Quinoline compounds and their uses
View Patent ↗The present invention provides quinoline compounds that inhibit the IgE receptor signaling cascade that leads to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and 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 structural formula (I):
and a salt, hydrate, solvate or N-oxide thereof, wherein:
R 1 is an alkyl group optionally substituted with one or more of the same or different R l0 groups;
R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are each, independently of one another, seleted from the group consisting of a hydrogen atom, —OR d , —SR d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR c -aryl, —NR c -heteroaryl, halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , (C1-C6) alkyl optionally substituted with one or more of the same or different R 10 groups, (C5-C10) aryl optionally substituted with one or more of the same or different R 10 groups, phenyl optionally substituted with one or more of the same or different R 10 groups, and 5-10 membered heteroaryl optionally substituted with one or more of the same or different R 10 groups;
R 9 is selected from the group consisting of (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , (C1-C6) alkyl optionally substituted with one or more of the same or different R 10 groups, (C5-C10) aryl optionally substituted with one or more of the same or different R 10 groups, phenyl optionally substituted with one or more of the same or different R 10 groups;
R 10 is selected from the group consisting of R a , R b , R a substituted with one or more of the same or different R a or R b , —OR a substituted with one or more of the same or different R a or R b , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b ,—S—(CH 2 ) m —R b , and-O—(CHR a ) m —R b ;
each R a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl;
each R b is a suitable group independently selected from the group consisting of —OR d , (C1-C3) haloalkyloxy, halogen, and —CF 3 ,
each R c is independently a protecting group, R a or R a optionally substituted with one or more of the same or different R a or suitable R b groups;
each R d is independently a protecting group, R a or R a optionally substituted with one or more of the same or different R a or suitable R b groups;
each m is independently an integer from 1 to 3;
A is NH or CO; and
B is CO, NH or O, provided that one of A or B is C(O).
2. A compound according to structural formula (I):
and a salt, hydrat; solvate or N-oxide thereof, wherein:
R 1 is an alkyl group optionally substituted with one or more of the same or different R 10 groups;
R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are each, independently of one another, selected from the group consisting of hydrogen, —OR d , —SR d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR c -aryl, —NR-heteroaryl, halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , (C1-C6) alkyl optionally substituted with one or more of the same or different R 10 groups, (C5-C10) aryl optionally substituted with one or more of the same or different R 10 groups, phenyl optionally substituted with one or more of the same or different R 10 groups, and 5-10 membered heteroaryl optionally substituted with one or more of the same or different R 10 groups;
R 9 is selected from the group consisting of (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , (C1-C6) alkyl optionally substituted with one or more of the same or different R 10 groups, and phenyl optionally substituted with one or more of the same or different R 10 groups;
R 10 is selected from the group consisting of R a , R b , R a substituted with one or more of the same or different R a or R b , —OR a substituted with one or more of the same or different R a or R b , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , —S—(CH 2 ) m —R b , and-O—(CHR a ) m —R b ;
each R a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, and benzyl;
each R b is a suitable group independently selected from the group consisting of —OR d , (C1-C3) haloalkyloxy, halogen, and —CF 3 ,
each R c is independently a protecting group, R a or R a optionally substituted with one or more of the same or different R a or suitable R b groups;
each R d is independently a protecting group, R a or R a optionally substituted with one or more of the same or different R a or suitable R b groups;
each m is independently an integer from 1 to 3;
A is NH or CO; and
B is CO, NH or O, provided that one of A or B is CO.
3. The compound of claim 1 or claim 2 in which R 1 is a methyl group.
4. The compound of claim 1 in which R 1 is a methyl group and R 9 is a substituted or unsubstituted phenyl group.
5. The compound of claim 1 or claim 2 in which R 1 is a methyl group and R 9 is a substituted phenyl group.
6. The compound of claim 5 in which the substituted phenyl group is selected from the group consisting of 2-chlorophenyl and 2-chloro-6-fluorophenyl.
7. The compound of claim 1 or claim 2 in which R 2 is selected from the group consisting of hydrogen, phenyl, methyl, —CO 2 Et, —CF 3 , Cl, —NHCH 3 ,
8. The compound of claim 1 or claim 2 in which R 6 is selected from the group consisting of hydrogen, F, —OCF 3 , and Br.
9. The compound of claim 1 or claim 2 in which R 7 is selected from the group consisting of hydrogen, Cl and —CF 3 .
10. The compound of claim 1 or claim 2 in which R 1 is a methyl group; R 9 is a substituted or unsubstituted phenyl group; R 2 is selected from the group consisting of hydrogen, phenyl, methyl, —CO 2 Et, —CF 3 , Cl, —NHCH 3 ,
R 6 is selected from the group consisting of hydrogen, F, —OCF 3 , and Br; and R 7 is selected from the group consisting of hydrogen, Cl and —CF 3 .
11. A compound according to structural formula (I):
and a salt, hydrate, solvate or N-oxide thereof, in which A, B, R 1 , R 2 , R 3 , R 5 . R 6 , R 7 , R 8 and R 9 are selected from the group of substituent combinations delineated below:
No.
A
B
R 1
R 2
R 3
R 5
R 6
R 7
R 8
R 9
1
CO
NH
Me
Ph
H
H
H
H
H
Me
3
NH
CO
Me
Me
H
H
H
H
H
Ph
5
O
CO
Me
H
H
H
H
H
H
Ph
7
O
CO
Me
H
H
H
H
Cl
H
Ph
9
O
CO
Me
Me
H
H
H
H
H
Ph
13
O
CO
Me
H
H
H
H
Cf 3
H
Ph
15
O
CO
Me
H
H
H
H
H
CF 3
Ph
17
O
CO
Me
H
COOEt
H
H
CF 3
H
Ph
19
O
CO
Me
COOEt
H
H
H
H
H
Ph
21
O
CO
Me
Me
H
H
F
H
H
Me
23
O
CO
Me
Me
H
H
F
H
H
25
O
CO
Me
Me
H
H
F
H
H
27
O
CO
Me
CF 3
H
H
OCF 3
H
H
Ph
29
O
CO
Me
CF 3
H
H
OCF 3
H
H
Me
31
O
CO
Me
CF 3
H
H
OCF 3
H
H
33
O
CO
Me
CF 3
H
H
OCF 3
H
H
35
NH
CO
Me
H
H
H
H
CF 3
H
Ph
37
NH
CO
Me
H
H
H
H
CF 3
H
Me
39
NH
CO
Me
H
H
H
H
CF 3
H
41
NH
CO
Me
H
H
H
H
CF 3
H
43
CO
NH
Me
Cl
H
H
Br
H
H
Ph
45
CO
NH
Me
Cl
H
H
Br
H
H
Me
47
CO
NH
Me
Me
H
H
F
H
H
Ph
49
CO
NH
Me
Me
H
H
F
H
H
Me
51
O
CO
Me
H
H
H
OCF 3
H
H
Ph
53
O
CO
Me
H
H
H
OCF 3
H
H
57
O
CO
Me
H
H
H
OCF 3
H
H
61
CO
NH
Me
Ph
H
H
H
H
H
Ph
63
CO
NH
Me
H
H
H
H
H
H
Ph
65
CO
NH
Me
H
H
Br
H
H
Ph
67
CO
NH
Me
—NHCH 3
H
H
Br
H
H
Ph
69
CO
NH
Me
H
H
Br
H
H
Ph
71
CO
NH
Me
H
H
Br
H
H
Ph; and
73
CO
NH
Me
H
H
Br
H
H
Ph.
12. The compound of claim 1 or claim 2 which inhibits mast cell or basophil cell degranulation with an IC 50 of about 20 μM or less as measured in an in vitro assay.
13. A pharmaceutical composition comprising a quinoline compound and a pharmaceutically acceptable excipient, carrier or diluent, said quinoline compound being a compound according to structural formula (I):
and a salt, hydrate, solvate or N-oxide thereof, wherein:
R 1 is an alkyl group optionally substituted with one or more of the same or different R 10 groups;
R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are each, independently of one another, selected from the group consisting of a hydrogen atom, —OR d , —SR d , (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR c -aryl, —NR c -heteroaryl, halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , (C1-C6) alkyl optionally substituted with one or more of the same or different R 10 groups, (C5-C10) aryl optionally substituted with one or more of the same or different R 10 groups, phenyl optionally substituted with one or more of the same or different R 10 groups, (and 5-10 membered heteroaryl optionally substituted with one or more of the same or different R 10 groups;
R 9 is selected from the group consisting of (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , (C1-C6) alkyl optionally substituted with one or more of the same or different R 10 groups, (C5-C10) aryl optionally substituted with one or more of the same or different R 10 groups, phenyl optionally substituted with one or more of the same or different R 10 groups;
R 10 is selected from the group consisting of R a , R b , R a substituted with one or more of the same or different R a or R b , —OR a substituted with one or more of the same or different R a or R b , —(CH 2 ) m —R b , —(CHR a ) m —R b , —O—(CH 2 ) m —R b , —S—(CH 2 ) m —R b , and —O—(CHR a ) m —R b ;
each R a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, and benzyl;
each R b is a suitable group independently selected from the group consisting of —OR d , (C1-C3) haloalkyloxy, halogen, and —CF 3 ,
each R c is independently a protecting group, R a or R a optionally substituted with one or more of the same or different R a or suitable R b groups;
each R d is independently a protecting group, R a or R a optionally substituted with one or more of the same or different R a or suitable R b groups;
each m is independently an integer from 1 to 3;
A is O, NH or CO; and
B is CO, NH or O, provided that one of A or B is CO.
14. The composition of claim 13 in which the quinoline compound is in the form of a pharmaceutically acceptable salt.
15. The composition of claim 14 in which the salt is a hydrochloride salt, a hydrogen sulfate salt, a sulfate salt or a phosphate salt.
16. The composition of claim 13 in which R 1 of the quinoline compound is methyl.
17. The composition of claim 16 in which R 9 of the quinoline compound is a substituted or unsubstituted phenyl.
18. The composition of claim 16 in which R 9 of the quinoline compound is a substituted phenyl.
19. The composition of claim 18 in which the substituted phenyl is 2-chlorophenyl or 2-chloro-6-fluorophenyl.
20. The composition of claim 13 in which R 2 is selected from the group consisting of hydrogen, phenyl, methyl, —CO 2 Et, —CF 3 , Cl, —NHCH 3 ,
21. The composition of claim 13 in which R 6 of the quinoline compound is selected from the group consisting of hydrogen, F, —OCF 3 and Br.
22. The composition of claim 13 in which R 7 of the quinoline compound is selected from the group consisting of hydrogen, Cl and —CF 3 .
23. The composition of claim 13 in which, in the quinoline compound,
R 1 is methyl;
R 9 is a substituted or unsubstituted phenyl group;
R 2 is selected from the group consisting of hydrogen, phenyl, methyl, —CO 2 Et, —CF 3 , Cl, —NHCH 3 ,
R 6 is selected from the group consisting of hydrogen, F, —OCF 3 and Br; and
R 7 is selected from the group consisting of hydrogen, Cl and —CF 3 .