Substituted purine compounds

Patent metadata

Field	Value
Publication number	US-9688714-B2
Application number	US-201414902150-A
Country	US
Kind code	B2
Filing date	Jul 3, 2014
Priority date	Jul 3, 2013
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

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.

First claim

What is claimed is:

1. An isolated compound of Formula (I):

wherein
each of l, 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
the sum of l, m, n, p, q, r, t, u, v, and w is 1, 2, or 3.

2. The isolated compound of claim 1 , wherein the compound is of Formula (IA) or (IB):

3. The isolated compound of claim 1 , wherein the sum of l, m, n, p, q, r, t, u, v, and w is 1.

4. The isolated compound of claim 1 , wherein (i) l is 1, and each of m, n, p, q, r, t, u, v, and w, independently is 0, (ii) m is 1, and each of l, n, p, q, r, t, u, v, and w, independently is 0, (iii) n is 1, and each of l, m, p, q, r, t, u, v, and w, independently is 0, (iv) u is 1, and each of l, m, n, p, q, r, t, v, and w, independently is 0, (v) w is 1, and each of l, m, n, p, q, r, t, u, and v, independently is 0, (vi) w is 1, and each of l, m, n, p, q, r, t, u, and v, independently is 0, or (vii) one of q, r, and t is 1.

5. A pharmaceutically acceptable salt of a compound of Formula (I):

wherein
each of l, 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
the sum of l, m, n, p, q, r, t, u, v, and w is 1, 2, or 3.

6. The pharmaceutically acceptable salt of claim 5 , wherein the salt is in an isolated form.

7. The pharmaceutically acceptable salt of claim 5 , wherein the compound of Formula (I) is of Formula (IA) or (IB):

8. The pharmaceutically acceptable salt of claim 5 , wherein (i) l is 1, and each of m, n, p, q, r, t, u, v, and w, independently is 0, (ii) m is 1, and each of l, n, p, q, r, t, u, v, and w, independently is 0, (iii) n is 1, and each of l, m, p, q, r, t, u, v, and w, independently is 0, (iv) u is 1, and each of l, m, n, p, q, r, t, v, and w, independently is 0, (v) v is 1, and each of l, m, n, p, q, r, t, u, and w, independently is 0, (vi) w is 1, and each of l, m, n, p, q, r, t, u, and v, independently is 0, or (vii) one of q, r, and t is 1.

9. A pharmaceutical composition comprising a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein
each of l, 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
the sum of l, m, n, p, q, r, t, u, v, and w is 1, 2, or 3.

10. The pharmaceutical composition of claim 9 , wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is in an isolated form.

11. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 9 .

12. A method of treating hematological cancer comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 9 .

13. 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 9 .

14. 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 pharmaceutical composition of claim 9 .

15. A method of treating leukemia comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 9 .

16. The method of claim 15 , wherein the leukemia is acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.

17. The method of claim 15 , wherein the leukemia is characterized by a chromosomal rearrangement.

18. The method of claim 17 , wherein said chromosomal rearrangement is chimeric fusion of mixed lineage leukemia gene (MLL) or partial tandem duplication of MLL (MLL-PTD).

19. The method of claim 15 , wherein the subject has an increased level of HOXA9, Fms-like tyrosine kinase 3 (FLT3), MEIS1, and/or DOT1L.

20. A method for treating leukemia in a subject comprising:
1) obtaining a sample from the subject;
2) (a) detecting the level of HOXA9, FLT3, MEIS1, and/or DOT1L, wherein an increased level of HOXA9, FLT3, MEIS1, and/or DOT1L indicates the subject is responsive to a compound of Formula (I):

 or
(b) detecting the presence of a genetic lesion of MLL in the sample; and
3) administering to the subject a therapeutically effective amount of the compound of Formula (I) when the subject is responsive to the compound or when the genetic lesion is present in the sample, wherein each of l, 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 the sum of l, m, n, p, q, r, t, u, v, and w is 1, 2, or 3.

21. The method of claim 20 , wherein the sample is selected from bone marrow, peripheral blood cells, blood, plasma, serum, urine, saliva, a cell, or a tumor tissue.

22. The method of claim 20 , wherein the genetic lesion is chimeric fusion of MLL or MLL-PTD.

Assignees

• Epizyme Inc

Inventors

• Waters Nigel J

Classifications

• G01N33/57505

  of the blood, e.g. leukaemia · CPC title

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• A61K31/706

  containing six-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• C12Q1/6886

  for cancer (immunoassay for cancer G01N33/575) · CPC title