Claims for Patent: 11,680,058

Summary for Patent: 11,680,058

Title:	Crystalline forms of a 4-pyrimidinesulfamide derivative aprocitentan
Abstract:	The present invention concerns novel crystalline forms of {5-(4-bromo-phenyl)-6 [2 (5 bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms, and their use as endothelin receptor antagonists. It also relates to new uses of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, either alone or in combination with other active ingredients or therapeutic agents.
Inventor(s):	Martin Bolli, Markus von Raumer
Assignee:	Actelion Pharmaceuticals Ltd , Idorsia Pharmaceuticals Ltd
Application Number:	US17/146,801
Patent Claims:	1. A method for the treatment of hypertension, pulmonary hypertension, a coronary disease, cardiac insufficiency, renal ischemia, myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers, portal hypertension, or chronic kidney disease (CKD); said method comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide: wherein said crystalline form is characterized by: the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; or the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 7.8°, 9.7°, 15.7°, 19.8° and 22.0°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the λθ values is in the range of 2θ+/−0.2°. 2. A method for the treatment of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure, or diastolic dysfunction; said method comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide: wherein said crystalline form is characterized by: the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; or the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 7.8°, 9.7°, 15.7°, 19.8° and 22.0°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 20 values is in the range of 2θ+/−0.2°. 3. A method for the treatment of hypertension, heart failure, or chronic kidney disease (CKD); said method comprising administering to a patient in need thereof an effective amount of a crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide: wherein said crystalline form is characterized by: the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; or the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 7.8°, 9.7°, 15.7°, 19.8° and 22.0°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°. 4. The method according to claim 1, wherein said method is for the treatment of hypertension. 5. The method according to claim 1, wherein said method is for the treatment of essential hypertension, resistant hypertension, pulmonary hypertension or pulmonary arterial hypertension. 6. The method according to claim 5, wherein said method is for the treatment of essential hypertension or resistant hypertension. 7. The method according to claim 5, wherein said method is for the treatment of resistant hypertension. 8. The method according to claim 1, wherein said method is for the treatment of CKD of stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines; wherein said CKD is caused by essential hypertension. 9. The method according to claim 2, wherein said method is for the treatment of diabetic nephropathy. 10. The method according to claim 2, wherein said method is for the treatment of chronic heart failure. 11. The method according to claim 1, wherein said crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°. 12. The method according to claim 2, wherein said crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°. 13. The method according to claim 3, wherein said crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°. 14. The method according to claim 6, wherein said crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°. 15. The method according to claim 6, wherein said crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°, 22.8°, 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°. 16. The method according to claim 6, wherein said crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide essentially shows the X-ray powder diffraction pattern as depicted in FIG. 1 . 17. The method according to claim 6, wherein said crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide. 18. The method according to claim 6, wherein said crystalline form of the compound {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide is administered in a solid pharmaceutical composition comprising said crystalline form of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide in a total amount from 5 to 25% in weight based on the total weight of the pharmaceutical composition; microcrystalline cellulose in a total amount from 20 to 30% in weight based on the total weight of the pharmaceutical composition; lactose in a total amount from 40 to 65% in weight based on the total weight of the pharmaceutical composition; hydroxypropylcellulose in a total amount from 1 to 3% in weight based on the total weight of the pharmaceutical composition; croscarmellose sodium in a total amount from 2 to 8% in weight based on the total weight of the pharmaceutical composition; and magnesium stearate in a total amount from 0.2 to 2% in weight based on the total weight of the pharmaceutical composition. 19. The method according to claim 18, wherein said solid pharmaceutical composition is in form of a tablet. 20. The method according to claim 17, wherein said pharmaceutical unit dosage form is a solid pharmaceutical composition comprising said crystalline form of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide in a total amount from 5 to 25% in weight based on the total weight of the pharmaceutical composition, wherein said crystalline form of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°; microcrystalline cellulose in a total amount from 20 to 30% in weight based on the total weight of the pharmaceutical composition; lactose in a total amount from 40 to 65% in weight based on the total weight of the pharmaceutical composition; hydroxypropylcellulose in a total amount from 1 to 3% in weight based on the total weight of the pharmaceutical composition; croscarmellose sodium in a total amount from 2 to 8% in weight based on the total weight of the pharmaceutical composition; and magnesium stearate in a total amount from 0.2 to 2% in weight based on the total weight of the pharmaceutical composition. 21. The method according to claim 20, wherein said solid pharmaceutical composition is in form of a tablet.