Crystalline solvated forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea
This disclosure relates to crystalline solvated forms of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea. It also relates to methods of making the disclosed crystalline forms, pharmaceutical compositions and kits comprising the forms, and methods of treatment and uses comprising their administration.
1 . A crystalline form of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea that exhibits an X-ray powder diffraction pattern comprising at least three 2-theta (2θ±0.2° 2θ) peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, and 14.1°.
2 . The crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern comprising at least five 2-theta (2θ±0.2° 2θ) peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, 14.1°, 18.0°, 19.1°, and 21.5°.
3 . The crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern comprising 2-theta (2θ+0.2° 2θ) peaks at 5.6°, 5.9°, 9.1°, 11.4° and 14.1°.
4 . The crystalline form of claim 3 , wherein the X-ray powder diffraction pattern further comprises one or more 2-theta (2θ+0.2° 2θ) peaks selected from 18.0°, 19.1°, and 21.5°.
5 . The crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern as shown in FIG. 1 .
6 . The crystalline form of claim 1 , characterized by a thermogravimetric (TG) thermogram indicating continuous weight loss of 8.6% between 32° C. and 120° C.
7 . The crystalline form of claim 1 , characterized by a TG thermogram as shown in FIG. 2 .
8 . The crystalline form of claim 1 , characterized by an onset of melting between 99° C. and 101° C.
9 . The crystalline form of claim 1 , characterized by an onset of melting at 100° C.
10 . The crystalline form of claim 1 , characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between 105° C. and 107° C.
11 . The crystalline form of claim 1 , characterized by a DSC thermogram comprising an endothermic peak at 106° C.
12 . The crystalline form of claim 1 , characterized by a DSC thermogram as shown in FIG. 3 .
13 . The crystalline form of claim 1 , characterized by having at least one of the following:
a) an onset of melting at 100° C. as measured by DSC; and
b) an endothermic peak at 106° C. as measured by DSC.
14 . A pharmaceutical composition comprising the crystalline form of claim 1 and a pharmaceutically acceptable carrier.
15 . A method for preparing a crystalline form of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, said method comprising:
a) suspending an anhydrous crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea in DMSO at room temperature;
b) isolating a white suspension resulting from step a); and
c) isolating precipitated solids from the white suspension to afford the crystalline form of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea,
wherein the crystalline form of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea is characterized by an X-ray powder diffraction pattern comprising at least three 2-theta (2θ+0.2° 2θ) peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, and 14.1°.
16 . A method for preparing a crystalline form of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, said method comprising:
a) suspending an anhydrous crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea in DMSO at room temperature;
b) isolating a white suspension resulting from step a);
c) subjecting the white suspension to a series of temperature cycles from 15° C. to 30° C. to 15° C., 10° C. to 30° C. to 10° C., and 5° C. to 35° C. to 5° C.; and
d) isolating precipitated solids from the white suspension to afford the crystalline form of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea wherein the crystalline form of a dimethyl sulfoxide solvate of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea is characterized by an X-ray powder diffraction pattern comprising at least three 2-theta (2θ+0.2° 2θ) peaks selected from 5.6°, 5.9°, 9.1°, 11.4°, and 14.1°.
17 . The crystalline form of claim 1 , wherein a single crystal structure of the crystalline form comprises one to five molecules of DMSO and one molecule of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea.
18 . The method of claim 15 , wherein the anhydrous crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea in step a) is characterized by an X-ray powder diffraction pattern comprising 2-theta (2θ) peaks at approximately 7.4°, 8.9°, 9.9°, 12.1°, 16.6°, 17.3°, 22.2°, 22.8°, and 27.4°.
19 . The method of claim 16 , wherein the anhydrous crystalline form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea in step a) is characterized by an X-ray powder diffraction pattern comprising 2-theta (2θ) peaks at approximately 7.4°, 8.9°, 9.9°, 12.1°, 16.6°, 17.3°, 22.2°, 22.8°, and 27.4°.