Granted Patent B2

US 12,735,430 · App. 18/636,642 · Granted Sep 15, 2026

Inventors: Petinka I. Vlahova (West Lafayette, IN); Jennifer Nelson (Kokomo, IN); Michael Thomas Brandl (Redwood City, CA); Adrienn Szentes (Porva, HU); Zoltán Kazsu (Budapest, HU); Ádám Demeter (Budapest, HU)

Assignees: Sumitomo Pharma Co., Ltd.; Richter Gedeon Nyrt.

C07D495/04A61K31/519

Abstract

Claims (35)

1 . A crystalline form of an ethanol 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 characterized as Form XIV of Compound 1.

2 . The crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ±0.2° 20.

3 . The crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern comprising at least five peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ±0.2° 20.

4 . The crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern comprising peaks at 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ±0.2° 20.

5 . The crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern substantially the same as the pattern shown in FIG. 1 .

6 . The crystalline form of claim 1 , characterized by a thermogravimetric (TG) thermogram indicating continuous weight loss of about 6.0% between about 49° C. and about 172° C.

7 . The crystalline form of claim 1 , characterized by a TG thermogram substantially the same as the pattern shown in FIG. 4 .

8 . The crystalline form of claim 1 , characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 147° C. and about 150° C.

9 . The crystalline form of claim 1 , characterized by a DSC thermogram comprising an endothermic peak at about 149° C.

10 . The crystalline form of claim 1 , characterized by a DSC thermogram substantially the same as the pattern shown in FIG. 5 .

11 . The crystalline form of claim 1 , characterized by an X-ray powder diffraction pattern comprising at least three peaks having approximate d-spacing value selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å.

12 . The crystalline form of claim 1 , characterized by having at least two of the following:

a) an X-ray powder diffraction pattern comprising at least three peaks selected from 7.31°, 8.38°, 9.96°, 10.69°, 15.43°, 19.02°, and 23.36° 2θ±0.2° 20;

b) an X-ray powder diffraction pattern comprising at least three peaks having approximate d-spacing value selected from 3.805 Å, 4.662 Å, 5.738 Å, 8.269 Å, 8.874 Å, 10.543 Å, and 12.083 Å; and

c) an endothermic peak at about 149° C. as measured by DSC.

13 . The crystalline form of claim 1 , wherein said crystalline form is substantially free of tetrahydrofuran (THF).

14 . A pharmaceutical composition comprising the crystalline form of claim 1 .

15 . The pharmaceutical composition of claim 14 , wherein said composition is substantially free of (THF).

16 . A method for preparing the crystalline form of claim 1 comprising:

a) dissolving a 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 dimethylformamide (DMF) to form a solution;

b) adding the solution of step a) to ethanol to form a second solution;

c) stirring the second solution to generate a suspension; and

d) isolating solids from the suspension to afford Form XIV of Compound 1.

17 . The method of claim 16 , wherein the second solution is cooled to between about −10° C. and −25° C.

18 . The method of claim 16 , wherein the second solution of step b) is cooled to between about −10° C. and −25° C., for 1 day.

19 . The method of claim 16 , wherein the stirring of step c) is carried between about −10° C. and −25° C.

20 . The method of claim 16 , wherein the isolating of step d) is accomplished using syringe filtration.

21 . A method for preparing the crystalline form of claim 1 comprising:

a) dissolving a 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 ethanol (EtOH) to form a solution;

b) cooling the solution of step a);

c) stirring the cooled solution to generate a suspension; and

d) isolating solids from the suspension to afford Form XIV of Compound 1.

22 . The method of claim 21 , wherein the solution of step a) is cooled to between about 5° C. and −10° C.

23 . The method of claim 21 , wherein the stirring of step c) is carried between about 5° C. and −10° C.

24 . The method of claim 21 , wherein the isolating of step d) is accomplished using filtration.

Assignments (7)

Continuity (3)

References Cited (171)