Fluorinated derivatives of deferiprone
The present invention relates to novel derivatives of deferiprone. In particular, the present invention relates to fluorinated derivatives of deferiprone or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising same, processes for the manufacture thereof and their use in the treatment of neurodegenerative diseases caused by the presence of free iron or iron accumulation in neural tissues and in diseases wherein excess iron must be removed or redistributed.
1. A compound of formula (I)
or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
(a) a compound of formula (II):
(b) a compound of formula (III):
(c) a compound of formula (IIIC):
and
(d) a compound of formula (IV):
wherein in formula I:
Y is O or NR 1 ,
R 1 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, cyclopropylmethyl, allyl and cyclopropyl:
R 2 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, CHF 2 , CH 2 CF 3 , CF 3 CHOH and R 5 CHOH,
R 5 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl and trifluoromethyl;
R 3 is selected from the group consisting of: methyl, hydrogen, CF 3 CHOH, C 1 -C 6 alkyl, CH 2 CF 3 , and CH(OCH 3 )CF 3 ; and
R 4 is selected from the group consisting of: CHF 2 , methyl, hydrogen, C 1 -C 6 alkyl, CH 2 CF 3 , and CF 3 CHOH;
provided that
(a) when the compound of formula (I) is a compound of formula (II), then
Y is NR 1 , wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R 2 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and R 5 CHOH wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl and trifluoromethyl;
R 3 is selected from the group consisting of methyl, hydrogen and CF 3 CHOH; and
R 4 is CHF 2 ;
and
(b) when the compound of formula (I) is a compound of formula (III), then:
Y is NR 1 , wherein R 1 is defined as above;
R 2 is selected from the group consisting of CHF 2 , CH 2 CF 3 , and CF 3 CHOH; and
R 3 and R 4 are each selected from the group consisting of methyl and hydrogen;
and
(c) when the compound of formula (I) is a compound of formula (IIIC), then;
Y is NR 1 and R 1 is defined as above;
R 2 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, with the proviso that when R 4 is hydrogen, R 2 is not hydrogen;
R 3 is CF 3 CHOH; and
R 4 is selected from the group consisting of hydrogen and methyl;
and
(d) when the compound of formula (I) is a compound of formula (IV) then:
Y is O;
R 2 is CF 3 CHOH;
R 3 is selected from the group consisting of methyl and hydrogen; and
R 4 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
or
Y is O;
R 2 is hydrogen;
R 3 is hydrogen; and
R 4 is difluoromethyl;
or;
Y is NR 1 , wherein R is defined as above;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and R 5 CHOH, wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and trifluoromethyl;
R 3 is hydrogen, methyl, C 1 -C 6 alkyl; and
R 4 is CH 2 CF 3 , and CF 3 CHOH;
or
Y is NR 1 , wherein R 1 is defined as above;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and R 5 CHOH, wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and trifluoromethyl;
R 3 is CH 2 CF 3 , CH(OCH 3 )CF 3 ; and
R 4 is hydrogen, methyl, C 1 -C 6 alkyl.
2. A compound according to claim 1 wherein
Y is NR 1 , wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and R 5 CHOH wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and trifluoromethyl;
R 3 is selected from the group consisting of methyl, hydrogen and CF 3 CHOH;
R 4 is CHF 2 ; and wherein the compound of formula (I) is a compound of formula (II)
3. A compound according to claim 1 wherein
Y is NR 1 , wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 5 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R 2 is selected from the group consisting of CHF 2 , CH 2 CF 3 , and CF 3 CHOH;
R 3 and R 4 are each selected from the group consisting of methyl and hydrogen; and
wherein the compound of formula (I) is a compound of formula (III)
4. A compound according to claim 1 wherein
Y is NR 1 and R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R 2 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, with the proviso that when R 4 is hydrogen, R 2 is not hydrogen;
R 3 is CF 3 CHOH;
R 4 is selected from the group consisting of hydrogen and methyl; and
wherein the compound of formula (I) is a compound of formula (IIIC)
5. A compound according to claim 1 wherein
Y is O;
R 2 is CF 3 CHOH;
R 3 is selected from the group consisting of methyl and hydrogen;
R 4 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; and
wherein the compound of formula (I) is a compound of formula (IV)
6. A compound according to claim 1 wherein
Y is O;
R 2 is hydrogen;
R 3 is hydrogen;
R 4 is difluoromethyl; and
wherein the compound is 2-difluoromethyl-5-hydroxy-pyran-4-one having the following formula:
7. A compound according to claim 1 wherein
Y is NR 1 , wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and R 5 CHOH, wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and trifluoromethyl; and
R 3 is selected from the group consisting of CH 2 CF 3 , and CH(OCH 3 )CF 3 and
R 4 is selected from the group consisting of methyl, hydrogen and C 1 -C 6 alkyl.
8. A compound according to claim 2 wherein R 1 is methyl, R 2 is hydrogen, R 3 is hydrogen, and the compound is 2-difluoromethyl-5-hydroxy-1-methyl-1H-pyridin-4-one, having the following formula:
9. A compound according to claim 2 wherein R 1 is cyclopropyl, R 2 is hydrogen, R 3 is hydrogen, and the compound is 1-cyclopropyl-2-difluoromethyl-5-hydroxy-1H-pyridin-4-one, having the following formula:
10. A compound according to claim 2 wherein R 1 is cyclopropylmethyl, R 2 is hydrogen, R 3 is hydrogen, and the compound is 1-cyclopropylmethyl-2-difluoromethyl-5-hydroxy-1H-pyridin-4-one, having the following formula:
11. A compound according to claim 2 wherein R 1 is allyl, R 2 is hydrogen, R 3 is hydrogen, and the compound is 1-allyl-2-difluoromethyl-5-hydroxy-1H-pyridin-4-one, having the following formula:
12. A compound according to claim 2 wherein R 1 is ethyl, R 2 is hydrogen, R 3 is hydrogen, and the compound is 2-difluoromethyl-1-ethyl-5-hydroxy-1H-pyridin-4-one, having the following formula:
13. A compound according to claim 2 wherein R 1 is methyl, R 2 is ethyl, R 3 is hydrogen, and the compound is 6-difluoromethyl-2-ethyl-3-hydroxy-1-methyl-1H-pyridin-4-one, having the following formula:
14. A compound according to claim 2 wherein R 1 is methyl, R 2 is 1-hydroxyethyl, R 3 is hydrogen, and the compound is 6-difluoromethyl-3-hydroxy-2-(1-hydroxy-ethyl)-1-methyl-1H-pyridin-4-one, having the following formula:
15. A compound according to claim 2 wherein R 1 is methyl, R 2 is 1-hydroxymethyl, R 3 is hydrogen, and the compound is 6-difluoromethyl-3-hydroxy-2-hydroxymethyl-1-methyl-1H-pyridin-4-one, having the following formula:
16. A compound according to claim 2 wherein R 1 is methyl, R 2 is methyl, R 3 is hydrogen, and the compound is 6-difluoromethyl-3-hydroxy-1,2-dimethyl-1H-pyridin-4-one, having the following formula:
17. A compound according to claim 2 wherein R 1 is methyl, R 2 is R 5 CHOH wherein is R 5 is trifluoromethyl, R 3 is hydrogen, and the compound is 6-difluoromethyl-3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one, having the following formula:
18. A compound according to claim 3 wherein R 1 is methyl, R 4 is methyl, R 3 is hydrogen, R 2 is 1-hydroxy-trifluoroethyl, and the compound is 3-hydroxy-1,6-dimethyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one, having the following formula:
19. A compound according to claim 3 wherein R 1 is methyl, R 4 is methyl, R 3 is hydrogen, R 2 is trifluoroethyl, and the compound is 3-hydroxy-1,6-dimethyl-2-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one, having the following formula:
20. A compound according to claim 3 wherein R 1 is methyl, R 4 is hydrogen, R 3 is hydrogen, R 2 is trifluoroethyl, and the compound is 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one, having the following formula:
21. A compound according to claim 3 wherein R 1 is methyl, R 4 is methyl, R 3 is hydrogen, R 2 is difluoromethyl, and the compound is 2-difluoromethyl-3-hydroxy-1,6-dimethyl-1H-pyridin-4-one, having the following formula:
22. A compound according to claim 3 wherein R 1 is hydrogen, R 4 is methyl, R 3 is hydrogen, R 2 is CF 3 CHOH, and the compound is 3-hydroxy-6-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one, having the following formula:
23. A compound according to claim 4 wherein R 1 is hydrogen, R 4 is hydrogen, R 2 is methyl, and the compound of formula (III) is 3-hydroxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one, having the following formula:
24. A compound according to claim 5 wherein R 3 is hydrogen and R 4 is methyl, and the compound of formula (IV) is 3-hydroxy-6-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyran-4-one, having the following formula:
25. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier.
26. The compound of claim 4 wherein Y is NR 1 , R 1 is methyl, R 2 is methyl, R 3 is CF 3 CHOH and R 4 is H, and the compound is 3-hydroxy-1,2-dimethyl-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one having the following formula:
27. The compound of claim 7 wherein Y is NR 1 , R 1 is methyl, R 2 is methyl, R 3 is CH 2 CF 3 and R 4 is H, and the compound is 3-hydroxy-1,2-dimethyl-5-(2,2,2-trifluoroethyl)pyridin-4(1H)-one having the following formula:
28. The compound of claim 7 wherein Y is NR 1 , R 1 is H, R 2 is methyl, R 3 is CH 2 CF 3 and R 4 is H, and the compound is 3-hydroxy-2-methyl-5-(2,2,2-trifluoroethyl)pyridin-4(1H)-one having the following formula:
29. The compound of claim 7 wherein Y is NR 1 , R 1 is H, R 2 is methyl, R 3 is CH(OCH 3 )CF 3 and R 4 is H, and the compound is 3-hydroxy-2-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)pyridin-4(1H)-one having the following formula:
30. The compound of claim 1 wherein Y=NR 1 , R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cyclopropylmethyl, allyl and cyclopropyl:
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and R 5 CHOH, wherein R 5 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and trifluoromethyl;
R 3 is hydrogen, methyl;
R 4 is CH 2 CF 3 and CF 3 CHOH.
31. The compound of claim 30 wherein Y is NR 1 , R 1 is methyl, R 2 is H, R 3 is H and R 4 is CH 2 CF 3 , and the compound is 5-hydroxy-1-methyl-2-(2,2,2-trifluoroethyl)pyridin-4(1H)-one having the following formula:
32. The compound of claim 30 wherein Y is NR 1 , R 1 is methyl, R 2 is H, R 3 , is H and R 4 is CH(OH)CF 3 , and the compound is 5-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one having the following formula:
33. The compound of claim 30 wherein Y is NR 1 , R 1 is methyl, R 2 is methyl, R 3 is H and R 4 is CH 2 CF 3 , and the compound is 3-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoroethyl)pyridin-4(1H)-one having the following formula:
34. The compound of claim 30 wherein Y is NR 1 , R 1 is methyl, R 2 is methyl, R 3 is H and R 4 is CH(OH)CF 3 , and the compound is 3-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one having the following formula:
35. The compound of claim 30 wherein Y is NR 1 , R 1 is methyl, R 2 is CH 2 OH, R 3 is H and R 4 is CH 2 CF 3 , and the compound is 3-hydroxy-2-(hydroxymethyl)-1-methyl-6-(2,2,2-trifluoroethyppyridin-4(1H)-one having the following formula:
36. The compound of claim 30 wherein Y is NR 1 , R 1 is methyl, R 2 is CH 2 OH, R 3 is H and R 4 is CH(OH)CF 3 and the compound is 3-hydroxy-2-(hydroxymethyl)-1-methyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one having the following formula:
37. A method for the preparation of a compound of formula (II)
wherein:
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cyclopropylmethyl, allyl and cyclopropyl;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, R 5 CHOH wherein R 5 is hydrogen, C 1 -C 6 alkyl and trifluoromethyl;
R 3 is hydrogen; and
wherein the method comprises the following processes:
Process (A) which comprises the following steps:
(a) oxidation of a compound (1) with an oxidating agent selected from the group consisting of 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO), potassium bromate, sodium hypochlorite and sulfur trioxide pyridine complex to give compound (2);
(b) reacting compound (2) from step (a) with diethylaminosulfur trifluoride (DAST) to give compound (3);
(c) reacting compound (3) with an amine of the formula R 1 NH 2 wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, allyl, cyclopropyl and cyclopropylmethyl to give compound (4) wherein R 1 is defined as in R 1 NH 2 ; and
(d) hydrogenation of compound (4) with palladium on charcoal to give compound of formula (IIA) wherein the compound of formula (IIA) is a compound of formula (II) when R 2 and R 3 are each hydrogen, with the proviso that when R 1 in compound (4) is allyl, boron tribromide is used instead of catalytic hydrogenation, or
Process (B) which comprises the following steps:
(e) debenzylation of compound (3) from Process (A), step (b), with BBr 2 to give compound (5);
(f) reacting compound (5) with an aliphatic aldehyde R 5 CHO wherein R 5 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl to give compound (6) wherein R 5 is as defined above;
(g) reacting compound (6) with benzyl bromide and sodium hydroxide to give compound (7) wherein R 5 is as defined above;
(h) reacting compound (7) with an amine of the formula R 1 NH 2 , wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, allyl, cyclopropyl and cyclopropylmethyl to give compound (8) wherein R 1 is as defined in R 1 NH 2 ; and
(i) hydrogenation of compound (8) with palladium on charcoal to give a compound of formula (IIB) with the proviso that R 1 is not allyl; a compound of formula (IIB) is a compound of formula (II) when R 2 is R 5 CHOH, or
Process (C) which comprises the following steps:
(j) reacting compound (7) from Process (B), step (g), with thionyl chloride to give the chloride (9) wherein R 5 is defined as above;
(k) reduction of compound (9), prepared from step i) in situ, without isolation, with zinc in hydrochloric acid to give compound (10);
(l) reacting compound (10) from step (k) with an amine of the formula R 1 NH 2 wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, allyl, cyclopropyl and cyclopropylmethyl to give compound (11) wherein R 1 is as defined in R 1 NH 2 ; and
(m) hydrogenation of compound (11) from step (l) with palladium on charcoal to give a compound of formula (IIC) with the proviso that R 1 is not allyl; a compound of formula (IIC) is the same as a compound of formula (II) when R 2 is CH 2 R 5 , or
Process (D) which comprises the following steps:
(n) reacting a compound (8) from Process (B) wherein R 5 is hydrogen with triethylamine and methanesulfonyl chloride to give compound (8A); and
(o) hydrogenation of compound (8A) with palladium on charcoal to give a compound of formula (IIC) wherein R 5 is hydrogen, with the proviso that R 1 is not allyl; a compound of formula (IIC) is the same as a compound of formula (II) when R 2 is CH 2 R 5 , or
Process (E) which comprises the following steps:
reacting a compound of formula (IIA) with CF 3 CH(O—C 1 -C 4 linear alkyl)OH in the presence of potassium carbonate at a temperature of about 100° C. to about 130° C. to give a compound of formula (IIB) wherein R 3 is hydrogen, and R 2 is R 5 CHOH wherein R 5 is trifluoromethyl.
38. A method for the preparation of a compound of formula (III)
wherein:
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, allyl, cyclopropyl and cyclopropylmethyl;
R 4 is selected from the group consisting of methyl and hydrogen;
R 3 is hydrogen;
R 2 is selected from the group consisting of CF 3 CHOH and CH 2 CF 3 ; and
wherein the method comprises the following steps;
(a) reaction of compound (12) with CF 3 CH(O—C 1 -C 4 linear alkyl)OH to give a compound of formula (IIIA); a compound of formula (IIIA) is a compound of formula (III) wherein R 2 is CF 3 CH(OH);
(b) reacting the product of formula (IIIA) from step (a) with benzyl bromide and sodium hydroxide to give compound (13) wherein R 3 , R 4 and R 1 are defined as above;
(c) converting compound (13) into the methanesulfonate (14) with methanesulfonyl chloride and triethylamine, wherein R 1 , R 3 and R 4 are as defined as above; and
(d) hydrogenation of compound (14) in the presence of palladium on charcoal to give a compound of formula (IIIB) wherein R 2 is CF 3 CH 2 with the proviso that R 1 is not allyl; a compound of formula (IIIB) is a compound of formula (III) wherein R 1 is selected from the group consisting of C 1 -C 4 alkyl, cyclopropyl and cyclopropylmethyl; R 4 is selected from the group consisting of methyl and hydrogen; R 3 is hydrogen; and R 2 is CF 3 CH 2 .
39. A process for the preparation of a compound of formula (IV) wherein
R 3 is selected from the group consisting of hydrogen and methyl;
R 4 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; and
R 2 is CF 3 CHOH,
wherein the process comprises reacting compound (18) wherein R 4 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; R 3 is selected from the group consisting of hydrogen and methyl, with CF 3 CH(O—C 1 -C 6 linear alkyl)OH in the presence of potassium carbonate.
40. A process for the preparation of a compound of formula (I)
wherein Y is O, R 3 is hydrogen, R 2 is hydrogen, and R 4 is CHF 2 , the compound is 2-difluoromethyl-5-hydroxy-pyran-4-one, wherein the process comprises the following steps:
(a) reacting kojic acid with sodium hydroxide and benzyl bromide to give 5-benzyloxy-2-hydroxymethyl-pyran-4-one;
(b) oxidizing the compound from step (a) with TEMPO, sodium hypochlorite and potassium bromate to give 5-benzyloxy-4-oxo-4H-pyran-2-carbaldehyde; or oxidizing the compound from step (a) with sulfur trioxide pyridine complex to give 5-benzyloxy-4-oxo-4H-pyran-2-carbaldehyde;
(c) reacting the compound from step (b) with DAST to give 5-benzyloxy-2-difluoromethyl-pyran-4-one; and
(d) reacting the compound from step (c) with boron tribromide to give 2-difluoromethyl-5-hydroxy-pyran-4-one.
41. A process for the preparation of a compound of the formula (IIIC)
wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, allyl, cyclopropyl and cyclopropylmethyl;
R 2 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; and
R 4 is selected from the group consisting of hydrogen and methyl; and
wherein the method comprises the following steps:
(a) reaction of compound (19) with CF 3 CH(O—C 1 -C 4 linear alkyl)OH to give compound (20); and
(b) hydrogenation of compound (20) in the presence of palladium on charcoal to give a compound of formula (IIIC), with the proviso that R 1 is not allyl.
42. A pharmaceutical composition comprising a compound according to claim 2 and at least one pharmaceutically acceptable carrier.
43. A pharmaceutical composition comprising a compound according to claim 3 and at least one pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising a compound according to claim 4 and at least one pharmaceutically acceptable carrier.
45. A pharmaceutical composition comprising a compound according to claim 5 and at least one pharmaceutically acceptable carrier.
46. A pharmaceutical composition comprising a compound according to claim 6 and at least one pharmaceutically acceptable carrier.
47. A pharmaceutical composition comprising a compound according to claim 7 and at least one pharmaceutically acceptable carrier.
48. A pharmaceutical composition comprising a compound according to claim 19 and at least one pharmaceutically acceptable carrier.
49. A pharmaceutical composition comprising a compound according to claim 20 and at least one pharmaceutically acceptable carrier.