5-oxo-ETE receptor antagonist compounds
The present invention relates to novel pharmaceutically-useful compounds which are antagonists of the 5-oxo-ETE receptors, such as the OXE receptor. These compounds have use as therapeutic and/or prophylactic agents for diseases characterized by tissue eosinophilia, such as inflammatory conditions including respiratory diseases. The invention also relates to pharmaceutical compositions, to the use of such compounds and compositions as medicaments, and to therapeutic methods.
1. A compound of Formula II:
wherein:
X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of H, halogen, alkyl group, aralkyl group and OR 5 wherein R 5 is selected from the group consisting of H, acyl, alkyl, aralkyl, alkenyl, alkoxy, aryl, haloalkyl, cycloalkyl, haloalkoxy, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl, any of which may be optionally substituted; and
i) R 3 is selected from H and an alkyl group having 4 or more carbon atoms, one of R 1 or R 2 is an alkyl group having 4 or more carbon atoms and optionally substituted with C 6-16 aryl, or C 3-7 cycloalkyl, and the other of said R 1 or R 2 is
or
ii) R 3 is
and
R 1 is selected from H and an alkyl group having 4 or more carbon atoms, and R 2 is an alkyl group having 4 or more carbon atoms and optionally substituted with C 6-16 aryl, or C 3-7 cycloalkyl; or
iii) R 1 , R 2 and R 3 are each selected from H and an alkyl group having 4 or more carbon atoms, wherein at least one of R 1 , R 2 and R 3 is an alkyl group having 4 or more carbon atoms, and at least one of R 1 , R 2 and R 3 is
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II:
wherein:
X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of H, halogen, alkyl group, aralkyl group and OR 5 wherein R 5 is selected from the group consisting of H, acyl, alkyl, aralkyl, alkenyl, alkoxy, aryl, haloalkyl, cycloalkyl, haloalkoxy, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl, any of which may be optionally substituted; and
i) R 3 is selected from H and an alkyl group having 4 or more carbon atoms, one of R 1 or R 2 is an alkyl group having 4 or more carbon atoms and optionally substituted with C 6-16 aryl, or C 3-7 cycloalkyl, and the other of said R 1 or R 2 is
or
ii) R 3 is
and
R 1 is selected from H and an alkyl group having 4 or more carbon atoms, and R 2 is an alkyl group having 4 or more carbon atoms and optionally substituted with C 6-16 aryl, or C 3-7 cycloalkyl; or
iii) R 1 , R 2 and R 3 are each selected from H and an alkyl group having 4 or more carbon atoms, wherein at least one of R 1 , R 2 and R 3 is an alkyl group having 4 or more carbon atoms, and at least one of R 1 , R 2 and R 3 is
or a pharmaceutically acceptable salt thereof;
and a pharmaceutically acceptable carrier.
3. A method of treating a respiratory condition in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula II:
wherein:
X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of H, halogen, alkyl group, aralkyl group and OR 5 wherein R 5 is selected from the group consisting of H, acyl, alkyl, aralkyl, alkenyl, alkoxy, aryl, haloalkyl, cycloalkyl, haloalkoxy, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl, any of which may be optionally substituted; and
i) R 3 is selected from H and an alkyl group having 4 or more carbon atoms, one of R 1 or R 2 is an alkyl group having 4 or more carbon atoms and optionally substituted with C 6-16 aryl, or C 3-7 cycloalkyl, and the other of said R 1 or R 2 is
or
ii) R 3 is
and
R 1 is selected from H and an alkyl group having 4 or more carbon atoms, and R 2 is an alkyl group having 4 or more carbon atoms and optionally substituted with C 6-16 aryl, or C 3-7 cycloalkyl; or
iii) R 1 , R 2 and R 3 are each selected from H and an alkyl group having 4 or more carbon atoms, wherein at least one of R 1 , R 2 and R 3 is an alkyl group having 4 or more carbon atoms, and at least one of R 1 , R 2 and R 3 is
or a pharmaceutically acceptable salt thereof;
wherein the respiratory condition is asthma, allergic rhinitis, chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis.
4. The method of claim 3 , wherein the respiratory condition is associated with inflammation.
5. The method of claim 3 , wherein the subject is a human.
6. The method of claim 3 , further comprising concomitant administration of a second agent to the subject, wherein the second agent is an analgesic, anti-inflammatory agent or anti-allergy agent.
7. The method of claim 6 , wherein the compound and the second agent are administered at the same time.
8. The method of claim 6 , wherein the compound and the second agent are administered sequentially.
9. The method of claim 6 , wherein the second agent is an NSAID, a bronchodilator or a leukotriene modifier.
10. A compound of Formula
wherein X is H, halogen or alkyl; R 3 and R 4 are H and H; H and CH 3 ; CH 3 and CH 3 or H and ethyl; or Formula
wherein X is H, halogen or alkyl; R 3 and R 4 are H and H; H and CH 3 ; CH 3 and CH 3 ; or H and ethyl and R 5 is H, CH 3 or CH 3 CH 2 ;
or a pharmaceutically acceptable salt thereof.
11. A compound selected from:
or a pharmaceutically acceptable salt thereof.
12. A compound according to claim 10 , wherein the aromatic group in the compound is substituted with F, CI, Br or I.
13. A method of treating inflammation associated with asthma, allergic rhinitis, chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula II:
wherein:
X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of H, halogen, alkyl group, aralkyl group and OR 5 wherein R 5 is selected from the group consisting of H, acyl, alkyl, aralkyl, alkenyl, alkoxy, aryl, haloalkyl, cycloalkyl, haloalkoxy, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl, any of which may be optionally substituted; and
i) R 3 is selected from H and an alkyl group having 4 or more carbon atoms, one of R 1 or R 2 is an alkyl group having 4 or more carbon atoms and optionally substituted with C 6-16 aryl, or C 3-7 cycloalkyl, and the other of said R 1 or R 2 is
or
ii) R 3 is
and
R 1 is selected from H and an alkyl group having 4 or more carbon atoms, and R 2 is an alkyl group having 4 or more carbon atoms and optionally substituted with C 6-16 aryl, or C 3-7 cycloalkyl; or
iii) R 1 , R 2 and R 3 are each selected from H and an alkyl group having 4 or more carbon atoms, wherein at least one of R 1 , R 2 and R 3 is an alkyl group having 4 or more carbon atoms, and at least one of R 1 , R 2 and R 3 is
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the action of eicosanoids is inhibited.
15. The method of claim 14 , wherein the eicosanoid is 5-oxo-ETE.