Hydrogen bond forming fluoro ketolides for treating diseases
View Patent ↗The invention described herein pertains to a novel macrolide antibacterial agent of formula (I): A-L-Q, as defined herein, and pharmaceutically acceptable salts, solvates, and hydrates thereof. Inter alia, the new macrolide antibacterial agent is active against a number of bacterial species, including resistant species.
1. A compound of formula I,
A-L-Q (I)
or a pharmaceutically acceptable salt thereof, wherein:
A indazolyl, or benzimidazolinyl, each of which is optionally substituted;
L is X a —Y b —Z c ;
a, b and c are each independently 0 or 1, provided at least one of a, b and c is 1;
X is CH 2 R a R b , O, S or NR c ;
Y is an optionally substituted triazolyl;
Z is (CH 2 ) m ; where m is 1, 2, 3 or 4; and each of said CH 2 groups is independently optionally substituted with one or two methyl groups or replaced with O, S or NR d ; and
R a , R b , R c and R d are each independently H or CH 3 ;
Q is
in which L is bonded to the 11-N of Q;
R 2 is H or F;
R 5 is an aminosaccharide residue; and
R 6 is H or (1-6C)alkyl.
2. The compound or salt of claim 1 wherein R 2 is F.
3. The compound or salt of claim 1 wherein R 5 is an optionally substituted desosaminyl.
4. The compound or salt of claim 1 wherein R 6 is methyl.
5. A compound of the formula
A-L-Q
or a salt thereof, wherein
A is 3-indolyl
L is X a —Y b —Z c ;
a, b and c are each independently 0 or 1, provided at least one of a, b and c is 1;
X is CH 2 R a R b , O, S or NR c ;
Y is an optionally substituted triazolyl;
Z is (CH 2 ) m ; where m is 1, 2, 3 or 4; and each of said CH 2 groups is independently optionally substituted with one or two methyl groups or replaced with O, S or NR d ; and
R a , R b , R c and R d are each independently H or CH 3 ;
Q is
where L is bonded to the 11-N of Q;
R 2 is H or F;
R 5 is an aminosaccharide residue; and
R 6 is H or (1-6C)alkyl.
6. The compound or salt of claim 1 wherein Z is —(CH 2 ) 4 —, —(CH 2 ) 3 —O—, —(CH 2 ) 3 —NH—, —(CH 2 ) 3 —, —(CH 2 ) 2 —O—, —(CH 2 ) 2 —NH—, or —(CH 2 ) 2 —.
7. A pharmaceutical composition comprising the compound or salt of claim 1 and further comprising at least one pharmaceutically acceptable carrier or excipient.
8. A method of treatment of a bacterial infection, a protozoal infection, or a disorder related to a bacterial infection or protozoal infection comprising the step of administering to a subject in need thereof a therapeutically effective amount of the compound or salt of claim 1 .
9. A compound of the formula
A-X—Y—Z-Q
or a salt thereof, wherein
A-X—Y is selected from the group consisting of
Z is (CH 2 ) m ; where m is 1, 2, 3 or 4; and each of said CH 2 groups is independently optionally substituted with one or two methyl groups or replaced with O, S or NR d ; and R d is independently H or CH 3 ;
Q is
where A-X—Y—Z is bonded to the 11-N of Q;
R 2 is H or F;
R 5 is an aminosaccharide residue; and
R 6 is H or (1-6C)alkyl.
10. The compound of claim 9 of the formula
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 9 of the formula
12. The compound of claim 9 of the formula
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 9 of the formula
14. The compound or salt of claim 1 wherein R 5 is desosaminyl.
15. The compound or salt of claim 1 wherein Z is (CH 2 ) 4 , (CH 2 ) 3 —O, (CH 2 ) 3 —NH, (CH 2 ) 3 , —(CH 2 ) 2 —O, or (CH 2 ) 2 —NH.
16. The compound or salt of claim 5 wherein R 2 is F.
17. The compound or salt of claim 5 wherein R 5 is an optionally substituted desosaminyl.
18. The compound or salt of claim 5 wherein R 5 is desosaminyl.
19. The compound or salt of claim 5 wherein R 6 is methyl.
20. The compound or salt of claim 5 wherein Z is (CH 2 ) 4 , (CH 2 ) 3 —O, (CH 2 ) 3 —NH, (CH 2 ) 3 , (CH 2 ) 2 —O, (CH 2 ) 2 —NH, or (CH 2 ) 2 .
21. The compound or salt of claim 5 wherein Z is (CH 2 ) 4 .
22. A pharmaceutical composition comprising the compound or salt of claim 5 and further comprising at least one pharmaceutically acceptable carrier or excipient.
23. A method of treatment of a bacterial infection, a protozoal infection, or a disorder related to a bacterial infection or protozoal infection comprising the step of administering to a subject in need thereof a therapeutically effective amount of the compound or salt of claim 5 .
24. The compound or salt of claim 9 wherein R 2 is F.
25. The compound or salt of claim 9 wherein R 5 is an optionally substituted desosaminyl.
26. The compound or salt of claim 9 wherein R 5 is desosaminyl.
27. The compound or salt of claim 9 wherein R 6 is methyl.
28. The compound or salt of claim 9 wherein Z is (CH 2 ) 4 , (CH 2 ) 3 —O, (CH 2 ) 3 —NH, (CH 2 ) 3 , (CH 2 ) 2 —O, (CH 2 ) 2 —NH, or (CH 2 ) 2 .
29. The compound or salt of claim 9 wherein Z is (CH 2 ) 4 .
30. A pharmaceutical composition comprising the compound or salt of claim 5 and further comprising at least one pharmaceutically acceptable carrier or excipient.
31. A method of treatment of a bacterial infection, a protozoal infection, or a disorder related to a bacterial infection or protozoal infection comprising the step of administering to a subject in need thereof a therapeutically effective amount of the compound or salt of claim 9 .