Fluorinated derivates of 3-hydroxypyridin-4-ones
Provided are compounds of Formula I which are derivatives of 3-Hydroxypyridin-4-ones. The compounds may be used in treatment of a medical condition related to a toxic concentration of iron. The compounds may be used for preparation of a medicament for treatment of a medical condition related to a toxic concentration of iron. The medical condition related to a toxic concentration of iron may be selected from the group consisting of: cancer, pulmonary disease, progressive kidney disease and Frederich's Ataxia.
1. An amine-containing fluorinated 3-hydroxypyridin-4-(1H)-one compound of Formula I:
or a salt thereof,
wherein:
G 1 is the amine-containing substituent —CH 2 NR 1 R 2 ;
G 2 is CH 2 CF 2 R 3 ;
G 3 is H or C 1 -C 1 alkyl;
G 4 is H or C 1 -C 4 alkyl,
R 1 and R 2 are either (a) two independent groups or (b) together form a single ring group including the N to which they are bonded, where
R 1 and R 2 , when independent groups, are independently selected from the group consisting of: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, allyl, and propargyl; or
R 1 and R 2 , when together form a single ring group including the N to which they are bonded, are selected from the group consisting of: piperazinyl, N—(C 1 -C 4 alkyl)-substituted piperazinyl, and piperidinyl;
R 3 is H, or F.
2. The compound according to of claim 1 , wherein G 4 is H.
3. The compound according to of claim 2 ,
wherein R 3 is H.
4. The compound according to claim 3 , wherein R 3 is F.
5. The compound according to of claim 4 , wherein G 1 is —CH 2 (CH 3 ) 2 and G 3 is methyl.
6. The compound according to claim 4 , wherein is —CH 2 N(CH 3 ) 2 and G 3 is H.
7. The compound according to of claim 4 , wherein G 1 is
and G 3 is methyl.
8. The compound according to of claim 3 , wherein G 1 is —CH 2 N(CH 3 ) 2 and G 3 is methyl.
9. An amine-containing fluorinated 3-hydroxypyridin-4-(1H)-one compound of Formula I:
or a salt thereof,
wherein:
G 1 is the amine-containing substituent CH(R 4 )CF 3 wherein R 4 is NR 1 R 2 or A—NH—R 10 ;
G 2 is H, C 1 -C 4 alkyl or cyclopropyl;
G 3 is H or C 1 -C 4 alkyl;
G 4 is H or C 1 -C 4 alkyl;
R 1 and R 2 are either (a) two independent groups or (b) together form a single ring group including the N to which they are bonded, where
R 1 and R 2 , when independent groups, are independently selected from the group consisting of: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, allyl, and propargyl; or
R 1 and R 2 , when together form a single ring group including the N to which they are bonded, are selected from the group consisting of: piperazinyl, N—(C 1 -C 4 alkyl)-substituted piperazinyl, and piperidinyl;
R 10 is H or C 1 -C 4 alkyl;
A is —NH—(CH 2 ) m —CO— or an alpha amino acid residue; and
m is 1, 2 or 3.
10. The compound according to claim 9 , wherein G 2 is methyl.
11. The compound according to claim 10 , wherein G 3 is and G 4 is H.
12. The compound according to claim 11 , wherein R 4 is NR 1 R 2 .
13. The compound according to claim 11 , wherein R 4 is A-NHR 10 ; A is D-alanyl; and R 10 is methyl.
14. The compound according, to claim 12 , wherein R 1 is methyl and R 2 is methyl.
15. The compound according to claim 12 , wherein R 1 is methyl and R 2 is propargyl.
16. The compound according to claim 12 , wherein R 1 is H and R 2 is cyclopropyl.
17. The compound according to claim 12 , wherein R 1 is H and R 2 is allyl.
18. The compound according to claim 12 , wherein R 4 is piperidinyl.
19. The compound according to claim 12 , wherein R 4 is N-methylpiperazinyl.
20. An amine-containing fluorinated 3-hydroxypyridin-4-(1H)-one compound of Formula I:
or a salt thereof,
wherein:
G 1 is —CH (R 4 )CF 3 wherein R 4 is H or OH;
G 2 is H, C 1 -C 4 alkyl or cyclopropyl;
G 3 is the amine-containing substituent CH 2 -A-OH, CH 2 -A-NHR 9 , or CH 2 NR 1 R 2 ;
G 4 is H or C 1 -C 4 alkyl;
R 1 and R 2 are either (a) two independent groups or (b) together form a single ring group including the N to which they are bonded, where
R 1 and R 2 , when independent groups, are independently selected from the group consisting of: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, allyl, and propargyl; or
R 1 and R 2 , When together form a single ring group including the N to which they are bonded, are selected from the group consisting of: piperazinyl,
N—(C 1 -C 4 alkyl)-substituted piperazinyl, and piperidinyl;
R 9 is H or C 1 -C 4 alkyl;
A is —NH—(CH 2 ) m —CO— or an alpha amino acid residue; and
m is 1, 2 or 3.
21. The compound according to claim 20 , wherein G 2 is methyl.
22. The compound according to claim 21 , wherein G 4 is H.
23. The compound according to claim 22 , wherein G 3 is CH 2 NR 1 R 2 ; R 1 is methyl; R 2 is methyl; and R 4 is H.
24. The compound according to claim 22 , wherein G 3 is CH 2 NR 1 R 2 ; R 1 is methyl; R 2 is methyl; and R 4 is OH.
25. The compound according to claim 22 , wherein G 3 is CH 2 -A-OH; A is L-alanyl; and R 4 is OH.
26. The compound according to claim 22 , wherein G 3 is CH 2 -A-NHR 9 ; A is L-alanyl; R 9 is methyl; and R 4 is OH.
27. An amine-containing fluorinated 3-hydroxypyridin-4-(1H)-one compound of Formula I:
or a salt thereof,
wherein:
G 1 is the amine-containing substituent —CH(R 4 )CF 3 , wherein R 4 is NR 1 R 2 or A-NH—R 10 ;
G 2 is H, C 1 -C 4 alkyl or cyclopropyl;
G 3 is H or C 1 -C 4 alkyl;
G 4 is halo;
R 1 and R 2 are either (a) two independent groups or (h) together form a single ring group including the N to which they are bonded, where
R 1 and R 2 , when independent groups, are independently selected from the group consisting of: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, allyl, and propargyl; or
R 1 and R 2 , when together form a single ring group including the N to which they are bonded, are selected from the group consisting of: piperazinyl, N—(C 1 -C 4 alkyl)-substituted piperazinyl, and piperidinyl;
R 10 is H or C 1 -C 4 alkyl;
A is —NH—(CH 2 ) m —CO— or an alpha amino acid residue; and
m is 1, 2 or 3.
28. The compound according to claim 27 , wherein G 2 is methyl.
29. The compound according to claim 28 , wherein G 4 is allow.
30. The compound according to claim 29 , wherein G 3 is methyl; R 4 is NR 1 R 2 ; R 1 is methyl; and R 2 is methyl.
31. The compound according to claim 29 , wherein G 3 is H; R 4 is NR 1 R 2 ; R 1 is methyl; and R 2 is methyl.
32. The compound according to claim 29 , wherein G 3 is H; R 4 is NR 1 R 2 ; and NR 1 R 2 is piperidinyl.
33. An amine-containing fluorinated 3-hydroxypyridin-4-(1H)-one compound of Formula I:
or a salt thereof,
wherein:
G 1 is H, or C 1 -C 4 alkyl;
G 2 is C 1 -C 4 alkyl, or cyclopropyl;
G 3 is or C 1 -C 4 alkyl;
G 4 is the amine-containing substituent —CH(CF 3 )(R 8 );
R 8 is NR 1 R 2 , imidazolyl or -A-NH—R 10 ;
R 1 and R 2 are either (a) two independent groups or (b) together form a single ring group including the N to which they are bonded, where
R 1 and R 2 , when independent groups, are independently selected from the group consisting of: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, allyl, and propargyl; or
R 1 and R 2 , when together form a single ring group including the N to which they are bonded, are selected from the group consisting of piperazinyl, N—(C 1 -C 4 alkyl)-substituted piperazinyl, and piperidinyl;
R 10 is H or C 1 -C 4 alkyl;
A is —NH—(CH 2 ) m —CO— or an alpha amino acid residue; and
m is 1, 2 or 3.
34. The compound according to claim 33 , wherein G 3 is H.
35. The compound according to claim 34 , wherein G 1 is methyl.
36. The compound according to claim 35 , wherein G 2 is H; R 8 is -A-NH—R 10 ; A is L-alanyl; and R 10 is methyl.
37. The compound according to claim 35 , wherein G 2 is methyl; R 8 is NR 1 R 2 ; R 1 is methyl and R 2 is methyl.
38. The compound according to claim 35 , wherein G 2 is methyl; R 8 is NR 1 R 2 ; R 1 is H and R 2 is methyl.
39. The compound according to claim 35 , wherein G 2 is methyl; R 8 is NR 1 R 2 ; and NR 1 R 2 is piperidinyl.
40. The compound according to claim 35 , wherein G 2 is methyl; R 8 is NR 1 R 2 ; and NR 1 R 2 is imidazolyl.
41. The compound according to claim 35 , wherein G 2 is methyl; R 8 is NR 1 R 2 ; and NR 1 R 2 is N-methylpiperazinyl.
42. An amine-containing fluorinated 3-hydroxypyridin-4-(1H)-one compound of Formula I:
or a salt thereof
wherein
G 1 is the amine-containing substituent CH 2 NR 1 R 2 or NR 1 R 2 ;
G 2 is C 1 -C 4 alkyl, or cyclopropyl;
G 3 is —CH(R 6 )(CF 3 );
G 4 is H, or C 1 -C 4 alkyl;
R 1 and R 2 are either (a) two independent groups or (b) together form a single ring group including the N to which they are bonded, where
R 1 and R 2 , when independent groups, are independently selected from the group consisting of: H, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and propargyl; or
R 1 and R 2 , when together form a single ring group including the N to which they are bonded, are selected from the group consisting of: piperazinyl, N—(C 1 -C 4 alkyl)-substituted piperazinyl, and piperidinyl; and
R 6 is H or OH.
43. The compound according to claim 42 , wherein G 4 is H.
44. The compound according to claim 43 , wherein G 2 is methyl.
45. The compound according to claim 44 , wherein G 1 is NR 1 R 2 ; R 1 is methyl; R 2 is methyl; and R 6 is H.
46. The compound according to claim 44 , wherein G 1 is CH 2 NR 1 R 2 ; R 1 is methyl; R 2 is methyl; and R 6 is OH.