Combination of 4-pyrimidinesulfonamide derivatives and SGLT-2 inhibitors for the treatment of endothelin-related diseases

Abstract

The present invention relates to the compound aprexitentan {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide: and its use as an endothelin receptor antagonist in combination with an SGLT-2 inhibitor. The present invention further relates to a pharmaceutical composition comprising aprexitentan in combination with the SGLT-2 inhibitor. The present invention further relates to such a pharmaceutical composition comprising a crystalline form of aprexitentan.

Description

Technical Field

[0001] The present invention relates to the compound aprocitentan and its use as an endothelin receptor antagonist in combination with other active ingredients or therapeutic agents including sodium glucose cotransporter 2 (SGLT-2) inhibitors to prevent or treat certain endothelin-related diseases. The present invention further relates to pharmaceutical compositions comprising aprocitentan in combination with said other active ingredients or therapeutic agents. The present invention further relates to such pharmaceutical compositions comprising novel crystalline forms of aprocitentan; pharmaceutical compositions prepared from such crystalline forms, and to the use of such crystalline forms in combination with said other active ingredients or therapeutic agents in preventing or treating said endothelin-related diseases. Background Art

[0002] Aprecitentan {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide (hereinafter also referred to as "compound") has the formula I

[0003]

[0004] The compound of formula I, also known under the trade name and referred to as ACT-132577, is an endothelin receptor antagonist. The compound of formula I is a member of the structural family previously generally disclosed in WO 02 / 053557. In particular, despite exhibiting endothelin receptor antagonist activity, the compound of formula I exhibits a much longer half-life in vivo and a much shorter clearance rate than the corresponding alkylated derivatives. This makes the compound of formula I particularly suitable for long-acting pharmaceutical compositions, as disclosed in WO 2009 / 024906.

[0005] Due to its ability to inhibit endothelin binding, the compounds of formula I can be used to treat endothelin-related diseases, which are associated with increased vasoconstriction, proliferation or inflammation due to the presence of endothelin in many cardio-renal metabolic diseases. Examples of such endothelin-related diseases are hypertension, especially including difficult to treat / refractory hypertension; pulmonary hypertension; coronary artery disease; cardiac insufficiency; renal and myocardial ischemia; chronic kidney disease (CKD) [especially as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines 1 to 4 CKD (and especially 3 CKD)], and especially CKD caused / associated with hypertension (especially these stages) or CKD caused / associated with diabetes (diabetic kidney disease (DKD), including DKD additionally associated with hypertension); diabetes and diabetes-related diseases such as diabetic arterial disease, diabetic nephropathy, diabetic retinopathy or diabetic vasculopathy; reducing the risk of patients with diabetes developing serious cardiovascular events (such as heart failure (heart failure, HF), heart failure (heart failure, HF) due to cardiovascular etiology, heart failure (heart failure, HF), ... myocardial infarction, stroke or death), especially in patients with diabetes mellitus who have at least one other cardiovascular risk factor such as hypertension, hyperlipidemia, thrombotic phenomena; treatment and prevention of diabetic complications; (acute and chronic) renal failure; glomerulonephritis; connective tissue diseases; atherosclerosis; peripheral arterial disease, including chronic peripheral (occlusive) arterial disease; digital ulcers; diabetic foot ulcers and / or reducing the risk of lower limb amputation in patients with diabetes mellitus, or who are smokers, or who have atherosclerosis; heart failure (HF), defined as including in particular chronic HF, in particular including systolic HF / HF with reduced ejection fraction (HF with reduced ejection fraction (HFrEF) (i.e., ejection fraction < about 40%), and diastolic HF / HF with preserved ejection fraction (HFpEF) (i.e., ejection fraction > about 50%); reducing the risk of developing serious cardiovascular events (such as heart failure (HF) due to cardiovascular etiology, myocardial infarction, stroke, or death) in patients at cardiovascular risk (such as patients with coronary artery disease and / or patients with clinical symptoms of confirmed congestive heart failure); angina pectoris; and diastolic dysfunction.The compounds of formula I may also be used to treat or prevent cerebral ischemia; dementia; migraine; subarachnoid hemorrhage; Raynaud's syndrome; portal hypertension; restenosis after balloon or intravascular stent angioplasty; inflammation; gastric and duodenal ulcers; cancer; melanoma; prostate cancer; prostatic hypertrophy; erectile dysfunction; convulsions; hearing loss; amaurosis; chronic bronchitis; asthma; pulmonary fibrosis; gram negative septicemia; shock; sickle cell anemia; renal colic; glaucoma; complications following vascular or myocardial surgery or organ transplantation; complications of cyclosporine therapy or equivalent therapy that exhibits a nephrotoxic profile; pain; dyslipidemia; and other diseases currently known to be associated with endothelin.

[0006] Clinical studies have shown that endothelin receptor antagonists (ERAs) can have significant therapeutic effects in patients with hypertension and / or nephropathy, whether or not associated with diabetes. Due to the effects of endothelin 1 (ET-1) on regulating plaque formation, thrombosis, vasoconstriction and vascular hypertrophy and because it enhances other systems, especially the effects of renin vasoconstriction and the sympathetic nervous system and / or insulin signaling, it may play a role in the pathogenic mechanism of chronic diabetic arteriopathies. Therefore, ERAs may be beneficial in the treatment of peripheral arterial occlusive diseases, including diabetic arteriopathies, by having acute (peripheral vasodilation) and chronic (vasodilation, vascular structure improvement and sympathetic nerve activity regulation, antithrombotic agent, anti-inflammatory) effects. In a clinical reticular analysis of studies conducted in adults with diabetes and CKD (157 studies including 43,256 patients), ERAs were rated as the most effective agent for preventing end-stage renal disease (SCPalmer et al., Lancet (2015), 385 (9982): 2047-2056). However, the therapeutic benefit needs to be weighed against potential side effects, such as the potential risk of teratogenic activity generally associated with ERAs. A Antagonists and ET A and ET B Dual antagonists of both receptors can both cause fluid retention, a common side effect associated with many previously studied ERAs and sometimes (e.g., if not managed with diuretics) lead to an increase in major adverse cardiac events such as heart failure or death. Although the risk-benefit balance favors the use of ERAs for indications such as pulmonary hypertension in most cases (as reflected in the past by the successive market approvals, e.g., for ERAs, the dual antagonists bosentan and macitentan, and ET AAlthough ERAs are selective antagonists such as ambrisentan, there is no role for ERAs in the management of essential hypertension (Laffin et al. Seminars in Nephrology 2015, 35, 168-175), and side effects such as fluid retention may remain a problem when considering the potential use of ERAs to treat difficult / resistant hypertension (rHT), chronic kidney disease (CKD) associated or unrelated to diabetes and / or hypertension, or other hypertension-related diseases.

[0007] Developed ET A The selective endothelin receptor antagonist darusentan is used to treat resistant hypertension (rHT) (Bakris et al., Hypertension 2010, 56, 824-830, see also WO2007 / 098390). In a 14-week phase 3 trial in patients with rHT, the efficacy of lowering ambulatory blood pressure was confirmed, but a significant therapeutic effect on the primary endpoint of systolic blood pressure was not demonstrated. If the patient has treatment-resistant hypertension (systolic blood pressure above 140 mm Hg), they are eligible for participation despite treatment with three or more antihypertensive drugs from different drug classes (including diuretics) at optimized doses. A minimum dose of 25 mg of hydrochlorothiazide (or its equivalent of other thiazide diuretic drugs) per day is required. Even during the trial, diuretic therapy can be intensified at the discretion of the investigator to manage fluid retention, and the most common adverse event associated with darusentan is fluid retention / edema, which is 28% vs. 12% in each of the other groups. More patients withdrew due to adverse events with darusentan compared with placebo.

[0008] In a trial investigating the effect of avosentan on the progression of overt diabetic nephropathy in patients with type 2 diabetes, ET AThe selective ERA avosentan demonstrated a significant treatment effect, which was associated with a significant increase in discontinuations of the trial drug due to adverse events primarily related to fluid overload 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 did not detect differences in the frequency of the primary outcomes between the groups. Avosentan significantly reduced ACR. Due to excessive cardiovascular events with avosentan, the trial was terminated early after an intermediate follow-up of 4 months (maximum 16 months), and the authors concluded that "a dose of 25 to 50 mg of avosentan may be appropriate for ET A The receptors are less selective and thus cause sodium and water retention and peripheral vasodilation, with fluid shifting from the intravascular to the extravascular space." Due to inhibition of renal ET A receptors, which may be considered to have an effect on albuminuria, since mixed types of ET have been previously found A / B Receptor antagonists have a weak or no effect on proteinuria. According to the authors, it is hypothesized that blocking ET with higher doses of avosentan B The receptors are further supported by data demonstrating selective ET A Receptor blockade in humans treated with ACE inhibitors has a natriuretic effect. Therefore, the natriuretic effect / fluid retention that may have led to trial interruption in the final results is attributed to ET A and ET B Dual blockade of the receptors prevents the use of dual-acting ERAs in this clinical setting.

[0009] Other preclinical data show that ET combined with the ACE inhibitor enalapril A Selective synergistic effects of ERA on blood pressure by simultaneous blockade of ET B Receptor ablation (Goddard et al., J. Am. Soc. Nephrol. 2004, 15, 2601-2610), thus, preventing the use of dual-acting ERAs in clinical settings where ACE inhibitors may be required as background therapy.

[0010] In a review of “Endothelin antagonists for diabetic and non-diabetic chronic kidney disease” (Br J Clin Pharmacol (2012), 76:4, 573-579), DE Kohan et al. stated that “In general, the main idea is to combine ETA / B In contrast, E.T. A Receptor antagonists are preferred for the treatment of CKD". Three years later, Kohan et al. concluded, regarding studies published in Clin J Am Soc Nephrol (2015), 10:1568-1574, that "the fluid-retaining effects of ERA most likely refer to direct effects on tubular sodium transport, while the antiproteinuric effects of ERA may be related to effects on the vasculature and / or glomeruli. Ultimately, it is foreseeable that ERA inhibition of proteinuria per se will favor renal fluid excretion; however, ERA may still promote fluid retention through separate effects on tubular sodium and water reabsorption".

[0011] WO2016 / 073846 provides a comprehensive disclosure of ERAs tested for various indications including diabetic and non-diabetic CKD and rHT. WO2016 / 073846 further provides examples where fluid retention can lead to increased side effects of the ERAs bosentan, tezosentan, ambrisentan and atrasentan. WO2016 / 073846 concludes by proposing the use of predictive value of fluid retention, using ERAs, especially ET A Method for treating CKD with selective ERA atrasentan; the method comprises determining the risk of fluid retention if ERA is administered to a subject; and administering ERA to a subject if the risk is at an acceptable level. The detailed study protocol of the Phase 3 clinical study (SONAR) evaluating the effect of the experimental compound atrasentan on the progression of renal disease in patients with stage 2 to 4 chronic kidney disease and type 2 diabetes when added to the medical standard was published in Heerspink et al., Diabetes Obes. Metab. 2018, 1-8. The protocol reflects the importance of dose optimization and simultaneous control of sodium retention / fluid retention in the study design, resulting in the need for the study design to "select individuals at high risk of disease (prognosis enrichment) who also demonstrate a good response to the study treatment (predicted enrichment)". However, on December 01, 2017, AbbVie announced its strategic decision to close the SONAR study. The press release states "Ongoing monitoring of renal events observed in the study has disclosed significantly fewer endpoints than expected at this time, which will likely impact the ability to test the hypotheses of the SONAR study. Therefore, AbbVie has determined that it cannot justify continued patient participation in the study. The decision to close the SONAR study early is not related to any safety issues."

[0012] Contrary to the conclusions drawn from the avosentan trial, preclinical and clinical data suggest that ET AThe selective antagonists sitaxentan and ambrisentan posed a greater risk of fluid retention than the dual ERAs bosentan and macitentan (Vercauteren et al., JPET 2017, 361, 322-333). The authors state that their findings "indicate that in rats, A Unblocked ET in the presence of receptor antagonists B Receptor stimulation, not ET A Functional antagonism of the receptors themselves may be disadvantageous, and blockade of both receptors is less likely to lead to water retention than blockade of a single receptor", and goes on to speculate that "plasma volume expansion combined with increased vascular permeability may explain the increase in ET A selective antagonists". The authors conclude that "using ET A Several clinical studies of selective antagonists have resulted in increased mortality associated with fluid retention problems, which has not been observed with dual ERA. However, in conditions of pre-existing fluid retention or increased arginine vasopressin (AVP), such as chronic heart failure or chronic renal failure, dual ERA has caused significant fluid retention."

[0013] It has been demonstrated in a phase 2 clinical trial that aprexitentan, an ERA that enables effective dual blockade of endothelin receptors, can enable effective control of blood pressure in subjects with essential hypertension (aprexitentan was administered as monotherapy, i.e. without background antihypertensive therapy) (Actelion Pharmaceuticals Ltd, press release of May 22, 2017). Even though some indications of potential fluid retention were observed (e.g., weight gain at higher doses, dose-related decrease in hemoglobin concentration, peripheral edema in four cases at higher doses), the overall frequency of adverse events was similar to that observed in the placebo group. Therefore, unlike the approach of WO2016 / 073846, for aprexitentan, no risk assessment and / or dose reduction may be required to reduce side effects regarding fluid retention when used for the treatment of hypertension-related diseases, especially resistant hypertension. Therefore, in contrast to the main ETs tested so far in resistant hypertension or chronic kidney disease in diabetic and non-diabetic patients, the A Aprecitentan may have a different pharmacological profile compared to selective antagonists.

[0014] In addition, it has been found in a rat model of hypertension that aprexitentan 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 channel blocker (CCB) amlodipine, compared to the effects of each active ingredient alone. ARBs, ACE inhibitors, and CCBs are standard treatments required by guidelines and are generally prescribed to hypertensive patients alone or in combination, usually in combination with a diuretic, especially a diuretic of the thiazide class (such as hydrochlorothiazide).

[0015] SGLT-2 inhibitors prevent glucose from being reabsorbed in the kidney, increase glucose excretion and lower blood glucose concentration. In addition to this well-characterized mode of action, SGLT-2 inhibitors also lower blood pressure, reduce vascular stiffness, improve endothelial function and have anti-inflammatory and anti-fibrotic properties similar to those of ERA (HJ Heerspink et al., Circulation (2016), 134 (10): 752-772). This unique mechanism of action has led to the development and market approval of several SGLT-2 inhibitors, including canagliflozin, dapagliflozin and empagliflozin, all of which are indicated to improve glycemic control in adults with type 2 diabetes, and empagliflozin is additionally indicated to reduce the risk of cardiovascular death in these patients with confirmed cardiovascular disease. Sotagliflozin is a dual SGLT-1 and SGLT-2 inhibitor that has been reported to be used in clinical trials for type 1 diabetes.

[0016] WO2010 / 138535 claims a method for treating type 2 diabetes in a mammalian patient who has been previously treated with one or more oral antidiabetic agents and / or one or more injectable antidiabetic agents, and who has failed previous treatment with such agents, the method comprising administering to the patient in need of treatment a therapeutically effective amount of an SGLT2 inhibitor, particularly dapagliflozin. Among a variety of other speculative combinations, WO2010 / 138535 further discloses this method of using an SGLT2 inhibitor such as dapagliflozin in combination with one or more antihypertensive agents, such as beta-adrenergic blockers, calcium channel blockers (L-type and / or T-type; for example, diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, benzflumethiazide, methylchlorothiazide, trichlorothiazide, polythiazide, benzthiazide, ethacrynic acid tricurenafine, thiazide ... acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, diazepam, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine, dapoxetine No data are provided to support the provision of combinations with antihypertensive agents compared to other proposed combinations, nor are there data to support the provision of any specific combination therapy among various antihypertensive agents.Similarly, Kissei Pharmaceuticals Ltd discloses in several patent applications that SGLT-1 and / or SGLT-2 inhibitors are useful for treating hyperglycemia, such as diabetes, diabetic complications or obesity (see, for example, US Pat. No. 7,732,596, US Pat. No. 5,832,779, filed on Oct. 29, 2009). 7,989,424), which are disclosed as being suitable for use in combination with an endothelin receptor antagonist, such as L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355, PD-180988, sitaxentan sodium, BMS-193884, darusentan, TBC-3711, bosentan, tezosentan sodium, J-104132, YM-598, S-0139, SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan, BMS-207940, or their analogs, among a variety of other speculative combinations.

[0017] Diabetes often exists with heart failure (HF) and can promote its development. SGLT-2 inhibitors such as empagliflozin can be suitable for treating chronic HF, including HFpEF, when treatment options are very limited. The EMPA-REGOUTCOME trial (empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes) randomly divided patients with type II diabetes with high cardiovascular risk into empagliflozin or medical standards. The results showed that cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for HF and death due to any cause were improved. Patients diagnosed with HF were observed at baseline, and post-analysis studies showed that cardiovascular death, HF hospitalization and hospitalization for all causes were significantly reduced (DHKim et al., "Pharmacologic Management for Heart Failure and Emerging Therapies" CurrCardiol.Rep (2017) 19: 94). The mode of action of SGLT-2 allows simultaneous inhibition of glucose and sodium absorption in the proximal tubules of the nephron, believing that the reset of tubular feedback causes the phenomenon of glomerular hyperfiltration. It is believed that the efficacy of SGLT-2 inhibitors decreases with decreasing plasma glucose levels or decreased glomerular filtration rate (GFR), and therefore, SGLT-2 inhibitors have an inherently low risk of developing hypoglycemia. Therefore, the properties of SGLT-2 inhibitors may open up a way to treat HF, including HFpEF, in non-diabetic patients (P. Martens et al., "Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond", Curr Treat Options Cardio Med (2017) 19: 23).

[0018] The side effects associated with the pharmacological effects of SGLT-2 inhibitors are volume depletion / intravascular volume contraction, which may lead to dehydration, hypovolemia, orthostatic hypotension or hypotension. Therefore, SGLT-2 inhibitors generally induce an increase in hematocrit (Hct) (a marker of hyperemia) and an increase in blood viscosity, which is the presumed cause of vascular damage in the case of peripheral vascular disease. In two large trials (CANVAS and CANVAS-R) evaluating the SGLT-2 inhibitor canagliflozin in patients with type 2 diabetes, an increased risk of lower limb amputation was observed. The European Medicines Agency (European Medicines Agency) evaluated these findings (EMA / PRAC / 637349 / 2016), given the potential class effects associated with reduced volume and impaired tissue perfusion in the lower limbs, so patients with already impaired perfusion may suffer from conditions that lead to amputation. EMA concluded that the class effect can neither be confirmed nor refuted.

[0019] In addition, data from large clinical trials suggest that SGLT2 inhibitors can induce acute renal injury and impairment of renal function, especially in patients who are susceptible to acute renal injury given hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant drug therapy (diuretics, ACE inhibitors, ARBs, and NSAIDs). The pharmacological effects of SGLT-2 inhibitors on the kidney include increases in serum creatinine and decreases in eGFR.

[0020] Thus, apremiflozin, an ERA that produces an effective dual blockade of endothelin receptors may be particularly suitable for the treatment of endothelin-related diseases, while being indicated in combination with an SGLT-2 inhibitor, such as atigliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, henagliflozin, ipragliflozin, luseogliflozin, remogliflozin, sogliflozin, tianagliflozin or tofogliflozin (particularly canagliflozin, dapagliflozin or empagliflozin; particularly canagliflozin). The use of the dual ERA apremitentan in combination with an SGLT-2 inhibitor may result in particularly beneficial complementary pharmacological effects of both modes of action in view of complementary, additive or even synergistic therapeutic effects and complementary inhibition of individual side effects of the active ingredients of the combination therapy.

[0021] When combining ERAs with SGLT-2 inhibitors, the diuretic effect of the SGLT-2 inhibitor and its potential pharmacological effect in reducing the risk of heart failure may be suitable for reducing the most prominent side effects generally associated with ERAs, such as fluid retention and the potentially associated increased risk of congestive heart failure. In particular, aprexitentan, which has shown a particularly mild safety profile in Phase II studies in patients with (essential) hypertension, may be suitable for this combination. The combination treatment may induce the pharmacological effects on the disclosed endothelin-related diseases while maintaining a mild side effect profile even at the optimal effective dose of aprexitentan, potentially even at increased doses of aprexitentan, when compared to the maximum tolerated dose of aprexitentan alone or aprexitentan in combination with, for example, a standard diuretic (such as a thiazide diuretic, including hydrochlorothiazide) and / or an aldosterone antagonist. When aprexitentan is used in combination with an SGLT-2 inhibitor, for example, the dose increase of aprexitentan that can be obtained due to the reduced side effects can allow for an enhanced effect on diseases caused by adverse effects on the endothelin paracrine system that is widely distributed in the organism. The combination therapy can improve the benefit / risk ratio and, for example, does not require the risk assessment method of WO2016 / 073846 and / or dose reduction to reduce side effects (e.g., regarding fluid retention).

[0022] In addition to the potential effects of the SGLT-2 inhibitors mentioned above on the pharmacological effects and / or side effect profiles of the ERA aprexitentan, the ERA aprexitentan may then have a complementary effect on the pharmacological effects and / or side effect profiles of the respective SGLT-2 inhibitors. It has been described that ERA reduces the hematocrit (Hct) by hemodilution. Therefore, when used in combination with an SGLT-2 inhibitor, aprexitentan may antagonize the most prominent side effects generally associated with SGLT-2 inhibitors, such as hyperemia due to volume depletion, which may lead to an increased risk of lower extremity / limb amputation. In addition, it has been described that ERA provides renal protection and improves renal hemodynamics. Therefore, when used in combination with an SGLT-2 inhibitor, aprexitentan may reduce the risk of acute renal failure, which is one of the reported risks of currently approved SGLT-2 inhibitors. In addition, ERA is expected to lower blood pressure by preventing the vasoconstrictive effect of ET-1 produced by its binding to ET receptors, and therefore, when used in combination with SGLT-2 inhibitors, apremilast may promote its significant pharmacological effects on blood pressure reduction and its consequences (vascular remodeling, end-organ damage, cardiovascular risk reduction caused by / associated with diabetes and / or hypertension). In addition, ERA has been described to improve blood glucose levels by various mechanisms (increased blood flow, improved insulin signaling). Therefore, when used in combination with SGLT-2 inhibitors, apremilast may have an additive or even synergistic effect on blood glucose reduction. In addition, volume consumption may be associated with increased blood viscosity. Sloop et al. (Ther Adv Cardiovasc Dis (2015), 9(1) 19-25) stated that "the pathogenesis of chronic vascular disease (including atherosclerosis, hypertension, and metabolic syndrome) is not fully understood by the mainstream because the role of blood viscosity has been neglected." and "in theory, because flow rate is inversely proportional to viscosity, reducing blood viscosity should improve muscle perfusion and increase glucose utilization, lowering blood glucose levels." Therefore, by complementary normalization of the volume depletion effects typically associated with SGLT-2 inhibitors and the fluid retention effects typically associated with ERAs, the combination of apremilast and an SGLT-2 inhibitor may produce the beneficial pharmacological effects mentioned above, and may produce other beneficial pharmacological effects related to blood viscosity. Finally, in combination with selective ET A Aprecitentan, which has the pharmacological effects of dual ERAs, may be particularly suitable for this combination therapy because it may have low counteracting activity against the beneficial effects of SGLT-2 inhibitors on sodium reabsorption, which is associated with the primary pharmacological effect of SGLT-2 on glucose reabsorption, when compared to SGLT-2 receptor antagonists. Summary of the invention

[0023] It has further been discovered that certain crystalline forms of aprexitentan suitable for making pharmaceutical compositions may be found under certain conditions. Such crystalline forms of aprexitentan may have advantageous properties in view of the potential use of aprexitentan as an active pharmaceutical ingredient. Such advantages may include better flow properties; less hygroscopicity; better reproducibility in manufacturing (e.g., better filtration parameters, better formation reproducibility, and / or better sedimentation); and / or defined morphology. Such crystalline forms of aprexitentan may be particularly useful in methods of making certain pharmaceutical compositions. It has also been discovered that aprexitentan or a pharmaceutically acceptable salt thereof is particularly useful for treating certain conditions, particularly when used in combination with other active ingredients or therapeutic agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The X-ray powder diffraction pattern of the compound in crystalline Form A as obtained from Example 1 is shown. The X-ray diffraction pattern shows peaks having the following percentages (relative peak intensities are given in parentheses) of relative intensities at the indicated refractive angles 2θ (peaks selected from the range 3-33° 2θ with relative intensities greater than 10% are reported) compared to the most intense peak in the pattern: 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° (5 4%), 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%).

[0025] Figure 2The X-ray powder diffraction pattern of the compound in crystalline Form C as obtained from Example 2 is shown. The X-ray diffraction pattern shows peaks having the following percentages (relative peak intensities are given in parentheses) of relative intensities at the indicated refractive angles 2θ (peaks selected from the range 3-33° 2θ with relative intensities greater than 10% are reported) compared to the most intense peak in the pattern: 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%)

[0026] It should be understood that the crystalline forms disclosed herein include compounds in the form of a free base (i.e., not in the form of a salt). In addition, the crystalline forms may include non-coordinating and / or coordinating solvents. Coordinating solvents are used herein as a term for crystalline solvates. Similarly, non-coordinating solvents are used herein as a term for physically adsorbed or physically coated solvents (according to the polymorphic phenomenon definition in Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: UJ Griesser: The Importance of Solvates). Crystalline forms A and C are anhydrous / non-solvate forms.

[0027] Figure 3 The acute effect of ACT-132577 on mean arterial blood pressure ("MAP") in conscious male hypertensive Dahl salt-sensitive rats is presented.

[0028] Figure 4 To demonstrate the acute effect of ACT-132577 on MAP in conscious male hypertensive deoxycorticosterone acetate rats.

[0029] Figure 5 To demonstrate the acute effect of ACT-132577 on MAP in conscious male spontaneously hypertensive rats.

[0030] Figure 6 To demonstrate the acute effects of ACT-132577 alone or in combination with valsartan on MAP in conscious male spontaneously hypertensive rats.

[0031] Figure 7 To demonstrate the acute effects of ACT-132577 alone or in combination with valsartan on MAP in conscious male hypertensive deoxycorticosterone acetate rats.

[0032] Figure 8 To demonstrate the acute effects of ACT-132577 alone or in combination with enalapril on MAP in conscious male spontaneously hypertensive rats.

[0033] Fig. 9 To demonstrate the acute effects of ACT-132577 alone or in combination with amlodipine on MAP in conscious male hypertensive deoxycorticosterone acetate rats.

[0034] Fig.10 The effect of chronic oral administration of ACT-132577 on MAP in conscious male hypertensive deoxycorticosterone acetate rats is presented.

[0035] Fig.11 To demonstrate the effect of chronic oral administration of ACT-132577 on renal vascular resistance in conscious male hypertensive deoxycorticosterone acetate rats.

[0036] Fig.12 The acute dose-response effect of aprecitentan (1 mg / kg, 3 mg / kg, 10 mg / kg, 30 mg / kg) on ​​hematocrit (Hct) 24 hours after a single oral administration to Wistar rats is shown.

[0037] Fig.13 Acute effects of ACT-132577 alone or in combination with canagliflozin on the maximal effect on MAP in conscious male spontaneously hypertensive rats are presented.

[0038] Fig.14 Acute effects of ACT-132577 alone or in combination with empagliflozin on the maximal effect on MAP in conscious male spontaneously hypertensive rats are presented.

[0039] Fig.15 Show EXFORGE EXFORGE alone and in combination with ACT-132577 Acute effects in male spontaneously hypertensive rats.

[0040] Fig.16 Show EXFORGE and EXFORGE combined with spironolactone Acute effects in male spontaneously hypertensive rats.

[0041] Fig.17 Show EXFORGE EXFORGE alone and in combination with ACT-132577 Acute effects of deoxycorticosterone acetate in male hypertensive rats.

[0042] Fig.18 Show EXFORGE EXFORGE alone and in combination with spironolactone Acute effects of deoxycorticosterone acetate in male hypertensive rats.

[0043] [Implementation Method]

[0044] 1) The first embodiment relates to a pharmaceutical composition comprising a combination of apremilast or a pharmaceutically acceptable salt thereof and an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as active ingredients, and at least one pharmaceutically acceptable excipient.

[0045] 2) Another embodiment relates to the pharmaceutical composition of embodiment 1), wherein the SGLT-2 inhibitor is apagliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliflozin, rupagliflozin, repagliflozin, sopagliflozin or togliflozin; or a pharmaceutically acceptable salt thereof.

[0046] 2(i) In one sub-embodiment, the SGLT-2 inhibitor is particularly bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliptin, rupagliflozin, sogliflozin or togliflozin (especially canagliflozin, dapagliflozin or empagliflozin; especially canagliflozin); or a pharmaceutically acceptable salt thereof.

[0047] 3) Another embodiment relates to the pharmaceutical composition of 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.

[0048] 4) Another embodiment relates to the pharmaceutical composition of embodiment 1), wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin or a pharmaceutically acceptable salt thereof.

[0049] 5) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 4), wherein the aprexitentan or a pharmaceutically acceptable salt thereof contained in the pharmaceutical unit dosage form is suitable for oral administration of 1 to 100 mg, preferably 2.5 to 100 mg (especially 10 to 50 mg) per day; especially 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg; especially 12.5 mg, 25 mg or 50 mg of aprexitentan;

[0050] 5(i) wherein in a sub-embodiment, the dose of aprexitentan is the dose at the expected tolerated effective dose of aprexitentan prescribed as monotherapy (e.g. for the treatment of hypertension) (particularly the dose will be 10 to 25 mg, particularly 10 mg, 12.5 mg or 25 mg),

[0051] 5(ii) wherein in another sub-embodiment, the dose of aprexitentan is a dose that would be expected to be at or above the tolerated effective dose of aprexitentan when given as monotherapy (e.g. for the treatment of hypertension) (particularly the dose would be 40 to 100 mg, especially 50 mg, of aprexitentan per day);

[0052] 5(iii) wherein in another sub-embodiment, the dose of apremitentan is a dose that would be expected to be at or below the tolerated effective dose of apremitentan when given as monotherapy (e.g. for the treatment of hypertension) (particularly the dose would be 1 mg, 2.5 mg or 5 mg of apremitentan per day).

[0053] 6) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 4), wherein aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg per day; (especially 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg; especially 12.5 mg, 25 mg or 50 mg) of aprexitentan;

[0054] 6(i) wherein in one sub-embodiment, aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 12.5 mg of aprexitentan per day (i.e., a dose that may be expected to be a tolerated effective dose of aprexitentan when given as monotherapy (e.g., for the treatment of hypertension);

[0055] 6(ii) wherein in another subembodiment, aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 25 mg of aprexitentan per day (i.e., a dose that would be expected to be a tolerated effective dose of aprexitentan when given as monotherapy (e.g., for the treatment of hypertension);

[0056] 6(iii) wherein in another subembodiment, aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg of aprexitentan per day (i.e., a dose that may be expected to be at or above the tolerated effective dose of aprexitentan when given as monotherapy (e.g., for the treatment of hypertension);

[0057] 6(iv) wherein in another subembodiment, aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 mg of aprexitentan per day (i.e., a dose that may be expected to be a tolerated effective dose of aprexitentan when given as monotherapy (e.g., for the treatment of hypertension);

[0058] 6(v) wherein in another subembodiment, aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 mg of aprexitentan per day (i.e., a dose that would be expected to be at or below the tolerated effective dose of aprexitentan when given as monotherapy (e.g., for the treatment of hypertension);

[0059] 6(vi) wherein in another subembodiment, aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 2.5 mg of aprexitentan per day (i.e., a dose that would be expected to be a tolerated effective dose of aprexitentan when given as monotherapy (e.g., for the treatment of hypertension);

[0060] 6(vii) wherein in another sub-embodiment, aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 mg of aprexitentan per day (i.e., a dose that may be expected to be lower than the tolerated effective dose of aprexitentan when given as monotherapy (e.g., for the treatment of hypertension)).

[0061] 7) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 6), wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of the SGLT-2 inhibitor, wherein

[0062] If bexagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 50 mg (especially 20 mg) of bexagliflozin per day;

[0063] If canagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 to 400 mg (especially 50 mg, 100 mg, 150 mg or 300 mg; in particular 100 mg or 300 mg; in particular 100 mg) of canagliflozin per day;

[0064] If dapagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 to 20 mg (especially 5 mg or 10 mg) of dapagliflozin per day;

[0065] If empagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 50 mg (especially 10 mg or 25 mg) of empagliflozin per day;

[0066] If ertogliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 2.5 to 50 mg (especially 5 mg or 15 mg) of ertogliflozin per day;

[0067] If hengagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 100 mg (especially 25 mg) of hengagliflozin per day;

[0068] If ipagliptin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 to 100 mg (especially 25 mg or 50 mg) of ipagliptin per day;

[0069] If rupagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 to 10 mg (especially 2.5 mg or 5 mg) of rupagliflozin per day;

[0070] If solafloxacin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 to 500 mg (especially 75 mg, 200 mg or 400 mg) of solafloxacin per day,

[0071] If topagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 to 50 mg (especially 20 mg) of topagliflozin per day.

[0072] 8) Another embodiment relates to the pharmaceutical composition of embodiment 4), wherein

[0073] aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 to 100 mg, preferably 2.5 to 100 mg (especially 10 to 50 mg); especially 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg; especially 12.5 mg, 25 mg or 50 mg of aprexitentan per day; and

[0074] Canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 to 400 mg (especially 50 mg, 100 mg, 150 mg or 300 mg; particularly 100 mg or 300 mg; especially 100 mg) of canagliflozin per day;

[0075] 8(i) wherein in one sub-embodiment, apremilast or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 12.5 mg of apremilast per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg, 100 mg, 150 mg or 300 mg (particularly 100 mg or 300 mg, especially 100 mg) of canagliflozin per day;

[0076] 8(ii) wherein in another sub-embodiment, apremilast or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 25 mg of apremilast per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg, 100 mg, 150 mg or 300 mg (particularly 100 mg or 300 mg, especially 100 mg) of canagliflozin per day;

[0077] 8(iii) wherein in another sub-embodiment, apremilast or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 mg of apremilast per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg, 100 mg, 150 mg or 300 mg (particularly 100 mg or 300 mg, especially 100 mg) of canagliflozin per day;

[0078] 8(iv) wherein in another sub-embodiment, apremilast or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 mg of apremilast per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg, 100 mg, 150 mg or 300 mg (particularly 100 mg or 300 mg, especially 100 mg) of canagliflozin per day;

[0079] 8(v) wherein in another sub-embodiment, apremilast or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 2.5 mg of apremilast per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg, 100 mg, 150 mg or 300 mg (particularly 100 mg or 300 mg, especially 100 mg) of canagliflozin per day;

[0080] 8(vi) wherein in another sub-embodiment, apremilast or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 mg of apremilast per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg, 100 mg, 150 mg or 300 mg (particularly 100 mg or 300 mg, especially 100 mg) of canagliflozin per day;

[0081] 8(vii) wherein in another sub-embodiment, apremilast or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg of apremilast per day; and canagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 50 mg, 100 mg, 150 mg or 300 mg (particularly 100 mg or 300 mg, especially 100 mg) of canagliflozin per day;

[0082] Likewise, when combined with dapagliflozin or empagliflozin, comprising apremilast or a pharmaceutically acceptable salt thereof as described in Example 8) and sub-embodiments 8(i) to 8(vii) above; and

[0083] If dapagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 to 20 mg (especially 5 mg or 10 mg) of dapagliflozin per day; and

[0084] If empagliflozin or a pharmaceutically acceptable salt thereof is present, it is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 50 mg (especially 10 mg or 25 mg) of empagliflozin per day.

[0085] 9) A second aspect of the present invention relates to a pharmaceutical composition as described in any one of embodiments 1) to 8); wherein the pharmaceutical composition is (intended) to be administered in the form of a combination / synergistic therapy with a conventional background therapy (or first-line therapy) suitable for preventing or treating: hypertension, including particularly difficult-to-treat / resistant hypertension; chronic kidney disease (CKD) [particularly, CKD stages 1 to 4 (and particularly stage 3 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria], and CKD particularly caused / associated with hypertension and / or CKD caused / associated with diabetes (diabetic kidney disease (DKD)); or diabetes.

[0086] 9(i) In a first sub-embodiment, the conventional background therapy may specifically include:

[0087] ACE inhibitors (especially enalapril and ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril) or pharmaceutically acceptable salts thereof; and / or

[0088] angiotensin receptor blockers (especially valsartan and losartan, candesartan, irbesartan, telmisartan, eprosartan, olmesartan, azilsartan, fimasartan) or pharmaceutically acceptable salts thereof; and / or

[0089] calcium channel blockers (especially amlodipine and aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine) or pharmaceutically acceptable salts thereof; and / or

[0090] Metformin; and / or

[0091] Insulin; and / or

[0092] Sulfonylurea (especially glibenclamide) or a pharmaceutically acceptable salt thereof; and / or

[0093] a DPP-4 inhibitor (particularly sitagliptin, vildagliptin, saxagliptin or linagliptin) or a pharmaceutically acceptable salt thereof; and / or

[0094] GLP-1 receptor agonists (especially exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, taspoglutide, semaglutide); and / or

[0095] Thiazolidinedione or a pharmaceutically acceptable salt thereof.

[0096] 9(ii) In a second sub-embodiment, conventional background therapy is preferred, which is a first-line therapy suitable for the prevention or treatment of hypertension and / or diabetes, in particular such as ACE inhibitors or angiotensin receptor blockers as treatment of hypertension; and / or metformin and / or DPP-4 inhibitors as treatment of diabetes.

[0097] 9(iii) In a third sub-embodiment, the background therapy as in any one of Embodiments 9), 9(i) or 9(ii) is administered at a dose corresponding to the tolerated effective dose of the corresponding active ingredient, for example, when given as a monotherapy, or in diabetic patients, when given in combination with a corresponding SGLT-2 inhibitor. In particular, if valsartan or a pharmaceutically acceptable salt thereof is present, it is administered in a dosage form suitable for oral administration of 160 mg or 320 mg of valsartan per day; if losartan or a pharmaceutically acceptable salt thereof is present, it is administered in a dosage form suitable for oral administration of 50 mg or 100 mg of losartan per day; if irbesartan or a pharmaceutically acceptable salt thereof is present, it is administered in a dosage form suitable for oral administration of 75 mg, 150 mg or 300 mg of irbesartan per day; if amlodipine or a pharmaceutically acceptable salt thereof is present, it is administered in a dosage form suitable for oral administration of 5 mg or 10 mg of amlodipine per day; if enalapril or a pharmaceutically acceptable salt thereof is present, it is administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg of enalapril per day; if lisinopril or a pharmaceutically acceptable salt thereof is present, it is administered in a dosage form suitable for oral administration of 2.5 mg to 40 mg of lisinopril per day. If ramipril or a pharmaceutically acceptable salt thereof is present, it is administered in a dosage form suitable for oral administration of 2.5 to 20 mg of ramipril per day; if metformin is present, it is administered in a dosage form suitable for oral administration of 500 to 2000 mg of metformin per day; if glibenclamide is present, it is administered in a dosage form suitable for oral administration of 1.25 to 5 mg of glibenclamide per day; if sitagliptin is present, it is administered in a dosage form suitable for oral administration of 25 to 100 mg of sitagliptin per day; if vildagliptin is present, it is administered in a dosage form suitable for oral administration of 50 mg of vildagliptin twice a day; if saxagliptin is present, it is administered in a dosage form suitable for oral administration of 2.5 or 5 mg of saxagliptin per day; if linagliptin is present, it is administered in a dosage form suitable for oral administration of 5 mg of linagliptin twice a day.

[0098] "Angiotensin receptor blocker" or "ARB" in particular in the present application means valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan or a pharmaceutically acceptable salt of one of these. Preferably the ARB is valsartan or a pharmaceutically acceptable salt thereof.

[0099] "Calcium channel blocker" or "CCB" means, in particular in the present application, amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, isradipine, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, verapamil or diltiazem or a pharmaceutically acceptable salt of one of these. Preferably, the CCB is amlodipine or a pharmaceutically acceptable salt thereof.

[0100] "Angiotensin converting enzyme inhibitor" or "ACE inhibitor" in particular in the present application means captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril or a pharmaceutically acceptable salt of one of these. Preferably, the ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

[0101] The term "DPP-4 inhibitor" or "DPP-IV inhibitor" refers to inhibitors of dipeptidyl peptidase 4, such as sitagliptin, vildagliptin, saxagliptin and linagliptin, as well as gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin and dutogliptin, among others.

[0102] The term "GLP-1 receptor agonist" refers to an agonist of the glucagon-like peptide-1 receptor, such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, tasiglutide, semaglutide, among others.

[0103] The term "sulfonylurea" refers in particular to glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glyclopyramide or glimepiride.

[0104] The term "thiazolidinedione", abbreviated to TZD, also known as glitazone, refers to agonists of PPARγ (peroxisome proliferator-activated receptor γ) and in particular to pioglitazone, rosiglitazone or lobeglitazone.

[0105] Another conventional background therapy, in particular for the treatment of patients with a history of hypertension, may be a diuretic. In addition to the conventional background therapy for hypertension mentioned above, the diuretic may also be specified in particular. The term "diuretic" in the present application refers to: loop diuretics, including furosemide, bumetanide, ethacrynic acid, torsemide; potassium-sparing diuretics, including aldosterone antagonists, such as spironolactone, eplerenone or finerenone or aldosterone synthase inhibitors; carbonic anhydrase inhibitors, including acetazolamide and methazolamide; and in particular to diuretics of the thiazide class (thiazide diuretics), in particular such as chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide or metolazone. Preferably, the thiazide diuretic is chlorthalidone or hydrochlorothiazide. For the avoidance of doubt, SGLT-2 inhibitors, even if having a diuretic pharmacological effect, are not encompassed by the term "diuretic" as used herein.

[0106] 10) A third aspect of the present invention relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), comprising aprexitentan in crystalline form A, characterized in that there are peaks at the following refraction angles 2θ in the X-ray powder diffraction pattern: 17.8°, 20.0° and 23.5°; wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation instead of Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ+ / -0.2°.

[0107] 11) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), comprising apremitentan in crystalline form A, characterized in that there are peaks at the following refraction angles 2θ in the X-ray powder diffraction pattern: 17.8°, 18.6°, 23.2° and 23.5°; wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation instead of Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ + / - 0.2°.

[0108] 12) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), comprising aprexitentan in crystalline form A, characterized in that there are peaks at the following refraction angles 2θ in the X-ray powder diffraction pattern: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°, 22.8°, 23.2° and 23.5°; wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation instead of Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ + / - 0.2°.

[0109] 13) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), comprising aprexitentan in crystalline form A, characterized in that in the X-ray powder diffraction pattern there are peaks at the following refractive angles 2θ: 9.8°, 9.9°, 11.7°, 14.5°, 15.4°, 15.6°, 16.9°, 17.2°, 17.8°, 18.6°, 19.9°, 20.0°, 21.5°, 21.9°, 22.8°, 23.2°, 23.5°, 24.9°, 25.1°, 25.3°, 25.6°, 25.9°, 27.1°, 27.3°, 28.5°, 29.0°, 29.4°, 30.1° and 30.6°; wherein the X-ray powder diffraction pattern is obtained by using a combination of Cu Kα1 and Kα2 radiation were obtained instead of Kα2 stripping; and the accuracy of the 2θ value was within the range of 2θ + / - 0.2°.

[0110] 14) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), which comprises aprexitentan in crystalline form A, characterized in that in the X-ray powder diffraction pattern, there are peaks at the following refraction 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 the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation rather than Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ+ / -0.2°.

[0111] The present data show peaks having the following percentages (relative peak intensities are given in parentheses) of relative intensity at the indicated refractive angles 2θ (peaks selected from the range 3-33° 2θ with relative intensities greater than 10% are reported) compared to the most intense peak in the graph.

[0112] 15) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 9), comprising apremilast in crystalline form A, wherein the crystalline form A exhibits substantially Figure 1 wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation rather than Kα2 stripping; and the accuracy of the 2θ values ​​is within the range of 2θ + / - 0.2°.

[0113] In this context, the term "substantially" means that at least the main peaks of the diagrams depicted in the figures (i.e. peaks having a relative intensity of more than 10%, especially more than 20% compared to the strongest peak in the diagram) must be present. However, a person skilled in the art of X-ray powder diffraction will recognize that the relative intensities in an X-ray powder diffraction pattern may be subject to stronger intensity variations due to preferred orientation effects.

[0114] 16) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 9), comprising aprexitentan in crystalline form A, which can be obtained by crystallizing the compound in aqueous solution at pH 6.2 to 6.8.

[0115] For the avoidance of any doubt, whenever one of the above examples refers to "a peak at the following refraction angle 2θ in an X-ray powder diffraction pattern", the X-ray powder diffraction pattern is obtained by using a combined Cu Kα1 and Kα2 radiation rather than Kα2 stripping; and it is understood that the accuracy of the 2θ values ​​provided herein is within the range of + / -0.1-0.2°. In particular, when the refraction angle 2theta (2θ) for a peak is specified in the examples and claims of the present invention, a given 2θ value is understood to be the interval of the value minus 0.2° to the value plus 0.2° (2θ+ / -0.2°); and preferably the value minus 0.1° to the value plus 0.1° (2θ+ / -0.1°).

[0116] When defining the presence of a peak in, for example, an X-ray powder diffraction pattern, a common way of doing so is in terms of the S / N ratio (S=signal, N=noise). According to this definition, when stating that a peak must be present in an X-ray powder diffraction pattern, it is understood that a peak in an X-ray powder diffraction pattern is defined by an S / N ratio (S=signal, N=noise) that is greater than x (x having a numerical value greater than 1), typically greater than 2, and especially greater than 3.

[0117] Unless used with respect to temperature, the term "about" preceding a numerical value "X" in this application refers to an interval extending from X minus 10%X to X plus 10%X and preferably to an interval extending from X minus 5%X to X plus 5%X. In the specific case of temperature, the term "about" preceding a temperature "Y" in this application refers to an interval extending from temperature Y minus 10°C to Y plus 10°C, preferably to an interval extending from Y minus 5°C to Y plus 5°C, in particular to an interval extending from Y minus 3°C to Y plus 3°C. Room temperature means a temperature of about 25°C. When the term n equivalents is used in this application, wherein n is a number, it is intended and within the scope of this application that n refers to approximately the number n, preferably n refers to the exact number n.

[0118] Whenever the words "between" or "to" are used to describe a numerical range, it should be understood that the endpoints of the specified range are explicitly included in the range. For example: if a temperature range is described between 40°C and 80°C (or 40°C to 80°C), this means that the endpoints 40°C and 80°C are included in the range; or if a variable is defined as an integer between 1 and 4 (or 1 to 4), this means that the variable is an integer of 1, 2, 3 or 4.

[0119] 17) A fourth aspect of the present invention relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), comprising apremilast in crystalline form C, characterized in that there are peaks at the following refraction angles 2θ in the X-ray powder diffraction pattern: 9.7°, 15.7° and 22.0°; wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation rather than Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ+ / -0.2°.

[0120] 18) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), comprising aprexitentan in crystalline form C, characterized in that there are peaks at the following refraction angles 2θ in the X-ray powder diffraction pattern: 7.8°, 9.7°, 15.7°, 19.8° and 22.0°; wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation instead of Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ + / - 0.2°.

[0121] 19) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), comprising apremitentan in crystalline form C, characterized in that there are peaks at the following refraction angles 2θ in the X-ray powder diffraction pattern: 7.8°, 9.7°, 15.7°, 17.2°, 17.8°, 18.8°, 19.8°, 22.0°, 23.6° and 25.3°; wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation instead of Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ + / - 0.2°.

[0122] 20) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), comprising aprexitentan in crystalline form C, characterized in that there are peaks at the following refraction angles 2θ in the X-ray powder diffraction pattern: 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 the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation instead of Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ + / - 0.2°.

[0123] 21) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), which comprises aprexitentan in crystalline form C, characterized in that in the X-ray powder diffraction pattern, there are peaks at the following refraction 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 the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation instead of Kα2 stripping; and the accuracy of the 2θ values ​​is within the range of 2θ+ / -0.2°.

[0124] The present data show peaks having the following percentages (relative peak intensities are given in parentheses) of relative intensity at the indicated refractive angles 2θ (peaks selected from the range 3-33° 2θ with relative intensities greater than 10% are reported) compared to the most intense peak in the graph.

[0125] 22) Another embodiment relates to a pharmaceutical composition as described in any one of embodiments 1) to 9), which comprises a pharmaceutical composition substantially showing Figure 3, wherein the X-ray powder diffraction pattern is obtained by using combined Cu Kα1 and Kα2 radiation rather than Kα2 stripping; and the accuracy of the 2θ value is within the range of 2θ + / - 0.2°.

[0126] In this context, the term "substantially" means that at least the main peaks of the diagrams depicted in the drawings (i.e. peaks having a relative intensity of more than 10%, especially more than 20% compared to the strongest peak in the diagram) must be present. However, a person skilled in the art of X-ray powder diffraction will recognize that the relative intensities in an X-ray powder diffraction pattern may be subject to stronger intensity variations due to preferred orientation effects.

[0127] 23) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 9), comprising aprexitentan in crystalline form C, which can be obtained by crystallizing the compound from MeOH, EtOH or propan-2-ol.

[0128] 24) Another embodiment relates to a pharmaceutical composition according to any one of embodiments 1) to 9), comprising apremilast in amorphous form. The 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 beads) at 30 Hz for 30 min at ambient temperature.

[0129] The manufacture of pharmaceutical compositions can be achieved in any manner with which those skilled in the art will be familiar (see, e.g., Remington, The Science and Practice of Pharmacy, 21st edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]), by incorporating the crystalline forms of the invention (optionally in combination with other therapeutically valuable substances) into galenic dosage forms together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if necessary, customary pharmaceutical adjuvants.

[0130] 25) Another embodiment relates to a solid pharmaceutical composition (especially in the form of a tablet) as described in any one of embodiments 1) to 24), in particular any one of embodiments 10) to 16) or any one of embodiments 17) to 22), which comprises inert microcrystalline cellulose, lactose, hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate as pharmaceutically acceptable excipients.

[0131] 26) In particular, the solid pharmaceutical composition of embodiment 25) will contain aprexitentan in a total amount of 5 to 25% by weight, based on the total weight of the pharmaceutical composition, microcrystalline cellulose in a total amount of 20 to 30% by weight, based on the total weight of the pharmaceutical composition, lactose in a total amount of 40 to 65% by weight, based on the total weight of the pharmaceutical composition, 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 0.2 to 2% by weight, based on the total weight of the pharmaceutical composition, whereby the total percentages by weight of the solid pharmaceutical composition will always be 100; the aforementioned solid pharmaceutical composition will in particular be in the form of a tablet.

[0132] 27) Another embodiment of the present invention relates to a pharmaceutical composition as in embodiment 25) or 26), wherein the pharmaceutical composition is in the form of a tablet. In a sub-embodiment, the pharmaceutically active ingredient is contained in the granules before being compressed into the tablet.

[0133] The tablets as in Example 27) may be coated with a suitable protective film as appropriate. The protective film will in particular prevent the pharmaceutical composition from coming into direct contact with moisture; it may also alleviate the need for stamping to distinguish the pharmaceutical composition from others.

[0134] The coating material used to prepare the protective pellicle may include a polymer with low water vapor permeability, such as polyvinyl alcohol (e.g., Polyvinyl Alcohol from the manufacturer Biogrund). White PVA) or dimethylaminoethyl methacrylate (e.g. E PO)). The coating material may further include a plasticizer (e.g., propylene glycol, triacetin, dibutyl phthalate or dibutyl sebacate), a surfactant (e.g., sodium lauryl sulfate or polysorbate, such as ) and / or lubricants / slip agents (e.g., stearic acid, magnesium stearate or calcium stearate or talc). In addition, the coating material may also include a pigment (e.g., iron (II) oxide, iron (III) oxide or titanium oxide) to give the tablet a colored aspect.

[0135] 28) Another embodiment of the present invention relates to a pharmaceutical composition as described in any one of embodiments 25) to 26), wherein the pharmaceutical composition is in the form of a capsule. In a sub-embodiment, the pharmaceutically active ingredient is contained in granules before being filled into the capsule.

[0136] For the avoidance of any doubt, the present invention further relates to crystalline forms of aprexitentan, in particular to crystalline Form A disclosed herein, wherein the crystalline form is suitable for / used as the final isolation step of aprexitentan (e.g., to meet the purity requirements for pharmaceutical manufacturing), and the final pharmaceutical composition (e.g., Examples 1 to 28) may or may not contain the crystalline form (e.g., because the initial crystalline form of aprexitentan is further converted and / or dissolved in a pharmaceutically acceptable carrier material during the manufacturing process; therefore, in the final pharmaceutical composition, aprexitentan may be present in a non-crystalline form, in another crystalline form, or in a dissolved form or the like).

[0137] The combined pharmaceutical compositions of Examples 1) to 28) are particularly suitable for treating endothelin-related diseases, and are suitable for methods of treating endothelin-related diseases in subjects in need of ERA.

[0138] The endothelin-related diseases may be defined as including, inter alia, hypertension, inter alia, including difficult to treat / resistant hypertension; ischemic heart disease, including angina, coronary artery disease and myocardial ischemia; cardiac insufficiency; chronic kidney disease (CKD) [particularly CKD stages 1 to 4 (and in particular stage 3 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines], and CKD (particularly of these stages) caused by / associated with hypertension, or CKD caused by / associated with diabetes (also known as diabetic kidney disease (DKD), wherein in particular the diabetes is type 2 diabetes); diabetes and diabetes-related diseases, such as diabetic arteropathy, diabetic nephropathy, diabetic retinopathy or diabetic vasculopathy; reducing the risk of patients with diabetes developing serious cardiovascular events (such as HF due to cardiovascular etiology, myocardial infarction, stroke or death), in particular patients with at least one other cardiovascular disease diabetic patients with vascular risk factors (especially such as hypertension); treatment and prevention of diabetic complications; (acute and chronic) renal failure; glomerulonephritis; connective tissue disease; atherosclerosis; peripheral arterial occlusive disease, including chronic peripheral arterial disease; digital ulcers; diabetic foot ulcers and / or reducing the risk of lower extremity / limb amputation in patients with diabetes; heart failure (HF), which is defined as including especially chronic HF, especially including systolic HF / HF with reduced ejection fraction (HFrEF) (i.e., ejection fraction < about 40%), and diastolic HF / HF with preserved ejection fraction (HFpEF) (i.e., ejection fraction > about 50%); reducing the risk of developing serious cardiovascular events (such as HF due to cardiovascular etiology, myocardial infarction, stroke or death) in patients at cardiovascular risk (such as patients with coronary artery disease and / or patients with confirmed clinical symptoms of congestive HF); and diastolic dysfunction.

[0139] For the avoidance of doubt, the term CKD (diabetic kidney disease, DKD) caused by / associated with diabetes mellitus may also include such DKD additionally being associated with hypertension; wherein the diabetes mellitus is in particular type 2 diabetes mellitus.

[0140] In particular, in the context of the present invention, endothelin-related diseases include

[0141] Chronic kidney disease (CKD) [especially CKD stages 1 to 4 (and especially stage 3 CKD) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines], and CKD especially caused by / associated with hypertension (especially these stages) and / or CKD caused by / associated with diabetes (diabetic kidney disease (DKD)); and renal failure (acute and chronic); diabetic nephropathy; and glomerulonephritis;

[0142] In a sub-embodiment, DKD as defined previously refers in particular to DKD in a patient diagnosed with type 2 diabetes; in particular to reducing the progression rate of DKD in a patient diagnosed with type 2 diabetes, wherein the reduced progression rate may in particular be manifested by a reduction in eGFR, a reduction in events of end-stage renal disease (ESKD) or a reduction in events of renal death; wherein in particular the patient additionally has a history of hypertension;

[0143] In another sub-example, DKD as defined previously refers in particular to diabetic nephropathy associated with elevated serum creatinine and / or proteinuria in patients with type 2 diabetes, in particular in such patients who additionally have a history of hypertension [in particular corresponding to CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria (and in particular corresponding to stage 3 CKD)];

[0144] In another sub-example, DKD as defined above refers in particular to said DKD which is additionally associated with hypertension; wherein diabetes mellitus is in particular type 2 diabetes mellitus;

[0145] diabetes and diabetes-related diseases, such as diabetic arteropathy, diabetic retinopathy or diabetic vasculopathy; and treatment and prevention of diabetic complications; and reducing the risk of developing serious cardiovascular events (such as HF, myocardial infarction, stroke or death due to cardiovascular etiology) in patients with diabetes, especially patients with diabetes with at least one other cardiovascular risk factor (such as, in particular, hypertension); and diabetic foot ulcers and / or reducing the risk of lower extremity amputation in patients with diabetes; and

[0146] Heart failure (HF), defined as including, inter alia, chronic HF, inter alia, systolic HF / HF with reduced ejection fraction (HFrEF) (i.e., ejection fraction < about 40%), and diastolic HF / HF with preserved ejection fraction (HFpEF) (i.e., ejection fraction > about 50%); and reducing the risk of developing serious cardiovascular events (such as HF due to cardiovascular etiology, myocardial infarction, stroke, or death) in patients at cardiovascular risk (such as patients with coronary artery disease and / or patients with clinical symptoms of confirmed congestive HF); angina pectoris; coronary artery disease; cardiac insufficiency; and diastolic dysfunction.

[0147] Essential hypertension (also known as primary hypertension or idiopathic hypertension) is a form of hypertension that by definition has no identifiable cause. It represents a major global public health problem, causing vascular and renal morbidity and contributing to cardiovascular mortality. When the average of multiple systolic blood pressure measurements on 2 or more consecutive visits is consistently equal to or above a certain threshold value T SBP Essential hypertension is diagnosed when the patient has a high normal blood pressure (T). Individuals with high normal blood pressure tend to maintain a higher than average pressure compared to the general population and are at greater risk for developing established hypertension and cardiovascular events. SBP is regularly discussed among clinicians (see, e.g., Mancia et al., J. Hypertens. (2013), 31, 1281-1357); therefore, depending on the patient's general condition and age, T SBP It may be 140 or 130 mm Hg or other suitable value.

[0148] The term "resistant hypertension" [equivalent to the term "refractory hypertension"] is defined in the present invention as a blood pressure that remains above target despite the simultaneous use of three different classes of antihypertensive agents. One of the three therapeutic agents should be a diuretic, and all agents should be prescribed in optimal / maximum dose amounts. As defined, patients with resistant hypertension include patients whose blood pressure is controlled by the use of more than three drugs. That is, patients whose blood pressure is controlled but require four or more drugs to control should be considered resistant to treatment (see, e.g., Mancia et al., J. Hypertens. (2013), 31, 1281-1357).

[0149] The term "diabetes" as used herein refers to all types of diabetes, particularly type 2 diabetes; as well as type 1 diabetes and potential autoimmune diabetes of adults, which is a form of type 1 diabetes presenting in adults, usually with a slower onset than type 1 diabetes diagnosed in adolescents.

[0150] 29) Therefore, the fifth aspect of the present invention relates to aprexitentan or a pharmaceutically acceptable salt thereof,

[0151] for the prevention / prevention or treatment of CKD [especially stage 1 to 4 CKD, especially stage 3 CKD]; and especially CKD caused / associated with hypertension (especially these stages) and / or CKD caused / associated with diabetes (DKD); and for the prevention / prevention or treatment of acute or chronic renal failure; diabetic nephropathy; or glomerulonephritis;

[0152] Wherein, in a first sub-embodiment, the use is in particular for treating said DKD in a patient diagnosed with type 2 diabetes, wherein in particular apremilast reduces the progression rate of DKD, wherein the reduced progression rate can be manifested in particular by a reduction in eGFR, a reduction in the events of end-stage renal disease (ESKD) or a reduction in the events of renal death; wherein in particular the patient additionally has a history of hypertension;

[0153] Wherein, in a second sub-embodiment, the use is particularly for treating the DKD, including treating diabetic nephropathy associated with elevated serum creatinine and / or proteinuria in patients with type 2 diabetes, especially in such patients who also have a history of hypertension [especially corresponding to CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria (and in particular corresponding to CKD stage 3)];

[0154] for the prevention / prevention or treatment of diabetes and diabetes-related diseases, such as diabetic arteropathy, diabetic retinopathy or diabetic vasculopathy; and diabetic complications; for reducing the risk of developing serious cardiovascular events (such as HF, myocardial infarction, stroke or death due to cardiovascular etiology) in patients with diabetes, especially patients with diabetes with at least one other cardiovascular risk factor (such as especially hypertension); and for the prevention / prevention or treatment of diabetic foot ulcers and / or for reducing the risk of lower extremity amputation in patients with diabetes;

[0155] for the prevention / prevention or treatment of heart failure (HF), which includes in particular chronic HF, including in particular systolic HF and diastolic HF; for reducing the risk of developing serious cardiovascular events (such as HF due to cardiovascular etiology, myocardial infarction, stroke or death) in patients at cardiovascular risk (such as patients with coronary artery disease and / or patients with confirmed clinical symptoms of congestive HF); and for the prevention / prevention or treatment of ischemic heart disease, including angina pectoris, coronary artery disease and myocardial ischemia; cardiac insufficiency; or diastolic dysfunction;

[0156] For the treatment of hypertension, especially including difficult-to-treat / resistant hypertension;

[0157] For the prevention / prevention or treatment of atherosclerosis; and peripheral arterial occlusive disease, including chronic peripheral arterial disease;

[0158] For the prophylaxis / prevention or treatment of digital ulcers; or

[0159] For the prevention / prevention or treatment of connective tissue diseases;

[0160] Wherein apremitentan (predetermined) is administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0161] 30) Another embodiment relates to apremitentan or a pharmaceutically acceptable salt thereof as used in embodiment 29); wherein apremitentan

[0162] For the prevention / prevention or treatment of CKD [especially stage 1 to 4 CKD, especially stage 3 CKD], including CKD caused by / associated with hypertension [especially stage 1 to 4 CKD, especially stage 3 CKD] and CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 CKD] (diabetic kidney disease, DKD);

[0163] wherein the use is in particular for treating said DKD in a patient diagnosed with type 2 diabetes, wherein in particular aprecitentan reduces the progression rate of DKD, wherein the reduced progression rate may in particular be manifested by a reduction in eGFR, a reduction in events of end-stage renal disease (ESKD) or a reduction in events of renal death; wherein in particular the patient additionally has a history of hypertension;

[0164] For the prevention / prevention or treatment of acute renal failure;

[0165] For the prevention / prevention or treatment of chronic renal failure;

[0166] For the prevention / prevention or treatment of diabetic nephropathy;

[0167] For the prevention / prevention or treatment of glomerulonephritis;

[0168] for reducing the risk of developing a serious cardiovascular event (such as HF, myocardial infarction, stroke or death due to cardiovascular etiology) in patients with diabetes, especially patients with diabetes who have at least one other cardiovascular risk factor (such as especially hypertension);

[0169] For the prevention / prevention or treatment of diabetic foot ulcers and / or for reducing the risk of lower limb amputation in patients with diabetes;

[0170] For use in the prophylaxis / prevention or treatment of heart failure (HF), which particularly includes chronic HF; particularly systolic HF or diastolic HF;

[0171] To reduce the risk of developing serious cardiovascular events (such as HF of cardiovascular etiology, myocardial infarction, stroke or death) in patients at cardiovascular risk (such as patients with coronary artery disease and / or patients with clinical symptoms of confirmed congestive HF);

[0172] For the prevention / prevention or treatment of diastolic dysfunction;

[0173] for the treatment of hypertension, especially including difficult-to-treat / resistant hypertension; or

[0174] For the prevention / prevention or treatment of atherosclerosis; and peripheral arterial occlusive disease, including chronic peripheral arterial disease;

[0175] Wherein apremitentan (predetermined) is administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0176] 31) Another embodiment relates to apremitentan or a pharmaceutically acceptable salt thereof as used in embodiment 29); wherein apremitentan

[0177] For the prevention / prevention or treatment of CKD caused by / associated with hypertension [especially stage 1 to 4 CKD, especially stage 3 CKD];

[0178] For the prevention / prevention or treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 CKD] (DKD);

[0179] wherein the use is in particular for treating said DKD in a patient diagnosed with type 2 diabetes, wherein in particular aprecitentan reduces the progression rate of DKD, wherein the reduced progression rate may in particular be manifested by a reduction in eGFR, a reduction in events of end-stage renal disease (ESKD) or a reduction in events of renal death; wherein in particular the patient additionally has a history of hypertension;

[0180] For the prevention / prevention or treatment of chronic renal failure caused by / related to hypertension or caused by / related to diabetes; diabetic nephropathy; or glomerulonephritis caused by / related to hypertension;

[0181] for reducing the risk of developing a serious cardiovascular event (such as HF, myocardial infarction, stroke or death due to cardiovascular etiology) in patients with diabetes, especially patients with diabetes who have at least one other cardiovascular risk factor (such as especially hypertension);

[0182] for the prophylaxis / prevention or treatment of diabetic foot ulcers and / or for reducing the risk of lower limb amputation in patients with diabetes; or

[0183] For use in the prophylaxis / prevention or treatment of heart failure (HF), which particularly includes chronic HF; particularly systolic HF or diastolic HF;

[0184] Wherein apremitentan (predetermined) is administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0185] 32) Another embodiment relates to apremitentan or a pharmaceutically acceptable salt thereof as used in embodiment 29); wherein apremitentan

[0186] For the prevention / prevention or treatment of CKD caused by / associated with hypertension [especially stage 1 to 4 CKD, especially stage 3 CKD]; and / or

[0187] For the prevention / prevention or treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 CKD] (DKD);

[0188] wherein the use is in particular for treating said DKD in a patient diagnosed with type 2 diabetes, wherein in particular aprecitentan reduces the progression rate of DKD, wherein said reduced progression rate may in particular be manifested by a reduction in eGFR, a reduction in events of end-stage renal disease (ESKD) or a reduction in events of renal death; wherein in particular said patient additionally has a history of hypertension; and / or

[0189] for reducing the risk of developing a serious cardiovascular event (such as HF, myocardial infarction, stroke or death due to cardiovascular etiology) in patients with diabetes, especially patients with diabetes who have at least one other cardiovascular risk factor (such as especially hypertension);

[0190] Wherein apremitentan (predetermined) is administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0191] 33) Another embodiment relates to apremitentan or a pharmaceutically acceptable salt thereof as used in embodiment 29); wherein apremitentan

[0192] For the prevention / prevention or treatment of CKD caused by / associated with hypertension [especially stage 1 to 4 CKD, especially stage 3 CKD]; and / or

[0193] For the prevention / prevention or treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 CKD] (DKD);

[0194] wherein the use is in particular for treating said DKD in a patient diagnosed with type 2 diabetes, wherein in particular aprecitentan reduces the progression rate of DKD, wherein the reduced progression rate may in particular be manifested by a reduction in eGFR, a reduction in events of end-stage renal disease (ESKD) or a reduction in events of renal death; wherein in particular the patient additionally has a history of hypertension;

[0195] Wherein apremitentan (predetermined) is administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0196] 34) Another embodiment relates to apremitentan or a pharmaceutically acceptable salt thereof as used in embodiment 29); wherein apremitentan

[0197] For the prevention / prevention or treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 CKD] (DKD);

[0198] Wherein, in a first sub-embodiment, the use is in particular for treating said DKD in a patient diagnosed with type 2 diabetes, wherein in particular apremilast reduces the progression rate of DKD, wherein the reduced progression rate can be manifested in particular by a reduction in eGFR, a reduction in the events of end-stage renal disease (ESKD) or a reduction in the events of renal death; wherein in particular the patient additionally has a history of hypertension;

[0199] Wherein, in a second sub-embodiment, the use is particularly for treating the DKD, including treating diabetic nephropathy associated with elevated serum creatinine and / or proteinuria in patients with type 2 diabetes, especially in such patients who also have a history of hypertension [especially corresponding to CKD stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria (and in particular corresponding to CKD stage 3)];

[0200] Wherein apremitentan (predetermined) is administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0201] 35) Another embodiment relates to apremitentan or a pharmaceutically acceptable salt thereof as used in embodiment 29); wherein apremitentan

[0202] for reducing the risk of developing a serious cardiovascular event (such as HF, myocardial infarction, stroke or death due to cardiovascular etiology) in patients with diabetes, especially patients with diabetes who have at least one other cardiovascular risk factor (such as especially hypertension);

[0203] Wherein apremitentan (predetermined) is administered in combination with an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof.

[0204] 36) Another embodiment relates to apremifloxacin or a pharmaceutically acceptable salt thereof as used in any one of embodiments 29) to 35); wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is apagliflozin, bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliptin, rupagliflozin, repagliflozin, sopagliflozin or topagliflozin or a pharmaceutically acceptable salt thereof.

[0205] 36(i) In one sub-embodiment, the SGLT-2 inhibitor is particularly bexagliflozin, canagliflozin, dapagliflozin, empagliflozin, ertogliflozin, hengagliflozin, ipagliptin, rupagliflozin, sogliflozin or togliflozin (especially canagliflozin, dapagliflozin or empagliflozin; especially canagliflozin) or a pharmaceutically acceptable salt thereof.

[0206] 37) Another embodiment relates to apremilast or a pharmaceutically acceptable salt thereof as used in any one of embodiments 29) to 35); wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin, dapagliflozin or empagliflozin (especially canagliflozin) or a pharmaceutically acceptable salt thereof.

[0207] 38) Another embodiment relates to apremilast or a pharmaceutically acceptable salt thereof as used in any one of embodiments 29) to 35); wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin or a pharmaceutically acceptable salt thereof.

[0208] 39) Another embodiment relates to apremilast or a pharmaceutically acceptable salt thereof as used in any one of embodiments 29) to 35); wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is dapagliflozin or a pharmaceutically acceptable salt thereof.

[0209] 40) Another embodiment relates to apremilast or a pharmaceutically acceptable salt thereof as used in any one of embodiments 29) to 35); wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is empagliflozin or a pharmaceutically acceptable salt thereof.

[0210] 41) Another embodiment relates to apremitentan or a pharmaceutically acceptable salt thereof as used in any one of embodiments 29) to 40), wherein the pharmaceutically active ingredient is administered in a pharmaceutical unit dosage form as disclosed in any one of embodiments 5), 6), 7) or 8) or in any one of sub-embodiments 5(i), 5(ii), 5(iii), 6(i), 6(ii), 6(iii), 6(iv), 6(v), 6(vi), 6(vii), 8(i), 8(ii), 8(iii), 8(iv), 8(v), 8(vi) or 8(vii) thereof, mutatis mutandis.

[0211] 42) Another embodiment relates to apremitentan or a pharmaceutically acceptable salt thereof for use in combination with an SGLT-2 inhibitor as described in any one of embodiments 29) to 41), wherein apremitentan is used in a crystalline form as defined in any one of embodiments 10) to 16) or 17) to 23) [in particular as defined in embodiments 10), 11) or 12); or 17), 18) or 19), respectively].

[0212] 43) Another embodiment relates to aprexitentan or a pharmaceutically acceptable salt thereof for use in combination with an SGLT-2 inhibitor as described in any one of embodiments 29) to 41), wherein aprexitentan is used in a crystalline form as defined in any one of embodiments 10) to 16) [in particular as defined in embodiment 10), 11) or 12)].

[0213] 44) Another embodiment relates to apremilast or a pharmaceutically acceptable salt thereof used in combination with an SGLT-2 inhibitor as described in any one of embodiments 29) to 41), wherein, mutatis mutandis, apremilast is administered in combination with a suitable conventional background therapy, wherein the background therapy is in particular as defined in embodiment 9) or its sub-embodiments 9(i), 9(ii) or 9(iii).

[0214] 45) Therefore, an important aspect of the present invention relates to aprexitentan or a pharmaceutically acceptable salt thereof, which is used in the form of a combination / synergistic therapy with an SGLT-2 inhibitor as described in any one of Examples 29) to 44). In particular, based on the interdependence of the different embodiments (or their respective sub-embodiments) disclosed above, the following embodiments are possible and desirable after mutatis mutandis in detail, and are specifically disclosed here in an individualized form:

[0215] 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.

[0216] In the above list, the numbers refer to embodiments according to the embodiment numbers provided above, and "+" indicates dependency on another embodiment. Different personalized embodiments are separated by commas. In other words, "34+9+8" refers, for example, to embodiment 34) which is dependent on embodiment 9) and dependent on embodiment 8) mutatis mutandis, i.e. embodiment "34+9+8" corresponding to embodiment 34) further limited by the features defined in embodiments 9) and 8) (or their respective sub-embodiments).

[0217] Therefore, aprexitentan or a pharmaceutically acceptable salt thereof according to the present invention is used in combination (or synergistic therapy) with the other pharmaceutically active ingredients.

[0218] The combined treatment (or co-therapy) may be performed simultaneously, separately or over a period of time (especially simultaneously).

[0219] When referring to the type of administration, "simultaneous" in this application means that the relevant type of administration is to administer two or more active ingredients and / or treatments at approximately the same time; wherein it is understood that simultaneous administration will expose the subject to the two or more active ingredients and / or treatments at the same time. When administered simultaneously, the two or more active ingredients may be administered in a fixed dose combination or in an equivalent non-fixed dose combination (e.g., by using two or more different pharmaceutical compositions to be administered at approximately the same time by the same route of administration), or by a non-fixed dose combination, using two or more different routes of administration; wherein the administration exposes the subject to the two or more active ingredients and / or treatments substantially simultaneously. When used in combination with an SGLT-2 inhibitor, aprexitentan may be used "simultaneously".

[0220] When referring to the administration types, "fixed dose combination" means in the present application that the relevant administration type consists in administering one single pharmaceutical composition comprising two or more active ingredients, in particular such as a pharmaceutical composition as any one of embodiments 1) to 28).

[0221] When referring to a type of administration, "separate" in the present application means that the relevant type of administration consists in administering two or more active ingredients and / or treatments at different time points; it is understood that separate administration will result in a treatment phase in which the subject is exposed to the two or more active ingredients and / or treatments simultaneously (e.g. for at least 1 hour, in particular for at least 6 hours, especially for at least 12 hours); but separate administration may also result in a treatment phase in which the subject is exposed to only one of the two or more active ingredients and / or treatments within a certain period of time (e.g. for at least 12 hours, in particular for at least one day). Separate administration refers in particular to the administration of one of the active ingredients and / or treatments in a regular dosing regimen that is substantially different from daily administration (such as once or twice a day) (e.g. one of the active ingredients and / or treatments is administered, for example, once or twice a day, and the other is administered, for example, every other day or once a week or at even greater time intervals).

[0222] In the present application, administration "over a period of time" means the sequential administration of two or more active ingredients and / or treatments at different times. The term refers in particular to a method of administration in which the entire administration of one active ingredient and / or treatment is completed before the administration of another / other active ingredient and / or treatment begins. In this way, it is possible to administer one of the active ingredients and / or treatments for several months, followed by the administration of the other active ingredients and / or treatments.

[0223] It is to be understood that any embodiment relating to apremitentan or a pharmaceutically acceptable salt thereof for use in treating certain endothelin-related diseases as specifically defined herein, wherein apremitentan is (intended) to be administered in combination with an SGLT-2 inhibitor, in particular an SGLT-2 inhibitor as specifically defined in that embodiment, also relates to

[0224] The SGLT-2 inhibitor as disclosed herein (intended) to be administered in combination with apremilast or a pharmaceutically acceptable salt thereof for use in treating said endothelin-related diseases;

[0225] Use of aprexitentan for the manufacture of a medicament / pharmaceutical composition comprising aprexitentan or a pharmaceutically acceptable salt thereof and the SGLT-2 inhibitor as disclosed herein for the treatment of such endothelin-related diseases;

[0226] Use of aprexitentan for the manufacture of a medicament / pharmaceutical composition comprising aprexitentan or a pharmaceutically acceptable salt thereof as an active ingredient for the treatment of said endothelin-related diseases; wherein said medicament / pharmaceutical composition is (intended) to be used in combination with an SGLT-2 inhibitor as disclosed herein;

[0227] Use of an SGLT-2 inhibitor as disclosed herein for the manufacture of a medicament / pharmaceutical composition comprising the SGLT-2 inhibitor as disclosed herein as an active ingredient for the treatment of such endothelin-related diseases; wherein the medicament / pharmaceutical composition is (intended) to be used in combination with apremilast;

[0228] Use of a pharmaceutical composition comprising aprexitentan or a pharmaceutically acceptable salt thereof and the SGLT-2 inhibitor as disclosed herein for treating such endothelin-related diseases;

[0229] A medicament for preventing or treating said endothelin-related diseases, said medicament comprising aprexitentan or a pharmaceutically acceptable salt thereof; wherein said medicament is (intended) to be administered in combination with said SGLT-2 inhibitor;

[0230] A method for treating said endothelin-related diseases, comprising administering to a subject (preferably a human) in need thereof an effective amount of aprexitentan or a pharmaceutically acceptable salt thereof in combination with an effective amount of said SGLT-2 inhibitor;

[0231] A method for treating such endothelin-related diseases, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising apremilast or a pharmaceutically acceptable salt thereof and the SGLT-2 inhibitor as disclosed herein; and

[0232] A method for treating such endothelin-related diseases, which comprises administering to a subject (preferably a human) in need thereof an effective amount of the SGLT-2 inhibitor as disclosed herein in combination with an effective amount of aprexitentan or a pharmaceutically acceptable salt thereof.

[0233] 46) Another embodiment relates to aprexitentan or a pharmaceutically acceptable salt thereof, which is used in the following method

[0234] Reducing fluid retention and / or reducing the risk of congestive heart failure in a subject (preferably a human) in need of an ERA, the method comprising administering to the subject an effective amount of aprexitentan, wherein the aprexitentan is administered in combination with an SGLT-2 inhibitor as disclosed herein, wherein the features of any one of Examples 1) to 45) apply mutatis mutandis;

[0235] Reducing volume consumption and / or normalizing blood viscosity and / or reducing the risk of lower extremity amputation in a subject (preferably a human) in need of an SGLT-2 inhibitor, such as in particular a subject diagnosed with type 2 diabetes and / or DKD, the method comprising administering to the subject an effective amount of the SGLT-2 inhibitor as disclosed herein, wherein the SGLT-2 inhibitor is administered in combination with an effective amount of aprexitentan, wherein the features of any one of embodiments 1) to 45) apply mutatis mutandis in detail;

[0236] Protecting the kidney and / or improving renal hemodynamics and / or reducing the risk of acute renal failure in a subject (preferably a human) in need of an SGLT-2 inhibitor, such as in particular a subject diagnosed with type 2 diabetes and / or DKD, the method comprising administering to the subject an effective amount of the SGLT-2 inhibitor as disclosed herein, wherein the SGLT-2 inhibitor is administered in combination with an effective amount of aprexitentan, wherein the features of any one of embodiments 1) to 45) apply mutatis mutandis in detail;

[0237] Reducing blood pressure in a subject, preferably a human, the method comprising administering to the subject an effective amount of aprexitentan, wherein aprexitentan is administered in combination with an SGLT-2 inhibitor as disclosed herein, wherein the features of any one of Examples 1) to 45) apply mutatis mutandis;

[0238] Reducing blood glucose levels in a subject, preferably a human, the method comprising administering to the subject an effective amount of aprexitentan, wherein aprexitentan is administered in combination with an SGLT-2 inhibitor as disclosed herein, wherein the features of any one of Examples 1) to 45) apply mutatis mutandis; and / or

[0239] Prevention or treatment of an endothelin-related disease as defined herein, the method comprising administering to the subject an effective amount of the SGLT-2 inhibitor as disclosed herein, wherein the SGLT-2 inhibitor is administered in combination with an effective amount of aprexitentan, wherein the features of any one of embodiments 1) to 45) apply mutatis mutandis; wherein the beneficial effect of the SGLT-2 inhibitor on sodium reabsorption remains unaffected by aprexitentan.

[0240] 47) Another aspect of the present invention relates to apremilast or a pharmaceutically acceptable salt thereof for use in the treatment of CKD caused by / associated with diabetes [especially stage 1 to 4 CKD, especially stage 3 CKD] (DKD) [including diabetic nephropathy associated with elevated serum creatinine and / or proteinuria [especially corresponding to these stages of CKD]]; wherein in a sub-embodiment, the use is especially for the treatment of said DKD in patients diagnosed with type 2 diabetes [especially such patients who also have a history of hypertension], wherein especially apremilast reduces the progression rate of DKD, wherein the reduced progression rate can be especially manifested by a reduction in eGFR, a reduction in the events of end-stage renal disease (ESKD) or a reduction in the events of renal death;

[0241] wherein apremilastan is used as monotherapy; or (preferably) in combination / concurrent therapy [implemented simultaneously, separately or within a period of time (especially simultaneously)] with an SGLT-2 inhibitor and / or conventional background therapy (or first-line therapy) as defined previously;

[0242] wherein the aprexitentan is administered in a suitable pharmaceutically effective unit dosage form as defined in Example 5) or 6) and each of its sub-embodiments 5(i), 5(ii), 5(iii), 6(i), 6(ii), 6(iii), 6(iv), 6(v), 6(vi) or 6(vii); [especially in a unit dosage form suitable for oral administration of 1 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg per day; (especially 10 mg, 12.5 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg; in particular 12.5 mg, 25 mg or 50 mg) of aprexitentan per day];

[0243] wherein the SGLT-2 inhibitor, if present, is in particular as defined in embodiment 7) or 8); wherein the SGLT-2 inhibitor is administered in a suitable pharmaceutically effective unit dosage form in particular as defined in embodiment 7) or 8) and subembodiments 8(i), 8(ii), 8(iii), 8(iv), 8(v), 8(vi) or 8(vii);

[0244] wherein the conventional background therapy, if present, is in particular as defined in embodiment 9) and its sub-embodiments; wherein the conventional background therapy is in particular administered in a suitable pharmaceutically effective unit dosage form as defined in embodiment 9) and its sub-embodiments 9(i), 9(ii) or 9(iii);

[0245] And where the conventional background therapy is suitable, it is preferably specified (ie, approved by a national health authority such as the FDA or EMA) for treating the DKD according to this embodiment.

[0246] Specific embodiments of the present invention are described in the following examples, which serve to illustrate the invention in more detail without limiting its scope in any way.

[0247] Experimental Procedure

[0248] abbreviation:

[0249] The following abbreviations are used throughout this specification and examples:

[0250] Ac Acetyl

[0251] AcOH Acetic acid

[0252] aq. Aqueous solution

[0253] DCM Dichloromethane

[0254] DMSO Dimethyl sulfoxide

[0255] EtOAc Ethyl acetate

[0256] eq. equivalent

[0257] FTIR Fourier Transform Infrared Spectroscopy or Spectroscopy

[0258] HPLC High Performance Liquid Chromatography

[0259] iPrOAc Isopropyl acetate

[0260] MeOH Methanol

[0261] MIBK Methyl Isobutyl Ketone

[0262] org. organic

[0263] rt room temperature

[0264] THF Tetrahydrofuran

[0265] vol. volume

[0266] w / w weight / weight ratio

[0267] wt. unit of weight

[0268] XRPD X-ray powder diffraction

[0269] Examples

[0270] Methods for obtaining XRPD patterns

[0271] All XRPD patterns of the solid forms described herein have been obtained as described below. X-ray powder diffraction patterns were collected on a Bruker D8 advanced X-ray diffractometer equipped with a Lynxeye detector operating CuKα radiation in reflection mode (coupled 2θ / θ). Typically, the X-ray tube was operated at 40kV / 40mA. A 0.02° (2θ) step size and a 76.8 second step time were applied over a 3-50° scan range of 2θ. The divergence slit was set to a fixed 0.3. The powder was slightly pressed into a silicon single crystal sample holder with a depth of 0.5mm and rotated in the sample's own plane during the measurement. Diffraction data were reported using a combined Cu Kα1 and Kα2 radiation rather than Kα2 stripping. The accuracy of the 2θ values ​​as provided herein is within the range of + / -0.1-0.2°, which is generally the case for known recorded X-ray powder diffraction patterns.

[0272] Example 1: Form A:

[0273] 1. A 1.3 L double jacketed reactor was charged with 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine (100 g, 0.213 mol, 1 eq.), sulfonamide (40.9 g, 0.425 mol, 2.0 eq.), K2CO3 (147 g, 1.06 mol, 5 eq.), and DMSO (500 mL, 5 vol.) doped with water (2 mL, 0.111 mol, 0.5 eq.). The heterogeneous mixture was heated to 70° C. over a period of approximately 3 h, after which time complete conversion was observed. After cooling to 20° C., most of the inorganic salt material was removed by filtration. The filter cake was washed with EtOAc / iPrOAc 1:1 (300 mL, 3 vol.). Celite (100 g, 1 wt.) with a layer of charcoal (20 g, 0.2 wt.) on top was pretreated with EtOAc / iPrOAc 1:1 (500 mL, 5 vol.) (filtrate discarded). The reaction mixture was filtered through this filter cake and rinsed with EtOAc / iPrOAc 1:1 (300 mL, 3 vol.). 1 M NaOAc aqueous solution (500 mL, 0.5 mol, 2.3 eq, 5 vol.) was then added while keeping the temperature at 25-35° C. The aqueous phase was washed a second time with EtOAc / iPrOAc 1:1 (500 mL, 5 vol.). 1 M H2SO4 (200 mL, 0.2 mol, 1 eq., 2 vol.) was added to the aqueous phase during 1 h at 25-30° C. Crystallization started at pH 8.5-8.0. The crude product was filtered out as XRPD pattern Form K (DMSO soluble) or a mixture of Form A and Form K. It was washed twice with water (2×1000 mL, 2×10 vol.). The solid was slurried in water (1000 mL, 10 vol.) for 3 h at rt. The solid was filtered out and slurried a second time in water (1000 mL, 10 vol.) for 3 h at rt. After washing with water (1000 mL, 10 vol.), the pure product was dried in vacuo at 40° C. to give {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide (75 g, 65% yield, XRPD pattern Form A) as a white to off-white solid.

[0274] 1.2. A reactor (200 L Hastelloy) was charged with 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine (24.2 kg, 51.5 mol), sulfonamide (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 within 4 hours. The contents were cooled to 20-25° C. and the solids were centrifuged off. Each load was washed with EtOAc / iPrOAc 1:1 (65 kg, 3 vol.). The filtrate was recharged to the reactor and charcoal (2.4 kg, 10% w / w) and (4.8 kg, 20% w / w). The contents were stirred at 15-20 ° C for 1 h and filtered back into the reactor through a cartridge filter. The filter was rinsed with EtOAc / iPrOAc 1: 1 (43 kg, 2 vol.). NaOAc (8% aqueous solution) (124 kg, 5 vol.) was added over 2 h, keeping the temperature below 25 ° C. After phase separation, the aqueous layer was washed with EtOAc / iPrOAc 1: 1 (109 kg, 5 vol.) at 20-25 ° C. Sulfuric acid (5% aqueous solution; 64 L, 32.6 mol, 0.63 eq.) was added to the aqueous layer at 25-30 ° C for 2 hours to reach pH 6.4. The contents were then cooled to 15-20 ° C for 1 h. The solid was filtered out and washed twice with water (2×24 L, 2×1 vol.). The solid was slurried twice in water (2 x 242 kg, 2 x 10 vol.) at 15-20 °C for 3 h, filtered each time and dried to give 5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide (21.6 g, 77% yield, XRPD pattern Form A) as a white solid.

[0275] Example 2: Form C:

[0276] A stock solution of 0.2 mL of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide dissolved in THF at 50 mg / mL was dispensed into 3 vials. The solvent was evaporated in a Combidancer apparatus operated at 35° C. and 200 mbar in Switzerland for 90 min. 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 sealed and left to stand for 3 days. For each of these solvents, a solid residue of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide in Form C was obtained.

[0277] Example 3: ACT-132577 tablets:

[0278] Tablets each containing 50 mg of ACT-132577 can be prepared using a wet granulation process. The tablet composition is as follows:

[0279]

[0280]

[0281] qs = sufficient quantity

[0282] Preferably ACT-132577 Form A (as described herein) will be used to prepare tablets.

[0283] Example 4: ACT-132577 tablets:

[0284] The tablet of Example 3 can be prepared by using a layer of White MS or White PVA (coating manufacturer: Biogrund) coating.

[0285] Example 5: ACT-132577 tablets:

[0286] Tablets each containing 50 mg of ACT-132577 can be prepared using a wet granulation process. The tablet composition is as follows:

[0287]

[0288] qs = sufficient quantity

[0289] Preferably, ACT-132577 Form A (as described herein) will be used to prepare tablets.

[0290] Example 6

[0291] The tablet of Example 5 can be prepared by a layer of White MS or White PVA (coating manufacturer: Biogrund) coating.

[0292] Example 7: ACT-132577 tablets:

[0293] Tablets each containing 12.5 mg of ACT-132577 can be prepared using a wet granulation process.

[0294] The tablet composition is as follows:

[0295]

[0296] qs = sufficient quantity

[0297] Preferably, ACT-132577 Form A (as described herein) will be used to prepare tablets.

[0298] Example 8: ACT-132577 tablets:

[0299] The tablet of Example 7 can be prepared by using a layer of White MS or White PVA (coating manufacturer: Biogrund) coating.

[0300] Example 9: ACT-132577 tablets:

[0301] Tablets each containing 12.5 mg of ACT-132577 can be prepared using a wet granulation process.

[0302] The tablet composition is as follows:

[0303]

[0304] qs = sufficient quantity

[0305] Preferably, ACT-132577 Form A (as described herein) will be used to prepare tablets.

[0306] Example 10: ACT-132577 tablets:

[0307] The tablet of Example 9 can be prepared by using a layer of White MS or White PVA (coating manufacturer: Biogrund) coating.

[0308] Properties of the crystal form

[0309] Example 11: Storage at room temperature

[0310] A sample of Form A crystals of the Compound (as obtained according to Example 1 above) has been stored at a temperature of 20-25°C and 92% relative humidity for 2 months. X-ray powder diffraction performed on the sample at the end of 2 months showed that the sample still consisted only of Form A crystals of the Compound. The same results were obtained after 8 weeks of storage under the above conditions. The HPLC control of the sample after 8 weeks of storage revealed no significant change in the peak area%, i.e., no significant degradation was observed under these conditions.

[0311] Example 12: Hygroscopicity

[0312] Form A is considered slightly hygroscopic as determined by gravimetric vapor sorption (GVS). The mass increase of the sample as obtained according to Example 1 in the first cycle from 40% rh to 80% rh corresponds to 0.4%. At 95% rh, 2.2% water is absorbed in a reversible manner without hysteresis after drying.

[0313] Examples of Therapeutic Uses of ACT-132577

[0314] The therapeutic effect can be modeled in multiple animal models. For example, the spontaneously hypertensive rat (SHR) is the most widely used animal model of genetic hypertension. It is characterized by increased stroke damage, insulin resistance syndrome and renal damage. Renal damage includes arteriolar damage, glomerular damage and proteinuria. Therefore, the SHR model can be used to simulate cardiovascular conditions associated with several risk factors, namely hypertension, insulin resistance and renal failure (MAPoteza et al. Am J Physiol Heart Circ Physiol (2005) 289: H813-H822; LG Feld et al. Kidney International (1981), 20, 606-614). Dahl salt-sensitive rats and DOCA salt rats are models of salt-sensitive hypertension associated with strong stimulation of mineralocorticoid receptors (DOCA salt model) or low / moderate stimulation of mineralocorticoid receptors (Dahl salt model). Both models are characterized by hypertension, endothelial cell dysfunction, and end-organ damage involving the heart, brain, and kidneys (YM Pinto et al. Cardiovascular Research 1998, 39, 77-88).

[0315] Example A: Acute Effects of ACT-132577 in Dahl Salt-Sensitive Rats:

[0316] The acute effects of ACT-132577 on blood pressure, in particular mean arterial blood pressure (hereinafter referred to as "MAP") and heart rate (hereinafter referred to as "HR"), can be assessed by telemetry in conscious male hypertensive Dahl salt-sensitive rats (hereinafter referred to as "Dahl-S rats" - see Rapp, Hypertension (1982), 4, 753-763 for details on this model).

[0317] Elevated blood pressure was induced in Dahl-S rats by providing 1% sodium chloride in the drinking water. Groups of 6-7 Dahl-S rats were used against vehicle (7.5% gelatin in water) and various doses of ACT-132577 (0.3, 1, 3, 10, 30, 100 and 300 mg / kg) were tested. The effects of ACT-132577 on HR and MAP were calculated for individual animals relative to the first 24 h period of dosing. The results obtained with respect to MAP (maximum MAP reduction was observed within 6 consecutive hours) are summarized in Figure 3 (Data are presented as mean ± standard error of the mean). In conclusion, ACT-132577 at a dose of 10 mg / kg reduced MAP by 19 ± 4 mm Hg in Dahl-S rats. In contrast to MAP, HR was not affected.

[0318] Example B: Acute Effects of ACT-132577 in Deoxycorticosterone Acetate Rats:

[0319] The acute effects of ACT-132577 on blood pressure, in particular mean arterial blood pressure (hereinafter "MAP") and heart rate (hereinafter "HR"), can be assessed by telemetry in conscious male hypertensive deoxycorticosterone acetate rats (hereinafter "DOCA rats" - see Gavras et al., Circ. Res. (1975), 36, 300-309 for details on this model).

[0320] In DOCA-salt rats, hypertension was induced by a combination of unilateral nephrectomy, implantation of a pellet of the mineralocorticoid analog DOCA, and provision of 1% sodium chloride in the drinking water. Groups of 6-11 DOCA-salt rats were used against vehicle (7.5% gelatin in water), and doses of ACT-132577 (0.3, 1, 3, 10, 30, 100, and 300 mg / kg) were tested. The effects of ACT-132577 on HR and MAP were calculated for individual animals relative to the 24 h period prior to dosing. The results obtained with respect to MAP (maximum MAP reduction was observed within 6 consecutive hours) are summarized in Figure 4(Data are presented as mean ± standard error of the mean). In conclusion, in DOCA-salt rats, ACT-132577 at a dose of 10 mg / kg reduced MAP by 29 ± 6 mm Hg. In contrast to MAP, HR was not affected.

[0321] Example C: Acute effects of ACT-132577 in spontaneously hypertensive rats:

[0322] The acute effects of ACT-132577 on blood pressure, in particular mean arterial blood pressure (hereinafter referred to as "MAP") and heart rate (hereinafter referred to as "HR"), can be assessed by telemetry in conscious male spontaneously hypertensive rats (hereinafter referred to as "SHR" - see Atanur et al., Genome Res. (2010), 20, 791-803 for details on this model).

[0323] Groups of 4-6 SHR were used against vehicle (7.5% gelatin in water) and each dose of ACT-132577 (1, 3, 10, 30, 100 and 300 mg / kg) was tested. The effects of ACT-132577 on HR and MAP were calculated for individual animals relative to the 24 h period prior to dosing. The results obtained with respect to MAP (maximum MAP reduction was observed within 6 consecutive hours) are summarized in Figure 5 (Data are presented as mean ± standard error of the mean). In conclusion, in SHR, ACT-132577 at a dose of 100 mg / kg reduced MAP by 18 ± 4 mm Hg. In contrast to MAP, HR was not affected.

[0324] Example D: Acute effects of ACT-132577 alone or in combination with valsartan in spontaneously hypertensive rats:

[0325] The acute effects of ACT-132577 administered orally at a single dose of 100 mg / kg on blood pressure, in particular on mean arterial blood pressure (hereinafter referred to as "MAP") and heart rate (hereinafter referred to as "HR"), where ACT-132577 is used alone or in combination with valsartan administered orally at a single dose of 10 mg / kg, can be assessed by telemetry in conscious male spontaneously hypertensive rats (hereinafter referred to as "SHR" - see Atanur et al., Genome Res. (2010), 20, 791-803 for details on this model).

[0326] Six SHRs per treatment group were used for this test. The results obtained with respect to MAP are summarized in Figure 6Figure 1 shows the results of the 6-hour mean of the blood pressure values ​​obtained after the administration of each compound separately. The results are shown in Figure 1 , where each data point is presented as a 6-hour mean (NB: the expected additive effect of the combination of the two drugs, called "predicted additive effect", was calculated by adding the reductions in blood pressure values ​​obtained after separate administration of each compound); vehicle (7.5% gelatin in water) treatment had no effect on MAP or HR, and therefore the obtained results are not presented in the figure. In short, co-administration of ACT-132577 and valsartan reduced MAP beyond the predicted (calculated) value, indicating a synergistic effect between the two molecules. Compared with MAP, HR was not affected in any of the treatment groups.

[0327] Example E: Acute effects of ACT-132577 alone or in combination with valsartan in deoxycorticosterone acetate rats:

[0328] The acute effects of ACT-132577 administered orally at a single dose of 10 mg / kg on blood pressure, in particular on mean arterial blood pressure (hereinafter referred to as "MAP") and heart rate (hereinafter referred to as "HR"), where ACT-132577 was used alone or in combination with valsartan administered orally at a single dose of 30 mg / kg, can be assessed by telemetry in conscious male hypertensive deoxycorticosterone acetate rats (hereinafter referred to as "DOCA-salt rats" - see Gavras et al., Circ. Res. (1975), 36, 300-309 for details on this model).

[0329] In DOCA-salt rats, hypertension was induced by a combination of unilateral nephrectomy, implantation of a bolus of the mineralocorticoid analog DOCA, and provision of 1% sodium chloride in the drinking water. For this test, 7-8 DOCA-salt rats per treatment group were used. The results obtained with respect to MAP are summarized in Figure 7 Figure 1 shows the results of the 6-hour mean of the blood pressure values ​​obtained after the administration of each compound separately. The results are shown in Figure 1 , where each data point is presented as a 6-hour mean (NB: the expected additive effect of the combination of the two drugs, called "predicted additive effect", was calculated by adding the reductions in blood pressure values ​​obtained after separate administration of each compound); vehicle (4% aqueous gelatin solution) treatment had no effect on MAP or HR, and therefore the obtained results are not presented in the figure. In short, co-administration of ACT-132577 and valsartan reduced MAP beyond the predicted (calculated) value, indicating a synergistic effect between the two molecules. Compared with MAP, HR was not affected in any of the treatment groups.

[0330] Example F: Acute effects of ACT-132577 alone or in combination with enalapril in spontaneously hypertensive rats:

[0331] The acute effects of ACT-132577 administered orally at a single dose of 100 mg / kg on blood pressure, in particular on mean arterial blood pressure (hereinafter referred to as "MAP") and heart rate (hereinafter referred to as "HR"), where ACT-132577 was used alone or in combination with enalapril administered orally at a single dose of 3 mg / kg, can be assessed by telemetry in conscious male spontaneously hypertensive rats (hereinafter referred to as "SHR" - see Atanur et al., Genome Res. (2010), 20, 791-803 for details on this model).

[0332] Seven SHRs per treatment group were used for this test. The results obtained with respect to MAP are summarized in Figure 8 Figure 1 shows the results of the 6-hour mean of the blood pressure values ​​obtained after the administration of each compound separately. The results are shown in Figure 1 , where each data point is presented as a 6-hour mean (NB: the expected additive effect of the combination of the two drugs, called "predicted additive effect", was calculated by adding the reductions in blood pressure values ​​obtained after separate administration of each compound); vehicle (4% aqueous gelatin solution) treatment had no effect on MAP or HR, and therefore the obtained results are not presented in the figure. In short, co-administration of ACT-132577 and enalapril reduced MAP beyond the predicted (calculated) value, indicating a synergistic effect between the two molecules. Compared with MAP, HR was not affected in any of the treatment groups.

[0333] Example G: Acute effects of ACT-132577 alone or in combination with amlodipine in deoxycorticosterone acetate rats:

[0334] The acute effects of ACT-132577 administered orally at a single dose of 10 mg / kg on blood pressure, in particular on mean arterial blood pressure (hereinafter referred to as "MAP") and heart rate (hereinafter referred to as "HR"), where ACT-132577 is used alone or in combination with amlodipine administered orally at a single dose of 1 mg / kg, can be assessed by telemetry in conscious male hypertensive deoxycorticosterone acetate rats (hereinafter referred to as "DOCA-salt rats" - see Gavras et al., Circ. Res. (1975), 36, 300-309 for details on this model).

[0335] In DOCA-salt rats, hypertension was induced by a combination of unilateral nephrectomy, implantation of a bolus of the mineralocorticoid analog DOCA, and provision of 1% sodium chloride in the drinking water. For this test, 6-8 DOCA-salt rats per treatment group were used. The results obtained with respect to MAP are summarized in Fig. 9Figure 1 shows the results of the 6-hour mean of the blood pressure values ​​obtained after the administration of each compound separately. The results are shown in Figure 1 , where each data point is presented as a 6-hour mean (NB: the expected additive effect of the combination of the two drugs, called "predicted additive effect", was calculated by adding the reductions in blood pressure values ​​obtained after separate administration of each compound); vehicle (4% gelatin in water) treatment had no effect on MAP or HR, and therefore the obtained results are not presented in the figure. In short, co-administration of ACT-132577 and amlodipine reduced MAP beyond the predicted (calculated) value, indicating a synergistic effect between the two molecules. Compared to MAP, HR was not affected in any of the treatment groups.

[0336] Example H: Acute Effects of ACT-132577 in Deoxycorticosterone Acetate Rats:

[0337] The chronic effects of repeated administration of ACT-132577 at doses of 1, 10 and 100 mg / kg / day, in particular on mean arterial blood pressure (hereinafter referred to as "MAP") and heart rate (hereinafter referred to as "HR") can be evaluated in conscious male hypertensive deoxycorticosterone acetate rats (hereinafter referred to as "DOCA-salt rats" - see details of this model in Gavras et al., Circ. Res. (1975), 36, 300-309). In DOCA-salt rats, hypertension is induced by a combination of unilateral nephrectomy, implantation of a bolus of the mineralocorticoid analog DOCA, and provision of 1% sodium chloride in the drinking water. The results of DOCA-salt rats treated with ACT-132577 can be compared with those obtained for Weiss rats or for DOCA-salt rats receiving vehicle only (4% gelatin in water).

[0338] a) The results obtained with respect to MAP are summarized in Fig.10 , where each data point is presented as a 24-hour average. Six rats (Weiss control rats ( Fig.10 ), DOCA-salt control rats ( Fig.10 ) and DOCA-salt rats receiving repeated administration of 1, 10, and 100 mg / kg / day of ACT-132577 (respectively Fig.10 In brief, oral administration of ACT-132577 over 4 weeks dose-dependently reduced the DOCA-salt-induced increase in MAP without altering HR.

[0339] b) The results obtained regarding renal vascular resistance are summarized in Fig.11 In which:

[0340] DOCA 2w means that DOCA-salt rats were sacrificed just before starting treatment with ACT-132577; and

[0341] The “*” symbol indicates statistical significance at p < 0.05 using one-way ANOVA followed by Newmal-Keuls multiple comparison post hoc test.

[0342] In conclusion, based on these tests, chronic oral administration of ACT-132577 to DOCA-salt rats dose-dependently increased renal blood flow and reduced renal vascular resistance. ACT-132577 also tended to reduce left ventricular hypertrophy, as indicated by a dose-dependent decrease in plasma concentrations of N-terminal pro-brain natriuretic peptide (NTproBNP),

[0343] Example I: Effects of ACT-132577 alone or in combination with ACE inhibitors or ARBs in animal models of diabetes:

[0344] The effects of ACT-132577 can be evaluated 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 effects of ACT-132577 alone or in combination on glucose tolerance, insulinemia, and end-organ damage can be studied. End-organ damage includes: vascular function, renal function (e.g., proteinuria), myocardial function and remodeling, and any other target organs affected by diabetes (e.g., the eye).

[0345] Example J: Evaluation of the Effect of ACT-132577 on Fluid Retention

[0346] A decrease in hematocrit (Hct) or heme is secondary to an increase in plasma volume and can be used as a marker for fluid retention. A single oral dose of ACT 132577 (1-30 mg / kg) or vehicle (gelatin) was administered by gavage to male Weiss rats. Twenty-four hours after administration, sublingual blood was sampled under isoflurane-induced anesthesia. Hematocrit was measured using a hematology analyzer. ACT-132577 had no effect on hematocrit (Hct) in this analysis, indicating a lower adverse effect on fluid retention ( Fig.12 ).

[0347] Example K: Hematocrit Measurement, Effect of SGLT-2 Inhibitors Alone or in Combination with ACT-132577

[0348] Male Weiss rats aged eight to 12 weeks [healthy or sick (streptozotocin diabetic rats) or under diuretic treatment (loop diuretics, e.g., furosemide)] were randomly divided into groups (n=12) according to their body weight and baseline hematocrit (Hct) in a stratified manner. SGLT-2 inhibitors (e.g., canagliflozin) were orally administered daily for one week at a dose of 30 mg / kg (canagliflozin). Subsequently, the same dose of SGLT-2 inhibitor and ACT-132577 (1 to 30 mg / kg) or vehicle (gelatin) were administered by gavage, n=6 / group. Sublingual blood was sampled twice a week under isoflurane-induced anesthesia (AttaneTM, MINRADINC. Buffalo, New York). Hematocrit (Hct), hemoglobin (Hb), and erythrocyte indices were measured using a hematology analyzer (Coulter AcT, Beckman Coulter, Nyon, Switzerland and Advia2120i, Siemens Healthcare Diagnostics GmBH, Zurich, Switzerland).

[0349] Example L: Blood pressure measurements, effects of SGLT-2 inhibitors alone or in combination with ACT-132577

[0350] Spontaneously hypertensive rats (SHR) were microsurgically equipped with a telemetric pressure transmitter (Data Science International, Minnesota, USA) implanted in the abdominal cavity under isoflurane-induced anesthesia. Briefly, a pressure catheter was inserted into the aorta, below the renal artery pointing upstream. The abdomen was closed and the transmitter was sutured to the abdominal musculature. Blood pressure was continuously collected using the Dataquest ART platinum acquisition system (version 4.36). Drugs (ACT-132577 or SGLT2 inhibitors) or vehicles, either alone or in combination, were administered by tube feeding (n=4-7 per group). Systolic, mean and diastolic arterial pressures and heart rate were collected at 5-minute intervals until the blood pressure curve returned to baseline.

[0351] Results: The greatest effect on MAP is summarized in Fig.13 and 14On. Since it takes several days for SGLT2 inhibitors to exert their effects on blood pressure, rats were first treated with vehicle (5 ml / kg / day) or canagliflozin (30 mg / kg / day) or empagliflozin (30 mg / kg / day) for 12 days, followed by co-administration of ACT-132577 (30 mg / kg / day) for 3 days. Canagliflozin and empagliflozin reduced MAP by -9±1 and -13±3 mm Hg, respectively. The data confirmed that ACT-132577 further reduced blood pressure by -14±1 and -18±3 mm Hg, respectively, when applied on top of canagliflozin or empagliflozin. Such reductions in blood pressure were similar to the reductions obtained when ACT-132577 was applied on top of the vehicle without canagliflozin or empagliflozin (-16±2 and -14±2 mm Hg, respectively).

[0352] In conclusion, based on these results, ACT-132577 at least maintains its hemodynamic efficacy when combined with two different SGLT2 inhibitors in a model of hypertension associated with insulin resistance.

[0353] Example M: ​​Independent kidney preparation, effect of SGLT-2 inhibitors alone or in combination with ACT-132577

[0354] Kidney from healthy or diabetic rats is removed and installed in perfusion system to monitor renal pressure.Male Weiss rats are put to death, lower abdomen is exposed and adipose tissue around left kidney and major blood vessels (aorta, vena cava, renal artery and vein) is excised.Kidney and related blood vessels are removed en bloc, and inox cannula (OD1mm, ID0.7mm, Hugo Sachs) cannula renal vein and subsequent renal artery are cannulated, and fixed with silk sutures.Kidney through cannula is subsequently connected to the perfusion system equipped with pressure sensor (No. 2 kidney equipment perfused, Hugo Sachs, Germany).Perfusion buffer is improved Krebs-Henseleit buffer.The initial perfusion flow rate is 2 ml / min, which is then increased to 5 ml / min incrementally.The experimental scheme is carried out when perfusion pressure is stabilized at 15-25mm Hg. Drugs (SGLT2 inhibitors, ACT-132577, combinations thereof) were administered to the perfusion buffer via the perfusion reservoir (200 ml volume) and the pressure was continuously recorded.

[0355] Example N: Single EXFORGE and EXFORGE in combination with ACT-132577 or spironolactone Acute effects in spontaneously hypertensive rats

[0356] Exforge in combination with ACT-132577 or spironolactone The acute effects of (i.e., a fixed dose combination of valsartan / amlodipine / hydrochlorothiazide; doses of 1.6 mg / kg / 0.1 mg / kg / 0.25 mg / kg for valsartan / amlodipine / hydrochlorothiazide, respectively) on blood pressure, in particular on mean arterial blood pressure (hereinafter referred to as "MAP") and heart rate (hereinafter referred to as "HR"), can be assessed by telemetry in conscious male spontaneously hypertensive rats (hereinafter referred to as "SHR" - see Atanur et al., Genome Res. (2010), 20, 791-803 for details on this model).

[0357] Nine SHRs per treatment group were used for this test. To match the maximal effects of co-administered drugs on blood pressure in this model, Exforge mg / kg 100 mg / kg aprecitentan was administered orally on day 3 after 3 days, and 300 mg / kg spironolactone was co-administered orally with Exforge on day 1 Then apply Exforge 2 days. The results obtained with respect to MAP are summarized in Fig.15 and 16 , where each data point is presented as a 6-hour average.

[0358] Added in Exforge On top, aprecitentan or spironolactone further reduced blood pressure. However, aprecitentan induced a greater reduction in blood pressure compared with spironolactone. HR was not affected in either treatment group compared with MAP.

[0359] Example O: Exforge alone and EXFORGE in combination with ACT-132577 or spironolactone Acute effects of deoxycorticosterone acetate in rats

[0360] Exforge in combination with ACT-132577 (10 mg / kg) or spironolactone (300 mg / kg), each administered orally as a single dose The acute effects (doses of 3.2 mg / kg / 0.2 mg / kg / 0.5 mg / kg for valsartan / amlodipine / hydrochlorothiazide, respectively) on blood pressure, in particular mean arterial blood pressure (hereinafter "MAP") and heart rate (hereinafter "HR"), can be assessed by telemetry in conscious male hypertensive deoxycorticosterone acetate rats (hereinafter "DOCA-salt rats" - see Gavras et al., Circ. Res. (1975), 36, 300-309 for details of this model).

[0361] In DOCA-salt rats, hypertension was induced by a combination of unilateral nephrectomy, implantation of a bolus of the mineralocorticoid analog DOCA, and provision of 1% sodium chloride in the drinking water. For this test, 7-9 DOCA-salt rats per treatment group were used. The results obtained with respect to MAP are summarized in Fig.17 and 18 , where each data point is presented as a 6-hour average.

[0362] In Exforge When added topically, 10 mg / kg aprecitentan or 300 mg / kg spironolactone further reduced blood pressure. However, aprecitentan induced a greater reduction in blood pressure compared to spironolactone. HR was not affected in either treatment group compared to MAP.

[0363] Example P: Effects of ACT-132577 alone or in combination with SGLT2 inhibitors in animal models of diabetic nephropathy

[0364] The effects of ACT-132577 alone or in combination with SGLT2 inhibitors can be evaluated in animal models of diabetic nephropathy, such as ZDF-1 rats (Su et al. Am J Nephrol. 2016 November; 44(5): 339-353), a diabetic rodent model with renal damage. In particular, the effects of ACT-132577 alone or in combination with SGLT2 inhibitors on blood pressure, blood glucose and blood HBA1c, insulinemia and renal damage can be studied. Renal damage includes: proteinuria, measurement of glomerular filtration rate via metabolic cages, biomarkers (e.g., Kim-1), urinary and plasma ketone bodies and creatinine, and end-stage histopathological examination of the kidney (glomerular damage, vascular lesions, fibrosis).

Claims

1. A pharmaceutical composition comprising a combination of apremilast or a pharmaceutically acceptable salt thereof and an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof as active ingredients, and at least one pharmaceutically acceptable excipient, wherein the SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof is canagliflozin, dapagliflozin or empagliflozin or a pharmaceutically acceptable salt thereof.

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 any one of claims 1 to 3, wherein aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 to 50 mg of aprexitentan per day.

5. The pharmaceutical composition according to claim 2, wherein Aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 to 50 mg of aprexitentan per day; and Empagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 5 to 50 mg of empagliflozin per day.

6. The pharmaceutical composition according to claim 3, wherein aprexitentan or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 10 to 50 mg of aprexitentan per day; and • Dapagliflozin or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical unit dosage form suitable for oral administration of 1 to 20 mg of dapagliflozin per day.

7. Use of a combination of aprexitentan or a pharmaceutically acceptable salt thereof and an SGLT-2 inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament, For the treatment of chronic kidney disease (CKD) caused by / associated with hypertension; For the treatment of diabetic kidney disease (DKD) associated with hypertension; for reducing the risk of major cardiovascular events in patients with diabetes mellitus who are associated with at least one other cardiovascular risk factor including hypertension; or For the treatment of hypertension, including refractory hypertension; The SGLT-2 inhibitor is canagliflozin, dapagliflozin or empagliflozin, or a pharmaceutically acceptable salt thereof.

8. The use according to claim 7, wherein the drug For the treatment of CKD caused by / associated with hypertension.

9. Use according to claim 7, wherein the medicament is for the treatment of diabetic kidney disease (DKD) which is additionally associated with hypertension.

10. The use according to any one of claims 7, 8 or 9; wherein the SGLT-2 inhibitor is empagliflozin or a pharmaceutically acceptable salt thereof.

11. The use according to any one of claims 7, 8 or 9; wherein the SGLT-2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt thereof.

12. The use according to any one of claims 7, 8 or 9; wherein the SGLT-2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof.

13. The use according to any one of claims 7, 8 or 9; wherein aprexitentan or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical unit dosage form suitable for oral administration of 10 to 50 mg of aprexitentan per day.

14. The use according to any one of claims 7, 8 or 9; wherein aprexitentan or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical unit dosage form suitable for oral administration of 10 to 50 mg of aprexitentan per day; and If canagliflozin or a pharmaceutically acceptable salt thereof is present, it is administered in a pharmaceutical unit dosage form suitable for oral administration of 50 to 400 mg of canagliflozin per day; If dapagliflozin or a pharmaceutically acceptable salt thereof is present, it is administered in a pharmaceutical unit dosage form suitable for oral administration of 1 to 20 mg of dapagliflozin per day; and If empagliflozin or a pharmaceutically acceptable salt thereof is present, it is administered in a pharmaceutical unit dosage form suitable for oral administration of 5 to 50 mg of empagliflozin per day.

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