EA045981B1 - COMBINATION OF 4-PYRIMIDINE SULPHAMIDE DERIVATIVE WITH SGLT-2 INHIBITOR FOR THE TREATMENT OF ENDOTHELIN-ASSOCIATED DISEASES - Google Patents

Description

The present invention relates to the compound aprocitentan and its use as an endothelin receptor antagonist in combination with other active substances or therapeutic agents including a sodium glucose cotransporter 2 (SGLT-2) inhibitor for the prevention or treatment of certain endothelin-related diseases. The invention also relates to pharmaceutical compositions containing aprocytentan in combination with said other active substances or therapeutic agents. In addition, the invention relates to such pharmaceutical compositions containing new crystalline forms of aprocytentan; to pharmaceutical compositions obtained from such crystalline forms, and to the use of such crystalline forms in combination with these other active substances or therapeutic agents for the prevention or treatment of these endothelin-related diseases.

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

Formula I

The compound of Formula I, also known as and referred to as ACT-132577, is an endothelin receptor antagonist. The compound of formula I is a member of a structural family that was previously outlined in WO 02/053557. In particular, the compound of formula I, although showing endothelin receptor antagonistic activity, in vivo exhibits a significantly longer half-life and significantly shorter clearance compared to the corresponding alkylated derivatives. This makes the compound of formula I particularly suitable for long-acting pharmaceutical compositions, as described in WO 2009/024906.

Due to its ability to inhibit endothelin binding, the compound of formula I can be used for the treatment of endothelin-related diseases that are associated with increased vasoconstriction, proliferation or inflammation due to endothelin, occurring in many cardiorenal metabolic diseases. Examples of such endothelin-related diseases are hypertension, including particularly intractable/resistant hypertension; pulmonary hypertension; coronary diseases; heart failure; renal and myocardial ischemia; Chronic kidney disease (CKD) (especially CKD stages 1–4, as defined in the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines (namely CKD stage 3), and in particular CKD (especially at these stages) caused by /related to hypertension or diabetes (diabetic kidney disease (DKD), including DKD that is also associated with hypertension); diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic nephropathy, diabetic retinopathy, or diabetic vasculopathy; reduced risk of developing significant cardiovascular complication (such as heart failure (HF), myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially in patients with diabetes that is accompanied by at least one other cardiovascular risk factor (such as hypertension, dyslipidemia, thrombosis phenomenon); therapy and prevention of diabetic complications; (acute and chronic) renal failure; glomerulonephritis; connective tissue diseases; atherosclerosis; peripheral arterial disease, including chronic peripheral arteriopathy; digital ulcers; diabetic foot ulcers and/or reduced risk of lower extremity/limb amputations in patients with diabetes, or smokers, or with atherosclerosis; Heart failure (HF), defined as including specifically chronic HF, including particularly systolic HF/HF with reduced ejection fraction (HFrEF) (ie, ejection fraction <about 40%), and diastolic HF/HF with preserved ejection fraction ejection (HFpEF) (ie, ejection fraction >about 50%); reducing the risk of developing a significant cardiovascular complication (such as heart failure (HF), myocardial infarction, stroke, or death from cardiovascular causes) in patients at cardiovascular risk (such as patients with coronary artery disease and/or patients who have demonstrated clinical signs of congestive heart failure); angina pectoris; and diastolic dysfunction. The compound of formula I can also be used in the treatment or prevention of cerebral ischemia; dementia; migraine; subarachnoid hemorrhage; Raynaud's syndrome; portal hypertension; restenosis after balloon or stent angioplasty; inflammation; peptic ulcer of the stomach and duodenum; cancer; melanoma; prostate cancer; prostate hypertrophy; erect

- 1 045981 tile dysfunction; eclampsia; hearing loss; blindness; chronic bronchitis; asthma; pulmonary fibrosis; gram-negative septicemia; shock, sickle cell anemia; renal colic; glaucoma; complications after vascular or cardiac surgery or after organ transplantation; complications of treatment with cyclosporine or equivalent treatments showing a nephrotoxic profile; pain; dyslipidemia; as well as other diseases currently known to be associated with endothelin.

Clinical studies have shown that endothelin receptor antagonists (ERAs) can have significant therapeutic effects in patients suffering from hypertension and/or renal disease, whether diabetes-related or not. It is likely that endothelium 1 (ET-1) plays a role in the pathogenic mechanisms of chronic diabetic arteriopathy due to its effects on indirect plaque formation, thrombosis, vasoconstriction and vascular hypertrophy and because it enhances the actions of other systems, particularly the renin-angiotensin and sympathetic systems. systems and/or insulin signals. Thus, ERA may be beneficial in the treatment of occlusive diseases of peripheral arteries, including diabetic arteriopathy, in the presence of acute (peripheral vasodilation) and chronic (vasodilation, improvement of vascular structure and modulation of sympathetic activity, antithrombotic, anti-inflammatory) effects. In a clinical network meta-analysis of adults with diabetes and CKD (157 studies including 43,256 patients), ERAs were rated as most effective in preventing end-stage kidney disease (SC Palmer et al., Lancet (2015), 385 (9982) ):2047-2056). However, therapeutic benefits must be weighed against potential side effects, such as the potential risk of teratogenic activity commonly associated with ARE. Additionally, and more importantly, both selective ETA antagonists and dual antagonists of both ET _A and ETB receptors can cause fluid retention, which is a common side effect associated with many previously studied AREs and sometimes (eg, if refractory). treatment with diuretics) leading to excessively serious adverse cardiac events such as heart failure or death. Whereas the risk-benefit ratio in most cases favors treatment with ERAs for indications such as pulmonary hypertension (as reflected in the past by successive marketing approvals of, for example, the ERA dual antagonists bosentan and macitentan, and the selective antagonist ET _A 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 a problem, making it difficult to consider potential treatments treatable resistant hypertension (rHT), chronic kidney disease (CKD), whether associated with diabetes and/or hypertension, or other hypertension-related diseases with AREs.

The ETA-selective endothelin receptor antagonist darusentan was developed for the treatment of resistant hypertension (rHT) (Bakris et al., Hypertension, 2010, 56,824-830, see also WO 2007/098390). In a 14-week phase 3 study in patients with rHT, it demonstrated efficacy in lowering ambulatory blood pressure but did not show a significant treatment effect on the primary endpoint of systolic blood pressure. Patients were eligible to participate if they had treatment-resistant hypertension (systolic blood pressure greater than 140 mm Hg) despite treatment with three or more antihypertensive drugs from different drug classes, including a diuretic, at optimized doses. A minimum dose of 25 mg hydrochlorothiazide per day (or its equivalent for other thiazide diuretics) was required. Even though diuretic therapy could be intensified during the trial at the discretion of the investigators to control fluid retention, the most common adverse effect associated with darusentan was fluid retention/edema at 28% compared to 12% in each study. other groups. A large number of patients stopped taking darusentan due to its side effects compared to placebo.

The ETA-selective ARE avosentate, in a study examining the effects of avosentan on the progression of clinical diabetic nephropathy in patients with type 2 diabetes, showed a significant treatment effect associated with significantly increased discontinuation of experimental drugs due to side effects, predominantly related to overload fluid and congestive heart failure (Mann et al., Avosentan for Overt Diabetic Nephropathy, J. Am. Soc. Nephrol., 2010, 21(3):527-535.). The composite primary outcome was time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. The study found no difference in the rate of the primary outcome between groups. Avosentan significantly reduced ACR. The study was stopped prematurely after a median follow-up of 4 months (maximum 16 months) due to excess cardiovascular events with avosentan, and the authors concluded that at dosages of 25 to 50 mg, avosentan may be less selective for ETA receptors and thus causes sodium and water retention and peripheral vasodilation with possible displacement of fluid from the intravascular to the extravascular space. The effect on albuminuria was considered likely due to inhibition of the renal ETA receptor because mixed-type ETAB receptor antagonists had previously been found to have weaker or no effect on proteinuria. According to the authors, the suggestion of ET _B receptor blockade by higher doses of avosentan is further supported by data that showed a natriuretic effect of selective ET _A receptor blockade in people treated with ACE inhibitors. Thus, the natriuretic effect/fluid retention that may ultimately lead to study discontinuation is attributed to dual blockade of ET _A and ETB receptors, which precludes the use of dual-acting AREs in this clinical setting.

Additional preclinical data showed that the synergistic effect on blood pressure of an ETA-selective ERA in combination with the ACE inhibitor enalapril was abolished by concomitant blockade of the ETB receptor (Goddard et al., J. Am. Soc. Nephrol., 2004, 15, 2601-2610) Therefore, the use of dual-acting AREs is not recommended in clinical settings where ACE inhibitors may be required as background therapy.

In a review of Endothelin antagonists for diabetic and non-diabetic chronic kidney disease (Br. J. Clin. Pharmacol. (2012), 76:4, 573-579), DEKohan et al. state that overall, the prevailing view is that _ETa , as opposed to combination ETAB, receptor antagonists are preferred for the treatment of CKD. Three years later, Kohan et al. concluded regarding a study published in Clin. J. Am. Soc. Nephrol. (2015), 10:1568–1574 that the fluid-retaining effect of ARE is likely due to a direct effect on renal tubular sodium transport, whereas the antiproteinuric effect of ARE is likely due to effects on the vasculature and/or the glomerulus. Finally, mitigation of the ERA of proteinuria would itself be expected to promote renal fluid excretion, but the ERA may still contribute to fluid retention through separate effects on tubular sodium and water reabsorption.

Application WO 2016/073846 provides a comprehensive description of ERAs tested for various indications, including diabetic and non-diabetic CKD and rHT. WO 2016/073846 provides additional examples in which fluid retention could lead to increased side effects for the ERA bosentan, tezosentan, ambrisentan and atrasentan. WO 2016/073 846 proposes a method for treating CKD with ERA, in particular with the ETA-selective ERA atrasentan, using predictive factors for fluid retention; said method comprising determining the risk of fluid retention if an ERA was administered to a subject; and administering ERA to the subject if the risk is at an acceptable level. A detailed protocol for a phase 3 clinical trial (SONAR) was published that assessed the effects of the investigational compound atrasentan - when added to standard treatment - on the progression of kidney disease in patients with stages 2-4 chronic kidney disease and type 2 diabetes, in Heerspink et al. , Diabetes Obes. Metab. 2018, 1-8. The protocol reflects the importance placed on dose optimization and concurrent monitoring of sodium retention/fluid retention in study design, resulting in a design that requires selection of individuals at high risk for disease (prognostic enrichment) who also demonstrate a good response to the investigational treatment (prognostic enrichment ). However, on December 1, 2017, AbbVie announced its strategic decision to close the SONAR study. The press release stated that ongoing monitoring of renal events observed in the study identified significantly fewer endpoints than expected at this time, which will likely impact the ability to test the SONAR study hypothesis. Therefore, AbbVie has determined that it cannot justify continued patient participation in the study. The decision to close the SONAR study early was not related to any safety concerns.

Contrary to the findings from the avosentan study, preclinical and clinical data suggest that the ETA-selective antagonists sitaxentan and ambrisentan pose a greater risk of fluid retention than the dual AREs bosentan and macitentan (Vercauteren et al., JPET, 2017, 361, 322 -333). The authors state that their findings indicate that in rats, stimulation of unblocked ET _B receptors in the presence of an ET _A receptor antagonist, but not functional ET _A receptor antagonism per se, may be deleterious, and that blockade of both receptors is less likely to cause water retention than single receptor blockade and continue to suggest that increased plasma volume combined with increased vascular permeability may explain the observations obtained with ETA-selective antagonists. The authors conclude that several clinical studies with ETA-selective antagonists resulted in increased mortality due to fluid retention problems, whereas this was not observed with dual AREs. However, dual AREs in the setting of preexisting fluid retention or elevated arginine vasopressin (AVP), such as chronic heart failure or chronic renal failure, caused significant fluid retention.

In a phase 2 clinical trial, it was shown that aprocytentan, an ERA leading to effective dual blockade of endothelin receptors, could provide effective blood pressure control in subjects with essential hypertension (aprocytentan was administered as monotherapy, i.e., without background antihypertensive therapy) ( Actelion Pharmaceuticals Ltd, press release May 22, 2017).

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Even though some evidence of potential fluid retention was observed (eg, weight gain at higher doses, dose-related decrease in hemoglobin concentration, four cases of peripheral edema at higher doses), the overall incidence of adverse effects was similar to those observed in placebo group. Thus, unlike the methods described in WO 2016/073846, aprocitentan may not require risk assessment and/or dose reduction to mitigate side effects associated with fluid retention when used to treat diseases associated with hypertension, especially resistant hypertension. hypertension. Thus, aprocitentan may have a different pharmacological profile than the predominantly ETA-selective antagonists that have so far been tested for resistant hypertension or chronic kidney disease in diabetic and non-diabetic patients.

In addition, in rat models of hypertension, it was found that aprocitentan may have a synergistic pharmacological effect in combination with the angiotensin receptor blocker (ARB) valsartan, a synergistic pharmacological effect in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril, and a synergistic pharmacological effect in combination with the calcium blocker. channels (BCC) with amlodipine, compared with the effect of only the corresponding active substances. ARBs, ACE inhibitors, and CCBs are standard regulatory treatments typically prescribed to patients with essential hypertension alone or in combination, often in combination with diuretics, particularly thiazide class diuretics such as hydrochlorothiazide.

SGLT-2 inhibitors block renal glucose reabsorption, increase glucose excretion, and decrease blood glucose concentrations. In addition to this well-characterized mode of action, SGLT-2 inhibitors lower blood pressure, reduce vascular stiffness, improve endothelial function, and have anti-inflammatory and antifibrotic properties reminiscent of ARE (H.J. Heerspink et al., Circulation (2016), 134(10): 752-772). This unique mechanism of action has led to the development and marketing approval of several SGLT-2 inhibitors, including canagliflozin, dapagliflozin and empagliflozin, which are all indicated to improve glycemic control in adults with type 2 diabetes, and empagliflozin is also indicated to reduce the risk of death from cardiovascular causes. -vascular diseases in such patients with established cardiovascular disease. Sotagliflozin, a dual inhibitor of SGLT-1 and SGLT-2, has been reported to be in clinical trials for the treatment of type 1 diabetes.

Application WO 2010/138535 claims a method of treating type 2 diabetes in a mammalian patient who has previously been treated with one or more oral antidiabetic agents and/or one or more injectable antidiabetic agents and has not previously been treated, the method comprising administering to said patient in need in treatment, a therapeutically effective amount of an SGLT2 inhibitor, particularly dapagliflozin. Application WO 2010/138535, among many other contemplated combinations, also discloses such a method using an SGLT2 inhibitor such as dapagliflozin in combination with one or more antihypertensive agents, which are, for example, beta-adrenergic blockers, calcium channel blockers (L -type and/or T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mibefradil), diuretics (e.g. chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, tricri nafen, chlorthalidone , furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (eg, captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-I receptor antagonists (eg, losartan, irbesartan, valsartan), ET receptor antagonists (eg, sitaxentan, atrasentan and the compounds disclosed in US Pat. Nos. 5,612,359 and 6,043,265), dual ET/AII antagonists, neutral endopeptidase (NEP) inhibitors, vasopeptidase inhibitors (dual inhibitors NEP-ACE) or nitrates. There are no data supporting combination with an antihypertensive agent over other proposed combinations, nor are there data supporting any specific combination therapy among different antihypertensive agents. Similarly, Kissei Pharmaceuticals Ltd has disclosed in several patent applications SGLT-1 and/or SGLT-2 inhibitors useful for the treatment of hyperglycemia such as diabetes, diabetic complications or obesity (see, for example, US 7732596, US 7989424), which among numerous other contemplated combinations are disclosed as useful in combination with endothelin receptor antagonists, such as L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355, PD-180988, sitaxentan sodium, BMS-193884 , darusentan, TVS-3711, bosentan, tesosentan sodium, J-104132, YM598, S-0139, SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan, BMS-207940 or similar to them.

Diabetes often coincides with heart failure (HF) and may contribute to its development. SGLT-2 inhibitors such as empagliflozin may be useful for the treatment of chronic HF, including in particular also HFpEF, where treatment options are very limited. The EMPA-REG OUTCOME trial (empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes) randomized

- 4 045981 recruited patients with type II diabetes at high cardiovascular risk to empaglilflozin or standard care. Results showed improvements in mortality from cardiovascular disease, nonfatal myocardial infarction, nonfatal stroke, hospitalization for HF, and mortality from any other cause. A post hoc study examining patients diagnosed with HF at baseline suggested significant reductions in cardiovascular mortality, hospitalization for HF, and other causes (D.H. Kim et al., Pharmacologic Management for Heart Failure and Emerging Therapies, Curr. Cardiol. Rep. (2017), 19:94). The mechanism of action of SGLT-2 results in the simultaneous inhibition of glucose and sodium uptake in the proximal tubule of the nephron, which is believed to lead to resetting of tubuloglomerular feedback, presumably causing the phenomenon of glomerular hyperfiltration. The effectiveness of SGLT-2 inhibitors is thought to be reduced by lower plasma glucose levels or decreased glomerular filtration rate (GFR), and therefore SGLT2 inhibitors have a low risk of hypoglycemia. As a consequence, the properties of SGLT-2 inhibitors may pave the way for the treatment of heart failure, including HFpEF, even in patients without diabetes (P. Martens et al., Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond, Curr. Treat. Options. Cardio Med (2017), 19:23).

A side effect associated with the pharmacological action of SGLT-2 inhibitors is interstitial fluid volume reduction/intravascular volume reduction, which can lead to dehydration, hypovolemia, orthostatic hypotension or hypotension. Thus, SGLT-2 inhibitors typically cause an increase in hematocrit (Hct), a marker of hemoconcentration and increased blood viscosity, a suspected cause of vascular injury in the context of peripheral vascular disease. Two large studies evaluating the SGLT-2 inhibitor canagliflozin in patients with type 2 diabetes (CANVAS and CANVAS-R) observed an increased risk of lower limb amputations. The European Medicines Agency (EMA) assessed these results (EMA/PRAC/637349/2016) in terms of a potential class effect associated with volume reduction and impaired tissue perfusion in the lower extremity, such that patients with already impaired perfusion are likely to have conditions leading to amputations will develop. The EMA concluded that the class effect can neither be proven nor disproved.

In addition, data from large clinical trials suggest that SGLT2 inhibitors may cause acute kidney injury and renal dysfunction, particularly in patients predisposed to acute kidney injury, where hypovolemia, chronic renal failure, congestive heart failure and concomitant medications should be considered (diuretics, ACE inhibitors, ARBs and NSAIDs). The pharmacological effects of SGLT-2 inhibitors on the kidney include an increase in serum creatinine and a decrease in estimated glomerular filtration rate.

Thus, aprocitentan, an ARE that results in effective dual blockade of endothelin receptors, may be particularly suitable for the treatment of endothelin-related diseases when given in combination with SGLT-2 inhibitors such as atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luceogliflozin, remogliflozin, sotagliflozin, tianagliflozin, or tofogliflozin (especially canagliflozin, dapagliflozin, or empagliflozin; especially canagliflozin). The use of the dual ARE aprocitentan in combination with an SGLT-2 inhibitor may result in particularly beneficial complementary pharmacological effects of the two modes of action, both in terms of complementary, additive or even synergistic treatment effects and additional relief of the respective side effects of each active substance of such combination therapy .

When an ARE is combined with an SGLT-2 inhibitor, the diuretic effect of such an SGLT-2 inhibitor and its potential pharmacological effect in reducing the risk of heart failure may be suitable for mitigating the most significant side effects commonly associated with ARE, such as fluid retention and the potentially associated increased risk of heart failure. insufficiency. In particular, aprocitentan, which demonstrated a particularly favorable safety profile in a phase II study in patients with (essential) hypertension, may be suitable for such a combination. Such combination treatment may result in pharmacological action against established endothelin-related diseases while maintaining a benign side effect profile even at optimal effective doses of aprocytentan, potentially even at increased doses of aprocytentan compared to the maximum tolerated dose of aprocytentan alone, or aprocytentan in combination, for example, with standard diuretics such as thiazide-like diuretics, including hydrochlorothiazide and/or aldosterone antagonists. Increased doses of aprocitentan, which may become available, for example due to attenuated side effects, if aprocitentan is used in combination with an SGLT-2 inhibitor, may increase the effect on diseases caused by the harmful effects of the paracrine endothelin system, which is widespread in the body. Such combination treatments may improve the benefit/risk ratio and, for example, do not require risk assessment methods according to WO 2016/073846 and/or dose reduction to mitigate side effects, such as those associated with fluid retention.

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In addition to the above-mentioned potential effects of an SGLT-2 inhibitor on the pharmacological effect and/or side effect profile of the ERA aprocitentan, the ERA aprocitentan may in turn have an additional effect on the pharmacological effect and/or side effect profile of the corresponding SGLT-2 inhibitor. AREs have been described to reduce hematocrit (Hct) through hemodilution. Thus, aprocitentan, when used in combination with SGLT-2 inhibitors, may counteract the most significant side effects commonly associated with SGLT-2 inhibitors, such as hemoconcentration due to the interstitial fluid volume-depleting effect, possibly contributing to an increased risk of limb/lower extremity amputations . In addition, AREs have been described to provide renal protection and improve renal hemodynamics. Therefore, aprocitentan, when used in combination with SGLT-2 inhibitors, may reduce the risk of acute renal failure, one of the risks described for currently approved SGLT-2 inhibitors. In addition, AREs are expected to lower blood pressure by preventing the vasoconstrictor effect of ET-1 resulting from its binding to ET receptors, thus aprocitentan, when used in combination with SGLT2 inhibitors, may contribute significant pharmacological effects in lowering blood pressure and its consequences (vascular remodeling, ischemic organ damage, reduction in cardiovascular risk caused/associated with diabetes and/or hypertension). In addition, AREs have been described to improve blood sugar levels through various mechanisms (increasing blood flow, improving insulin signaling).

Thus, aprocitentan, when used in combination with SGLT-2 inhibitors, may have additive or even synergistic effects in lowering blood sugar. In addition, a decrease in the volume of intercellular fluid may be associated with increased blood viscosity. Sloop et al. (Ther. Adv. Cardiovasc. Dis. (2015), 9(1)19-25) argue that the reason why the pathogenesis of chronic vascular diseases, including atherosclerosis, hypertension and metabolic syndrome is not fully understood by the mainstream because it has been ignored the role of blood viscosity, and that Theoretically, since flow is inversely proportional to viscosity, reducing blood viscosity should improve muscle perfusion and increase glucose utilization, reducing blood glucose levels. Thus, the combination of aprocitentan and an SGLT-2 inhibitor may further normalize both the interstitial fluid volume reduction effect typically associated with SGLT-2 inhibitors and the fluid retention effect typically associated with ARE, the beneficial pharmacological effects mentioned above, and potentially leading to additional beneficial pharmacological effects related to blood viscosity. Finally, aprocitentan, which has dual ARE pharmacological effects, may be particularly suitable for such combination therapy compared with a selective ETA receptor antagonist, as it may have low antagonizing activity against the beneficial effects of SGLT-2 inhibitors on sodium reabsorption, which is due to the underlying pharmacological effect of SGLT-2 on glucose reuptake.

In addition, it has been discovered that certain crystalline forms of aprocytentan, which are suitable for the production of pharmaceutical compositions, can be detected under certain conditions. These crystalline forms of aprocytentan may have advantageous properties due to the potential use of aprocytentan as an active pharmaceutical ingredient. Such benefits may include improved flow properties; less hygroscopicity; better manufacturing reproducibility (eg, better filtration parameters, better molding reproducibility and/or better sedimentation); and/or a certain morphology. Such crystalline forms of aprocytentan may be particularly useful in the manufacture of certain pharmaceutical compositions. Aprocitentan 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 agents or therapeutic agents.

Description of the figures

In fig. 1 shows an X-ray powder diffraction pattern of the compound in crystalline form A as obtained from Example 1. The X-ray powder diffraction pattern shows peaks having relative intensities, compared to the most intense peak in the diagram, of the following percentages (relative peak intensities are given in parentheses) at the indicated reflection angles 2 theta (selected peaks from the range 3-33° 2 theta with relative intensity greater than 10% reported): 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%).

In fig. 2 shows an X-ray powder diffraction pattern of the compound in crystalline form C as obtained from Example 2. The X-ray powder diffraction pattern shows peaks having relative intensities compared to the most intense peak in the diagram, following

- 6,045,981 blowing percent (relative peak intensities are given in parentheses) at the indicated 2 theta reflection angles (selected peaks from the 3-33° 2 theta range with relative intensities greater than 10% are reported): 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%) .

It is understood that the crystalline forms described herein contain the compound in free base crystalline form (ie, not in salt form). In addition, said crystalline forms may contain a non-coordinated and/or coordinated solvent.

Coordinated solvent is used herein as the term for crystalline solvate. Likewise, non-coordinated solvent is used herein as a term for physisorbed or physically entrapped solvent (defined according to Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: U.J. Griesser: The Importance of Solvates). Crystalline forms A and C are anhydrate/ansolvate forms.

In fig. Figure 3 shows the acute effects of ACT-132577 on mean arterial pressure (MAP) in awake hypertensive, salt-sensitive male Dahl rats.

In fig. Figure 4 shows the acute effects of ACT-132577 on SBP in awake hypertensive male deoxycorticosterone acetate-sensitive rats.

In fig. Figure 5 shows the acute effects of ACT-132577 on SBP in awake spontaneously hypertensive male rats.

In fig. Figure 6 shows the acute effects of ACT-132577, used alone or in combination with valsartan, on SBP in awake spontaneously hypertensive male rats.

In fig. Figure 7 shows the acute effects of ACT-132577, used alone or in combination with valsartan, on SBP in awake hypertensive male deoxycorticosterone acetate-sensitive rats.

In fig. Figure 8 shows the acute effects of ACT-132577, used alone or in combination with enalapril, on SBP in awake spontaneously hypertensive male rats.

In fig. Figure 9 shows the acute effects of ACT-132577, used alone or in combination with amlodipine, on SBP in awake hypertensive male deoxycorticosterone acetate-sensitive rats.

In fig. Figure 10 shows the effects of chronic oral administration of AST-132577 on SBP in awake hypertensive male rats sensitive to deoxycorticosterone acetate.

In fig. Figure 11 shows the effects of chronic oral administration of AST-132577 on renal vascular resistance in awake hypertensive male rats sensitive to deoxycorticosterone acetate.

In fig. Figure 12 shows the acute dose-dependent effect of aprocitentan 1, 3, 10, 30 mg/kg on hematocrit (Hct) 24 hours after a single oral administration to Wistar rats.

In fig. Figure 13 shows the acute effects of ACT-132577, used alone or in combination with canagliflozin, for maximum effects on SBP in awake spontaneously hypertensive male rats.

In fig. Figure 14 shows the acute effects of ACT-132577, used alone or in combination with empagliflozin, for maximum effects on SBP in awake spontaneously hypertensive male rats.

In fig. 15 shows the acute effects of EXFORGE HCT® alone and EXFORGE HCT® in combination with ACT-132577 in spontaneously hypertensive male rats.

In fig. 16 shows the acute effects of EXFORGE NCT® alone and EXFORGE NCT® in combination with spironolactone in spontaneously hypertensive male rats.

In fig. 17 shows the acute effects of EXFORGE HCT® alone and EXFORGE HCT® in combination with ACT-132577 in hypertensive male rats sensitive to deoxycorticosterone acetate.

In fig. 18 shows the acute effects of EXFORGE NCT® alone and EXFORGE NCT® in combination with spironolactone in hypertensive male rats sensitive to deoxycorticosterone acetate.

Detailed Description of the Invention

1. The first embodiment relates to a pharmaceutical composition containing as an active substance aprocytentan or a pharmaceutically acceptable salt thereof, in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

2. Another embodiment relates to a pharmaceutical composition according to embodiment 1, wherein the SGLT-2 inhibitor is atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin or tofogliflozin; or a pharmaceutically acceptable salt thereof.

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2i. In a sub-embodiment, the SGLT-2 inhibitor is specifically bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, sotagliflozin, or tofogliflozin (especially canagliflozin, dapagliflozin, or empagliflozin; especially canagliflozin); or a pharmaceutically acceptable salt thereof.

3. Another embodiment provides a pharmaceutical composition according to Embodiment 1, wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin, dapagliflozin, or empagliflozin (especially canagliflozin), or a pharmaceutically acceptable salt thereof.

4. Another embodiment provides a pharmaceutical composition according to embodiment 1), wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin, or a pharmaceutically acceptable salt thereof.

5. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-4, wherein aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration from 1 to 100 mg, preferably from 2.5 to 100 mg (exactly from 10 to 50 mg); in particular 10, 12.5, 20, 25, 30, 40 or 50 mg; in particular, 12.5, 25 or 50 mg of aprocitentan per day;

5i) wherein, in a sub-embodiment, said dose of aprocitentan is a dose that would be expected to be a tolerable effective dose of aprocitentan when administered as monotherapy (eg, for the treatment of hypertension) (specifically, such dose would be from 10 to 25 mg, especially 10, 12.5 or 25 mg);

5ii) wherein in another sub-embodiment, said dose of aprocitentan is a dose that would be expected to be a tolerable effective dose or greater than a tolerable effective dose of aprocitentan when administered as monotherapy (eg, for the treatment of hypertension) (in particular, such dose would be be from 40 to 100 mg, especially 50 mg of aprocitentan per day);

5iii) wherein in another sub-embodiment, said dose of aprocitentan is a dose that would be expected to be a tolerable effective dose or less than a tolerable effective dose of aprocitentan when administered as monotherapy (eg, for the treatment of hypertension) (in particular, such dose would be be 1, 2.5 or 5 mg of aprocitentan per day).

6. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-4, wherein aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration 1, 2.5, 5, 10, 12. 5, 20, 25, 30, 40 or 50 mg; (especially 10, 12.5, 20, 25, 30, 40 or 50 mg; specifically 12.5, 25 or 50 mg) aprocitentan per day;

6i) wherein in a sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 12.5 mg of aprocitentan per day (i.e., a dose that would be expected to be a tolerable effective dose of aprocitentan when taken as monotherapy (for example, in relation to the treatment of hypertension));

6ii) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 25 mg of aprocitentan per day (i.e., a dose that would be expected to be a tolerable effective dose of aprocitentan when administered at as monotherapy (for example, in relation to the treatment of hypertension));

6iii) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg of aprocitentan per day (i.e., a dose that would be expected to be a tolerable effective dose or greater than a tolerable effective dose doses of aprocitentan when taken as monotherapy (for example, in relation to the treatment of hypertension));

6iv) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 mg of aprocitentan per day (i.e., a dose that would be expected to be a tolerable effective dose of aprocitentan when administered at as monotherapy (for example, in relation to the treatment of hypertension));

6v) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 mg of aprocitentan per day (i.e., a dose that would be expected to be a tolerable effective dose or less than a tolerable effective dose doses of aprocitentan when taken as monotherapy (for example, in relation to the treatment of hypertension));

6vi) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 2.5 mg of aprocitentan per day (i.e., a dose that can be expected to be less than tolerated

- 8 045981 effective dose of aprocitentan when taken as monotherapy (for example, in relation to the treatment of hypertension));

6vii) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 mg of aprocitentan per day (i.e., a dose that would be expected to be below the tolerable effective dose of aprocitentan when administered as monotherapy (for example, in relation to the treatment of hypertension)).

7. Another embodiment provides a pharmaceutical composition according to one of embodiments 1-6, wherein said SGLT-2 inhibitor, or a pharmaceutically acceptable salt thereof, is contained in a pharmaceutical unit dosage form suitable for oral administration of said SGLT-2 inhibitor, wherein bexagliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 50 mg (in particular, 20 mg) of bexagliflozin per day;

canagliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 to 400 mg (especially 50, 100, 150 or 300 mg; specifically 100 or 300 mg; especially 100 mg) of canagliflozin per day;

dapagliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 to 20 mg (in particular, 5 or 10 mg) of dapagliflozin per day;

empagliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 50 mg (in particular, 10 or 25 mg) of empagliflozin per day;

ertugliflozin, or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 2.5 to 50 mg (in particular, 5 or 15 mg) of ertugliflozin per day;

henagliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 100 mg (in particular, 25 mg) of henagliflozin per day;

ipragliflozin, or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 to 100 mg (in particular, 25 or 50 mg) of ipragliflozin per day;

luseogliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 to 10 mg (especially 2.5 or 5 mg) of luseogliflozin per day;

sotagliflozin, or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 to 500 mg (in particular, 75, 200 or 400 mg) of sotagliflozin per day;

tofogliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 to 50 mg (in particular, 20 mg) of tofogliflozin per day.

8) Another embodiment relates to a pharmaceutical composition in accordance with embodiment 4, wherein aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration from 1 to 100 mg, preferably from 2.5 to 100 mg (namely from 10 to 50 mg); in particular 10, 12.5, 20, 25, 30, 40 or 50 mg, in particular 12.5, 25 or 50 mg, aprocitentan per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 to 400 mg (in particular 50, 100, 150 or 300 mg, namely 100 or 300 mg, in particular 100 mg) of canagliflozin per day ;

8i) wherein in a sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 12.5 mg of aprocitentan per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50, 100, 150 or 300 mg (namely 100 or 300 mg, especially 100 mg) of canagliflozin per day;

8ii) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 25 mg of aprocitentan per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50, 100, 150 or 300 mg (namely 100 or 300 mg, especially 100 mg) of canagliflozin per day;

8iii) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration

- 9 045981 administration of 10 mg of aprocitentan per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50, 100, 150 or 300 mg (namely 100 or 300 mg, especially 100 mg) of canagliflozin per day;

8iv) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 mg of aprocitentan per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50, 100, 150 or 300 mg (namely 100 or 300 mg, especially 100 mg) of canagliflozin per day;

8v) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 2.5 mg of aprocitentan per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50, 100, 150 or 300 mg (namely 100 or 300 mg, especially 100 mg) of canagliflozin per day;

8vi) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 mg of aprocitentan per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50, 100, 150 or 300 mg (namely 100 or 300 mg, especially 100 mg) of canagliflozin per day;

8vii) wherein in another sub-embodiment, aprocitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg of aprocitentan per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50, 100, 150 or 300 mg (namely 100 or 300 mg, especially 100 mg) of canagliflozin per day.

Likewise, when combined with dapagliflozin or empagliflozin, aprocitentan or a pharmaceutically acceptable salt thereof is contained as set forth in embodiment 8) and its sub-embodiments 8i-8vii above; and dapagliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 to 20 mg (in particular, 5 or 10 mg) of dapagliflozin per day; and empagliflozin or a pharmaceutically acceptable salt thereof, when available, is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 50 mg (in particular, 10 or 25 mg) of empagliflozin per day.

9. The second aspect of the present invention relates to a pharmaceutical composition in accordance with one of embodiments 1-8; wherein said pharmaceutical composition is (intended) for administration in combination/co-therapy with conventional background therapy (or first-line therapy) suitable for the prevention or treatment of hypertension, including particularly intractable/resistant hypertension; chronic kidney disease (CKD) (specifically CKD stages 1-4 as defined in the Kidney Disease: Improving Global Outcomes (KDIGO) clinical guidelines (and especially CKD stage 3)) and, in particular, CKD (specifically these stages) caused by /associated with hypertension and/or caused by/associated with diabetes (diabetic kidney disease (DKD)); or diabetes.

9i. In a first sub-embodiment, such conventional background therapy may in particular include an ACE inhibitor (especially enalapril, but also ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril), or a pharmaceutically acceptable salt thereof; and/or an angiotensin receptor blocker (especially valsartan, but also losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or a pharmaceutically acceptable salt thereof; and/or a calcium channel blocker (especially amlodipine, but also aranidipine, azelnidipine, barnidipine, benidipine, silnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine ) or a pharmaceutically acceptable salt thereof; and/or metformin; and/or insulin; and/or a sulfonylurea (especially glibenclamide) or a pharmaceutically acceptable salt thereof; and/or a DPP-4 inhibitor (especially sitagliptin, vildagliptin, saxagliptin or linagliptin), or a pharmaceutically acceptable salt thereof; and/or a GLP-1 receptor agonist (especially exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, semaglutide); and/or a thiazolidinedione or a pharmaceutically acceptable salt thereof.

9ii. In a second sub-embodiment, traditional background therapies are preferred, which are first-line therapies useful for the prevention or treatment of hypertension and/or diabetes, such as in particular an ACE inhibitor or an angiotensin receptor blocker

- 10 045981 zina as a treatment for hypertension; and/or metformin and/or a DII-4 inhibitor as a treatment for diabetes.

9iii. In a third sub-embodiment, said background therapy according to one of Embodiments 9, 9i or 9ii should be administered at a dosage corresponding to the tolerated effective dose of the corresponding active substance, for example when taken as monotherapy, or in diabetic patients when taken in combination with an appropriate SGLT-2 inhibitor. In particular, valsartan or a pharmaceutically acceptable salt thereof, when available, should be administered in a dosage form suitable for oral administration of 160 or 320 mg of valsartan per day; losartan or a pharmaceutically acceptable salt thereof, if available, should be administered in a dosage form suitable for oral administration of 50 or 100 mg of losartan per day; irbesartan or a pharmaceutically acceptable salt thereof, if available, should be administered in a dosage form suitable for oral administration of 75, 150 or 300 mg of irbesartan per day; amlodipine or a pharmaceutically acceptable salt thereof, if available, should be administered in a dosage form suitable for oral administration of 5 or 10 mg amlodipine per day; enalapril or a pharmaceutically acceptable salt thereof, if available, should be administered in a dosage form suitable for oral administration from 2.5 to 40 mg of enalapril per day; lisinopril or a pharmaceutically acceptable salt thereof, if available, should be administered in a dosage form suitable for oral administration of 2.5 to 40 mg of lisinopril per day; ramipril or a pharmaceutically acceptable salt thereof, if available, should be administered in a dosage form suitable for oral administration of 2.5 to 20 mg of ramipril per day; Metformin, if available, should be administered in a dosage form suitable for oral administration, 500 to 2000 mg of metformin per day; Glibenclamide, if available, should be administered in a dosage form suitable for oral administration from 1.25 to 5 mg of glibenclamide per day; If available, sitagliptin should be administered in a dosage form suitable for oral administration of 25 to 100 mg of sitagliptin per day; Vildagliptin, if available, should be administered in a dosage form suitable for oral administration, twice 50 mg of vildagliptin per day; Saxagliptin, if available, should be administered in a dosage form suitable for oral administration of 2.5 or 5 mg of saxagliptin per day; When available, linagliptin should be administered in a dosage form suitable for oral administration, twice 5 mg linagliptin per day.

The term angiotensin receptor blocker or ARB, in particular, means in this application valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan or a pharmaceutically acceptable salt of one of them. A preferred ARB is valsartan or a pharmaceutically acceptable salt thereof.

The term calcium channel blocker or CCB, in particular, in this application means amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, silnidipine, 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.

The term angiotensin-converting enzyme inhibitor or AIF inhibitor, in particular in this application, means captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril, or a pharmaceutically acceptable salt of one of them. The preferred AIF inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

The term DII-4 inhibitor or DII-IV inhibitor refers to dipeptidyl peptidase 4 inhibitors, such as, in particular, sitagliptin, vildagliptin, saxagliptin and linagliptin, as well as gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin and dutogliptin.

The term GII-1 receptor agonist refers to glucagon-like peptide-1 receptor agonists such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, semaglutide, among others.

The term sulfonylurea refers in particular to glibenclamide (glyburide), glybornuride, gliclazide, glipizide, gliquidone, glisoxepide, glycopyramide or glimepiride.

The term thiazolidinediones, abbreviated as TZDs, also known as glitazones, refers to PPARy (peroxisome proliferator-activated receptor gamma) agonists and refers in particular to pioglitazone, rosiglitazone or lobeglitazone.

Another traditional background therapy, particularly for treating a patient with a history of hypertension, may be a diuretic. Such a diuretic may especially be prescribed in addition to the above-mentioned conventional background treatments for hypertension. The term diuretic as used herein refers to loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics, including aldosterone antagonists such as spironolactone, eplerenone or finrenone, or aldosterone synthase inhibitors; carbonic anhydrase inhibitors, including acetazolamide and methazolamide; and in particular to diuretics of the thiazide class (thiazide-like diuretics), such as in particular chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone. The preferred thiazide-like diuretics are chlorthalidone or hydrochlorothiazide. To avoid any ambiguity, although they are

- 11 045981 provide a diuretic pharmacological effect, SGLT-2 inhibitors are not included in the term diuretic as used in this application.

10. The third aspect of the invention relates to a pharmaceutical composition in accordance with one of embodiments 1-9, 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 reflection angles 2θ: 17.8, 20.0 and 23.5°; wherein said X-ray powder diffraction pattern is obtained by applying combined Cu Ka radiation. 1 and Ka2, without Ka2 desorption; and the accuracy of 2θ values is in the range of 2θ±0.2°.

11. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, 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 reflection angles 2θ: 17.8, 18.6, 20.0, 23.2 and 23.5°; wherein said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without desorption of Ka2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

12. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, 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 reflection 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 X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without desorption of Ka2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

13. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, 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 reflection 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, 2 8.5, 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 desorption of Ka2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

14. Another embodiment provides a pharmaceutical composition in accordance with one of embodiments 1-9, 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 reflection 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° (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 desorption of Ka2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

The data presented shows peaks having relative intensities, compared to the most intense peak in the diagram, of the following percentages (relative peak intensities are given in parentheses) at the indicated reflection angles of 2 theta (selected peaks from the range of 3-33° 2 theta with relative intensities are reported more than 10%).

15) Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, wherein said composition contains aprocytentan in crystalline form A, which essentially shows an X-ray powder diffraction pattern as depicted in FIG. 1, where the specified X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without desorption of Ka2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

In this context, the term essentially means that at least the major peaks of the diagram depicted in the indicated figures must be present, i.e. those that have a relative intensity greater than 10%, especially greater than 20% relative to the most intense peak in the chart. However, one skilled in the art of powder X-ray diffraction will appreciate that the relative intensities in X-ray powder diffraction patterns can be subject to large variations in intensity due to preferential orientation effects.

16. Another embodiment provides a pharmaceutical composition in accordance with one of embodiments 1-9, wherein said composition contains aprocytentan in crystalline Form A obtained by crystallizing the compound in an aqueous solution at pH 6.2-6.8.

For the avoidance of any doubt, whenever one of the above embodiments refers to peaks in the X-ray powder diffraction pattern at the following reflection angles 2θ, said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without desorption of Ka2; and it should be understood that the accuracy of the 2θ values as provided herein is in the range of ±0.1-0.2°. It is noteworthy that when determining

- 12 045981 reflection angle 2 theta (2θ) for the peak in the embodiments and claims, this 2θ value should be understood as the interval from the specified value minus 0.2° to the specified value plus 0.2° (2θ±0.2°); and preferably from the specified value minus 0.1° to the specified value plus 0.1° (2θ±0.1°).

When determining the presence of a peak, for example in an X-ray powder diffraction pattern, a common approach is to do so in terms of the S/N ratio (L=signal. H=noise). According to this definition, when it is stated that a peak should be present in an X-ray powder diffraction pattern, it is meant that the peak in the X-ray powder diffraction pattern is determined by the presence of a ratio S/N (^=signal, N=noise) greater than x (x is a numerical value greater than 1) , usually more than 2, especially more than 3.

Unless used in relation to temperatures, the term approximately appearing before the numerical value of X in this application refers to the range extending from X minus 10% of X to X plus 10% of X, and preferably to the range extending from X minus 5 % from X to X plus 5% of X. In the particular case of temperatures, the concept approximately, located before temperature Y, in this application refers to the interval extending from temperature Y minus 10°C to Y plus 10°C, preferably to the interval extending from Y minus 5°C to Y plus 5°C, namely to the interval extending from Y minus 3°C to Y plus 3°C. Room temperature means a temperature of approximately 25°C. When the term n equivalent(s) is used herein, where n is a number, it is intended within the scope of this application that n refers to the approximate number of n, preferably n refers to the exact number of n.

Whenever the word between or to is used to describe a numerical range, it should be understood that the end points of the specified range are expressly included in the range. For example, if a temperature range is described between 40 and 80°C (or from 40 to 80°C), then this means that the end points of 40 and 80°C are included in the range; or if a variable is defined as an integer between 1 and 4 (or 1 to 4), then this means that the variable is an integer 1, 2, 3 or 4.

17. The fourth aspect of the invention relates to a pharmaceutical composition in accordance with one of embodiments 1-9, wherein the composition contains aprocytentan in crystalline form C, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following reflection angles 2θ: 9.7, 15.7 and 22.0°; wherein said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Κα1 and Κα2, without desorption of Κα2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

18) Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, wherein the composition contains aprocytentan in crystalline form C, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following reflection angles 2θ: 7.8, 9.7, 15.7, 19.8 and 22.0°; wherein said X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Κα1 and Κα2, without desorption of Κα2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

19. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, wherein the composition contains aprocytentan in crystalline form C, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following reflection 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 applying the combined radiation of Cu Κα1 and Κα2, without desorption of Κα2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

20. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, wherein the composition contains aprocytentan in crystalline form C, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following reflection 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 X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Κα1 and Κα2, without desorption of Κα2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

21. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, wherein the composition contains aprocytentan in crystalline form C, characterized by the presence of peaks in the X-ray powder diffraction pattern at the following reflection 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 Κα1 and Κα2, without desorption of Κα2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

The data presented shows peaks having relative intensities compared

- 13 045981 with the most intense peak on the diagram, the following percentages (relative peak intensities are given in parentheses) at the indicated 2 theta reflection angles (selected peaks from the range 3-33° 2 theta with relative intensities greater than 10% are reported).

22. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1) - 9), wherein said composition contains aprocytentan in crystalline form C, which essentially shows an X-ray powder diffraction pattern as depicted in FIG. 3, where the specified X-ray powder diffraction pattern is obtained by applying the combined radiation of Cu Ka1 and Ka2, without desorption of Ka2; and the accuracy of 2θ values is in the range of 2θ±0.2°.

In this context, the term essentially means that at least the major peaks of the diagram depicted in the indicated figures must be present, i.e. those that have a relative intensity greater than 10%, especially greater than 20%, relative to the most intense peak in the chart. However, one skilled in the art of powder X-ray diffraction will appreciate that the relative intensities in X-ray powder diffraction patterns can be subject to large variations in intensity due to preferential orientation effects.

23. Another embodiment provides a pharmaceutical composition in accordance with one of embodiments 1-9, wherein the composition contains aprocytentan in crystalline Form C obtained by crystallizing the compound from MeOH, EtOH or propan-2-ol.

24. Another embodiment relates to a pharmaceutical composition in accordance with one of embodiments 1-9, wherein said composition contains aprocytentan in amorphous form. This 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, 2 agate balls), 30 min at 30 Hz at ambient temperature.

The manufacture of pharmaceutical compositions can be carried out in a manner that will be 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 introducing crystalline forms in accordance with the present invention, optionally in combination with other therapeutically valuable substances, into a galenic dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and, if desired, conventional pharmaceutical excipients .

25. A further embodiment relates to a solid pharmaceutical composition (especially in the form of a tablet) in accordance with one of embodiments 1-24, in particular in accordance with one of embodiments 10-16, or in accordance with one of embodiments 17 -22, containing as a pharmaceutically acceptable excipient inert microcrystalline cellulose, lactose, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate.

26. Specifically, the solid pharmaceutical composition of embodiment 25 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 the total weight of the pharmaceutical composition composition, lactose in a total amount of 40 to 65% by weight based on the total weight of the pharmaceutical composition, hydroxypropyl cellulose 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 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, whereby the total percentage by weight of the solid pharmaceutical composition will always be 100; the above-mentioned solid pharmaceutical composition will particularly be in the form of a tablet.

27. A further embodiment of the invention relates to a pharmaceutical composition in accordance with embodiments 25 or 26, wherein said pharmaceutical composition is presented in the form of a tablet. In a sub-embodiment, the pharmaceutically active substances are contained in granules before being compressed into said tablet.

The tablet according to embodiment 27 may optionally be coated with a suitable protective film. Said protective film will, in particular, prevent direct contact of the pharmaceutical composition with moisture; it may also facilitate labeling, which is desirable for the purpose of distinguishing the pharmaceutical composition from others.

The coating material for making such a protective film may include a polymer with low water vapor permeability (such as polyvinyl alcohol (for example, Aquapolish® white PVA from the manufacturer Biogrund) or dimethylaminoethyl methacrylate (for example, EUDRAGIT® E PO)). The coating material may further include a plasticizing agent (for example, propylene glycol, triacetin, dibutyl phthalate or dibutyl sebacate), a surfactant (for example, sodium lauryl sulfate or a polysorbate such as Tween®) and/or a lubricant/glidant (for example, stearic acid , magnesium or calcium stearate or talc). In addition, mate

- 14 045981 rial The coating may also include a pigment (for example, iron(I) oxide, iron(III) oxide or titanium oxide) to impart a colored tint to the tablet.

28. A further embodiment of the invention relates to a pharmaceutical composition in accordance with one of embodiments 25-26, wherein said pharmaceutical composition is presented in the form of a capsule. In a sub-embodiment, the pharmaceutically active substances are contained in granules before being compressed into said capsules.

For the avoidance of any doubt, the invention further relates to crystalline forms of aprocytentan, in particular crystalline form A disclosed in this application, such crystalline form being suitable/applicable as a final step in the isolation of aprocytentan (for example, to meet the purity requirements of pharmaceutical production) , whereas the final pharmaceutical composition in accordance with embodiments 1-28 may or may not contain the specified crystalline form (for example, because the initially crystalline form of aprocytentan is further transformed during the manufacturing process and/or dissolved in pharmaceutically acceptable carrier material(s); thus, in the final pharmaceutical composition, aprocytentan may be present in a non-crystalline form, in another crystalline form, or in a dissolved form, or the like).

Such a combination of pharmaceutical compositions in accordance with embodiments 1-28 is particularly useful for the treatment of endothelin-related diseases and in a method of treating endothelin-related diseases in a subject in need of ERA.

Such endothelin-related diseases may be specifically defined to include hypertension, particularly including refractory/resistant hypertension; coronary heart disease, including angina pectoris, coronary disease and myocardial ischemia; heart failure; chronic kidney disease (CKD) (specifically CKD stages 1–4 as defined in the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines (namely CKD stage 3)), and in particular CKD (specifically these stages) caused by/ associated with hypertension, or caused/associated with diabetes (also referred to as diabetic kidney disease (DKD), where in particular such diabetes is type 2 diabetes); diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic nephropathy, diabetic retinopathy, or diabetic vasculopathy; reducing the risk of developing a significant cardiovascular event (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially in patients with diabetes that is accompanied by at least one other cardiovascular risk factor (such as especially hypertension); therapy and prevention of diabetic complications; (acute and chronic) renal failure; glomerulonephritis; connective tissue diseases; atherosclerosis; obliterating diseases of peripheral arteries, including chronic peripheral arteriopathy; digital ulcers; diabetic foot ulcers and/or reduced risk of lower extremity/limb amputation in patients with diabetes; Heart failure (HF), defined as including specifically chronic HF, including particularly systolic HF/HF with reduced ejection fraction (HFrEF) (ie, ejection fraction <about 40%), and diastolic HF/HF with preserved ejection fraction ejection (HFpEF) (ie, ejection fraction >about 50%); reducing the risk of developing a significant cardiovascular complication (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients at cardiovascular risk (such as patients with coronary artery disease and/or patients with clinical signs of congestive heart failure) ; and diastolic dysfunction.

To avoid ambiguity, the concept of CKD caused/associated with diabetes (diabetic kidney disease, DKD) may also include DKD associated with hypertension; diabetes in particular being type 2 diabetes.

Particularly in the context of the present invention, endothelin-related diseases include chronic kidney disease (CKD) (especially CKD stages 1-4 as defined in the Kidney Disease: Improving Global Outcomes (KDIGO) clinical guidelines (namely CKD stages 3) ) and, in particular, CKD (precisely these stages), caused/associated with hypertension, and/or caused/associated with diabetes (diabetic kidney disease (DKD)); as well as (acute and chronic) renal failure; diabetic nephropathy; and glomerulonephritis;

in a sub-embodiment, DKD as defined above specifically refers to DKD in a patient diagnosed with type 2 diabetes mellitus; in particular, to a reduction in the rate of progression of DKD, for example, in a patient diagnosed with type 2 diabetes mellitus, where such a reduced rate of progression may, in particular, be expressed by a decrease in eGFR, a decrease in the incidence of end-stage kidney disease (ESKD), or a decrease in the incidence of renal death; wherein, in particular, said patient additionally has a history of hypertension;

in an additional sub-option, DKD as defined above specifically refers to diabetic nephropathy associated with elevated serum creatinine and/or proteinuria (especially corresponding to CKD stages 1-4 as defined in the Kidney Disease clinical practice guidelines:

- 15 045981 improvement of global treatment outcomes (KDIGO) (namely CKD stage 3) in patients with type 2 diabetes, especially in such patients additionally with a history of hypertension;

in an additional sub-embodiment, DKD as defined above, specifically refers to such DKD, also associated with hypertension; wherein, in particular, the diabetes is type 2 diabetes;

diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic retinopathy, or diabetic vasculopathy; as well as therapy and prevention of diabetic complications; and reducing the risk of developing a significant cardiovascular complication (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, particularly in patients with diabetes that is accompanied by at least one other cardiovascular risk factor ( such as especially hypertension); as well as diabetic foot ulcers and/or reducing the risk of lower limb amputation in patients with diabetes; and heart failure (HF), defined to include specifically chronic HF, including particularly systolic HF/HF with reduced ejection fraction (HFrEF) (ie, ejection fraction <about 40%), and diastolic HF/HF with preserved ejection fraction (HFpEF) (i.e. ejection fraction >about 50%); and reducing the risk of developing a significant cardiovascular event (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients at cardiovascular risk (such as patients with coronary artery disease and/or patients with clinical evidence of congestive heart failure ); angina pectoris;

coronary diseases; heart failure; and diastolic dysfunction.

Essential hypertension (also called primary hypertension or idiopathic hypertension) is a form of hypertension that, by definition, has no identifiable cause. It represents a major public health problem worldwide, contributing to the morbidity of vascular and renal diseases and mortality from cardiovascular diseases. The diagnosis of essential hypertension is made when the average of multiple systolic blood pressure measurements at 2 or more subsequent visits is consistently equal to or greater than a specified threshold T _SBP value. People with borderline blood pressure tend to maintain blood pressure that is higher than the average for the general population and are at greater risk of developing certain hypertension and cardiovascular events than the general population. The T _SBP threshold above which treatment is recommended is regularly debated among clinicians (see, for example, Mancia et al., J. Hypertens. (2013), 31, 1281-1357); accordingly, depending on the general condition and age of the patient, T _SBP can be 140 or 130 mmHg. or have another suitable meaning.

The concept of resistant hypertension (equivalent to the concept of difficult-to-treat hypertension) is defined in the present invention as blood pressure that remains above the target value despite the simultaneous use of three antihypertensive drugs of different classes. One of the three therapeutic agents must be a diuretic, and all agents must be prescribed at optimal/maximum dosage levels. As defined, patients with resistant hypertension include patients whose blood pressure is controlled using more than three medications. Those. patients whose blood pressure is controlled but requires four or more medications should be considered treatment resistant (see, e.g., Mancia et al., J. Hypertens. (2013), 31, 1281-1357).

The term diabetes as used herein refers to all types of diabetes, especially type 2 diabetes; as well as type 1 diabetes and latent autoimmune diabetes of adulthood, a form of type 1 diabetes that occurs in adulthood, often with a slower onset than type 1 diabetes diagnosed in juveniles.

29. Thus, the fifth aspect of the invention relates to aprocitentan or a pharmaceutically acceptable salt thereof, for use in the prevention/prevention or treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3); and, in particular, CKD (precisely these stages), caused/associated with hypertension, and/or caused/associated with diabetes (DKD); as well as in the prevention/prevention or treatment of acute or chronic renal failure; diabetic nephropathy; or glomerulonephritis;

wherein in the first sub-embodiment, such use is specifically intended for the treatment of such DKD in a patient diagnosed with type 2 diabetes mellitus, wherein in particular aprocitentan reduces the rate of progression of DKD, where such reduced rate of progression may particularly be expressed by a decrease in eGFR, a decrease in the incidence of end-stage disease kidney disease (ESKD), or decreased incidence of renal death; Moreover, it is the specified patient who additionally has a history of hypertension;

wherein in the second sub-embodiment such use is specifically intended for the treatment of such DKD, including the treatment of diabetic nephropathy associated with elevated serum creatinine and/or proteinuria [particularly corresponding to CKD stages 1-4, as defined in the Kidney Disease: Improving Global Clinical Practice Guidelines results of treatment (KDIGO) (namely to such CKD stage 3)), in patients with type 2 diabetes, especially in such patients additionally have

- 16 045981 with a history of hypertension;

for use in the prevention/prevention or treatment of diabetes and diabetes-related diseases such as diabetic arteriopathy, diabetic retinopathy, or diabetic vasculopathy; as well as diabetic complications; to reduce the risk of developing a significant cardiovascular complication (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially in patients with diabetes that is accompanied by at least one other cardiovascular risk factor (such as , in particular hypertension); and for use in the prophylaxis/prevention or treatment of diabetic foot ulcers and/or to reduce the risk of lower limb amputation in patients with diabetes;

for use in the prevention/prevention or treatment of heart failure (HF), including in particular chronic HF, including in particular systolic HF and diastolic HF; to reduce the risk of developing a significant cardiovascular complication (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients at cardiovascular risk (such as patients with coronary artery disease and/or patients with clinical signs of congestive heart failure). HF phenomena); and also for use in the prophylaxis/prevention or treatment of coronary heart disease, including angina pectoris, coronary disease and myocardial ischemia; heart failure; or diastolic dysfunction;

for use in the treatment of hypertension, including in particular difficult-to-treat/resistant hypertension;

for use in the prevention/prevention or treatment of atherosclerosis; as well as obliterating diseases of peripheral arteries, including chronic peripheral arteriopathy;

for use in the prophylaxis/prevention or treatment of digital ulcers; or for use in the prophylaxis/prevention or treatment of connective tissue diseases;

wherein aprocitentan is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

30. A further embodiment provides aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with embodiment 29, wherein aprocitentan is for use in the prophylaxis/prevention or treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3), including CKD (especially CKD stages 1-4, specifically CKD stage 3) caused/associated with hypertension, and CKD (especially CKD stages 1-4, specifically CKD stage 3) caused/associated with diabetes (diabetic kidney disease, DKD) ;

wherein such use is particularly intended for the treatment of such DKD in a patient diagnosed with type 2 diabetes mellitus, where in particular aprocitentan reduces the rate of progression of DKD, where such reduced rate of progression may be particularly expressed by a decrease in eGFR, a decrease in the incidence of end-stage kidney disease (ESKD), or a reduction in the incidence of renal death; Moreover, it is the specified patient who additionally has a history of hypertension;

for use in the prophylaxis/prevention or treatment of acute renal failure;

for use in the prophylaxis/prevention or treatment of chronic renal failure;

for use in the prophylaxis/prevention or treatment of diabetic nephropathy;

for use in the prophylaxis/prevention or treatment of glomerulonephritis;

to reduce the risk of developing a significant cardiovascular event (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially in patients with diabetes that is accompanied by at least one other cardiovascular risk factor ( such as, in particular, hypertension);

for use in the prophylaxis/prevention or treatment of diabetic foot ulcers and/or to reduce the risk of lower limb amputation in patients with diabetes;

for use in the prophylaxis/prevention or treatment of heart failure (HF), including in particular chronic HF; in particular, systolic HF or diastolic HF;

to reduce the risk of developing a significant cardiovascular complication, such as HF, myocardial infarction, stroke, or death from cardiovascular causes in patients at cardiovascular risk (such as patients with coronary artery disease and/or patients with clinical signs of congestive heart failure);

for use in the prophylaxis/prevention or treatment of diastolic dysfunction such as;

for use in the treatment of hypertension, including in particular difficult-to-treat/resistant hypertension; or for use in the prophylaxis/prevention or treatment of atherosclerosis; as well as obliterating diseases of peripheral arteries, including chronic peripheral arteriopathy;

wherein aprocitentan is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

31. A further embodiment relates to aprocitentan or its pharmaceutical

- 17 045981 acceptable salt for use in accordance with embodiment 29, wherein aprocitentan is for use in the prevention/prevention or treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3) caused by/associated with hypertension;

for use in the prevention/prevention or treatment of CKD (especially CKD stages 1-4, namely CKD stage 3) caused by/associated with diabetes (DKD);

wherein such use is particularly intended for the treatment of such DKD in a patient diagnosed with type 2 diabetes mellitus, where in particular aprocitentan reduces the rate of progression of DKD, where such reduced rate of progression may be particularly expressed by a decrease in eGFR, a decrease in the incidence of end-stage kidney disease (ESKD), or a reduction in the incidence of renal death; Moreover, it is the specified patient who additionally has a history of hypertension;

for use in the prophylaxis/prevention or treatment of chronic renal failure caused by/associated with hypertension or caused by/associated with diabetes; diabetic nephropathy; or glomerulonephritis caused/associated with hypertension;

to reduce the risk of developing a significant cardiovascular event (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially in patients with diabetes that is accompanied by at least one other cardiovascular risk factor ( such as, in particular, hypertension);

for use in the prophylaxis/prevention or treatment of diabetic foot ulcers and/or to reduce the risk of lower limb amputation in patients with diabetes; or for use in the prophylaxis/prevention or treatment of heart failure (HF), including especially chronic HF; in particular, systolic HF or diastolic HF;

wherein aprocitentan is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

32. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with embodiment 29); wherein aprocitentan is intended for use in the prevention/prevention or treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3) caused by/associated with hypertension; and/or for use in the prevention/prevention or treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3) caused by/associated with diabetes (DKD);

wherein such use is particularly intended for the treatment of such DKD in a patient diagnosed with type 2 diabetes mellitus, where in particular aprocitentan reduces the rate of progression of DKD, where such reduced rate of progression may be particularly expressed by a decrease in eGFR, a decrease in the incidence of end-stage kidney disease (ESKD), or a reduction in the incidence of renal death; Moreover, it is the specified patient who additionally has a history of hypertension; and/or to reduce the risk of developing a significant cardiovascular complication (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, especially in patients with diabetes that is accompanied by at least one other cardiovascular event a risk factor (such as, in particular, hypertension);

wherein aprocitentan is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

33. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with embodiment 29; wherein aprocitentan is intended for use in the prevention/prevention or treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3) caused by/associated with hypertension; and/or for use in the prevention/prevention or treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3) caused by/associated with diabetes (DKD);

wherein such use is specifically intended for the treatment of such DKD in a patient diagnosed with type 2 diabetes mellitus, where in particular aprocitentan reduces the rate of progression of DKD, where such reduced rate of progression may be particularly expressed by a decrease in eGFR, a decrease in the incidence of end-stage kidney disease (ESKD), or a reduction in the incidence of renal death; Moreover, it is the specified patient who additionally has a history of hypertension;

wherein aprocitentan is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

34. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with embodiment 29; wherein aprocitentan is intended for use in the prevention/prevention or treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3) caused by/associated with diabetes (DKD);

- 18 045981 wherein in the first sub-embodiment such use is intended particularly for the treatment of such DKD in a patient diagnosed with type 2 diabetes mellitus, wherein in particular aprocitentan reduces the rate of progression of DKD, where such reduced rate of progression may in particular be expressed by a decrease in eGFR, a decrease in the incidence of terminal stage of kidney disease (ESKD), or a decrease in the incidence of kidney death; Moreover, it is the specified patient who additionally has a history of hypertension;

wherein in the second sub-option, such use is specifically intended for the treatment of such DKD, including the treatment of diabetic nephropathy associated with elevated serum creatinine and/or proteinuria (especially corresponding to CKD stages 1-4 as defined in the Kidney Disease: Improving Global Outcomes clinical guidelines treatment (KDIGO) (namely for such CKD stage 3)), in patients with type 2 diabetes, especially in such patients additionally with a history of hypertension;

wherein aprocitentan is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

35. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with embodiment 29); wherein aprocitentan is intended to reduce the risk of developing a significant cardiovascular event (such as HF, myocardial infarction, stroke, or death from cardiovascular causes) in patients with diabetes, particularly in patients with diabetes that is accompanied by at least one other cardiovascular event a risk factor (such as, in particular, hypertension);

wherein aprocitentan is intended to be administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

36. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with one of embodiments 29-35; wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sotagliflozin, or tofogliflozin or a pharmaceutically acceptable salt thereof.

36i. In a sub-embodiment, the SGLT-2 inhibitor is specifically bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, sotagliflozin, or tofogliflozin (especially canagliflozin, dapagliflozin, or empagliflozin; especially canagliflozin), or pharmaceutically acceptable salt .

37. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with one of embodiments 29-35; wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin, dapagliflozin, or empagliflozin (in particular canagliflozin) or a pharmaceutically acceptable salt thereof.

38. A further embodiment relates to aprocytentan or a pharmaceutically acceptable salt thereof for use in accordance with one of embodiments 29-35; wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin or a pharmaceutically acceptable salt thereof.

39. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with one of embodiments 29-35; wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is dapagliflozin or a pharmaceutically acceptable salt thereof.

40. A further embodiment relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with one of embodiments 29-35; wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is empagliflozin or a pharmaceutically acceptable salt thereof.

41. A further embodiment provides aprocitentan or a pharmaceutically acceptable salt thereof for use in accordance with one of embodiments 29-40, wherein, mutatis mutandis, the pharmaceutically active agents are administered in a pharmaceutical unit dosage form as described in any of embodiments 5 , 6, 7, or 8), or any of their respective subembodiments 5i, 5ii, 5iii, 6i, 6ii, 6iii, 6iv, 6v, 6vi, 6vii, 8i, 8ii, 8iii, 8iv, 8v, 8vi, or 8vii.

42. A further embodiment provides aprocytentan or a pharmaceutically acceptable salt thereof for use in combination with an SGLT-2 inhibitor in accordance with one of embodiments 29-41, wherein aprocytentan is used in the crystalline form defined in any of embodiments 10-16 or 17-23) (especially as defined in embodiment 10, 11 or 12; or 17, 18 or 19, respectively).

43. A further embodiment relates to aprocitentan or its pharmaceutical

- 19 045981 an acceptable salt for use in combination with an SGLT-2 inhibitor in accordance with one of embodiments 29-41, wherein aprocytentan is used in the crystalline form defined in any of embodiments 10-16 (especially as defined in embodiment 10 , 11 or 12).

44. A further embodiment provides aprocitentan or a pharmaceutically acceptable salt thereof for use in combination with an SGLT-2 inhibitor in accordance with one of embodiments 29-41, wherein, mutatis mutandis, aprocitentan should be administered in combination with appropriate conventional background therapy, wherein said background therapy is particularly as defined in embodiment 9 or its sub-embodiments 9i, 9ii or 9iii.

45. Thus, one important aspect of the invention relates to aprocitentan, or a pharmaceutically acceptable salt thereof, for use in combination/co-therapy with an SGLT-2 inhibitor in accordance with one of embodiments 29-44. In particular, based on the dependencies of the various embodiments (or their respective sub-embodiments) as disclosed above, the following embodiments are possible and contemplated, mutatis mutandis, and are thereby specifically disclosed in customized form: 29+5, 29+6, 29 +7, 29+8, 29+9+5, 29+9+6, 29+9+7, 29+9+8, 29+12+5, 29+12+6, 29+12+7, 29 +12+8, 29+12+9+5, 29+12+9+6, 29+12+9+7, 29+12+9+8, 31+5, 31+6, 31+7, 31 +8, 31+9+5, 31+9+6, 31+9+7, 31+9+8, 31+12+5, 31+12+6, 31+12+7, 31+12+8 , 31+12+9+5, 31+12+9+6, 31+12+9+7, 31+12+9+8, 32+5, 32+6, 32+7, 32+8, 32 +9+5, 32+9+6, 32+9+7, 32+9+8, 32+12+5, 32+12+6, 32+12+7, 32+12+8, 32+12 +9+5, 32+12+9+6, 32+12+9+7, 32+12+9+8, 33+5, 33+6, 33+7, 33+8, 33+9+5 , 33+9+6, 33+9+7, 33+9+8, 33+12+5, 33+12+6, 33+12+7, 33+12+8, 33+12+9+5 , 33+12+9+6, 33+12+9+7, 33+12+9+8, 34+5, 34+6, 34+7, 34+8, 34+9+5, 34+9 +6, 34+9+7, 34+9+8, 34+12+5, 34+12+6, 34+12+7, 34+12+8, 34+12+9+5, 34+12 +9+6, 34+12+9+7, 34+12+9+8, 36+5, 36+6, 36+7, 36+9+5, 36+9+6, 36+9+7 , 36+9+8, 36+12+5, 36+12+6, 36+12+7, 36+12+8, 36+12+9+5, 36+12+9+6, 36+12 +9+7, 36+12+9+8, 36+29+5, 36+29+6, 36+29+7, 36+29+8, 36+29+9+5, 36+29+9 +6, 36+29+9+7, 36+29+9+8, 36+29+12+5, 36+29+12+6, 36+29+12+7, 36+29+12+8 , 36+29+12+9+5, 36+29+12+9+6, 36+29+12+9+7, 36+29+12+9+8, 36+31+5, 36+31 +6, 36+31+7, 36+31+8, 36+31+9+5, 36+31+9+6, 36+31+9+7, 36+31+9+8, 36+31 +12+5, 36+31+12+6, 36+31+12+7, 36+31+12+8, 36+31+12+9+5, 36+31+12+9+6, 36 +31+12+9+7, 36+31+12+9+8, 36+32+5, 36+32+6, 36+32+7, 36+32+8, 36+32+9+5 , 36+32+9+6, 36+32+9+7, 36+32+9+8, 36+32+12+5, 36+32+12+6, 36+32+12+7, 36 +32+12+8, 36+32+12+9+5, 36+32+12+9+6, 36+32+12+9+7, 36+32+12+9+8, 36+33 +5, 36+33+6, 36+33+7, 36+33+8, 36+33+9+5, 36+33+9+6, 36+33+9+7, 36+33+9 +8, 36+33+12+5, 36+33+12+6, 36+33+12+7, 36+33+12+8, 36+33+12+9+5, 36+33+12 +9+6, 36+33+12+9+7, 36+33+12+9+8, 36+34+5, 36+34+6, 36+34+7, 36+34+8, 36 +34+9+5, 36+34+9+6, 36+34+9+7, 36+34+9+8, 36+34+12+5, 36+34+12+6, 36+34 +12+7, 36+34+12+8, 36+34+12+9+5, 36+34+12+9+6, 36+34+12+9+7, 36+34+12+9 +8, 37+5, 37+6, 37+7, 37+9+5, 37+9+6, 37+9+7, 37+9+8, 37+12+5,37+12+6 ,37+12+7,37+12+8, 37+12+9+5, 37+12+9+6, 37+12+9+7, 37+12+9+8, 37+29+5 , 37+29+6, 37+29+7, 37+29+8, 37+29+9+5, 37+29+9+6, 37+29+9+7, 37+29+9+8 , 37+29+12+5, 37+29+12+6, 37+29+12+7, 37+29+12+8, 37+29+12+9+5, 37+29+12+9 +6, 37+29+12+9+7, 37+29+12+9+8, 37+31+5, 37+31+6, 37+31+7, 37+31+8, 37+31 +9+5, 37+31+9+6, 37+31+9+7, 37+31+9+8, 37+31+12+5, 37+31+12+6, 37+31+12 +7, 37+31+12+8, 37+31+12+9+5, 37+31+12+9+6, 37+31+12+9+7, 37+31+12+9+8 , 37+32+5, 37+32+6, 37+32+7, 37+32+8, 37+32+9+5, 37+32+9+6, 37+32+9+7, 37 +32+9+8, 37+32+12+5, 37+32+12+6, 37+32+12+7, 37+32+12+8, 37+32+12+9+5, 37 +32+12+9+6, 37+32+12+9+7, 37+32+12+9+8, 37+33+5, 37+33+6, 37+33+7, 37+33 +8, 37+33+9+5, 37+33+9+6, 37+33+9+7, 37+33+9+8, 37+33+12+5, 37+33+12+6 , 37+33+12+7, 37+33+12+8, 37+33+12+9+5, 37+33+12+9+6, 37+33+12+9+7, 37+33 +12+9+8, 37+34+5, 37+34+6, 37+34+7, 37+34+8, 37+34+9+5, 37+34+9+6, 37+34 +9+7, 37+34+9+8, 37+34+12+5, 37+34+12+6, 37+34+12+7, 37+34+12+8, 37+34+12 +9+5, 37+34+12+9+6, 37+34+12+9+7, 37+34+12+9+8, 38+5, 38+6, 38+8, 38+9 +5, 38+9+6, 38+9+7, 38+9+8, 38+12+5, 38+12+6, 38+12+7, 38+12+8, 38+12+9 +5, 38+12+9+6, 38+12+9+7, 38+12+9+8, 38+29+5, 38+29+6, 38+29+7, 38+29+8 , 38+29+9+5, 38+29+9+6, 38+29+9+7, 38+29+9+8, 38+29+12+5, 38+29+12+6, 38 +29+12+7, 38+29+12+8, 38+29+12+9+5, 38+29+12+9+6, 38+29+12+9+7, 38+29+12 +9+8, 38+31+5, 38+31+6, 38+31+7, 38+31+8, 38+31+9+5, 38+31+9+6, 38+31+9 +7, 38+31+9+8, 38+31+12+5, 38+31+12+6, 38+31+12+7, 38+31+12+8, 38+31+12+9 +5, 38+31+12+9+6,

38+31+12+9+7, 38+31+12+9+8, 38+32+5, 38+32+6, 38+32+7, 38+32+8, 38+32+9+ 5, 38+32+9+6, 38+32+9+7, 38+32+9+8, 38+32+12+5, 38+32+12+6, 38+32+12+7, 38+32+12+8, 38+32+12+9+5, 38+32+12+9+6,

38+32+12+9+7, 38+32+12+9+8, 38+33+5, 38+33+6, 38+33+7, 38+33+8, 38+33+9+ 5, 38+33+9+6, 38+33+9+7, 38+33+9+8, 38+33+12+5, 38+33+12+6, 38+33+12+7, 38+33+12+8, 38+33+12+9+5, 38+33+12+9+6,

38+33+12+9+7, 38+33+12+9+8, 38+34+5, 38+34+6, 38+34+7, 38+34+8, 38+34+9+ 5, 38+34+9+6, 38+34+9+7, 38+34+9+8, 38+34+12+5, 38+34+12+6, 38+34+12+7, 38+34+12+8, 38+34+12+9+5, 38+34+12+9+6,

38+34+12+9+7, 38+34+12+9+8.

In the above list, numbers refer to embodiments according to their numbering presented above, while + indicates a dependency on another embodiment. The various customized embodiments are separated by commas. In other words, 34+9+8, for example, refers to embodiment 34, depending mutatis mutandis on embodiment 9, depending on embodiment 8, i.e. implementation option

- 20 045981 leniya 34+9+8 corresponds to embodiment 34, further limited by the features defined in embodiments 9 and 8 (or their respective additional embodiments).

Accordingly, aprocitentan or a pharmaceutically acceptable salt thereof according to the present invention is intended for use in combination (or co-therapy) with these additional pharmaceutically active substances.

Combination treatment (or concurrent therapy) can be administered simultaneously, separately, or over a period of time (especially simultaneously).

The term "simultaneous" when referring to a type of administration in this application means that the corresponding type of administration consists of administering two or more active substances and/or courses of treatment at approximately the same time; it is intended that simultaneous administration will result in the subject being exposed to two or more active substances and/or treatments at the same time. When administered simultaneously, the two or more active substances may be administered in a fixed dose combination or in an equivalent non-fixed dose combination (for example, using two or more different pharmaceutical compositions that are administered by the same route of administration at approximately the same time), or in a combination of a non-fixed dose using two or more different routes of administration; wherein said administration results in substantially simultaneous exposure of the subject to two or more active substances and/or courses of treatment. When used in combination with an SGLT-2 inhibitor, aprocitentan may be administered concomitantly.

Fixed dose combination, when referring to the type of administration, in the present application means that the corresponding type of administration consists of the administration of one single pharmaceutical composition containing two or more active substances, such as in particular the pharmaceutical compositions according to one of embodiments 1-28 .

Separately, when referring to the type of administration, in this application it means that the corresponding type of administration consists of administering two or more active substances and/or treatments at different points in time; it is intended that a single administration will lead to a treatment phase (e.g. at least 1 hour, namely at least 6 hours, in particular at least 12 hours) in which the subject is exposed to two or more active substances and/or courses of treatment at the same time; but a single administration may also lead to a treatment phase where, for a specified period of time (e.g., at least 12 hours, especially at least one day), the subject is exposed to only one of two or more active substances and/or treatments . Single administration particularly refers to situations where at least one of the active substances and/or treatments is administered at a frequency substantially different from daily (eg, once or twice daily) administration (eg, when one active substance and /or a course of treatment is prescribed, for example, once or twice a day, and another is administered, for example, every other day, or once a week or at even longer intervals).

By administration over a period of time, as used herein, is meant the subsequent administration of two or more active substances and/or courses of treatment at different times. The term particularly refers to a mode of administration whereby complete administration of one of the active substances and/or courses of treatment is completed before administration of the other(s) begins. Thus, it is possible to administer one of the active substances and/or treatments for several months before administering the other active substance(s) and/or treatments.

It is understood that any embodiment relating to aprocitentan or a pharmaceutically acceptable salt thereof for use in the treatment of certain endothelin-related diseases, as specifically defined herein, wherein aprocitentan is to be administered in combination with an SGLT-2 inhibitor (especially an SGLT inhibitor -2, as defined in such embodiment) also refers to such an SGLT-2 inhibitor described herein (intended) for administration in combination with aprocytentan or a pharmaceutically acceptable salt thereof for use in the treatment of these endothelin-related diseases;

to the use of aprocytentan for the manufacture of a medicament/pharmaceutical composition containing aprocytentan or a pharmaceutically acceptable salt thereof, and the specified SGLT-2 inhibitor described herein, for use in the treatment of specified endothelin-related diseases;

to the use of aprocytentan for the manufacture of a medicinal product/pharmaceutical composition containing aprocytentan or a pharmaceutically acceptable salt thereof as an active substance, for use in the treatment of these diseases associated with endothelin; wherein said drug/pharmaceutical composition (intended) should be used in combination with an SGLT-2 inhibitor as described herein;

to the use of the SGLT-2 inhibitor described in this application for the manufacture of a medicinal product/pharmaceutical composition containing as an active substance such as in

- 21 045981 SGLT-2 inhibitor described in this application for use in the treatment of these diseases associated with endothelin; wherein said drug/pharmaceutical composition is (intended) for use in combination with aprocytentan;

to the use of a pharmaceutical composition containing aprocytentan or a pharmaceutically acceptable salt thereof and such an SGLT-2 inhibitor described herein for the treatment of these endothelin-related diseases;

for a medicinal product for the prevention or treatment of the above diseases associated with endothelin, the specified medicinal product containing aprocytentan or a pharmaceutically acceptable salt thereof; wherein said drug is intended to be administered in combination with said SGLT-2 inhibitor;

a method of treating said endothelin-related diseases, comprising administering to a subject in need thereof (preferably a human) an effective amount of aprocytentan or a pharmaceutically acceptable salt thereof, which should be administered in combination with an effective amount of said SGLT-2 inhibitor;

a method of treating said endothelin-related diseases, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising aprocytentan or a pharmaceutically acceptable salt thereof and said SGLT-2 inhibitor described herein; and a method of treating said endothelin-related diseases, comprising administering to a subject in need thereof (preferably a human) an effective amount of said SGLT-2 inhibitor described herein, which should be administered in combination with an effective amount of aprocytentan or a pharmaceutically acceptable salt thereof .

46. A further embodiment provides aprocitentan or a pharmaceutically acceptable salt thereof for use in a method of reducing fluid retention and/or reducing the risk of congestive heart failure in a subject (preferably a human) in need of an ERA, comprising administering to said subject an effective amount of aprocitentan, wherein aprocitentan should be administered in combination with an SGLT-2 inhibitor described herein, wherein the characteristics of any of embodiments 1-45 apply mutatis mutandis;

reducing interstitial fluid volume and/or normalizing blood viscosity, and/or reducing the risk of lower extremity amputation in a subject (preferably a human) requiring an SGLT-2 inhibitor (such as, in particular, a subject diagnosed with type 2 diabetes and/or DKD) comprising administering to said subject an effective amount of said SGLT-2 inhibitor described herein, wherein said SGLT-2 inhibitor is administered in combination with an effective amount of aprocitentane, wherein the characteristics of any of embodiments 1-45 apply mutatis mutandis;

protect the kidneys and/or improve renal hemodynamics, and/or reduce the risk of acute renal failure in a subject (preferably a human) requiring an SGLT-2 inhibitor (for example, in particular in a subject diagnosed with type 2 diabetes and/or DKD), comprising: yourself administering to said subject an effective amount of said SGLT-2 inhibitor described herein, wherein said SGLT-2 inhibitor is administered in combination with an effective amount of aprocitentane, wherein the characteristics of any of embodiments 1-45 apply mutatis mutandis;

lowering blood pressure in a subject (preferably a human), comprising administering to said subject an effective amount of aprocytentan, wherein aprocytentan is administered in combination with an SGLT-2 inhibitor described herein, wherein the characteristics of any of embodiments 1-45 apply mutatis mutandis ;

lowering blood sugar levels in a subject (preferably a human), comprising administering to said subject an effective amount of aprocytentan, wherein aprocytentan is administered in combination with an SGLT-2 inhibitor described herein, wherein the characteristics of any of embodiments 1-45 are used with necessary changes; and/or preventing or treating an endothelin-related disease as defined herein, comprising administering to said subject an effective amount of said SGLT-2 inhibitor described herein, wherein said SGLT-2 inhibitor is administered in combination with an effective amount of aprocitentan, where the characteristics of any of embodiments 1) - 45) apply with necessary modifications; and the beneficial effect of said SGLT-2 inhibitor on sodium reabsorption remains unaffected by aprocitentane.

47. An additional aspect of the invention relates to aprocitentan or a pharmaceutically acceptable salt thereof for use in the treatment of CKD (especially CKD stages 1-4, specifically CKD stage 3) caused by/associated with diabetes (DKD) (including diabetic nephropathy associated with elevated creatinine levels in serum and/or proteinuria (especially corresponding to CKD of such stages)); wherein in a sub-embodiment such use is intended in particular for the treatment

- 22 045981 such DKD in a patient diagnosed with type 2 diabetes mellitus (precisely in such patients additionally having a history of hypertension), where in particular aprocitentan reduces the rate of progression of DKD, and such a reduced rate of progression may be particularly expressed by a decrease in eGFR, a decrease in the incidence of end-stage disease kidney disease (ESKD), or decreased incidence of kidney death;

moreover, aprocitentan is used in monotherapy; or (preferably) in combination/co-therapy (given simultaneously, separately or over a period of time (especially simultaneously)) with an SGLT-2 inhibitor, and/or conventional background therapy (or first-line therapy) as defined above;

wherein said aprocitentan is to be administered in a suitable pharmaceutically effective unit dosage form as defined in embodiments 5) or 6) and their respective sub-embodiments 5i, 5ii, 5iii, 6i, 6ii, 6iii, 6iv, 6v, 6vi or 6vii; (in particular, in a unit dosage form suitable for oral administration of 1, 2.5, 5, 10, 12.5, 20, 25, 30, 40 or 50 mg;

(especially 10, 12.5, 20, 25, 30, 40 or 50 mg; specifically 12.5, 25 or 50 mg) of aprocitentan per day);

wherein said SGLT-2 inhibitor, if present, is particularly as defined in embodiments 7 or 8; wherein said SGLT-2 inhibitor is specifically to be administered in a suitable pharmaceutically effective unit dosage form as defined in embodiments 7 or 8 and their sub-embodiments 8i, 8ii, 8iii, 8iv, 8v, 8vi or 8vii;

wherein said conventional background therapy, if any, is particularly as defined in Embodiment 9 and its sub-embodiments; wherein said conventional background therapy, in particular, should be administered in a suitable pharmaceutically effective unit dosage form as defined in embodiment 9 and its sub-embodiments 9i, 9ii or 9iii; and where said conventional background therapy is appropriate, preferably said conventional background therapy is indicated (ie, approved by a national health authority such as the FDA or EMA) for the treatment of such DKD in accordance with this embodiment.

Specific 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 procedures.

Abbreviations.

The following abbreviations are used in the description and examples:

Ac - acetyl;

AcOH - acetic acid;

aq. - water;

DCM - dichloromethane;

DMSO - dimethyl sulfoxide;

EtOAc - ethyl acetate;

eq. - equivalent(s);

FTIR - Fourier transform infrared spectroscopy or Spectrum;

HPLC - high performance liquid chromatography;

iPrOAc - isopropyl acetate;

MeOH - methanol;

MIBK - methyl isobutyl ketone;

org. - organic;

room temperature;

THF - tetrahydrofuran;

volume. - volume(s);

w/w - weight to weight ratio;

wt. - unit of weight;

XRPD - X-ray powder diffractometry.

Examples

Method for obtaining XRPD radiographs.

All XRPD X-ray diffraction patterns for the solid forms described in this application were obtained as described below. X-ray powder diffraction patterns were obtained on a Bruker D8 Advance X-ray diffractometer equipped with a Lynxeye detector operating CuKa radiation in reflection mode (dual theta/theta combination). Typically, the X-ray tube was operated at 40 kV/40 mA. A step size of 0.02° (2θ) and a step time of 76.8 s were used over a scan range of 3–50° in 2θ. The divergence gap was set to 0.3. The powders were lightly pressed into a silicon monocrystalline sample holder to a depth of 0.5 mm, and the samples were rotated in their plane during measurement. Diffraction data are presented using combined Cu Ka1 and

- 23 045981

Κα2, without desorption of Κα2. The accuracy of the 2θ values presented in this application is in the range of ±0.1-0.2°, as is typically the case for conventionally recorded X-ray powder diffraction patterns.

Example 1. Form A.

1.1. A 3 L double jacketed reactor was loaded with 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2yl)oxy)ethoxy)-6-fluoropyrimidine (100 g, 0.213 mol, 1 eq.), sulfonamide (40.9 g, 0.425 mol, 2.0 eq.), K ₂ CO ₃ (147 g, 1.06 mol, 5 eq.) and DMSO (500 ml, 5 vol.) added water (2 ml, 0.111 mol, 0.5 eq.) . The heterogeneous mixture was heated to 70°C for approx. 3 h, after which complete conversion 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 pre-treated with

EtOAc/iPrOAc 1:1 (500 ml, 5 vol.) (filtrate discarded). The reaction mixture was filtered through this precipitate and washed with EtOAc/iPrOAc 1:1 (300 ml, 3 vol). Then 1 M aq. was added. NaOAc solution (500 ml, 0.5 mol, 2.3 eq., 5 vol.), maintaining the temperature at 25-35°C. Vodn. the phase was washed a second time with EtOAc/iPrOAc 1:1 (500 ml, 5 vol). To water phase was added 1 M H ₂ SO ₄ (200 ml, 0.2 mol, 1 eq., 2 vol.) for 1 hour at 25-30°C. Crystallization began at pH 8.5-8.0. The crude product was filtered as XRPD Form K (DMSO solvate) or a mixture of Form A and Form K. 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 40°C to give {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy) ethoxy]pyrimidin-4-yl}sulfamide as a white to off-white solid (75 g, 65% yield, XRPD Form A).

1.2. 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2yl)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 reactor were heated to 70-75°C. Monitoring by HPLC showed complete conversion after 4 hours. The contents were cooled to 20-25°C and the solids were centrifuged. Each batch was washed with EtOAc/iPrOAc 1:1 (65 kg, 3 vol). The filtrate was re-charged into the reactor and charcoal (2.4 kg, 10% w/w) and Celite® (4.8 kg, 20% w/w) were added. The contents were stirred for 1 hour at 15-20°C. and filtered through a cartridge filter back into the reactor. The filters were washed with EtOAc/iPrOAc 1:1 (43 kg, 2 vol). NaOAc (8% in water) (124 kg, 5 vol.) was added over 2 hours, maintaining the temperature below 25°C. After phase separation, aq. the layer was washed with EtOAc/iPrOAc 1:1 (109 kg, 5 vol.) at 20-25°C. Sulfuric acid (5% in water; 64 L, 32.6 mol, 0.63 eq.) was added to aq. layer at 25-30°C for 2 hours until pH 6.4 is reached. The contents were then cooled to 15-20°C over 1 hour. The solids were filtered off and washed twice with water (2x24 L, 2x1 vol). The solid was suspended twice in water (2x242 kg, 2x10 vol.) at 15-20°C for 3 hours each, filtered and dried, yielding 5-(4-bromophenyl)-6-[2-(5- bromopyrimidin-2-yloxy)ethoxy]pyrimidin-4-yl}sulfonamide as a white solid (21.6 g, 77% yield, XRPD form A).

Example 2. Form C.

0.2 ml of a stock solution of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2yloxy)ethoxy]pyrimidin-4-yl}sulfamide dissolved in THF at 50 mg/ml was distributed over 3 bottles. The solvent was evaporated for 90 min in a Combidancer from Hettich AG (Bach, Switzerland) operating at 35°C and 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. A solid {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)ethoxy]pyrimidin-4yl}sulfamide residue in form C was obtained for each of these solvents.

Example 3. Tablets AST-132577.

Tablets, each containing 50 mg of AST-132577, can be prepared using a wet granulation process. The tablet has the following composition.

- 24 045981

Tablets AST-132577 (250 mg) Substance (chemical name) mg/tablet Mass. %/tablet and ν hcIkitvh edj is1t<n d AST-132577 (amorphous, solid Form A or solid Form C, as described herein) 50.00 20.00 Microcrystalline cellulose 61.50 24.60 Lactose (200 M) 122.25 48.90 Hydroxypropyl cellulose 5.50 2.20 Croscarmellose sodium 4.50 1.80 Water qs qs Extra granular Croscarmellose sodium 5.00 2.00 Magnesium stearate 1.25 0.50 Total 250.00 100.00

qs=gocmamo4Hoe quantity.

Preferably AST-132577, Form A (as described herein) will be used to make tablets.

Example 4. Tablets AST-132577.

The tablets of Example 3 can be coated with Aquapolish® white CM or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 5. Tablets AST-132577.

Tablets, each containing 50 mg of AST-132577, can be prepared using a wet granulation process. The tablet has the following composition.

Tablets AST-132577 (250 mg) Substance (chemical name) mg/tablet Mass. %/tablet In well trigranular AST-132577 (amorphous, solid Form A or solid Form C, as described herein) 50.00 20.00 Microcrystalline cellulose 61.25 24.50 Lactose (200 M) 122.50 49.00 Hydroxypropyl cellulose 5.00 2.00 Croscarmellose sodium 5.00 2.00 Water qs qs In non-granular Croscarmellose sodium 5.00 2.00 Magnesium stearate 1.25 0.50 Total 250.00 100.00

qs=sufficient quantity.

Preferably AST-132577, Form A (as described herein) will be used to make tablets.

Example 6.

The tablets of Example 5 can be coated with Aquapolish® white CM or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 7. AST-132577 tablets.

Tablets, each containing 12.5 mg of AST-132577, can be prepared using a wet granulation process. The tablet has the following composition.

- 25 045981

Tablets AST-132577 (100 mg) Substance (chemical name) mg/tablet Mass. %/tablet Intragranular AST-132577 (amorphous, solid Form A or solid Form C, as described herein) 12.50 12.50 Microcrystalline cellulose 27.00 27.00 Lactose (200 M) 54.00 54.00 Hydroxypropyl cellulose 2.00 2.00 Croscarmellose sodium 2.00 2.00 Water qs qs In non-granular Croscarmellose sodium 2.00 2.00 Magnesium stearate 0.50 0.50 Total 100.00 100.00

qs=gocmamo4Hoe quantity.

Preferably AST-132577, Form A (as described herein) will be used to make tablets.

Example 8. Tablets AST-132577.

The tablets of Example 7 can be coated with Aquapolish® white CM or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 9. Tablets AST-132577.

Tablets, each containing 12.5 mg of AST-132577, can be prepared using a wet granulation process. The tablet has the following composition.

Tablets AST-132577 (100 mg) Substance (chemical name) mg/tablet Mass. %/tablet Intragranular AST-132577 (amorphous, solid Form A or solid Form C, as described herein) 12.50 12.50 Microcrystalline cellulose 27.50 27.50 Lactose (200 M) 53.50 53.50 Hydroxypropyl cellulose 2.20 2.20 Croscarmellose sodium 1.80 1.80 Water qs qs Extragranular Croscarmellose sodium 2.00 2.00 Magnesium stearate 0.50 0.50 Total 100.00 100.00

qs=sufficient quantity.

Preferably AST-132577, Form A (as described herein) will be used to make tablets.

Example 10. Tablets AST-132577.

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

Properties of crystalline forms.

Example 11: Storage at room temperature.

A sample of Form A crystals of the compound (as prepared in accordance with Example 1 above) was stored at 20-25 °C at 92% relative humidity for 2 months. X-ray powder diffraction performed on this sample after 2 months showed that the sample still consisted only of Form A crystals of the compound. The same result was obtained after storage for 8 weeks under the above conditions. H HPLC monitoring of the sample after storage for 8 weeks did not reveal a significant change in the area% of the peaks, i.e. didn't observe

- 26 045981 significant decay under such conditions.

Example 12. Hygroscopicity.

Form A is regarded as slightly hygroscopic according to gravimetric vapor sorption (GVS). The increase in the mass of the sample obtained in accordance with example 1 in the first cycle from 40% rel. ow. up to 80% rel. ow. corresponds to 0.4%. at 95% rel. ow. 2.2% of moisture was absorbed in a reversible manner without hysteresis during drying.

Examples of therapeutic use of AST-132577.

Therapeutic effects can be modeled in several animal models. For example, the spontaneously hypertensive rat (SHR) is the most widely used animal model for genetic hypertension. It is characterized by increased stroke damage, insulin resistance syndrome, and renal failure. Renal failure includes arteriolar damage, glomerular damage and proteinuria. Therefore, the SHR model can be used to simulate cardiovascular diseases associated with several risk factors, namely hypertension, insulin resistance and renal failure (M.A. Poteza et al., Am. J. Physiol. Heart. Circ. Physiol. (2005), 289:H813-H822; L. G. Feld et al., Kidney International (1981), 20, 606-614). The Dahl salt-sensitive rat and the DOCA salt rat are models of salt-sensitive hypertension associated with either strong mineralocorticoid receptor stimulation (DOCA salt model) or low/moderate mineralocorticoid receptor stimulation (Dahl salt model). Both models are characterized by high blood pressure, endothelial dysfunction, and ischemic damage to organs including the heart, brain, and kidneys (Y.M. Pinto et al., Cardiovascular Research, 1998, 39, 77-88).

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

The acute effects of ACT-132577 on blood pressure, particularly mean arterial pressure (hereafter MAP), and heart rate (hereinafter HR), can be assessed using telemetry in awake hypertensive, salt-sensitive male Dahl rats (hereinafter rats). Dahl-S; see Rapp, Hypertension (1982), 4, 753-763 for details on this model.

High blood pressure in Dahl-S rats is induced by providing 1% sodium chloride in drinking water. Groups of 6-7 Dahl-S rats are treated with a drug base (7.5% aqueous gelatin solution) and tested at each dose of ACT-132577 (0.3, 1, 3, 10, 30, 100 and 300 mg/kg). The effects of AST-132577 on HR and SBP were calculated for individual animals relative to the 24-hour period before administration. The results obtained for SBP (maximum decrease in SBP observed for 6 consecutive hours) are summarized in FIG. 3 (data presented as mean±standard error of mean). As a result, a dose of 10 mg/kg AST-132577 reduced SBP by 19±4 mmHg. in Dahl-S rats. Unlike SBP, HR was not affected.

Example B: Acute effects of AST-132577 in deoxycorticosterone acetate-sensitive rats.

The acute effects of ACT-132577 on blood pressure, particularly mean arterial pressure (hereafter MAP), and heart rate (hereinafter HR), can be assessed using telemetry in awake hypertensive male deoxycorticosterone acetate-sensitive rats (hereinafter rats). DOCA salts; see Gavras et al., Circ. Res. (1975), 36, 300-309 for details on this model.

In DOCA salt rats, hypertension is induced by a combination of unilateral nephrectomy, implantation of mineralocorticoid analogue DOCA pellets, and provision of 1% sodium chloride in drinking water. Groups of 6-11 rats used DOCA salts for the drug base (7.5% aqueous gelatin solution) and tested each dose of ACT-132577 (0.3, 1, 3, 10, 30, 100 and 300 mg/kg). The effects of AST-132577 on HR and SBP were calculated for individual animals relative to the 24-hour period before administration. The results obtained for SBP (maximum decrease in SBP observed for 6 consecutive hours) are summarized in FIG. 4 (data presented as mean ± standard error of the mean). As a result, a dose of 10 mg/kg AST-132577 reduced SBP by 29±6 mmHg. DOCA salts in rats. Unlike SBP, HR was not affected.

Example C: Acute effects of AST-132577 in spontaneously hypertensive rats.

The acute effects of AST-132577 on blood pressure, particularly mean arterial pressure (hereafter MAP), and heart rate (hereinafter HR) can be assessed using telemetry in awake hypertensive male rats with spontaneous hypertension (hereinafter SHR; see Atanur et al., Genome Res. (2010), 20, 791-803 for details regarding this model.

Groups of 4-6 DRGs are used for the drug base (7.5% aqueous gelatin solution) and each dose of AST-132577 is tested (1, 3, 10, 30, 100 and 300 mg/kg). The effects of AST-132577 on HR and SBP were calculated for individual animals relative to the 24 hour period before administration. The results obtained for SBP (maximum decrease in SBP observed for 6 consecutive hours) are summarized in FIG. 5 (data presented as mean ± standard error of the mean). IN

- 27 045981 As a result, a dose of 100 mg/kg AST-132577 reduced SBP by 18±4 mmHg. at KSG. Unlike SBP, HR was not affected.

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

Acute effects of AST-132577, administered orally at a single dose of 100 mg/kg, on blood pressure, in particular on mean arterial pressure (hereinafter MAP), and heart rate (hereinafter HR), with AST-132577, which is used either alone or in combination with valsartan administered orally at a single dose of 10 mg/kg, can be assessed by telemetry in awake spontaneously hypertensive male rats (hereinafter referred to as DSH; see Atanur et al. for details regarding this model). Genome Res (2010), 20, 791-803).

For this test, 6 DRGs are used per treatment group. The results obtained regarding SBP are summarized in FIG. 6, where each data point is represented as a 6-hour average (note: the expected additive effect of a two-drug combination, called the predicted additive effect, is calculated by adding the blood pressure reduction values obtained after administration of each compound separately); treatment with the drug vehicle (7.5% aqueous gelatin solution) had no effect on SBP or HR, and therefore the results are not presented in the figure. Briefly, coadministration of AST-132577 and valsartan reduced SBP beyond predicted (calculated) values, demonstrating synergy between the two molecules. Unlike SBP, HR was not affected in either treatment group.

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

Acute effects of AST-132577 administered orally at a single dose of 10 mg/kg on blood pressure, particularly mean arterial pressure (hereinafter MAP), and heart rate (hereinafter HR), with AST-132577 used alone or , or in combination with valsartan administered orally at a single dose of 30 mg/kg, can be assessed by telemetry in awake hypertensive male deoxycorticosterone acetate-sensitive rats (hereafter DOCA salt rats; see Gavras et al for details regarding this model). ., Circ. Res. (1975), 36, 300-309).

In DOCA salt rats, hypertension is induced by a combination of unilateral nephrectomy, implantation of mineralocorticoid analogue DOCA pellets, and provision of 1% sodium chloride in drinking water. For this test, 7-8 DOCA salt rats are used per treatment group. The results obtained regarding SBP are summarized in FIG. 7, where each data point is represented as a 6-hour average (note: the expected additive effect of a two-drug combination, called the predicted additive effect, is calculated by adding the blood pressure reduction values obtained after administration of each compound separately); treatment with the drug vehicle (4% aqueous gelatin solution) had no effect on SBP or HR, and therefore the results are not presented in the figure. Briefly, coadministration of AST-132577 and valsartan reduced SBP beyond predicted (calculated) values, demonstrating synergy between the two molecules. Unlike SBP, HR was not affected in either treatment group.

Example F: Acute effects of ACT-132577, alone or in combination with enalapril, in spontaneously hypertensive rats.

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

For this test, 7 DRGs are used per treatment group. The results obtained regarding SBP are summarized in FIG. 8, where each data point is represented as a 6-hour average (note: the expected additive effect of a two-drug combination, called the predicted additive effect, is calculated by adding the blood pressure reduction values obtained after administration of each compound separately); treatment with the drug base (4% aqueous gelatin solution) had no effect on SBP or HR and therefore the results obtained are not presented in the figure. Briefly, co-administration of AST-132577 and enalapril reduced SBP beyond predicted (calculated) values, demonstrating synergy between the two molecules. Unlike SBP, HR was not affected in either treatment group.

Example G Acute effects of ACT-132577, alone or in combination with amlodipine, in deoxycorticosterone acetate-sensitive rats.

Acute effects of AST-132577, administered orally at a single dose of 10 mg/kg, on blood pressure, in particular on mean arterial pressure (hereinafter MAP), and heart rate (hereinafter HR), with AST-132577, which is used either alone or in combination with amlodipine administered orally at a single dose of 1 mg/kg, can be assessed using telemetry

- 28 045981 in awake hypertensive male deoxycorticosterone acetate-sensitive rats (hereinafter DOCA salt rats; see Gavras et al., Circ. Res. (1975), 36, 300-309 for details regarding this model).

In DOCA salt rats, hypertension is induced by a combination of unilateral nephrectomy, implantation of mineralocorticoid analogue DOCA pellets, and provision of 1% sodium chloride in drinking water. For this test, 6-8 DOCA salt rats are used per treatment group. The results obtained regarding SBP are summarized in FIG. 9, each data point is presented as a 6-hour average (Note: the expected additive effect of a two-drug combination, called the predicted additive effect, is calculated by adding the blood pressure reduction values obtained after administration of each compound separately); treatment with the drug base (4% aqueous gelatin solution) had no effect on SBP or HR and therefore the results obtained are not presented in the figure. Briefly, coadministration of ACT-132577 and amlodipine reduced SBP beyond predicted (calculated) values, demonstrating synergy between the two molecules. Unlike SBP, HR was not affected in either treatment group.

Example H: Chronic effects of AST-132577 in deoxycorticosterone acetate-sensitive rats.

The chronic effects of repeated doses of 1, 10, and 100 mg/kg/day AST-132577, particularly mean arterial pressure (hereinafter MAP), and heart rate (hereinafter HR), can be assessed in awake hypertensive male rats. deoxycorticosterone acetate-sensitive (hereinafter DOCA salt rats; see Gavras et al., Circ. Res. (1975), 36, 300-309 for details on this model). In DOCA salt rats, hypertension is induced by a combination of unilateral nephrectomy, implantation of mineralocorticoid analogue DOCA pellets, and provision of 1% sodium chloride in drinking water. The results of DOCA salt rats that were treated with ACT-132577 can be compared with the results obtained for Wistar rats or DOCA salt rats that received only the drug vehicle (4% aqueous gelatin solution).

a) The results obtained regarding SBP are summarized in FIG. 10, where each data point is represented as a 24-hour average. For each of the 5 test groups, 6 rats were used (Wistar control rats (bottom line in FIG. 10), DOCA salt control rats (top line in FIG. 10), and DOCA salts receiving repeated doses of 1, 10 and 100 mg/kg/day AST-132577 (second and third row from top, respectively, in Fig. 10)). Briefly, oral administration of ACT-132577 for 4 weeks dose-dependently attenuated the DOCA salt-induced increase in SBP without changing HR.

b) The results obtained regarding renal vascular resistance are summarized in FIG. 11, on which

DOCA 0 2w represents DOCA salt rats sacrificed immediately before treatment with ACT-132577; and the symbol * represents a statistical significance factor of p < 0.05 using one-way ANOVA followed by NewmalKeuls' multiple-comparative post hoc analysis.

In summary, based on these tests, chronic oral administration of ACT-132577 DOCA salt to rats dose-dependently increased renal blood flow and decreased renal vascular resistance. ACT-132577 also tended to reduce left ventricular hypertrophy, as evidenced by a dose-dependent decrease in plasma concentrations of N-terminal pro-brain natriuretic peptide (NTproBNP).

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

The effects of ACT-132577 can be assessed in diabetic rodent models (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 effect of ACT-132577 alone or in combination on glucose tolerance, insulinemia and ischemic organ damage could be investigated. Ischemic organ damage includes: vascular function, renal function (eg, proteinuria), cardiac function and remodeling, and any other target organ affected by diabetes (eg, the eye).

Example J. Evaluation of the effect of ACT-132577 on fluid retention.

A decrease in hematocrit (Hct) or hemoglobin occurs in conjunction with an increase in plasma volume and can be used as a marker of fluid retention. A single oral dose of ACT 132577 (1-30 mg/kg) or drug vehicle (gelatin) was administered via gavage to male Wistar rats. Twenty-four hours after administration, sublingual blood was collected under isoflurane-induced anesthesia. Hematocrit is measured using a hematology analyzer. ACT-132577 had no effect on hematocrit (Hct), indicating low responsibility for fluid retention (Figure 12).

Example K: Hematocrit Measurements, Effects of SGLT-2 Inhibitor Alone or in Combination with

- 29 045981

AST-132577.

Male Wistar rats 8 to 12 weeks old (healthy or diseased (streptozotocin-induced diabetic rats) or on diuretic treatment (loop diuretic, e.g. furosemide)) were assigned to groups (n=12) stratified randomly in according to their body weight and initial hematocrit (Hct). An SGLT-2 inhibitor (eg, canagliflozin) is administered orally daily at a dose of 30 mg/kg (for canagliflozin) for one week. A combination of the same dose of SGLT-2 inhibitor and AST-132577 (1 to 30 mg/kg) or drug base (gelatin) is then administered via gastric tube, n=6/group. Sublingual blood is collected twice weekly under isoflurane-induced anesthesia (AttaneTM, MINRAD INC. Buffalo, New York). Hematocrit (Hct), hemoglobin (Hb) and red blood cell indices were measured using a hematology analyzer (Coulter AcT, Beckman Coulter, Nyon, Switzerland and Advia 2120i, Siemens Healthcare Diagnostics GmBH, Zurich, Switzerland).

Example L: Blood Pressure Measurements, Effects of SGLT-2 Inhibitor Alone or in Combination with ACT-132577.

Spontaneously hypertensive rats (SHR) are microsurgically treated with a telemetric pressure sensor implanted in the peritoneal cavity (Data Science International, Minnesota, USA) under isoflurane-induced anesthesia. Briefly, a pressure catheter is inserted into the aorta below the upstream renal artery. The abdominal cavity is closed, and the transmitter is sutured to the abdominal muscles. Blood pressure is measured continuously using the Dataquest ART Platinum data acquisition system (version 4.36). Drugs (AST-132577 or SGLT2 inhibitors) or drug carriers were administered by gavage (n=4-7 per group) alone or in combination. Systolic, mean and diastolic blood pressure and heart rate are collected at 5-minute intervals until the blood pressure waveform returns to baseline.

Results. The maximum effects on SBP are shown in Fig. 13 and 14. Because SGLT2 inhibitors take several days to have an effect on blood pressure, rats are first given either drug vehicle for 12 days (5 ml/kg/day), either canagliflozin (30 mg/kg/day) or empagliflozin ( 30 mg/kg/day), then AST-132577 (30 mg/kg/day) was coadministered for 3 additional days. Canagliflozin and empagliflozin reduced SBP by -9±1 and -13±3 mmHg. respectively. Data show that ACT-132577, when administered in addition to canagliflozin or empagliflozin, further reduced blood pressure by -14±1 and -18±3 mmHg. respectively. These blood pressure reductions were similar to those obtained when ACT-132577 was administered in addition to a drug carrier without canagliflozin or empagliflozin (-16±2 and -14±2 mmHg, respectively).

Thus, based on these results, ACT-132577 at least maintained its hemodynamic efficacy when combined with two different SGLT2 inhibitors in a model of insulin resistance-associated hypertension.

Example M. Dissection of an isolated kidney, effects of an SGLT-2 inhibitor alone or in combination with AST-132577.

Kidneys from healthy or diabetic rats are removed and placed in a perfusion system to monitor renal pressure. Male Wistar rats are euthanized, the lower abdomen is exposed, and the surrounding adipose tissue is excised around the left kidney and major vessels (aorta, vena cava, renal artery, and vein). The kidney and associated vessels are removed en bloc, and the renal vein and then the renal artery are cannulated using inox cannulas (1 mm outer diameter, 0.7 mm inner diameter, Hugo Sachs) and secured with silk suture. The cannulated kidney is then connected to a perfusion system equipped with pressure sensors (kidney perfusion machine, size 2, Hugo Sachs, Germany). The perfusion buffer is a modified Krebs-Henseleit buffer. The initial perfusion flow rate is 2 ml/min and then gradually increased to 5 ml/min. Experimental protocols are completed when perfusion pressure stabilizes at 15-25 mm Hg. Drugs (SGLT2 inhibitor, AST-132577, combination thereof) are injected into the perfusion buffer through a perfusion reservoir (volume 200 ml) and the pressure is continuously recorded.

Example N. Acute effects of EXFORGE NCT® alone and EXFORGE NCT® in combination with ACT-132577 or spironolactone in spontaneously hypertensive rats.

Acute effects 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, in Specifically, mean arterial pressure (hereinafter MAP), and heart rate (hereinafter HR) in combination with AST-132577 or spironolactone can be assessed by telemetry in awake spontaneously hypertensive male rats (hereinafter DHR; see details). regarding this model, see Atanur et al., Genome Res. (2010), 20, 791-803).

For this test, 9 DRGs are used per treatment group. To match maximum impact

-

Claims (7)

effect on blood pressure of co-administered drugs in this model, aprocitentan 100 mg/kg was administered orally on day 3 after 3 days of oral administration of Exforge HCT® mg/kg, and spironolactone 300 mg/kg was administered orally with Exforge HCT® on day 1, followed by Exforge HCT® for 2 days. The results obtained regarding SBP are shown in Fig. 15 and 16, where each data point is represented as a 6-hour average. When added in addition to Exforge HCT®, aprocytentan or spironolactone further reduced blood pressure. However, aprocitentane caused a greater reduction in blood pressure than spironolactone. Unlike SBP, HR was not affected in either treatment group. Example O: Acute effects of EXFORGE NCT® alone and EXFORGE NCT® in combination with AST-132577 or spironolactone in deoxycorticosterone acetate-sensitive rats. Acute effects of Exforge HCT® (dosage adapted to 3.2/0.2/0.5 mg/kg for valsartan/amlodipine/hydrochlorothiazide, respectively) on blood pressure, in particular mean arterial pressure (hereinafter MAP), and frequency heart rate (hereinafter HR) in combination with AST-132577 (10 mg/kg) or spironolactone (300 mg/kg), each administered orally in single doses, can be assessed by telemetry in awake hypertensive male rats sensitive to deoxycorticosterone acetate (hereinafter DOCA salt rats; see Gavras et al., Circ. Res. (1975), 36, 300-309 for details regarding this model). In DOCA salt rats, hypertension is induced by a combination of unilateral nephrectomy, implantation of mineralocorticoid analogue DOCA pellets, and provision of 1% sodium chloride in drinking water. For this test, 7-9 DOCA salt DOCA rats are used per treatment group. The results obtained regarding SBP are summarized in FIG. 17 and 18, each data point is presented as a 6-hour average. When added in addition to Exforge HCT®, 10 mg/kg aprocytentan or 300 mg/kg spironolactone further reduced blood pressure. However, aprocitentane caused a greater reduction in blood pressure than spironolactone. Unlike SBP, HR was not affected in any of the treatment groups. Example P: Effects of ACT-132577 alone or in combination with an SGLT2 inhibitor in an animal model of diabetic kidney disease. The effects of ACT-132577 alone or in combination with an SGLT2 inhibitor can be assessed in an animal model of diabetic kidney disease such as the ZDF-1 rat (Su et al., Am. J. Nephrol., 2016 Nov;44(5):339- 353), a diabetic rodent model of renal failure. In particular, the effects of ACT-132577, alone or in combination with an SGLT2 inhibitor, on blood pressure, blood glycemia and HBA1c, insulinemia and kidney damage may be investigated. Renal damage includes proteinuria, measurement of glomerular filtration rate through metabolic cells, biomarkers (eg, Kim-1), ketone bodies and creatinine in urine and plasma, terminal histological examination of the kidney (glomerular damage, vasculopathy, fibrosis). CLAIM 1. A pharmaceutical composition containing as an active substance aprocitentan or a pharmaceutically acceptable salt thereof in combination with an SGLT-2 inhibitor, which is canagliflozin, dapagliflozin or empagliflozin or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient. 2. The pharmaceutical composition according to claim 1, wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is empagliflozin or a pharmaceutically acceptable salt thereof. 3. The pharmaceutical composition according to claim 1, wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is dapagliflozin or a pharmaceutically acceptable salt thereof. 4. The pharmaceutical composition according to claim 1, wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin or a pharmaceutically acceptable salt thereof. 5. The pharmaceutical composition according to any one of claims 1 to 4, which contains from 10 to 50 mg of aprocitentan or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition is presented in the form of a pharmaceutical unit dosage form suitable for oral administration. 6. The pharmaceutical composition according to claim 4, which contains from 10 to 50 mg of aprocitentan or a pharmaceutically acceptable salt thereof; and from 50 to 400 mg of canagliflozin or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition is in the form of a pharmaceutical unit dosage form suitable for oral administration. 7. The use of aprocitentan or a pharmaceutically acceptable salt thereof for the preparation of a medicinal product, wherein said medicinal product is intended for the prevention or treatment of chronic kidney disease (CKD) caused by/associated with hypertension; treatment of diabetic kidney disease (DKD), also associated with hypertension, -