Patent Description:
Aprocitentan, {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide has the formula I
<CHM>.

Aprocitentan, also known under the name ACT-<NUM>, is an endothelin receptor inhibitor and useful as endothelin receptor antagonist. The compound of formula I is a member of a structural family that was previously generically disclosed in <CIT>. In particular, the compound of formula I, while showing endothelin receptor antagonist activity, exhibits in vivo a much longer half-life and a much shorter clearance in comparison to corresponding alkylated derivatives. This makes the compound of formula I particularly suitable for long-acting pharmaceutical compositions, as disclosed in <CIT>. Certain manufacturing processes relating to aprocitentan are disclosed in <CIT>.

Because of its ability to inhibit the endothelin binding, COMPOUND can be used for treatment of endothelin related diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such endothelin related diseases are hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers and portal hypertension. They can also be used in the treatment or prevention of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction, they can further be used in the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, hyperlipidemia as well as other diseases, presently known to be related to endothelin.

According to the <NUM> American Society of Hypertension and International Society of Hypertension joint statement [<NPL>], the<NPL>], as well as several national guidelines [<NPL>; <NPL>], resistant hypertension (rHT) (or difficult to treat hypertension) is defined as uncontrolled blood pressure (BP) (i.e., failure to lower BP to a pre-defined threshold) despite concurrent administration of three antihypertensive therapies of different pharmacological classes at maximal or optimal doses, including a diuretic. Thus, resistant hypertension patients include patients whose blood pressure is controlled with use of more than three medications. That is, patients whose blood pressure is controlled but require four or more medications to do so should be considered resistant to treatment (see e.g. <NPL>)).

Clinical studies have shown that endothelin receptor antagonists (ERAs) may have significant treatment effect in patients suffering from hypertension and/ or renal disease. However, therapeutic benefit needs to be weighted against potential side effects, such as the potential risk of teratogenic activity. In addition, both, selective ETA-antagonists and dual antagonists of both the ETA and ETB receptor, may cause cause fluid retention, a common side effect associated with many previously studied ERAs and sometimes (e.g. if not manageable with diuretics) leading to exaggerated major adverse cardiac events such as heart failure or death. Whereas the risk-benefit balance is in most cases in favor of treatment with an ERA for indications such as pulmonary hypertension (as reflected in the past by successive market approvals e.g. for the ERAs the dual antagonists bosentan and macitentan, the ETA-selective antagonist ambrisentan), ERAs have no role in the management of primary hypertension (<NPL>), and side effects such as fluid retention may remain an issue when a potential treatment of rHT, chronic kidney disease or other hypertension related diseses with an ERA is considered.

The ETA-selective endothelin receptor antagonist darusentan has been in development for the treatment of rHT (<NPL>, see also <CIT>). In a <NUM> week phase <NUM> trial in patients with rHT, it demonstrated efficacy on the reduction of ambulatory blood pressure, but failed to show significant treatment effect on the primary endpoint systolic blood pressure. Patients were eligible to participate if they had treatment resistant hypertension (systolic blood pressure of higher than <NUM> Hg) despite treatment with three or more antihypertensive drugs from different drug classes, including a diuretic, at optimized doses. A minimum dose of <NUM> per day of hydrochlorothiazide (or its equivalent for other thiazide diuretic drugs) was required. Even though during the trial diuretic therapy could be intensified at the discretion of the investigators to manage fluid retention, the most frequent adverse event associated with darusentan was fluid retention/edema at <NUM>% versus <NUM>% in each of the other groups. More patients withdrew because of adverse events on darusentan as compared with placebo.

<NPL>) discloses a randomised, double-blind study involving <NUM> patients with systolic blood pressure of <NUM> Hg or more (≥<NUM> Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses.

<CIT> provides a comprehensive summary of ERAs tested for various indications including chronic kidney disease (CKD) and rHT. Similarly to the observations made for darusentan mentioned above, also the ETA-selective ERA avosentan, in a trial that investigated the use of avosentan to reduce proteinuria in patients with diabetes, showed significant treatment effect, associated with a significantly increased discontinuation of trial medications due to adverse events, predominantly related to fluid overload and congestive heart failure. The trial was terminated prematurely, and the authors conclude that "it may be that at dosages of <NUM> to <NUM>, avosentan is less selective for the ETA receptor and thus caused sodium and water retention and peripheral vasodilation with a potential fluid shift from the intravascular to extravascular space. The assumption of ETB receptor blockade with higher dosages of avosentan is further supported by data that showed a natriuretic effect of selective ETA receptor blockade in people who were treated with ACEIs (<NPL>. " <CIT> provides further examples where fluid retention may have led to increased side effects for the ERAs bosentan, tezosentan, ambrisentan, and atrasentan. <CIT> concludes in proposing a method of treating CKD with an ERA, especially with the ETA-selective ERA atrasentan, using predictors of fluid retention; said method comprising the determination of a risk of fluid retention if an ERA were administered to the subject; and administering the ERA to the subject if the risk is at an acceptable level.

<CIT>) discloses a pharmaceutical composition which contains a renin angiotensin system inhibitor and an endothelin antagonist.

<CIT> reports aprocitentan as an endothelin receptor antagonist and its use in the treatment of hypertension and associated conditions.

Preclinical and clinical data suggest that the ETA-selective antagonists sitaxentan and ambrisentan pose a greater risk of fluid retention than the dual ERAs bosentan and macitentan (<NPL>). On the other hand, pre-clinical data showed that the synergistic effect on blood pressure of an ETA-selective ERA in combination with the ACE inhibitor enalapril was abolished by simultaneous blockade of the ETB-receptor (<NPL>). It has been shown in a phase <NUM> trial that aprocitentan, an ERA resulting in effective dual blockade of the endothelin receptors, may result in efficacious control of blood pressure in subjects having essential hypertension. (aprocitentan was administered as monotherapy, i.e. without background anti-hypertensive therapy) (Actelion Pharmaceuticals Ltd, press release May <NUM>, <NUM>). Even though some indications of potential fluid retention were observed (e.g. increased body weight at higher doses, dose related decrease in the hemoglobin concentration, four cases of peripheral edema at higher doses), the overall frequency of adverse events was similar to those observed in the placebo group. Thus, different from the methods of <CIT> no risk assessment and/or dose reduction to mitigate side effects related to fluid retention may be required for aprocitentan when used in the treatment of hypertension related diseases, especially resistant hypertension. Thus, aprocitentan may have a different pharmacological profile than the predominantly ETA-selective antagonists so far tested in resistant hypertension or chronic kidney disease in diabetic and non-diabetic patients.

It has been found that certain crystalline forms (not part of the invention, which is defined by the claims) of COMPOUND may under certain conditions be found. Said crystalline forms of COMPOUND may have advantageous properties in view of the potential use of COMPOUND as active pharmaceutical ingredient. Such advantages may include better flow properties; less hygroscopicity; better reproducibiliy in manufacturing (for example better filtration parameters, better reproducibility of formation, and/or better sedimentation); and/or defined morphology. Such crystalline forms of COMPOUND may be particularly suitable in a process of manufacturing certain pharmaceutical compositions. It has also been found that COMPOUND or a pharmaceutically acceptable salt thereof is particularly useful to treat certain disorders, in particular when used in combination with other active ingredients or therepeutic agents.

Subject matter which is not encompassed in the claims does not form part of the presently claimed invention.

Such pharmaceutical compositions according to embodiment <NUM>) are disclosed to be especially useful for the treatment of hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers or portal hypertension as well as for the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain or hyperlipidemia. The pharmaceutical compositions according to embodiment <NUM>) are also useful for the treatment of Chronic Kidney Disease (CKD), especially CKD of stages <NUM> to <NUM> as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage <NUM>), and in particular CKD (notably of these stages) caused by essential hypertension. Preferably, they are useful for in the treatment of a disease selected from the group consisting of hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and CKD [especially CKD of stages <NUM> to <NUM> as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage <NUM>); and in particular CKD (notably of these stages) caused by essential hypertension].

Moreover, they are useful in the treatment of a disease selected from the group consisting of essential hypertension, resistant hypertension, pulmonary hypertension and pulmonary arterial hypertension (and notably in the treatment of resistant hypertension).

Any reference to a method of treatment in this description is to be interpreted as reference to the compounds, pharmaceutical compositions or medicaments of the present invention for use in such method of treatment.

Essential hypertension (also called primary hypertension or idiopathic hypertension) is the form of hypertension that by definition has no identifiable cause. It represents a significant global public health concern, contributing to vascular and renal morbidity and to cardiovascular mortality. The diagnosis of essential hypertension is made when the average of multiple systolic blood pressure measurements on <NUM> or more subsequent visits is consistently equal to or above a certain threshold value TSBP. Individuals with high normal blood pressure tend to maintain pressures that are above average for the general population and are at greater risk for development of definite hypertension and cardiovascular events than the general population. The threshold value TSBP above which treatment is recommended is regularly discussed among clinicians (see e.g. <NPL>); accordingly, depending on the patient's general condition and age, TSBP could be <NUM> or <NUM> Hg, or another suitable value.

The term "resistant hypertension" in the present invention is defined as blood pressure that remains above goal in spite of the concurrent use of <NUM> antihypertensive agents of different classes. One of the <NUM> agents should be a diuretic and all agents should be prescribed at optimal/maximal dose amounts. As defined, resistant hypertension patients include patients whose blood pressure is controlled with use of more than <NUM> medications. That is, patients whose blood pressure is controlled but require <NUM> or more medications to do so should be considered resistant to treatment (see e.g. <NPL>).

"Diuretic" in particular means in the present application a diuretic of the thiazide class (a thiazide-like diuretic) such as especially chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide, or metolazone. Preferred diuretics are chlorthalidone or hydrochlorothiazide.

Further disclosed is COMPOUND, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>) (in particular crystalline Form A or C), wherein COMPOUND / said crystalline form is used as a medicament, especially for the treatment of resistant hypertension; wherein COMPOUND / said crystalline form is used alone or (preferably) in combination (preferably for simultaneously adminiatration, including a fixed dose combination) with a diuretic, in particular hydrochlorothiazide (HCTZ or HCT). In a sub-embodiment, said combination of COMPOUND / said crystalline form according to any one of embodiments <NUM>) to <NUM>) (in particular crystalline Form A or C) with a diuretic, in particular hydrochlorothiazide (HCTZ or HCT) for the treatment of resistant hypertension; may require further combination (preferably for simultaneously adminiatration, including a fixed dose combination) with one or two additional active ingredients that are antihypertensive agents of different classes (especially a CCB and/or an ARB), in particular valsartan. The invention, thus, especially relates to pharmaceutical compositions comprising COMPOUND / the respective crystalline form of COMPOUND as defined in any one of embodiments <NUM>) to <NUM>) below; comprising as active ingredients, in addition to COMPOUND / the respective crystalline form of COMPOUND, a diuretic, in particular hydrochlorothiazide (HCTZ or HCT); and optionally further comprising one or two active ingredients that are antihypertensive agents of different classes (especially a CCB and/or an ARB); in particular further comprising valsartan.

<NUM>) Another embodiment discloses a pharmaceutical composition comprising as active ingredient a crystalline form of the COMPOUND according to any one of embodiments <NUM>) to <NUM>), and at least one therapeutically inert excipient.

<NUM>) Further disclosed is a solid pharmaceutical composition (in particular in the form of a tablet) comprising COMPOUND, especially a crystalline form of the COMPOUND according to any one of embodiments <NUM>) to <NUM>) (especially solid form A of the COMPOUND, as described in any one of embodiments <NUM>) to <NUM>)), microcrystalline cellulose, lactose, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate; it will in particular relate to a solid pharmaceutical composition (in particular in the form of a tablet) consisting of a crystalline form of the COMPOUND according to any one of embodiments <NUM>) to <NUM>) (especially solid form A thereof, as described in any one of embodiments <NUM>) to <NUM>)), microcrystalline cellulose, lactose, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate.

<NUM>) Preferably, the solid pharmaceutical composition of embodiment <NUM>) will comprise COMPOUND, especially the crystalline form of the COMPOUND according to any one of embodiments <NUM>) to <NUM>) (especially solid form A of the COMPOUND, as described in any one of embodiments <NUM>) to <NUM>)) in a total amount from <NUM> to <NUM>% (especially <NUM> to <NUM>%) in weight based on the total weight of the pharmaceutical composition, microcrystalline cellulose in a total amount from <NUM> to <NUM> % (especially <NUM> to <NUM>%) in weight based on the total weight of the pharmaceutical composition, lactose in a total amount from <NUM> to <NUM>% in weight based on the total weight of the pharmaceutical composition, hydroxypropylcellulose in a total amount from <NUM> to <NUM>% in weight based on the total weight of the pharmaceutical composition, croscarmellose sodium in a total amount from <NUM> to <NUM>% in weight based on the total weight of the pharmaceutical composition and magnesium stearate in a total amount from <NUM> to <NUM>% in weight based on the total weight of the pharmaceutical composition, whereby the total percent in weight of the solid pharmaceutical composition will always be <NUM>; the aforementioned solid pharmaceutical composition will particularly be in the form of a tablet.

Such pharmaceutical compositions according to any of embodiments <NUM>) to <NUM>) are disclosed to be especially useful for the treatment of endothelin related diseases and disorders, notably the diseases and disorders of embodiment <NUM>).

<NUM>) A further embodiment discloses a pharmaceutical composition according to any one of embodiments <NUM>) to <NUM>), wherein said pharmaceutical composition is in form of a tablet. <NUM>) In particular, the pharmaceutical composition of embodiment <NUM>) will be in the form of a tablet consisting of the solid form A of the COMPOUND (as described in any one of embodiments <NUM>) to <NUM>)) in a total amount from <NUM> to <NUM>% (especially <NUM> to <NUM>%) in weight based on the total weight of the pharmaceutical composition, microcrystalline cellulose in a total amount from <NUM> to <NUM> % (especially <NUM> to <NUM>%) in weight based on the total weight of the pharmaceutical composition, lactose in a total amount from <NUM> to <NUM>% in weight based on the total weight of the pharmaceutical composition, hydroxypropylcellulose in a total amount from <NUM> to <NUM>% in weight based on the total weight of the pharmaceutical composition, croscarmellose sodium in a total amount from <NUM> to <NUM>% in weight based on the total weight of the pharmaceutical composition and magnesium stearate in a total amount from <NUM> to <NUM>% in weight based on the total weight of the pharmaceutical composition, whereby the total percent in weight of the solid pharmaceutical composition will always be <NUM>.

A tablet according to embodiment <NUM>) or <NUM>) can optionally be coated with a suitable protective pellicle. Said protective pellicle will notably prevent direct contact of the pharmaceutical composition with moisture; it may also ease imprints that may be desired to be used in order to distinguish the pharmaceutical composition from others.

The coating material for making such protective pellicle may include a low water vapour permeability polymer (such as a polyvinyl alcohol (e.g. Aquapolish® white PVA from manufacturer Biogrund) or dimethylaminoethyl methacrylate (e.g. EUDRAGIT® E PO)). The coating material can further include a plasticizing agent (e.g. propylene glycol, triacetyne, dibutyl phthalate or dibutyl sebacate), a surfactant (e.g. sodium lauryl sulphate or a polysorbate such as Tween®) and/or a lubricant/glidant (e.g. stearic acid, magnesium or calcium stearate or talc). Moreover, the coating material can also include a pigment (e.g. iron(II) oxide, iron(III) oxide or titanium oxide) to give the tablet a coloured aspect.

<NUM>) A further embodiment discloses a pharmaceutical composition according to any one of embodiments <NUM>) to <NUM>), wherein said pharmaceutical composition is in form of a capsule. For avoidance of any doubt, embodiments <NUM>), <NUM>), <NUM>), <NUM>), <NUM>), <NUM>) or <NUM>) especially discloses the crystalline forms according to any one of embodiments <NUM>) to <NUM>) which is suitable / which is used as final isolation step of COMPOUND (e.g. in order to meet the purity requirements of pharmaceutical production), whereas the final pharmaceutical composition according to embodiment <NUM>), <NUM>), <NUM>), <NUM>) , <NUM>), <NUM>) or <NUM>) may or may not contain said crystalline form (e.g. because the originally crystalline form of COMPOUND is further transformed during the manufacturing process and / or is dissolved in the pharmaceutically acceptable carrier material(s); thus, in the final pharmaceutical composition, COMPOUND may be present in non-crystalline form, in another crystalline form, or in dissolved form, or the like).

<NUM>) A further embodiment disclosesCOMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers or portal hypertension as well as for the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, hyperlipidemia or CKD [especially CKD of stages <NUM> to <NUM> as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage <NUM>), and in particular CKD (notably of these stages) caused by essential hypertension].

<NUM>) A further embodiment discloses COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of a disease selected from the group consisting of hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and CKD [especially CKD of stages <NUM> to <NUM> as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage <NUM>), and in particular CKD (notably of these stages) caused by essential hypertension].

<NUM>) A further embodiment discloses COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of a disease selected from the group consisting of essential hypertension, resistant hypertension, pulmonary hypertension and pulmonary arterial hypertension (and notably for use in the treatment of resistant hypertension).

For avoidance of any doubt, if a certain crystalline form of COMPOUND is described as useful for the prevention / prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases. Likewise, such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.

<NUM>) A further embodiment discloses the use of COMPOUND or a pharmaceutically acceptable salt thereof, especially of a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for the preparation of a medicament intended for the treatment of any one of the diseases or disorders mentioned in embodiment <NUM>).

<NUM>) Yet another embodiment discloses the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of a disorder selected from the group consisting of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction.

<NUM>) One sub-embodiment of embodiment <NUM>) discloses the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of CKD, especially CKD of stages <NUM> to <NUM> as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage <NUM>), and in particular CKD (notably of these stages) caused by essential hypertension.

<NUM>) Another sub-embodiment of embodiment <NUM>) discloses the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of diabetes (that is, type <NUM> or type <NUM> diabetes).

<NUM>) Another sub-embodiment of embodiment <NUM>) discloses the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of diabetic nephropathy.

<NUM>) Another sub-embodiment of embodiment <NUM>) discloses the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of diabetic retinopathy.

<NUM>) Another sub-embodiment of embodiment <NUM>) discloses the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of diabetic vasculopathy.

<NUM>) Another sub-embodiment of embodiment <NUM>) discloses the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of chronic heart failure.

<NUM>) According to one variant of sub-embodiment <NUM>), the chronic heart failure of sub-embodiment <NUM>) will be heart failure with preserved ejection fraction.

<NUM>) According to another variant of sub-embodiment <NUM>), the chronic heart failure of sub-embodiment <NUM>) will be diastolic heart failure.

<NUM>) Another sub-embodiment of embodiment <NUM>) discloses the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>), for use in the treatment of diastolic dysfunction.

<NUM>) Preferably, the COMPOUND or a pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>)] according to any one of embodiments <NUM>) to <NUM>) will be comprised in a pharmaceutical unit dosage form suitable for the oral administration of <NUM> to <NUM> (in particular <NUM> or <NUM> to <NUM>, notably <NUM> or <NUM>) per day of the COMPOUND {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide or of a pharmaceutically acceptable salt thereof.

<NUM>) Preferably, the COMPOUND or pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>)] according to any one of embodiments <NUM>) to <NUM>) will be for use in combination with an Angiotensin Converting Enzyme (ACE) inhibitor, an Angiotensin Receptor Blocker (ARB) or a Calcium Channel Blocker (CCB), or with a pharmaceutically acceptable salt of one of these.

"Angiotensin Converting Enzyme inhibitor" or "ACE inhibitor" in particular means in the present application captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril, or a pharmaceutically acceptable salt of one of these. A preferred ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.

"Angiotensin Receptor Blocker" or "ARB" in particular means in the present application valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan, or a pharmaceutically acceptable salt of one of these. A preferred ARB is valsartan or a pharmaceutically acceptable salt thereof.

"Calcium Channel Blocker" or "CCB" in particular means 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. A preferred CCB is amlodipine or a pharmaceutically acceptable salt thereof.

Accordingly, the COMPOUND or a pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>)] according to any one of embodiments <NUM>) to <NUM>) can be for use in combination with an ACE inhibitor, an ARB, and/or a CCB. The corresponding combined treatment may be effected simultaneously, separately, or over a period of time (especially simultaneously).

"Simultaneously", when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and/or treatments at approximately the same time; wherein it is understood that a simultaneous administration will lead to exposure of the subject to the two or more active ingredients and/or treatments at the same time. When administered simultaneously, said 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 by the same route of administration at approximately the same time), or by a non-fixed dose combination using two or more different routes of administration; wherein said administration leads to essentially simultaneous exposure of the subject to the two or more active ingredients and/or treatments. For example, when used in combination with an ACE inhibitor, an ARB, and/or a CCB, the COMPOUND would possibly be used "simultaneously". Likewise, when used in combination with a diuretic, the COMPOUND would possibly be used "simultaneously".

"Fixed dose combination", when referring to an administration type, means in the present application that the administration type concerned consists in the administration of one single pharmaceutical composition comprising the two or more active ingredients.

"Separately", when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and/or treatments at different points in time; wherein it is understood that a separate administration will lead to a treatment phase (e.g. at least <NUM> hour, notably at least <NUM> hours, especially at least <NUM> hours) where the subject is exposed to the two or more active ingredients and/or treatments at the same time; but a separate administration may also lead to a treatment phase where for a certain period of time (e.g. at least <NUM> hours, especially at least one day) the subject is exposed to only one of the two or more active ingredients and/or treatments. Separate administration especially refers to situations wherein at least one of the active ingredients and/or treatments is given with a periodicity substantially different from daily (such as once or twice daily) administration (e.g. wherein one active ingredient and/or treatment is given e.g. once or twice a day, and another is given e.g. every other day, or once a week or at even longer distances).

By administration "over a period of time" is meant in the present application the subsequent administration of two or more active ingredients and/or treatments at different times. The term in particular refers to an administration method according to which the entire administration of one of the active ingredients and/or treatments is completed before the administration of the other / the others begins. In this way it is possible to administer one of the active ingredients and/or treatments for several months before administering the other active ingredient(s) and/or treatment(s).

<NUM>) Also preferably, the COMPOUND or pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>)] according to any one of embodiments <NUM>) to <NUM>) will be for use in combination with a diuretic (in particular for use in combination with hydrochlorothiazide (HCT)).

Accordingly, the COMPOUND or a pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments <NUM>) to <NUM>)] according to any one of embodiments <NUM>) to <NUM>) can be for use in combination with a diuretic (in particular for use in combination with HCT). The corresponding combined treatment may be effected simultaneously, separately, or over a period of time (especially simultaneously), as defined hereabove.

The present invention as claimed relates to:
A first claimed embodiment relates to the compound {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide:
<CHM>
or a pharmaceutically acceptable salt thereof, for combination use in the treatment of chronic kidney disease (CKD) of stages <NUM> to <NUM> as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines, wherein said CKD is caused by essential hypertension wherein said compound is to be administered in combination with an Angiotensin Receptor Blocker (ARB) which is is valsartan, or a pharmaceutically acceptable salt thereof.

Another claimed embodiment relates to the compound {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide, or a pharmaceutically acceptable salt thereof, for use according to claimed embodiment <NUM>, wherein said combination use is for the treatment of CKD of stage <NUM> wherein said CKD is caused by essential hypertension.

Another claimed embodiment relates to the compound {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide for use according to claimed embodiments <NUM> or <NUM>, wherein said compound is to be administered in the form of a tablet, wherein said tablet consists of a pharmaceutical composition comprising:.

wherein the total percent in weight of the solid pharmaceutical composition is <NUM>.

Another claimed embodiment relates to the compound {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide for use according to any one of claimed embodiments <NUM> to <NUM>, wherein said compound is formulated to be administrable in a pharmaceutical unit dosage form suitable for the oral administration of <NUM> to <NUM> per day of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide.

Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail.

The following abbreviations are used throughout the specification and the examples:.

All XRPD patterns for the solid forms described herein have been obtained as described hereafter. X-ray powder diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a Lynxeye detector operated with CuKα-radiation in reflection mode (coupled two Theta/Theta). Typically, the X-ray tube was run at of 40kV/40mA. A step size of <NUM>° (2θ) and a step time of <NUM> sec over a scanning range of <NUM> - <NUM>° in 2θ were applied. The divergence slit was set to fixed <NUM>. Powders were slightly pressed into a silicon single crystal sample holder with depth of <NUM> and samples were rotated in their own plane during the measurement. Diffraction data are reported using combined Cu Kα1 and Kα2 radiation, without Kα2 stripping. The accuracy of the 2θ values as provided herein is in the range of +/- <NUM>-<NUM>° as it is generally the case for conventionally recorded X-ray powder diffraction patterns.

Measurements are performed on a multi sample instrument SPS-100n (Projekt Messtechnik, Ulm, Germany) operated in stepping mode at <NUM>. The sample is allowed to equilibrate at <NUM>% RH before starting a pre-defined humidity program (<NUM>-<NUM>-<NUM>-<NUM>-<NUM>-<NUM>% RH, steps of <NUM>% ΔRH and with a maximal equilibration time of <NUM> hours per step are applied. About <NUM> to <NUM> of each sample is used.

The hygroscopic classification is done according to the European Pharmacopeia Technical Guide (<NUM>, page <NUM>), e.g., slightly hygroscopic: increase in mass is less than <NUM>% and equal to or greater than <NUM>% mass/mass; hygroscopic: increase in mass is less than <NUM>% and equal to or greater than <NUM>% mass/mass. The mass change between <NUM>% relative humidity and <NUM>% relative humidity in the first adsorption scan is considered.

DSC data are collected on a Mettler Toledo STARe System (DSC822e module, measuring cell with ceramic sensor and STAR software version <NUM>) equipped with a <NUM>-position auto-sampler. The instrument is calibrated for energy and temperature using certified indium. Typically, <NUM>-<NUM> of each sample, in an automatically pierced aluminium pan, is heated at <NUM> min-<NUM>, unless stated otherwise, from -<NUM> to <NUM>. A nitrogen purge at <NUM> min-<NUM> is maintained over the sample. Peak temperatures are reported for melting points.

TGA data are collected on a Mettler Toledo STARe System (TGA851e module and STAR software version <NUM>) equipped with a <NUM> position auto-sampler. Typically about <NUM> of a sample, in an automatically pierced aluminium pan, is heated at <NUM> min-<NUM>, unless stated otherwise, from <NUM> to <NUM>. A nitrogen purge at <NUM> min-<NUM> is maintained over the sample.

A <NUM> double jacketed reactor was charged with <NUM>-(<NUM>-bromophenyl)-<NUM>-(<NUM>-((<NUM>-bromopyrimidin-<NUM>-yl)oxy)ethoxy)-<NUM>-fluoropyrimidine (<NUM>, <NUM> mol, <NUM> eq. (<CIT>)), sulfamide (<NUM>, <NUM> mol, <NUM> eq. ), K<NUM>CO<NUM> (<NUM>, <NUM> mol, <NUM> eq. ) and DMSO (<NUM>, <NUM> vol. ) doped with water (<NUM>, <NUM> mol, <NUM> eq. The heterogeneous mixture was heated to <NUM> during ca. <NUM>, after which time complete conversion was observed. After cooling to <NUM>, most of the inorganic salt freight was removed by filtration. The filter cake was washed with EtOAc/iPrOAc <NUM>: <NUM> (<NUM>, <NUM> vol. Celite (<NUM>, <NUM> wt. ) topped with a layer of charcoal (<NUM>, <NUM> wt. ) was preconditioned with EtOAc/iPrOAc <NUM>: <NUM> (<NUM>, <NUM> vol. ) (filtrate discarded). The reaction mixture was filtered over this cake and rinsed with EtOAc/iPrOAc <NUM>:<NUM> (<NUM>, <NUM> vol. Then <NUM>M aq. NaOAc solution (<NUM>, <NUM> mol, <NUM> eq, <NUM> vol. ) was added while keeping the temperature at <NUM>-<NUM>. phase was washed a second time with EtOAc/iPrOAc <NUM>:<NUM> (<NUM>, <NUM> vol. phase, <NUM> H<NUM>SO<NUM> (<NUM>, <NUM> mol, <NUM> eq. , <NUM> vol. ) was added during <NUM> at <NUM>-<NUM>. Crystallization started at pH <NUM>-<NUM>. The crude product was filtered off as XRPD pattern form K (DMSO solvate) or a mixture of form A and form K. It was washed twice with water (<NUM> x <NUM>, <NUM> x <NUM> vol. The solid was slurried in water (<NUM>, <NUM> vol. ) at rt for <NUM>. The solid was filtered off and slurried a second time in water (<NUM>, <NUM> vol. ) at rt for <NUM>. After washing with water (<NUM>, <NUM> vol. ), the pure product was dried in vacuum at <NUM> to afford {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide as a white to off-white solid (<NUM>, <NUM>% yield, XRPD pattern form A).

A reactor (<NUM> Hastelloy) was charged with <NUM>-(<NUM>-bromophenyl)-<NUM>-(<NUM>-((<NUM>-bromopyrimidin-<NUM>-yl)oxy)ethoxy)-<NUM> fluoropyrimidine (<NUM>, <NUM> mol), sulfamide (<NUM>, <NUM> mol, <NUM> eq. ), potassium carbonate (<NUM>, <NUM> mol, <NUM> eq. ), DMSO (<NUM>, <NUM> vol. ) and water (<NUM>, <NUM> mol, <NUM> eq. The contents of the reactor were heated to <NUM>-<NUM>. Monitoring by HPLC showed complete conversion in <NUM> hours. The contents were cooled to <NUM>-<NUM> and the solids were centrifuged off. Each load was washed with EtOAc/iPrOAc <NUM>:<NUM> (<NUM>, 3vol. The filtrate was re-charged in the reactor and charcoal (<NUM>, <NUM>%w/w) and Celite® (<NUM>, <NUM>% w/w) were added. The contents were agitated for <NUM> at <NUM>-<NUM> and filtered through a cartridge filter back into the reactor. The filters were rinsed with EtOAc/iPrOAc <NUM>:<NUM> (<NUM>, <NUM> vol. NaOAc (<NUM>% in water) (<NUM>, <NUM> vol. ) was added over <NUM>, keeping the temperature below <NUM>. After phase separation, the aq. layer was washed with EtOAc/iPrOAc <NUM>: <NUM> (<NUM>, <NUM> vol. ) at <NUM>-<NUM>. Sulfuric acid (<NUM>% in water; <NUM>, <NUM> mol, <NUM> eq. ) was added to the aq. layer at <NUM>-<NUM> over <NUM> hours to reach pH <NUM>. The contents were then cooled to <NUM>-<NUM> for <NUM>. The solids were filtered off and washed twice with water (<NUM> x <NUM>, <NUM> x <NUM> vol. The solid was slurried twice in water (<NUM> x <NUM>, <NUM> x <NUM> vol. ) at <NUM>-<NUM> for <NUM> hours each, filtered and dried, to yield <NUM>-(<NUM>-bromophenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide as a white solid (<NUM>, <NUM>% yield, XRPD pattern Form A).

<NUM>-(<NUM>-bromophenyl)-<NUM>-(<NUM>-((<NUM>-bromopyrimidin-<NUM>-yl)oxy)ethoxy)-<NUM> fluoropyrimidine (<NUM>, <NUM> mmol, <NUM> eq. ), sulfamide (<NUM>, <NUM> mmol, <NUM> eq. ) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> eq. ) were suspended in DMSO (<NUM>, <NUM> vol. ) and heated to <NUM> for <NUM>. The mixture was cooled to rt and EtOAc (<NUM>, <NUM> vol. ) followed by water (<NUM>, <NUM> vol. ) were added. After separation of the layers (org. phase discarded), the aq. phase was extracted with DCM (<NUM>, <NUM> vol. The DCM layer was acidified from pH <NUM> to pH <NUM> with conc. AcOH (<NUM>, <NUM> mmol, <NUM> eq. ), resulting in crystallization of the product. The suspension was cooled to <NUM> for <NUM>, then to -<NUM> for <NUM>. The solid was filtered, washed with cold DCM (<NUM>, <NUM> vol. ) and dried to yield a DCM solvate of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form B as a white solid (<NUM>, <NUM>% yield).

<NUM> of a stock solution of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide dissolved in THF at <NUM>/mL was dispensed to <NUM> vials. The solvent was evaporated for <NUM> in a Combidancer device from Hettich AG (Bäch, Switzerland) operated at <NUM> and <NUM> mbar. Immediately thereafter <NUM> of MeOH for the first vial, EtOH for the second vial and iPrOH for the third vial was added and the vials were allowed to stand closed for <NUM> days. Solid residue of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form C was obtained for each of these solvents.

A reactor was charged with sulfamide (<NUM> eq. ), K<NUM>CO<NUM> (<NUM> eq. ), <NUM>-(<NUM>-bromophenyl)-<NUM>-(<NUM>-((<NUM>-bromopyrimidin-<NUM>-yl)oxy)ethoxy)-<NUM>-fluoropyrimidine (<NUM> eq. ), DMSO (<NUM> vol. ) and water (<NUM> vol. The mixture was heated to <NUM> for <NUM>.

After cooling to <NUM>, the suspension was filtered and rinsed with EtOAc/iPrOAc <NUM>: <NUM> (<NUM> vol. ) through the reactor. The filtrate was again filtered through an in-line filter and rinsed with EtOAc/iPrOAc <NUM>: <NUM> (<NUM> vol. A solution of <NUM> NaOAc in water (<NUM> vol. ) was added at <NUM>, and the layers were separated. phase was washed with EtOAc/iPrOAc <NUM>:<NUM> (<NUM> vol. phase was acidified to pH <NUM> using <NUM>M H<NUM>SO<NUM> in water (<NUM> vol. ) over <NUM>, leading to crystallization. After <NUM> stirring at <NUM>, the suspension was filtered and washed with water (<NUM> x <NUM> vol. The solid was slurried twice in water (<NUM> x <NUM> vol. ) at <NUM> for <NUM> each, filtered, washed with water (<NUM> vol. ) and dried to give {<NUM>-(<NUM>-bromophenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form D.

<NUM> of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form A was dissolved in <NUM> methyl-ethylketone in a new <NUM> glass vial. After sonication in an ultrasound bath for <NUM>, the vial was allowed to stand open at rt for <NUM> days. The solid residue was {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form D.

{<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form A was heated to reflux in <NUM> volumes of MeCN. After <NUM> it was allowed to cool down to <NUM> within <NUM> (heating bath removed). It was filtered off and dried under reduced pressure and <NUM>. Solid residue was a MeCN solvate of {<NUM>-(<NUM>-bromophenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form E.

The DCM solvate of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide Form B (<NUM>, <NUM> mmol, <NUM> eq. ) was dissolved in DMSO (<NUM>, <NUM> vol. The solution was added into H<NUM>O (<NUM>, <NUM> vol. ) and stirred at rt for <NUM>. The resulting suspension was filtered, washed twice with H<NUM>O (<NUM> x <NUM>, <NUM> x <NUM> vol. ) and dried to provide {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide Form J as a white solid (<NUM>, <NUM>% yield).

{<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide Form A (<NUM>, <NUM> mmol, <NUM> eq. ) was dissolved in DMSO (<NUM>, <NUM> vol. To this solution, <NUM>% H<NUM>O in DMSO (<NUM>, <NUM> vol. ) was added slowly, followed by pure H<NUM>O (<NUM>, <NUM> vol. Seeding with form K triggered crystallization of the product. The suspension was filtered, washed with H<NUM>O (<NUM> x <NUM>, <NUM> x <NUM> vol. ) and dried to give a DMSO solvate {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form K as a white solid (<NUM>, <NUM>% yield).

<NUM>-(<NUM>-bromophenyl)-<NUM>-(<NUM>-((<NUM>-bromopyrimidin-<NUM>-yl)oxy)ethoxy)-<NUM>-fluoropyrimidine (<NUM>, <NUM> mmol, <NUM> eq. ), sulfamide (<NUM>, <NUM> mmol, <NUM> eq. ) and K<NUM>CO<NUM> (<NUM>, <NUM> mmol, <NUM> eq. ) were suspended in DMSO (<NUM>, <NUM> vol. ) and heated to <NUM> for <NUM>. The mixture was cooled to rt and MIBK (<NUM>, <NUM> vol. ) followed by water (<NUM>, <NUM> vol. ) were added. After separation of the layers (org. phase discarded), the aq. phase was acidified from pH <NUM> to pH <NUM> with conc. AcOH (<NUM>, <NUM> mmol, <NUM> eq. ), resulting in crystallization of the product. The solid was filtered, washed with water (<NUM> x <NUM>, <NUM> x <NUM> vol. ) and dried to afford a DMSO solvate of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form K as a beige solid (<NUM>, <NUM>% yield).

The DMSO solvate of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide Form K (<NUM>, <NUM> mmol, <NUM> eq. ) was slurried in EtOH (<NUM>, <NUM> vol. ) at rt for <NUM>. The suspension was filtered, washed twice with H<NUM>O (<NUM> x <NUM>, <NUM> x <NUM> vol. ) and dried to afford an EtOH solvate of {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide in Form L as a white solid (<NUM>, <NUM>% yield).

Tablets containing each <NUM> of COMPOUND can be prepared using a wet granulation process. The tablet composition is the following:
<IMG>.

Preferably, COMPOUND in crystalline Form A (as described herein) will be used for making the tablets.

The tablets of Example <NUM> can be coated with a layer of Aquapolish® white MS or Aquapolish® white PVA (coating manufacturer: Biogrund).

A sample of Form A crystals of the COMPOUND (as obtained according to Example <NUM> above) has been stored at a temperature of <NUM>-<NUM> at <NUM>% relative humidity for <NUM> months. X-ray powder diffraction performed on that sample at the end of the <NUM> months showed that the sample was still consisting only in Form A crystals of the COMPOUND. The same result was obtained after storage for <NUM> weeks under the above coditions. HPLC control of the sample after <NUM> weeks storage revealed no significant change in peak area%, i.e. no significant degradation was observed under such conditions.

A sample of Form B crystals of a dichloromethane solvate of the COMPOUND (as obtained according to Example <NUM> above) has been stored in a closed vial (<NUM> of Form B crystals being placed in a closed <NUM> vial) at a temperature of <NUM>-<NUM> for about <NUM> weeks. X-ray powder diffraction performed on that sample at the end of the <NUM> weeks showed that the Form B crystals were transformed into Form A crystals of the COMPOUND.

A sample of Form K crystals of a dimethylsulfoxide solvate of the COMPOUND (as obtained according to Example <NUM> above) has been stored in a closed vial (<NUM> of Form K crystals being placed in a closed <NUM> vial) at a temperature of <NUM>-<NUM> for about <NUM> weeks. X-ray powder diffraction performed on that sample at the end of the <NUM> weeks showed that the Form K crystals were transformed into Form A crystals of the COMPOUND.

Form A of COMPOUND (as obtained by example <NUM>) melts and decomposes concomitantly. By DSC an endothermic/exothermic signal is observed, with a peak of the endotherm observed at about <NUM>.

Form C of COMPOUND (as obtained by example <NUM>) melts and decomposes concomitantly. By DSC an endothermic/exothermic signal is observed, with a peak of the endotherm observed at about <NUM>.

Form A e.g. as obtained from Example <NUM> is considered to be non-hygroscopic as determined by gravimetric vapor sorption (GVS) (see <FIG>).

Form C e.g. as obtained from Reference Example <NUM> is considered to be slightly hygroscopic as determined by gravimetric vapor sorption (GVS) (see <FIG>).

The acute effects of COMPOUND on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR") were evaluated by means of telemetry in conscious, male hypertensive Dahl salt-sensitive rats (hereafter "Dahl-S rats" - see details about this model in <NPL>).

Elevated blood pressure is induced in Dahl-S rats by providing <NUM>% sodium chloride in drinking water. Groups of <NUM>-<NUM> Dahl-S rats were used for the vehicle (<NUM>% gelatin aquous solution) and each dose of COMPOUND tested (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg). Effects of COMPOUND on HR and MAP were calculated for individual animals relative to the <NUM> period before administering. The results obtained regarding MAP (maximal MAP decrease observed over <NUM> consecutive hours) are summarised in <FIG> (data are presented as mean ± standard error of the mean). In summary, a dose of <NUM>/kg COMPOUND decreased MAP by <NUM> ± <NUM> Hg in Dahl-S rats. In contrast to MAP, HR was not affected.

The acute effects of COMPOUND on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR") were evaluated by means of telemetry in conscious, male hypertensive deoxycorticosterone acetate salt rats (hereafter "DOCA-salt rats" - see details about this model in <NPL>).

In the DOCA-salt rats, hypertension is induced by the combination of unilateral nephrectomy, implantation of pellets of the mineralocorticoid analog DOCA, and provision of <NUM>% sodium chloride in drinking water. Groups of <NUM>-<NUM> DOCA-salt rats were used for the vehicle (<NUM>% gelatin aquous solution) and each dose of COMPOUND tested (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg). Effects of COMPOUND on HR and MAP were calculated for individual animals relative to the <NUM> period before administering. The results obtained regarding MAP (maximal MAP decrease observed over <NUM> consecutive hours) are summarised in <FIG> (data are presented as mean ± standard error of the mean). In summary, a dose of <NUM>/kg COMPOUND decreased MAP by <NUM> ± <NUM> Hg in DOCA-salt rats. In contrast to MAP, HR was not affected.

The acute effects of COMPOUND on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR") were evaluated by means of telemetry in conscious, male spontaneaously hypertensive rats (hereafter "SHRs" - see details about this model in <NPL>).

Groups of <NUM>-<NUM> SHRs were used for the vehicle (<NUM>% gelatin aquous solution) and each dose of COMPOUND tested (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>/kg). Effects of COMPOUND on HR and MAP were calculated for individual animals relative to the <NUM> period before administering. The results obtained regarding MAP (maximal MAP decrease observed over <NUM> consecutive hours) are summarised in <FIG> (data are presented as mean ± standard error of the mean). In summary, a dose of <NUM>/kg COMPOUND decreased MAP by <NUM> ± <NUM> Hg in SHRs. In contrast to MAP, HR was not affected.

The acute effects of COMPOUND administered orally at a single dose of <NUM>/kg on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR"), with COMPOUND being used either alone or in combination with valsartan administered orally at a single dose of <NUM>/kg, were evaluated by means of telemetry in conscious, male spontaneaously hypertensive rats (hereafter "SHRs" - see details about this model in <NPL>).

<NUM> SHRs per treatment group were used for this test. The results obtained regarding MAP are summarised in <FIG> wherein each data point is presented as a <NUM>-hour mean (NB: the expected additive effect of the combination of the two drugs, referred to as "Predicted additive effect", was calculated by adding the decreases in blood pressure values obtained after administration of each compound separately); the vehicle (<NUM>% gelatin aquous solution) treatment had no effect on MAP or HR and the results obtained are therefore not represented in the figure. In brief, co-administration of COMPOUND and valsartan decreased MAP beyond the predicted (calculated) values, demonstrating synergism between the two molecules. In contrast to MAP, HR was not affected in any of the treatment groups.

The acute effects of COMPOUND administered orally at a single dose of <NUM>/kg on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR"), with COMPOUND being used either alone or in combination with valsartan administered orally at a single dose of <NUM>/kg, were evaluated by means of telemetry in conscious, male hypertensive deoxycorticosterone acetate salt rats (hereafter "DOCA-salt rats" - see details about this model in<NPL>).

In the DOCA-salt rats, hypertension is induced by the combination of unilateral nephrectomy, implantation of pellets of the mineralocorticoid analog DOCA, and provision of <NUM>% sodium chloride in drinking water. <NUM>-<NUM> DOCA-salt rats per treatment group were used for this test. The results obtained regarding MAP are summarised in <FIG> wherein each data point is presented as a <NUM>-hour mean (NB: the expected additive effect of the combination of the two drugs, referred to as "Predicted additive effect", was calculated by adding the decreases in blood pressure values obtained after administration of each compound separately); the vehicle (<NUM>% gelatin aquous solution) treatment had no effect on MAP or HR and the results obtained are therefore not represented in the figure. In brief, co-administration of COMPOUND and valsartan decreased MAP beyond the predicted (calculated) values, demonstrating synergism between the two molecules. In contrast to MAP, HR was not affected in any of the treatment groups.

The acute effects of COMPOUND administered orally at a single dose of <NUM>/kg on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR"), with COMPOUND being used either alone or in combination with enalapril administered orally at a single dose of <NUM>/kg, were evaluated by means of telemetry in conscious, male spontaneaously hypertensive rats (hereafter "SHRs" - see details about this model in <NPL>).

<NUM> SHRs per treatment group were used for this test. The results obtained regarding MAP are summarised in <FIG> wherein each data point is presented as a <NUM>-hour mean (NB: the expected additive effect of the combination of the two drugs, referred to as "Predicted additive effect", was calculated by adding the decreases in blood pressure values obtained after administration of each compound separately); the vehicle (<NUM>% gelatin aquous solution) treatment had no effect on MAP or HR and the results obtained are therefore not represented in the figure. In brief, co-administration of COMPOUND and enalapril decreased MAP beyond the predicted (calculated) values, demonstrating synergism between the two molecules. In contrast to MAP, HR was not affected in any of the treatment groups.

The acute effects of COMPOUND administered orally at a single dose of <NUM>/kg on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR"), with COMPOUND being used either alone or in combination with amlodipine administered orally at a single dose of <NUM>/kg, were evaluated by means of telemetry in conscious, male hypertensive deoxycorticosterone acetate salt rats (hereafter "DOCA-salt rats" - see details about this model in <NPL>).

In the DOCA-salt rats, hypertension is induced by the combination of unilateral nephrectomy, implantation of pellets of the mineralocorticoid analog DOCA, and provision of <NUM>% sodium chloride in drinking water. <NUM>-<NUM> DOCA-salt rats per treatment group were used for this test. The results obtained regarding MAP are summarised in <FIG> wherein each data point is presented as a <NUM>-hour mean (NB: the expected additive effect of the combination of the two drugs, referred to as "Predicted additive effect", was calculated by adding the decreases in blood pressure values obtained after administration of each compound separately); the vehicle (<NUM>% gelatin aquous solution) treatment had no effect on MAP or HR and the results obtained are therefore not represented in the figure. In brief, co-administration of COMPOUND and amlodipine decreased MAP beyond the predicted (calculated) values, demonstrating synergism between the two molecules. In contrast to MAP, HR was not affected in any of the treatment groups.

The chronic effects of repeated administrations of doses of <NUM>, <NUM> and <NUM>/kg/day of COMPOUND, in particular mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR"), were evaluated in conscious, male hypertensive deoxycorticosterone acetate salt rats (hereafter "DOCA-salt rats" - see details about this model in <NPL>). In the DOCA-salt rats, hypertension is induced by the combination of unilateral nephrectomy, implantation of pellets of the mineralocorticoid analog DOCA, and provision of <NUM>% sodium chloride in drinking water. The results of the DOCA-salt rats treated with COMPOUND were compared to those obtained for Wistar rats or for DOCA-salt rats that received only the vehicle (<NUM>% gelatin aquous solution).

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

The effects of COMPOUND can be assessed in diabetic rodent models (in this regard, see the models described in the following references: <NPL>;<NPL>; and <NPL>). In particular, the effect of COMPOUND, alone or in combination, on glucose tolerance, insulinemia and end organ damage can be investigated. End organ damage includes: vascular function, renal function (e.g. proteinuria), cardiac function and remodelling and any other target organ affected by diabetes (e.g. the eye).

A decrease in haematocrit (Hct) or haemoglobin occurs secondary to an increase in plasma volume and can be used as a marker of fluid retention. A single oral dose of aprocitentan (<NUM>-<NUM>/kg) or vehicle (gelatin) was administered by gavage to male Wistar rats. Twenty-four hours after administration, sublingual blood was sampled under isoflurane-induced anesthesia. Haematocrit was measured using a hematology analyser. COMPOUND did not impact on haematocrit (Hct) suggesting low liability on fluid retention (<FIG>).

The acute effects of spironolactone on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR") in combination with valsartan, each administered orally as single doses, were also evaluated by means of telemetry in conscious, male spontaneaously hypertensive rats (hereafter "SHRs" - see details about this model in <NPL>) using a protocol analog to that described in Example D.

Unlike for COMPOUND, no synergistic effect was seen on MAP reduction for the combination of spironolactone treatment with valsartan treatment.

The acute effects of spironolactone on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR") in combination with valsartan, each administered orally as single doses, were also evaluated by means of telemetry in conscious, male hypertensive deoxycorticosterone acetate salt rats (hereafter "DOCA-salt rats" - see details about this model in <NPL>) using a protocol analog to that described in Example E.

The acute effects of spironolactone on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP"), and heart rate (hereafter "HR") in combination with valsartan, each administered orally as single doses, were also evaluated by means of telemetry in conscious, male spontaneaously hypertensive rats (hereafter "SHRs" - see details about this model in <NPL>) using a protocol analog to that described in Example F.

Claim 1:
The compound {<NUM>-(<NUM>-bromo-phenyl)-<NUM>-[<NUM>-(<NUM>-bromo-pyrimidin-<NUM>-yloxy)-ethoxy]-pyrimidin-<NUM>-yl}-sulfamide:
<CHM>
or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic kidney disease (CKD) of stages <NUM> to <NUM> as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines, wherein said CKD is caused by essential hypertension wherein said compound is to be administered in combination with an Angiotensin Receptor Blocker (ARB) which is valsartan, or a pharmaceutically acceptable salt thereof.