Biaryl nitrogen-heterocycle inhibitors of LTA4H for treating inflammation
View Patent ↗The present invention relates to a chemical genus of biaryl nitrogen-attached heterocycles that are inhibitors of LTA4H (leukotriene A4 hydrolase). The compounds have the general formula They are useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders.
1. A compound of formula:
wherein
Ar is selected from the group consisting of phenyl, and phenyl substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweralkoxy, fluoroloweralkyl, 5-membered heteroaryl, and 5-membered heteroaryl substituted with halogen;
X is O;
R 2 is selected from the group consisting of H, loweralkyl, and —Z—W;
Y is
wherein the wavy lines indicate ring bonds;
Q is —OH or —COOH;
n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, provided that n is not 1 when Q is —OH;
Z is (CH 2 ) 1-10 ; in which one or two (CH 2 ) may optionally be replaced by a —O—, —NR 10 —, or —C(═O)—, provided that said —O— —NR 10 —, or —C(═O)— are separated by at least one —(CH 2 ) 2 —;
R 10 is selected from the group consisting of H and lower alkyl;
W is selected from acyl, hydroxyl, carboxyl, and COOalkyl.
2. A compound according to claim 1 of formula:
wherein each occurrence of R 3 or R 6 is selected from the group consisting of H, halogen, lower alkyl, fluoro-loweralkyl, lower alkoxy, 5-membered heteroaryl, and 5-membered heteroaryl substituted with halogen.
3. A compound according to claim 2 , wherein n is 1, 2 or 3 and Q is —COOH.
4. A compound according to claim 2 , wherein R 6 is H and R 3 is in the para position.
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 1 .
6. A compound according to claim 4 , wherein X is O, and R 3 is 5-membered heteroaryl.
7. A compound according to claim 6 , wherein said 5-membered heteroaryl is thiophene, n is 2, and Q is COOH.
8. A compound of formula:
or a salt thereof.
9. A compound of formula:
wherein
Ar is phenyl substituted with 5-membered heteroaryl, said heteroaryl optionally substituted with halogen;
X is O;
R 2 is selected from the group consisting of H, loweralkyl, and —Z—W;
Y is
wherein the wavy lines indicate ring bonds;
R 5 is H;
Z is (CH 2 ) 1-10 ; in which one or two (CH 2 ) may optionally be replaced by a —O—, —NR 10 —, or —C(═O)—, provided that said —O—, —NR 10 —, or —C(═O)— are separated by at least one —(CH 2 ) 2 —;
R 10 is selected from the group consisting of H and lower alkyl; and
W is selected from acyl, hydroxyl, carboxyl, and COOalkyl.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 9 .
11. A compound of formula:
wherein
Ar is selected from the group consisting of phenyl, and phenyl substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweralkoxy, fluoroloweralkyl, 5-membered heteroaryl, and 5-membered heteroaryl substituted with halogen;
X is O;
R 2 is —Z—W;
Y is
wherein the wavy lines indicate ring bonds;
R 5 is chosen from hydrogen and lower alkyl;
Z is (CH 2 ) 1-10 ; in which one or two (CH 2 ) may optionally be replaced by a —O—, —NR 10 —, or —C(═O)—, provided that said —O— —NR 10 —, or —C(═O)— are separated by at least one —(CH 2 ) 2 —;
R 10 is selected from the group consisting of H and lower alkyl; and
W is selected from acyl, hydroxyl, carboxyl, and COOalkyl.
12. A compound according to claim 11 of formula:
wherein each occurrence of R 3 or R 6 is selected from the group consisting of H, halogen, lower alkyl, fluoro-loweralkyl, lower alkoxy, 5-membered heteroaryl, and 5-membered heteroaryl substituted with halogen.
13. A compound according to claim 12 , wherein R 6 is H and R 3 is in the para position.
14. A compound according to claim 13 , wherein R 3 is a 5-membered heteroaryl.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 11 .
16. A compound according to claim 14 , wherein said 5-membered heteroaryl is thiophene, Z is —(CH 2 ) 2 —, and W is carboxyl.
17. A compound of formula:
wherein
Ar 1 is phenyl substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweralkoxy, fluoroloweralkyl, 5-membered heteroaryl, and 5-membered heteroaryl substituted with halogen;
X is O;
Y is
wherein the wavy lines indicate ring bonds;
R 5 is —Z—W,
Z is (CH 2 ) 1-10 ; in which one or two (CH 2 ) may optionally be replaced by a —O—, —NR 10 —, or —C(═O)—, provided that said —O— —NR 10 —, or —C(═O)— are not at the point of attachment to nitrogen and are separated by at least one —(CH 2 ) 2 —;
R 10 is selected the group consisting of H and lower alkyl; and
W is selected from acyl, carboxyl and COOalkyl.
18. A compound according to claim 17 of formula:
wherein each occurrence of R 3 or R 6 is selected from the group consisting of H, halogen, lower alkyl, fluoro-loweralkyl, lower alkoxy, 5-membered heteroaryl, and 5-membered heteroaryl substituted with halogen;
with the proviso that both R 3 and R 6 cannot be H.
19. A compound according to claim 18 , wherein Z is (CH 2 ) 1-3 .
20. A compound according to claim 18 , wherein R 6 is H and R 3 is in the para position.
21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to claim 17 .
22. A compound according to claim 20 , wherein X is O, and R 3 is 5-membered heteroaryl.
23. A compound according to claim 22 , wherein said 5-membered heteroaryl is thiophene, Z is —(CH 2 ) 2 —, and W is carboxyl.