Claims for Patent: 11,174,247

Summary for Patent: 11,174,247

Title:	Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
Abstract:	The present invention concerns the compound aprocitentan, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, and its use as endothelin receptor antagonist, in combination with other active ingredients or therapeutic agents including an angiotenin receptor blocker, and/or a calcium channel blocker, and preferably a diuretic which is a thiazide-like diuretic, in the prophylaxis or treatment of certain endothelin related diseases. The invention further relates to pharmaceutical compositions comprising aprocitentan in combination with said other active ingredients or therapeutic agents. The invention further relates to such pharmaceutical compositions comprising novel crystalline forms of aprocitentan.
Inventor(s):	Bellet Marc, Bolli Martin, Clozel Martine, Iglarz Marc
Assignee:	IDORSIA PHARMACEUTICALS LTD
Application Number:	US16489227
Patent Claims:	1. A pharmaceutical composition containing , as active principles , aprocitentan , or a pharmaceutically acceptable salt thereof , in combination with:an angiotensin receptor blocker, or a pharmaceutically acceptable salt thereof;as well as at least one pharmaceutically acceptable excipient.2. The pharmaceutical composition according to wherein said angiotensin receptor blocker is valsartan claim 1 , or a pharmaceutically acceptable salt thereof.3. The pharmaceutical composition according to claim 1 , said composition comprising aprocitentan in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 1 , 20.0° claim 1 , and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 1 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.4. A pharmaceutical composition according to claim 1 , said composition comprising aprocitentan in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 1 , 18.6° claim 1 , 20.0° claim 1 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 1 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.5. The pharmaceutical composition according to claim 1 , said composition comprising aprocitentan in crystalline Form A which essentially shows the X-ray powder diffraction pattern as depicted in claim 1 , wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 1 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.6. The pharmaceutical composition according to claim 1 , further comprising:a calcium channel blocker, or a pharmaceutically acceptable salt thereof; anda diuretic which is a thiazide-like diuretic, or a pharmaceutically acceptable salt thereof.7. The pharmaceutical composition according to claim 6 , wherein the diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof claim 6 , or chlorthalidone or a pharmaceutically acceptable salt thereof.8. The pharmaceutical composition according to claim 6 , wherein angiotensin receptor blocker is valsartan claim 6 , or a pharmaceutically acceptable salt thereof; the calcium channel blocker is amlodipine claim 6 , or a pharmaceutically acceptable salt thereof; and the diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof claim 6 , or chlorthalidone or a pharmaceutically acceptable salt thereof.9. The pharmaceutical composition according to claim 8 , wherein the diuretic is hydrochlorothiazide claim 8 , or a pharmaceutically acceptable salt thereof.10. A pharmaceutical composition according to wherein:aprocitentan is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 2.5 to 100 mg per day of aprocitentan;valsartan or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 100 to 320 mg per day of valsartan;amlodipine or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 2 to 10 mg per day of amlodipine; andhydrochlorothiazide or a pharmaceutically acceptable salt thereof, if present, is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 5 to 25 mg per day of hydrochlorothiazide; and chlorthalidone or a pharmaceutically acceptable salt thereof, if present, is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 150 mg per day of chlorthalidone.11. A pharmaceutical composition according to wherein:aprocitentan is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 2.5 to 100 mg per day of aprocitentan;valsartan or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 100 to 320 mg per day of valsartan;amlodipine or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 2 to 10 mg per day of amlodipine; andhydrochlorothiazide or a pharmaceutically acceptable salt thereof is comprised in a pharmaceutical unit dosage form suitable for the oral administration of 5 to 25 mg per day of hydrochlorothiazide.13. The method according to claim 12 , wherein said angiotensin receptor blocker is valsartan claim 12 , or a pharmaceutically acceptable salt thereof.14. The method according to claim 12 , wherein aprocitentan is further administered in combination with:a calcium channel blocker, or a pharmaceutically acceptable salt thereof; anda diuretic which is a thiazide-like diuretic, or a pharmaceutically acceptable salt thereof.15. The method according to claim 14 , wherein the angiotensin receptor blocker is valsartan claim 14 , or a pharmaceutically acceptable salt thereof; the calcium channel blocker is amlodipine claim 14 , or a pharmaceutically acceptable salt thereof; and the diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof claim 14 , or chlorthalidone or a pharmaceutically acceptable salt thereof.16. The method according to wherein:aprocitentan or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical unit dosage form suitable for the oral administration of 2.5 to 100 mg per day of aprocitentan;valsartan or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical unit dosage form suitable for the oral administration of 100 to 320 mg per day of valsartan;amlodipine or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical unit dosage form suitable for the oral administration of 2 to 10 mg per day of amlodipine; andhydrochlorothiazide or a pharmaceutically acceptable salt thereof, if present, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 5 to 25 mg per day of hydrochlorothiazide; and chlorthalidone or a pharmaceutically acceptable salt thereof, if present, is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 150 mg per day of chlorthalidone.17. The method according to claim 12 , wherein said method is for the treatment of hypertension.18. The method according to claim 14 , wherein said method is for the treatment of hypertension.20. The method according to claim 19 , wherein said angiotensin receptor blocker is valsartan claim 19 , or a pharmaceutically acceptable salt thereof.21. The method according to claim 18 , wherein said diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof claim 18 , or chlorthalidone or a pharmaceutically acceptable salt thereof.22. The method according to claim 18 , wherein said diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof.23. The method according to claim 18 , wherein said diuretic is chlorthalidone or a pharmaceutically acceptable salt thereof.24. The method according to claim 15 , wherein said method is for the treatment of resistant hypertension.25. The method according to claim 24 , wherein said diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof.26. The method according to claim 16 , wherein said method is for the treatment of resistant hypertension.27. The method according to claim 12 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 12 , 18.6° claim 12 , 20.0° claim 12 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 12 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.28. The method according to claim 13 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 13 , 18.6° claim 13 , 20.0° claim 13 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 13 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.29. The method according to claim 14 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 14 , 18.6° claim 14 , 20.0° claim 14 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 14 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.30. The method according to claim 15 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 15 , 18.6° claim 15 , 20.0° claim 15 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 15 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.31. The method according to claim 16 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 16 , 18.6° claim 16 , 20.0° claim 16 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 16 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.32. The method according to claim 18 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 18 , 18.6° claim 18 , 20.0° claim 18 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 18 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.33. The method according to claim 24 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 24 , 18.6° claim 24 , 20.0° claim 24 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 24 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.34. The method according to claim 26 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 26 , 18.6° claim 26 , 20.0° claim 26 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 26 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.35. The method according to claim 16 , wherein aprocitentan is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of aprocitentan.36. The method according to claim 26 , wherein aprocitentan is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of aprocitentan.37. The method according to claim 19 , wherein said method is for the treatment of chronic kidney disease (CKD).38. The method according to claim 37 , wherein said method is for the treatment of CKD of stages 1 to 4 caused by or associated with essential hypertension.39. The method according to claim 20 , wherein said method is for the treatment of chronic kidney disease (CKD).40. The method according to claim 39 , wherein said method is for the treatment of CKD of stages 1 to 4 caused by or associated with essential hypertension.41. The method according to claim 37 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 37 , 18.6° claim 37 , 20.0° claim 37 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 37 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.42. The method according to claim 39 , wherein the aprocitentan is in crystalline Form A characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 17.8° claim 39 , 18.6° claim 39 , 20.0° claim 39 , 23.2° and 23.5°; wherein said X-ray powder diffraction diagram is obtained by using combined Cu Kα1 and Kα2 radiation claim 39 , without Kα2 stripping; and the accuracy of the 2θ values is in the range of 2θ+/−0.2°.43. The method according to claim 17 , wherein said hypertension is resistant hypertension.44. The method according to claim 18 , wherein said hypertension is resistant hypertension.45. The method according to claim 12 , wherein the method to be treated is chronic heart failure.46. The method according to claim 17 , wherein aprocitentan is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of aprocitentan.47. The method according to claim 23 , wherein aprocitentan is administered in a pharmaceutical unit dosage form suitable for the oral administration of 10 to 50 mg per day of aprocitentan.