Substituted purine compounds
View Patent ↗The present invention relates to substituted purine compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating disorders in which DOT1-mediated protein methylation plays a part, such as cancer, by administering these compounds and pharmaceutical compositions to subjects in need thereof.
1. A compound of Formula (II):
or a pharmaceutically acceptable salt or ester thereof, wherein
R 1 is t-butyl substituted with one or more substituents selected from hydroxyl and oxo;
R 2 is H, hydroxyl, unsubstituted i-propyl, or i-propyl substituted with one or more hydroxyl;
l′ is 0, 1, 2, or 3;
each of m′ and n′, independently, is 0, 1, or 2;
each of p′, q′, r′, t′, u′, v′, and w′, independently, is 0 or 1; and
when R 1 is t-butyl substituted with only one hydroxyl, R 2 is H, hydroxyl, or i-propyl substituted with one or more hydroxyl; and wherein
(1) the compound of Formula (II) is a carboxylic acid;
(2) R 1 is t-butyl substituted with one hydroxyl, and (i) R 2 is H, and each of l′, m′, n′, u′, v′, and w′ is 0, (ii) R 2 is hydroxyl or i-propyl substituted with one or two hydroxyl, and each of l′, m′, n′, u′, v′, and w′ is 0, or (iii) R 2 is H, hydroxyl or i-propyl optionally substituted with one hydroxyl, and the sum of l′, m′, n′, u′, v′, and w′ is 1;
(3) R 1 is t-butyl substituted with two hydroxyl, and (i) R 2 is H, hydroxyl or i-propyl optionally substituted with one hydroxyl, and each of l′, m′, n′, u′, v′, and w′ is 0, or (ii) R 2 is H, hydroxyl or i-propyl optionally substituted with one hydroxyl, and the sum of l′, m′, n′, u′, v′, and w′ is 1, or
(4) R 1 is t-butyl substituted with three hydroxyl, R 2 is H or unsubstituted i-propyl, and each of l′, m′, n′, u′, v′, and w′ is 0.
2. The compound of claim 1 or the pharmaceutically acceptable salt or ester thereof, being in an isolated form.
3. The compound of claim 1 , being of Formula (IIA):
or Formula (IIB):
4. The compound of claim 1 , comprising one hydroxyl in addition to the two hydroxyls on the tetrahydrofuran ring.
5. The compound of claim 1 , wherein R 1 is t-butyl substituted with one hydroxyl, R 2 is H, and each of l′, m′, n′, u′, v′, and w′ is 0.
6. The compound of claim 1 , being of a carboxylic acid.
7. The compound of claim 1 , wherein R 1 is t-butyl substituted with one hydroxyl and one oxo, and wherein the hydroxyl and oxo together with the carbon to which they are attached form —COOH.
8. The compound of claim 1 , wherein R 1 is —C(CH 3 ) 2 COOH), R 2 is H or unsubstituted i-propyl, and each of l′, m′, n′, u′, v′, and w′ is 0.
9. The compound of claim 1 , comprising two or three hydroxyls in addition to the two hydroxyls on the tetrahydrofuran ring.
10. The compound of claim 1 , wherein R 1 is t-butyl substituted with one hydroxyl, and (i) R 2 is hydroxyl or i-propyl substituted with one or two hydroxyl, and each of l′, m′, n′, u′, v′, and w′ is 0, or (ii) R 2 is H, hydroxyl, or i-propyl optionally substituted with one hydroxyl, and the sum of l′, m′, n′, u′, v′, and w′ is 1.
11. The compound of claim 1 , wherein R 1 is t-butyl substituted with two hydroxyl, and (i) R 2 is H, hydroxyl or i-propyl optionally substituted with one hydroxyl, and each of l′, m′, n′, u′, v′, and w′ is 0, or (ii) R 2 is H, hydroxyl or i-propyl optionally substituted with one hydroxyl, and the sum of l′, m′, n′, u′, v′, and w′ is 1.
12. The compound of claim 1 , wherein R 1 is t-butyl substituted with three hydroxyl, R 2 is H or unsubstituted i-propyl, and each of l′, m′, n′, u′, v′, and w′ is 0.
13. The compound of claim 1 , comprising four hydroxyls in addition to the two hydroxyls on the tetrahydrofuran ring.
14. The compound of claim 1 , comprising five or more hydroxyls in addition to the two hydroxyls on the tetrahydrofuran ring.
15. The compound of claim 1 , wherein the compound is selected from the group consisting of Compounds 49-54, 56, 57, 63-89, 107, and 110-112.
16. A pharmaceutical composition comprising a compound of Formula (II):
or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, wherein
R 1 is t-butyl substituted with one or more substituents selected from hydroxyl and oxo;
R 2 is H, hydroxyl, unsubstituted i-propyl, or i-propyl substituted with one or more hydroxyl;
l′ is 0, 1, 2, or 3;
each of m′ and n′, independently, is 0, 1, or 2;
each of p′, q′, r′, t′, u′, v′, and w′, independently, is 0 or 1; and
when R 1 is t-butyl substituted with only one hydroxyl, R 2 is H, hydroxyl, or i-propyl substituted with one or more hydroxyl; and wherein
(1) the compound of Formula (II) is a carboxylic acid;
(2) R 1 is t-butyl substituted with one hydroxyl, and (i) R 2 is H, and each of l′, m′, n′, u′, v′, and w′ is 0, (ii) R 2 is hydroxyl or i-propyl substituted with one or two hydroxyl, and each of l′, m′, n′, u′, v′, and w′ is 0, or (iii) R 2 is H, hydroxyl or i-propyl optionally substituted with one hydroxyl, and the sum of l′, m′, n′, u′, v′, and w′ is 1;
(3) R 1 is t-butyl substituted with two hydroxyl, and (i) R 2 is H, hydroxyl or i-propyl optionally substituted with one hydroxyl, and each of l′, m′, n′, u′, v′, and w′ is 0, or (ii) R 2 is H, hydroxyl or i-propyl optionally substituted with one hydroxyl, and the sum of l′, m′, n′, u′, v′, and w′ is 1; or
(4) R 1 is t-butyl substituted with three hydroxyl, R 2 is H or unsubstituted i-propyl, and each of l′, m′, n′, u′, v′, and w′ is 0.
17. The pharmaceutical composition of claim 16 , wherein the compound of Formula (II) or the pharmaceutically acceptable salt or ester thereof is in an isolated form.
18. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 16 .
19. A method of treating hematological cancer comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 16 .
20. A method of treating a disorder mediated by a translocation of a gene on chromosome 11q23, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 16 .
21. A method of treating a disorder mediated by DOT1L-mediated protein methylation, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 16 .
22. A method of treating leukemia comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 16 .
23. The method of claim 22 , wherein the leukemia is acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.
24. The method of claim 22 , wherein the leukemia is characterized by a chromosomal rearrangement.
25. The method of claim 24 , wherein said chromosomal rearrangement is chimeric fusion of mixed lineage leukemia gene (MLL) or partial tandem duplication of MLL (MLL-PTD).
26. The method of claim 25 , wherein the subject has an increased level of HOXA9, Fms-like tyrosine kinase 3 (FLT3), MEIS1, and/or DOT1L.
27. A method for treating leukemia in a subject comprising:
1) (a) detecting the level of HOXA9, FLT3, MEIS1, and/or DOT1L in a biological sample obtained from the subject, wherein an increased level of HOXA9, FLT3, MEIS1, and/or DOT1L indicates the subject is responsive to the compound of claim 1 , or (b) detecting the presence of a genetic lesion of MLL in the sample; and
2) administering to the subject a therapeutically effective amount of the compound of claim 1 when the subject is responsive to the compound or when the genetic lesion is present in the sample.
28. The method of claim 27 , wherein the sample is selected from bone marrow, peripheral blood cells, blood, plasma, serum, urine, saliva, a cell, or a tumor tissue.
29. The method of claim 28 , wherein the genetic lesion is chimeric fusion of MLL or MLL-PTD.