Crystalline forms of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl) oxy) ethoxy) pyrimidin-4-yl) (sulfamoyl) amide

Abstract

The present invention relates to a novel crystalline form of an aprocetentan sodium salt, processes for their preparation, pharmaceutical compositions comprising said crystalline form, pharmaceutical compositions prepared from such crystalline forms and their use as endothelin receptor antagonists.

Description

Technical Field

[0001] The present invention relates to a novel crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide (hereinafter also referred to as the "compound"), a preparation process thereof, a pharmaceutical composition containing the crystalline form, and their use as endothelin receptor inhibitors / antagonists.

[0002] Sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide can be represented by Formula I Background Art

[0003] Aprocitentan (({5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide, compound in free acid form), also known as ACT-132577) is an endothelin receptor inhibitor useful as an endothelin receptor antagonist. Aprocitentan is a member of a series of structural compounds previously disclosed in WO02 / 053557. As disclosed in WO2009 / 024906, aprocitentan is suitable for use in long-acting pharmaceutical compositions. WO2018 / 153513 and WO2019 / 106066 relate to combinations comprising aprocitentan. Certain manufacturing processes relating to aprocitentan are disclosed in WO2015 / 121397. WO2018 / 154101 discloses certain crystalline forms of aprocitentan.

[0004] Because it can inhibit endothelin binding, aprocitentan can be used to treat endothelin-related diseases related to vasoconstriction, proliferation or increased inflammation caused by endothelin. Examples of such endothelin-related diseases are hypertension, pulmonary hypertension, coronary heart disease, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, digital ulcers and portal hypertension. They can also be used to treat or prevent chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction. They may also be used to treat or prevent atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, Gram-negative sepsis, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, treatment and prevention of complications of diabetes, complications after vascular or cardiac surgery or organ transplantation, complications of cyclosporine therapy, pain, hyperlipidemia, and other diseases currently known to be associated with endothelin. Summary of the invention

[0005] It has now been discovered that certain crystalline forms of the compound (sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide) can be found under certain conditions. The crystalline forms of the compound are novel and may have advantageous properties in view of the potential use of the compound as an active pharmaceutical ingredient. These advantages may include physical and / or chemical stability; lower hygroscopicity; better flowability; better reproducibility in manufacturing (e.g., better filtration parameters, better formation reproducibility, and / or better sedimentation); and / or a well-defined morphology. This crystalline form of the compound may be particularly suitable for use in certain pharmaceutical composition manufacturing processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figures 1 to 4 The X-ray powder diffraction patterns (XRPD) of crystalline forms 1 to 4 of the compound (sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide) obtained in Examples 1 to 4 are shown (see the table below). The XRPD shows the relative intensities of the peaks at the indicated diffraction angles 2θ (theta) as compared to the most intense peak in the diffraction pattern as the following percentages (relative peak intensities are given in parentheses) (selected peaks with a relative intensity greater than 10% in the range of 3-30° 2θ are reported; for Form 3, selected related peaks with a relative intensity less than 10% are also reported):

[0007] exist Figures 1 to 4 In the X-ray diffraction pattern of , the diffraction angle 2θ is plotted on the horizontal axis and the counts are plotted on the vertical axis. For the avoidance of any doubt, the peaks listed above describe Figures 1 to 4 It should be understood that, unlike the peak lists above (see table above), only characteristic peaks need to be selected to fully and unambiguously characterize the compounds of each crystalline form of the invention. DETAILED DESCRIPTION

[0008] 1) The first aspect of the present invention relates to a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide:

[0009] in Form 1 of the compound is characterized in that, in an X-ray powder diffraction pattern, there are at least four, or in particular at least six, or in particular at least eight peaks at diffraction angles 2θ (2 theta) selected from the group consisting of 4.3°, 13.1°, 13.5°, 14.8°, 17.2°, 19.5°, 21.1°, 21.6°, 22.6° and 25.0°; Form 2 of the compound is characterized in that, in an X-ray powder diffraction pattern, there are at least four, or in particular at least six, or in particular at least eight peaks at diffraction angles 2θ (2 theta) selected from the group consisting of 4.2°, 13.3°, 16.7°, 16.9°, 18.9°, 20.8°, 22.5°, 23.5°, 25.6° and 27.2°; or Form 3 of the compound is characterized in that, in an X-ray powder diffraction pattern, at least four, or in particular at least six, or in particular at least eight peaks are present at diffraction angles 2θ (2 theta) selected from the group consisting of 3.9°, 11.9°, 15.0°, 15.8°, 17.0°, 19.8°, 22.4°, 23.3°, 23.8° and 27.8°; or Form 4 of the compound is characterized in that, in an X-ray powder diffraction pattern, there are at least four, or in particular at least six, or especially at least eight peaks at diffraction angles 2θ (2 theta) selected from the group consisting of 5.9°, 7.7°, 13.9°, 17.0°, 17.6°, 19.4°, 20.0°, 20.7°, 21.9° and 23.5°.

[0010] 2) One embodiment of the present invention relates to a crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium, wherein Form 1 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 4.3°, 17.2° and 22.6°; Form 2 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 13.3°, 20.8° and 22.5°; Form 3 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in its X-ray powder diffraction pattern: 3.9°, 15.8° and 19.8°; or Form 4 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 5.9°, 20.7° and 21.9°.

[0011] 3) Another embodiment of the present invention relates to a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide, wherein Form 1 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 4.3°, 17.2°, 21.1°, 21.6° and 22.6°; Form 2 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 4.2°, 13.3°, 18.9°, 20.8° and 22.5°; Form 3 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 3.9°, 15.8°, 19.8°, 23.8° and 27.8°; or • Form 4 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 5.9°, 13.9°, 17.6°, 20.7° and 21.9°.

[0012] 4) Another embodiment of the present invention relates to a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide, wherein Form 1 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 4.3°, 13.1°, 13.5°, 14.8°, 17.2°, 19.5°, 21.1°, 21.6°, 22.6° and 25.0°; Form 2 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 4.2°, 13.3°, 16.7°, 16.9°, 18.9°, 20.8°, 22.5°, 23.5°, 25.6° and 27.2°; Form 3 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 3.9°, 11.9°, 15.0°, 15.8°, 17.0°, 19.8°, 22.4°, 23.3°, 23.8°, and 27.8°; or Form 4 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ (2 theta) in an X-ray powder diffraction pattern: 5.9°, 7.7°, 13.9°, 17.0°, 17.6°, 19.4°, 20.0°, 20.7°, 21.9° and 23.5°.

[0013] 5) Another embodiment of the present invention is directed to a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide which exhibits substantially the following X-ray powder diffraction pattern of the crystalline form: · Figure 1 The form shown in 1; · Figure 2 The form shown in 2; · Figure 3 3; or · Figure 4 The form shown in 4.

[0014] The term "substantially" as used in embodiment 5) means that at least the main peak of the diffraction pattern depicted in the figure (i.e. a peak having a relative intensity greater than 10%, in particular greater than 20%, compared to the most intense peak in the diffraction pattern) must be present. However, those skilled in the art of X-ray powder diffraction will recognize that the relative intensities in the X-ray powder diffraction pattern may undergo strong intensity variations due to preferred orientation effects.

[0015] 6) A specific embodiment of the present invention relates to a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 5), wherein the crystalline form is Form 1.

[0016] It should be understood that the crystalline form of the present invention may include non-coordinating and / or coordinating solvents. Coordinating solvents are used herein as the term for crystalline solvates. For the avoidance of doubt, in the present application, the term "(crystalline) solvate" covers non-stoichiometric solvates. Similarly, non-coordinating solvents are used herein as the term for physical adsorption or physical encapsulation solvents (according to Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: UJ Griesser: The Importance of Solvates). It should be further understood that the crystalline form of the present invention may contain different amounts of coordinated water as a function of relative humidity, so the X-ray powder diffraction pattern may vary with relative humidity. For the avoidance of doubt, the present invention encompasses all crystalline sub-forms of the crystalline form, which can be reversibly converted to each other according to relative humidity.

[0017] The compound of crystalline form 1 and form 2 may be a hydrate, in particular a non-stoichiometric hydrate, in particular it may contain up to about 1.6% (relative to the dry weight of the compound) of coordinated water at 25°C and 90% relative humidity, determined according to the GVS method described below. Form 3 may be a solvate; in particular a non-stoichiometric solvate; in particular comprising a solvent, such as water and / or an organic solvent, such as methanol. Forms 1, 2 and 3 may also contain a non-coordinating solvent, such as water and / or an organic solvent, such as ethyl acetate, methanol, ethanol, n-propanol, isopropanol and / or cyclopropanol.

[0018] For the avoidance of any doubt, when an embodiment or claim refers to "a peak at the following diffraction angle 2θ in an X-ray powder diffraction pattern", the X-ray powder diffraction pattern is obtained using a combined CuKα1 and Kα2 radiation, without Kα2 stripping; and it should be understood that the accuracy of the 2θ values ​​provided herein is in the range of + / -0.1°-0.2°. It is worth noting that when a diffraction angle of 2θ (2θ) is specified for a peak in the embodiments and claims of the present invention, the 2θ value given should be understood as an interval from the value minus 0.2° to the value plus 0.2° (2θ+ / -0.2°); in particular, an interval from the value minus 0.1° to the value plus 0.1° (2θ+ / -0.1°).

[0019] When defining the presence of a peak in, for example, an X-ray powder diffraction pattern, a common approach is to do so in terms of the depicted pattern (S = signal, N = noise). According to this definition, when stating that a peak must be present in an X-ray powder diffraction pattern, it is understood that a peak in an X-ray powder diffraction pattern is defined as having an S / N ratio (S = signal, N = noise) greater than x (x being a number greater than 1), typically greater than 2, and especially greater than 3.

[0020] In particular, the crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 5) refers to the compound of crystalline form 1 or crystalline form 4 (especially crystalline form 1) defined therein.

[0021] 7) Another aspect of the present invention relates to a crystalline form 1 of a compound according to any one of embodiments 1 to 6, which can be obtained by a process comprising the following steps: a) reacting {5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide (i.e. the compound in free acid form) with (particularly about 1 equivalent) a sodium-containing base in (particularly about 5 to about 15 volumes; particularly about 7 to about 11 volumes; particularly about 9.0 volumes) selected from C 1-6 -alkyl-OH in a first solvent; b) optionally distilling off part of the first solvent (particularly until the total volume is about 1 to about 7 volumes; especially about 2 to about 6 volumes; especially about 4 volumes); c) adding (particularly from about 5 to about 15 volumes; especially from about 7 to about 12 volumes; especially about 10.0 volumes) selected from C 1-4 - a second solvent of an alkyl acetate; d) optionally distilling off a portion of the mixture of the first and second solvents (particularly until the total volume is about 1 to about 11 volumes; especially about 3 to about 9 volumes; especially about 6 volumes); and e) Isolation of crystalline Form 1.

[0022] 8) Another aspect of the present invention relates to a process for the manufacture of a compound of crystalline form 1 according to any one of embodiments 1 to 5, said process comprising the steps defined in embodiment 7).

[0023] As used herein, the term "sodium-containing base" refers to an organic and / or inorganic Bronsted base; it is noteworthy that the base is capable of accepting a proton (H + ions), thereby obtaining the compound. Suitable Bronsted bases may be sodium alcoholates (e.g. sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide or sodium butoxide), sodium hydride, sodium oxide and / or sodium hydroxide; in particular sodium alcoholates, sodium hydride or sodium hydroxide; especially sodium methoxide.

[0024] The term "alkyl" as used herein, alone or in combination, refers to a saturated, straight-chain or branched, acyclic or cyclic (especially acyclic) hydrocarbon containing one to six carbon atoms. x-y -alkyl" (x and y are each an integer) refers to an alkyl group as defined above containing x to y carbon atoms. Therefore, the term "C 1-6 "-alkyl" refers to a C- x-y -alkyl. C 1-6 Examples of -alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl or cyclohexyl. 1-6 Examples of -alkyl-OH [i.e. alkanols containing 1 to 6 (especially 1 to 4; especially 1 or 2) carbon atoms] are methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, cyclopropanol, cyclobutanol or mixtures thereof; especially methanol, ethanol, n-propanol, isopropanol, cyclopropanol or mixtures thereof; especially such C 1-6 -Alkyl-OH refers to methanol.

[0025] The term "sodium alkoxide" as used herein refers to 1-6 -alkyl-ONa compounds.

[0026] The term "C 1-4 -alkyl acetate" refers to the formula C 1-4 -alkyl-OC(=O)CH 3 Compounds in which C 1-6 -Alkyl refers to a C group as defined above containing from one to six carbon atoms. x-y -alkyl. Examples are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate or mixtures thereof; in particular ethyl acetate.

[0027] It is to be understood that any of steps b) or d) may independently be carried out at normal pressure or at reduced pressure; in particular at reduced pressure (eg at 100 mbar).

[0028] It should be further understood that the separation of the crystalline form 1 of step e) of any one of embodiments 7) or 8) refers to the process of separating the solid phase of the solid-liquid mixture from its liquid phase. It should be understood that the separation can be carried out by any solid-liquid separation method, such as by filtration (e.g., gravity filtration or vacuum filtration). It should be further understood that the separation process can further include washing (particularly with ethyl acetate) and / or drying (particularly at a temperature of up to about 70°C).

[0029] In a preferred variant of any one of embodiments 7) or 8), step b) is not optional. In another preferred variant of any one of embodiments 7) or 8), step d) is not optional. However, in another preferred variant of any one of embodiments 7) or 8), step b) and step d) are not optional.

[0030] Unless used for temperature, in the present application, the term "about" before a numerical value "X" refers to an interval from X minus 10% of X to X plus 10% of X, and preferably refers to an interval from X minus 5% of X to X plus 5% of X. In the specific case of temperature, in the present application, the term "about" before a temperature "Y" refers to an interval from temperature Y minus 10°C to Y plus 10°C, preferably from Y minus 5°C to Y plus 5°C, and particularly from Y minus 3°C to Y plus 3°C. Room temperature refers to a temperature of about 25°C.

[0031] When the term n equivalents (wherein n is a number) is used in the present application, this means and within the scope of the present application that n refers to approximately the number n, preferably n refers to the exact number n.

[0032] Whenever the term "between" or "to" is used to describe a numerical range, it should be understood that the endpoints of the indicated range are explicitly included in the range. For example: if a temperature range is described as being between 40°C and 80°C (or 40°C to 80°C), this means that the endpoints 40°C and 80°C are included in the range; or if a variable is defined as an integer between 1 and 4 (or 1 to 4), this means that the variable is an integer 1, 2, 3 or 4.

[0033] 9) Therefore, another embodiment relates to a crystalline form, especially a substantially pure crystalline form, of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7), for use as a medicament (e.g. in the form of a pharmaceutical composition for enteral or parenteral administration).

[0034] The crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7), especially the substantially pure crystalline form (especially crystalline form 1) can be used as a drug as a single component, a mixture with other crystalline forms and / or an amorphous form of a compound.

[0035] In the context of the present invention, the term "substantially pure" is to be understood as meaning in particular that at least 90% by weight, preferably at least 95% by weight and most preferably at least 99% by weight of the compound is present in the crystalline form of the invention.

[0036] 10) Another embodiment relates to the use of a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7) for the preparation of a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound {5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide as an active ingredient and at least one therapeutically inert excipient.

[0037] 11) Another embodiment relates to a pharmaceutical composition comprising a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7 as an active ingredient, and at least one therapeutically inert excipient.

[0038] 12) Another embodiment relates to the pharmaceutical composition according to embodiment 11), wherein the pharmaceutical composition is in the form of a tablet or a capsule.

[0039] The production of the pharmaceutical composition can be achieved in a manner familiar to those skilled in the art by the following operations (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]): the crystalline form of the present invention (optionally in combination with other therapeutically valuable substances) is made into a galenical administration form together with a suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier material and, if necessary, a conventional pharmaceutical adjuvant. Examples of pharmaceutical compositions suitable for aprocitentan are disclosed in WO2018 / 153513 and WO2019 / 106066.

[0040] For the avoidance of any doubt, embodiment 10) refers specifically to the crystalline form described in any one of embodiments 1) to 7), which is suitable for / used as the final isolation step of the compound (e.g. in order to meet the purity requirements for drug production), while the final pharmaceutical composition obtained according to embodiment 10) may or may not contain the crystalline form (e.g. because the original crystalline form of the compound is further converted and / or dissolved in a pharmaceutically acceptable carrier material during the manufacturing process; therefore, in the final pharmaceutical composition, the compound may be present in a non-crystalline form, another crystalline form, a dissolved form, etc.).

[0041] 13) Another embodiment relates to a method for preparing a pharmaceutical composition comprising the compound {5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide as an active ingredient, wherein the method comprises mixing sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7 and at least one therapeutically inert excipient; wherein the pharmaceutical composition is in particular in solid or liquid form.

[0042] The crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7 and such pharmaceutical compositions according to any one of embodiments 11) or 12) are particularly useful for the treatment of endothelin-related diseases and disorders, in particular for the treatment of hypertension, pulmonary hypertension, coronary heart disease, heart failure, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, finger ulcers, ulcer or portal hypertension and for the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, Gram-negative sepsis, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue disease, complications of diabetes, complications after vascular or cardiac surgery or organ transplantation, complications of cyclosporine treatment, pain or hyperlipidemia. The pharmaceutical composition according to any one of embodiments 11) or 12) is also used to treat chronic kidney disease (CKD), especially CKD stages 1 to 4 (especially stage 3 or 4 CKD) defined by the Kidney Disease Improving Global Outcomes Organization (KDIGO) guidelines, especially CKD associated with or caused by hypertension (including essential hypertension) (especially CKD of these stages).

[0043] Preferably, the crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7 and such pharmaceutical compositions according to any one of embodiments 12) or 12) can be used to treat a disease selected from hypertension, pulmonary hypertension, diabetic arterial disease, heart failure, erectile dysfunction, angina pectoris and CKD [especially stage 1 to 4 CKD (especially stage 3 or 4 CKD) defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines; especially CKD associated with or caused by hypertension (including essential hypertension), and / or CKD associated with or caused by diabetes].

[0044] Such endothelin-related diseases and disorders may be defined in particular as including hypertension, including in particular refractory / resistant hypertension; ischemic heart disease, including angina, coronary heart disease and myocardial ischemia; cardiac insufficiency; chronic kidney disease (CKD) [in particular CKD stages 1 to 4 (in particular CKD stage 3 or 4) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines], in particular CKD caused by / associated with hypertension (in particular these stages), or CKD caused by / associated with diabetes (also known as diabetic nephropathy (DKD), in particular such diabetes is type 2 diabetes); diabetes, and diabetes-related diseases such as diabetic arteropathy, diabetic nephropathy, diabetic retinopathy or diabetic vasculopathy; reducing the risk of major cardiovascular events (such as HF, myocardial infarction, stroke or cardiovascular death) in diabetic patients, in particular those with at least diabetic patients with one other cardiovascular risk factor (such as hypertension); treatment and prevention of diabetic complications; (acute and chronic) renal failure; glomerulonephritis; connective tissue disease; atherosclerosis; peripheral arterial occlusive disease, including chronic peripheral arterial disease; finger ulcers; diabetic foot ulcers and / or reducing the risk of lower limb / limb amputation in diabetic patients; heart failure (HF), which is defined as including, inter alia, chronic HF, particularly including systolic HF / HF with reduced ejection fraction (HFrEF) (i.e., ejection fraction < about 40%) and diastolic HF / HF with preserved ejection fraction (HFpEF) (i.e., ejection fraction > about 50%); reducing the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke or cardiovascular death) in patients at cardiovascular risk (e.g., patients with coronary artery disease and / or patients showing clinical symptoms of congestive HF); and diastolic dysfunction.

[0045] For the avoidance of doubt, the term CKD caused by / associated with diabetes (diabetic nephropathy, DKD) may also include DKD also associated with hypertension; wherein the diabetes is in particular type 2 diabetes.

[0046] In addition, the pharmaceutical composition according to any one of embodiments 11) or 12) can be used to treat a disease selected from essential hypertension, resistant hypertension, pulmonary hypertension and pulmonary arterial hypertension (especially for the treatment of resistant hypertension).

[0047] Essential hypertension (also called primary hypertension or idiopathic hypertension) is a type of hypertension whose cause cannot be clearly determined. It is a major public health problem worldwide, causing vascular and renal morbidity and cardiovascular mortality. If the average of multiple systolic blood pressure measurements for two or more consecutive visits is always equal to or above a certain threshold TSBP, it can be diagnosed as essential hypertension. Individuals with high normal blood pressure tend to maintain blood pressure above the average level of the general population and face a greater risk of developing definite hypertension and cardiovascular events than the general population. Clinicians often discuss threshold TSBP, above which treatment is recommended (see, for example, Mancia et al, J. Hypertens. (2013), 31, 12811357); therefore, depending on the patient's general condition and age, TSBP may be 140 or 130 mm Hg, or other appropriate values.

[0048] The term "resistant hypertension" in the present invention is defined as blood pressure that is above target despite the simultaneous use of three different classes of antihypertensive drugs. One of the three drugs should be a diuretic, and all drugs should be prescribed at optimal / maximum doses. By definition, patients with resistant hypertension include patients who use more than three drugs to control their blood pressure. That is, patients whose blood pressure is controlled but require four or more drugs to control should be considered resistant to treatment (see, e.g., Mancia et al, J. Hypertens. (2013), 31, 12811357).

[0049] The term "diuretic" in this application refers to loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics, including, for example, amiloride, especially including aldosterone antagonists (or alternatively referred to as mineralocorticoid receptor antagonists (MRA)), such as spironolactone, eplerenone or phenarenone; or aldosterone synthase inhibitors (such as batroxostat); carbonic anhydrase inhibitors, including acetazolamide and methazolamide; in particular, thiazide-type diuretics (thiazide diuretics), such as, in particular, chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone. Preferred thiazide diuretics are chlorthalidone or hydrochlorothiazide. For the avoidance of doubt, even if there is a diuretic pharmacological effect, SGLT-2 inhibitors are not included in the term "diuretic" used herein. In addition, some potassium-sparing diuretics may be primarily considered to have the pharmacological effects of mineralocorticoid receptor antagonists (MRA) / aldosterone antagonists (e.g., finerenone) or aldosterone synthase inhibitors (e.g., baxdrostat), rather than the diuretic effect of potassium-sparing diuretics. Such potassium-sparing diuretics are included in the definition of diuretics herein. It should be further understood that background therapy may include a combination of several diuretics defined herein. Specific combinations of diuretics are (i) a combination of an aldosterone antagonist and a thiazide diuretic; (ii) a combination of an aldosterone antagonist and a loop diuretic; (iii) a combination of an aldosterone synthase inhibitor and a thiazide diuretic; (iv) a combination of an aldosterone synthase inhibitor and a loop diuretic; and (v) a loop diuretic and a thiazide diuretic. "Diuretics" in the present application refer in particular to diuretics of the thiazide type (thiazide diuretics), such as, inter alia, chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone. Preferred diuretics are chlorthalidone or hydrochlorothiazide.

[0050] Therefore, the present invention further relates to a compound, in particular a crystalline form of compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium according to any one of embodiments 1) to 7, wherein the compound / the crystalline form of the compound is used as a medicament, in particular for the treatment of resistant hypertension; wherein the compound / the crystalline form is used alone or (preferably) in combination (preferably simultaneously, including fixed dose combinations), for example in combination with a diuretic, in particular hydrochlorothiazide (HCTZ or HCT) or chlorthalidone; or in combination with angiotensin 2 receptor blockers (ARBs), such as valsartan; or in combination with angiotensin converting enzyme (ACE) inhibitors, such as enalapril; or in combination with an SGLT2 inhibitor, such as in particular empagliflozin, dapagliflozin or canagliflozin. In a sub-embodiment, the combination of a compound for treating resistant hypertension / a crystalline form according to any one of embodiments 1) to 7) and a diuretic, in particular hydrochlorothiazide (HCTZ or HCT) or chlorthalidone; may need to be further combined (preferably administered simultaneously, including fixed dose combinations) with one or two other active ingredients, in particular valsartan, which are antihypertensive agents of different classes (in particular CCBs and / or ARBs). Therefore, the present invention particularly relates to a pharmaceutical composition comprising a compound / a corresponding crystalline form of a compound as defined in any one of embodiments 11) or 12); in addition to the compound / the corresponding crystalline form of the compound, a diuretic, in particular hydrochlorothiazide (HCTZ or HCT) or chlorthalidone as an active ingredient; and optionally one or two active ingredients, which are antihypertensive agents of different classes (in particular CCBs and / or ARBs); in particular valsartan; or in addition to the compound / the corresponding crystalline form of the compound, an angiotensin 2 receptor blocker (ARB) such as valsartan; or an angiotensin converting enzyme (ACE) inhibitor such as enalapril as an active ingredient; or in addition to the compound / the corresponding crystalline form of the compound, an SGLT2 inhibitor such as in particular empagliflozin, dapagliflozin or canagliflozin as an active ingredient.

[0051] The term "SGLT-2 inhibitor" refers to inhibitors of the sodium-glucose co-transporter 2, such as in particular apagliflozin, bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, hengagliflozin, ipagliptin, lucigliptin, rempagliflozin, sopagliflozin, tigliflozin or topagliflozin (in particular canagliflozin, dapagliflozin or empagliflozin).

[0052] 14) Another embodiment relates to a crystalline form of a compound according to any one of embodiments 1) to 7) for use in the treatment of hypertension, pulmonary hypertension, coronary heart disease, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, digital ulcers or portal hypertension and for the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma Asthma, pulmonary fibrosis, gram-negative sepsis, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue disease, complications of diabetes, complications following vascular or cardiac surgery or organ transplantation, complications of cyclosporine therapy, pain, hyperlipidemia, or CKD [particularly CKD stages 1 to 4 (particularly CKD stage 3 or 4) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, particularly CKD caused by / associated with hypertension (including essential hypertension) (particularly these stages)].

[0053] 15) Another embodiment relates to a crystalline form of the compound according to any one of embodiments 1) to 7), for use in the treatment of a disease selected from hypertension, pulmonary hypertension, diabetic arterial disease, heart failure, erectile dysfunction, angina pectoris and CKD [especially CKD stages 1 to 4 (especially CKD stage 3 or 4) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, especially CKD caused / associated with hypertension (including essential hypertension) (especially these stages)].

[0054] 16) Another embodiment relates to a crystalline form of a compound according to any one of embodiments 1) to 7), for use in the treatment of a disease selected from essential hypertension, resistant hypertension, pulmonary hypertension and pulmonary arterial hypertension (especially for the treatment of resistant hypertension).

[0055] For the avoidance of any doubt, if a compound, in particular a crystalline form of a compound according to any one of embodiments 1) to 7) is described as being useful for preventing / preventing or treating certain diseases, then this crystalline form is also suitable for preparing a medicament for preventing / preventing or treating said disease. Similarly, this crystalline form is also suitable for a method for preventing / preventing or treating such a disease, the method comprising administering an effective amount of this crystalline form to a subject (mammal, in particular a human) in need thereof.

[0056] 17) Another embodiment relates to the use of a crystalline form of a compound according to any one of embodiments 1) to 7) for the preparation of a medicament for the treatment of any of the diseases or conditions mentioned in embodiment 14).

[0057] 18) Another embodiment relates to the use of a crystalline form of a compound according to any one of embodiments 1) to 7) for the preparation of a medicament for the treatment of any one of the diseases or conditions mentioned in embodiment 15).

[0058] 19) Another embodiment relates to the use of a crystalline form of a compound according to any one of embodiments 1) to 7) for the preparation of a medicament for the treatment of any of the diseases or conditions mentioned in embodiment 16).

[0059] 20) Another embodiment relates to a method for treating any of the diseases or conditions mentioned in embodiment 14), which comprises administering to a patient an effective amount of a crystalline form of a compound according to any one of embodiments 1) to 7) or a pharmaceutical composition according to any one of embodiments 11) or 12).

[0060] 21) Another embodiment relates to a method for treating any of the diseases or conditions mentioned in embodiment 15), comprising administering to a patient an effective amount of a crystalline form of a compound according to any one of embodiments 1) to 7) or a pharmaceutical composition according to any one of embodiments 11) or 12).

[0061] 22) Another embodiment relates to a method for treating any of the diseases or conditions mentioned in embodiment 16), which comprises administering to a patient an effective amount of a crystalline form of a compound according to any one of embodiments 1) to 7) or a pharmaceutical composition according to any one of embodiments 11) or 12).

[0062] 23) Yet another embodiment relates to a crystalline form of the compound according to any one of embodiments 1) to 7), for use in the treatment of a disease selected from chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction.

[0063] 24) A sub-embodiment of embodiment 23) relates to a crystalline form of a compound according to any one of embodiments 1) to 7), for use in the treatment of CKD, in particular CKD stages 1 to 4 (especially stage 3 or 4 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, in particular CKD (especially these stages) caused by / associated with hypertension (including essential hypertension).

[0064] 25) Another sub-embodiment of embodiment 23) relates to a crystalline form of a compound according to any one of embodiments 1) to 7) for use in the treatment of diabetes (ie type 1 or type 2 diabetes).

[0065] 26) Another sub-embodiment of embodiment 23) relates to a crystalline form of the compound according to any one of embodiments 1) to 7) for use in the treatment of diabetic nephropathy.

[0066] 27) Another sub-embodiment of embodiment 23) relates to a crystalline form of the compound according to any one of embodiments 1) to 7) for use in the treatment of diabetic retinopathy.

[0067] 28) Another sub-embodiment of embodiment 23) relates to a crystalline form of a compound according to any one of embodiments 1) to 7) for use in the treatment of diabetic angiopathy.

[0068] 29) Another sub-embodiment of embodiment 23) relates to a crystalline form of the compound according to any one of embodiments 1) to 7) for use in the treatment of chronic heart failure.

[0069] 30) According to a variant of sub-embodiment 29), the chronic heart failure of sub-embodiment 29) is heart failure with preserved ejection fraction.

[0070] 31) According to another variant of sub-embodiment 29), the chronic heart failure of sub-embodiment 29) is diastolic heart failure.

[0071] 32) Another sub-embodiment of embodiment 23) relates to a crystalline form of the compound according to any one of embodiments 1) to 7) for use in the treatment of diastolic dysfunction.

[0072] 33) Preferably, the crystalline form of the compound according to any one of embodiments 23) to 32) will be contained in a pharmaceutical unit dosage form suitable for daily oral administration of 2.5 to 100 mg (especially 10 to 50 mg, especially 12.5 mg or 25 mg) of {5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide.

[0073] 34) Preferably, the crystalline form of the compound according to any one of embodiments 23) to 32) will be Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and / or calcium channel blockers (CCBs), or used in combination with a pharmaceutically acceptable salt thereof.

[0074] "Angiotensin converting enzyme inhibitor" or "ACE inhibitor" in the present application refers in particular to captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril, or a pharmaceutically acceptable salt of one of these drugs. Preferred ACE inhibitors are enalapril or a pharmaceutically acceptable salt thereof.

[0075] "Angiotensin receptor blocker" or "ARB" in the present application refers in particular to valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan or a pharmaceutically acceptable salt of one of these drugs. A preferred ARB is valsartan or a pharmaceutically acceptable salt thereof.

[0076] "Calcium channel blocker" or "CCB" in the present application refers in particular to amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, isradipine, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, verapamil or diltiazem or a pharmaceutically acceptable salt of one of these drugs. A preferred CCB is amlodipine or a pharmaceutically acceptable salt thereof.

[0077] Therefore, the crystalline form of the compound according to any one of embodiments 23) to 32) can be used in combination with an ACE inhibitor or an ARB and / or a CCB. The corresponding combined therapy can be carried out simultaneously, separately or over a period of time (especially simultaneously).

[0078] "Simultaneously" when referring to an administration type, in this application means that the administration type involved includes the administration of two or more active ingredients and / or treatments at about the same time; wherein it is understood that simultaneous administration will result in the subject being exposed to two or more active ingredients and / or treatments at the same time. When administered simultaneously, the two or more active ingredients may be administered in combination with a fixed dose, or in combination with an equivalent non-fixed dose (e.g., by using two or more different pharmaceutical compositions to be administered via the same administration route at about the same time), or in combination with a non-fixed dose using two or more different administration routes; wherein the administration results in the subject being exposed to two or more active ingredients and / or treatments substantially at the same time. For example, when used in combination with an ACE inhibitor, an ARB, and / or a CCB, the compound may be used "simultaneously". Similarly, when used in combination with a diuretic, the compound may be used "simultaneously".

[0079] "Fixed dose combination" when referring to an administration type, in this application means that the administration type involved involves the administration of a single pharmaceutical composition comprising two or more active ingredients.

[0080] "Single" when referring to an administration type, in the present application means that the administration type involved includes the administration of two or more active ingredients and / or treatments at different time points; it is understood that single administration will result in a treatment phase (e.g. at least 1 hour, in particular at least 6 hours, especially at least 12 hours) in which the subject is exposed to two or more active ingredients and / or treatments simultaneously; but single administration may also result in a treatment phase in which the subject is exposed to only one of the two or more active ingredients and / or treatments over a certain period of time (e.g. at least 12 hours, in particular at least one day). Single administration refers in particular to an administration cycle of at least one active ingredient and / or treatment that is significantly different from daily (e.g. once or twice daily) administration (e.g., one active ingredient and / or treatment is administered, for example, once or twice daily, while another active ingredient and / or treatment is administered every other day, once a week or at longer intervals).

[0081] In the present application, administration "over a period of time" refers to the sequential administration of two or more active ingredients and / or treatments at different times. The term refers in particular to an administration method according to which the entire administration of one of the active ingredients and / or treatments is completed before the administration of the other / other active ingredients and / or treatments begins. Thus, one of the active ingredients and / or treatments may be administered several months prior to the administration of the other active ingredients and / or treatments.

[0082] 35) Also preferably, the crystalline form of the compound according to any one of embodiments 23) to 32) or 33), or when combined with an ACE inhibitor or ARB and / or CCB according to embodiment 34), is used in combination with a diuretic (in particular in combination with hydrochlorothiazide (HCT) or chlorthalidone).

[0083] Therefore, the crystalline form of the compound according to any one of embodiments 23) to 32) can be used in combination with a diuretic (in particular in combination with HCT or chlorthalidone). The corresponding combination therapy can be carried out simultaneously, separately or over a period of time (in particular simultaneously), as defined above.

[0084] 36) Another aspect of the present invention relates to sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide compound according to any one of embodiments 1) to 7), for the prevention / prevention or treatment of CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD]; especially CKD caused by / associated with hypertension, and / or caused by / associated with diabetes (especially these stages) (DKD); and for the prevention / prevention or treatment of acute or chronic renal failure; diabetic nephropathy; or glomerulonephritis; Wherein, in a first sub-embodiment, this use is particularly used to treat such DKD in patients diagnosed with type 2 diabetes, wherein in particular aprocitentan reduces the rate of progression of DKD, wherein this reduction in the rate of progression can be particularly expressed by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; wherein it is worth noting that the patient also has a history of hypertension; Wherein, in a second sub-embodiment, this use is particularly for the treatment of such DKD in patients with type 2 diabetes, especially in such patients with a history of hypertension, including the treatment of diabetic nephropathy associated with elevated serum creatinine and / or proteinuria [particularly corresponding to stage 1 to 4 CKD (especially stage 3 or 4 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines]; for the prevention / prevention or treatment of diabetes and diabetes-related diseases, such as diabetic arteritis, diabetic retinopathy or diabetic vasculopathy; and diabetic complications; for reducing the risk of major cardiovascular events (such as HF, myocardial infarction, stroke or cardiovascular death) in diabetic patients, especially those with at least one other cardiovascular risk factor (such as hypertension); and for the prevention / prevention or treatment of diabetic foot ulcers and / or for reducing the risk of lower limb amputation in diabetic patients; for the prevention / prevention or treatment of heart failure (HF), particularly including chronic HF, particularly including systolic HF and diastolic HF; for reducing the risk of major cardiovascular events (such as HF, myocardial infarction, stroke or cardiovascular death) in patients at cardiovascular risk (such as patients with coronary artery disease and / or patients showing clinical symptoms of congestive HF); and for the prevention / prevention or treatment of ischemic heart disease, including angina pectoris, coronary artery disease and myocardial ischemia; cardiac insufficiency; or diastolic dysfunction; For the treatment of hypertension, including particularly difficult-to-treat / resistant hypertension; For the prevention / prevention or treatment of atherosclerosis; and peripheral arterial occlusive disease, including chronic peripheral arterial disease; For the prophylaxis / prevention or treatment of digital ulcers; or For the prevention / prevention or treatment of connective tissue diseases; Wherein the compound is (intended to be) administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0085] In particular, such CKD may be associated with macroalbuminuria (defined as UACR>300 mg / g).

[0086] UACR is a biomarker of renal dysfunction that is monitored in patients with renal insufficiency (Levey et al., Uses of GFR and albuminuria level in acute and chronic kidney disease. N Engl J Med. 2022; 386(22): 2120–28].

[0087] It should be understood that this method of treating CKD (especially stage 3 or stage 4 CKD) caused by / associated with hypertension and optionally further associated with diabetes mellitus (diabetic nephropathy (DKD)) also refers to the treatment of difficult-to-control hypertension and resistant hypertension, wherein the hypertension includes the hypertension that causes / is associated with such CKD, and wherein the CKD is optionally associated with diabetes mellitus in addition to the hypertension.

[0088] 37) Another embodiment relates to compounds for use according to embodiment 36); wherein the compound for the prevention / prevention or treatment of CKD [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD], including CKD caused / associated with hypertension [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD], and CKD caused / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] (diabetic nephropathy, DKD); Wherein, this use is particularly for treating such DKD in patients diagnosed with type 2 diabetes, wherein in particular aprocitentan reduces the rate of progression of DKD, wherein the reduction in the rate of progression can be particularly expressed by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; wherein it is worth noting that the patient also has a history of hypertension; For the prevention / prevention or treatment of acute renal failure; For the prevention / prevention or treatment of chronic renal failure; For the prevention / prevention or treatment of diabetic nephropathy; For the prevention / prevention or treatment of glomerulonephritis; To reduce the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially those with at least one other cardiovascular risk factor (e.g., hypertension); For the prevention / prevention or treatment of diabetic foot ulcers and / or for reducing the risk of lower limb amputation in patients with diabetes; For the prevention / prevention or treatment of heart failure (HF), especially including chronic HF, especially systolic HF or diastolic HF; To reduce the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke, or cardiovascular death) in patients at risk for cardiovascular disease (e.g., patients with coronary artery disease and / or patients showing clinical signs of congestive HF); For the prevention / prevention or treatment of diastolic dysfunction; for the treatment of hypertension, including particularly difficult-to-treat / resistant hypertension; or For the prevention / prevention or treatment of atherosclerosis; and peripheral arterial occlusive disease, including chronic peripheral arterial disease; wherein the compound is (intended to be) administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0089] 38) Another embodiment relates to compounds for use according to embodiment 36); wherein the compound For the prevention / prevention or treatment of CKD caused by / associated with hypertension [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD], For the prevention / prevention or treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] (DKD); Wherein, this use is particularly for treating such DKD in patients diagnosed with type 2 diabetes, wherein in particular aprocitentan reduces the rate of progression of DKD, wherein the reduction in the rate of progression can be particularly expressed by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; wherein it is worth noting that the patient also has a history of hypertension; For the prevention or treatment of chronic renal failure caused by / related to hypertension or caused by / related to diabetes; diabetic nephropathy; or glomerulonephritis caused by / related to hypertension; To reduce the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially those with at least one other cardiovascular risk factor (e.g., hypertension); for the prophylaxis / prevention or treatment of diabetic foot ulcers and / or for reducing the risk of lower limb amputation in patients with diabetes; or For the prevention / prevention or treatment of heart failure (HF), especially including chronic HF, especially systolic HF or diastolic HF; wherein the compound is (intended to be) administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0090] 39) Another embodiment relates to compounds for use according to embodiment 36); wherein the compound For the prevention / prevention or treatment of CKD caused by / associated with hypertension [particularly stage 1 to 4 CKD, especially stage 3 or 4 CKD], and / or For the prevention / prevention or treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] (DKD); Wherein, this use is particularly for treating such DKD in patients diagnosed with type 2 diabetes, wherein in particular aprocitentan reduces the progression rate of DKD, wherein the reduction in the progression rate can be particularly expressed by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; wherein it is worth noting that the patient also has a history of hypertension; and / or To reduce the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially those with at least one other cardiovascular risk factor (e.g., hypertension); wherein the compound is (intended to be) administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0091] 40) Another embodiment relates to compounds for use according to embodiment 36); wherein the compound For the prevention / prevention or treatment of CKD caused by / associated with hypertension [particularly stage 1 to 4 CKD, especially stage 3 or 4 CKD], and / or For the prevention / prevention or treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] (DKD); Wherein, this use is particularly for treating such DKD in patients diagnosed with type 2 diabetes, wherein in particular aprocitentan reduces the rate of progression of DKD, wherein the reduction in the rate of progression can be particularly expressed by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; wherein it is worth noting that the patient also has a history of hypertension; wherein the compound is (intended to be) administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0092] 41) Another embodiment relates to compounds for use according to embodiment 36); wherein the compound For the prevention / prevention or treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 or 4 CKD] (DKD); Wherein, in a first sub-embodiment, this use is particularly used to treat such DKD in patients diagnosed with type 2 diabetes, wherein in particular aprocitentan reduces the rate of progression of DKD, wherein this reduction in the rate of progression can be particularly expressed by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; wherein it is worth noting that the patient also has a history of hypertension; Wherein, in a second sub-embodiment, this use is particularly for the treatment of such DKD in patients with type 2 diabetes, especially in such patients with a history of hypertension, including the treatment of diabetic nephropathy associated with elevated serum creatinine and / or proteinuria [particularly corresponding to stage 1 to 4 CKD (especially stage 3 or 4 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines]; wherein the compound is (intended to be) administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0093] 42) Another embodiment relates to compounds for use according to embodiment 36); wherein the compound To reduce the risk of major cardiovascular events (e.g., HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially those with at least one other cardiovascular risk factor (e.g., hypertension); wherein the compound is (intended to be) administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0094] 43) Another embodiment relates to a compound for use according to any one of embodiments 29) to 35); wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is in particular bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, hengagliflozin, ipagliptin, luciglipflozin, sopagliflozin or topagliflozin (especially canagliflozin, dapagliflozin or empagliflozin; in particular empagliflozin) or a pharmaceutically acceptable salt thereof.

[0095] It is to be understood that any embodiment involving compounds for use in treating certain endothelin-related diseases and conditions specifically defined herein, wherein the compound is (intended to be) administered in combination with another active ingredient (e.g., one or more diuretics, ARBs or ACE inhibitors, CCBs and / or SGLT-2 inhibitors) also involves Such active ingredients disclosed herein (intended to be) administered in combination with compounds for the treatment of said endothelin-related diseases and disorders; Use of a compound for the manufacture of a medicament / pharmaceutical composition comprising the compound and such active ingredients disclosed herein for the treatment of said endothelin-related diseases and disorders; Use of a compound for the manufacture of a medicament / pharmaceutical composition comprising the compound as an active ingredient for treating said endothelin-related diseases and disorders; wherein said medicament / pharmaceutical composition is (intended to be) used in combination with an active ingredient disclosed herein; Use of such active ingredients disclosed herein for the manufacture of a medicament / pharmaceutical composition comprising such active ingredients disclosed herein as an active ingredient for treating said endothelin-related diseases and disorders; wherein said medicament / pharmaceutical composition is (intended to be) used in combination with a compound; Use of a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof and an active ingredient disclosed herein for treating said endothelin-related diseases and disorders; A medicament for preventing or treating said endothelin-related diseases and disorders, said medicament comprising a compound; wherein said medicament is (intended to be) administered in combination with said active ingredient; A method of treating said endothelin-related diseases and disorders, comprising administering to a subject (preferably a human) in need thereof an effective amount of a compound in combination with an effective amount of such an active ingredient; A method for treating such endothelin-related diseases and disorders, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound and such active ingredient disclosed herein; and - A method of treating such endothelin-related diseases and disorders, comprising administering to a subject (preferably a human) in need thereof an effective amount of such active ingredient disclosed herein in combination with an effective amount of a compound.

[0096] 44) The present invention also relates to a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7, in particular a substantially pure crystalline form, for use in preventing or treating endothelin-related diseases and disorders as defined above, wherein the crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide is administered in combination with one or more active ingredients [in particular at least two (in particular three or four) other active ingredients], wherein the one or more active ingredients are independently selected from the following active ingredient groups: angiotensin receptor blockers (particularly valsartan, as well as losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; or ACE inhibitors (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; and / or calcium channel blockers (particularly amlodipine, as well as aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or pharmaceutically acceptable salts thereof; and / or an aldosterone antagonist such as spironolactone, eplerenone or fenirone; or an aldosterone synthase inhibitor (such as batroxostat); and / or Diuretics selected from: loop diuretics, which include furosemide, bumetanide, ethacrynic acid, or torsemide; Carbonic anhydrase inhibitors, which include acetazolamide or methazolamide; in particular a diuretic of the thiazide type (thiazide diuretics), such as, inter alia, chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferred diuretics are thiazide diuretics, in particular chlorthalidone or hydrochlorothiazide); or a potassium-sparing diuretic that is not an aldosterone antagonist or aldosterone synthase inhibitor (an example is amiloride); and / or beta-blockers (beta-adrenergic blockers), especially acebutolol, atenolol, bisoprolol, metoprolol (immediate release or extended release), nadolol, nebivolol, propranolol (immediate release or extended release); and / or SGLT-2 inhibitors (especially atagliflozin, bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, hengagliflozin, ipragliflozin, lucigliflozin, remogliflozin, sotagliflozin or tofogliflozin; or a pharmaceutically acceptable salt thereof; especially bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, hengagliflozin, ipragliflozin, lucigliflozin, sotagliflozin or tofogliflozin; in particular canagliflozin, dapagliflozin or empagliflozin) or a pharmaceutically acceptable salt thereof.

[0097] 45) The present invention also relates to a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7, in particular a substantially pure crystalline form, for use in preventing or treating endothelin-related diseases and disorders as defined above, wherein the crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide is administered in combination with one or more active ingredients [in particular at least two (in particular three or four) other active ingredients], wherein the one or more active ingredients are independently selected from the following active ingredient groups: angiotensin receptor blockers (particularly valsartan, as well as losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; or ACE inhibitors (particularly enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; and / or calcium channel blockers (particularly amlodipine, as well as aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or pharmaceutically acceptable salts thereof; and / or Loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; and / or Another diuretic selected from Potassium-sparing diuretics that are not aldosterone antagonists or aldosterone synthase inhibitors, such as amiloride; an aldosterone antagonist, such as spironolactone, eplerenone, or finarezone; or an aldosterone synthase inhibitor (such as batroxostat); carbonic anhydrase inhibitors, which include acetazolamide and methazolamide; or In particular, a diuretic of the thiazide type (thiazide diuretics), such as, inter alia, chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferred diuretics are thiazide diuretics, in particular chlorthalidone or hydrochlorothiazide); and / or beta-blockers (beta-adrenergic blockers), especially acebutolol, atenolol, bisoprolol, metoprolol (immediate release or extended release), nadolol, nebivolol, propranolol (immediate release or extended release); and / or SGLT-2 inhibitors (especially atagliflozin, bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, hengagliflozin, ipragliflozin, lucigliflozin, remogliflozin, sotagliflozin or tofogliflozin; or a pharmaceutically acceptable salt thereof; especially bepagliflozin, canagliflozin, dapagliflozin, empagliflozin, erpagliflozin, hengagliflozin, ipragliflozin, lucigliflozin, sotagliflozin or tofogliflozin; in particular canagliflozin, dapagliflozin or empagliflozin) or a pharmaceutically acceptable salt thereof.

[0098] The term "beta-blocker" refers to such beta-adrenergic blocking agents, in particular acebutolol, atenolol, bisoprolol, metoprolol (including immediate release or extended release formulations), nadolol, nebivolol and propranolol (including immediate release or extended release formulations); in particular atenolol, bisoprolol, metoprolol, nebivolol and propranolol.

[0099] In some cases, further background treatment may include active ingredients suitable for the treatment of diabetes, such as metformin; and / or insulin; and / or sulfonylurea (especially glibenclamide), or a pharmaceutically acceptable salt thereof; and / or a DPP-4 inhibitor (especially sitagliptin, vildagliptin, saxagliptin or linagliptin), or a pharmaceutically acceptable salt thereof; and / or a GLP-1 receptor agonist (especially exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, tasiglutide, semaglutide, or a dual GLP-1 / GIP agonist such as triazolidine); and / or a thiazolidinedione, or a pharmaceutically acceptable salt thereof.

[0100] The term "DPP-4 inhibitor" or "DPP-IV inhibitor" refers to inhibitors of dipeptidyl peptidase 4, such as, in particular, sitagliptin, vildagliptin, saxagliptin and linagliptin, and also gemagliptin, anagliptin, tiligliptin, alogliptin, trelagliptin, omagliptin, emlagliptin and dulagliptin.

[0101] The term "GLP-1 receptor agonist" refers to an agonist of the glucagon-like peptide-1 receptor, such as, inter alia, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, tasiglutide, semaglutide.

[0102] The term "dual GLP-1 / GIP receptor agonist" refers to a dual agonist of the glucagon-like peptide-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as, in particular, a triazole salt.

[0103] The term "sulfonylurea" refers in particular to glibenclamide (glyburide), glibourea, gliclazide, glipizide, gliquidone, glisopaide, glypyruvide or glimepiride.

[0104] The term "thiazolidinedione", abbreviated as TZD, also known as glitazone, refers to an agonist of PPAR (peroxisome proliferator-activated receptor gamma), in particular pioglitazone, rosiglitazone or rosiglitazone.

[0105] Background therapy is preferably administered in a dosage corresponding to the tolerated effective dose of each active ingredient, for example, when administered as a monotherapy. Specifically, valsartan or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 160 mg or 320 mg valsartan per day; losartan or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 50 mg or 100 mg losartan per day; irbesartan or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 75 mg, 150 mg or 300 mg irbesartan per day; amlodipine or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 5 mg or 10 mg amlodipine per day; enalapril or its pharmaceutically acceptable salt is administered in a dosage form suitable for oral administration of 10 mg or 5 mg amlodipine per day; The salt of enalapril (if present) is administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg of enalapril per day; lisinopril or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg of lisinopril per day; ramipril or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 2.5 mg to 20 mg of ramipril per day; metformin (if present) is administered in a dosage form suitable for oral administration of 500 mg to 2000 mg of metformin per day; glibenclamide (if present) is administered in a dosage form suitable for oral administration of 1.25 mg to 5 mg of glibenclamide per day; sitagliptin (such as if present), is administered in a dosage form suitable for oral administration of 25 mg to 100 mg of sitagliptin per day; vildagliptin (if present) is administered in a dosage form suitable for oral administration of 50 mg of vildagliptin twice a day; saxagliptin (if present) is administered in a dosage form suitable for oral administration of 2.5 mg or 5 mg of saxagliptin per day; linagliptin (if present) is administered in a dosage form suitable for oral administration of 5 mg of linagliptin twice a day; bepagliflozin or a pharmaceutically acceptable salt thereof (if present) is administered in a dosage form suitable for oral administration of 5 to 50 mg (particularly 20 mg) of bepagliflozin per day; canagliflozin or a pharmaceutically acceptable salt thereof (if present) is administered in a dosage form suitable for oral administration of 100 mg of linagliptin twice a day; 50 to 400 mg (especially 50 mg, 100 mg, 150 mg or 300 mg; especially 100 mg or 300 mg; especially 100 mg) of canagliflozin is administered orally; dapagliflozin or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for daily oral administration of 1 to 20 mg (especially 5 mg or 10 mg) of dapagliflozin; empagliflozin or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for daily oral administration of 5 to 50 mg (especially 10 mg or 25 mg) of empagliflozin; erpagliflozin or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for daily oral administration of 2.5 to 50 mg (especially 5 mg or 15 mg) of erpagliflozin is administered in a dosage form suitable for oral administration of 5 to 100 mg (especially 25 mg) of erpagliflozin per day; ipagliptin or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 10 to 100 mg (especially 25 mg or 50 mg) of ipagliptin per day; lucigliptin or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 5 to 50 mg (especially 5 mg or 15 mg) of ipagliptin per day; lucigliptin or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 5 to 100 mg (especially 25 mg or 50 mg) of ipagliptin per day Administered in a dosage form suitable for oral administration of 1 to 10 mg (especially 2.5 mg or 5 mg) of lucigafloxacin per day; sotagliflozin or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 50 to 500 mg (especially 75 mg, 200 mg or 400 mg) of sotagliflozin per day; tofogliflozin or its pharmaceutically acceptable salt (if present) is administered in a dosage form suitable for oral administration of 10 to 50 mg (especially 20 mg) of tofogliflozin per day.

[0106] 46) Another embodiment relates to a pharmaceutical composition comprising as active ingredient a crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium) according to any one of embodiments 1) to 7, one or more other active ingredients as defined above (e.g. in embodiment 44) or 45)) (in particular including a diuretic, such as an aldosterone antagonist, such as eplerenone, or an aldosterone synthase inhibitor, such as batroxostat; and / or a thiazide diuretic, such as HTC or chlorthalidone; and / or an ARB or an ACE inhibitor; and / or a CCB; and / or an SGLT-2 inhibitor), as defined above, and at least one therapeutically inert excipient.

[0107] 47) Another embodiment relates to the pharmaceutical composition according to embodiment 46), wherein the pharmaceutical composition is in the form of a tablet or a capsule.

[0108] 48) The present invention also relates to a kit comprising a pharmaceutical composition / medicament comprising a compound in crystalline form according to any one of embodiments 1) to 7) and a pharmaceutically acceptable carrier material, and optionally another active ingredient as defined above; And instructions for using the pharmaceutical composition / medicament for the prevention / prevention or treatment of endothelin-related diseases or disorders defined herein in combination with other active ingredients as defined above (as defined above, for example in Embodiment 44) or 45), in particular including a diuretic, for example an aldosterone antagonist, for example eplerenone, or an aldosterone synthase inhibitor, for example batroxostat; and / or a thiazide diuretic, for example HTC or chlorthalidone; and / or an ARB or an ACE inhibitor; and / or a CCB; and / or an SGLT-2 inhibitor).

[0109] The amount of crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide administered according to any one of embodiments 1) to 7 corresponds in particular to 10 to 50 mg, in particular 10 to 25 mg, in particular 12.5 mg or 25 mg of aprocitentan in free acid form per day (wherein the amount is preferably administered once a day in the morning).

[0110] Therefore, any pharmaceutical composition mentioned herein particularly comprises sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of embodiments 1) to 7) in a pharmaceutical unit dosage form suitable for oral administration of an amount of aprocitentan (free acid form) corresponding to 10 to 50 mg (especially 10 to 25 mg, in particular 12.5 mg or 25 mg) per day.

[0111] Specific embodiments of the invention are described in the following examples, which serve to illustrate the invention in more detail without limiting its scope in any way. Experimental Section

[0112] The following abbreviations are used throughout the specification and examples: ° degree ℃ Celsius EtOAc Ethyl acetate eq. equivalent g GVS Gravimetric Vapor Sorption h hour HPLC High Performance Liquid Chromatography kg kilogram kV kilovolt L (or l) liter m / m mass / mass ratio mA mbar millibar MeCN Acetonitrile MeOH Methanol mg milligram min mL (or ml) milliliters mol mole mm Millimeters NaOH Sodium hydroxide rpm revolutions per minute s seconds RH (or rh) relative humidity THF Tetrahydrofuran vol. volume w / w weight / weight ratio wt. unit of weight All temperatures are in °C. X-ray powder diffraction (XRPD) analysis

[0113] All XRPD patterns of solid forms described herein were obtained as described below. TM Sample stage, CuKα radiation (40kV, 40mA) and 1D-Linear LynxEye TM The diffraction patterns were measured on a Bruker D8Advance diffractometer with a detector. The samples were prepared on a silicon single crystal sample holder with a cavity diameter of 25 mm and a depth of 0 mm, 0.2 mm or 0.5 mm. The powder was spread with a microscope slide to obtain a flat surface. The diffraction pattern was collected in reflection mode with a coupled θ / 2θ angle in the range of 3-50°2θ with an increment of 0.02° and an accumulation time of 0.4 seconds per step. The divergence and anti-scatter slits were set to 0.3°. During the measurement, the sample was rotated continuously at a speed of 30 rpm. The accuracy of the 2θ value of the peak position is + / -0.2°. This is usually the same as the conventionally recorded X-ray powder diffraction patterns. Differential Scanning Calorimetry (DSC)

[0114] DSC data were collected on a Mettler-Toledo STARe system (DSC822e module, measurement cell with ceramic sensor, and STAR software version 9.20) equipped with a 34-position autosampler. The instrument was calibrated for energy and temperature using certified indium. Typically, 1–5 mg of each sample placed in an automatically perforated aluminum pan was heated at 10 °C min -1 Unless otherwise stated, the sample was heated from -20°C to 280°C. The sample was kept on for 20 ml min -1 The peak temperatures reported are melting points. Thermogravimetric analysis (TGA)

[0115] TGA data were collected on a Mettler Toledo STARe system (TGA851e module and STAR software version 9.20) equipped with a 34-position autosampler. Typically, approximately 5 mg of sample was placed in an automatically perforated aluminum pan and heated at 10 °C min -1 Unless otherwise stated, the heating rate is from 30°C to 250°C. -1 The sample was purged with nitrogen at a rate of . Gravimetric Vapor Sorption (GVS)

[0116] Hygroscopicity is characterized by measuring the water sorption isotherm at 25°C on a Hiden Analytical Ltd. IGASORP Model HAS-036-080. After equilibration at 40% rh, the relative humidity of the sample is increased in steps of 5% to 80% rh, allowing a minimum equilibration time of 720 minutes and a maximum equilibration time of 1440 minutes for each step. Hygroscopicity is based on the definition provided by EUROPEAN PHARMACOPOEIA 7.0 "5.11. Characters section in monographs", where non-hygroscopic: mass increase less than 0.2% m / m; slightly hygroscopic: mass increase less than 2% m / m and equal to or greater than 0.2% m / m; hygroscopic: mass increase less than 15% m / m and equal to or greater than 2% m / m. Determined by HPLC assay

[0117] UV-HPLC (e.g., Shimadzu Nexera X2 system) was used for determination, with the autosampler temperature set at 25°C and the column temperature set at 50°C. Typically, 1 μL of sample was injected and a Phenomenex Gemini 5.0 μm The separation was performed on a 50×2.0 mm column at a flow rate of 1.5 mL / min. The sample was usually prepared by dissolving in acetonitrile / carbonate buffer at pH 10 1 / 1. A gradient method was used, with solvent A consisting of Trizma base buffer 50 mM pH 9 (adjusted with HCl) and solvent B consisting of acetonitrile + 5% (v / v) Trizma base buffer 50 mM pH 9 (adjusted with HCl). The following gradient was usually used: Example Example 1a: Compound in Crystalline Form 1

[0118] The mixture consisting of 5mL MeOH, 50mg free acid form of aprocitentan and 1eq.1M NaOH mixture was evaporated. 0.5mL MeOH and 0.5mL MeCN were added to the remaining oily residue, and the mixture was sealed and left to stand overnight at ambient temperature. The solid residue was collected, washed with 0.2mL MeCN, and dried under reduced pressure of 2mbar for 1 hour. The solid was a compound of crystalline form 1. Example 1b: Compound in Crystalline Form 1

[0119] 250 mg of aprocitentan in free acid form was dissolved in 15 mL THF and 5 mL MeOH. 0.458 mL 1M NaOH solution was added to the solution. The solution was allowed to stand for 5 minutes and then concentrated on a rotary evaporator. The remaining oil was briefly dried under high vacuum, dissolved in 2 mL hot MeOH, 15 mL MeCN was added, and the mixture was allowed to stand in a closed container under ambient conditions. After 3 hours, the solid material was collected, washed with 2×2 mL MeCN, and dried at 2 mbar for 1 hour. The solid was a compound in crystalline form 1. Example 1c: Compound in Crystalline Form 1

[0120] A reactor was charged with aprocitentan in free acid form (3.5 kg, 6.4 mol, 1.0 eq.) and MeOH (24.9 kg, 9.0 vol.). Sodium methoxide methanol solution (30%; 1.16 kg, 6.4 mol, 1.0 eq.) was added and rinsed with MeOH (2.8 kg, 1.0 vol.). The mixture was stirred at 20°C for 4 hours and then concentrated to a residual volume of 14 L (4 vol.) at 20°C and 100 mbar. EtOAc (31.5 kg, 10.0 vol.) was added and more solvent was removed by distillation under the same conditions until the final volume was 21 L (6 vol.). EtOAc (15.8 kg, 5 vol.) was added and the mixture was stirred at 20°C overnight and then at 0°C for 2 hours. Filtration, washing with cold EtOAc (20 kg, 5.7 vol.) and drying at 30-55°C afforded the compound (3.15 kg, 87% yield) as a white solid. The solid was the compound in crystalline form 1. The data are summarized in the table below. Table 1: Characterization data of the compound in crystalline form 1 Example 2: Compound in Crystalline Form 2

[0121] The compound in crystalline form 1 was stored at 23°C and 92% rh for 9 weeks. The solid was immediately measured by XRPD. The data are summarized in the table below. The solid is the compound in crystalline form 2. Table 2: Characterization data of the compound of crystalline form 2 technology Data Summary Remark XRPD crystallization See Figure 2 TGA The mass loss in the range of 34℃ to 199℃ is 0.9% Example 3: Compound in Crystalline Form 3

[0122] A solution consisting of 9.2 mL 0.1 M NaOH, 500 mg aprocitentan free acid form and 25 mL MeCN was evaporated to dryness on a rotary evaporator at 40°C. 5 mL MeOH was added to the solid residue and stirred at ambient temperature. After 2-3 hours the suspension was filtered and the solid immediately analyzed was the compound in crystalline form 3. Table 3: Characterization data of the compound in crystalline form 3 technology Data Summary Remark XRPD crystallization See Figure 3 Example 4: Compound in Crystalline Form 4

[0123] Aprocitentan free acid form (3.5 kg, 6.4 mol, 1.0 equiv) and MeOH (24.9 kg, 9.0 vol.) were charged to the reactor. Sodium methoxide methanol solution (30%; 1.16 kg, 6.4 mol, 1.0 equiv.) was added and rinsed with MeOH (2.8 kg, 1.0 vol.). The mixture was stirred at 20°C for 4 hours, then transferred to a rotary evaporator and stripped at 30°C. The stripped product was returned to the reactor and rinsed with ethyl acetate (31.5 kg, 10 vol.). The mixture was stirred at 20°C for 2 hours, cooled to 0-5°C, the product was filtered, washed with cold ethyl acetate (7 L, 2.0 vol.) to obtain a wet product, which was then dried under vacuum at 30°C for 4 days with nitrogen gas, and the dry weight was 3.05 kg (yield 84%). The final solid material was the compound in crystalline form 4. Table 4: Characterization data of the compound of crystalline form 4 technology Data Summary Remark XRPD crystallization See Figure 4 Stability comparison test

[0124] A head-to-head stability comparison evaluation of aprocitentan in free form (aprocitentan in crystalline form A) (prepared according to Example 1 of WO2018 / 154101) and a compound of crystalline form 1 according to the present invention was performed, including storing samples of the above materials in open vials in parallel at a certain temperature and relative humidity (RH), and measuring the content in the stored samples by HPLC (method described above) at different time points. The results are summarized in the table below. Table 5

[0125] The data presented in Table 5 indicate that under certain experimental conditions, crystalline Form 1 of the compound has superior chemical stability compared to aprocitentan free acid form (crystalline Form A).

Claims

1. Crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium in Form 1 of the compound is characterized in that, in an X-ray powder diffraction pattern, there are at least four, or at least six, or at least eight peaks at diffraction angles 2θ selected from the group consisting of 4.3°, 13.1°, 13.5°, 14.8°, 17.2°, 19.5°, 21.1°, 21.6°, 22.6°, and 25.0°; Form 2 of the compound is characterized in that, in an X-ray powder diffraction pattern, there are at least four, or at least six, or at least eight peaks at diffraction angles 2θ selected from the group consisting of 4.2°, 13.3°, 16.7°, 16.9°, 18.9°, 20.8°, 22.5°, 23.5°, 25.6°, and 27.2°; or Form 3 of the compound is characterized in that, in an X-ray powder diffraction pattern, there are at least four, at least six, or at least eight peaks at diffraction angles 2θ selected from the group consisting of: 3.9°, 11.9°, 15.0°, 15.8°, 17.0°, 19.8°, 22.4°, 23.3°, 23.8°, and 27.8°; wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation, without Kα2 exfoliation; and the accuracy of the 2θ value is within the range of + / -0.1°-0.2°.

2. A crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium, wherein Form 1 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ in an X-ray powder diffraction pattern: 4.3°, 17.2° and 22.6°; Form 2 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ in an X-ray powder diffraction pattern: 13.3°, 20.8° and 22.5°; or Form 3 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ in an X-ray powder diffraction pattern: 3.9°, 15.8° and 19.8°; wherein the X-ray powder diffraction pattern is obtained using combined Cu Kα1 and Kα2 radiation, without Kα2 exfoliation; and the accuracy of the 2θ value is within the range of + / -0.1°-0.2°.

3. A crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium, wherein Form 1 of the compound is characterized in that, in an X-ray powder diffraction pattern, peaks are present at the following diffraction angles 2θ: 4.3°, 17.2°, 21.1°, 21.6° and 22.6°; Form 2 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ in an X-ray powder diffraction pattern: 4.2°, 13.3°, 18.9°, 20.8° and 22.5°; or Form 3 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ in an X-ray powder diffraction pattern: 3.9°, 15.8°, 19.8°, 23.8° and 27.8°; wherein the X-ray powder diffraction pattern is obtained using combined Cu Kα1 and Kα2 radiation, without Kα2 exfoliation; and the accuracy of the 2θ value is within the range of + / -0.1°-0.2°.

4. A crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium, wherein The form of Compound 1 is characterized by the presence of peaks at the following diffraction angles 2θ in an X-ray powder diffraction pattern: 4.3°, 13.1°, 13.5°, 14.8°, 17.2°, 19.5°, 21.1°, 21.6°, 22.6°, and 25.0°; Form 2 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ in an X-ray powder diffraction pattern: 4.2°, 13.3°, 16.7°, 16.9°, 18.9°, 20.8°, 22.5°, 23.5°, 25.6° and 27.2°; or Form 3 of the compound is characterized by the presence of peaks at the following diffraction angles 2θ in an X-ray powder diffraction pattern: 3.9°, 11.9°, 15.0°, 15.8°, 17.0°, 19.8°, 22.4°, 23.3°, 23.8° and 27.8°; wherein the X-ray powder diffraction pattern is obtained using combined Cu Kα1 and Kα2 radiation, without Kα2 exfoliation; and the accuracy of the 2θ value is within the range of + / -0.1°-0.2°.

5. A crystalline form of the compound sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide showing essentially the following X-ray powder diffraction pattern: · Form 1 shown in Figure 1; · Form 2 as shown in Figure 2; or · Form 3 shown in Figure 3; wherein the X-ray powder diffraction pattern is obtained using combined Cu Kα1 and Kα2 radiation, without Kα2 exfoliation; and the accuracy of the 2θ value is within the range of + / -0.1°-0.2°.

6. A crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium according to any one of claims 1 to 5 for use in the manufacture of a pharmaceutical composition, wherein the pharmaceutical composition comprises: the compound {5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide as an active ingredient, and at least one therapeutically inert excipient.

7. A pharmaceutical composition comprising a crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium according to any one of claims 1 to 5 as an active ingredient, and at least one therapeutically inert excipient.

8. A crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of claims 1 to 5 for use in the treatment of hypertension, pulmonary hypertension, coronary heart disease, heart failure, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, digital ulcers or portal hypertension, and for the treatment or prevention of atherosclerosis ulceration, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, cancer, melanoma, prostate cancer, prostate hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram-negative sepsis, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue disease, complications of diabetes, complications after vascular or cardiac surgery or organ transplantation, complications of cyclosporine therapy, pain, or hyperlipidemia.

9. A crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide compound according to any one of claims 1 to 5 for use in the treatment of hypertension, including particularly refractory / resistant hypertension; CKD, including CKD caused by / associated with hypertension, and / or CKD caused by / associated with diabetes (DKD); acute or chronic renal failure; diabetic nephropathy; glomerulonephritis; or heart failure (HF), including chronic HF.

10. A crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of claims 1 to 5 for use in the treatment of essential hypertension, resistant hypertension, pulmonary hypertension or pulmonary arterial hypertension.

11. A crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of claims 1 to 5 for use in the treatment of resistant hypertension.

12. Use of a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of claims 1 to 5 in the preparation of a medicament for treating: hypertension, including particularly difficult-to-treat hypertension / resistant hypertension; CKD, including CKD caused by / associated with hypertension, and / or CKD caused by / associated with diabetes (DKD); acute or chronic renal failure; diabetic nephropathy; glomerulonephritis; or heart failure (HF), including chronic HF.

13. A method for treating hypertension, including particularly refractory hypertension / resistant hypertension; CKD, including CKD caused by / associated with hypertension, and / or CKD caused by / associated with diabetes (DKD); acute or chronic renal failure; diabetic nephropathy; glomerulonephritis; or heart failure (HF), including chronic HF, the method comprising administering to the patient an effective amount of a crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 7.

14. A method for treating resistant hypertension, comprising administering to a patient an effective amount of a crystalline form of the compound (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide sodium according to any one of claims 1 to 5, or a pharmaceutical composition according to claim 7.

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