Salts of an LSD1 inhibitor
The present disclosure relates to tosylate salts 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid, methods of preparation thereof, and intermediates in the preparation thereof, which are useful in the treatment of the LSD1-associated or mediated diseases such as cancer.
1. A method of treating cancer comprising administering to a patient in need of treatment of said cancer a therapeutically effective amount of a salt which is 1-{[4-(methoxymethyl)-4-({[(1R,2 S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid bis(4-methylbenzenesulfonate), or a hydrate or solvate thereof, wherein the salt is crystalline and has Form I, Form HI, Form HII, Form HIII, or Form DH.
2. The method of claim 1 , wherein the cancer is selected from the group consisting of hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.
3. The method of claim 2 , wherein the hematological cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), and multiple myeloma.
4. The method of claim 1 , wherein the salt has Form I.
5. The method of claim 4 , wherein the salt exhibits a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 94.6° C. and a peak temperature of about 103.1° C.
6. The method of claim 4 , wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at 3.6±0.3 degrees 2-theta.
7. The method of claim 4 , wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at 4.9±0.3 degrees 2-theta.
8. The method of claim 4 , wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at 6.2±0.3 degrees 2-theta.
9. The method of claim 4 , wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at 7.7±0.3 degrees 2-theta.
10. The method of claim 4 , wherein the salt has an X-ray powder diffraction pattern comprising a characteristic peak at 22.7±0.3 degrees 2-theta.
11. The method of claim 4 , wherein the salt has an X-ray powder diffraction pattern comprising at least two characteristic peaks selected from 3.6±0.3, 4.9±0.3, 6.2±0.3, 7.7±0.3 and 22.7±0.3 degrees 2-theta.
12. The method of claim 11 , wherein the salt has an X-ray powder diffraction pattern further comprising one or more characteristic peak at a position selected from 8.9±0.3, 10.0±0.3, 11.5±0.3, 14.3±0.3, 15.0±0.3, 15.5±0.3, 16.3±0.3, 17.8±0.3, 19.1±0.3, 19.8±0.3, 20.9±0.3, 22.2±0.3 degrees 2-theta, and combinations thereof.
13. The method of claim 4 , wherein the salt has an X-ray powder diffraction pattern with characteristic peaks as substantially shown in FIG. 1 .
14. The method of claim 4 , wherein the salt exhibits a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 94.6° C. and a peak temperature of about 103.1° C.; and an X-ray powder diffraction pattern comprising a characteristic peak at 3.6±0.3, 4.9±0.3, 6.2±0.3, 7.7±0.3 or 22.7±0.3 degrees 2-theta.
15. The method of claim 4 , wherein the salt has a melting point of about 103.1° C.
16. The method of claim 4 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), and multiple myeloma.
17. The method of claim 1 , wherein the salt has Form DH.
18. The method of claim 17 , wherein the salt exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 98° C.
19. The method of claim 17 , wherein the salt exhibits an X-ray powder diffraction pattern comprising a characteristic peak selected from 7.5±0.3, 9.6±0.3, 10.7±0.3, 14.8±0.3, 20.1±0.3, 20.7±0.3, 21.6±0.3, 22.9±0.3, and 24.7±0.3 degrees 2-theta.
20. The method of claim 17 , wherein the salt exhibits an X-ray powder diffraction pattern comprising two or more characteristic peaks selected from 7.5±0.3, 9.6±0.3, 10.7±0.3, 14.8±0.3, 20.1±0.3, 20.7±0.3, 21.6±0.3, 22.9±0.3, and 24.7±0.3 degrees 2-theta.
21. The method of claim 17 , wherein the salt exhibits an X-ray powder diffraction pattern comprising three or more characteristic peaks selected from 7.5±0.3, 9.6±0.3, 10.7±0.3, 14.8±0.3, 20.1±0.3, 20.7±0.3, 21.6±0.3, 22.9±0.3, and 24.7±0.3 degrees 2-theta.
22. The method of claim 17 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), and multiple myeloma.
23. The method of claim 1 , wherein the salt is a hydrate.
24. The method of claim 23 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), and multiple myeloma.
25. The method of claim 23 , wherein the salt has Form HI.
26. The method of claim 25 , wherein the salt exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 80° C.
27. The method of claim 25 , wherein the salt exhibits an X-ray powder diffraction pattern comprising a characteristic peak selected from 7.0±0.3, 10.4±0.3, 13.6±0.3, 15.5±0.3, 17.3±0.3, 22.2±0.3, and 24.0±0.3 degrees 2-theta.
28. The method of claim 25 , wherein the salt exhibits an X-ray powder diffraction pattern comprising two or more characteristic peaks selected from 7.0±0.3, 10.4±0.3, 13.6±0.3, 15.5±0.3, 17.3±0.3, 22.2±0.3, and 24.0±0.3 degrees 2-theta.
29. The method of claim 25 , wherein the salt exhibits an X-ray powder diffraction pattern comprising three or more characteristic peaks selected from 7.0±0.3, 10.4±0.3, 13.6±0.3, 15.5±0.3, 17.3±0.3, 22.2±0.3, and 24.0±0.3 degrees 2-theta.
30. The method of claim 25 , wherein the salt exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
31. The method of claim 25 , wherein the salt exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 80° C.; and an X-ray powder diffraction pattern comprising a characteristic peak selected from 7.0±0.3, 10.4±0.3, 13.6±0.3, 15.5±0.3, 17.3±0.3, 22.2±0.3, and 24.0±0.3 degrees 2-theta.
32. The method of claim 25 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), and multiple myeloma.
33. The method of claim 23 , wherein the salt has Form HII.
34. The method of claim 33 , wherein the salt exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 52° C.
35. The method of claim 33 , wherein the salt exhibits an X-ray powder diffraction pattern comprising a characteristic peak selected from 8.7±0.3, 10.1±0.3, 14.8±0.3, 21.3±0.3, 22.0±0.3, 22.7±0.3, and 24.3±0.3 degrees 2-theta.
36. The method of claim 33 , wherein the salt exhibits an X-ray powder diffraction pattern comprising two or more characteristic peaks selected from 8.7±0.3, 10.1±0.3, 14.8±0.3, 21.3±0.3, 22.0±0.3, 22.7±0.3, and 24.3±0.3 degrees 2-theta.
37. The method of claim 33 , wherein the salt exhibits an X-ray powder diffraction pattern comprising three or more characteristic peaks selected from 8.7±0.3, 10.1±0.3, 14.8±0.3, 21.3±0.3, 22.0±0.3, 22.7±0.3, and 24.3±0.3 degrees 2-theta.
38. The method of claim 33 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), and multiple myeloma.
39. The method of claim 23 , wherein the salt has Form HIII.
40. The method of claim 39 , wherein the salt exhibits a differential scanning calorimetry thermogram having an endothermic peak at a temperature of about 67° C.
41. The method of claim 40 , wherein the salt exhibits an endothermic peak at a temperature of about 98° C.
42. The method of claim 39 , wherein the salt exhibits an X-ray powder diffraction pattern comprising a characteristic peak selected from 7.0±0.3, 9.0±0.3, 9.2±0.3, 10.2±0.3, 17.9±0.3, 20.3±0.3, 22.0±0.3, and 23.8±0.3 degrees 2-theta.
43. The method of claim 39 , wherein the salt exhibits an X-ray powder diffraction pattern comprising two or more characteristic peaks selected from 7.0±0.3, 9.0±0.3, 9.2±0.3, 10.2±0.3, 17.9±0.3, 20.3±0.3, 22.0±0.3, and 23.8±0.3 degrees 2-theta.
44. The method of claim 39 , wherein the salt exhibits an X-ray powder diffraction pattern comprising three or more characteristic peaks selected from 7.0±0.3, 9.0±0.3, 9.2±0.3, 10.2±0.3, 17.9±0.3, 20.3±0.3, 22.0±0.3, and 23.8±0.3 degrees 2-theta.
45. The method of claim 39 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasia syndrome (MDS), and multiple myeloma.