, C 1-3 alkyl, and C 1-3 alkoxy;
X is selected from the group consisting of:
(a) —OCH 2 —, and
(b) —C(R 3 )(R 4 )O—,
wherein the carbon at the end of X is attached to the carbon adjacent to the phenyl;
Y 1 is -linker1-, which is selected from the group consisting of
(a) —C(O)—(CH 2 ) r —C(O)—,
(b) —C(O)-aryl-C(O)—,
(c) —C(O)—(CH 2 ) r —(O—(CH 2 ) s ) t —C(O)—, and
(d) —C(O)—(CH 2 ) r —CH—(CH 2 ) s —C(O)—,
wherein r, s and t are each independently integers ranging from 0 to 6; and
Z 1 is selected from the group consisting of:
(a) —OR 5 , and
(b) —NR 5 R 6 .
2. A compound according to claim 1 of Formula I
3. A compound according to claim 2 wherein:
R 1 is phenyl, optionally substituted at positions 3 and 4 with fluorine.
4. A compound according to claim 2 wherein:
R 2 is —S(O) 2 CH 3 .
5. A compound according to claim 2 wherein:
R 3 is selected from the group consisting of
(a) hydrogen,
(b) methyl, and
(c) ethyl.
6. A compound according to claim 2 wherein:
X 1 and X 2 are each is selected from the group consisting of:
(a) —OCH 2 —, and
(b) —OC(R 3 )(R 4 )—.
7. A compound according to claim 2 wherein:
Y is hydrogen or —OCH 3 .
8. A compound according to claim 2 wherein:
Z is hydroxyl or —OCH 3 .
9. A compound according to claim 2 wherein:
R 1 is phenyl, optionally substituted at positions 3 and 4 with fluorine;
R 2 is —(O) 2 CH 3 ;
R 3 is selected from the group consisting of
(a) hydrogen,
(b) methyl, and
(c) ethyl;
R 4 is selected from the group consisting of
(a) methyl, and
(b) ethyl;
X 1 and X 2 are each is selected from the group consisting of:
(a) —OCH 2 —, and
(b) —OC(R 3 )(R 4 )—;
Y is hydrogen or —OCH 3 ; and
Z is hydroxyl or —OCH 3 .
10. A compound according to claim 1 of Formula II
11. A compound according to claim 10 wherein:
R 1 is phenyl, optionally substituted at positions 3 and 4 halogens.
12. A compound according to claim 11 wherein:
R 2 is —S(O) 2 CH 3 .
13. A compound according to claim 12 wherein:
R 3 is selected from the group consisting of
(a) hydrogen,
(b) methyl, and
(c) ethyl.
14. A compound according to claim 13 wherein:
Y 1 is selected from —(O)C(H)═C(H)C(O)— and —(O)C(CH 2 ) 2 C(O)—.
15. A compound according to claim 14 wherein:
Z 1 is hydroxyl or —OCH 3 .
16. A compound according to claim 15 wherein:
R 1 is phenyl, optionally substituted at positions 3 and 4 halogens;
R 2 is —(O) 2 CH 3 ;
R 3 is selected from the group consisting of
(a) hydrogen,
(b) methyl, and
(c) ethyl;
Y 1 is selected from —(O)C(H)═C(H)C(O)— and —(O)C(CH 2 ) 2 C(O)—; and
Z 1 is hydroxyl or —OCH 3 .
17. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
18. A compound according to claim 1 selected from