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 method for treating inflammation or a disease selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), atopic dermatitis and acne, in a patient in need thereof said method comprising administering an effective amount of a compound of Formula II
wherein
X1, X2, X3 and X4 are independently selected from the group consisting of H, halogen, alkyl group, aralkyl group and OR5 wherein R5 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) R1 is (CO)alkyl-COOH, said alkyl is straight or branched and optionally substituted with C3-7 cycloalkyl;
R2 is alkyl, said alkyl is straight or branched and optionally substituted with OH, SH, COOR6, NR6R7, a C6-16 aryl, a C6-16 heterocycle, a C3-7 cycloalkyl, or a heterocyclic ring, wherein R6 and R7 are a C6-16 aryl, C6-16 heterocycle, C3-7 cycloalkyl, a heterocyclic ring or a hydrophobic group;
R3 is alkyl;
or ii)
R1 is H
R2 is alkyl, said alkyl is straight or branched and optionally substituted with OH, SH, COOR6, NR6R7, C6-16 aryl, C6-16 heterocycle, C3-7 cycloalkyl, or a heterocyclic ring, wherein R6 and R7are a C6-16 aryl, C6-16 heterocycle, C3-7 cycloalkyl, or a heterocyclic
R3 is (CO)alkyl-COOH, said alkyl is straight or branched and optionally substituted with C3-7 cycloalkyl;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 for treating atopic dermatitis or acne.
3. The method of claim 1 , wherein one of X 1 , X 2 , X 3 or X 4 is selected from the group consisting of H, halogen and alkyl group and the remaining of said X 1 , X 2 , X 3 or X 4 are H.
4. The method of claim 1 , wherein one of X 2 or X 3 is halogen and the remaining of said X 1 , X 2 , X 3 or X 4 are H.
5. The method of claim 1 , wherein R 2 is an alkyl comprising up to 10 carbon atoms, provided that when said alkyl is an unsaturated, it is comprising 2 or more carbon atoms.
6. The method of claim 1 , wherein in i) R1 is (CO)alkyl-COOH, said alkyl is optionally substituted with C6-16 aryl or C3-7 cycloalkyl.
7. The method of claim 6 , wherein said alkyl portion of said (CO)alkyl-COOH is comprising 2 to 4 carbon atoms.
8. The method of claim 1 , wherein in i) R1 is
9. The method of claim 1 , wherein in i), R 3 is C 1-2 alkyl.
10. The method of claim 1 , wherein in ii) R3 is (CO)alkyl-COOH, said alkyl is optionally substituted with C6-16 aryl or C3-7 cycloalkyl.
11. The method of claim 9 , wherein said alkyl portion of said (CO)alkyl-COOH is comprising 2 to 4 carbon atoms.
12. The method of claim 1 , wherein in ii) R3 is
13. The method of claim 1 , wherein one of X 2 or X 3 is halogen and the remaining of said X 1 , X 2 , X 3 or X 4 are H; and
R 3 is C 1-2 alkyl , R 1 is
14. The method of claim 1 , wherein one of X 2 or X 3 is halogen and the remaining of said X 1 , X 2 , X 3 or X 4 are H; ii) R 3 is
and R 1 is H.
15. The method of claim 13 , wherein said halogen is Cl.
16. The method of claim 14 , wherein said halogen is Cl.
17. The method of claim 1 , wherein said compound is selected from:
18. A method for antagonizing the 5-oxo-ETE receptors in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of Formula II
wherein
X1, X2, X3 and X4 are independently selected from the group consisting of H, halogen, alkyl group, aralkyl group and OR5 wherein R5 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) R1 is (CO)alkyl-COOH, said alkyl is straight or branched and optionally substituted with C3-7 cycloalkyl;
R2 is alkyl, said alkyl is straight or branched and optionally substituted with OH, SH, COOR6, NR6R7, a C6-16 aryl, a C6-16 heterocycle, a C3-7 cycloalkyl, or a heterocyclic ring, wherein R6 and R7 are a C6-16 aryl, C6-16 heterocycle, C3-7 cycloalkyl, a heterocyclic ring or a hydrophobic group;
R3 is alkyl;
or ii)
R1 is H
R2 is alkyl, said alkyl is straight or branched and optionally substituted with OH, SH, COOR6, NR6R7, C6-16 aryl, C6-16 heterocycle, C3-7 cycloalkyl, or a heterocyclic ring, wherein R6 and R7are a C6-16 aryl, C6-16 heterocycle, C3-7 cycloalkyl, or a heterocyclic
R3 is (CO)alkyl-COOH, said alkyl is straight or branched and optionally substituted with C3-7 cycloalkyl;
or a pharmaceutically acceptable salt thereof.