Crystal form 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 aprocitentan sodium salt, a method for producing the same, a pharmaceutical composition having the crystalline form, a pharmaceutical composition produced from such a crystalline form, 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 "compound"), a method for producing the same, a pharmaceutical composition having 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 may be represented by Formula I.

[0003]

Chemical Formula

Background Art

[0004] Aprocitentan ({5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yl-oxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, the "Compound" in free acid form) is also known by the name ACT-132577 and is an endothelin receptor inhibitor useful as an endothelin receptor antagonist. Aprocitentan is a member of a structural family of compounds previously disclosed in WO02 / 053557 in its entirety. As disclosed in WO2009 / 024906, Aprocitentan is suitable for pharmaceutical compositions with sustained efficacy. WO2018 / 153513 and WO2019 / 106066 relate to combination agents having Aprocitentan. A specific manufacturing method for Aprocitentan is disclosed in WO2015 / 121397. WO2018 / 154101 discloses a specific crystalline form of Aprocitentan.

[0005] By virtue of its ability to inhibit the binding of endothelin, Aprocitentan can be used in the treatment of endothelin-related diseases associated with increased vasoconstriction, proliferation or inflammation caused by endothelin. Examples of such endothelin-related diseases are hypertension, pulmonary hypertension, coronary artery disease, heart failure, renal or myocardial ischemia, renal insufficiency, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, digital ulcers and portal hypertension. They can also be used in the treatment or prevention of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction. Furthermore, they can be used in the treatment and prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, cancer, melanoma, prostate cancer, benign prostatic hyperplasia, erectile dysfunction, hearing loss, cataract, chronic bronchitis, asthma, pulmonary fibrosis, gram-negative sepsis, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, treatment or prevention of connective tissue diseases, diabetic complications, complications after vascular or cardiac surgery, or after organ transplantation, complications of cyclosporine treatment, pain, hyperlipidemia, and treatment and prevention of other diseases currently known to be related to endothelin. Summary of the Invention

[0006] Summary of the Invention It has been found that a specific crystalline form of the "compound" (sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide) can be obtained under specific conditions. The said crystalline form of the "compound" is novel and would have advantageous properties from the viewpoint of the usability of the "compound" as a pharmaceutically active ingredient. Such advantages would include physical and / or chemical stability; lower hygroscopicity; better flow properties; better reproducibility in production (e.g., better filtration parameters, better formation reproducibility and / or better sedimentation); and / or a defined morphology. Such a crystalline form of the "compound" would be particularly suitable for a method for producing a specific pharmaceutical composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0007]

Figure 1

Figure 2

Figure 3

Figure 4

[0008]

Table 1

[0009] In the X-ray diffractograms of Figures 1 to 4, the diffraction angle 2 theta is plotted on the horizontal axis and the count is plotted on the vertical axis. To avoid any ambiguity, the above peaks describe the experimental results of the diffractograms shown in Figures 1 to 4. In contrast to the above list of peaks (see the above table), it should be understood that only selected characteristic peaks are necessary to fully and clearly characterize the "compound" of each crystalline form of the present invention.

[0010] Detailed description of the present invention 1) A 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

[0011]

Chemical formula

[0012] and - The crystalline form 1 of the "compound" is characterized by the presence of at least 4, or particularly at least 6, or especially at least 8 peaks at the refractive angles 2θ (2 theta) selected from 4.3°, 13.1°, 13.5°, 14.8°, 17.2°, 19.5°, 21.1°, 21.6°, 22.6° and 25.0° in the powder X-ray diffractogram; - The crystalline form 2 of the "compound" is characterized by the presence of at least 4, or particularly at least 6, or especially at least 8 peaks at the refractive angles 2θ (2 theta) selected from 4.2°, 13.3°, 16.7°, 16.9°, 18.9°, 20.8°, 22.5°, 23.5°, 25.6° and 27.2° in the powder X-ray diffractogram; - The crystalline form 3 of the "compound" is characterized by the presence of at least 4, or particularly at least 6, or especially at least 8 peaks at the refractive angles 2θ (2 theta) selected from 3.9°, 11.9°, 15.0°, 15.8°, 17.0°, 19.8°, 22.4°, 23.3°, 23.8° and 27.8° in the powder X-ray diffractogram; or, - The crystalline form 4 of the "compound" is characterized by the presence of at least 4, or particularly at least 6, or especially at least 8 peaks at the refractive angles 2θ (2 theta) selected from 5.9°, 7.7°, 13.9°, 17.0°, 17.6°, 19.4°, 20.0°, 20.7°, 21.9° and 23.5° in the powder X-ray diffractogram.

[0013] 2) One aspect of the present invention relates to a crystalline form of the "compound", sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide, - The crystalline form 1 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (2 theta) in the powder X-ray diffractogram: 4.3°, 17.2° and 22.6°; - The crystalline form 2 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (two-theta) in the powder X-ray diffractogram: 13.3°, 20.8°, and 22.5°; - The crystalline form 3 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ ( two-theta) in the powder X-ray diffractogram: 3.9°, 15.8°, and 19.8°; or, - The crystalline form 4 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (two-theta) in the powder X-ray diffractogram: 5.9°, 20.7°, and 21.9°.

[0014] 3) Another aspect of the present invention relates to the crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide, - The crystalline form 1 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (two-theta) in the powder X-ray diffractogram: 4.3°, 17.2°, 21.1°, 21.6°, and 22.6°; - The crystalline form 2 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (two-theta) in the powder X-ray diffractogram: 4.2°, 13.3°, 18.9°, 20.8°, and 22.5°; - The crystalline form 3 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (two-theta) in the powder X-ray diffractogram: 3.9°, 15.8°, 19.8°, 23.8°, and 27.8°; or, - The crystalline form 4 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (two-theta) in the powder X-ray diffractogram: 5.9°, 13.9°, 17.6°, 20.7°, and 21.9°.

[0015] 4) Another aspect of the present invention relates to the crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide, - The crystalline form 1 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (2 theta) in the powder X-ray diffractogram: 4.3°, 13.1°, 13.5°, 14.8°, 17.2°, 19.5°, 21.1°, 21.6°, 22.6° and 25.0°; - The crystalline form 2 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (2 theta) in the powder X-ray diffractogram: 4.2°, 13.3°, 16.7°, 16.9°, 18.9°, 20.8°, 22.5°, 23.5°, 25.6° and 27.2°; - The crystalline form 3 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (2 theta) in the powder X-ray diffractogram: 3.9°, 11.9°, 15.0°, 15.8°, 17.0°, 19.8°, 22.4°, 23.3°, 23.8° and 27.8°; or, - The crystalline form 4 of the "compound" is characterized by the presence of peaks at the following refractive angles 2θ (2 theta) in the powder X-ray diffractogram: 5.9°, 7.7°, 13.9°, 17.0°, 17.6°, 19.4°, 20.0°, 20.7°, 21.9° and 23.5°.

[0016] 5) Another aspect of the present invention is - The crystalline form 1 represented in Figure 1; - The crystalline form 2 represented in Figure 2; - The crystalline form 3 represented in Figure 3; or, - The crystalline form 4 represented in Figure 4; relates to a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide that essentially exhibits the powder X-ray diffractogram thereof.

[0017] The term "essentially" as used in embodiment 5) means that there must be no peaks having a relative intensity exceeding 10%, especially exceeding 20%, compared to at least the major peaks of the diffractogram represented in the figure, i.e., the strongest peaks in the diffractogram. However, those skilled in the art of powder X-ray diffraction technology should recognize that the relative intensities of powder X-ray diffractograms can be subject to strong intensity variations due to favorable orientation effects.

[0018] 6) A particular 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 crystalline form 1.

[0019] The crystalline forms according to the present invention may have non-coordinating and / or coordinating solvents. Coordinating solvents are used herein as the term for crystalline solvates. To avoid ambiguity, in the present application, the term "(crystalline) solvate" includes non-stoichiometric solvates. Similarly, non-coordinating solvents are used herein as the term for physically adsorbed or physically entrapped solvents (defined by Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: U.J. Griesser: The Importance of Solvates). Furthermore, the crystalline forms of the present invention may have different amounts of coordinated water as a function of relative humidity, and thus the powder X-ray diffraction diagram varies with relative humidity. To avoid ambiguity, the present invention is intended to include all crystalline sub-forms of the crystalline forms that are reversibly convertible into each other depending on the relative humidity.

[0020] The "compounds" of crystalline forms 1 and 2 may be hydrates, particularly non-stoichiometric hydrates, and may have, inter alia, up to about 1.6% coordinated water (relative to the dry weight of the "compound") at 25 °C and 90% relative humidity measured according to the following GVS method. Crystalline form 3 may be a solvate; particularly a non-stoichiometric solvate; and may have, inter alia, solvents such as water and / or organic solvents, for example methanol. Crystalline forms 1, 2 and 3 may further have non-coordinating solvents such as water and / or organic solvents, for example ethyl acetate, methanol, ethanol, n-propanol, isopropanol and / or cyclopropanol.

[0021] To avoid any doubt, whenever an aspect or claim refers to "a peak at the following diffraction angle 2θ in the powder X-ray diffractogram", the powder X-ray diffractogram is always obtained using combined Cu Kα1 and Kα2 radiation without Kα2 stripping; and it should be understood that the accuracy of the above 2θ values described herein is in the range of + / −0.1 to 0.2°. In particular, in the aspects and claims of the present invention, when specifying the diffraction angle 2 theta (2θ) for a peak, the stated 2θ value is between the value minus 0.2° and the value plus 0.2° (2θ±0.2°); and in particular, between the value minus 0.1° and the value plus 0.1° (2θ±0.1°).

[0022] For example, when defining the presence of a peak in a powder X-ray diffractogram, the normal method is to do this for the presented diagram (S = signal, N = noise). According to this definition, when stating that a peak must be present in the powder X-ray diffractogram, the peak in the powder X-ray diffractogram is defined as having an S / N ratio (S = signal, N = noise) greater than x (where x is a number greater than 1). Typically greater than 2, particularly greater than 3.

[0023] 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 aspects 1) to 5) means the "compound" of crystalline form 1 or crystalline form 4 (in particular crystalline form 1) as defined herein.

[0024] 7) Another aspect of the present invention is a) Reacting {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide (i.e., the "compound" in free acid form) with a sodium-containing base (in particular about 1 eq.) in a first solvent selected from C 1-6 -alkyl-OH (in particular about 5 to about 15 vol.; especially about 7 to about 11 vol.; particularly about 9.0 vol.); b) Optionally, removing a portion of the first solvent (in particular about 1 to about 7 vol.; especially about 2 to about 6 vol.; particularly until a total volume of about 4 vol.) by distillation; c) Adding a second solvent selected from C 1-4 -alkyl acetate (in particular about 5 to about 15 vol.; especially about 7 to about 12 vol.; particularly about 10.0 vol.); d) Optionally, removing a portion of the mixture of the first and second solvents (in particular about 1 to about 11 vol.; especially about 3 to about 9 vol.; particularly until a total volume of about 6 vol.) by distillation; and e) Isolating crystalline form 1; relates to crystalline form 1 of the "compound" according to any one of aspects 1) to 6), which can be obtained by a method having.

[0025] 8) Another aspect of the present invention relates to a method for producing the crystalline form 1 of the "compound" according to any one of aspects 1 to 5, having the steps defined in aspect 7).

[0026] As used herein, the term "sodium-containing base" means an organic and / or inorganic Bronsted base having sodium; in particular, the base can receive a proton (H + ion) from the "compound" in free acid form, and the "compound" is obtained. Suitable Bronsted bases are sodium alkoxides (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 alkoxides, sodium hydride or sodium hydroxide; especially it may be sodium methoxide.

[0027] As used herein, the term "alkyl" used alone or in combination means a straight-chain or branched, acyclic or cyclic (especially acyclic) saturated hydrocarbon having 1 to 6 carbon atoms. As used herein, the term "C x-y -alkyl" (x and y are integers respectively) means an alkyl as defined above having x to y carbon atoms. Thus, as used herein, the term "C 1-6 -alkyl" means a C x-y -alkyl as defined above having 1 to 6 carbon atoms. Examples of C 1-6 -alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl or cyclohexyl. Examples of C 1-6 -alkyl-OH [i.e., alkanol having 1 to 6 (especially 1 to 4; particularly 1 or 2) carbon atoms] used herein are methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, cyclopropanol, cyclobutanol or mixtures thereof; in particular, me thanol, ethanol, n-propanol, isopropanol, cyclopropanol or mixtures thereof; especially, C 1-6-Alkyl-OH is methanol.

[0028] As used herein, the term "sodium alkoxide" means a compound of the formula C 1-6 -Alkyl-ONa.

[0029] As used herein, the term "C 1-4 -Alkyl acetate" means a compound of the formula C 1-4 -Alkyl-O-C(=O)CH 3 wherein C 1-6 -Alkyl has 1 to 6 carbon atoms and means the C x-y -Alkyl defined above. Examples include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate or mixtures thereof; particularly ethyl acetate.

[0030] Either step b) or d) may be carried out independently, under normal pressure or reduced pressure, particularly under reduced pressure (e.g., at 100 mbar).

[0031] Furthermore, the step of isolating crystalline form 1 in step e) of either embodiment 7) or 8) is meant to separate the solid phase of the solid-liquid mixture from the liquid phase. The isolation may be carried out by any method for solid-liquid separation such as filtration (e.g., gravity filtration or vacuum filtration). Furthermore, the isolation step may further include washing (particularly with ethyl acetate) and / or drying (particularly at a temperature of up to about 70 °C). In a preferred variant of either embodiment 7) or 8), step b) is not optional. In another preferred variant of either embodiment 7) or 8), step d) is not optional. In yet another preferred variant of either embodiment 7) or 8), both step b) and step d) are not optional.

[0032]

[0033] ​When not used with respect to temperature, the term "about" placed before the numerical value "X" means, in this application, between X - 10% of X and X + 10% of X, preferably between X - 5% of X and X + 5% of X. In the specific case of temperature, the term "about" placed before the temperature "Y" means, in this application, between Y - 10°C and Y + 10°C, preferably between Y - 5°C and Y + 5°C, particularly between Y - 3°C and Y + 3°C. Room temperature means a temperature of about 25°C. In this application, when the term n equivalents (where n is a number) is used, within the scope of this application, n shall mean about n, preferably n shall mean exactly n.

[0034] When the words "between" or "from (... ) to" are used to describe a numerical range, the end points of the indicated range are always understood to be explicitly included in that range. This means, for example, when the temperature range is described as being between 40°C and 80°C (or from 40°C to (... ) 80°C), the end points 40°C and 80°C are included in that range; or when a variable is defined as being an integer between 1 and 4 (or from 1 to (... ) 4), the variable means the integer 1, 2, 3, or 4.

[0035] 9) Accordingly, another aspect relates to 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 aspects 1) to 7) for use as a medicament (e.g., in the form of a pharmaceutical composition for enteral or parenteral administration), particularly to an essentially pure crystalline form.

[0036] 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 aspects 1) to 7), particularly an essentially pure crystalline form (particularly crystalline form 1), may be used as a medicament, either as a single component or as a mixture with other crystalline and / or amorphous forms of the "compound".

[0037] The term "essentially pure", in the context of the present invention, is understood to mean that at least 90, preferably at least 95, and most preferably at least 99 weight percent of the "compound" is present in the crystalline form of the present invention.

[0038] 10) Another aspect relates to the use of 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 aspects 1)-7) in the manufacture of a pharmaceutical composition, said pharmaceutical composition having, as an active ingredient, the compound, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, and further having at least one therapeutically inert excipient.

[0039] 11) Another aspect relates to a pharmaceutical composition having, as an active ingredient, 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 aspects 1)-7), and further having at least one therapeutically inert excipient.

[0040] 12) A further aspect relates to a pharmaceutical composition according to aspect 11), wherein the pharmaceutical composition is in the form of a tablet or a capsule.

[0041] The manufacture of pharmaceutical compositions can be carried out by methods well known to any person skilled in the art (for example, see 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 can be optionally combined with other therapeutically beneficial substances and formulated into a suitable non-toxic inert pharmaceutically acceptable solid or liquid carrier material and, if necessary, together with conventional pharmaceutical adjuvants to form a pharmaceutical dosage form. Examples of suitable pharmaceutical compositions for aprositantan are disclosed in WO2018 / 153513 and WO2019 / 106066.

[0042] To avoid any doubt, aspect 10) relates in particular to a crystalline form according to any one of aspects 1) to 7), such a crystalline form being suitable / used as the final isolation step of the "compound" (for example, to meet the purity requirements of pharmaceutical manufacture), but (for example, because the original crystalline form of the "compound" is further transformed during the manufacturing process and / or dissolved in a pharmaceutically acceptable carrier material; that is, in the final pharmaceutical composition, the "compound" may exist in an amorphous form, another crystalline form or a dissolved form, etc.) the final pharmaceutical composition obtained according to aspect 10) may or may not contain such a crystalline form.

[0043] 13) A further aspect relates to a method for manufacturing a pharmaceutical composition having as an active ingredient the compound, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yl-oxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, which comprises mixing sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of aspects 1) to 7) with at least one therapeutically inert excipient, the pharmaceutical composition being in particular in solid or liquid form.

[0044] 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 aspects 1) to 7) and such a pharmaceutical composition according to any one of aspects 11) or 12) are particularly useful for the treatment of endothelin-related diseases and disorders, especially for the treatment of hypertension, pulmonary hypertension, coronary artery disease, heart failure, renal or myocardial ischemia, renal insufficiency, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, digital 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 hyperplasia, erectile dysfunction, hearing loss, cataract, chronic bronchitis, asthma, pulmonary fibrosis, gram-negative sepsis, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, diabetic complications, complications after vascular or cardiac surgery, or organ transplantation, complications of cyclosporine treatment, pain or hyperlipidemia. A pharmaceutical composition according to any one of aspects 11) or 12) is also useful for the treatment of chronic kidney disease (CKD), especially stages 1 to 4 of CKD as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (especially stage 3 or 4 of CKD), especially for the treatment of CKD associated with or caused by hypertension, including essential hypertension (especially at these stages).

[0045] 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 aspects 1) to 7) and such a pharmaceutical composition according to any one of aspects 12) or 12) are useful for the treatment of diseases selected from the group consisting of hypertension, pulmonary hypertension, diabetic arterial disease, heart failure, erectile dysfunction, angina pectoris and CKD [in particular, CKD at stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (in particular, CKD at stage 3 or 4); especially CKD associated with or caused by hypertension including essential hypertension and / or associated with or caused by diabetes (in particular, at these stages)].

[0046] Such endothelin-related diseases and disorders include, in particular, hypertension, particularly treatment-resistant / refractory hypertension; ischemic heart diseases including angina pectoris, coronary artery disease and myocardial ischemia; heart failure; chronic kidney disease (CKD) [in particular, CKD at stages 1-4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (in particular, CKD at stage 3 or 4)] and, in particular, CKD (also referred to as diabetic kidney disease (DKD)) caused by / associated with hypertension or caused by / associated with diabetes (particularly at these stages); diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic nephropathy, diabetic retinopathy or diabetic angiopathy; reducing the risk of major cardiovascular events (such as HF, myocardial infarction, stroke or death due to cardiovascular causes) in patients with diabetes, particularly patients with diabetes accompanied by at least one other cardiovascular risk factor (such as, in particular, hypertension); treatment and prevention of diabetic complications; (acute and chronic) renal failure; glomerulonephritis; connective tissue diseases; atherosclerosis; obliterative atherosclerotic diseases including chronic obliterative arteriopathy; digital ulcers; reducing the risk of lower limb amputation in patients with diabetic foot ulcers and / or diabetes; heart failure (HF) including, inter alia, HF with reduced systolic HF / ejection fraction (HFrEF) (i.e., ejection fraction < about 40%) and HF with preserved diastolic HF / ejection fraction (HFpEF) (i.e., ejection fraction > about 50%), particularly defined as including chronic HF; reducing the risk of major cardiovascular events (such as HF, myocardial infarction, stroke or death due to cardiovascular causes) in patients with cardiovascular risk (such as patients with coronary artery disease and / or patients showing clinical symptoms of congestive HF); and may be defined as including diastolic dysfunction.

[0047] To avoid doubt, the term CKD caused by / associated with diabetes (diabetic kidney disease, DKD) may also include such DKD associated with hypertension; in particular, the diabetes is type 2 diabetes.

[0048] Furthermore, a pharmaceutical composition according to any one of embodiments 11) or 12) is useful for the treatment of a disease selected from the group consisting of essential hypertension, resistant hypertension, pulmonary hypertension, and pulmonary arterial hypertension (in particular, for the treatment of resistant hypertension).

[0049] Essential hypertension (also called primary or idiopathic hypertension) is, by definition, a form of hypertension that has no identifiable cause. It is a major worldwide public health concern that affects the vascular and renal systems and cardiovascular mortality. The average of multiple systolic blood pressure measurements over 2 or more consecutive clinic visits consistently equals or exceeds a specific threshold value T SBP is diagnosed as essential hypertension. Individuals with high normal blood pressure tend to maintain blood pressure above the average of the general population and have a greater risk of developing definite hypertension and cardiovascular events than the general population. The threshold value T SBP above which treatment is recommended is regularly debated among clinicians (see, for example, Mancia et al., J. Hypertens. (2013), 31, 1281 - 1357); thus, depending on the overall situation and age of the patient, T SBP can be 140 or 130 mmHg, or another appropriate value.

[0050] In the present invention, the term "resistant hypertension" is defined as blood pressure that remains above target despite the concurrent use of 3 different classes of antihypertensive agents. One of the 3 agents should be a diuretic, and all agents should be prescribed at optimal / maximal doses. As defined, patients with resistant hypertension include those in whom blood pressure is controlled by the use of more than 3 medications. That is, patients whose blood pressure is controlled but who require 4 or more medications to do so should be considered treatment - resistant (see, for example, Mancia et al., J. Hypertens. (2013), 31, 1281 - 1357).

[0051] The term "diuretic" in this application refers to loop diuretics including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics including, for example, amiloride, and in particular, aldosterone antagonists (or mineralocorticoid receptor antagonists (MRAs) as they are called), such as spironolactone, eplerenone or finerenone; or aldosterone synthase inhibitors (such as baxdrostat); carbonic anhydrase inhibitors including acetazolamide and methazolamide; and in particular, thiazide-class diuretics (thiazide-like diuretics) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone. Preferred thiazide-like diuretics are chlorthalidone or hydrochlorothiazide. For the avoidance of doubt, SGLT-2 inhibitors are not included in the term "diuretic" as used herein, even if they have a diuretic pharmacological effect. Further, certain potassium-sparing diuretics may be regarded as mineralocorticoid receptor antagonists (MRAs) / aldosterone antagonists (such as finerenone) or aldosterone synthase inhibitors (such as baxdrostat) mainly by virtue of their pharmacological actions rather than being regarded as potassium-sparing diuretics by virtue of their diuretic action. Such potassium-sparing diuretics are included in the definition of diuretics herein. Further, background therapy may have a combination of several diuretics as defined herein. Specific combinations of diuretics are: (i) combination of an aldosterone antagonist with a thiazide-like diuretic; (ii) combination of an aldosterone antagonist with a loop diuretic; (iii) combination of an aldosterone synthase inhibitor with a thiazide-like di Combination with a diuretic; (iv) combination of an aldosterone synthase inhibitor with a loop diuretic; and (v) combination of a loop diuretic with a thiazide-like diuretic. "Diuretic" in this application particularly means a diuretic of the thiazide class (thiazide-like diuretic) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone. Preferred diuretics are chlorthalidone or hydrochlorothiazide.

[0052] Accordingly, the present invention further provides that the said crystalline form of the “compound” / “compound” is used as a medicament, particularly for the treatment of resistant hypertension; the “compound” / the said crystalline form is used alone or (preferably) (preferably, for co-administration including a fixed-dose combination) with, for example, a diuretic, particularly hydrochlorothiazide (HCTZ or HCT) or chlorthalidone; or with an angiotensin II receptor blocker (ARB) such as valsartan; or with an angiotensin-converting enzyme (ACE) inhibitor such as enalapril; or particularly, in combination with an SGLT2 inhibitor such as empagliflozin or dapagliflozin or canagliflozin, the “compound”, particularly the “compound” according to any one of embodiments 1) to 7), relates to the crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide. In a sub-aspect, for the treatment of resistant hypertension, the said combination (formulation) of the “compound” / the said crystalline form according to any one of embodiments 1) to 7) with a diuretic, particularly hydrochlorothiazide (HCTZ or HCT) or chlorthalidone may require a further combination (preferably, for co-administration including a fixed-dose combination) with one or two further active ingredients which are different classes of antihypertensive agents (particularly CCB and / or ARB), particularly valsartan.Accordingly, the present invention particularly relates to a pharmaceutical composition having each of the crystal forms of the "compound" as defined in "compound" / Aspect 11) or 12); as an active ingredient, in addition to the "compound" / each of the crystal forms of the "compound", having a diuretic, particularly hydrochlorothiazide (HCTZ or HCT) or chlorthalidone; optionally further having one or two active ingredients which are different classes of antihypertensive agents (particularly CCB and / or ARB); particularly further having valsartan; or, as an active ingredient, in addition to the "compound" / each of the crystal forms of the "compound", having an angiotensin II receptor blocker (ARB) such as valsartan; or having an angiotensin-converting enzyme (ACE) inhibitor such as enalapril; or, as an active ingredient, in addition to the "compound" / each of the crystal forms of the "compound", having an SGLT2 inhibitor such as empagliflozin or dapagliflozin or canagliflozin; relating to a pharmaceutical composition.

[0053] The term "SGLT-2 inhibitor" particularly means an inhibitor of sodium-glucose cotransporter 2 such as atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin, tianagliflozin or tofogliflozin (especially canagliflozin or dapagliflozin or empagliflozin).

[0054] 14) A further aspect relates to a crystalline form of a "compound" according to any one of aspects 1) to 7) for use in the treatment of hypertension, pulmonary hypertension, coronary artery disease, heart failure, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, digital ulcer or portal hypertension, and for atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, cancer, melanoma, prostate cancer, prostatic hyperplasia, erectile dysfunction, hearing loss, cataract, chronic bronchitis, asthma, pulmonary fibrosis, gram-negative sepsis, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue disease, diabetic complications vascular or cardiac surgery, or complications after organ transplantation, complications of cyclosporine treatment, pain, hyperlipidemia or CKD [in particular, CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (in particular, stage 3 or 4 CKD), especially CKD resulting from / associated with hypertension including essential hypertension (in particular, CKD at these stages)] for the treatment or prevention of.

[0055] 15) A further aspect relates to a crystalline form of a "compound" according to any one of aspects 1) to 7) for use in the treatment of a disease selected from the group consisting of hypertension, pulmonary hypertension, diabetic arterial disease, heart failure, erectile dysfunction, angina pectoris and CKD [in particular, CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (in particular, stage 3 or 4 CKD), especially CKD resulting from / associated with hypertension including essential hypertension (in particular, CKD at these stages)].

[0056] 16) A further aspect relates to a crystalline form of a "compound" according to any one of aspects 1) to 7) for use in the treatment of a disease selected from the group consisting of essential hypertension, resistant hypertension, pulmonary hypertension and pulmonary arterial hypertension (in particular, for use in the treatment of resistant hypertension).

[0057] To avoid any ambiguity, when it is stated that a "compound", particularly a crystalline form of a "compound" according to any one of embodiments 1) to 7), is useful for the prevention (prevention / prophylaxis) or treatment of a certain disease, such a crystalline form is similarly suitable for use in the manufacture of a medicament for the prevention or treatment of said disease. Similarly, such a crystalline form is also appropriate for a method of preventing or treating such a disease, which comprises administering an effective amount thereof to a subject (mammal, particularly human) in need thereof.

[0058] 17) A further aspect relates to the use of a crystalline form of a "compound" according to any one of embodiments 1) to 7) for the manufacture of a medicament intended for the treatment of any one of the diseases or disorders described in embodiment 14).

[0059] 18) A further aspect relates to the use of a crystalline form of a "compound" according to any one of embodiments 1) to 7) for the manufacture of a medicament intended for the treatment of any one of the diseases or disorders described in embodiment 15).

[0060] 19) A further aspect relates to the use of a crystalline form of a "compound" according to any one of embodiments 1) to 7) for the manufacture of a medicament intended for the treatment of any one of the diseases or disorders described in embodiment 16).

[0061] 20) A further aspect relates to a method of treating any one of the diseases or disorders described 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).

[0062] 21) A further aspect relates to a method for the treatment of any one of the diseases or disorders described in embodiment 15), 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).

[0063] 22) Another aspect relates to a method for treating any one of the diseases or disorders described in aspect 16), which comprises administering to a patient a crystalline form of a "compound" according to any one of aspects 1)-7) or a pharmaceutical composition according to any one of aspects 11) or 12).

[0064] 23) Still another aspect relates to a crystalline form of a "compound" according to any one of aspects 1)-7) for use in the treatment of a disorder selected from the group consisting of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure, and diastolic dysfunction.

[0065] 24) One sub-aspect of aspect 23) is for use in the treatment of CKD, particularly stage 1-4 CKD (especially stage 3 or 4 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines, particularly CKD caused by / associated with hypertension including essential hypertension (especially at these stages), and relates to a crystalline form of a "compound" according to any one of aspects 1)-7).

[0066] 25) Another sub-aspect of aspect 23) relates to a crystalline form of a "compound" according to any one of aspects 1)-7) for use in the treatment of diabetes (i.e., type 1 or type 2 diabetes).

[0067] 26) Another sub-aspect of aspect 23) relates to a crystalline form of a "compound" according to any one of aspects 1)-7) for use in the treatment of diabetic nephropathy.

[0068] 27) Another sub-aspect of aspect 23) relates to a crystalline form of a "compound" according to any one of aspects 1)-7) for use in the treatment of diabetic retinopathy.

[0069] ​28) Another sub-aspect of aspect 23) relates to a crystalline form of the "compound" according to any one of aspects 1)-7) for use in the treatment of diabetic vasculopathy.

[0070] 29) Another sub-aspect of aspect 23) relates to a crystalline form of the "compound" according to any one of aspects 1)-7) for use in the treatment of chronic heart failure.

[0071] 30) According to one modification of sub-aspect 29), the chronic heart failure of sub-aspect 29) is heart failure with preserved ejection fraction.

[0072] 31) According to another modification of sub-aspect 29), the chronic heart failure of sub-aspect 29) is diastolic heart failure.

[0073] 32) Another sub-aspect of aspect 23) relates to a crystalline form of the "compound" according to any one of aspects 1)-7) for use in the treatment of diastolic dysfunction.

[0074] 33) Preferably, the crystalline form of the "compound" according to any one of aspects 23)-32) is contained in a pharmaceutical unit dosage form suitable for oral administration of 2.5-100 mg per day (especially 10-50 mg, particularly 12.5 or 25 mg) of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide.

[0075] 34) Preferably, the crystalline form of the "compound" according to any one of aspects 23)-32) is - an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB), - and / or a calcium channel blocker (CCB), or a pharmaceutically acceptable salt of one of these, It is intended to be used in combination with

[0076] "Angiotensin-converting enzyme inhibitor" or "ACE inhibitor" as used in this application specifically means captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril, cilazapril or a pharmaceutically acceptable salt of one of these. A preferred ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

[0077] "Angiotensin receptor blocker" or "ARB" as used in this application specifically means valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan or a pharmaceutically acceptable salt of one of these. A preferred ARB is valsartan or a pharmaceutically acceptable salt thereof.

[0078] "Calcium channel blocker" or "CCB" as used in this application specifically refers 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 any of these. A preferred CCB is amlodipine or a pharmaceutically acceptable salt thereof.

[0079] Accordingly, the crystalline form of the "compound" according to any one of aspects 23) to 32) may be for use in combination with an ACE inhibitor, or an ARB and / or a CCB. The corresponding combination therapy may be carried out simultaneously, separately or over a period of time (in particular, simultaneously).

[0080] When related to the dosage form, "simultaneously" as used in this application means that the related dosage forms are substantially simultaneous administrations of two or more active ingredients and / or treatments; by simultaneous administration, the subject is understood to be simultaneously exposed to the two or more active ingredients and / or treatments described above. When administered simultaneously, the two or more active ingredients may be in the form of a fixed dose combination or, (for example, by using two or more different pharmaceutical compositions to be administered substantially simultaneously by the same route of administration) an equivalent non-fixed dose as a "fixed-dose combination" or administered by a non-fixed-dose combination using two or more different routes of administration, whereby the subject will be essentially simultaneously exposed to the two or more active ingredients and / or treatments. For example, when used in combination with an ACE inhibitor, an ARB and / or a CCB, the "compounds" may in some cases be used "simultaneously". Similarly, when used in combination with a diuretic, the "compounds" may in some cases be used "simultaneously".

[0081] When related to the dosage form, "fixed-dose combination" in the present application means that the related dosage form is the administration of a single pharmaceutical composition having two or more active ingredients.

[0082] When related to the dosage form, the term "separately" in the present application means that the related dosage form is the administration of two or more active ingredients and / or treatments at different times; separate administrations lead to a treatment phase in which the subject is simultaneously exposed to the two or more active ingredients and / or treatments (e.g., for at least 1 hour, particularly at least 6 hours, especially at least 12 hours), but separate administrations may also lead to a treatment phase in which the subject is exposed to only one of the two or more active ingredients and / or treatments for a certain period of time (e.g., for at least 12 hours, particularly at least 1 day). Separate administrations particularly mean a situation where at least one active ingredient and / or treatment is administered at a cycle substantially different from that of daily administration (e.g., once or twice a day, etc.) (e.g., one active ingredient and / or treatment is administered, for example, once or twice a day, and another is administered, for example, every other day, or once a week, or at longer intervals).

[0083] "Administered over a period" means, in the present application, administering two or more active ingredients and / or treatments successively at different times. This term particularly means an administration method in which, after the entire administration of one active ingredient and / or treatment is completed, the administration of one or more other treatments is started. In this case, it is possible to administer other active ingredients and / or treatments after administering one of the above active ingredients and / or treatments for several months.

[0084] 35) Also preferably, the crystalline form of the "compound" according to any one of aspects 23) to 32) or 33), or when combined with an ACE inhibitor, or an ARB and / or a CCB according to aspect 34), is intended to be used in combination with a diuretic (in particular, it is intended to be used in combination with hydrochlorothiazide (HCT) or chlorthalidone).

[0085] Therefore, the crystalline form of the "compound" according to any one of aspects 23) to 32) may be intended to be used in combination with a diuretic (in particular, used in combination with HCT or chlorthalidone). The corresponding combination therapy may be carried out simultaneously, separately or over a period (in particular, simultaneously) as defined above.

[0086] 36) A further aspect of the present invention is - for use in the prevention or treatment of CKD [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD]; and in particular, CKD (DKD) caused by / related to hypertension and / or caused by / related to diabetes (especially at these stages); and in the prevention or treatment of acute or chronic renal insufficiency; diabetic nephropathy; or glomerulonephritis; In a first sub-aspect, such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, especially when apocynin reduces the progression rate of DKD, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; in particular, the patient additionally shows a history of hypertension; In a second sub-aspect, such use is particularly intended for the treatment of DKD, especially in patients with type 2 diabetes, particularly in such patients showing a history of hypertension in addition, [corresponding particularly to CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (especially such CKD of stage 3 or 4)] including the treatment of diabetic nephropathy associated with an increase in serum creatinine and / or proteinuria; - For use in the prevention or treatment of diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic retinopathy or diabetic angiopathy; and for reducing the risk of developing major cardiovascular events (e.g., HF, myocardial infarction, stroke or death due to cardiovascular causes) in patients with diabetes, particularly patients with diabetes accompanied by at least one other cardiovascular risk factor (e.g., particularly hypertension); and for use in the prevention or treatment of diabetic foot ulcers and / or for reducing the risk of lower limb amputation in patients with diabetes; - For use in the prevention or treatment of heart failure (HF), particularly including chronic HF, including systolic HF and diastolic HF in particular; for reducing the risk of developing major cardiovascular events (e.g., HF, myocardial infarction, stroke or death due to cardiovascular causes) in patients with cardiovascular risk (e.g., patients with coronary artery disease and / or patients showing clinical symptoms of congestive HF); and for use in the prevention or treatment of ischemic heart diseases including angina pectoris, coronary artery disease and myocardial ischemia; heart failure; or diastolic dysfunction; - For use in the treatment of hypertension, particularly including treatment-resistant / resistant hypertension; - For use in the prevention or treatment of atherosclerosis; and obliterative atherosclerotic diseases including chronic obliterative arteriopathy; - For use in the prevention or treatment of finger ulcers; or - For use in the prevention or treatment of connective tissue diseases; Regarding the "compound" according to any one of aspects 1) to 7), sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide; the "compound" is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0087] In particular, the above CKD may be related to macroproteinuria (defined as UACR > 300 mg / g).

[0088] UACR is a biomarker of renal dysfunction and is monitored in patients with kidney disorders (Levey et al., Uses of GFR and albuminuria level in acute and chronic kidney disease. N Engl J Med. 2022;386(22):2120-28).

[0089] Such a treatment method for CKD caused by / related to hypertension, optionally, additionally related to diabetes (diabetic kidney disease (DKD)), especially stage 3 or 4 CKD, also means treating hypertension including difficult-to-control and resistant hypertension, the hypertension including the hypertension that causes / relates to such CKD, and the CKD, optionally, is further related to diabetes in addition to the hypertension.

[0090] 37) A further aspect is that the "compound" - is intended to be used in the prevention or treatment of CKD [especially stage 1 to 4 CKD, particularly stage 3 or 4 CKD], including CKD caused by / related to hypertension [especially stage 1 to 4 CKD, particularly stage 3 or 4 CKD] and CKD caused by / related to diabetes (diabetic kidney disease, DKD) [especially stage 1 to 4 CKD, particularly stage 3 or 4 CKD]; Such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, and in particular, apocynin reduces the progression rate of DKD, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events, or a reduction in renal death events; in particular, the patient additionally shows a history of hypertension; - It is intended to be used in the prevention or treatment of acute kidney injury; - It is intended to be used in the prevention or treatment of chronic kidney disease; - It is intended to be used in the prevention or treatment of diabetic nephropathy; - It is intended to be used in the prevention or treatment of glomerulonephritis; - It is intended to reduce the risk of occurrence of major cardiovascular events (e.g., HF, myocardial infarction, stroke, or death due to cardiovascular causes) in patients with diabetes, particularly those with diabetes accompanied by at least one other cardiovascular risk factor (e.g., particularly hypertension); - It is intended to be used in the prevention or treatment of diabetic foot ulcers and / or to reduce the risk of lower limb amputation in patients with diabetes; - Heart failure (HF), particularly including chronic HF; in particular, it is intended to be used in the prevention or treatment of systolic HF or diastolic HF; - In patients with cardiovascular risk factors (e.g., patients with coronary artery disease and / or patients showing clinical symptoms of congestive HF), it is intended to reduce the risk of occurrence of major cardiovascular events such as HF, myocardial infarction, stroke, or death due to cardiovascular causes; - It is intended to be used in the prevention or treatment of diastolic dysfunction; - It is particularly intended to be used in the treatment of hypertension, particularly including treatment-resistant / resistant hypertension; or, - Atherosclerosis; and it is intended to be used in the prevention or treatment of obliterative atherosclerotic diseases including chronic obliterative arteriopathy; Regarding the "compound" for use according to embodiment 36); the "compound" is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0091] 38) A further embodiment is that the "compound" is - intended to be used in the prevention or treatment of CKD caused by / associated with hypertension [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD]; - intended to be used in the prevention or treatment of CKD caused by / associated with diabetes [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD] (DKD); such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, and in particular, apocynum tannin reduces the progression rate of DKD, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events, or a reduction in renal death events; in particular, the patient additionally shows a history of hypertension; - intended to be used in the prevention or treatment of chronic renal failure caused by / associated with hypertension, or caused by / associated with diabetes; diabetic nephropathy; or glomerulonephritis caused by / associated with hypertension; - intended to reduce the risk of occurrence of major cardiovascular events (such as HF, myocardial infarction, stroke, or death due to cardiovascular causes) in patients with diabetes, particularly those with diabetes accompanied by at least one other cardiovascular risk factor (such as, in particular, hypertension); - intended to be used in the prevention or treatment of diabetic foot ulcers and / or intended to reduce the risk of lower limb amputation in patients with diabetes; or - intended to be used in the prevention or treatment of heart failure (HF) particularly including chronic HF; especially systolic HF or diastolic HF; Regarding the "compound" for use according to embodiment 36), the "compound" is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0092] 39) A further aspect is that the “compound” is - intended to be used in the prevention or treatment of CKD caused by / associated with hypertension [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD]; and / or, - intended to be used in the prevention or treatment of CKD caused by / associated with diabetes [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD] (DKD); Such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, and in particular, apocynum venetum tannin reduces the progression rate of DKD, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage kidney disease (ESKD) events or a reduction in kidney death events; in particular, the patient additionally shows a history of hypertension; and / or , - intended to reduce the risk of occurrence of major cardiovascular events (such as HF, myocardial infarction, stroke or death due to cardiovascular causes) in patients with diabetes, particularly patients with diabetes accompanied by at least one other cardiovascular risk factor (such as, particularly, hypertension); Regarding the “compound” for use according to aspect 36), the “compound” is (intended to be) administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0093] 40) A further aspect is that the “compound” is - intended to be used in the prevention or treatment of CKD caused by / associated with hypertension [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD]; and / or, - intended to be used in the prevention or treatment of CKD caused by / associated with diabetes [especially CKD stages 1 to 4, particularly stage 3 or 4 CKD] (DKD); Such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, and in particular, apocynin reduces the progression rate of DKD, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; in particular, the patient additionally shows a history of hypertension; Regarding the "compound" for use according to embodiment 36), the "compound" is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0094] 41) A further aspect is that the "compound" is - intended to be used in the prevention or treatment of CKD caused by / associated with diabetes [especially CKD stages 1 to 4, especially stage 3 or 4 CKD] (DKD); In a first sub-aspect, such use is particularly intended for the treatment of such DKD in patients diagnosed with type 2 diabetes, and in particular, apocynin reduces the progression rate of DKD, and such reduced progression rate may be particularly represented by a reduction in eGFR, a reduction in end-stage renal disease (ESKD) events or a reduction in renal death events; in particular, the patient additionally shows a history of hypertension; In a second sub-aspect, such use is particularly intended for the treatment of such DKD, including the treatment of diabetic nephropathy associated with an increase in serum creatinine and / or proteinuria [especially corresponding to CKD stages 1 to 4 (especially such stage 3 or 4 CKD) as defined in the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines] in patients with type 2 diabetes, especially in such patients who additionally show a history of hypertension; Regarding the "compound" for use according to embodiment 36), the "compound" is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0095] 42) A further aspect is that the "compound" is - It is intended to reduce the risk of developing major cardiovascular events (e.g., HF, myocardial infarction, stroke, or death due to cardiovascular causes) in patients with diabetes, particularly in patients with diabetes accompanied by at least one other cardiovascular risk factor (e.g., particularly hypertension). Regarding the "compound" for use according to embodiment 36), the "compound" is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0096] 43) A further embodiment relates to the "compound" for use according to any one of embodiments 29) to 35), wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is particularly bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, sotagliflozin or tofogliflozin (particularly canagliflozin, dapagliflozin or empagliflozin; especially empagliflozin) or a pharmaceutically acceptable salt thereof.

[0097] Any embodiment regarding the "compound" for use in the treatment of specific endothelin-related diseases and disorders specifically defined herein, wherein the "compound" is intended to be administered in combination with another active ingredient (e.g., one or more diuretics, ARB or ACE inhibitors, CCB and / or SGLT-2 inhibitors), - Such active ingredients disclosed herein, which are intended to be administered in combination with the "compound" for use in the treatment of such endothelin-related diseases and disorders; - Use of the "compound" for the manufacture of a medicament / pharmaceutical composition for use in the treatment of such endothelin-related diseases and disorders, comprising the "compound" and such active ingredients disclosed herein; - Use of the "compound" for the manufacture of a medicament / pharmaceutical composition for use in the treatment of such endothelin-related diseases and disorders, wherein the medicament / pharmaceutical composition has the "compound" as an active ingredient and is intended to be used in combination with such active ingredients disclosed herein. - Use of such active ingredient disclosed herein for the manufacture of a medicament / pharmaceutical composition for use in the treatment of said endothelin-related diseases and disorders, having such active ingredient as the active ingredient; wherein the 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 such active ingredient disclosed herein for the treatment of said endothelin-related diseases and disorders. - A medicament for the prevention or treatment of said endothelin-related diseases and disorders, wherein the medicament has a "compound"; and the medicament is intended to be administered in combination with such active ingredient. - A method for treating said endothelin-related diseases and disorders, comprising administering to a subject (preferably a human) in need thereof an effective amount of a "compound" to be administered in combination with an effective amount of such active ingredient. - A method for treating said 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 for treating said 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 to be administered in combination with an effective amount of a "compound". It is understood to also relate to the following.

[0098] 44) The present invention further 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 aspects 1) to 7) for the prevention or treatment of the endothelin-related diseases and disorders defined above, particularly to an essentially pure crystalline form. 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 [particularly, at least two (especially three or four) other active ingredients], and the one or more active ingredients are independently selected from the active ingredients of the following group: - an angiotensin receptor blocker (particularly, valsartan and losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; or, an ACE inhibitor (particularly, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or a pharmaceutically acceptable salt thereof; and / or, - a calcium channel blocker (particularly, amlodipine and aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or a pharmaceutically acceptable salt thereof; and / or, - an aldosterone antagonist such as spironolactone, eplerenone or finerenone; an aldosterone synthase inhibitor (such as baxdrostat); and / or, - a diuretic selected from the following: -- a loop diuretic containing furosemide, bumetanide, ethacrynic acid or torsemide; ​-- A carbonic anhydrase inhibitor containing acetazolamide or methazolamide; -- In particular, diuretics of the thiazide class (thiazide-like diuretics) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferred diuretics are thiazide-like diuretics, particularly chlorthalidone or hydrochlorothiazide); or, -- A potassium-sparing diuretic that is not an aldosterone antagonist or an aldosterone synthase inhibitor (an example is amiloride); and / or, - Beta blockers (beta-adrenergic blocking agents), particularly acebutolol, atenolol, bisoprolol, metoprolol (immediate release or sustained release), nadolol, nebivolol, propranolol (immediate release or sustained release); and / or, - SGLT-2 inhibitors (particularly atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin or tofogliflozin; or a pharmaceutically acceptable salt thereof; in particular, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, luseogliflozin, sotagliflozin or tofogliflozin; especially canagliflozin, or dapagliflozin, or empagliflozin) or a pharmaceutically acceptable salt thereof.

[0099] 45) The present invention further 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 aspects 1) to 7) for the prevention or treatment of the endothelin-related diseases and disorders defined above, particularly an essentially pure crystalline form, 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 [particularly, at least two (especially three or four) other active ingredients], and the one or more active ingredients are independently selected from the active ingredients of the following group: - an angiotensin receptor blocker (particularly, valsartan and losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; or, an ACE inhibitor (particularly, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril,trandolapril, cilazapril) or a pharmaceutically acceptable salt thereof; and / or, - a calcium channel blocker (particularly, amlodipine and aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or a pharmaceutically acceptable salt thereof; and / or, - loop diuretics including furosemide, bumetanide, ethacrynic acid, torsemide; and / or, - a further diuretic selected from the following: -- a potassium-sparing diuretic (e.g., amiloride) that is not an aldosterone antagonist or an aldosterone synthase inhibitor; -- An aldosterone antagonist such as spironolactone, eplerenone or finerenone; or, an aldosterone synthase inhibitor (such as baxdrostat); -- A carbonic anhydrase inhibitor including acetazolamide and methazolamide; or, -- In particular, a diuretic of the thiazide class (thiazide-like diuretic) such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone (preferred diuretics are thiazide-like diuretics, in particular chlorthalidone or hydrochlorothiazide); and / or, - A beta-blocker (sympathetic beta-receptor blocker), in particular, acebutolol, atenolol, bisoprolol, metoprolol (immediate release or sustained release), nadolol, nebivolol, propranolol (immediate release or sustained release); and / or, - An SGLT-2 inhibitor (in particular, atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, lesogliflozin, remogliflozin, sotagliflozin or tofogliflozin; or a pharmaceutically acceptable salt thereof; especially, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henaagliflozin, ipragliflozin, lesogliflozin, sotagliflozin or tofogliflozin; particularly, canagliflozin, or dapagliflozin, or empagliflozin) or a pharmaceutically acceptable salt thereof.

[0100] The term "beta-blocker" means such a sympathetic beta-receptor blocker, in particular, acebutolol, atenolol, bisoprolol, metoprolol (including immediate release or sustained release formulations), nadolol, nebivolol and propranolol (including immediate release or sustained release formulations); especially, it means atenolol, bisoprolol, metoprolol, nebivolol and propranolol.

[0101] In certain cases, additional background treatment may include an active ingredient 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, taspoglutide, semaglutide, or a dual GLP-1 / GIP agonist such as trizepatide); and / or a thiazolidinedione or a pharmaceutically acceptable salt thereof.

[0102] The term "DPP-4 inhibitor" or "DPP-IV inhibitor" means, in particular, inhibitors of dipeptidyl peptidase 4 such as sitagliptin, vildagliptin, saxagliptin and linagliptin, as well as gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogl iptin and dutogliptin.

[0103] The term "GLP-1 receptor agonist" means, in particular, agonists of the glucagon-like peptide-1 receptor such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, semaglutide and the like.

[0104] The term "dual GLP-1 / GIP receptor agonist" means a dual agonist of the glucagon-like peptide-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, particularly such as trizepatide.

[0105] The term "sulfonylurea" means, in particular, glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glyclopyramide or glimepiride.

[0106] The term "thiazolidinedione", abbreviated as TZD and also known as glitazone, means an agonist of PPARγ (peroxisome proliferator-activated receptor gamma), particularly pioglitazone, rosiglitazone or lobeglitazone.

[0107] Background treatment should preferably be administered at a dosage corresponding to the effective dosage of each active ingredient when administered, for example, as monotherapy. In particular, valsartan or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 160 mg or 320 mg of valsartan per day; losartan or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 50 mg or 100 mg of losartan per day; irbesartan or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 75 mg, 150 mg or 300 mg of irbesartan per day; amlodipine or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 5 mg or 10 mg of amlodipine per day; enalapril or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg of enalapril per day; lisinopril or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg of lisinopril per day; ramipril or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 2.5 mg to 20 mg of ramipril per day; metformin, if present, should be administered in a dosage form suitable for oral administration of 500 mg to 2000 mg of metformin per day; glibenclamide, if present, should be administered in a dosage form suitable for oral administration of 1.25 mg to 5 mg of glibenclamide per day; sitagliptin, if present, should be administered in a dosage form suitable for oral administration of 25 mg to 100 mg of sitagliptin per day; vildagliptin, if present, should be administered in a dosage form suitable for oral administration of 50 mg of vildagliptin twice a day; saxagliptin, if present, should be administered 2. per dayIt should be administered in a dosage form suitable for oral administration of 5 mg or saxagliptin at 5 mg; linagliptin, if present, should be administered in a dosage form suitable for twice-daily oral administration of 5 mg of linagliptin per day; bexagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of 5 to 50 mg (particularly 20 mg) of bexagliflozin per day; canagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered per day... It should be administered in a dosage form suitable for oral administration of canagliflozin at 50 to 400 mg (especially 50 mg, 100 mg, 150 mg or 300 mg; particularly 100 mg or 300 mg; especially 100 mg); dapagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of dapagliflozin at 1 to 20 mg (especially 5 mg or 10 mg) per day; empagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of empagliflozin at 5 to 50 mg (especially 10 mg or 25 mg) per day; ertugliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of ertugliflozin at 2.5 to 50 mg (especially 5 mg or 15 mg) per day; henaagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of henaagliflozin at 5 to 100 mg (especially 25 mg) per day; ipragliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of ipragliflozin at 10 to 100 mg (especially 25 mg or 50 mg) per day; luseogliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of luseogliflozin at 1 to 10 mg (especially 2.5 mg or 5 mg) per day; sotagliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of sotagliflozin at 50 to 500 mg (especially 75 mg, 200 mg or 400 mg) per day, and tofogliflozin or a pharmaceutically acceptable salt thereof, if present, should be administered in a dosage form suitable for oral administration of tofogliflozin at 10 to 50 mg (especially 20 mg) per day.

[0108] 46) Another aspect is a pharmaceutical composition having, as an active ingredient, a "compound" according to any one of aspects 1) to 7), a crystalline form of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide, a diuretic such as an aldosterone antagonist like finerenone or an aldosterone synthase inhibitor like baxdrostat (as defined above); and / or a thiazide-like diuretic such as HTC or chlorthalidone; and / or an ARB or an ACE inhibitor; and / or a CCB; and / or an SGLT-2 inhibitor (specifically included, for example, as defined above in aspects 44) or 45)), one or more other active ingredients, and further having at least one therapeutically inactive excipient.

[0109] 47) A further aspect relates to a pharmaceutical composition according to aspect 46), wherein the pharmaceutical composition is in the form of a tablet or a capsule.

[0110] 48) The present invention further relates to a kit having the following: - A pharmaceutical composition / pharmaceutical having a crystalline "compound" according to any one of aspects 1) to 7), a pharmaceutically acceptable carrier material, and optionally another active ingredient as defined above. And instructions for use of the pharmaceutical composition / pharmaceutical for the prevention or treatment of the endothelin-related diseases and disorders defined above in combination with another or other active ingredients (specifically included, for example, as defined above in aspects 44) or 45), such as a diuretic like an aldosterone antagonist like finerenone or an aldosterone synthase inhibitor like baxdrostat; and / or a thiazide-like diuretic such as HTC or chlorthalidone; and / or an ARB or an ACE inhibitor; and / or a CCB; and / or an SGLT-2 inhibitor).

[0111] The amount of 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 modes of administration 1) to 7) to be administered is in particular 10 to 50 mg per day, in particular 10 to 25 mg, especially 12.5 mg or 25 mg of the free acid form of aprocitentan (preferably, said amount should be administered once a day in the morning). (i.e., preferably, said amount should be administered once a day in the morning).

[0112] Accordingly, any pharmaceutical composition described herein particularly has sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)(sulfamoyl)amide according to any one of modes 1) to 7) in a pharmaceutical unit dosage form suitable for oral administration of an amount corresponding to 10 to 50 mg (in particular 10 to 25 mg, especially 12.5 mg or 25 mg) of aprocitentan (in the free acid form) per day.

[0113] Specific embodiments of the present invention are described in the following examples, which are provided to explain the present invention in more detail and do not limit its scope in any way.

[0114] Experimental section The following abbreviations are used throughout the specification and examples: ° degree ℃ degree Celsius EtOAc ethyl acetate eq. equivalent g gram 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 milliampere mbar millibar MeCN acetonitrile MeOH Methanol mg milligram min mL (or ml) milliliter mol 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. Weight unit All temperatures are given in degrees Celsius.

[0115] Powder X-ray diffraction (XRPD) analysis All XRPD patterns of the solid forms described herein were obtained as described below. X-ray diffractograms were obtained using a FlipStick® sample stage, CuKα radiation (40 kV, 40 mA) and a 1D-linear LynxEye® detector. Diffractograms were measured on a Bruker D8 Advance diffractometer equipped with a diffractometer. Samples were prepared on silicon single crystal sample holders with a cavity of 25 mm diameter and a depth of none, 0.2 or 0.5 mm. The powder was spread with a glass slide to obtain a flat surface. Diffractograms were collected in reflectance mode with combined θ / 2θ angles in the range 3-50° 2θ, increments of 0.02° per step and an accumulation time of 0.4 s. Divergence and antiscatter slits were set at 0.3°. Samples were rotated continuously at 30 rpm during the measurements. As is typical for previously recorded powder X-ray diffraction patterns, the 2θ values ​​of the peak positions are reported with an accuracy of + / - 0.2°.

[0116] Differential scanning calorimetry (DSC) DSC data was collected on a Mettler Toledo STARe System equipped with a 34-position autosampler (DSC822e module, measuring cell with a ceramic sensor, and STAR software version 9.20). The instrument was calibrated for energy and temperature using an indium standard. Typically, each sample of 1 - 5 mg was placed in an automatically pierced aluminum pan and heated from -20 °C to 280 °C at 10 °C min -1 with a nitrogen purge maintained at 20 ml min -1 over the sample. Peak temperatures were reported for melting points.

[0117] Thermogravimetric analysis (TGA) TGA data was collected on a Mettler Toledo STARe System equipped with a 34-position autosampler (TGA851e module and STAR software version 9.20). Typically, a sample of approximately 5 mg was placed in an automatically pierced aluminum pan and heated from 30 °C to 250 °C at 10 °C min -1 with a nitrogen purge maintained at 10 ml min -1 over the sample.

[0118] Gravimetric vapor sorption (GVS) Hygroscopicity was characterized by measuring the water sorption isotherm at 25 °C on an IGASORP Model HAS - 036 - 080 from Hiden Analytical Ltd. After equilibrating the sample at 40% r.h., the relative humidity was increased to 80% r.h. in 5% steps, with a minimum equilibration time of 720 minutes and a maximum equilibration time of 1440 minutes per step. Hygroscopicity was determined in accordance with EUROPEAN PHARMACOPEIA 7.0 "5.11. Based on the definitions described in the "Characters section in monographs", non-hygroscopic: mass increase less than 0.2 percent m / m; slightly hygroscopic: mass increase less than 2 percent m / m and not less than 0.2 percent m / m; hygroscopic: mass increase less than 15 percent m / m and not less than 2 percent m / m.

[0119] Measurement of assay by HPLC analysis The assay was measured using UV-HPLC (e.g., Shimadzu Nexera X2 System) with the autosampler temperature set at 25 °C and the column temperature set at 50 °C. Typically, 1 μL of the sample is injected, and separation is carried out at a flow rate of 1.5 mL / min using a Phenomenex Gemini 5.0 μm 110 Å, 50X2.0 mm column. The sample is typically prepared by solubilizing it in acetonitrile / carbonate buffer pH 10 1 / 1. A gradient method is used with solvent A consisting of 50 mM pH 9 Trizma base buffer (adjusted with HCl) and solvent B consisting of acetonitrile + 5% (v / v) 50 mM pH 9 Trizma base buffer (adjusted with HCl). Typically, the following gradient is used:

[0120]

Table 2

[0121] Examples Example 1a: “Compound” of Crystal Form 1 Evaporate a mixture consisting of 5 mL of MeOH, 50 mg of aprocitentan as the free acid form, and 1 eq. of 1M NaOH. To the remaining oily residue, add 0.5 mL of MeOH and 0.5 mL of MeCN, let the mixture stand overnight, and seal at ambient temperature. Collect the solid residue, wash it with 0.2 mL of MeCN, and dry it under a reduced pressure of 2 mbar for 1 h. This solid is the "compound" in crystalline form 1.

[0122] Example 1b: “Compound” of Crystal Form 1 Aprositantan as the free acid form (250 mg) is dissolved in 15 mL of THF and 5 mL of MeOH. To this solution, 0.458 mL of 1 M NaOH solution is added. The solution is left for 5 min and then concentrated on a rotavapor. The remaining oil is dried under high vacuum for a short time, dissolved in 2 mL of hot MeOH, 15 mL of MeCN is added, and the mixture is sealed and left under ambient conditions. After 3 h, the solid material is collected, washed twice with 2 mL of MeCN, and dried at 2 mbar for 1 h. This solid is the "compound" in crystalline form 1.

[0123] Example 1c: “Compound” of Crystal Form 1 Charge the reactor with aprositantan as the free acid form (3.5 kg, 6.4 mol, 1.0 eq.) and MeOH (24.9 kg, 9.0 vol). A methanol solution of sodium methoxide (30%, 1.16 kg, 6.4 mol, 1.0 eq.) is added while rinsing with MeOH (2.8 kg, 1.0 vol). The mixture is stirred at 20 °C for 4 h and then concentrated at 20 °C and 100 mbar to a volume of 14 L (4 vol.). EtOAc (31.5 kg, 10.0 vol.) is added and more solvent is removed by distillation under the same conditions to a final volume of 21 L (6 vol.). EtOAc (15.8 kg, 5 vol.) is added and the mixture is stirred at 20 °C overnight and then at 0 °C for 2 h. Filtration, washing with cold EtOAc (20 kg, 5.7 vol.) and drying at 30 - 55 °C gives the "compound" (3.15 kg, 87% yield) as a white solid. This solid is the "compound" in crystalline form 1. The data is summarized in the table below.

[0124]

Table 3

[0125] Example 2: “Compound” of Crystal Form 2 The "compound" in crystalline form 1 is stored at 23 °C and 92% r.h. for 9 weeks. The solid is measured rapidly by XRPD. The data is summarized in the table below. This solid is the "compound" in crystalline form 2.

[0126]

Table 4

[0127] Example 3: “Compound” of Crystal Form 3 A solution consisting of 9.2 mL of 0.1 M NaOH, 500 mg of aprocitentan free acid form, and 25 mL of MeCN is evaporated to dryness at 40 °C using a rotavapor. 5 mL of MeOH is added to the solid residue and stirred at ambient temperature. After 2 - 3 h, the suspension is filtered and analyzed promptly. This solid is the "compound" in crystalline form 3.

[0128]

Table 5

[0129] Example 4: “Compound” of Crystal Form 4 Charge the reactor with aprocitentan free acid form (3.5 kg, 6.4 mol, 1.0 eq.) and MeOH (24.9 kg, 9.0 vol). Add a methanol solution of sodium methoxide (30%; 1.16 kg, 6.4 mol, 1.0 eq.) while rinsing with MeOH (2.8 kg, 1.0 vol). Stir the mixture at 20 °C for 4 h, then transfer it to a rotary evaporator and concentrate at 30 °C. Return the concentrated product to the reactor while rinsing with ethyl acetate (31.5 kg, 10 vol.). Stir the mixture at 20 °C for 2 h, cool it to 0 - 5 °C, filter the product, wash it with cold ethyl acetate (7 L, 2.0 vol.) to obtain a hydrated product, and then dry it under vacuum at 30 °C for 4 days using a nitrogen stream to obtain a dry weight of 3.05 kg (yield 84%). The final solid substance is the "compound" in crystalline form 4.

[0130]

Table 6

[0131] Comparative stability experiment (Manufactured according to Example 1 of WO2018 / 154101) The free form of aprocitentan (aprocitentan in crystalline form A) and the "compound" of crystalline form 1 according to the present invention were subjected to a head-to-head stability evaluation. The test was carried out by storing samples of the above substances in parallel in open vials at specific temperatures and relative humidities (RH), and measuring the assays of the stored samples by HPLC at different time points (the method described above). The results are summarized in the table below.

[0132] [Table 7]

[0133] The data shown in Table 5 indicate that under specific experimental conditions, the "compound" of crystalline form 1 has excellent chemical stability compared to the free acid form of aprocitentan (crystalline form A).

Claims

1. Compound, sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide 【Chemistry 1】 It is a crystal of, The crystals of the above compound - Crystal form 1 characterized by the presence of at least four, at least six, or at least eight peaks in a powder X-ray diffractogram at refraction angles 2θ selected from 4.3°, 13.1°, 13.5°, 14.8°, 17.2°, 19.5°, 21.1°, 21.6°, 22.6°, and 25.0°; - At least four, or at least six, or at least one, refraction angle 2θ selected from 4.2°, 13.3°, 16.7°, 16.9°, 18.9°, 20.8°, 22.5°, 23.5°, 25.6°, and 27.2° in the powder X-ray diffractogram. Crystal form 2 characterized by the presence of eight peaks; or, - Crystal form 3 characterized by the presence of at least four, at least six, or at least eight peaks at refraction angles 2θ selected from 3.9°, 11.9°, 15.0°, 15.8°, 17.0°, 19.8°, 22.4°, 23.3°, 23.8°, and 27.8° in a powder X-ray diffractogram; It has the crystal form, A crystal in which the powder X-ray diffractogram is obtained using bonded Cu Kα1 and Kα2 irradiation without removing Kα2; and the accuracy of the 2θ value is within the range of + / - 0.1 to 0.2°.

2. The compound is a crystal of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide, The crystals of the above compound - Crystal form 1 characterized by the presence of peaks at the following refraction angles 2θ: 4.3°, 17.2°, and 22.6° in the powder X-ray diffractogram; - Crystal form 2 characterized by the presence of peaks at the following refraction angles 2θ: 13.3°, 20.8°, and 22.5° in the powder X-ray diffractogram; or, - Crystal form 3 characterized by the presence of peaks at the following refraction angles 2θ: 3.9°, 15.8°, and 19.8° in the powder X-ray diffractogram; It has the crystal form, A crystal in which the powder X-ray diffractogram is obtained using bonded Cu Kα1 and Kα2 irradiation without removing Kα2; and the accuracy of the 2θ value is within the range of + / - 0.1 to 0.2°.

3. The compound is a crystal of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide, The crystals of the above compound - Crystal form 1 characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffractogram: 4.3°, 17.2°, 21.1°, 21.6°, and 22.6°; - Crystal form 2 characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffractogram: 4.2°, 13.3°, 18.9°, 20.8°, and 22.5°; or, - Crystal form 3 characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffractogram: 3.9°, 15.8°, 19.8°, 23.8°, and 27.8°; It has the crystal form, A crystal in which the powder X-ray diffractogram is obtained using bonded Cu Kα1 and Kα2 irradiation without removing Kα2; and the accuracy of the 2θ value is within the range of + / - 0.1 to 0.2°.

4. The compound is a crystal of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide, The crystals of the above compound - Crystal form 1 characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffractogram: 4.3°, 13.1°, 13.5°, 14.8°, 17.2°, 19.5°, 21.1°, 21.6°, 22.6°, and 25.0°; - Crystal form 2 characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffractogram: 4.2°, 13.3°, 16.7°, 16.9°, 18.9°, 20.8°, 22.5°, 23.5°, 25.6° and 27.2°; or, - Crystal form 3 characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffractogram: 3.9°, 11.9°, 15.0°, 15.8°, 17.0°, 19.8°, 22.4°, 23.3°, 23.8°, and 27.8°; It has the crystal form, A crystal in which the powder X-ray diffractogram is obtained using bonded Cu Kα1 and Kα2 irradiation without removing Kα2; and the accuracy of the 2θ value is within the range of + / - 0.1 to 0.2°.

5. A crystalline compound of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide according to any one of claims 1 to 4, for use in the manufacture of a pharmaceutical composition having the compound {5-(4-bromophenyl)-6-[2-(5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide as an active ingredient and further comprising at least one therapeutically inactive excipient.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, a crystal of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide as an active ingredient, and further comprising at least one therapeutically inactive excipient.

7. For use in the treatment of hypertension, pulmonary hypertension, coronary artery disease, heart failure, renal or myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's syndrome, finger 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, benign prostatic hyperplasia, 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 of vascular or cardiac surgery, or complications after organ transplantation, complications of cyclosporine treatment, pain, or hyperlipidemia, the compound according to any one of claims 1 to 4, sodium Crystals of (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide.

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

9. A compound according to any one of claims 1 to 4, a crystal of sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide, for use in the treatment of essential hypertension, resistant hypertension, pulmonary hypertension, or pulmonary artery hypertension.

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

11. Use of the compound according to any one of claims 1 to 4, sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide crystals for the manufacture of a pharmaceutical for the treatment of hypertension, particularly refractory / resistant hypertension; CKD, including hypertension-related CKD and / or CKD, including diabetes-related CKD (DKD); acute or chronic renal failure; diabetic nephropathy; glomerulonephritis; or heart failure (HF), including chronic HF.

12. A therapeutic agent for hypertension, particularly including refractory / resistant hypertension; CKD, including hypertension-related CKD and / or diabetes-related CKD (DKD); acute or chronic renal failure; diabetic nephropathy; glomerulonephritis; or heart failure (HF), including chronic HF, comprising the compound according to any one of claims 1 to 4, sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide crystals as an active ingredient.

13. A therapeutic agent for resistant hypertension comprising the compound according to any one of claims 1 to 4, sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide crystals as an active ingredient.

14. A pharmaceutical composition for the treatment of hypertension, particularly including refractory / resistant hypertension; CKD, including hypertension-related CKD and / or diabetes-related CKD (DKD); acute or chronic renal failure; diabetic nephropathy; glomerulonephritis; or heart failure (HF), including chronic HF, comprising the compound according to any one of claims 1 to 4, sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide crystals as an active ingredient, and further comprising at least one therapeutically inactive excipient.

15. A pharmaceutical composition for the treatment of resistant hypertension, comprising the compound according to any one of claims 1 to 4, sodium (5-(4-bromophenyl)-6-(2-((5-bromopyrimidine-2-yl)oxy)ethoxy)pyrimidine-4-yl)(sulfamoyl)amide crystals as an active ingredient, and further comprising at least one therapeutically inactive excipient.

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