2-substituted quinoline compounds and their uses
View Patent ↗The present disclosure provides 2-substituted-quinoline compounds that inhibit the IgE receptor signaling cascade that leads to the release of chemical mediators, prodrugs of the compounds, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and/or prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE receptor signaling cascade.
1. A compound according to any one of structural formulae (I)-(IV):
and salts and N-oxides thereof, wherein:
R 4 is selected from hydrogen, (C1-C6) alkyl, and —C(O)NR b R b ;
R 6 is selected from hydrogen and halo;
R 8 is selected from hydrogen and halo;
R 9 is selected from hydrogen, halo, cyano, —C(O)OR b , and —C(O)NR b R b ;
R 10 is selected from hydrogen, (C1-C6) alkyl, branched (C1-C6) alkyl, phenyl, para-(C1-C6)alkoxyphenyl, para-methoxyphenyl, 5-membered heteroaryl, and thienyl; and
each R b is, independently of the others, selected from hydrogen and (C1-C6) alkyl,
wherein alkyl refers to a saturated or unsaturated branched, straight chain or cyclic monovalent radical that is derived by the removal of one hydrogen atom from a single carbon of a parent alkane, alkene, or alkyne;
with the proviso that at least one of R 4 , R 6 and R 8 is other than hydrogen.
2. The compound of claim 1 in which each R b is, independently of the others, selected from hydrogen and methyl.
3. The compound of claim 1 in which R 4 is hydrogen, one of R 6 or R 8 is chloro and the other one of R 6 or R 8 is hydrogen.
4. The compound of claim 1 in which R 4 is methyl or —C(O)NHMe and R 6 R 8 are each hydrogen.
5. The compound of claim 1 in which R 9 is hydrogen and R 10 is other than hydrogen.
6. The compound of claim 5 in which R 10 is selected from phenyl, para-methoxyphenyl and thien-2-yl.
7. The compound of claim 1 in which R 10 is hydrogen and R 9 is other than hydrogen.
8. The compound of claim 7 in which R 9 is selected from —C(O)NH 2 and —C(O)OR b , where R b is (C1-C4) alkyl.
9. The compound of claim 1 in which R 9 and R 10 are each other than hydrogen.
10. The compound of claim 1 in which R 9 is bromo and R 10 is phenyl.
11. The compound of claim 1 in which R 9 and R 10 are each hydrogen.
12. The compound of claim 1 in which R 4 , R 6 , R 8 , R 9 and R 10 are selected from any combination of substituents delineated in TABLE 1.
13. The compound of claim 1 that is selected from any compound delineated in TABLE 1, or a salt, or N-oxide thereof.
14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent and/or excipient.
15. The composition of claim 14 in which the compound is in the form of a pharmaceutically acceptable salt.
16. A method of inhibiting degranulation of a mast or basophil cell, comprising contacting the mast or basophil cell with an amount of a compound according to claim 1 effective to inhibit degranulation.
17. The method of claim 16 in which the mast or basophil cell is a human mast or basophil cell.
18. A method of inhibiting degranulation of a mast or basophil cell, comprising contacting the mast or basophil cell with an amount of a composition according to claim 14 effective to inhibit degranulation.
19. The method of claim 18 in which the mast or basophil cell is a human mast or basophil cell.