EA043547B1 - PHARMACEUTICAL COMPOSITION CONTAINING APROCYTENTANE IN COMBINATION WITH OTHER ACTIVE INGREDIENTS, APPLICATION OF APROCYTENTANE DURING THE TREATMENT OF RESISTANT ARTERIAL HYPERTENSION IN COMBINATION WITH OTHER ACTIVE INGREDIENTS TENTS - Google Patents

Description

The invention relates to the compound aprocitentan and its use as an endothelin receptor antagonist, in combination with other active ingredients or therapeutic agents, including an angiotensin receptor blocker (in particular valsartan), and/or a calcium channel blocker (in particular amlodipine), and preferably a diuretic that is a thiazide-like diuretic (especially hydrochlorothiazide or chlorthalidone) during the prevention or treatment of certain endothelin-related diseases. In addition, the invention relates to pharmaceutical compositions containing aprocytentan in combination with these other active ingredients or therapeutic agents. In addition, the invention relates to such pharmaceutical compositions containing new crystalline forms of aprocytentan; to pharmaceutical compositions prepared from such crystalline forms, and to the use of such crystalline forms in combination with these other active ingredients or therapeutic agents during the prevention or treatment of these endothelin-related diseases.

Aprocytentan, (5-(4-bromophenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}sulfamide (hereinafter also referred to as compound), has formula I

The compound of Formula I, also known as ACT-132577, is an endothelin receptor inhibitor and can be used as an endothelin receptor antagonist. The compound of formula I is a member of a structural family that was previously generally disclosed in WO 02/053557. In particular, the compound of formula I, while exhibiting endothelin receptor antagonist activity, exhibits in vivo a significantly longer half-life and a significantly shorter clearance period compared to the corresponding alkylated derivatives. As a result, the compound of formula I is particularly suitable for long-acting pharmaceutical compositions, as disclosed in WO 2009/024906.

Because of its ability to inhibit endothelin binding, the compound of formula I can be used to treat endothelin-related diseases that cause increased vasoconstriction, proliferation or inflammation due to the action of endothelin. Examples of such diseases are arterial hypertension, pulmonary hypertension, coronary artery disease, heart failure, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoid hemorrhage, Raynaud's phenomenon, digital ulcers and portal hypertension. They can also be used during the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, malignant tumors, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis , asthma, pulmonary fibrosis, gram-negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, treatment and prevention of diabetic complications, complications of vascular or cardiac surgery or complications after organ transplantation, complications of treatment with cyclosporine, pain , hyperlipidemia, as well as other diseases currently known as endothelin-related diseases. Specific examples of endothelin-related diseases are hypertension-related diseases, which encompass arterial hypertension, including, but not limited to, refractory/resistant hypertension; pulmonary hypertension; heart failure, including in particular chronic heart failure; the risk of developing a significant cardiovascular complication (such as heart failure, myocardial infarction, stroke, or death from cardiovascular causes) in patients who have cardiovascular risk (for example, patients with coronary artery disease and/or patients who have significant clinical signs of congestive heart failure); angina pectoris; as well as diastolic dysfunction; erectile dysfunction; CKD (specifically, CKD stages 1–4 as defined in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines (and especially CKD stages 3) and, in particular, CKD stages specified caused by/associated with essential arterial hypertension, in particular resistant arterial hypertension); as well as diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy; and the risk of developing a significant cardiovascular complication (such as heart failure, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes that is accompanied by at least one other cardiovascular risk factor (such as such as arterial hypertension, in particular resistant arterial hypertension).

According to the 2014 joint statement of the American Society of Hypertension and the International Society of Hypertension [Weber et al., Clinical Practice Guidelines for the Management of Hypertension in the Community. A Statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (2014), 16(1), 14-26], joint guidelines of the European Society of Hypertension and the European Society of Cardiology 2013 [Mancia et al., J. Hypertens. (2013), 31, 1281-1357], as well as several national guidelines [Denolle et al., J Hum Hypertens. (2016), 30(11), 657-663; McCormack et al., Br J Cardiol (2013), 20 (suppl. 1), S1-S16], resistant arterial hypertension (rHTN) (or difficult-to-treat hypertension) is defined as uncontrolled blood pressure (BP) (i.e. inability to reduce blood pressure to a certain limit), despite the simultaneous use of three antihypertensive drugs of different pharmacological classes with maximum or optimal doses, including a diuretic. Thus, patients with resistant hypertension include patients whose blood pressure is controlled using more than three medications. That is, patients whose blood pressure is controlled but require four or more medications should be considered treatment resistant (see, for example, Mancia et al., J. Hypertens. (2013)).

Clinical studies have shown that endothelin receptor antagonists (ERA) can have significant therapeutic effects in patients suffering from hypertension and/or kidney disease. However, therapeutic benefits must be weighed against potential side effects, such as the potential risk of teratogenicity. In addition, both selective ET _A antagonists and dual ETA and ET _B receptor antagonists can cause fluid retention, a common side effect associated with many previously studied ERAs. While the risk-benefit ratio is generally favorable for treatment with ERAs for indications such as pulmonary hypertension (as reflected in past years by the successful market approvals of, for example, ERAs, the dual antagonists bosentan and macitentan , the ET _A -selective antagonist ambrisentan), AREs have no role in the treatment of primary hypertension (Laffin et al. Seminars in Nephrology 2015, 35, 168-175), and side effects such as fluid retention may remain problematic when considered potential treatment through the use of ERA for diseases such as rHTN, chronic kidney disease or other diseases associated with hypertension.

The ET _A -selective endothelin receptor antagonist darusentan was developed for the treatment of rAH (Bakris et al., Hypertension 2010, 56,824-830, see also WO 2007/098390). In a 14-week phase 3 clinical trial in patients with rHTN, it demonstrated efficacy in lowering ambulatory blood pressure but failed to show a significant treatment effect on the primary endpoint of systolic blood pressure. Patients were eligible to participate in the study if they had treatment-resistant hypertension (systolic blood pressure greater than 140 mm Hg) despite treatment with three or more antihypertensive drugs from different classes of drugs, including a diuretic, in optimized doses. A minimum dose of 25 mg per day of hydrochlorothiazide (or its equivalent in the case of other thiazide diuretics) was required. Although diuretic therapy could be intensified during the clinical study at the discretion of the investigators in order to control fluid retention, the most common adverse event associated with darusentan was fluid retention/edema at 28% versus 12% each. groups. Many patients withdrew from the study due to adverse events resulting from darusentan compared to placebo.

WO 2016/073846 provides an extensive description of ERAs studied for various indications, including CKD and rAH. Similar to the observations made with darusentan mentioned above, in a clinical trial examining the use of avosentan to reduce proteinuria in diabetic patients, the ET _A -selective ARE avosentan also showed a significant treatment effect, which was associated with significant cessation of clinically investigational drugs due to adverse events, mainly related to hypervolemia and congestive heart failure. The clinical trial was stopped early and the authors concluded that it may be that at doses as low as 25-50 mg, avosentan is less selective for the ETA receptor and thus causes sodium and water retention and dilation of peripheral blood vessels with possible movement of fluid from the intravascular space to the extravascular space. The suggestion of ETA receptor blockade resulting from higher doses of avosentan is further supported by data that showed a natriuretic effect of selective ETA receptor blockade in patients treated with ACEIs (Angiotensin Converting Enzyme Inhibitors) (Mann et al., J Am Soc Nephrol. 2010, 21(3): 527-535.WO 2016/073846 provides additional examples where fluid retention may lead to increased side effects from the use of ERAs such as bosentan, tezosentan, ambrisentan, and atrasentan.WO 2016/ 073846 provides a method of treating CKD through the use of an ERA, in particular through the use of the ETA-selective ERA atrasentan, using predictive factors for fluid retention, said method comprising determining the risk of fluid retention if an ERA is administered to a patient; and administering an ERA to a patient if the risk is at an acceptable level.

Preclinical and clinical data suggest that the ET _A -selective antagonists sitaxentan and ambrisentan carry a higher risk of fluid retention than the dual AREs bosentan and macitentan (Vercauteren et al., JPET 2017, 361, 322-333). On the other hand, preclinical data showed that the synergistic effect on blood pressure of the ETA-selective ARE in combination with the ACE inhibitor enalapril was eliminated by concomitant blockade of the ET _B receptor (Goddard et al., J. Am. Soc. Nephrol. 2004, 15, 2601- 2610).

A phase 2 clinical trial showed that aprocitentan, an ERA that results in effective dual blockade of endothelin receptors, can lead to effective blood pressure control in patients suffering from essential hypertension, that is, without baseline therapy (Actelion Pharmaceuticals Ltd, press release, May 22, 2017). The overall incidence of adverse events was similar to the overall incidence of adverse events observed in the placebo group. Thus, unlike the methods described in WO 2016/073846, aprocitentane may not require risk assessment and/or dose reduction to reduce side effects associated with fluid retention when used during the treatment of hypertension-related diseases in particularly with resistant arterial hypertension.

Moreover, in rat models of hypertension, it was found that aprocitentan may have synergistic pharmacological effects in combination with valsartan, as well as synergistic pharmacological effects in combination with amlodipine, compared with the effects of the corresponding active ingredients alone. In particular, when combined with three antihypertensive drugs of different pharmacological classes, including valsartan, amlodipine, and a thiazide-class diuretic, such as the commercially available Exforge HCT® (i.e., a fixed combination of valsartan/amlodipine/hydrochlorothiazide), aprocytentan may lead to a better effect than spironolactone, which is used in the standard available adjunctive treatment. Moreover, aprocitentan may have a different pharmacological profile than the predominantly ETA-selective antagonists that have so far been studied for effects on resistant hypertension and other endothelin-related diseases. Thus, aprocitentan, an ARE that results in effective dual blockade of endothelin receptors, may be particularly suitable for the treatment of resistant hypertension when given in combination with one or more antihypertensive drugs of different pharmacological classes, including in particular an angiotensin receptor blocker, in particular such as valsartan, a calcium channel blocker, in particular such as amlodipine, and a diuretic, in particular a thiazide class diuretic (thiazide-like diuretic), in particular such as chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, or metolazone . Such combination treatment may result in better blood pressure control compared with treatment with such antihypertensive drugs alone, while maintaining a moderate side effect profile, even with optimal effective doses of aprocitentan, and, for example, does not require a risk assessment according to WO 2016/073 846 and/or dose reduction to reduce side effects, for example those associated with fluid retention.

Additionally, it has been discovered that, under certain conditions, certain crystalline forms of aprocytentan may appear that are suitable for the preparation of pharmaceutical compositions. These crystalline forms of the compound are new and may have advantageous properties from the point of view of the potential use of the compound as an active pharmaceutical ingredient. Such benefits may include better rheological properties; less hygroscopicity; better manufacturing reproducibility (eg, better filtration parameters, better formation reproducibility, and/or better sedimentation); and/or a specific structure. Such crystalline forms of the compound may be particularly suitable for the process of preparing certain pharmaceutical compositions. The compound or a pharmaceutically acceptable salt thereof has also been found to be particularly useful for the treatment of certain disorders, particularly when used in combination with other active ingredients or therapeutic agents.

Description of the figures

Fig. 1 shows the X-ray powder diffraction pattern of the compound in crystalline form A that was obtained in Example 1. The X-ray diffraction pattern shows peaks that have relative intensities compared to the most intense peak in the chart, which are expressed in the following percentages (relative peak intensities are represented by in parentheses) at the indicated refraction angles 2theta (selected peaks shown

- 3 043547 from the range 3-33° 2theta with a relative intensity greater than 10%): 9.8° (18%), 9.9° (18%), 11.7° (14%), 14.5° (10%), 15.4° (14%), 15.6° (29%), 16.9° (19%), 17.2° (16%), 17.8° (100%), 18.6° (50%), 19.9° (54%), 20.0° (67%), 21.5° (24%), 21.9° (10%), 22.8° ( 18%), 23.2° (49%), 23.5° (83%), 24.9° (32%), 25.1° (20%), 25.3° (24%), 25 .6° (33%), 25.9° (16%), 27.1° (23%), 27.3° (39%), 28.5° (13%), 29.0° (23 %), 29.4° (15%), 30.1° (12%) and 30.6° (10%).

Fig. 2 shows a powder X-ray diffraction pattern of dichloromethane solvate of compound in crystalline form B, which was prepared in Example 2. The X-ray diffraction pattern shows peaks that have relative intensities compared to the most intense peak in the chart, which are expressed in the following percentages (relative intensities peaks are presented in parentheses) at the indicated refractive angles 2theta (selected peaks from the range 3-33° 2theta with a relative intensity greater than 10%) are presented: 11.2° (16%), 16.2° (57%), 18. 0° (21%), 18.6° (71%), 18.8° (36%), 19.8° (19%), 20.3° (100%), 22.4° (45% ), 22.9° (28%), 24.3° (44%), 24.8° (11%), 25.0° (41%), 25.7° (22%), 26.1 ° (31%), 27.4° (20%), 29.4° (16%), 29.8° (38%) and 32.4° (12%).

Fig. 3 shows the X-ray powder diffraction pattern of the compound in crystalline form B that was obtained in Example 3. The X-ray diffraction pattern shows peaks that have relative intensities compared to the most intense peak in the chart, which are expressed in the following percentages (relative peak intensities are represented by in parentheses) at the indicated refraction angles 2theta (selected peaks from the range 3-33° 2theta with relative intensity greater than 10%) are presented: 7.8° (23%), 9.7° (42%), 15.7° (37%), 17.2° (16%), 17.8° (15%), 18.8° (26%), 19.8° (71%), 20.1° (51%), 20.6° (15%), 21.6° (15%), 22.0° (100%), 23.4° (27%), 23.6° (40%), 24.1° ( 23%), 24.5° (16%), 25.1° (13%), 25.3° (39%), 25.7° (28%), 26.8° (19%), 27 .1° (16%), 28.5° (31%), 30.8° (13%) and 30.8° (13%).

Fig. 4 shows the X-ray powder diffraction pattern of the compound in crystalline form G, which was obtained in Example 4. The X-ray diffraction pattern shows peaks that have relative intensities compared to the most intense peak in the chart, which are expressed in the following percentages (relative peak intensities are represented by in parentheses) at the indicated refraction angles 2theta (selected peaks from the range 3-33° 2theta with relative intensity greater than 10%) are presented: 4.6° (27%), 8.4° (15%), 8.6° (11%), 16.4° (17%), 16.8° (26%), 17.2° (10%), 18.6° (11%), 18.9° (18%), 19.3° (40%), 19.6° (45%), 20.1° (100%), 20.6° (55%), 20.8° (26%), 22.0° ( 10%), 22.7° (14%), 23.0° (24%), 23.5° (32%), 23.8° (12%), 24.2° (17%), 24 .7° (20%), 25.1° (55%), 25.4° (22%), 25.6° (14%), 26.2° (16%), 26.8° (17 %), 27.2° (28%), 28.1° (21%) and 28.1° (19%).

Fig. 5 shows a powder X-ray diffraction pattern of acetonitrile solvate of compound in crystalline form D, which was prepared in Example 5. The X-ray diffraction pattern shows peaks that have relative intensities compared to the most intense peak in the chart, which are expressed in the following percentages (relative intensities peaks are presented in parentheses) at the indicated refractive angles 2theta (selected peaks from the range 3-33° 2theta with a relative intensity greater than 10%) are presented: 9.0° (21%), 9.5° (56%), 11. 3° (61%), 14.5° (41%), 14.8° (15%), 15.6° (47%), 16.0° (26%), 16.5° (100% ), 18.2° (84%), 18.7° (73%), 18.9° (56%), 20.2° (20%), 20.7° (56%), 22.8 ° (96%), 23.9° (22%), 24.5° (70%), 25.3° (77%), 25.6° (29%), 26.0° (14%) , 26.6° (66%), 27.5° (27%), 29.6° (31%), 30.2° (66%), and 33.0° (13%).

Fig. 6 shows the X-ray powder diffraction pattern of the compound in crystalline form I, which was obtained in Example 6. The X-ray diffraction pattern shows peaks that have relative intensities compared to the most intense peak in the chart, which are expressed in the following percentages (relative peak intensities are represented by in parentheses) at the indicated refraction angles 2theta (selected peaks from the range 3-33° 2theta with a relative intensity greater than 10% are presented): 4.0° (44%), 4.7° (14%), 6.5° (23%), 9.0° (27%), 16.1° (40%), 17.2° (11%), 18.7° (22%), 19.0° (58%), 19.4° (28%), 19.8° (46%), 20.7° (57%), 21.2° (17%), 21.9° (100%), 22.6° ( 14%), 23.2° (23%), 24.1° (37%), 24.8° (40%), 25.6° (42%), 27.0° (29%), 28 .2° (27%), 29.0° (20%), 30.3° and 30.8° (10%).

Fig. 7 shows a powder X-ray diffraction pattern of the dimethyl sulfoxide solvate of compound in crystalline form J, which was prepared in Example 7. The X-ray diffraction pattern shows peaks that have relative intensities compared to the most intense peak in the chart, which are expressed in the following percentages (relative intensities peaks are presented in parentheses) at the indicated refractive angles 2theta (selected peaks from the range 3-33° 2theta with a relative intensity greater than 10% are presented): 10.9° (16%), 16.9° (18%), 18. 2° (26%), 18.4° (30%), 18.6° (29%), 18.7° (55%), 19.3° (100%), 20.8° (35% ), 21.2° (47%), 21.9° (26%), 24.3° (21%), 24.8° (24%), 25.4° (29%), 25.8 ° (22%), 26.7° (34%), 27.7° (13%), 27.8° (14%), 28.6° (15%), 29.4° (18%) , 31.5° (23%) and 31.8° (12%).

Fig. 8 shows an X-ray powder diffraction pattern of the ethanol solvate of the compound in crystalline form K, which was obtained in Example 8. X-ray diffraction pattern

- 4 043547 shows peaks that have a relative intensity, compared to the most intense peak in the diagram, which is expressed in the following percentages (relative peak intensities are presented in parentheses) at specified refractive angles 2theta (selected peaks from the range 3-33° 2theta s relative intensity greater than 10% are represented by: 9.1° (31%), 9.3° (34%), 11.3° (49%), 12.2° (10%), 14.6° ( 17%), 14.8° (46%), 15.7° (16%), 16.1° (10%), 16.4° (80%), 17.9° (17%), 18 .2° (19%), 18.7° (96%), 20.0° (38%), 20.3° (100%), 22.6° (11%), 22.8° (76 %), 23.2° (50%), 24.1° (14%), 24.5° (56%), 24.7° (68%), 25.4° (46%), 25, 9° (32%), 26.4° (14%), 26.8° (22%), 27.7° (38%), 28.2° (12%), 29.7° (11% ), 29.5° (64%), 29.8° (14%), 30.3° (14%), 30.5° (13%) and 32.4° (16%).

It is understood that the crystalline forms disclosed in this invention contain the compound in free base crystalline form (ie, not as a salt). In addition, said crystalline forms may contain a non-coordinating and/or coordinating solvent. The term coordination solvent is used in this invention to refer to a crystalline solvate. Likewise, the term non-coordinating solvent is used in this invention to refer to an adsorbed or physically entrapped solvent (defined in accordance with Polymorphism in the Pharmaceutical Industry (ed. R. Hilfiker, VCH, 2006), chapter 8: U.J. Griesser: The Importance of Solvates) . Crystal forms A and B are the anhydrate or ansolvate forms, crystal form B is a DCM solvate, crystal form E is a MeCN solvate, and crystal form I is a DMSO solvate.

Fig. 9 shows the short-term effect of ACT-132577 on mean arterial pressure (MAP) in awake male salt-sensitive hypertensive Dahl rats.

Fig. 10 shows the short-term effect of ACT-132577 on MAP in awake male deoxycorticosterone-acetate-salt-sensitive hypertensive rats.

Fig. 11 shows the short-term effect of ACT-132577 on MAP in awake male spontaneously hypertensive rats.

Fig. 12 shows the short-term effect of ACT-132577, administered alone or in combination with valsartan, on MAP in awake male spontaneously hypertensive rats.

Fig. 13 shows the short-term effect of ACT-132577, administered alone or in combination with valsartan, on MAP in awake male deoxycorticosterone acetate-salt-sensitive hypertensive rats.

Fig. 14 shows the short-term effect of ACT-132577, administered alone or in combination with enalapril, on MAP in awake male spontaneously hypertensive rats.

Fig. 15 shows the short-term effect of ACT-132577, administered alone or in combination with amlodipine, on MAP in awake male deoxycorticosterone acetate-salt-sensitive hypertensive rats.

Fig. 16 shows the effects of chronic oral administration of ACT-132577 on MAP in awake male deoxycorticosterone acetate salt sensitive hypertensive rats.

Fig. 17 shows the effects of chronic oral administration of ACT-132577 on renal vascular hemodynamic resistance in awake male deoxycorticosterone-acetate-salt-sensitive hypertensive rats.

Fig. 18 shows the short-term dose-dependent effects of aprocitentan at doses of 1, 3, 10, 30 mg/kg) on hematocrit (Hct) 24 hours after a single oral administration to Wistar rats.

Fig. 19 shows the short-term effects of EXFORGE HCT® alone, and EXFORGE HCT® in combination with ACT-132577, in spontaneously hypertensive male rats.

Fig. 20 shows the short-term effects of EXFORGE HCT® alone, and EXFORGE HCT® in combination with spironolactone, in spontaneously hypertensive male rats.

Fig. 21 shows the short-term effects of EXFORGE HCT® alone, and EXFORGE HCT® in combination with ACT-132577, in male deoxycorticosterone acetate-salt-sensitive hypertensive rats.

Fig. 22 shows the short-term effects of EXFORGE HCT® alone, and EXFORGE HCT® in combination with spironolactone, in male deoxycorticosterone acetate-salt-sensitive hypertensive rats.

Detailed Description of the Invention

1. The first embodiment relates to a pharmaceutical composition containing as active substances aprocitentan or a pharmaceutically acceptable salt thereof, in combination with an angiotensin receptor blocker, which in particular is valsartan, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

2. The second aspect of the present invention relates to a pharmaceutical composition containing as active substances aprocitentan or a pharmaceutically acceptable salt thereof, in combination with an angiotensin receptor blocker, which in particular is valsartan, or a pharmaceutically acceptable salt thereof, and/or

- 5 043547 calcium channel blocker, which in particular is amlodipine, or a pharmaceutically acceptable salt thereof;

and at least one pharmaceutically acceptable excipient.

3. The third aspect of the present invention relates to a pharmaceutical composition containing as active substances aprocytentan or a pharmaceutically acceptable salt thereof, in combination with an angiotensin receptor blocker, which in particular is valsartan, or a pharmaceutically acceptable salt thereof;

a calcium channel blocker, which in particular is amlodipine, or a pharmaceutically acceptable salt thereof; and a diuretic, which is a thiazide-like diuretic (especially hydrochlorothiazide or chlorthalidone, especially hydrochlorothiazide), or a pharmaceutically acceptable salt thereof;

and at least one pharmaceutically acceptable excipient.

4. A further embodiment provides a pharmaceutical composition according to embodiment 3, wherein the angiotensin receptor blocker is valsartan or a pharmaceutically acceptable salt thereof; the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof; and the diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof, or chlorthalidone or a pharmaceutically acceptable salt thereof.

5. A further embodiment relates to a pharmaceutical composition according to embodiment 3, wherein said pharmaceutical composition comprises aprocytentan or a pharmaceutically acceptable salt thereof, in combination with valsartan or a pharmaceutically acceptable salt thereof, and amlodipine or a pharmaceutically acceptable salt thereof; and also in combination with hydrochlorothiazide or a pharmaceutically acceptable salt thereof, or chlorthalidone or a pharmaceutically acceptable salt thereof; wherein aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration from 2.5 to 100 mg (in particular 5 or 10-50 mg, in particular 12.5, 25 or 50 mg, in particular 12.5 or 25 mg) aprocitentan per day;

valsartan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 100 to 320 mg (in particular 160 or 320 mg, in particular 160 mg) of valsartan per day;

amlodipine or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 2 to 10 mg (in particular 5 or 10 mg, in particular 5 mg) of amlodipine per day; and hydrochlorothiazide or a pharmaceutically acceptable salt thereof, if present, is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 25 mg (especially 12.5 or 25 mg) per day of hydrochlorothiazide; and chlorthalidone or a pharmaceutically acceptable salt thereof, if present, is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 to 150 mg (especially 15 or 30 mg) of chlorthalidone per day.

6. A further embodiment provides a pharmaceutical composition according to embodiment 4), wherein the diuretic is a hydrochlorothiazide.

7. A further embodiment relates to a pharmaceutical composition in accordance with embodiment 6), wherein aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 2.5 to 100 mg (especially 5 or 10- 50 mg, in particular 12.5, 25 or 50 mg, in particular 12.5 or 25 mg) aprocitentan per day;

valsartan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 100 to 320 mg (in particular 160 or 320 mg, in particular 160 mg) of valsartan per day;

amlodipine or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 2 to 10 mg (in particular 5 or 10 mg, in particular 5 mg) of amlodipine per day; and hydrochlorothiazide or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 25 mg (especially 12.5 or 25 mg) of hydrochlorothiazide per day.

In a sub-embodiment, aprocitentan is contained in a pharmaceutical unit dosage form suitable for oral administration of 12.5 or 25 mg of aprocitentan per day; valsartan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 160 mg of valsartan per day; amlodipine or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 or 10 mg of amlodipine per day; and hydrochlorothiazide or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 12.5 or 25 mg per day of hydrochlorothiazide; where clearly revealed

- 6 043547 each combination of dosages, that is, 12.5/160/5/12.5; 12.5/160/10/12.5; 12.5/160/5/25; 12.5/160/10/25;

25/160/5/12.5; 25/160/10/12.5; 25/160/5/25 and 25/160/10/25 mg.

As used herein, the term angiotensin receptor blocker or ARB specifically means valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan, or a pharmaceutically acceptable salt of one thereof. A preferred ARB is valsartan or a pharmaceutically acceptable salt thereof.

In the present invention, the term calcium channel blocker or CCB specifically means amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, isradipine, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, verapamil or diltiazem or a pharmaceutically acceptable salt of one of them. A preferred CCB is amlodipine or a pharmaceutically acceptable salt thereof.

In the present invention, the term diuretic particularly means a diuretic of the thiazide class (thiazide-like diuretic), in particular such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide, or metolazone. The preferred diuretics are chlorthalidone or hydrochlorothiazide; Thus, one aspect of the present invention relates to the combination of aprocytentan, the ARB valsartan, and the CCB amlodipine, with chlorthalidone; Another aspect of the present invention relates to the combination of aprocytentan, the ARB valsartan, and the CCB amlodipine, with hydrochlorothiazide.

In addition, pharmaceutical compositions containing as active substances aprocitentan or a pharmaceutically acceptable salt thereof, in combination with an angiotensin-converting enzyme inhibitor, which in particular is enalapril, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient are further disclosed.

In the present invention, the term angiotensin-converting enzyme inhibitor or ACE inhibitor specifically means captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril, or a pharmaceutically acceptable salt of one thereof. The preferred ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

8. A further embodiment relates to a pharmaceutical composition in accordance with any of embodiments 1-7, wherein said composition contains aprocytentan in crystalline form A, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 17.8, 20 .0 and 23.5°; wherein said X-ray powder diffraction pattern is obtained by using Cu Ka combined radiation. 1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

9. A further embodiment relates to a pharmaceutical composition in accordance with any of embodiments 1-7, wherein said composition contains aprocytentan in crystalline form A, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 17.8, 18 .6, 20.0, 23.2 and 23.5°; wherein said powder X-ray diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

10. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein the composition contains aprocytentan in crystalline form A, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 9.8, 9 .9, 11.7, 17.8, 18.6, 20.0, 21.5, 22.8, 23.2 and 23.5°; wherein said powder X-ray diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without removing Ka2 y; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

11. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein the composition contains aprocytentan in crystalline form A, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 9.8, 9 .9, 11.7, 14.5, 15.4, 15.6, 16.9, 17.2, 17.8, 18.6, 19.9, 20.0, 21.5, 21.9 , 22.8, 23.2, 23.5, 24.9, 25.1, 25.3, 25.6, 25.9, 27.1, 27.3, 28.5, 29.0, 29 ,4, 30.1 and 30.6°; wherein said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

12. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein the composition contains aprocytentan in crystalline form A, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 9.8° ( 18%), 9.9° (18%), 11.7° (14%), 14.5° (10%), 15.4° (14%), 15.6° (29%), 16 .9° (19%), 17.2° (16%), 17.8° (100%), 18.6° (50%), 19.9° (54%), 20.0°

- 7 043547 (67%), 21.5° (24%), 21.9° (10%), 22.8° (18%), 23.2° (49%), 23.5° (83 %), 24.9° (32%), 25.1° (20%), 25.3° (24%), 25.6° (33%), 25.9° (16%), 27, 1° (23%), 27.3° (39%), 28.5° (13%), 29.0° (23%), 29.4° (15%), 30.1° (12% ) and 30.6° (10%); wherein said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without removing Ka2; and accuracy of values

2θ is in the range of 2θ +/-0.2°.

This data shows peaks that have relative intensities compared to the most intense peak in the diagram, which are expressed in the following percentages (relative peak intensities are presented in parentheses) at the indicated refractive angles 2theta (selected peaks from the range 3-33° 2θ s are presented relative intensity greater than 10%).

13. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein said composition contains aprocytentan in crystalline form A, which essentially shows powder x-ray diffraction spectra as depicted in FIG. 1, wherein said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without removing Ka2; and the accuracy of the values 20 is in the range of 2θ +/-0.2°.

In this context, the term essentially means that the diagram must contain at least the major peaks that are depicted in the figures, that is, those peaks that have a relative intensity of more than 10%, in particular more than 20%, when compared with the most intense peak on the diagram. However, one skilled in the art of powder X-ray diffraction will recognize that the relative intensities in powder X-ray diffraction patterns can be subject to large variations in intensity due to preferred orientation effects.

14. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein said composition contains aprocytentan in crystalline form A, which can be obtained by crystallizing the compound in an aqueous solution with a pH value of 6.2-6.8 .

For greater clarity, it is clarified that in all cases where one of the above embodiments refers to peaks in the powder X-ray diffraction pattern at the following refractive angles 2θ, then the specified powder X-ray diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without removing Ka2; and it should be understood that the accuracy of the 2θ values as presented in this invention is within the range of +/-0.1-0.2°. In particular, when a refractive angle of 2 theta (2θ) is indicated for a peak in accordance with embodiments of the invention and the claims, the reported 2θ value should be understood as the interval of the said value minus 0.2° from the said value and plus 0.2° to specified value (2θ +/-0.2°); and preferably minus 0.1° from the specified value and plus 0.1° to the specified value (2θ +/-0.1°).

For example, when determining the presence of a peak in an X-ray powder diffraction pattern, a common approach is to do so using the S/N ratio (S = signal, N = noise). According to this definition, when it is stated that there is a peak in the X-ray powder diffraction pattern, it is understood that the peak in the X-ray powder diffraction pattern is determined by the S/N ratio (S = signal, N = noise) which is greater than x (x in this case represents a numerical value greater than 1), usually greater than 2, in particular greater than 3.

Unless used in relation to temperatures, in the present invention the term about, located before the numerical value of X, refers to the range that extends from X minus 10% of X to X plus 10% of X, and preferably to the range that extends from X minus 5% from X to X plus 5% from X. In the specific case of temperatures, the term approximately located before the value of temperature Y, in the present invention refers to the interval that extends from temperature Y minus 10°C to Y plus 10°C, preferably to a range that extends from Y minus 5°C to Y plus 5°C, in particular to a range that extends from Y minus 3°C to Y plus 3°C. Room temperature means a temperature of approximately 25°C. When the present invention uses the term n equivalent(s), where n is a number, within the scope of the present invention it means that n refers to the approximate number of n, preferably n refers to the exact number of n.

In all cases where the word between or from - to is used to describe a numerical range, it must be understood that the boundary points of the specified range are clearly included in that range. For example: if a temperature range is described as being between 40 and 80°C (or being between 40 and 80°C), this means that the cut-off points of 40 and 80°C are within that range; or, if a variable is defined to represent an integer between 1 and 4 (or 1 to 4), this means that the variable represents an integer 1, 2, 3, or 4.

15. A further embodiment provides a pharmaceutical composition according to any of embodiments 1-7, wherein said composition contains aprocytentan

- 8 043547 in crystalline form B, characterized by the presence of peaks in the powder X-ray diffraction pattern at the following refractive angles 2θ: 9.7, 15.7 and 22.0°; wherein said powder X-ray diffraction pattern is obtained through the use of combined radiation

Cu Ka. 1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

16. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein the composition contains aprocytentan in crystalline Form B characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 7,8,9 .7, 15.7, 19.8 and 22.0°; wherein said powder X-ray diffraction pattern is obtained by applying the combined radiation of Cu Ka.1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

17. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein the composition contains aprocytentan in crystalline form B, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 7,8,9 .7, 15.7, 17.2, 17.8, 18.8, 19.8, 22.0, 23.6 and 25.3°; wherein said X-ray powder diffraction pattern is obtained by using Cu Ka combined radiation. 1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

18. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein the composition contains aprocytentan in crystalline Form B characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 7,8,9 ,7, 15.7, 17.2, 17.8, 18.8, 19.8, 20.1, 20.6, 21.6, 22.0, 23.4, 23.6, 24.1 , 24.5, 25.1, 25.3, 25.7, 26.8, 27.1, 28.5, 30.8 and 30.8°; wherein said powder X-ray diffraction pattern is obtained by applying the combined radiation of Cu Ka.1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

19. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein the composition contains aprocytentan in crystalline form B, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following refractive angles 2θ: 7.8° ( 23%), 9.7° (42%), 15.7° (37%), 17.2° (16%), 17.8° (15%), 18.8° (26%), 19 .8° (71%), 20.1° (51%), 20.6° (15%), 21.6° (15%), 22.0° (100%), 23.4° (27 %), 23.6° (40%), 24.1° (23%), 24.5° (16%), 25.1° (13%), 25.3° (39%), 25, 7° (28%), 26.8° (19%), 27.1° (16%), 28.5° (31%), 30.8° (13%) and 30.8° (13% ); wherein said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

The present data shows peaks that have relative intensities compared to the most intense peak in the diagram, which are expressed in the following percentages (relative peak intensities are presented in parentheses) at the indicated 2theta refractive angles (selected peaks from the range 3-33° 2theta s are shown) relative intensity greater than 10%).

20. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-7, wherein said composition contains aprocytentan in crystalline Form B, which essentially exhibits a powder x-ray diffraction spectrum as depicted in FIG. 3, wherein said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka.1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°.

In this context, the term essentially means that the diagram must contain at least the main peaks that are depicted in the indicated figures x, that is, those peaks that have a relative intensity of more than 10%, in particular more than 20%, when compared with the most intense peak on the diagram. However, one skilled in the art of powder X-ray diffraction will recognize that the relative intensities in powder X-ray diffraction patterns can be subject to large variations in intensity due to preferred orientation effects.

21. A further embodiment provides a pharmaceutical composition according to any of embodiments 1-7, wherein the composition contains aprocytentan in crystalline Form B, which can be obtained by crystallizing the compound from MeOH, EtOH or propan-2-ol.

22. A further embodiment provides a pharmaceutical composition according to any of embodiments 1-7, wherein said composition contains aprocytentan in amorphous form. Such an amorphous form can be obtained by grinding Form A. For example, the amorphous form can be obtained by grinding in a ball mill (MM200 Retsch Ball Mill, with 2 agate balls), 30 minutes at 30 Hz at ambient temperature.

- 9 043547

The preparation of pharmaceutical compositions can be carried out in a manner known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st edition (2005), part 5, Pharmaceutical Manufacturing [published by Lippincott Williams & Wilkins]) by bringing the crystalline forms of the present invention, optionally in combination with other therapeutically useful substances, into a galenic dosage form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, conventional pharmaceutical adjuvants.

23. A further embodiment relates to a solid pharmaceutical composition (particularly in tablet form) in accordance with any of embodiments 1-22, in particular in accordance with any of embodiments 8-14, or in accordance with any of embodiments 15-21, containing as a pharmaceutically acceptable excipient inert microcrystalline cellulose, lactose, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate.

24. Specifically, the solid pharmaceutical composition in accordance with embodiment 23 will contain aprocytentan in a total amount of from 5 to 25% by weight, based on the total weight of the pharmaceutical composition, microcrystalline cellulose in a total amount of from 20 to 30% by weight, based on total weight of the pharmaceutical composition, lactose in a total amount from 40 to 65% by weight, based on the total weight of the pharmaceutical composition, hydroxypropylcellulose in a total amount from 1 to 3% by weight, based on the total weight of the pharmaceutical composition, croscarmellose sodium in a total amount from 2 up to 8% by weight, based on the total weight of the pharmaceutical composition, and magnesium stearate in a total amount of from 0.2 to 2% by weight, based on the total weight of the pharmaceutical composition, and the total percentage by weight of the solid pharmaceutical composition will always be 100; the above-mentioned solid pharmaceutical composition will in particular be presented in the form of a tablet.

25. A further embodiment of the invention relates to a pharmaceutical composition in accordance with embodiments 23-24, wherein said pharmaceutical composition is in the form of a tablet. In a sub-embodiment, the pharmaceutically active ingredients are contained in granules before being compressed into said tablet.

The tablet according to embodiment 25 may optionally be coated with a suitable protective coating. Said protective coating will, in particular, prevent direct contact of the pharmaceutical composition with moisture; it may also facilitate marking, which may be desirable in order to distinguish the pharmaceutical composition from others.

The coating material to form such a protective shell may include a polymer with low water vapor permeability (such as polyvinyl alcohol (eg, Aquapolish® PVA white from Biogrund) or dimethylaminoethyl methacrylate (eg, EUDRAGIT® E PO)). The coating material may further include a plasticizer (e.g., propylene glycol, triacetin, dibutyl phthalate, or dibutyl sebacate), a surfactant (e.g., sodium lauryl sulfate or a polysorbate such as Tween®), and/or a glidant/glidant (e.g., stearic acid, magnesium or calcium stearate or talc). Moreover, the coating material may also include a pigment (eg, iron(I) oxide, iron(III) oxide or titanium oxide) to impart color to the tablet.

26. A further embodiment of the invention relates to a pharmaceutical composition in accordance with any of embodiments 23-24, wherein said pharmaceutical composition is in the form of a capsule. In a sub-embodiment, the pharmaceutically active ingredients are contained in granules before being filled into said capsules.

Furthermore, the invention certainly relates to crystalline forms of aprocytentan, in particular to crystalline form A disclosed in this invention, wherein said crystalline form is suitable/used as a final step in the preparation of aprocytentan (for example, to meet the purity requirements of pharmaceutical production ), while the finished pharmaceutical composition in accordance with embodiments 1-26 may or may not contain the specified crystalline form (for example, due to the fact that the original crystalline form of aprocytentan is further transformed during the manufacturing process and/or dissolved in the pharmaceutical suitable carrier material(s); such that in the finished pharmaceutical composition, aprocytentan may be present in non-crystalline form, in another crystalline form, or in dissolved form, or the like).

Such combination pharmaceutical compositions in accordance with embodiments 1-26 are particularly useful for the treatment of diseases associated with endothelin, including arterial hypertension, pulmonary hypertension, coronary artery disease, heart failure, renal and myocardial ischemia, renal failure, ischemia brain, dementia, migraine, subarachnoid hemorrhage, Raynaud's phenomenon, finger or pore ulcers

- 10 043547 total hypertension, as well as suitable for the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, gastric and duodenal ulcers, malignant tumors, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram-negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporine treatment, pain or hyperlipidemia.

The combination pharmaceutical compositions in accordance with embodiments 1-26 are also useful for the treatment of chronic kidney disease (CKD), particularly CKD stages 1-4, as defined in the Kidney Disease Improving Global Outcomes (KDIGO) guideline (and, in in particular, stage 3 CKD), and, in particular, for the treatment of CKD of these stages caused by essential arterial hypertension.

The pharmaceutical compositions in accordance with embodiments 1-26 are particularly useful for the treatment of hypertension-related diseases that include hypertension, including in particular intractable/resistant hypertension; pulmonary hypertension; heart failure, including in particular chronic heart failure; to reduce the risk of developing a significant cardiovascular complication (such as heart failure, myocardial infarction, stroke, or death from cardiovascular causes) in patients who have cardiovascular risk (such as patients with coronary artery disease and/or patients who have pronounced clinical signs of congestive heart failure); angina pectoris; and diastolic dysfunction; erectile dysfunction; CKD (specifically CKD stages 1–4 as defined in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines (and specifically CKD stage 3), and in particular CKD stages 1–4 as defined by/associated with essential hypertension, particularly resistant hypertension; and diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy; and to reduce the risk of developing a significant cardiovascular complication (such as cardiac failure, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes that is accompanied by at least one other cardiovascular risk factor (such as hypertension, in particular resistant hypertension).

Preferably, the pharmaceutical compositions according to embodiments 1-26 are useful during the treatment of certain endothelin-related diseases, which can be defined as a disease selected from the group consisting of arterial hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction , angina and CKD (in particular, CKD stages 1–4, as defined in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines (and, in particular, CKD stage 3), and, in particular, CKD stages 1–4 as defined by essential arterial hypertension).

Moreover, the pharmaceutical compositions in accordance with embodiments 1-19 are useful during the treatment of a disease selected from the group consisting of essential arterial hypertension, resistant arterial hypertension, pulmonary hypertension and pulmonary arterial hypertension (and, in particular, during the treatment of resistant arterial hypertension). arterial hypertension).

Essential hypertension (also called primary hypertension or idiopic hypertension) is a type of hypertension that essentially has no known cause. It poses a significant threat to global public health, contributing to vascular and renal morbidity and cardiovascular disease mortality. The diagnosis of essential arterial hypertension is made when the average of several systolic blood pressure measurements after 2 or more consecutive visits is consistently equal to or above a certain threshold _TSA value. Typically, people with high usual blood pressure maintain pressure that is above the average for general population, and they have a higher risk of developing significant hypertension and cardiovascular complications than the general population. The threshold _TSA d value above which treatment is recommended is regularly discussed among practitioners (see, for example, Mancia et al. J. Hypertens. (2013), 31, 1281-1357); accordingly, depending on the general condition of the patient and age, _TSA d may be 140 or 130 mmHg, or another suitable value.

The term resistant hypertension [equivalent to the term intractable hypertension] is defined herein as blood pressure that remains above the target value despite the concomitant use of 3 different classes of antihypertensive drugs. One of the 3 drugs must be a diuretic and all drugs must be prescribed in optimal/maximum doses. Patients with resistant hypertension have been defined to include patients whose blood pressure is controlled by more than 3 medications. That is, patients whose blood pressure is controlled but require 4 or more medications to achieve this should be considered treatment resistant (see, for example, Mancia et al. J.

Hypertens. (2013), 31, 1281-1357).

27. The fourth aspect of the invention accordingly relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of arterial hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and chronic kidney disease (in particular, during the treatment resistant arterial hypertension), where aprocitentan is to be used in combination with an angiotensin receptor blocker, which in particular is valsartan or a pharmaceutically acceptable salt thereof.

28. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of arterial hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and chronic kidney disease (particularly during the treatment of resistant arterial hypertension ), wherein aprocitentan is to be used in combination with an angiotensin receptor blocker, which is particularly valsartan, or a pharmaceutically acceptable salt thereof, and a calcium channel blocker, which is particularly amlodipine, or a pharmaceutically acceptable salt thereof.

29. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of arterial hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and chronic kidney disease (particularly during the treatment of resistant arterial hypertension ), wherein aprocitentan is to be used in combination with an angiotensin receptor blocker, which is particularly valsartan, or a pharmaceutically acceptable salt thereof, a calcium channel blocker, which is particularly amlodipine, or a pharmaceutically acceptable salt thereof; and a diuretic which is a thiazide-like diuretic (in particular hydrochlorothiazide or chlorthalidone, in particular hydrochlorothiazide), or a pharmaceutically acceptable salt thereof.

30. A further embodiment provides a pharmaceutical composition in accordance with any of embodiments 1-26 for use during the treatment of arterial hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and chronic kidney disease (e.g. during treatment of resistant arterial hypertension).

31. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of hypertension, including resistant hypertension; heart failure, including chronic heart failure; diastolic dysfunction; CKD, including stage 3 CKD caused by or associated with essential arterial hypertension; or to reduce the risk of developing a significant cardiovascular complication in patients suffering from diabetes, which is accompanied by at least one other cardiovascular risk factor containing hypertension, where aprocitentan is to be used in combination with an angiotensin receptor blocker, which in particular is valsartan, or a pharmaceutically acceptable salt thereof, a calcium channel blocker which is particularly amlodipine, or a pharmaceutically acceptable salt thereof; and a diuretic which is a thiazide-like diuretic (in particular hydrochlorothiazide or chlorthalidone, in particular hydrochlorothiazide), or a pharmaceutically acceptable salt thereof.

32. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with embodiments 29 or 31, wherein the angiotensin receptor blocker is valsartan or a pharmaceutically acceptable salt thereof; the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof; and the diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof, or chlorthalidone or a pharmaceutically acceptable salt thereof.

33. A further embodiment provides aprocytentan or a pharmaceutically acceptable salt thereof for use in accordance with embodiment 32, wherein the diuretic is a hydrochlorothiazide.

34. A further embodiment provides aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with embodiments 32 or 33, wherein, mutatis mutandis, the pharmaceutically active ingredients are to be used in a dosage as

- 12 043547 is disclosed in embodiments 5 or 7.

35. Another embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof; which are to be used in combination as defined in any of embodiments 27-29, or 31-34; or to a pharmaceutical composition containing aprocytentan or a pharmaceutically acceptable salt thereof, as defined in any of embodiments 1-26; intended for use during 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.

36. One sub-embodiment of Embodiment 35 provides aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of CKD, particularly CKD stages 1-4 as defined in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. (and, in particular, stage 3 CKD), and, in particular, CKD of these stages caused by essential arterial hypertension.

37. Another sub-embodiment of Embodiment 35 relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of diabetes (ie, type 1 or type 2 diabetes).

38. Another sub-embodiment of Embodiment 35 relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of diabetic nephropathy.

39. Another sub-embodiment of Embodiment 35 relates to aprocytentan or a pharmaceutically acceptable salt thereof for use during the treatment of diabetic retinopathy.

40. Another sub-embodiment according to embodiment 35 relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of diabetic vasculopathy.

41. Another sub-embodiment of Embodiment 35 relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of chronic heart failure.

42. According to one embodiment of sub-embodiment 41, the chronic heart failure of sub-embodiment 47 will be heart failure with preserved ejection fraction.

43. According to another embodiment of sub-embodiment 41, the chronic heart failure of sub-embodiment 47 will be diastolic heart failure.

44. Another sub-embodiment according to embodiment 35 relates to aprocitentan or a pharmaceutically acceptable salt thereof for use during the treatment of diastolic dysfunction.

Accordingly, aprocitentan or a pharmaceutically acceptable salt thereof is intended for use in combination with these additional pharmaceutically active ingredients. The respective combination treatments may be administered simultaneously, separately, or over a period of time (especially simultaneously).

In the present invention, the term concurrent, when referring to a type of use, means that the type of use in question consists of the use of two or more active ingredients and/or drugs at approximately the same time; it is understood that simultaneous use will result in the patient being exposed to two or more active ingredients and/or drugs at the same time. If used concomitantly, the two or more active ingredients may be administered as a fixed dosage combination preparation (fixed combination), or as an equivalent non-fixed combination (for example, by using two or more different pharmaceutical compositions to be administered by the same route of administration at approximately the same time), or through an unfixed combination using two or more different routes of administration; wherein said use essentially results in simultaneous exposure of the patient to two or more active ingredients and/or drugs. For example, if used in combination with an ARB and/or a CCB and, if present, a diuretic, the compound may be administered simultaneously.

In the present invention, the term fixed-dose combination drug, when referring to a type of use, means that the type of use in question consists of the use of a single pharmaceutical composition containing two or more active ingredients, in particular such as the pharmaceutical compositions according to embodiments 1-26.

In the present invention, the term alone, when referring to a type of application, means

- 13 043547 that the type of use in question consists of the use of two or more active ingredients and/or medicinal products at different points in time; it is understood that a single application will lead to a treatment phase (e.g. of at least 1 hour, in particular at least 6 hours, in particular at least 12 hours) where the patient is exposed to two or more active ingredients and /or medications at the same time; however, individual use may also lead to a treatment phase where, over a period of time (for example, at least 12 hours, in particular at least one day), the patient is exposed to only one of two or more active ingredients and/or medicines. Single use specifically refers to situations where at least one of the active ingredients and/or drugs is administered at a frequency significantly different from daily (such as once or twice daily) dosing (for example, when one active ingredient and/or drug, for example, is prescribed once or twice a day, and another, for example, is prescribed every other day, or once a week, or even at longer intervals).

In the present invention, by use over a period of time means the sequential use of two or more active ingredients and/or drugs at different points in time. The term particularly refers to a mode of administration whereby the complete use of one of the active ingredients and/or drugs is completed before the use of the other(s) begins. Thus, it is possible to use one of the active ingredients and/or drugs for several months before using the other active ingredient(s) and/or drug(s).

45. A further embodiment provides a pharmaceutical composition according to any of embodiments 1-26 for use during the treatment of hypertension, including resistant hypertension; heart failure, including chronic heart failure; diastolic dysfunction; CKD, including stage 3 CKD caused by or associated with essential arterial hypertension; or to reduce the risk of developing a significant cardiovascular complication in patients with diabetes that is accompanied by at least one other cardiovascular risk factor including hypertension.

It is understood that any embodiment relating to aprocytentan or a pharmaceutically acceptable salt thereof is intended for use during the treatment of certain endothelin-related diseases, and aprocytentan is to be used in combination with additional active ingredients, such as:

an angiotensin receptor blocker, which in particular is valsartan or a pharmaceutically acceptable salt thereof; or an angiotensin receptor blocker, which in particular is valsartan or a pharmaceutically acceptable salt thereof; as well as a calcium channel blocker, which in particular is amlodipine or a pharmaceutically acceptable salt thereof; or an angiotensin receptor blocker, which in particular is valsartan or a pharmaceutically acceptable salt thereof; a calcium channel blocker, which in particular is amlodipine or a pharmaceutically acceptable salt thereof; as well as a diuretic, which is a thiazide-like diuretic (in particular hydrochlorothiazide or chlorthalidone, in particular hydrochlorothiazide) or a pharmaceutically acceptable salt thereof;

this embodiment also relates to such additional active ingredients that are to be used in combination with aprocytentan or a pharmaceutically acceptable salt thereof; to the use of aprocytentan for the preparation of a pharmaceutical composition containing aprocytentan and these additional active ingredients; to the use of a pharmaceutical composition containing aprocytentan and such additional active ingredients for the treatment of such diseases; as well as a method of treating said diseases, comprising administering to a subject (preferably a human) in need thereof, an effective amount of aprocitentan, which is to be used in combination with said additional active ingredients, or comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition containing aprocitentan and said additional active ingredients as disclosed in this invention.

46. A further embodiment relates to a method of treating arterial hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and chronic kidney disease (particularly during treatment of resistant arterial hypertension);

comprising administering a pharmaceutically effective amount of aprocytentan or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein aprocytentan is used in combination with

- 14 043547 a pharmaceutically effective amount of an angiotensin receptor blocker, which is, in particular, valsartan, or a pharmaceutically acceptable salt thereof, a pharmaceutically effective amount of a calcium channel blocker, which is, in particular, amlodipine, or a pharmaceutically acceptable salt thereof; and a pharmaceutically effective amount of a diuretic, which is a thiazide-like diuretic (especially hydrochlorothiazide or chlorthalidone, especially hydrochlorothiazide), or a pharmaceutically acceptable salt thereof.

47. A further embodiment relates to a method of treating arterial hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and chronic kidney disease (particularly during treatment of resistant arterial hypertension); comprising the use of a pharmaceutical composition in accordance with any of embodiments 1-26.

48. A further embodiment relates to a method of treating hypertension, including resistant hypertension; heart failure, including chronic heart failure; diastolic dysfunction; CKD, including stage 3 CKD caused by or associated with essential arterial hypertension; or to a method of reducing the risk of developing a significant cardiovascular complication in patients suffering from diabetes, which is accompanied by at least one other cardiovascular risk factor, including hypertension;

which comprises administering a pharmaceutically effective amount of aprocitentan, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein aprocitentan is used in combination with a pharmaceutically effective amount of an angiotensin receptor blocker, which in particular is valsartan, or a pharmaceutically acceptable salt thereof, a pharmaceutically effective amount a calcium channel blocker, which in particular is amlodipine, or a pharmaceutically acceptable salt thereof; and a pharmaceutically effective amount of a diuretic, which is a thiazide-like diuretic (especially hydrochlorothiazide or chlorthalidone, especially hydrochlorothiazide), or a pharmaceutically acceptable salt thereof;

49. A further embodiment relates to a method of treating hypertension, including resistant hypertension; heart failure, including chronic heart failure; diastolic dysfunction; CKD, including stage 3 CKD caused by or associated with essential arterial hypertension; or to a method of reducing the risk of developing a significant cardiovascular complication in patients suffering from diabetes, which is accompanied by at least one other cardiovascular risk factor, including hypertension; which includes the use of a pharmaceutical composition in accordance with any of embodiments 1-26.

50. A further embodiment relates to the method of Embodiments 46 or 48, wherein the angiotensin receptor blocker is valsartan or a pharmaceutically acceptable salt thereof; the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof; and the diuretic is hydrochlorothiazide or a pharmaceutically acceptable salt thereof, or chlorthalidone or a pharmaceutically acceptable salt thereof.

51. A further embodiment relates to the method of Embodiment 50, wherein the diuretic is a hydrochlorothiazide.

52. A further embodiment relates to the method of Embodiments 50 or 51, wherein, mutatis mutandis, the pharmaceutically active ingredients are administered in dosage as disclosed in Embodiments 5 or 7.

Certain embodiments of the invention are described in the following examples, which serve to illustrate the invention in more detail without in any way limiting its scope:

experimental part;

abbreviations:

in the description and examples the following abbreviations are used:

Ac - acetyl;

AcOH - acetic acid;

aq. - water;

DCM - dichloromethane;

DMSO - dimethyl sulfoxide;

EtOAc - ethyl acetate;

eq. - equivalent^);

Fourier-IR - infrared spectroscopy or spectrum with Fourier transform;

HPLC - high performance liquid chromatography;

iPrOAc - isopropyl acetate;

- 15 043547

MeOH - methanol;

MIBK - methyl isobutyl ketone;

org. - organic;

RT - room temperature;

THF - tetrahydrofuran;

about. - volume(s);

wt./wt. - mass ratio;

wt. - unit mass;

PXD - powder x-ray diffractometry.

Examples

Method for obtaining PXR spectra.

All PRD spectra for the solid forms described in this invention were obtained as described below. Powder X-ray diffraction spectra were obtained on a Bruker D8 Advance X-ray diffractometer equipped with a Lynxeye detector operating using CuKa radiation in reflection mode (coupled two theta/theta). Typically, the X-ray tube power supply parameters were 40 kV/40 mA. A step size of 0.02° (2θ) and a step duration of 76.8 sec were used over a sweep range of 3–50° for 2θ. The divergence slit was set to a fixed value of 0.3. The powders were lightly pressed into a 0.5 mm deep single-crystalline silicon sample holder, and the samples were rotated in their plane during measurement. Diffraction data were obtained by applying the combined radiation of Cu Ka.1 and Ka2, without removing Ka2. The accuracy of the 2θ values as presented in this invention is in the range of +/0.1-0.2°, as is typically the case for conventionally recorded powder X-ray diffraction spectra.

Example 1. Form A.

1.1. A 3 L double jacketed chemical reactor was charged with 5-(4-bromophenyl)-4-(2-((5bromopyrimidin-2-yl)oxy)ethoxy)-6 fluoropyrimidine (100 g, 0.213 mol, 1 eq.), sulfamide (40.9 g, 0.425 mol, 2.0 eq.), K2CO3 (147 g, 1.06 mol, 5 eq.) and DMSO (500 ml, 5 vol.), add water (2 ml, 0.111 mol , 0.5 eq.). The heterogeneous mixture was heated to a temperature of 70°C for approx. 3 h, after which complete transformation was observed. After cooling to 20°C, most of the inorganic salt was removed by filtration. The filter cake was washed with EtOAc/iPrOAc 1:1 (300 ml, 3 vol.). Celite (100 g, 1 wt.) coated with a layer of charcoal (20 g, 0.2 wt.) was pretreated using EtOAc/iPrOAc 1:1 (500 ml, 5 vol.) (filtrate discarded). The reaction mixture was filtered through this filter cake and washed with EtOAc/iPrOAc 1:1 (300 ml, 3 vol). Then 1M aq was added. NaOAc solution (500 ml, 0.5 mol, 2.3 eq., 5 vol.), while maintaining the temperature at 25-35°C. Vodn. the phase was washed a second time using EtOAc/iPrOAc 1:1 (500 ml, 5 vol). To water phase, add 1M H ₂ SO ₄ (200 ml, 0.2 mol, 1 eq., 2 vol.) over 1 hour at a temperature of 25-30°C. Crystallization began at a pH value of 8.5-8.0. The crude product was filtered as in the case of Form I of the PRD spectrum (DMSO solvate), or as in the case of a mixture of Form A and Form I. It was washed twice with water (2x1000 ml, 2x10 vol.). The solid was suspended in water (1000 ml, 10 vol.) at rt for 3 hours. The solid was filtered and suspended a second time in water (1000 ml, 10 vol.) at rt for 3 hours. After washing with water (1000 ml , 10 vol.), the pure product was dried in vacuum at a temperature of 40°C, resulting in {5-(4-bromo-phenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]pyrimidine -4-yl}-sulfamide in the form of a white to almost white solid (75 g, 65% yield, Form A of the PRD spectrum).

1.2. A chemical reactor (200 L, Hastelloy) was charged with 5-(4-bromophenyl)-4-(2-((5bromopyrimidin-2-yl)oxy)ethoxy)-6 fluoropyrimidine (24.2 kg, 51.5 mol) , sulfamide (9.7 kg, 100.9 mol, 1.96 eq.), potassium carbonate (35.5 kg, 256.9 mol, 5.0 eq.), DMSO (133 kg, 5 vol.) and water (490 g, 27.2 mol, 0.53 eq.). The contents of the chemical reactor were heated to a temperature of 70-75°C. HPLC monitoring showed complete conversion within 4 hours.

The contents were cooled to 20-25°C and the solids were centrifuged. Each batch was washed using EtOAc/iPrOAc 1:1 (65 kg, 3 vol). The filtrate was re-charged into the chemical reactor and charcoal (2.4 kg, 10 wt%) and Celite® (4.8 kg, 20 wt%) were added. The contents were shaken for 1 hour at a temperature of 15-20°C, and filtered through a cartridge filter back into the chemical reactor. Filters were washed using EtOAc/iPrOAc 1:1 (43 kg, 2 vol). NaOAc (8% in water) (124 kg, 5 vol) was added over 2 hours while maintaining the temperature below 25°C. After phase separation, aq. the layer was washed with EtOAc/iPrOAc 1:1 (109 kg, 5 vol.) at a temperature of 20–25°C. In water layer at a temperature of 25-30°C, sulfuric acid (5% in water; 64 L, 32.6 mol, 0.63 eq.) was added over 2 hours to achieve a pH of 6.4. The contents were then cooled to 15-20°C over 1 hour. The solids were filtered and washed twice with water (2x24 L, 2x1 vol). Each solid was suspended twice in water (2x242 kg, 2x10 vol) at 15-20°C for 3 hours, filtered and dried to give 5-(4-bromophenyl)-6-[2 -(5-bromo-16 043547 pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}-sulfamide as a white solid (21.6 g, 77% yield, PRD spectrum form A).

Example 2. Form B (solvate of DCM compound).

5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine (10.0 g, 21.3 mmol, 1.00 eq.), sulfonamide (4.1 g, 42.5 mmol, 2.0 eq.) and K ₂ CO ₃ (14.7 g, 106 mmol, 5.0 eq.) were suspended in DMSO (50 ml, 5 vol.) and heated to a temperature of 70°C over 5 hours. The mixture was cooled to rt and EtOAc (40 ml, 4 vol.) was added, followed by the addition of water (100 ml, 10 vol.). After separation of the layers (the organic phase was discarded), aq. the phase was extracted with DCM (100 ml, 10 vol). The DCM layer was acidified to pH 11.5 - pH 7.0 using conc. AcOH (3 ml, 52 mmol, 2.5 eq.), which led to crystallization of the product. The suspension was cooled to 0°C for 1 hour, then to -5°C for 15 minutes. The solid was filtered, washed with cold DCM (10 ml, 1 vol) and dried to give DCM solvate {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy )-ethoxy]pyrimidin-4-yl}sulfamide in form B as a white solid (9.8 g, 84% yield).

Example 3. Form B.

0.2 ml of stock solution of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl}-sulfamide dissolved in THF with a concentration of 50 mg/ml, distributed into 3 vials. The solvent was evaporated for 90 min in a Combidancer evaporator from Hettich AG (Bech, Switzerland), operating at a temperature of 35°C and a pressure of 200 mbar. Immediately thereafter, 0.015 mL of MeOH was added to the first vial, EtOH to the second vial, and iPrOH to the third vial, and the vials were left sealed for 3 days. For each of these solvents, a solid residue of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl} sulfamide in form B was obtained.

Example 4. Form G.

4.1. The chemical reactor was charged with sulfamide (2.00 eq.), K2CO3 (5.00 eq.), 5-(4-bromophenyl)-4(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6 -fluoropyrimidine (1.00 eq.), DMSO (5.0 vol.) and water (0.02 vol.). The mixture was heated to 75°C for 2 hours. After cooling to 23°C, the suspension was filtered and washed with EtOAc/iPrOAc 1:1 (5.5 vol) using a chemical reactor. The filtrate was filtered again through the in-line filter and washed using EtOAc/iPrOAc 1:1 (1.5 vol). At 27°C, a solution of 1 M NaOAc in water (5.0 vol) was added and the layers were separated. Vodn. the phase was washed using EtOAc/iPrOAc 1:1 (5.0 vol). Vodn. the phase was acidified to pH 5.8 using 0.5M H ₂ SO ₄ in water (2.35 vol.) for 2.5 hours, which led to crystallization. After stirring for 1 hour at 20°C, the suspension was filtered and washed with water (2x10 vol). The solid was suspended twice in water (2x10 vol) at 20°C for 3 hours each time, filtered, washed with water (10 vol) and dried to give {5-(4-bromophenyl)-6 -[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}-sulfamide in form G.

4.2. 50 mg of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}-sulfamide in form A was dissolved in 3 ml of methyl ethyl ketone in new glass bottle with a capacity of 7 ml. After sonication in an ultrasonic bath for 1 min, the vial was left open at rt for 3 days. The solid residue was (5-(4-bromo-phenyl)-6-[2-(5-bromopyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}-sulfamide in form G.

Example 5. Form D (MeCN solvate of the compound).

{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}-sulfamide in form A was heated to reflux in 10 volumes of MeCN. After 10 minutes, it was allowed to cool to a temperature of 20°C for 1 hour (the heating bath was removed). It was filtered and dried under reduced pressure and at a temperature of 45°C. The solid residue was a solvate of MeCN (5-(4bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}-sulfamide in form D.

Example 6. Form I.

DCM solvate (5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl} sulfonamide form B (9.4 g, 17.2 mmol, 1.00 eq.) was dissolved in DMSO (19 ml, 2 vol.).The solution was added to H2O (94 ml, 10 vol.) and stirred at rt for 5 minutes. The resulting suspension was filtered, washed twice with H2O (2x94 ml, 2x10 vol) and dried to give {5(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl }-sulfamide form I as a white solid (6.8 g, 72% yield).

Example 7. Form J (DMSO solvate of the compound).

7.1. {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl}-sulfonamide Form A (1.00 g, 1.83 mmol , 1.00 eq.) was dissolved in DMSO (2 ml, 2 vol.). To this solution, 10% H2O in DMSO (10 ml, 10 vol.) was slowly added, after which pure H2O (2 ml, 2 vol.) was added. Addition of a seed in the form of Form I triggered the crystallization of the product. The suspension was filtered, washed with H2O (5x10 ml, 5x10 vol) and dried to give DMSO solvate {5-(4bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)- ethoxy]pyrimidin-4-yl}-sulfonamide in form I as a white solid (0.95 g, 95% yield).

- 17 043547

7.2. 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine (10.0 g, 21.3 mmol, 1.00 eq.), sulfonamide (4.1 g, 42.5 mmol, 2.0 eq.) and K ₂ CO ₃ (14.7 g, 106 mmol, 5.0 eq.) were suspended in DMSO (50 ml, 5 vol.) and heated to a temperature of 50°C over 20 hours. The mixture was cooled to rt, and MIBK (100 ml, 10 vol.) was added, followed by the addition of water (100 ml, 10 vol.). After separation of the layers (the organic phase was discarded), aq. the phase was acidified to pH 11.4-pH 6.5 using conc. AcOH (4 ml, 70 mmol, 3.3 eq.), which led to crystallization of the product. The solid was filtered, washed with water (4x50 ml, 4x5 vol) and dried to give DMSO solvate {5-(4-bromo-phenyl)-6-[2-(5bromo-pyrimidin-2-yloxy)-ethoxy ]pyrimidin-4-yl}-sulfonamide in form J as a beige solid (10.4 g, 90% yield).

Example 8. Form K (EtOH solvate of the compound).

DMSO solvate of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]pyrimidin-4-yl} sulfonamide form I (100 mg, 0.183 mmol, 1, 00 eq.) was suspended in EtOH (0.5 ml, 5 vol.) at rt for 4 hours. The suspension was filtered, washed twice with H ₂ O (2x0.5 ml, 2x5 vol.) and dried, resulting in which produced EtOH {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2yloxy)-ethoxy]pyrimidin-4-yl}-sulfonamide solvate in form K as a white solid (40 mg, yield 40%).

Example 9. Tablets ACT-132577.

Tablets, each containing 50 mg of ACT-132577, can be prepared using the wet method. granulation. The composition of the tablet is as follows:__________

Tablets AST-132577 (250 mg) MATERIAL (CHEMICAL NAME) mg/tablet Weight % / tablet In well trigranular AST-132577 (amorphous, solid Form A or solid Form B, as described in this invention) 50.00 20.00 Microcrystalline cellulose 61.50 24.60 Lactose (200M) 122.25 48.90 Hydroxypropyl cellulose 5.50 2.20 Croscarmellose sodium 4.50 1.80 Water dk dk Extragranular Croscarmellose sodium 5.00 2.00 Magnesium stearate 1.25 0.50 Total 250.00 100.00

dk = sufficient quantity.

Preferably Form A (as described in this invention) of ACT-132577 will be used for the manufacture of tablets.

Example 10: ACT-132577 tablets.

The tablets of Example 9 can be coated with Aquapolish® MS white or Aquapolish® PVA white (coating manufacturer: Biogrund).

Example 11: ACT-132577 tablets.

Tablets each containing 50 mg of ACT-132577 can be prepared by using a wet granulation method. The composition of the tablet is as follows:

Tablets AST-132577 (250 mg) MATERIAL (CHEMICAL NAME) mg/tablet Weight % / tablet Intragranular AST-132577 (amorphous, solid Form A or solid Form B, as described in this invention) 50.00 20.00 Microcrystalline cellulose 61.25 24.50 Lactose (200M) 122.50 49.00 Hydroxypropyl cellulose 5.00 2.00 Croscarmellose sodium 5.00 2.00 Water dk dk Extragranular Croscarmellose sodium 5.00 2.00 Magnesium stearate 1.25 0.50 Total 250.00 100.00

dk = sufficient quantity.

Preferably Form A (as described in this invention) of ACT-132577 will be used for the manufacture of tablets.

Example 12.

Example 11 tablets can be coated with white Aquapolish® MS or Aquapolish® PVA

- 18 043547 white (coating manufacturer: Biogrund).

Example 13: ACT-132577 tablets.

Tablets each containing 12.5 mg of ACT-132577 can be prepared by using a wet granulation method. The composition of the tablet is as follows:

Tablets AST-132577 (250 mg) MATERIAL (CHEMICAL NAME) mg/tablet Weight % / tablet Intragranular AST-132577 (amorphous, solid Form A or solid Form B, as described in this invention) 50.00 20.00 Microcrystalline cellulose 61.25 24.50 Lactose (200M) 122.50 49.00 Hydroxypropyl cellulose 5.00 2.00 Croscarmellose sodium 5.00 2.00 Water dk dk extragranular Croscarmellose sodium 5.00 2.00 Magnesium stearate 1.25 0.50 Total 250.00 100.00

dk = sufficient quantity.

Preferably, Form A of ACT-132577 (as described in this invention) will be used for the manufacture of tablets.

Example 14: ACT-132577 tablets.

The tablets of Example 13 can be coated with Aquapolish® MS white or Aquapolish® PVA white (coating manufacturer: Biogrund).

Example 15: ACT-132577 tablets.

Tablets each containing 12.5 mg of ACT-132577 can be prepared by using a wet granulation method. The composition of the tablet is as follows:

Tablets AST-132577 (100 mg) MATERIAL (CHEMICAL NAME) mg/tablet Weight % / tablet Intragranular AST-132577 (amorphous, solid form A or solid form B, as described in this invention) 12.50 12.50 Microcrystalline cellulose 27.50 27.50 Lactose (20OM) 53.50 53.50 Hydroxypropyl cellulose 2.20 2.20 Croscarmellose sodium 1.80 1.80 Water DK DK Extragranular Croscarmellose sodium 2.00 2.00 Magnesium stearate 0.50 0.50 Total 100.00 100.00

dk = sufficient quantity

Preferably Form A (as described in this invention) of ACT-132577 will be used for the manufacture of tablets.

Example 16: ACT-132577 tablets.

The tablets of Example 15 can be coated with Aquapolish® MS white or Aquapolish® PVA white (coating manufacturer: Biogrund).

Properties of crystalline forms.

Example 17: Storage at room temperature.

A sample of crystals of Form A of the compound (which was obtained in accordance with Example 1 above) was stored at a temperature of 20-25°C, at 92% relative humidity for 2 months. Powder X-ray diffractometry performed on this sample at the end of 2 months showed that the sample still consisted only of crystals of Form A of the compound. The same result was obtained after storage for 8 weeks under the above conditions. HPLC testing of the sample after 8 weeks of storage did not reveal significant changes in % peak area, meaning no significant degradation was observed under these conditions.

A sample of Form B crystals of the dichloromethane solvate of the compound (which was prepared in accordance with Example 2 above) was stored in a closed vial (20 mg Form B crystals placed in a closed 4 ml vial) at a temperature of 20-25°C, at for approximately 3 weeks. Powder X-ray diffractometry performed on this sample at

- 19 043547 at the end of the 3rd week, showed that the crystals of form B turned into crystals of form A of the compound.

A sample of dimethyl sulfoxide solvate Form Y crystals of the compound (which was prepared in accordance with Example 7 above) was stored in a closed vial (20 mg of Form Y crystals placed in a closed 4 ml vial) at a temperature of 20-25°C, at for approximately 3 weeks. X-ray powder diffractometry performed on this sample at the end of the 3rd week showed that Form J crystals had converted to Form A crystals of the compound.

Example 18. Hygroscopicity.

Form A is considered slightly hygroscopic, as determined by gravimetric vapor sorption (GVA). The increase in sample mass, which was obtained in accordance with example 1 in the first cycle in the range from 40 to 80% r.h., corresponds to 0.4%. At 95% r.v. 2.2% moisture was absorbed as a reversible process without hysteresis after drying.

Examples of therapeutic applications of ACT-132577.

Example A: Short-term effects of ACT-132577 in salt-sensitive Dahl rats.

The short-term effects of ACT-132577 on blood pressure, specifically mean arterial pressure (MAP) and heart rate (HR), were assessed by telemetry in awake male Dahl salt-sensitive hypertensive rats (Dahl salt-sensitive rats). - see more about this model in Rapp, Hypertension (1982), 4, 753-763).

Increased blood pressure in salt-sensitive Dahl rats was induced by adding 1% sodium chloride to drinking water. As a control (7.5% aqueous gelatin solution), groups of 6-7 salt-sensitive Dahl rats were used, and each dose of ACT132577 (0.3, 1, 3, 10, 30, 100, and 300 mg/ kg). The effects of ACT-132577 on HR and MAP were calculated for individual animals relative to the 24-hour period before administration. The results obtained for MAP (maximum reduction in MAP observed over 6 consecutive hours) are summarized in FIG. 9 (data presented as mean ± standard error of the mean). As a result, in salt-sensitive Dahl rats, a dose of 10 mg/kg ACT-132577 reduced MAP by 19 ± 4 mmHg. Unlike MAP, HR did not change.

Example B: Short-term effects of ACT-132577 in deoxycorticosterone-acetate-salt-sensitive rats.

The short-term effects of ACT-132577 on blood pressure, specifically mean arterial pressure (MAP) and heart rate (HR), were assessed by telemetry in awake male deoxycorticosterone-acetate-salt-sensitive hypertensive rats (DOX-sensitive). sensitive rats - see Gavras et al. Circ. Res. (1975), 36, 300-309 for more details on this model.

In doxa-salt-sensitive rats, hypertension was induced by a combination of unilateral nephrectomy, implantation of pellets of the mineralocorticoid analogue dox, and the addition of 1% sodium chloride to drinking water. As a control (7.5% aqueous gelatin solution), groups of 6-11 doxa-salt-sensitive rats were used and each dose of ACT-132577 was tested (0.3, 1, 3, 10, 30, 100, and 300 mg/kg). The effects of ACT-132577 on HR and MAP were calculated for individual animals relative to the 24-hour period before administration. The results obtained for MAP (maximum reduction in MAP observed over 6 consecutive hours) are summarized in FIG. 10 (data presented as mean±standard error of mean). Ultimately, a dose of 10 mg/kg ACT-132577 reduced MAP by 29 ± 6 mmHg. in doxa-salt-sensitive rats. Unlike MAP, HR did not change.

Example B: Short-term effects of ACT-132577 in spontaneously hypertensive rats.

The short-term effects of ACT-132577 on blood pressure, specifically mean arterial pressure (MAP) and heart rate (HR), were assessed using telemetry in awake male spontaneously hypertensive rats (SHC - see Atanur for more details on this model). et al. Genome Res. (2010), 20, 791-803).

Groups of 4-6 SGCs were used as a control (7.5% aqueous gelatin solution) and each dose of ACT-132577 was tested (1, 3, 10, 30, 100, and 300 mg/kg). The effects of ACT-132577 on HR and MAP were calculated for individual animals relative to the 24-hour period before administration. The results obtained for MAP (maximum reduction in MAP observed over 6 consecutive hours) are summarized in FIG. 11 (data presented as mean±standard error of mean). Ultimately, a dose of 100 mg/kg ACT-132577 reduced MAP in SHCs by 18±4 mmHg. Unlike MAP, HR did not change.

Example D: Short-term effects of ACT-132577, alone or in combination with valsartan, in spontaneously hypertensive rats.

Short-term effects of ACT-132577, administered orally at a single dose of 100 mg/kg, on blood pressure, particularly mean arterial pressure (MAP) and heart rate (HR), where ACT-132577 was administered either alone or in combination with valsartan administered orally in a single dose of 10 mg/kg,

- 20 043547 was assessed using telemetry in awake male spontaneously hypertensive rats (hereinafter

SGC - see more about this model in Atanur et al. Genome Res. (2010), 20, 791-803).

For this study, 6 SGCs were used per treatment group. The results obtained regarding MAP are summarized in FIG. 12, where each observation is presented as a 6-hour average (note that the expected additive effect of the combination of two drugs, called the Predicted Additive Effect, was calculated by adding the blood pressure reduction values obtained after administration of each compound separately); administration of placebo (7.5% aqueous gelatin) had no effect on MAP or HR and therefore the results are not shown in FIG. . In brief, co-administration of ACT-132577 and valsartan reduced MAP above predicted (calculated) values, demonstrating synergy between the two molecules. In contrast to MAP, HR did not change in any of the treatment groups.

Example E: Short-term effects of ACT-132577, alone or in combination with valsartan, in deoxycorticosterone acetate-salt-sensitive rats.

Short-term effects of ACT-132577, administered orally at a single dose of 10 mg/kg, on blood pressure, particularly mean arterial pressure (MAP) and heart rate (HR), where ACT-132577 was administered either alone or in combination with valsartan, administered orally at a single dose of 30 mg/kg, was assessed by telemetry in awake male deoxycorticosterone acetate-salt-sensitive hypertensive rats (hereafter dox-salt-sensitive rats - see more about this model in Gavras et al. Circ. Res. (1975), 36, 300-309).

Hypertension was induced in dox-salt-sensitive rats by a combination of unilateral nephrectomy, implantation of pellets of the mineralocorticoid analogue dox, and the addition of 1% sodium chloride to drinking water. For this study, 7-8 doxa-salt-sensitive rats were used per treatment group. The results obtained regarding MAP are summarized in FIG. 13, where each observation is presented as a 6-hour average (note that the expected additive effect of the combination of two drugs, called the Predicted Additive Effect, was calculated by adding the reduction in blood pressure values obtained after administration of each compound separately); administration of placebo (4% aqueous gelatin) had no effect on MAP or HR and therefore the results are not shown in FIG. . In brief, co-administration of ACT-132577 and valsartan reduced MAP above predicted (calculated) values, demonstrating synergy between the two molecules. In contrast to MAP, HR did not change in any of the treatment groups.

Example E: Short-term effects of ACT-132577, alone or in combination with enalapril, in spontaneously hypertensive rats.

Short-term effects of ACT-132577, administered orally at a single dose of 100 mg/kg, on blood pressure, particularly mean arterial pressure (MAP) and heart rate (HR), where ACT-132577 was administered either alone or in combination with enalapril administered orally at a single dose of 3 mg/kg, was assessed by telemetry in awake male spontaneously hypertensive rats (hereinafter SHC - see Atanur et al. Genome Res. (2010) for more details on this model ), 20, 791-803).

For this study, 7 SGCs were used per treatment group. The results obtained regarding MAP are summarized in FIG. 14, where each observation is presented as a 6-hour average (note that the expected additive effect of the combination of two drugs, called the Predicted Additive Effect, was calculated by adding the blood pressure reduction values obtained after administration of each compound separately); administration of placebo (4% aqueous gelatin) had no effect on MAP or HR and therefore the results are not shown in the figure. In brief, co-administration of ACT-132577 and enalapril reduced MAP above predicted (calculated) values, demonstrating synergy between the two molecules. In contrast to MAP, HR did not change in any of the treatment groups.

Example E: Short-term effects of ACT-132577, alone or in combination with amlodipine, in deoxycorticosterone acetate-salt-sensitive rats.

Short-term effects of ACT-132577, administered orally at a single dose of 10 mg/kg, on blood pressure, particularly mean arterial pressure (MAP) and heart rate (HR), where ACT-132577 was administered either alone or in combination with amlodipine, administered orally at a single dose of 1 mg/kg, was assessed by telemetry in awake male deoxycorticosterone acetate-salt-sensitive hypertensive rats (hereafter dox-salt-sensitive rats - see more about this model in Gavras et al. Circ. Res. (1975), 36, 300-309).

Hypertension was induced in doxa-salt-sensitive rats by a combination of unilateral nephrectomy, implantation of mineralocorticoid analogue doxa pellets, and the addition of 1% chloride

- 21 043547 sodium in drinking water. For this study, 6-8 DOX-salt-sensitive rats were used per treatment group. The results obtained regarding MAP are summarized in FIG. 15, where each observation is presented as a 6-hour average (note that the expected additive effect of the combination of two drugs, called the Predicted Additive Effect, was calculated by adding the blood pressure reduction values obtained after administration of each compound separately); administration of placebo (4% aqueous gelatin) had no effect on MAP or HR and therefore the results are not shown in the figure. In brief, co-administration of ACT-132577 and amlodipine reduced MAP above predicted (calculated) values, demonstrating synergy between the two molecules. In contrast to MAP, HR did not change in any of the treatment groups.

Example G: Long-term exposure to ACT-132577 in deoxycorticosterone acetate-salt-sensitive rats.

The long-term effects of regular administration of doses of 1, 10 and 100 mg/kg/day ACT132577, specifically on mean arterial pressure (MAP) and heart rate (HR), were assessed in awake male deoxycorticosterone-acetate-salt-sensitive hypertensives. rats (hereinafter referred to as doxa-salt-sensitive rats - see more about this model in Gavras et al. Circ. Res. (1975), 36, 300-309). Hypertension was induced in dox-salt-sensitive rats by a combination of unilateral nephrectomy, implantation of pellets of the mineralocorticoid analogue dox, and the addition of 1% sodium chloride to drinking water. The results of doxa-salt-sensitive rats that were treated with ACT-132577 were compared with the results obtained for Wistar rats or for doxa-salt-sensitive rats that received placebo (4% aqueous gelatin solution) only.

A. The results obtained regarding MAP are summarized in FIG. 16, where each observation is presented as a 24-hour average. 6 rats were used for each of the 5 study groups (Wistar control rats (lower curve in Fig. 16), doxa-salt control rats (upper curve in Fig. 16) and doxa-salt-sensitive rats, which received regular dosing , components 1, 10 and

100 mg/kg/day ACT-132577 (second and third curves from the top, respectively, in Fig. 16)). In brief, oral administration of ACT-132577 for 4 weeks dose-dependently attenuated the DOX-induced increase in MAP, without changing HR.

b. The results obtained regarding hemodynamic resistance in the renal vessels are summarized in FIG. 17, where:

doxa 0 2w represents doxa-salt-sensitive rats sacrificed immediately before the start of ACT-132577 administration; and * represents the level of statistical significance of p < 0.05, using one-way analysis of variance (ANOVA), followed by post hoc analysis using the Newman-Keuls multiple comparison test.

In summary, consistent with the results of these studies, chronic oral administration of ACT-132577 to dox-salt-sensitive rats dose-dependently increased renal blood flow and decreased hemodynamic resistance in the renal vessels. ACT-132577 also showed a tendency to reduce left ventricular hypertrophy, as demonstrated by a dose-dependent decrease in plasma concentrations of TV-terminal fragment of brain natriuretic peptide (NTproBNP).

Example 3: Effects of ACT-132577, alone or in combination with an ACE inhibitor or ARB, from studies in animal models of diabetes.

The effects of ACT-132577 can be assessed in rodent models of diabetes (in this regard, see the models described in the following references: Sen et al. Life Sci. (2012), 91(13-14), 658-668; Janiak et al Eur J Pharmacol (2006), 534, 271-279 and Iglarz et al J Pharmacol Exp Ther (2008), 327(3), 736-745). In particular, the effects of ACT-132577, alone or in combination, on glucose tolerance, insulinemia, and ischemic organ damage may be examined. Ischemic organ damage includes: damage to vascular function, renal function (eg, proteinuria), cardiac function and remodeling, and damage to any other target organ affected by diabetes (eg, the eye).

Example I: Evaluation of the effects of ACT-132577 on fluid retention.

A decrease in hematocrit (Hct) or hemoglobin occurs due to an increase in blood plasma volume and can be used as a marker of fluid retention. A single oral dose of aprocitentan (1–30 mg/kg) or placebo (gelatin) was administered by gavage to male Wistar rats. Twenty-four hours after administration, a sublingual blood sample was collected under isoflurane-induced anesthesia. Hematocrit was measured using a hematology analyzer. ACT-132577 had no effect on hematocrit (Hct), suggesting a low potential for effect on fluid retention (Figure 18).

Comparative Example 1: Short-term action of spironolactone used in combination

- 22 043547 with valsartan, in spontaneously hypertensive rats.

The short-term effects of spironolactone (300 mg/kg) on blood pressure, particularly mean arterial pressure (MAP) and heart rate (HR), in combination with valsartan, each administered orally in single doses, were also evaluated with using telemetry in awake male spontaneously hypertensive rats (hereinafter SHC - see more about this model in Atanur et al. Genome Res. (2010), 20, 791-803), using a protocol similar to the protocol described in example D.

In contrast to ACT-132577, no synergistic effects were observed with the combination of spironolactone and valsartan on MAP reduction.

Comparative Example 2: Short-term effects of spironolactone administered in combination with valsartan in deoxycorticosterone acetate-salt-sensitive rats.

The short-term effects of spironolactone (300 mg/kg) on blood pressure, particularly mean arterial pressure (MAP) and heart rate (HR), in combination with valsartan, each administered orally in single doses, were also evaluated with using telemetry in awake male deoxycorticosterone-acetate-salt-sensitive hypertensive rats (hereinafter referred to as DOXA-salt-sensitive rats - see Gavras et al. Circ. Res. (1975), 36, 300-309 for more details on this model), using protocol similar to the protocol described in example D.

In contrast to ACT-132577, no synergistic effects were observed with the combination of spironolactone and valsartan on MAP reduction.

Comparative Example 3: Short-term effects of spironolactone administered in combination with enalapril in spontaneously hypertensive rats.

The short-term effects of spironolactone (300 mg/kg) on blood pressure, particularly mean arterial pressure (MAP) and heart rate (HR), in combination with valsartan, each administered orally in single doses, were also evaluated with using telemetry in awake male spontaneously hypertensive rats (hereinafter referred to as SHC - see Atanur et al. Genome Res. (2010), 20, 791-803 for more details on this model), using a protocol similar to that described in Example E.

In contrast to ACT-132577, no synergistic effects were observed with the combination of spironolactone and enalapril on MAP reduction.

Example J: Short-term effects of EXFORGE HCT® alone, and EXFORGE HCT® in combination with ACT-132577 or spironolactone, in spontaneously hypertensive rats.

Short-term effect of Exforge HCT® (i.e. fixed-dose combination of valsartan/amlodipine/hydrochlorothiazide; dosage adjusted to 1.6/0.1/0.25 mg/kg for valsartan/amlodipine/hydrochlorothiazide, respectively) on blood pressure , specifically mean arterial pressure (MAP) and heart rate (HR), in combination with ACT-132577 or spironolactone, were also assessed by telemetry in awake male spontaneously hypertensive rats (SHC - see details of this model). in Atanur et al. Genome Res. (2010), 20, 791-803).

For this study, 9 SGCs were used per treatment group. To match the maximum effect on blood pressure of coadministered drugs in this model, 100 mg/kg aprocitentan was administered orally on day ³ , following 3 days of oral administration of Exforge HCT® mg/kg, and 300 mg/kg spironolactone was administered orally with Exforge HCT® on day ¹ , followed by 2 days of Exforge HCT® administration. The results obtained regarding MAP are summarized in FIG. 19 and 20, where each observation is presented as a 6-hour average.

When HCT®, aprocytentan or spironolactone was added to Exforge, there was an additional reduction in blood pressure. However, aprocitentane resulted in a greater reduction in blood pressure than spironolactone. In contrast to MAP, HR did not change in any of the treatment groups.

Example K: Short-term effects of EXFORGE HCT® alone, and EXFORGE HCT® in combination with ACT-132577 or spironolactone, in deoxycorticosterone acetate-salt-sensitive rats

Short-term effect of Exforge HCT® (dosage adjusted to 3.2/0.2/0.5 mg/kg for valsartan/amlodipine/hydrochlorothiazide, respectively) on blood pressure, in particular on mean arterial pressure (hereinafter referred to as MAP) and heart rate (hereinafter referred to as HR), in combination with ACT-132577 (10 mg/kg) or spironolactone (300 mg/kg), each administered orally in single doses, was also assessed by telemetry in awake male deoxycorticosterone acetate salt- sensitive hypertensive rats (hereinafter referred to as dox-salt-sensitive rats, see Gavras et al. Circ. Res. (1975), 36, 300-309 for more details on this model).

Hypertension was induced in doxa-salt-sensitive rats by a combination of unilateral nephrectomy, implantation of mineralocorticoid analogue doxa pellets, and the addition of 1% chloride

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Claims (6)

sodium in drinking water. For this study, 7-9 doxa-salt-sensitive rats per treatment group were used. The results obtained regarding MAP are summarized in FIG. 21 and 22, where each observation is presented as a 6-hour average. When added to Exforge HCT®, 10 mg/kg aprocitentan or 300 mg/kg spironolactone further reduced blood pressure. However, aprocitentane resulted in a greater reduction in blood pressure than spironolactone. In contrast to MAP, HR did not change in any of the treatment groups. CLAIM 1. A pharmaceutical composition containing aprocytentan or a pharmaceutically acceptable salt thereof as active substances, in combination with three antihypertensive drugs of different classes, in which these antihypertensive drugs are: an angiotensin receptor blocker or a pharmaceutically acceptable salt thereof; a calcium channel blocker or a pharmaceutically acceptable salt thereof; and a diuretic, which is hydrochlorothiazide; and at least one pharmaceutically acceptable excipient. 2. The pharmaceutical composition according to claim 1, containing aprocytentan or a pharmaceutically acceptable salt thereof as active substances, in combination with three antihypertensive drugs of different classes, in which these antihypertensive drugs are: an angiotensin receptor blocker, which is valsartan, or a pharmaceutically acceptable salt thereof; a calcium channel blocker, which is amlodipine, or a pharmaceutically acceptable salt thereof; and a diuretic, which is hydrochlorothiazide; and at least one pharmaceutically acceptable excipient. 3. The pharmaceutical composition according to claim 1 or 2, wherein said composition contains aprocytentan in crystalline form A, characterized by the presence of peaks in the powder X-ray diffraction diagram at the following refractive angles 2θ: 17.8, 18.6, 20.0, 23.2 and 23.5°; wherein said powder X-ray diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without removing Ka2; and the accuracy of the 2θ values is in the range of 2θ +/-0.2°. 4. Use of aprocitentan or its pharmaceutically acceptable salt during the treatment of resistant arterial hypertension; in this case, aprocitentan is to be used in combination with three antihypertensive drugs of various classes, in which these antihypertensive drugs are: an angiotensin receptor blocker or a pharmaceutically acceptable salt thereof; a calcium channel blocker or a pharmaceutically acceptable salt thereof; and a diuretic, which is hydrochlorothiazide. 5. The use of aprocitentan or its pharmaceutically acceptable salt according to claim 4; wherein aprocitentan is to be used in combination with an angiotensin receptor blocker, which is valsartan, or a pharmaceutically acceptable salt thereof, a calcium channel blocker, which is amlodipine, or a pharmaceutically acceptable salt thereof; and a diuretic, which is hydrochlorothiazide. 6. The use of aprocitentan or a pharmaceutically acceptable salt thereof according to claim 4 or 5; wherein aprocitentan is to be used in the form of a solid pharmaceutical composition, which is presented in the form of a tablet, said solid pharmaceutical composition contains aprocitentan in a total amount of 5 to 25% by weight, based on the total weight of the pharmaceutical composition, microcrystalline cellulose in a total amount of 20 to 30% by weight, based on the total weight of the pharmaceutical composition, lactose in a total amount of 40 to 65% by weight, based on the total weight of the pharmaceutical composition, hydroxypropylcellulose in a total amount of 1 to 3% by weight, based on the total weight of the pharmaceutical composition, croscarmellose sodium in a total amount of from 2 to 8% by weight, based on the total weight of the pharmaceutical composition, and magnesium stearate in a total amount of from 0.2 to 2% by weight, based on the total weight of the pharmaceutical composition, with total percentages by weight of the solid pharmaceutical composition will always be 100. -