EP3525778A1 - Combination containing sgc activators and mineralocorticoid receptor antagonists - Google Patents

Combination containing sgc activators and mineralocorticoid receptor antagonists

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Publication number
EP3525778A1
EP3525778A1 EP17777302.5A EP17777302A EP3525778A1 EP 3525778 A1 EP3525778 A1 EP 3525778A1 EP 17777302 A EP17777302 A EP 17777302A EP 3525778 A1 EP3525778 A1 EP 3525778A1
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Prior art keywords
diseases
treatment
combination
prophylaxis
formula
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EP17777302.5A
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German (de)
French (fr)
Inventor
Peter Kolkhof
Peter Sandner
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Bayer Pharma AG
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Bayer Pharma AG
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Publication of EP3525778A1 publication Critical patent/EP3525778A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the combination of activators of soluble guanylate cyclase (sGC activators) with mineralocorticoid receptor antagonists (MR antagonists) and the use of the combination for the treatment and / or prophylaxis of cardiovascular diseases, kidney and cardio -renal diseases, pulmonary and cardio-pulmonary diseases, as well as for the treatment and / or prophylaxis of fibrotic diseases.
  • sGC activators soluble guanylate cyclase
  • MR antagonists mineralocorticoid receptor antagonists
  • the object of the present invention is to provide combinations of pharmaceutically active substances, which act in more than one regulatory circuit and for the treatment of diseases of the cardiovascular system, renal and cardio-renal system or the lung and cardio-pulmonary system and fibrotic disorders can be used.
  • renin-angiotensin-aldosterone system It is a central cascade system of hormones and enzymes that control the salt and water balance and thus the body's blood pressure. Due to lack of salt and fluid or blood pressure drops, the hormone renin is formed in special kidney cells and distributed. Renin cleaves the liver-formed angiotensinogen into angiotensin I, while the angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II has potent vasoconstrictive and thus hypertensive effects and stimulates the formation of the steroid hormone aldosterone in the adrenal cortex. Aldosterone calls for the recovery of sodium from the urine into the blood, increasing blood volume.
  • ACE angiotensin-converting enzyme
  • angiotensin II The specific effects of angiotensin II are mediated through corresponding extracellular receptors (angiotensin receptor, AT-R) expressed on target cells of the cardiovascular system.
  • aldosterone the specific effects of aldosterone are mediated via an intracellular receptor, the aldosterone or mineralocorticoid receptor (MR).
  • MR mineralocorticoid receptor
  • both angiotensin II and aldosterone have direct pro-inflammatory and fibrotic properties.
  • Both hormones play particularly in remodeling processes in the heart, kidneys and vessels, e.g. induced by a heart attack or an acute renal failure, an essential role: Aldosterone the incorporation of collagen proteins in the heart muscle, which can lead to increased stiffness and thus in the long term to a reduced functionality.
  • Aldosterone and angiotensin II form a classic, feed-forward 'regulatory circuit: in addition to potassium, angiotensin II is the main stimulus for the release of aldosterone from the adrenal glands, and conversely, aldosterone in cardiac and vascular tissues stimulates the production of ACE, the precursor enzyme - angiotensin which generates angiotensin II.
  • MR antagonists such as the steroidal compounds spironolactone, canrenone / canrenoate and eplerenone, as well as newer non-steroidal MR antagonists such as MT-3995 according to the compound of formula (VI), CS-3150 according to the compound of formula (V), LY2623091 PF-03882845 according to the compound of the formula (XIV) and finerenones, according to the compound of the formula (IV), counteract the aldosterone-mediated sodium retention in the kidneys (natriuretic action).
  • MR antagonists lead to increased sodium excretion, which is a proven therapeutic concept in hypertensive patients and / or in patients with heart failure and / or renal insufficiency.
  • MR antagonists can exert their natriuretic effect only in the kidney segments, in which aldosterone is also physiologically effective via MR.
  • these are, in particular, the late distal tubule and collection tube sections, which are involved in sodium reabsorption only to a limited extent, while the majority of sodium secretion and reabsorption occurs in proximal tubule sections.
  • NO nitric oxide
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterase
  • sGC soluble guanylate cyclase
  • GTP guanosine triphosphate
  • This cGMP is an important second messenger molecule and binds to a variety of intracellular proteins, including cGMP-dependent protein kinases (G-kinases) .G-kinases mediate the phosphorylation of various target proteins, such as potassium channels.
  • G-kinases cGMP-dependent protein kinases
  • NO stimulates vascular dilatation and thus lowers blood pressure by stimulating the sGC / cGMP pathway
  • cGMP also has numerous other effects, such as anti-thrombotic, anti-fibrotic or anti-thrombotic effects These effects, however, are less well understood than vascular dilation and have not yet been fully elucidated.
  • the NO / cGMP signaling cascade and the effects of cGMP are terminated by degradation of the cGMP to inactive GMP cyclic phosphate ring and the image 5 'GMP is catalyzed by phosphodiesterases (PDE).
  • PDE phosphodiesterases
  • the PDEs are a large family of enzymes with up to now 11 identified members and over 100 different so-called splicing variants.
  • the various PDEs differ, above all, in terms of tissue specificity (eg PDE6 is expressed exclusively in the eye), substrate specificity (eg cAMP or cGMP-specific) and regulation (eg by calcium / calmodulin or cyclic nucleotides).
  • PDE5 type 5
  • PDE6 PDE6
  • PDE9 PDE9
  • PDE5 inhibitors are limited, since they require a sufficiently high endogenous cGMP level for their effectiveness, which is then protected by the compounds from degradation. In many diseases, especially in cardiovascular diseases or lung diseases, however, the endogenous NO production and thus also the cGMP formation is at least partially disturbed. Therefore, PDE5 inhibitors also do not work comparatively well in all patients or are also treatment-resistant patients, for example in erectile dysfunction or in pulmonary hypertension. In order to circumvent this limitation of both nitrates and PDE5 inhibitors, it was attempted to stimulate the sGC directly pharmacologically.
  • sGC stimulators and sGC activators therefore represents a milestone in the pharmacology of the NO / cGMP signaling pathway.
  • sGC stimulators and sGC activators independently stimulate sGC NO and result in NO-independent production of cGMP.
  • these classes of compounds also act synergistically (sGC stimulators) and additively (sGC activators) to endogenously formed NO.
  • the main difference is the binding to the sGC.
  • the sGC is a heterodimeric protein formed from one alpha and one beta subunit, the last one carrying the NO-binding heme group.
  • the sGC stimulators bind to the alpha subunit of the non-oxidized and heme-containing sGC and cause the direct, non-independent formation of cGMP (Stasch et al. (A) 2001; Stasch & Hobbs 2009).
  • the sGC activators bind to the beta subunit of the oxidized and heme-free sGC, activate it and thus lead to the NO-independent formation of cGMP (Stasch et al. (B) 2001, Schmidt et al., 2009).
  • the sGC stimulator riociguat was approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) (Ghofrani et al. (A), Ghofrani et al. (B) 2013, 2013 Hambly & Granton 2015).
  • PAH pulmonary arterial hypertension
  • CTEPH chronic thromboembolic pulmonary hypertension
  • the sGC stimulator vericiguat is in Phase II / III for the treatment of heart failure (Pieske et al 2014, Gheorghiade et al., 2015).
  • MRAs MR antagonists
  • Steroidal MRAs such as spironolactone or its active metabolite kanrenone not only interact with the MR but also with the homologous androgen and progesterone receptors. These interactions may have undesirable effects on sex hormone metabolism such as gynecomastia, dysmenorrhea and libido loss to lead.
  • Nonsteroidal MRAs such as finerenones interact specifically with the MR, so that corresponding side effects that may result from interactions with other steroid hormone receptors are not to be expected.
  • steroidal mineralocorticoid receptor antagonists are (the subject matter published in the following publications with regard to the steroidal MR antagonists should also be the subject of the present application)
  • Eplerenones (epoxymexerenone) of the formula (II)
  • Kanrenone (10,13 -dimethylspiro [2,8,9,11,12,14,15,16-octahydro- lH-cyclopenta [a] phenanthrene-17,5'-oxolane] -2 ', 3-dione) of Formula (III)
  • Kanrenone is also known as Potassium Salt, Potassium Kanrenoate, and is commercially available.
  • non-steroidal mineralocorticoid receptor antagonists are (the subject matter published in the following publications with respect to the non-steroidal MR antagonists is also intended to be the subject of the present application):
  • Finereneone (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide), as a selective antagonist, which is based on a Dihydropyridingrundgerüst, the formula (IV)
  • Esaxerenone (1- (2-hydroxyethyl) -4-methyl-N- (4- (methylsulfonyl) phenyl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrrole-3-carboxamide) of the formula (V)
  • MR antagonists based on an aryl sulfonamide structure such as those described in Futatsugi K, Piotrowski DW, Casimiro-Garcia A, et al. Design and synthesis of aryl sulfonamide-based nonsteroidal mineralocorticoid receptor antagonists. Bioorg Med Chem Lett 2013; 23: 6239-6242 are disclosed
  • Suitable sGC activators are known from the following publications (the subject matter published in the following publications should also be the subject of the present application): WO2013 / 157528, WO2015 / 056663, WO2009 / 123316, WO2016 / 001875, WO2016 / 001876, WO2016 / 001878, WO2000 / 02851, WO2012 / 122340, WO2013 / 025425, WO2014 / 039434, WO2016 / 014463, WO2009 / 068652, WO2009 / 071504, WO2010 / 015652, WO2010 / 015653, WO2015 / 033307, WO2016 / 042536, WO2009 / 032249, WO2010 / 099054, WO2012 / 058132,
  • Both the RAAS and the NO / cGMP pathway play an important role in maintaining body homeostasis and regulate important functions in the cardiovascular, renal and cardio-renal systems or in the pulmonary and cardio-pulmonary systems.
  • the use of MR antagonists and the use of sGC activators as monotherapies in cardiovascular, renal and cardio-renal diseases, pulmonary and cardiopulmonary diseases or fibrotic diseases is also described. In fact, both the proportion of dysregulation of the two signaling pathways in these various diseases, as well as the absolute efficiency of the two mechanisms in the direct comparison is unknown.
  • Combinations of MR antagonists with sGC activators were used in these experiments and also tested in direct comparison to the individual compounds. Surprisingly, an extraordinary effectiveness of these combinations, which goes far beyond the efficacy of the individual components, and suggests a synergistic effect of the combination of MR antagonists and sGC activators.
  • the solution to the above problem can thus be seen in the provision of combinations which contain at least one sGC activator and at least one substance which intervenes in the RAAS system and which are used for the targeted treatment of cardiovascular diseases, Renal and cardio-renal diseases, pulmonary and cardio-pulmonary diseases and fibrotic diseases with over-additive effects can be used.
  • the invention therefore provides i.a. a combination containing MR antagonists and sGC activators ready.
  • the combination shows acute and especially chronic use, positive effects on end organ protection of the heart and kidneys, reduction of renal protein excretion, reduction of morbidity and mortality under experimental conditions.
  • These experimental conditions consist of healthy animals or animals with hypertension, cardiac and / or renal insufficiency (e.g., transgenic renin rats), L-NAME treated animals (e.g., transgenic renin rats + L-NAME treatment).
  • combinations containing at least one sGC activator and at least one non-steroidal MR antagonist having an oxazolidinedione scaffold are also preferred.
  • the at least one sGC activator and at least one steroidal MR antagonist selected from the group
  • Eplerenones (epoxymexerenone) of the formula (II)
  • Canrenone (10, 13 -dimethylspiro [2,8,9,1 1 1, 12,14,15,16-octahydro- lH-cyclopenta [a
  • potassium salt potassium canenoate
  • the at least one sGC activator and at least one non-steroidal MR antagonist selected from the group Finereneone, ((S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl - 1, 4-dihydro-1, 6-naphthyridine-3-carboxamide) of the formula (IV)
  • Esaxerenone (1- (2-hydroxyethyl) -4-methyl-N- (4- (methylsulfonyl) phenyl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrrole-3-carboxamide) of the formula (V)
  • combinations containing at least one sGC activator containing a carboxylic acid function and at least one MR antagonist are also preferred. Also preferred are combination, the at least one sGC activator selected from the group
  • Esaxerenone (1- (2-hydroxyethyl) -4-methyl-N- (4- (methylsulfonyl) phenyl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrrole-3-carboxamide) of the formula (V)
  • Another object of the invention is the use of MR antagonists in combination with sGC activators for the treatment of cardiovascular diseases such as cardiac and cardiovascular diseases.
  • Cardiac insufficiency with preserved ejection fraction or cardiac insufficiency with reduced ejection fraction, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis for the treatment of renal and cardio-renal diseases, e.g. chronic renal failure or diabetic nephropathy, lung diseases and cardio-pulmonary diseases, e.g. pulmonary hypertension, central nervous system disorders, for the treatment and / or prophylaxis of fibrotic diseases, as well as other manifestations of disease (e.g., end-organ damage affecting the brain, kidney, heart or lung).
  • renal and cardio-renal diseases e.g. chronic renal failure or diabetic nephropathy
  • lung diseases and cardio-pulmonary diseases e.g. pulmonary hypertension, central nervous system disorders
  • other manifestations of disease e.g., end-organ damage affecting
  • An object of the present invention is a pharmaceutical formulation containing a combination of an MR antagonist and a sGC Aktivaotrs, and the salts, solvates and solvates of the salts of the components to be combined.
  • the components to be combined may be present as salts.
  • Salts which are preferred in the context of the present invention are physiologically acceptable salts of the compounds to be combined. Also included are salts which are not suitable for pharmaceutical applications, but which can be used, for example, for the isolation or purification of the compounds to be combined.
  • the combinations according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular for the treatment and / or prophylaxis of cardiovascular diseases such as heart failure with preserved ejection fraction or cardiac insufficiency with reduced ejection fraction, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, renal and cardiorenal diseases such as chronic renal failure or diabetic nephropathy , Pulmonary and cardiopulmonary disorders, such as pulmonary hypertension, central nervous system disorders, for the treatment and / or prophylaxis of fibrotic disorders, as well as other pathologies (eg end organ damage affecting the brain, kidney or heart).
  • cardiovascular diseases such as heart failure with preserved ejection fraction or cardiac insufficiency with reduced ejection fraction
  • atrial fibrillation such as chronic renal failure or diabetic nephropathy
  • Pulmonary and cardiopulmonary disorders such as pulmonary hypertension, central nervous system disorders, for the treatment and / or prophylaxi
  • the combinations according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular for the treatment and / or prophylaxis of a disease selected from the group consisting of hypertension, heart failure (acute and chronic), decompensated heart failure, left ventricular dysfunction , hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful vascular remodeling, myocardial infarction and sequelae thereof, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and nondiabetic), heart failure, angina pectoris, diabetes, secondary hyperaldosteronism, primary and secondary pulmonary hypertension, glomerulonephritis, scleroderma and systemic sclerosis, glomerular sclerosis, proteinuria as a result of primary renal disease, renal vascular Hypertension, diabetic and nondiabetic retin
  • Another object of the present invention is the use of the combinations according to the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • combinations according to the invention can be used alone or as needed in combination with other active ingredients.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the combinations according to the invention and one or more further active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin receptor blockers (ARBs), ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers and rho Kinase inhibitors; ⁇ Diuretics, especially loop diuretics and thiazides and thiazide-like diuretics; • Antidiabetics, by way of example and preferably insulin and derivatives, sulfonureas, biguanides, thiazolidinediones, acarbose, DPP4 inhibitors, GLP-1 analogs, or SGLT inhibitors
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorber, bile acid
  • cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorber, bile acid
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • Positive-inotropic compounds such as cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • sildenafil sildenafil
  • Vardenafil tadalafil
  • PDE 3 inhibitors such as amrinone and milrinone
  • Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
  • ABP atrial natriuretic peptide
  • BNP B-type natriuretic peptide
  • CNP C-type natriuretic peptide
  • urodilatin urodilatin
  • NEP inhibitors e.g. Sacubitril, omapatrilat or AVE-7688
  • 'ARNIs' angiotensin receptor blockers
  • valsartan e.g. LCZ696
  • Calcium sensitizers such as by way of example and preferably levosimendan
  • If-channel blockers such as by way of example and preferably ivabradine;
  • Myosin activators by way of example and preferably Omecamtiv mecarbil;
  • HNE human neutrophil elastase
  • the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib; and or • the energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazines or trimetazidines.
  • the combination according to the invention is used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, Dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethi
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin receptor blocker, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-loosen, beta-receptor-B loosely, rho-kinase Inhibitors and diuretics understood.
  • the combined preparation according to the invention is used in combination with an antidiabetic, such as by way of example and preferably insulin and derivatives, sulfonylureas such as tolbutamide, carbutamide, acetohexamide, chlorpropamide, glipizide, gliclazide, glibenclamide, glyburide, glibornuride, gliquidone, glisoxepid, glyclopyramide, Glimepiride, JB253 and JB558, meglitinides such as repaglinide and nateglinide, biguanides such as metformin and buformin, thiazolidinediones such as rosiglitazone and pioglitazone, alpha-glucosidase inhibitors such as miglitol, acarbose and voglibose, DPP4 inhibitors such as vildagliptin, sitagliptin
  • an antidiabetic
  • the combination according to the invention is administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an angiotensin all-antagonist, such as by way of example and with preference losartan, candesartan, valsartan, olmesartan, telmisartan or embursatan.
  • an angiotensin all-antagonist such as by way of example and with preference losartan, candesartan, valsartan, olmesartan, telmisartan or embursatan.
  • the combination according to the invention is administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the combination according to the invention is administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the combination according to the invention is administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.
  • the combination according to the invention is administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the combination according to the invention is used in combination with a beta-receptor B, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol , Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor B such as by way of example and preferably propranolol, atenolol, timolol,
  • the combination according to the invention is used in combination with a rho-kinase inhibitor, such as by way of example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049 administered.
  • a rho-kinase inhibitor such as by way of example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049 administered.
  • the combination according to the invention in combination with prostanoids and prostacyclin receptor agonists, such as by way of example and preferably iloprost, beraprost, cicaprost, epoprostenol or treprostinil
  • Antithrombotic agents are preferably understood to mean compositions from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the combination according to the invention is administered in combination with a platelet aggregation inhibitor, such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the combination according to the invention is administered in combination with a thrombin inhibitor, such as by way of example and preferably ximelagatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as by way of example and preferably ximelagatran, melagatran, bivalirudin or Clexane.
  • the combination according to the invention is administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the combination according to the invention in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112 , YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112 , YM-150, KFA-1982, EMD-503982, MCM-17,
  • the combination according to the invention is administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bil
  • the combination according to the invention is administered with a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant) ,
  • a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant) ,
  • the combination according to the invention is administered in combination with a thyroid receptor agonist, such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the combination according to the invention is administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
  • the combination according to the invention is administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the combination according to the invention is administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the combination according to the invention is administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • the combination according to the invention is administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone.
  • a PPAR-delta agonist such as by way of example and preferably GW-501516 or BAY 68-5042.
  • the combination according to the invention with a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, Tiqueside or Pamaqueside administered.
  • the combination according to the invention with a lipase inhibitor such as by way of example and preferably orlistat, administered.
  • the combination according to the invention is administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 AK-105
  • SC-435 SC-635.
  • the combination according to the invention is administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • the combination according to the invention is administered in combination with anti-fibrotic compounds such as, for example and preferably, sorafenib, regorafenib, imatinib, dasatinib, nilotinib, nintedanib, bortezomib or pirfenidone.
  • anti-fibrotic compounds such as, for example and preferably, sorafenib, regorafenib, imatinib, dasatinib, nilotinib, nintedanib, bortezomib or pirfenidone.
  • the combination according to the invention is administered in combination with anti-inflammatory compounds such as by way of example and preferably cyclophosphamide, methotrexate, rapamycin, azathioproin, tocilizumab, infliximab, rituximab, adalimumab, belimumab, abatacept, SARI 00842 or thalidomide derivatives.
  • anti-inflammatory compounds such as by way of example and preferably cyclophosphamide, methotrexate, rapamycin, azathioproin, tocilizumab, infliximab, rituximab, adalimumab, belimumab, abatacept, SARI 00842 or thalidomide derivatives.
  • the combinations according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the combinations according to the invention can be administered in suitable administration forms.
  • the inventive combinations rapidly and / or modified donating application forms, the contain the compounds of the invention in crystalline and / or amorphous and / or dissolved form, such as tablets (uncoated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings, which control the release of the combinations of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings, which control the release of the combinations of the invention
  • in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or
  • Preferred forms of application include tablet form (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the combinations of the invention), tablets disintegrating rapidly in the oral cavity or films / wafers.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures), lipophilic suspensions
  • Ointments creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • oral or parenteral administration with oral administration being more preferred.
  • oral administration by means of tablet form.
  • the combinations according to the invention can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • These adjuvants include, among others.
  • Carrier materials for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers for example antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odor remedies include, among others.
  • Carrier materials for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example
  • the components may be used together or sequentially or separately in a combined unit dosage form or in two separate ones Unit dosage forms are administered.
  • the unit dosage form may also be a fixed combination.
  • a therapeutically effective amount of each component of the combination of the invention may be administered simultaneously or sequentially in any order.
  • the components may be in a so-called sustained-release formulation in which the release of the components according to the invention takes place at different times.
  • a sustained-release formulation in which the release of the components according to the invention takes place at different times.
  • the MR antagonists and sGC activators may each be provided as a capsule or tablet.
  • the dosage of finerenone according to the compound of formula (IV) is about 1 to 100 mg od, preferably about 2.5 to 50 mg od and most preferably 10 to 40 mg od.
  • the invention also relates to the combination of separate pharmaceutical compositions in kit form.
  • kit form This is a kit comprising two separate entities: a pharmaceutical composition of at least one MR antagoinst and a pharmaceutical composition of at least one sGC activator.
  • the invention also relates to a preferred kit form comprising two units: A pharmaceutical composition containing at least one MR antagonist and a pharmaceutical composition containing at least one sGC activator.
  • the kit is particularly advantageous when the separate components have to be administered in different dosage forms or administered at different dose intervals.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows: Tablet:
  • a granular solution of the compound of formula (IV) in crystalline form in micronised form, hypromellose 5 cP, sodium lauric sulfate in purified water was prepared.
  • Cellulose microcrystalline, lactose monohydrate and croscarmellose sodium were mixed in a container or a fluidized bed granulator (premix).
  • the premix and the granule solution were granulated in the fluid-bed granulator.
  • the Lubricant Magnesium Stearate was added after the granules were dried and sieved. Thus, a press-ready mixture was prepared.
  • a homogeneous coating suspension was made from hypromellose, talc, titanium dioxide, yellow iron oxide, red iron oxide and purified water. In a suitable coating device, the coating suspension was sprayed onto the tablets.
  • Titanium dioxide 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196
  • Wistar rats 250-450 g body weight are kept with free access to feed (Altromin) and drinking water. Starting approx. 72 hours before the start of the experiment, instead of the normal diet, the animals are given only salt-reduced food with a content of 0.02% sodium chloride (ssniff R / MH, 10 mm with 0.02% Na, S0602-E081, ssniff Spezialdi decisiven GmbH). D-59494 Soest). During the experiment, the animals are kept individually for about 24 hours in suitable for rats of this weight category metabolic cages (Tecniplast Germany GmbH, D-82383 Hohenpeissenberg) with free access to salt-reduced feed and drinking water.
  • the substance to be tested is administered to the animals in a volume of 0.5 ml / kg body weight of a suitable solvent in the stomach by means of a gavage.
  • Control animals receive only solvents.
  • Controls and substance testing are done in parallel on the same day.
  • Control groups and substance dose groups each consist of 6 to 8 animals.
  • the urine excreted by the animals is continuously collected in a container on the floor of the cage.
  • the urine volume per unit of time is determined separately for each animal, and the concentration of the sodium or potassium ions excreted in the urine is measured by standard flame photometric methods.
  • the measuring intervals are typically the period up to 8 hours after the start of the test (day interval) and the period from 8 to 24 hours after the start of the test (night interval).
  • DHA desoxycorticosterone acetate
  • a high salt diet and unilateral renal clearance in the rat induces hypertension characterized by relatively low renin levels.
  • endocrine hypertension (DOCA is a direct precursor of aldosterone), depending on the DOCA concentration chosen, cardiac hypertrophy and other end organ damage, e.g. the kidney, the u.a. characterized by proteinuria and glomerulosclerosis.
  • test substances can thus be tested for the presence of antihypertrophic and endorphin protective effects.
  • Uninephrectomized SD rats receive 1% sodium chloride in drinking water and once weekly a subcutaneous injection of DOCA (company SIGMA, dissolved in sesame oil, high dose: 100 mg / kg / wk s.c., normal dose: 30 mg / kg / wk s.c.) injected between the shoulder blades.
  • DOCA company SIGMA, dissolved in sesame oil, high dose: 100 mg / kg / wk s.c., normal dose: 30 mg / kg / wk s.c.
  • the substances to be tested for their protective effect in vivo are administered by gavage or by food (Ssniff, Germany).
  • the substances (combinations) are administered once a day for 4-12 weeks by gavage or by food.
  • the placebo group used is animals that are treated in exactly the same way, but receive either only the solvent or the feed without the test substance.
  • Hemodynamic parameters blood pressure, heart rate, inotropy [dp / dt], relaxation time [tau], maximal left ventricular pressure, left ventricular enddiastolic pressure [LVEDP]), heart, kidney and lung weights, protein excretion and gene expression of Biomarkers (eg BNP, brain natriuretic peptides, plasma renin activity, angiotensin and aldosterone) are determined by RIA, ELISA or RT / TaqMan PCR after RNA isolation from cardiac and renal tissue.
  • Biomarkers eg BNP, brain natriuretic peptides, plasma renin activity, angiotensin and aldosterone
  • the transgenic renin rat, TGR (mRen2) 27 ' is a hypertensive rat line developed by Mullins and Ganten that overexpresses the mouse Ren-2 gene. Additional administration of the nitric oxide synthase inhibitor L-NAME induces endothelial dysfunction, which increases morbidity and mortality in this model. Homozygous animals die of secondary complications, such as heart and kidney failure, or stroke, unless they undergo lifelong, antihypertensive therapy.
  • renin rats Male TGR (mRen2) Twenty-seven renin rats aged 10 to 20 weeks are randomized to various pharmacological treatment groups and a placebo group.
  • the nitric oxide synthase inhibitor, L-NAME is administered via the drinking water at a concentration of 30 to 100 mg / l.
  • the substances are administered daily for 4-10 weeks by gavage or by food.
  • the placebo group used is animals that are treated in exactly the same way, but receive either only the solvent or the feed without the test substance.
  • tail cuff systolic blood pressure is measured at regular intervals, as well as the determination of proteinuria and urinary electrolyte composition by urine collection in metabolic cages.
  • Hemodynamic parameters blood pressure, heart rate, inotropy [dp / dt], relaxation time [tau], maximal left ventricular pressure, left ventricular enddiastolic pressure [LVEDP]
  • weights of heart, kidney and lung are determined, protein excretion and biomarkers (eg ANP , RIA Kit RK 005-24, Phoenix Pharmaceuticals, Inc., USA, cGMP, RIA Kit RE29075, IBL International GmbH, Hamburg, Renin, Angiotensin I, RIA Kit CA-1533, DiaSorin SpA, Italy, and Aldosterone, P2714, DiaSorin SpA, Italy), as well as gene expression of biomarkers by RT / TaqMan PCR after RNA isolation from cardiac and renal tissue.
  • Heart and cardiovascular diseases as well as kidney and cardiorenal diseases are characterized by a high morbidity of the patients but also by a high mortality.
  • This morbidity and mortality together with various risk factors, e.g. High blood pressure can be mapped very well in the previously described animal model of the L-NAME-treated renin transgenic rat. Therefore, e.g. this animal model uses MR antagonists, e.g. Finerenones according to the compound of formula (IV) and sGC activators, e.g. to study the compound of formula (X) and combinations of both:
  • the MR antagonist finerenone corresponding to the compound of formula (IV) and the sGC activator corresponding to the compound of formula (X) were tested alone and in combinations in TGR (mRen2) 27 renin rats at 10 to 20 weeks of age.
  • TGR mRen2
  • the animals were given drinking water and food ad libitum.
  • the substances were administered daily for 4-10 weeks by gavage.
  • the placebo group used were animals that were treated in the same way, but only received the solvent for the test substance.

Abstract

The invention relates to the combination of activators of soluble guanylate cyclase (sGC activators) with mineralocorticoid receptor antagonists (MR antagonists) and to the use of the combination to treat and/or prevent cardiac and cardiovascular diseases, renal and cardiorenal diseases, pulmonary and cardiopulmonary disease, and to treat and/or prevent fibrotic diseases.

Description

Kombination enthaltend sGC Aktivatoren und Mineralocorticoid-Rezeptor-Antagonisten  Combination containing sGC activators and mineralocorticoid receptor antagonists
Die vorliegende Erfindung betrifft die Kombination von Aktivatoren der löslichen Guanylatzyklase (sGC Aktivatoren) mit Mineralocorticoid-Rezeptor Antagonisten (MR Antagonisten) sowie die Verwendung der Kombination zur Behandlung und/oder Prophylaxe von Herz- und Herz-Kreislauf- Erkrankungen, von Nieren- und kardio-renalen Erkrankungen, von Lungen- und kardio-pulmonären Erkrankungen, sowie zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen.  The present invention relates to the combination of activators of soluble guanylate cyclase (sGC activators) with mineralocorticoid receptor antagonists (MR antagonists) and the use of the combination for the treatment and / or prophylaxis of cardiovascular diseases, kidney and cardio -renal diseases, pulmonary and cardio-pulmonary diseases, as well as for the treatment and / or prophylaxis of fibrotic diseases.
Die gesamte Körperfunktion von Mensch und Tier wird durch Regelkreisläufe kontrolliert und aufrechterhalten. Bestandteile dieser physiologischen Regelkreisläufe sind wiederum Kaskadensysteme körpereigener Hormone, Enzyme und Rezeptoren. Diese Regelkreisläufe sind miteinander verbunden und werden zentral gesteuert. Pathophysiologische Veränderungen innerhalb des Körpers, aber auch Einflüsse von außen wie z.B. Klima, Stress, Nahrungsbestandteile einschließlich Medikamente, haben direkte Einflüsse auf diese Regelkreisläufe. Dadurch verminderte oder überschießende Aktivitäten einzelner Komponenten dieser Kaskaden und Regelsysteme können durch Gegensteuerung mittels sogenannter Rückkopplungs- (,feed-back') oder auch Vorwärtskopplungs- (,feed-forward') Mechanismen ausgeglichen werden. Eine kurzfristige Gegensteuerung, z.B. durch eine kompensatorische Freisetzung eines bestimmten körpereigenen Hormons ist somit für die Aufrechterhaltung der Körperfunktion in Notsituationen (z.B. bei Verletzungen) lebenswichtig. Allerdings kann auch eine permanente kompensatorische Gegenregulation langfristig fatale Folgen für den Gesamtorganismus haben.  The entire body function of humans and animals is controlled and maintained by regulating cycles. Components of these physiological regulatory circuits are again cascade systems of endogenous hormones, enzymes and receptors. These control circuits are interconnected and centrally controlled. Pathophysiological changes within the body, but also external influences such. Climate, stress, nutritional components including medications have a direct influence on these regulatory circuits. This reduced or excessive activities of individual components of these cascades and control systems can be counterbalanced by means of so-called 'feed-back' or even feed-forward mechanisms. A short-term counter-control, e.g. compensatory release of a particular endogenous hormone is thus vital to the maintenance of body function in emergency situations (e.g., injuries). However, a permanent compensatory counterregulation can have fatal consequences for the entire organism in the long term.
Die meisten Therapieansätze zur Behandlung von Erkrankungen des Herz- und Herzkreislaufsystems, Nieren- und kardio-renalen oder des Lungen und kardio-pulmonären Systems und fibrotischen Erkrankungen greifen in eines der angesprochenen Regelsysteme ein. Dies kann den Nachteil haben, dass aufgrund einer kompensatorischen Gegenregulation des Körpers bereits nach kurzer Zeit eine Desensitierung erfolgt und die gewünschte Wirkung weniger oder nicht mehr erzielt wird und dadurch u.a. höhere Dosierungen verwendet werden müssen. Damit gehen Nachteile einher, wie bspw. ein höheres Nebenwirkungspotential. Most therapeutic approaches for the treatment of diseases of the cardiovascular system, renal and cardio-renal or the pulmonary and cardio-pulmonary system and fibrotic diseases intervene in one of the mentioned control systems. This may have the disadvantage that due to a compensatory counterregulation of the body desensitization takes place after a short time and the desired effect is less or no longer achieved and thereby u.a. higher dosages must be used. This is associated with disadvantages, such as, for example, a higher side-effect potential.
Die Aufgabe der vorliegenden Erfindung besteht in der Bereitstellung von Kombinationen pharmazeutisch aktiver Substanzen, die in mehr als einen Regelkreislauf einwirken und die zur Behandlung von Erkrankungen des Herz- und Herzkreislaufsystems, Nieren- und kardio-renalen Systems oder des Lungen und kardio-pulmonären Systems und fibrotischen Erkrankungen verwendet werden können. The object of the present invention is to provide combinations of pharmaceutically active substances, which act in more than one regulatory circuit and for the treatment of diseases of the cardiovascular system, renal and cardio-renal system or the lung and cardio-pulmonary system and fibrotic disorders can be used.
Eines dieser oben genannten essentiellen Regelsysteme ist das sogenannte Renin-Angiotensin- Aldosteron-System (RAAS). Es ist ein zentrales Kaskadensystem von Hormonen und Enzymen, die den Salz- und Wasserhaushalt und damit den Blutdruck des Körpers steuern. Durch Salz- und Flüssigkeitsmangel oder Blutdruckabfälle wird in speziellen Nierenzellen das Hormon Renin gebildet und ausgeschüttet. Renin spaltet das in der Leber gebildete Angiotensinogen in Angiotensin I, während das Angiotensin Conversions-Enzym (ACE) Angiotensin I in Angiotensin II umwandelt. Angiotensin II besitzt potente gefäßverengende und damit blutdrucksteigernde Wirkungen und stimuliert die Bildung des Steroidhormons Aldosteron in der Nebennierenrinde. Aldosteron fordert die Rückaufhahme von Natrium aus dem Urin ins Blut, wodurch das Blutvolumen steigt. One of the above-mentioned essential control systems is the so-called renin-angiotensin-aldosterone system (RAAS). It is a central cascade system of hormones and enzymes that control the salt and water balance and thus the body's blood pressure. Due to lack of salt and fluid or blood pressure drops, the hormone renin is formed in special kidney cells and distributed. Renin cleaves the liver-formed angiotensinogen into angiotensin I, while the angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II has potent vasoconstrictive and thus hypertensive effects and stimulates the formation of the steroid hormone aldosterone in the adrenal cortex. Aldosterone calls for the recovery of sodium from the urine into the blood, increasing blood volume.
Die spezifischen Effekte von Angiotensin II werden über entsprechende extrazelluläre Rezeptoren (Angiotensin-Rezeptor, AT-R) vermittelt, die auf Zielzellen des kardiovaskulären Systems exprimiert werden. Dagegen werden die spezifischen Effekte von Aldosteron über einen intrazellulären Rezeptor, dem Aldosteron- oder Mineralocorticoid-Rezeptor (MR) vermittelt. Neben ihrer zentralen Bedeutung bei der Salz-, Wasser- und Blutdruckregulation besitzen sowohl Angiotensin II als auch Aldosteron direkte pro-inflammatorische und -fibrotische Eigenschaften. Beide Hormone spielen insbesondere bei Umbauprozessen (,remodeling') in Herz, Nieren und Gefäßen, die z.B. durch einen Herzinfarkt oder ein akutes Nierenversagen induziert werden, eine wesentliche Rolle: So stimuliert z.B. Aldosteron die Einlagerung von Kollagenproteinen im Herzmuskel, was zu einer erhöhten Steifigkeit und damit langfristig zu einer verminderten Funktionalität führen kann.  The specific effects of angiotensin II are mediated through corresponding extracellular receptors (angiotensin receptor, AT-R) expressed on target cells of the cardiovascular system. In contrast, the specific effects of aldosterone are mediated via an intracellular receptor, the aldosterone or mineralocorticoid receptor (MR). In addition to their central importance in the regulation of salt, water and blood pressure, both angiotensin II and aldosterone have direct pro-inflammatory and fibrotic properties. Both hormones play particularly in remodeling processes in the heart, kidneys and vessels, e.g. induced by a heart attack or an acute renal failure, an essential role: Aldosterone the incorporation of collagen proteins in the heart muscle, which can lead to increased stiffness and thus in the long term to a reduced functionality.
Aldosteron und Angiotensin II bilden einen klassischen ,feed-forward' Regelkreis: Neben Kalium ist Angiotensin II der wichtigste Stimulus zur Freisetzung von Aldosteron aus der Nebenniere und umgekehrt stimuliert Aldosteron in Herzgewebe und Gefäßen die Produktion von ACE, also dem Enzym, das aus dem Vorläufer- Angiotensin das Angiotensin II generiert.  Aldosterone and angiotensin II form a classic, feed-forward 'regulatory circuit: in addition to potassium, angiotensin II is the main stimulus for the release of aldosterone from the adrenal glands, and conversely, aldosterone in cardiac and vascular tissues stimulates the production of ACE, the precursor enzyme - angiotensin which generates angiotensin II.
Die pathopysiologischen Wirkungen von Angiotensin II und Aldosteron können durch entsprechende Inhibitoren der ACE, des AT-R und des MR vermindert werden, jedoch unterliegen diese singulären Blockaden den o.g. ,feed-back' Kompensationsmechanismen, d.h. Blockade des Mineralocorticoid- Rezeptors führt zu einer kompensatorischen Freisetzung von Aldosteron, ähnlich wie AT-R Blockade zu einem Anstieg von Angiotensin II führt. The pathophysiological effects of angiotensin II and aldosterone can be diminished by appropriate inhibitors of ACE, AT-R and MR, however, these singular blockages are subject to the above-mentioned. 'feed-back' compensation mechanisms, i. Blockade of the mineralocorticoid receptor leads to compensatory release of aldosterone, similar to AT-R blockade leading to an increase in angiotensin II.
Langfristige Kompensationsmechanismen spielen beim klinisch bedeutsamen ,Aldosterone Escape' Phänomen eine besondere Rolle: Da die Aldosteron-Freisetzung sozusagen der letzte Schritt in der RAAS-Kaskade darstellt, war man lange Zeit der Meinung, dass die Blockade der initialen RAAS- Schlüsselschritte wie der ACE- Aktivität oder des AT-Rs ausreichen, um auch den letzten Schritt, die Aldosteronbildung und -freisetzung in der Nebenniere zu verhindern. Allerdings zeigte die RESOLVD Studie (McKelvie et al., Circulation 1999;100;1056-1064), dass sowohl unter singulärer ACE oder AT-R Blockade, als auch unter dualer ACE/AT-R Blockade die Aldosteron-Plasmaspiegel bei Patienten mit Herzinsuffizienz zwar innerhalb der ersten 17 Behandlungs-Wochen gegenüber dem Ausgangswert vermindert wird, allerdings nach 43 Wochen den Ausgangswert sogar übersteigt. Die Ergebnisse dieser Studie belegen, dass eine Verhinderung der Bindung von Aldosteron an den Mineralocorticoid-Rezeptor zusätzlich zur Angiotensin Blockade klinisch enorm bedeutsam ist. MR Antagonisten (wie z.B. die steroidalen Verbindungen Spironolactone, Canrenone/Canrenoat und Eplerenone, sowie neuere nicht-steroidale MR Antagonisten wie z.B. MT-3995 gemäß der Verbindung der Formel (VI), CS-3150 gemäß der Verbindung der Formel (V), LY2623091, PF- 03882845 gemäß der Verbindung der Formel (XIV) und Finerenone, gemäß der Verbindung der Formel (IV)) wirken der, durch Aldosteron vermittelten Natriumretention in den Nieren entgegen (natriuretische Wirkung). Somit führen MR Antagonisten zu einer vermehrten Natriumausscheidung, was bei hypertensiven Patienten und/oder bei Patienten mit Herzinsuffizienz und/oder Niereninsuffizienz ein bewährtes Therapiekonzept darstellt. Allerdings können MR Antagonisten ihre natriuretische Wirkung nur in den Nierensegmenten entfalten, in denen Aldosteron auch über den MR physiologisch wirksam ist. Das sind v.a. die spät distalen Tubulus- und Sammelrohrabschnitte, die nur zu einem begrenzten Teil an der Natriumrückresorption beteiligt sind, während der Hauptanteil der Natriumsekretion und -rückresorption in proximalen Tubulusabschnitten abläuft. Long-term compensatory mechanisms play a special role in the clinically meaningful 'Aldosterone Escape' phenomenon: since aldosterone release is, so to speak, the last step in the RAAS cascade, it was for a long time believed that the blockade of the initial RAAS key steps such as the ACE- Activity or the AT-Rs to prevent even the last step, aldosterone formation and release in the adrenal gland. However, the RESOLVD study (McKelvie et al., Circulation 1999; 100; 1056-1064) showed that aldosterone plasma levels in patients with heart failure both under single ACE or AT-R blockade and under dual ACE / AT-R blockade Although it is reduced from baseline within the first 17 weeks of treatment, it even exceeds baseline levels after 43 weeks. The results of this study demonstrate that preventing the binding of aldosterone to the mineralocorticoid receptor in addition to angiotensin blockade is clinically important. MR antagonists (such as the steroidal compounds spironolactone, canrenone / canrenoate and eplerenone, as well as newer non-steroidal MR antagonists such as MT-3995 according to the compound of formula (VI), CS-3150 according to the compound of formula (V), LY2623091 PF-03882845 according to the compound of the formula (XIV) and finerenones, according to the compound of the formula (IV), counteract the aldosterone-mediated sodium retention in the kidneys (natriuretic action). Thus, MR antagonists lead to increased sodium excretion, which is a proven therapeutic concept in hypertensive patients and / or in patients with heart failure and / or renal insufficiency. However, MR antagonists can exert their natriuretic effect only in the kidney segments, in which aldosterone is also physiologically effective via MR. These are, in particular, the late distal tubule and collection tube sections, which are involved in sodium reabsorption only to a limited extent, while the majority of sodium secretion and reabsorption occurs in proximal tubule sections.
Neben dem RAAS gibt es aber auch noch andere sehr wichtige Regelsysteme und eines davon ist der Stickstoffmonoxid (Nitric Oxide/NO) cyclische Guanosinmonophosphat (cGMP) und Phosphodiesterase (PDE) Signalweg (NO/cGMP Weg). Durch Blutdruckerhöhung und daraus resultierende Schärkräfte auf die Endothelzellen in Blutgefässen wird durch Enzyme in den Endothelzellen aber auch in Nervenendigungen, den sogenannten NO-Synthasen (NOS), aus L- Arginin das NO gebildet. Dieses NO ist gasförmig und diffundiert über die Zellmembranen hinweg in verschiedene Zielzellen, insbesondere zu den Gefäßmuskelzellen. Dort bindet es an die Hämgruppe in der löslichen Guanylatzyklase (sGC), einem hetrodimeren, aus einer alpha- und einer beta- Untereinheit bestehenden, intrazellulären Hämprotein. Die NO-Bindung aktiviert das Enzym, welches dann die Umwandlung von Guanosin-Triphosphat (GTP) in cGMP katalysiert. Dieses cGMP stellt ein wichtiges sogenanntes „Second Messenger" Molekül dar und bindet an eine Vielzahl von intrazellulären Proteinen, unter anderem die cGMP-abhängien Proteinkinasen (G-Kinasen). G-Kinasen vermitteln über Phosphorylierung verschiedener Zielproteine, z.B. von Kaliumkanälen, eine Senkung des intrazellulären Kalziumspiegels, wodurch z.B. eine Relaxation der Gefäßmuskulatur ausgelöst wird. Daher wirkt NO über eine Stimulation des sGC/cGMP Weges gefäßdilatierend und damit blutdrucksenkend. Darüber hinaus sind für cGMP auch zahlreiche andere Wirkungen, wie z.B. eine anti-thrombotische, anti-fibrotische oder anti-inflammatorische Wirkung, beschrieben worden. Diese Wirkungen sind allerdings molekular weniger gut verstanden als die Gefäßdilatation und noch nicht vollständig aufgeklärt. Die NO/cGMP Signalkaskade und die Wirkungen von cGMP werden durch Abbau des cGMP zu unwirksamen GMP beendet. Dieser Schritt, die Hydrolyse des zyklischen Phosphatringes und die Bildung von 5 'GMP wird durch Phosphodiesterasen (PDE) katalysiert. Bei den PDEs handelt es sich um eine große Familie von Enzymen mit bisher elf identifizierten Mitgliedern und über 100 verschiedene sogenannten Splicingvarianten. Die verschiedenen PDEs unterscheiden sich vor allem hinsichtlich der Gewebespezifität (z.B. PDE6 wird ausschließlich im Auge exprimiert), der Substratspezifität (z.B. cAMP- oder cGMP-spezifisch) und der Regulation (z.B. durch Kalzium/Calmodulin oder zyklische Nukleotide). Für die spezifische Spaltung von cGMP sind vor allem die PDEs vom Typ 5 (PDE5), 6 (PDE6) und 9 (PDE9) verantwortlich, (vgl. Übersichtsarbeiten zum NO/cGMP/PDE Signalweg, z.B. Conti & Beavo 2007, Schmidt et al. (Herausgeber) 2009; Stasch et al. 2011, Derbyshire and Marletta 2012, Monica et al. 2016) In addition to the RAAS, there are also other very important control systems and one of them is the nitric oxide (nitric oxide / NO) cyclic guanosine monophosphate (cGMP) and phosphodiesterase (PDE) signaling pathway (NO / cGMP pathway). By increasing blood pressure and the resulting sharpness of the endothelial cells in blood vessels, NO is formed by enzymes in the endothelial cells as well as in nerve endings, the so-called NO synthases (NOS), from L-arginine. This NO is gaseous and diffuses across the cell membranes into various target cells, particularly vascular muscle cells. There it binds to the heme group in soluble guanylate cyclase (sGC), a hetrodimere, one-alpha and one beta-subunit intracellular heme protein. The NO bond activates the enzyme, which then catalyzes the conversion of guanosine triphosphate (GTP) into cGMP. This cGMP is an important second messenger molecule and binds to a variety of intracellular proteins, including cGMP-dependent protein kinases (G-kinases) .G-kinases mediate the phosphorylation of various target proteins, such as potassium channels Thus, NO stimulates vascular dilatation and thus lowers blood pressure by stimulating the sGC / cGMP pathway, and cGMP also has numerous other effects, such as anti-thrombotic, anti-fibrotic or anti-thrombotic effects These effects, however, are less well understood than vascular dilation and have not yet been fully elucidated.The NO / cGMP signaling cascade and the effects of cGMP are terminated by degradation of the cGMP to inactive GMP cyclic phosphate ring and the image 5 'GMP is catalyzed by phosphodiesterases (PDE). The PDEs are a large family of enzymes with up to now 11 identified members and over 100 different so-called splicing variants. The various PDEs differ, above all, in terms of tissue specificity (eg PDE6 is expressed exclusively in the eye), substrate specificity (eg cAMP or cGMP-specific) and regulation (eg by calcium / calmodulin or cyclic nucleotides). For the specific cleavage of cGMP mainly the PDEs of type 5 (PDE5), 6 (PDE6) and 9 (PDE9) are responsible, (see reviews on the NO / cGMP / PDE signaling pathway, eg Conti & Beavo 2007, Schmidt et al (Editor) 2009, Stasch et al., 2011, Derbyshire and Marletta 2012, Monica et al., 2016)
In Anbetracht der großen Bedeutung des NO/cGMP Signalweges für die physiologische Regulation und Aufrechterhaltung von Körperfunktionen, insbesondere für die Funktion des Herz- und Herz- Kreislaufsystemes, des Gefäßsystems, der Nierenfunktion oder der Lungen und kardio-pulmonären Funktion, aber auch von anitifibrotischen Effekten, wurden eine Reihe von Pharmaka erforscht und entwickelt die an verschiedenen wichtigen Umschaltstellen in diesen Signalweg eingreifen. Dies war umso mehr notwendig, da bekannt ist, dass verschieden Erkrankungen der oben genannten Organsysteme mit einer verminderten Bildung von NO einhergehen, was zu einer unzureichenden cGMP Versorgung führt und eine der zugrunden liegenden Pathomechanismen bei der Entwicklung von Herz- und Herz-Kreislauf, Nieren-, Lungen- und fibrotischen Erkrankungen sein könnte. In view of the great importance of the NO / cGMP signaling pathway for the physiological regulation and maintenance of bodily functions, in particular for the function of the cardiovascular system, the vascular system, the kidney function or the lungs and cardio-pulmonary function, but also of anitifibrotic effects , a number of pharmaceuticals have been researched and developed that intervene in this important signaling pathway at several important switching points. This was even more necessary since it is known that various diseases of the above-mentioned organ systems are associated with a reduced formation of NO, resulting in insufficient cGMP supply and one of the underlying pathomechanisms in the development of cardiovascular, renal -, lung and fibrotic diseases could be.
Seit langem bekannt ist z.B. die Verwendung von Nitraten und NO-Donoren, die bei der Behandlung von Angina Pectoris, sowohl zur akuten Anfallskupierung als auch bei der Anfallsprophylaxe, eingesetzt werden. Diese Verbindungen setzten enzymatisch oder nicht- enzymatisch NO frei, das dann an die sGC binden kann und zur cGMP Erhöhung führt. Allerdings stellen neben den kinetischen Limitationen dieser Verbindungen, vor allem eine erhöhte Radikalbildung die gefäß- und organschädigend wirken können, sowie die Entwicklung einer Tachyphylaxie eine signifikante Einschränkung des therapeutischen Potentials dar.  It has been known for a long time, e.g. the use of nitrates and NO donors, which are used in the treatment of angina pectoris, both for acute seizure and in seizure prophylaxis. These compounds released NO enzymatically or non-enzymatically, which can then bind to the sGC and lead to cGMP elevation. However, in addition to the kinetic limitations of these compounds, especially increased radical formation, which can have vascular and organ damage, and the development of tachyphylaxis represent a significant limitation of the therapeutic potential.
Daher fokussierten sich neuere Entwicklungen unter anderem auf die Hemmung des cGMP Abbaus durch die Hemmung von spezifischen PDEs, insbesondere die Hemmung der PDE5. Die Entwicklung von potenten und selektiven PDE5 Inhibitoren, wie z.B. Sildenafil, Vardenafil oder Tadalafil, zeigten erneut die Wirksamkeit dieses Signalweges für die Regulation des Gefäßtonus. Es erfolgten klinische Zulassungen von Präparaten für die Behandlung von erektiler Dysfunktion (ED), von pulmonaler arterieller Hypertonie (PAH) und von benigner Prostatahyperaplasie (BPH). Außerdem werden diese Verbindungen auch für den Einsatz bei Herz- und Herz-Kreislauferkrankungen und bei Nierenerkrankungen klinisch erprobt. Dies zeigt erneut die ubiquitäre Bedeutung dieses NO/cGMP Signalweges und unterstreicht das breite Anwendungspotential dieser cGMP erhöhenden Verbindungen. Die Behandlungsmöglichkeiten mit PDE5 Inhibitoren sind allerdings beschränkt, da diese für Ihre Wirksamkeit einen ausreichend hohen endogenen cGMP Spiegel benötigen, der durch die Verbindungen dann vor Abbau geschützt ist. In vielen Erkrankungen, insbesondere auch in Herz- und Herzkreislauferkrankungen oder Lungenerkrankungen ist aber die endogene NO-Produktion und damit auch die cGMP Bildung zumindest teilweise gestört. Daher wirken PDE5 Inhibitoren auch nicht in allen Patienten vergleichsweise gut bzw. gibt es auch behandlungsresistente Patienten, z.B. bei der erektilen Dysfunktion oder bei pulmonaler Hypertonie. Um diese Limitation sowohl von Nitraten wie von PDE5 Inhibitoren zu umgehen wurde versucht die sGC direkt pharmakologisch zu stimulieren. Dies sollte zum Einen die NO-abhängige Radikalbildung der Nitrate, zum Anderen aber auch die Abhängigkeit der Wirksamkeit vom produzierten cGMP, wie sie für PDE5 Inhibitoren beschrieben ist, umgehen. Die Erforschung und Entwicklung von sGC Stimulatoren und sGC Aktivatoren stellt daher einen Meilenstein in der Pharmakologie des NO/cGMP Signalweges dar. Diese beiden Verbindungsklassen, sGC Stimulatoren und sGC Aktivatoren, stimulieren die sGC NO unabhängig und führen zu einer NO-unabhängigen Produktion von cGMP. Daneben wirken aber diese Verbindungsklassen auch synergistisch (sGC Stimulatoren) und additiv (sGC Aktivatoren) zum endogen gebildeten NO. Der Hauptunterschied, soweit dies momentan bekannt ist, besteht in der Bindung an die sGC. Die sGC ist ein heterodimeres Protein, das aus einer alpha- und einer beta-Untereinheit, letzter trägt die NO-bindende Hämgruppe, gebildet wird. Die sGC Stimulatoren binden an die alpha Untereinheit der nicht oxidierten und hämhaltigen sGC und bewirken die direkte, NO unabhängige Bildung von cGMP (Stasch et al. (A) 2001 ; Stasch & Hobbs 2009). Die sGC Aktivatoren binden hingegen an die beta-Untereinheit der oxidierten und hämfreien sGC, aktivieren diese und führen so zur NO-unabhängigen Bildung von cGMP (Stasch et al. (B) 2001, Schmidt et al. 2009). Obgleich dieser prinzipielle Unterschied sehr gut unter in vitro Bedingungen etabliert ist, sind die physiologischen und pathophysiologischen Konsequenzen des Vorkommens von hämhaltiger und oxidierter-hämfreier sGC und das sich daraus ableitete Behandlungspotential dieser Verbindungsklassen noch unvollständig verstanden. Dennoch wurde der pharmakologische Nutzen von sGC Stimulatoren und sGC Aktivatoren in zahlreichen präklinischen Modellen und für zahlreiche verschiedene Indikationen, insbesondere im Bereich von Herz- und Herz-Kreislauf-Erkrankungen, von Nieren- und kardio-renalen Erkrankungen, von Lungen- und kardio-pulmonären Erkrankungen gezeigt (Evgenov et al. 2009, Stasch et al. 2011). Dies konnte auch in klinischen Studien bestätigt werden und so wurde im Jahre 2013 der sGC Stimulator Riociguat für die Behandlung von pulmonaler arterieller Hypertonie (PAH) und von chronisch thrombo-embolischer pulmonaler Hypertonie (CTEPH) zugelassen (Ghofrani et al. (A), Ghofrani et al. (B) 2013, 2013Hambly & Granton 2015). Zudem befindet sich der sGC Stimulator Vericiguat in Phase II/III für die Behandlung von Herzinsuffizienz (Pieske et al. 2014, Gheorghiade et al. 2015). Diese Beispiele belegen auch klinisch die breite Einsatzmöglichkeit von sGC Stimulatoren und sGC Aktivatoren, im Bereich der Behandlung und/oder Prophylaxe von Herz- und Herz-Kreislauf-Erkrankungen, von Nieren- und kardio-renalen Erkrankungen bzw. von Lungen- und kardio-pulmonären Erkrankungen. Zudem konnte präklinisch sehr gut eine anti-fibrotische Wirkung von sGC Stimulatoren und sGC Aktivatoren gezeigt werden.Therefore, recent developments focused, inter alia, on the inhibition of cGMP degradation by the inhibition of specific PDEs, in particular the inhibition of PDE5. The development of potent and selective PDE5 inhibitors, such as sildenafil, vardenafil or tadalafil, again demonstrated the efficacy of this pathway for the regulation of vascular tone. There have been clinical approvals for erectile dysfunction (ED), pulmonary arterial hypertension (PAH) and benign prostatic hyperplasia (BPH). In addition, these compounds are also clinically tested for use in cardiovascular and renal diseases. This again demonstrates the ubiquitous importance of this NO / cGMP signaling pathway and underlines the broad application potential of these cGMP enhancing compounds. However, the treatment options with PDE5 inhibitors are limited, since they require a sufficiently high endogenous cGMP level for their effectiveness, which is then protected by the compounds from degradation. In many diseases, especially in cardiovascular diseases or lung diseases, however, the endogenous NO production and thus also the cGMP formation is at least partially disturbed. Therefore, PDE5 inhibitors also do not work comparatively well in all patients or are also treatment-resistant patients, for example in erectile dysfunction or in pulmonary hypertension. In order to circumvent this limitation of both nitrates and PDE5 inhibitors, it was attempted to stimulate the sGC directly pharmacologically. On the one hand, this should obviate the NO-dependent radical formation of the nitrates, and on the other hand, the dependence of the activity on the produced cGMP, as described for PDE5 inhibitors. The discovery and development of sGC stimulators and sGC activators therefore represents a milestone in the pharmacology of the NO / cGMP signaling pathway. These two classes of compounds, sGC stimulators and sGC activators, independently stimulate sGC NO and result in NO-independent production of cGMP. In addition, however, these classes of compounds also act synergistically (sGC stimulators) and additively (sGC activators) to endogenously formed NO. The main difference, as far as is currently known, is the binding to the sGC. The sGC is a heterodimeric protein formed from one alpha and one beta subunit, the last one carrying the NO-binding heme group. The sGC stimulators bind to the alpha subunit of the non-oxidized and heme-containing sGC and cause the direct, non-independent formation of cGMP (Stasch et al. (A) 2001; Stasch & Hobbs 2009). In contrast, the sGC activators bind to the beta subunit of the oxidized and heme-free sGC, activate it and thus lead to the NO-independent formation of cGMP (Stasch et al. (B) 2001, Schmidt et al., 2009). Although this principal difference is well established under in vitro conditions, the physiological and pathophysiological consequences of the presence of hematopoietic and oxidized-hemorrhagic sGC and the resulting treatment potential of these classes of compounds are still incompletely understood. Nevertheless, the pharmacological utility of sGC stimulators and sGC activators has been demonstrated in numerous preclinical models and for a variety of indications, particularly in the fields of cardiovascular, renal and cardio-renal diseases, pulmonary and cardio-pulmonary Diseases (Evgenov et al, 2009, Stasch et al., 2011). This was also confirmed in clinical studies, and in 2013, the sGC stimulator riociguat was approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) (Ghofrani et al. (A), Ghofrani et al. (B) 2013, 2013 Hambly & Granton 2015). In addition, the sGC stimulator vericiguat is in Phase II / III for the treatment of heart failure (Pieske et al 2014, Gheorghiade et al., 2015). These examples also clinically demonstrate the wide range of possible use of sGC stimulators and sGC activators in the field of treatment and / or prophylaxis of cardiovascular diseases, kidney and cardio-renal diseases or of pulmonary and cardio-pulmonary diseases diseases. In addition, an anti-fibrotic effect of sGC stimulators and sGC activators could be shown very well.
Grundsätzlich unterscheidet man MR Antagonisten (MRAs) mit einer steroidalen Grundstruktur von solchen, die über einen nicht-steroidale Grundstruktur verfügen. Steroidale MRAs wie Spironolakton oder dessen aktiver Metabolit Kanrenone interagieren nicht nur mit dem MR, sondern auch mit den homologen Androgen und Progesteron Rezeptoren. Diese Interaktionen können zu unerwünschten Wirkungen auf den Sexualhormonstoffwechsel wie Gynecomastie, Dysmenorrhoe und Libidoverlust führen. Nicht-steroidale MRAs wie Finerenone interagieren spezifisch mit dem MR, so dass entsprechende Nebenwirkungen, die aus Interaktionen mit anderen Steroidhormonrezeptoren resultieren können, nicht zu erwarten sind. Basically, a distinction is made between MR antagonists (MRAs) with a steroidal basic structure of those that have a non-steroidal basic structure. Steroidal MRAs such as spironolactone or its active metabolite kanrenone not only interact with the MR but also with the homologous androgen and progesterone receptors. These interactions may have undesirable effects on sex hormone metabolism such as gynecomastia, dysmenorrhea and libido loss to lead. Nonsteroidal MRAs such as finerenones interact specifically with the MR, so that corresponding side effects that may result from interactions with other steroid hormone receptors are not to be expected.
Beispiele für steroidale Mineralocorticoid Rezeptor Antagonisten sind (der in den folgenden Publikationen hinsichtlich der steroidalen MR Antagonisten veröffentlichte Gegenstand soll hiermit auch Offenbarungsgegenstand der vorliegenden Anmeldung sein)  Examples of steroidal mineralocorticoid receptor antagonists are (the subject matter published in the following publications with regard to the steroidal MR antagonists should also be the subject of the present application)
Spironolakton (7a- Acetylthio-3 -oxo- 17a-pregn-4-en-21 , 17 ?-carbolacto-7a- Acetylthio-3 -oxo- 17a- pregn-4-en-21,17ß-carbolacton) der Formel (I)  Spironolactone (7-acetylthio-3-oxo-17a-pregn-4-en-21, 17-carbolacto-7-acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone) of the formula ( I)
welches aus der Literatur bekannt und als Medikament bereits u.a. mit den Handelsnamen Aldactone, Jenasprion, Asyrol, Spirobene, Verospiron, Xenalon auf dem Markt erhältlich ist, which is known from the literature and as a drug already u.a. with the trade names Aldactone, Jenasprion, Asyrol, Spirobene, Verospiron, Xenalon is available on the market,
Eplerenone (Epoxymexerenon) der Formel (II)  Eplerenones (epoxymexerenone) of the formula (II)
welches aus der Literatur bekannt und als Medikament bereits u.a. mit den Handelsnamen Inspra auf dem Markt erhältlich ist, which is known from the literature and as a drug already u.a. available in the market with the trade names Inspra,
Kanrenone (10,13 -Dimethylspiro [2,8,9,11,12,14,15,16-octahydro- lH-cyclopenta[a]phenanthrene- 17,5'-oxolane]-2',3-dione) der Formel (III) Kanrenone (10,13 -dimethylspiro [2,8,9,11,12,14,15,16-octahydro- lH-cyclopenta [a] phenanthrene-17,5'-oxolane] -2 ', 3-dione) of Formula (III)
welches einen aktiven Metaboliten von Spironolakton darstellt, aus der Literatur bekannt und als Medikament bereits u.a. mit den Handelsnamen Contaren, Luvion und Phanurane auf dem Markt erhältlich ist. Kanrenone ist auch als Kaliumsalz, als Kalium Kanrenoate bekannt und kommerziell erhältlich. which is an active metabolite of spironolactone, known from the literature and as a drug already u.a. available with the trade names Contaren, Luvion and Phanurane on the market. Kanrenone is also known as Potassium Salt, Potassium Kanrenoate, and is commercially available.
Beispiele für nicht-steroidale Mineralocorticoid-Rezeptor Antagonisten sind (der in den folgenden Publikationen hinsichtlich der nicht-steroidalen MR Antagonisten veröffentlichte Gegenstand soll hiermit auch Offenbarungsgegenstand der vorliegenden Anmeldung sein):  Examples of non-steroidal mineralocorticoid receptor antagonists are (the subject matter published in the following publications with respect to the non-steroidal MR antagonists is also intended to be the subject of the present application):
Finereneone ((S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l ,4-dihydro-l ,6-naphthyridin- 3-carboxamid), als ein selektiver Antagonist, der auf einem Dihydropyridingrundgerüst basiert, der Formel (IV)  Finereneone ((S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide), as a selective antagonist, which is based on a Dihydropyridingrundgerüst, the formula (IV)
welches in der DE 10 2007009494 AI und WO 2008 104 306 A2 beschrieben ist, which is described in DE 10 2007009494 A1 and WO 2008 104 306 A2,
Esaxerenone (l -(2-hydroxyethyl)-4-methyl-N-(4-(methylsulfonyl)phenyl)-5-(2-(trifluoromethyl) phenyl)-lH-pyrrole-3-carboxamide) der Formel (V) Esaxerenone (1- (2-hydroxyethyl) -4-methyl-N- (4- (methylsulfonyl) phenyl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrrole-3-carboxamide) of the formula (V)
welches in der WO2006/012642 offenbart ist, which is disclosed in WO2006 / 012642,
Apararenone (N-(4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4] yl)methanesulfonamide) der Formel (VI)  Apararenones (N- (4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [l, 4] yl) methanesulfonamides) of the formula (VI)
welches in der WO07/089034 offenbart ist, which is disclosed in WO07 / 089034,
PF-03882845 ((3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydi enzo[g]indazole-7-carbonsäure) der Formel (XIV)  PF-03882845 ((3S, 3aR) -2- (3-chloro-4-cyanophenyl) -3-cyclopentyl-3,3a, 4,5-tetrahydor enzo [g] indazole-7-carboxylic acid) of the formula (XIV)
welches in den folgenden Publikationen offenbart ist: Meyers, M.J., Arhancet, G.B., Hockerman, S.L., Chen, X., Long, S.A., Mahoney, M.W., Rico, J.R., Garland, DJ., Blinn, J.R., Collins, J.T., Yang, S., Huang, H.C., McGee, K.F., Wendling, J.M., Dietz, J.D., Payne, M.A., Homer, B.L., Heron, M.I., Reitz, D.B., Hu,X., 2010. Discovery of (3S, 3aR)-2-(3- chloro-4-cyanophenyl)-3-cyclopentyl-3, 3a, 4, 5-tetrahydro-2H-b enzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy. J. Med. Chem. 53, 5979-6002, which is disclosed in the following publications: Meyers, MJ, Arhancet, GB, Hockerman, SL, Chen, X, Long, SA, Mahoney, MW, Rico, JR, Garland, DJ., Blinn, JR, Collins, JT, Yang, S., Huang, HC , McGee, KF, Wendling, JM, Dietz, JD, Payne, MA, Homer, BL, Heron, MI, Reitz, DB, Hu, X, 2010. Discovery of (3S, 3aR) -2- (3- chloro 4-cyano-phenyl) -3-cyclopentyl-3, 3a, 4, 5-tetrahydro-2H-benzo [g] indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy. J. Med. Chem. 53, 5979-6002,
(R)-6-(l-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-lH-pyrazol-3-yl)-2- methoxynicotinsäure der Formel (VIII)  (R) -6- (1- (4-cyano-3-methylphenyl) -5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl) -2-methoxynicotinic acid of the formula (VIII)
welche in den folgenden Publikationen offenbart ist: which is disclosed in the following publications:
Casimiro-Garcia A, Piotrowski DW, Ambler C, et al. Identification of (R)-6-(l-(4-cyano-3- methylphenyl)-5-cyclopentyl-4,5-dihydro-lH-pyrazol-3-yl)-2-methoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor antagonist. J Med Chem 2014; 57:4273-4288, Casimiro-Garcia A, Piotrowski DW, Ambler C, et al. Identification of (R) -6- (1- (4-cyano-3-methylphenyl) -5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl) -2-methoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor antagonist. J Med Chem 2014; 57: 4273-4288,
MR Antagoniten, die auf eine Aryl Sulfonamid Struktur aufbauen, wie diese, die in Futatsugi K, Piotrowski DW, Casimiro-Garcia A, et al. Design and synthesis of aryl sulfonamide-based nonsteroidal mineralocorticoid receptor antagonists. Bioorg Med Chem Lett 2013; 23:6239-6242 offenbart sind, MR antagonists based on an aryl sulfonamide structure, such as those described in Futatsugi K, Piotrowski DW, Casimiro-Garcia A, et al. Design and synthesis of aryl sulfonamide-based nonsteroidal mineralocorticoid receptor antagonists. Bioorg Med Chem Lett 2013; 23: 6239-6242 are disclosed
KBP-5074, welches in der US2015/0126501 offenbart ist,  KBP-5074, which is disclosed in US2015 / 0126501,
(S)-N- {3-[l-cyclopropyl-l -(2,4-difluoro-phenyl)-ethyl]-lH-indol-7-yl}-methanesulfonamid, welches auf einem Indolgrundgerüst basiert der Formel (IX) (S) -N- {3- [1-Cyclopropyl-1- (2,4-difluoro-phenyl) -ethyl] -H-indol-7-yl} -methanesulfonamide, which is based on an indole skeleton of the formula (IX)
welches in den folgenden Publikationen offenbart ist: which is disclosed in the following publications:
Bell MG, Gernert DL, Grese TA, Belvo MD, Borromeo PS, Kelley SA, Kennedy JH, Kolis SP, Lander PA, Richey R, Sharp VS, Stephenson GA, Williams JD, Yu H, Zimmerman KM, Steinberg MI, Jadhav PK. (S)-N- {3-[l-cyclopropyl-l-(2,4-difluoro-phenyl)-ethyl]-lH-indol-7-yl}- methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor. J Med Chem. 2007; 50:6443-6445.  Bell MG, Gernert DL, Grese TA, Belvo MD, Borromeo PS, Kelley SA, Kennedy JH, Kolis SP, Lander PA, Richey R, Sharp VS, Stephenson GA, Williams JD, Yu H, Zimmerman KM, Steinberg MI, Jadhav PK , (S) -N- {3- [l-cyclopropyl-1- (2,4-difluoro-phenyl) -ethyl] -lH-indol-7-yl} -methanesulfonamide: a potent, nonsteroidal, functional antagonist of the mineralocorticoid receptor. J Med Chem. 2007; 50: 6443-6445.
Bisaryloxinidole, die in Neel DA, Brown ML, Lander PA, Grese TA, Defauw JM, Doti RA, Fields T, Kelley SA, Smith S, Zimmerman KM, Steinberg MI, Jadhav PK. 3,3-Bisaryloxindoles as mineralocorticoid receptor antagonists. Bioorg Med Chem Lett. 2005; 15:2553-2557 offenbart sind, sowie MR Antagonisten, die auf ein Oxazolidindiongerüst aufbauen, die in den folgenden Publikationen offenbart sind:  Bisaryloxinidols available in Neel DA, Brown ML, Lander PA, Grese TA, Defauw JM, Doti RA, Fields T, Kelley SA, Smith S, Zimmerman KM, Steinberg MI, Jadhav PK. 3,3-Bisaryloxindoles as mineralocorticoid receptor antagonists. Bioorg Med Chem Lett. 2005; 15: 2553-2557, and MR antagonists based on an oxazolidinedione skeleton disclosed in the following publications:
Yang C, Shen HC,Wu Z, et al. Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists. Bioorg Med Chem Lett 2013; 23:4388-4392. Cox JM, Chu HD, Yang C, et al. Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series. Bioorg Med Chem Lett 2014; 24: 1681-1684. Yang C, Balsells J, Chu HD, Cox JM, Crespo A, Ma X, Contino L, Brown P, Gao S, Zamlynny B, Wiltsie J, Clemas J, Lisnock J, Gibson J, Zhou G, Garcia-Calvo M, Bateman TJ, Tong V, Xu L, Crook M, Sinclair P, Shen HC. Discovery of benzimidazole oxazolidinediones as novel and selective nonsteroidal mineralocorticoid receptor antagonists. ACS Med Chem Lett. 2015; 6:461-465,  Yang C, Shen HC, Wu Z, et al. Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists. Bioorg Med Chem Lett 2013; 23: 4388 to 4392. Cox JM, Chu HD, Yang C, et al. Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series. Bioorg Med Chem Lett 2014; 24: 1681-1684. Yang C, Balsells J, Chu HD, Cox JM, Crespo A, Ma X, Contino L, Brown P, Gao S, Zamlynny B, Wiltsie J, Clemas J, Lisnock J, Gibson J, Zhou G, Garcia-Calvo M, Bateman TJ, Tong V, Xu L, Crook M, Sinclair P, Shen HC. Discovery of benzimidazole oxazolidinediones as novel and selective nonsteroidal mineralocorticoid receptor antagonists. ACS Med Chem Lett. 2015; 6: 461-465,
Mineralocorticoid Receptor Antagonisten, die auf einem Indol- oder Indazolgerüst basieren, wie in, WO2012/097744, WO2013055606, WO2013055607, WO2013055608, WO2014014794, WO2012139495 offenbart.  Mineralocorticoid receptor antagonists based on an indole or indazole skeleton as disclosed in WO2012 / 097744, WO2013055606, WO2013055607, WO2013055608, WO2014014794, WO2012139495.
Geeignete sGC Aktivatoren sind aus den folgenden Veröffentlichungen bekannt (der in den folgenden Publikationen veröffentlichte Gegenstand soll hiermit auch Offenbarungsgegenstand der vorliegenden Anmeldung sein): WO2013/157528, WO2015/056663, WO2009/123316, WO2016/001875, WO2016/001876, WO2016/001878, WO2000/02851, WO2012/122340, WO2013/025425, WO2014/039434, WO2016/014463, WO2009/068652, WO2009/071504, WO2010/015652, WO2010/015653, WO2015/033307, WO2016/042536, WO2009/032249, WO2010/099054, WO2012/058132,Suitable sGC activators are known from the following publications (the subject matter published in the following publications should also be the subject of the present application): WO2013 / 157528, WO2015 / 056663, WO2009 / 123316, WO2016 / 001875, WO2016 / 001876, WO2016 / 001878, WO2000 / 02851, WO2012 / 122340, WO2013 / 025425, WO2014 / 039434, WO2016 / 014463, WO2009 / 068652, WO2009 / 071504, WO2010 / 015652, WO2010 / 015653, WO2015 / 033307, WO2016 / 042536, WO2009 / 032249, WO2010 / 099054, WO2012 / 058132,
US2010/0216764, WO01/19776, WO01/19780, WO01/19778, WO02/070459, WO02/070460,US2010 / 0216764, WO01 / 19776, WO01 / 19780, WO01 / 19778, WO02 / 070459, WO02 / 070460,
WO02/070510, WO02/070462, WO2007/045366, WO2007/045369, WO2007/045433,WO02 / 070510, WO02 / 070462, WO2007 / 045366, WO2007 / 045369, WO2007 / 045433,
WO2007/045370, WO2007/045367, WO2014/012935, WO2014/012934, WO2011/141409,WO2007 / 045370, WO2007 / 045367, WO2014 / 012935, WO2014 / 012934, WO2011 / 141409,
WO2008/119457, WO2008/119458, WO2009/127338, WO2010/102717, WO2011/051165, WO2012/076466, WO2012/139888, WO2013/174736. WO2008 / 119457, WO2008 / 119458, WO2009 / 127338, WO2010 / 102717, WO2011 / 051165, WO2012 / 076466, WO2012 / 139888, WO2013 / 174736.
Besondere Bedeutung haben die folgenden sGC Aktivatoren:  Of particular importance are the following sGC activators:
(3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4-chloφhenyl)-4,4,4-trifluor-3-methylbutanoyl]amino}  (3S) -3- (4-Chloro-3- {[(2S, 3R) -2- (4-chloro-phenyl) -4,4,4-trifluoro-3-methyl-butanoyl] -amino}
phenyl)-3-cyclopropylpropansäure der Formel (X) phenyl) -3-cyclopropylpropanoic acid of the formula (X)
welche in der WO2012/139888 offenbart ist, which is disclosed in WO2012 / 139888,
4-( {(4-carboxybutyl) [2-(2- { [4-(2-phenylethyl)benzyl] oxy } phenyl)ethyl] amino } methyl)carbonsäure der Formel (XI) 4- ({(4-carboxybutyl) [2- (2- {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) carboxylic acid of the formula (XI)
welche in der WO 01/019780 offenbart ist, which is disclosed in WO 01/019780,
5- {(4-Carboxybutyl)[2-(2- {[3-chlor-4'-(trifluormethyl)biphenyl-4-yl]methoxy}phenyl)ethyl] 5,6,7,8-tetrahydrochinolin-2-carbonsäure der Formel (XII)  5- {(4-carboxybutyl) [2- (2- {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] 5,6,7,8-tetrahydroquinoline-2 carboxylic acid of the formula (XII)
welche in der WO2014/012934 offenbart ist, which is disclosed in WO2014 / 012934,
5- { [2-(4-Carboxyphenyl)ethyl] [2-(2- { [3-chlor-4'-(trifluormethyl)biphenyl-4-yl]methoxy} phenyl)- ethyl]amino} -5,6,7,8-tetrahydrochinolin-2-carbonsäure der Formel (XIII)) welche in der WO2014/012934 offenbart ist, und der sGC Aktivator BI 703704, der von der Firma Boehringer Ingelheim in der klinischen Entwicklung untersucht wird, sowie andere in der präklinischen Forschung und Entwicklung befindliche sGC Aktivatoren. 5- {[2- (4-Carboxyphenyl) ethyl] [2- (2- {[3-chloro-4 '- (trifluoromethyl) -biphenyl-4-yl] -methoxy} -phenyl) -ethyl] -amino} -5,6 , 7,8-tetrahydroquinoline-2-carboxylic acid of the formula (XIII)) which is disclosed in WO2014 / 012934 and the sGC activator BI 703704, which is being investigated by Boehringer Ingelheim in clinical development, as well as other sGC activators in preclinical research and development.
Sowohl das RAAS wie der NO/cGMP Weg spielen eine wichtige Rolle bei der Aufrechterhaltung der Körperhomeostase und regeln wichtige Funktionen im Herz- und Herzkreislaufsystem, Nieren- und kardio-renalen System oder im Lungen und kardio-pulmonären System. Die Verwendung von MR- Antagonisten sowie die Verwendung von sGC Aktivatoren, als Monotherapien bei Herz- und Herz- Kreislauf-Erkrankungen, bei Nieren- und kardio-renalen Erkrankungen, bei Lungen- und kardio- pulmonären Erkrankungen oder bei fibrotischen Erkrankungen ist ebenfalls beschrieben. Tatsächlich ist aber sowohl der Anteil der Dysregulation der beiden Signalwege bei diesen verschiedenen Erkrankungen, als auch die absolute Effizienz der beiden Mechanismen im direkten Vergleich unbekannt. Both the RAAS and the NO / cGMP pathway play an important role in maintaining body homeostasis and regulate important functions in the cardiovascular, renal and cardio-renal systems or in the pulmonary and cardio-pulmonary systems. The use of MR antagonists and the use of sGC activators as monotherapies in cardiovascular, renal and cardio-renal diseases, pulmonary and cardiopulmonary diseases or fibrotic diseases is also described. In fact, both the proportion of dysregulation of the two signaling pathways in these various diseases, as well as the absolute efficiency of the two mechanisms in the direct comparison is unknown.
Daher wurden Versuche durchgeführt um sGC Aktivatoren mit MR-Antagonisten direkt zu vergleichen. Dadurch sollten Aufschlüsse über die qualitative- und quantitative Krankheitsrelevanz dieser beiden Pathomechanismen und die sich daraus ableitbaren Behandlungsparadigmen erforscht werden. Therefore, experiments were performed to directly compare sGC activators with MR antagonists. This should provide insights into the qualitative and quantitative relevance of these two pathomechanisms and the treatment paradigms that can be derived from them.
Es wurden in diesen Versuchen Kombinationen von MR-Antagonisten mit sGC Aktivatoren eingesetzt und auch im direkten Vergleich zu den Einzelverbindungen getestet. Überraschend zeigte sich eine außergewöhnliche Wirksamkeit dieser Kombinationen die weit über die Wirksamkeit der Einzelkomponenten hinaus geht und eine synergistische Wirkung der Kombination aus MR- Antagonisten und sGC Aktivatoren nahe legt. Die Lösung der oben gestellten Aufgabe kann somit in der Bereitstellung von Kombinationen gesehen werden, die mindestens einen sGC Aktivator und mindestens einen Stoff, der in das RAAS-System eingreift enthalten, und die zur gezielten Behandlung von Herz- und Herz-Kreislauf-Erkrankungen, Nieren- und kardio-renalen Erkrankungen, Lungen- und kardio-pulmonären Erkrankungen und fibrotischen Erkrankungen mit über-additiven Effekten verwendet werden können. Combinations of MR antagonists with sGC activators were used in these experiments and also tested in direct comparison to the individual compounds. Surprisingly, an extraordinary effectiveness of these combinations, which goes far beyond the efficacy of the individual components, and suggests a synergistic effect of the combination of MR antagonists and sGC activators. The solution to the above problem can thus be seen in the provision of combinations which contain at least one sGC activator and at least one substance which intervenes in the RAAS system and which are used for the targeted treatment of cardiovascular diseases, Renal and cardio-renal diseases, pulmonary and cardio-pulmonary diseases and fibrotic diseases with over-additive effects can be used.
Die Erfindung stellt daher u.a. eine Kombination enthaltend MR- Antagonisten und sGC Aktivatoren bereit. Die Kombination zeigt unter akutem und insbesondere unter chronischem Einsatz, positive Effekte bzgl. Endorganschutz von Herzen und Nieren, Verminderung der renalen Proteinausscheidung, Verminderung von Morbidität und Mortalität unter experimentellen Bedingungen. Diese experimentellen Bedingungen bestehen zum einen aus gesunden Tieren oder auch Tieren mit Bluthochdruck, Herz- und/oder Niereninsuffizienz (z.B. transgene Renin-Ratten), L- NAME behandelten Tieren (z.B. transgene Renin-Ratten + L-NAME Behandlung).  The invention therefore provides i.a. a combination containing MR antagonists and sGC activators ready. The combination shows acute and especially chronic use, positive effects on end organ protection of the heart and kidneys, reduction of renal protein excretion, reduction of morbidity and mortality under experimental conditions. These experimental conditions consist of healthy animals or animals with hypertension, cardiac and / or renal insufficiency (e.g., transgenic renin rats), L-NAME treated animals (e.g., transgenic renin rats + L-NAME treatment).
Bevorzugt sind Kombinationen, die mindestens einen sGC Aktivator und mindestens einen MR Antagonist enthalten. Ebenfalls bevorzugt sind Kombinationen, die mindestens einen sGC Aktivator und mindestens einen steroidalen MR Antagonisten enthalten.  Preferred are combinations containing at least one sGC activator and at least one MR antagonist. Also preferred are combinations containing at least one sGC activator and at least one steroidal MR antagonist.
Ebenfalls bevorzugt sind Kombinationen, die mindestens einen sGC Aktivator und mindestens einen nicht-steroidalen MR Antagonisten enthalten. Also preferred are combinations containing at least one sGC activator and at least one non-steroidal MR antagonist.
Ebenfalls bevorzugt sind Kombinationen, die mindestens einen sGC Aktivator und mindestens einen nicht-steroidalen MR Antagonisten mit einem Dihydropyridingrundgerüst enthalten. Also preferred are combinations containing at least one sGC activator and at least one non-steroidal MR antagonist with a dihydropyridine backbone.
Ebenfalls bevorzugt sind Kombinationen, die mindestens einen sGC Aktivator und mindestens einen nicht-steroidalen MR Antagonisten mit einem Indol- oder Indazolgrundgerüst enthalten. Also preferred are combinations containing at least one sGC activator and at least one non-steroidal MR antagonist with an indole or indazole backbone.
Ebenfalls bevorzugt sind Kombinationen, die mindestens einen sGC Aktivator und mindestens einen nicht-steroidalen MR Antagonisten mit einem Oxazolidindiongrundgerüst enthalten. Ebenfalls bevorzugt sind Kombination, die mindestens einen sGC Aktivator und mindestens einen steroidalen MR Antagonisten ausgewählt aus der Gruppe Also preferred are combinations containing at least one sGC activator and at least one non-steroidal MR antagonist having an oxazolidinedione scaffold. Also preferred are combination, the at least one sGC activator and at least one steroidal MR antagonist selected from the group
Spirono lakton (7 -Acetylthio-3 -oxo- 17 -pregn-4-en-21 , 17ß-carbolacto-7 -Acetylthio-3-oxo- 17a- pregn-4-en-21,17ß-carbolacton) der Formel (I) Spirono lactone (7-acetylthio-3-oxo-17-pregn-4-en-21, 17β-carbolacto-7-acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone) of the formula (II) I)
Eplerenone (Epoxymexerenon) der Formel (II)  Eplerenones (epoxymexerenone) of the formula (II)
Kanrenone (10, 13 -Dimethylspiro [2,8,9, 1 1 ,12,14, 15,16-octahydro- lH-cyclopenta[a  Canrenone (10, 13 -dimethylspiro [2,8,9,1 1 1, 12,14,15,16-octahydro- lH-cyclopenta [a
17,5'-oxolane]-2',3-dione) der Formel (III) 17.5'-oxolanes] -2 ', 3-diones) of the formula (III)
und dessen Kaliumsalz (Kalium Kanrenoat),enthalten. and its potassium salt (potassium canenoate).
Ebenfalls bevorzugt sind Kombination, die mindestens einen sGC Aktivator und mindestens einen nicht-steroidalen MR Antagonisten ausgewählt aus der Gruppe Finereneone, ((S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6- naphthyridin-3-carboxamid) der Formel (IV) Also preferred are combination, the at least one sGC activator and at least one non-steroidal MR antagonist selected from the group Finereneone, ((S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl - 1, 4-dihydro-1, 6-naphthyridine-3-carboxamide) of the formula (IV)
Esaxerenone (l-(2-hydroxyethyl)-4-methyl-N-(4-(methylsulfonyl)phenyl)-5-(2-(trifluoromethyl) phenyl)-lH-pyrrole-3-carboxamide) der Formel (V)  Esaxerenone (1- (2-hydroxyethyl) -4-methyl-N- (4- (methylsulfonyl) phenyl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrrole-3-carboxamide) of the formula (V)
Apararenone (N-(4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4] yl)methanesulfonamide) der Formel (VI)  Apararenones (N- (4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [l, 4] yl) methanesulfonamides) of the formula (VI)
(3 S, 3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-b enzo[g]indazole-7- carbonsäure) der Formel (XIV) (3S, 3aR) -2- (3-chloro-4-cyanophenyl) -3-cyclopentyl-3,3a, 4,5-tetrahydro-2H-benzo [g] indazole-7-carboxylic acid) of the formula (XIV )
(R)-6-(l-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-lH-pyrazol-3-yl)-2- methoxynicotinsäure der Formel (VIII)  (R) -6- (1- (4-cyano-3-methylphenyl) -5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl) -2-methoxynicotinic acid of the formula (VIII)
(S)-N- {3-[l-cyclopropyl-l-(2,4-difluoro-phenyl)-ethyl]-lH-indol-7-yl}-methanesulfonamid Formel (IX)  (S) -N- {3- [1-Cyclopropyl-1- (2,4-difluoro-phenyl) -ethyl] -H-indol-7-yl} -methanesulfonamide. Formula (IX)
enthalten. I i contain. I i
Ebenfalls bevorzugt sind Kombination, die mindestens einen sGC Aktivator und Finerenone, (S)-4-(4- Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridin-3-carboxamid der Formel (IV)  Also preferred are combinations containing at least one sGC activator and finerenones, (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-carboxamide of the formula (IV)
enthalten. contain.
Ebenfalls bevorzugt sind Kombination, die mindestens einen sGC Aktivator, enthaltend mindestens eine Carbonsäurefunktion und Finerenone, (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- l,4-dihydro-l,6-naphthyridin-3-carboxamid der Formel (IV) Likewise preferred are combinations which contain at least one sGC activator containing at least one carboxylic acid function and finerenones, (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxamide of the formula (IV)
enthalten. contain.
Ebenfalls bevorzugt sind Kombination, die mindestens einen sGC Aktivator, ausgewählt aus der Gruppe Also preferred are combination containing at least one sGC activator selected from the group
(3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4-chlo^henyl)-4,4,4 rifluor-3-methylbutanoyl]amino}phenyl)-3- cyclopropylpropansäure der Formel (X) (3S) -3- (4-Chloro-3- {[(2S, 3R) -2- (4-chloro-4-yl) -4,4,4-trifluoro-3-methylbutanoyl] -amino} -phenyl) -3-cyclopropyl-propanoic acid of the formula (X)
4-({(4-carboxybutyl)[2-(2- {[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)carbonsäure der Formel (XI)  4 - ({(4-carboxybutyl) [2- (2- {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) carboxylic acid of the formula (XI)
5- {(4-Carboxybutyl)[2-(2- {[3-chlor-4'-(trifluormethyl)biphenyl-4-yl]methoxy}phenyl)ethyl] 5,6,7,8-tetrahydrochinolin-2-carbonsäure der Formel (XII)  5- {(4-carboxybutyl) [2- (2- {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] 5,6,7,8-tetrahydroquinoline-2 carboxylic acid of the formula (XII)
i),i)
5- { [2-(4-Carboxyphenyl)ethyl] [2-(2- { [3-chlor-4'-(trifluormethyl)biphenyl-4-yl]methoxy} phenyl)- ethyl]amino} -5,6,7,8-tetrahydrochinolin-2-carbonsäure der Formel (ΧΠΙ) 5- {[2- (4-Carboxyphenyl) ethyl] [2- (2- {[3-chloro-4 '- (trifluoromethyl) -biphenyl-4-yl] -methoxy} -phenyl) -ethyl] -amino} -5,6 , 7,8-tetrahydroquinoline-2-carboxylic acid of the formula (II)
(XIII), und Finerenone, (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6- naphthyridin-3-carboxamid der Formel (IV)  (XIII), and finerenone, (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1, 6-naphthyridine-3-carboxamide of the formula (IV)
enthalten. contain.
Ebenfalls bevorzugt sind Kombination, die mindestens einen sGC Aktivator, enthaltend mindestens eine Carbonsäurefunktion und mindestens einen MR Antagonist, enthalten. Also preferred are combinations containing at least one sGC activator containing at least one carboxylic acid function and at least one MR antagonist.
Ebenfalls bevorzugt sind Kombination, die mindestens einen sGC Aktivator, enthaltend eine Carbonsäurefunktion und mindestens einen MR Antagonist, enthalten. Ebenfalls bevorzugt sind Kombination, die mindestens einen sGC Aktivator ausgewählt aus der Gruppe Also preferred are combinations containing at least one sGC activator containing a carboxylic acid function and at least one MR antagonist. Also preferred are combination, the at least one sGC activator selected from the group
(3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4-chlorphenyl)-4,4,4-trifluor-3-methylbutanoyl]amino} phenyl)-3- cyclopropylpropansäure der Formel (X) (3S) -3- (4-Chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of Formula (X)
5- {(4-Carboxybutyl)[2-(2- {[3-chlor-4'-(trifluormethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino} - 5,6,7,8-tetrahydrochinolin-2-carbonsäure der Formel (XII) 5- {(4-Carboxybutyl) [2- (2- {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} -5,6,7,8-tetrahydroquinoline -2-carboxylic acid of the formula (XII)
(XII), 5- { [2-(4-Carboxyphenyl)ethyl] [2-(2- { [3-chlor-4'-(trifluormethyl)biphenyl-4-yl]methoxy} phenyl)- ethyl]amino} -5,6,7,8-tetrahydrochinolin-2-carbonsäure der Formel (XIII) (XII), 5- {[2- (4-Carboxyphenyl) ethyl] [2- (2- {[3-chloro-4 '- (trifluoromethyl) biphenyl-4-yl] methoxy} phenyl) ethyl] amino} 5,6,7,8-tetrahydroquinoline-2-carboxylic acid of the formula (XIII)
(XIII), und einen MR Antagonist enthalten.  (XIII), and contain an MR antagonist.
Ebenfalls bevorzugt sind Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der FormelAlso preferred are combinations containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula
(X) (X)
und mindestens einen MR Antagonist enthalten. and at least one MR antagonist.
Besonders bevorzugt sind Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der FormelParticularly preferred are combinations containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula
(X) (X)
und mindestens einen steroidalen MR Antagonist enthalten. and at least one steroidal MR antagonist.
Besonders bevorzugt sind Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der FormelParticularly preferred are combinations containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula
(X) (X)
und mindestens einen nicht-steroidalen MR Antagonist enthalten. and at least one non-steroidal MR antagonist.
Besonders bevorzugt sind Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der FormelParticularly preferred are combinations containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula
(X) (X)
und mindestens einen nicht-steroidalen MR Antagonist, aufbauend auf einem Dihydropyridingrundgerüst, enthalten. and at least one non-steroidal MR antagonist based on a dihydropyridine backbone.
Besonders bevorzugt sind Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der FormelParticularly preferred are combinations containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula
(X) (X)
und mindestens einen nicht-steroidalen MR Antagonist, aufbauend auf einem Indol- oder Indazolgrundgerüst, enthalten. and at least one non-steroidal MR antagonist based on an indole or indazole backbone.
Besonders bevorzugt sind Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropansäure der FormelParticularly preferred are combinations containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula
(X) (X)
und mindestens einen nicht-steroidalen MR Antagonist, aufbauend auf einem Oxazolidindiongrundgerüst, enthalten. and at least one non-steroidal MR antagonist based on an oxazolidinedione scaffold.
Besonders bevorzugt sind Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der FormelParticularly preferred are combinations containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula
(X) (X)
und mindestens einen steroidalen MR Antagonist ausgewählt aus der Gruppe and at least one steroidal MR antagonist selected from the group
Spirono lakton (7a-Acetylthio-3 -oxo- 17a-pregn-4-en-21 , 17ß-carbolacto-7a-Acetylthio pregn-4-en-21,17ß-carbolacton) der Formel (I) Spirono lactone (7a-acetylthio-3-oxo-17a-pregn-4-en-21, 17β-carbolacto-7a-acetylthio pregn-4-ene-21,17β-carbolactone) of the formula (I)
Kanrenone (10,13 -Dimethylspiro [2,8,9,11,12,14,15,16-octahydro- lH-cyc lopenta[a]phenanthrene- 17,5'-oxolane]-2',3-dione) der Formel (III) Canrenones (10,13 -dimethylspiro [2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta [a] phenanthrene-17,5'-oxolanes] -2 ', 3-diones) of the formula (III)
und dessen Kaliumsalz, enthalten. and its potassium salt.
Besonders bevorzugt sind Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der Formel (X) Particularly preferred are combinations containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula (X)
und mindestens einen nicht-steroidalen MR Antagonist ausgewählt aus der Gruppe and at least one non-steroidal MR antagonist selected from the group
Finereneone, ((S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l ,4-dihydro-l ,6- naphthyridin-3-carboxamid) der Formel (IV) Finereneones, ((S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide) of the formula (IV)
Esaxerenone (l-(2-hydroxyethyl)-4-methyl-N-(4-(methylsulfonyl)phenyl)-5-(2-(trifluoromethyl) phenyl)-lH-pyrrole-3-carboxamide) der Formel (V) Esaxerenone (1- (2-hydroxyethyl) -4-methyl-N- (4- (methylsulfonyl) phenyl) -5- (2- (trifluoromethyl) phenyl) -1H-pyrrole-3-carboxamide) of the formula (V)
Apararenone (N-(4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4] yl)methanesulfonamide) der Formel (VI)  Apararenones (N- (4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo [b] [l, 4] yl) methanesulfonamides) of the formula (VI)
(3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7- carbonsäure) der Formel (XIV)  (3S, 3aR) -2- (3-chloro-4-cyanophenyl) -3-cyclopentyl-3,3a, 4,5-tetrahydro-2H-benzo [g] indazole-7-carboxylic acid) of the formula (XIV)
(R)-6-(l-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-lH-pyrazol-3-yl)-2- methoxynicotinsäure der Formel (VIII) (R) -6- (1- (4-cyano-3-methylphenyl) -5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl) -2-methoxynicotinic acid of the formula (VIII)
enthalten. contain.
Ganz besonders bevorzugt ist die Kombination, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2- (4-chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der FormelVery particularly preferred is the combination containing the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3 - methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula
(X) (X)
und (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l ,4-dihydro-l ,6-naphthyridin-3- carboxamid der Formel (IV) and (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (IV)
enthält. Die gleichzeitige Blockade der Bindung von Aldosteron an MR und der Aktivierung der löslichen Guanylatcyclase durch sGC Aktivatoren durch die erfindungsgemäße Kombination, führt zu überadditiven Effekten bzgl. des Endorgan-Schutz, der Verminderung der renalen Proteinausscheidung und Verminderung von Morbidität und Mortalität. contains. Simultaneous blockade of aldosterone binding to MR and activation of soluble guanylate cyclase by sGC activators by the combination of the present invention result in over-additive effects on end-organ protection, reduction of renal protein excretion, and reduction of morbidity and mortality.
Ein weiterer erfindungsgemäßer Gegenstand ist die Anwendung von MR Antagonisten in Kombination mit sGC Aktivatoren zur Behandlung von Herz- und Herz-Kreislauf-Erkrankungen wie z.B. Herzinsuffizienz mit erhaltener Ejektionsfraktion oder Herzinsuffizienz mit reduzierter Ejektionsfraktion, Behandlung und/oder Prophylaxe von Vorhofflimmern, Schlaganfall oder Atherosklerose, zur Behandlung von renalen und cardio-renalen Erkrankungen wie z.B. chronisches Nierenversagen oder diabetische Nephropathie, von Lungenerkrankungen und cardio-pulmonären Erkrankungen, wie z.B. von Pulmonaler Hypertonie, Erkrankungen des Zentralnervensystems, zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen sowie anderen Krankheitserscheinungen (z.B. Endorganschäden, die Hirn, Niere, Herz oder Lunge betreffen).  Another object of the invention is the use of MR antagonists in combination with sGC activators for the treatment of cardiovascular diseases such as cardiac and cardiovascular diseases. Cardiac insufficiency with preserved ejection fraction or cardiac insufficiency with reduced ejection fraction, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, for the treatment of renal and cardio-renal diseases, e.g. chronic renal failure or diabetic nephropathy, lung diseases and cardio-pulmonary diseases, e.g. pulmonary hypertension, central nervous system disorders, for the treatment and / or prophylaxis of fibrotic diseases, as well as other manifestations of disease (e.g., end-organ damage affecting the brain, kidney, heart or lung).
Ein Gegenstand der vorliegenden Erfindung ist ein pharmazeutische Formulierung enthaltend eine Kombination eines MR Antagonisten und eines sGC Aktivaotrs, sowie die Salze, Solvate und Solvate der Salze der zu kombinierenden Komponenten.  An object of the present invention is a pharmaceutical formulation containing a combination of an MR antagonist and a sGC Aktivaotrs, and the salts, solvates and solvates of the salts of the components to be combined.
Die zu kombinierenden Komponenten können als Salze vorliegen. Als Salze sind im Rahmen der vorliegenden Erfindung physiologisch unbedenkliche Salze der zu kombinierenden Verbindungen bevorzugt. Umfasst sind auch Salze, die für pharmazeutische Anwendungen selbst nicht geeignet sind, jedoch beispielsweise für die Isolierung oder Reinigung der zu kombinierenden Verbindungen verwendet werden können.  The components to be combined may be present as salts. Salts which are preferred in the context of the present invention are physiologically acceptable salts of the compounds to be combined. Also included are salts which are not suitable for pharmaceutical applications, but which can be used, for example, for the isolation or purification of the compounds to be combined.
Die erfindungsgemäßen Kombinationen ist geeignet für die Prophylaxe und/oder Behandlung von verschiedenen Erkrankungen und krankheitsbedingten Zuständen, insbesondere zur Behandlung und/oder Prophylaxe von Herz- und Herz-Kreislauf-Erkrankungen wie z.B. Herzinsuffizienz mit erhaltener Ejektionsfraktion oder Herzinsuffizienz mit reduzierter Ejektionsfraktion, Behandlung und/oder Prophylaxe von Vorhofflimmern, Schlaganfall oder Atherosklerose, renalen und kardio- renalen Erkrankungen wie z.B. chronisches Nierenversagen oder diabetische Nephropathie, Lungenerkrankungen und kardiopulmonäre wie z.B. von Pulmonaler Hypertonie, Erkrankungen des Zentralnervensystems, zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen sowie anderen Krankheitserscheinungen (z.B. Endorganschäden, die Hirn, Niere oder Herz betreffen). The combinations according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular for the treatment and / or prophylaxis of cardiovascular diseases such as heart failure with preserved ejection fraction or cardiac insufficiency with reduced ejection fraction, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, renal and cardiorenal diseases such as chronic renal failure or diabetic nephropathy , Pulmonary and cardiopulmonary disorders, such as pulmonary hypertension, central nervous system disorders, for the treatment and / or prophylaxis of fibrotic disorders, as well as other pathologies (eg end organ damage affecting the brain, kidney or heart).
Weiterhin sind die erfindungsgemäßen Kombinationen geeignet für die Prophylaxe und/oder Behandlung von verschiedenen Erkrankungen und krankheitsbedingten Zuständen, insbesondere zur Behandlung und/oder Prophylaxe von einer Krankheit ausgewählt aus der Gruppe bestehend aus Bluthochdruck, Herzinsuffizienz (akut und chronisch), dekompensierter Herzinsuffizienz, linksventrikulärer Dysfunktion, hypertrophischer Kardiomyopathie, diabetischer Kardiomyopathie, supraventrikulären und ventrikulären Arrythmien, Vorhofflimmern, Vorhofflattern, schädlichem Gefäßumbau, Herzinfarkt und Folgeerscheinungen davon, Atherosklerose, Angina (instabil oder stabil), Niereninsuffizienz (diabetisch und nichtdiabetisch), Herzinsuffizienz, Angina pektoris, Diabetes, sekundärem Hyperaldosteronismus, primärer und sekundärer pulmonaler Hypertonie, Glomerulonephritis, Sklerodermie und Systemischer Sklerose, glomulerärer Sklerose, Proteinurie als Folge einer primären Nierenkrankheit, renaler vaskulärer Hypertonie, diabetischer und nichtdiabetischer Retinopathie, Migräne, periphärer Gefäßkrankheit, Raynaud-Krankheit, luminaler Hyperplasie, kognitiver Dysfunktion, Glaukom und Schlaganfall.  Furthermore, the combinations according to the invention are suitable for the prophylaxis and / or treatment of various diseases and disease-related conditions, in particular for the treatment and / or prophylaxis of a disease selected from the group consisting of hypertension, heart failure (acute and chronic), decompensated heart failure, left ventricular dysfunction , hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, harmful vascular remodeling, myocardial infarction and sequelae thereof, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and nondiabetic), heart failure, angina pectoris, diabetes, secondary hyperaldosteronism, primary and secondary pulmonary hypertension, glomerulonephritis, scleroderma and systemic sclerosis, glomerular sclerosis, proteinuria as a result of primary renal disease, renal vascular Hypertension, diabetic and nondiabetic retinopathy, migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction, glaucoma and stroke.
Weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung der erfindungsgemäßen Kombinationen zur Herstellung eines Arzneimittels zur Behandlung und/oder Prävention von Erkrankungen, insbesondere der zuvor genannten Erkrankungen.  Another object of the present invention is the use of the combinations according to the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
Weiterer Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Behandlung und/oder Prävention von Erkrankungen, insbesondere der zuvor genannten Erkrankungen.  Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
Die erfindungsgemäßen Kombinationen können allein oder bei Bedarf in Kombination mit anderen Wirkstoffen eingesetzt werden. Weiterer Gegenstand der vorliegenden Erfindung sind Arzneimittel, enthaltend mindestens eine der erfindungsgemäßen Kombinationen und einen oder mehrere weitere Wirkstoffe, insbesondere zur Behandlung und/oder Prävention der zuvor genannten Erkrankungen. Als geeignete Kombinationswirkstoffe seien beispielhaft und vorzugsweise genannt:  The combinations according to the invention can be used alone or as needed in combination with other active ingredients. Another object of the present invention are pharmaceutical compositions containing at least one of the combinations according to the invention and one or more further active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:
• den Blutdruck senkende Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Calcium- Antagonisten, Angiotensin Rezeptor Blocker (ARBs), ACE-Hemmer, Endothelin-Antagonisten, Renin-Inhibitoren, alpha-Rezeptoren-Blocker, beta-Rezeptoren-Blocker und Rho-Kinase- Inhibitoren; · Diuretika, insbesondere Schleifendiuretika sowie Thiazide und Thiazid-ähnliche Diuretika; • Antidiabetika, beispielhaft und vorzugsweise Insulin und Derivative, Sulfonharnstoffe, Biguanide, Thiazolidinedione, Acarbose, DPP4 Inhibitoren, GLP-1 Analoge, oder SGLT Inhibitoren Antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin receptor blockers (ARBs), ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers and rho Kinase inhibitors; · Diuretics, especially loop diuretics and thiazides and thiazide-like diuretics; • Antidiabetics, by way of example and preferably insulin and derivatives, sulfonureas, biguanides, thiazolidinediones, acarbose, DPP4 inhibitors, GLP-1 analogs, or SGLT inhibitors
(Gliflozine);  (Gliflozine);
• antithrombotisch wirkende Mittel, beispielhaft und vorzugsweise aus der Gruppe der Thrombozytenaggregationshemmer, der Antikoagulantien oder der profibrinolytischen Substanzen;  Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
• den Fettstoffwechsel verändernde Wirkstoffe, beispielhaft und vorzugsweise aus der Gruppe der Thyroidrezeptor- Agonisten, Cholesterinsynthese- Inhibitoren wie beispielhaft und vorzugs-weise HMG-CoA-Reduktase- oder Squalensynthese-Inhibitoren, der ACAT-Inhibitoren, CETP- Inhibitoren, MTP-Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta- Agonisten, Cholesterin- Absorptionshemmer, Lipase- Inhibitoren, polymeren Gallensäureadsorber, Gallensäure-Lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorber, bile acid
Reabsorptionshemmer und Lipoprotein(a)-Antagonisten; Reabsorption inhibitors and lipoprotein (a) antagonists;
• organische Nitrate und NO-Donatoren, wie beispielsweise Natriumnitroprussid, Nitroglycerin, Isosorbidmononitrat, Isosorbiddinitrat, Molsidomin oder SIN-1, sowie inhalatives NO; • organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
• positiv-inotrop wirksame Verbindungen, wie beispielsweise Herzglycoside (Digoxin), beta- adrenerge und dopaminerge Agonisten wie Isoproterenol, Adrenalin, Noradrenalin, Dopamin undPositive-inotropic compounds such as cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and
Dobutamin; dobutamine;
• Verbindungen, die den Abbau von cyclischem Guanosinmonophosphat (cGMP) und/oder cyclischem Adenosinmonophosphat (cAMP) inhibieren, wie beispielsweise Inhibitoren der Phosphodiesterasen (PDE) 1, 2, 3, 4 und/oder 5, insbesondere PDE 5-Inhibitoren wie Sildenafil, Vardenafil und Tadalafil, sowie PDE 3 -Inhibitoren wie Amrinone und Milrinone;  Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, Vardenafil and tadalafil, as well as PDE 3 inhibitors such as amrinone and milrinone;
• natriuretische Peptide, wie z.B. "atrial natriuretic peptide" (ANP, Anaritide), "B-type natriuretic peptide" oder "brain natriuretic peptide" (BNP, Nesiritide), "C-type natriuretic peptide" (CNP) sowie Urodilatin; Natriuretic peptides, e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
• Hemmstoffe der Endopeptidasen (NEP-Inhibitoren) wie z.B. Sacubitril, Omapatrilat oder AVE- 7688, oder in dualer Kombination (,ARNIs') mit Angiotensin Rezeptor Blockern (z.B. Valsartan), wie z.B. LCZ696,  Inhibitors of endopeptidases (NEP inhibitors), e.g. Sacubitril, omapatrilat or AVE-7688, or in dual combination ('ARNIs') with angiotensin receptor blockers (e.g., valsartan), e.g. LCZ696,
• Calcium-Sensitizer, wie beispielhaft und vorzugsweise Levosimendan;  Calcium sensitizers, such as by way of example and preferably levosimendan;
• If-Kanal-Blocker, wie beispielhaft und vorzugsweise Ivabradin;  If-channel blockers, such as by way of example and preferably ivabradine;
• Myosin Aktivatoren, wie beispielhaft und vorzugsweise Omecamtiv mecarbil; Myosin activators, by way of example and preferably Omecamtiv mecarbil;
· Inhibitoren der humanen neutrophilen Elastase (HNE), wie beispielsweise Sivelestat oder DX-890 (Reltran); · Inhibitors of human neutrophil elastase (HNE), such as Sivelestat or DX-890 (Reltran);
• die Signaltransduktionskaskade inhibierende Verbindungen, wie beispielsweise Tyrosinkinase- Inhibitoren, insbesondere Sorafenib, Imatinib, Gefitinib und Erlotinib; und/oder • den Energiestoffwechsel des Herzens beeinflussende Verbindungen, wie beispielhaft und vorzugsweise Etomoxir, Dichloracetat, Ranolazine oder Trimetazidine. The signal transduction cascade inhibiting compounds, such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib; and or • the energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazines or trimetazidines.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Diuretikum, wie beispielhaft und vorzugsweise Furosemid, Bumetanid, Torsemid, Bendroflumethiazid, Chlorthiazid, Hydrochlorthiazid, Hydroflumethiazid, Methyclothiazid, Polythiazid, Trichlormethiazid, Chlorthalidon, Indapamid, Metolazon, Quinethazon, Acetazolamid, Dichlorphenamid, Methazolamid, Glycerin, Isosorbid, Mannitol, Amilorid oder Triamteren, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is used in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, Dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
Unter den Blutdruck senkenden Mitteln werden vorzugsweise Verbindungen aus der Gruppe der Calcium- Antagonisten, Angiotensin Rezeptor Blocker, ACE-Hemmer, Endothelin- Antagonisten, Renin-Inhibitoren, alpha-Rezeptoren-B locker, beta-Rezeptoren-B locker, Rho-Kinase-Inhibitoren sowie der Diuretika verstanden.  Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin receptor blocker, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-loosen, beta-receptor-B loosely, rho-kinase Inhibitors and diuretics understood.
Bei einer bevorzugten Ausführungsform der Erfindung wird das erfindungsgemäße Kombinationspräparat in Kombination mit einem Antidiabetikum, wie beispielhaft und vorzugsweise Insulin und Derivatives, Sulfonylharnstoffe wie Tolbutamid, Carbutamid, Acetohexamid, Chlorpropamid, Glipizid, Gliclazid, Glibenclamid, Glyburid, Glibornurid, Gliquidon, Glisoxepid, Glyclopyramid, Glimepirid, JB253 und JB558, Meglitinide wie Repaglinid und Nateglinid, Biguanide wie Metformin und Buformin, Thiazolidinedione wie Rosiglitazone und Pioglitazone, Alpha- Glucosidase Inhibitoren wie Miglitol, Acarbose und Voglibose, DPP4 Inhibitoren wie Vildagliptin, Sitagliptin, Saxagliptin, Linagliptin, Alogliptin, Septagliptin und Teneligliptin, GLP-1 Analoge wie Exenatid (auch Exendin-4), Liraglutid, Lixisenatid und Taspoglutid, oder SGLT Inhibitoren (Gliflozine) wie Canagliflozin, Dapagliflozin und Empagliflozin.  In a preferred embodiment of the invention, the combined preparation according to the invention is used in combination with an antidiabetic, such as by way of example and preferably insulin and derivatives, sulfonylureas such as tolbutamide, carbutamide, acetohexamide, chlorpropamide, glipizide, gliclazide, glibenclamide, glyburide, glibornuride, gliquidone, glisoxepid, glyclopyramide, Glimepiride, JB253 and JB558, meglitinides such as repaglinide and nateglinide, biguanides such as metformin and buformin, thiazolidinediones such as rosiglitazone and pioglitazone, alpha-glucosidase inhibitors such as miglitol, acarbose and voglibose, DPP4 inhibitors such as vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin, septagliptin and Teneligliptin, GLP-1 analogues such as exenatide (also exendin-4), liraglutide, lixisenatide and taspoglutide, or SGLT inhibitors (gliflozines) such as canagliflozin, dapagliflozin and empagliflozin.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Calcium-Antagonisten, wie beispielhaft und vorzugsweise Nifedipin, Amlodipin, Verapamil oder Diltiazem, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
Bei einer bevorzugten Ausführungsform der Erfindung werden die erfindungsgemäßen Verbindungen in Kombination mit einem Angiotensin All- Antagonisten, wie beispielhaft und vorzugs-weise Losartan, Candesartan, Valsartan, Olmesartan, Telmisartan oder Embursatan, verabreicht.  In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin all-antagonist, such as by way of example and with preference losartan, candesartan, valsartan, olmesartan, telmisartan or embursatan.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem ACE-Hemmer, wie beispielhaft und vorzugsweise Enalapril, Captopril, Lisinopril, Ramipril, Delapril, Fosinopril, Quinopril, Perindopril oder Trandopril, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Endothelin-Antagonisten, wie beispielhaft und vorzugsweise Bosentan, Darusentan, Ambrisentan oder Sitaxsentan, verabreicht. Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombinationt in Kombination mit einem Renin-Inhibitor, wie beispielhaft und vorzugsweise Aliskiren, SPP-600, SPP- 635, SPP-676, SPP-800 oder SPP-1148, verabreicht. In a preferred embodiment of the invention, the combination according to the invention is administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan. In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem alpha- 1 -Rezeptoren-Blocker, wie beispielhaft und vorzugsweise Prazosin, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem beta-Rezeptoren-B locker, wie beispielhaft und vorzugsweise Propranolol, Atenolol, Timolol, Pindolol, Alprenolol, Oxprenolol, Penbutolol, Bupranolol, Metipranolol, Nadolol, Mepindolol, Carazalol, Sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol oder Bucindolol, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is used in combination with a beta-receptor B, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol , Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Rho-Kinase-Inhibitor, wie beispielhaft und vorzugsweise Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 oder BA-1049, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is used in combination with a rho-kinase inhibitor, such as by way of example and preferably Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049 administered.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombinationt in Kombination mit Prostanoiden und Prostacyclinrezeptor Agonisten, wie beispielhaft und vorzugsweise Iloprost, Beraprost, Cicaprost, Epoprostenol oder Treprostinil In a preferred embodiment of the invention, the combination according to the invention in combination with prostanoids and prostacyclin receptor agonists, such as by way of example and preferably iloprost, beraprost, cicaprost, epoprostenol or treprostinil
Unter antithrombotisch wirkenden Mitteln (Antithrombotika) werden vorzugsweise Zusammensetzungen aus der Gruppe der Thrombozytenaggregationshemmer, der Antikoagulantien oder der profibrinolytischen Substanzen verstanden.  Antithrombotic agents (antithrombotics) are preferably understood to mean compositions from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Thrombozytenaggregationshemmer, wie beispielhaft und vorzugsweise Aspirin, Clopidogrel, Ticlopidin oder Dipyridamol, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a platelet aggregation inhibitor, such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Thrombin-Inhibitor, wie beispielhaft und vorzugsweise Ximelagatran, Melagatran, Bivalirudin oder Clexane, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a thrombin inhibitor, such as by way of example and preferably ximelagatran, melagatran, bivalirudin or Clexane.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem GPIIb/IIIa-Antagonisten, wie beispielhaft und vorzugsweise Tirofiban oder Abciximab, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäß Kombination in Kombination mit einem Faktor Xa-Inhibitor, wie beispielhaft und vorzugsweise Rivaroxaban (BAY 59-7939), DU-176b, Apixaban, Otamixaban, Fidexaban, Razaxaban, Fondaparinux, Idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 oder SSR-128428, verabreicht. Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit Heparin oder einem low molecular weight (LMW)-Heparin-Derivat verabreicht.In a preferred embodiment of the invention, the combination according to the invention in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112 , YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428. In a preferred embodiment of the invention, the combination according to the invention is administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Vitamin K-Antagonisten, wie beispielhaft und vorzugsweise Coumarin, verabreicht. In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
Unter den Fettstoffwechsel verändernden Mitteln werden vorzugsweise Verbindungen aus der Gruppe der CETP-Inhibitoren, Thyroidrezeptor-Agonisten, Cholesterinsynthese-Inhibitoren wie HMG-CoA- Reduktase- oder Squalensynthese- Inhibitoren, der ACAT-Inhibitoren, MTP-Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta-Agonisten, Cholesterin-Absorptionshemmer, polymeren Gallensäureadsorber, Gallensäure-Reabsorptionshemmer, Lipase-Inhibitoren sowie der Lipoprotein(a)-Antagonisten verstanden.  Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination mit einem CETP-Inhibitor, wie beispielhaft und vorzugsweise Torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 oder CETP-vaccine (Avant), verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered with a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine (Avant) ,
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Thyroidrezeptor-Agonisten, wie beispielhaft und vorzugsweise D-Thyroxin, 3,5,3'-Triiodothyronin (T3), CGS 23425 oder Axitirome (CGS 26214), verabreicht. In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a thyroid receptor agonist, such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem HMG-CoA-Reduktase-Inhibitor aus der Klasse der Statine, wie beispielhaft und vorzugsweise Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, Rosuvastatin, Cerivastatin oder Pitavastatin, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Squalensynthese-Inhibitor, wie beispielhaft und vorzugsweise BMS-188494 oder TAK-475, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem ACAT-Inhibitor, wie beispielhaft und vorzugsweise Avasimibe, Melinamide, Pactimibe, Eflucimibe oder SMP-797, verabreicht. In a preferred embodiment of the invention, the combination according to the invention is administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem MTP-Inhibitor, wie beispielhaft und vorzugsweise Implitapide, BMS-201038, R- 103757 oder JTT-130, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem PPAR-gamma-Agonisten, wie beispielhaft und vorzugsweise Pioglitazone oder Rosiglitazone, verabreicht. Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination mit einem PPAR-delta-Agonisten, wie beispielhaft und vorzugsweise GW-501516 oder BAY 68-5042, verabreicht. In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone. In a preferred embodiment of the invention, the combination according to the invention is administered with a PPAR-delta agonist, such as by way of example and preferably GW-501516 or BAY 68-5042.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination mit einem Cholesterin- Absorptionshemmer, wie beispielhaft und vorzugsweise Ezetimibe, Tiqueside oder Pamaqueside, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, Tiqueside or Pamaqueside administered.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination mit einem Lipase-Inhibitor, wie beispielhaft und vorzugsweise Orlistat, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention with a lipase inhibitor, such as by way of example and preferably orlistat, administered.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem polymeren Gallensäureadsorber, wie beispielhaft und vorzugsweise Cholestyramin, Colestipol, Colesolvam, CholestaGel oder Colestimid, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Gallensäure-Reabsorptionshemmer, wie beispielhaft und vorzugsweise ASBT (= IBAT)-Inhibitoren wie z.B. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 oder SC-635, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is used in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.
Bei einer bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit einem Lipoprotein(a)-Antagonisten, wie beispielhaft und vorzugsweise Gemcabene calcium (CI-1027) oder Nicotinsäure, verabreicht.  In a preferred embodiment of the invention, the combination according to the invention is administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
Bei der bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit anti-fibrotisch wirksamen Verbindungen, wie beispielhaft und vorzugsweise Sorafenib, Regorafenib, Imatinib, Dasatinib, Nilotinib Nintedanib, Bortezomib oder Pirfenidone verabreicht.  In the preferred embodiment of the invention, the combination according to the invention is administered in combination with anti-fibrotic compounds such as, for example and preferably, sorafenib, regorafenib, imatinib, dasatinib, nilotinib, nintedanib, bortezomib or pirfenidone.
Bei der bevorzugten Ausführungsform der Erfindung wird die erfindungsgemäße Kombination in Kombination mit anti- inflammatorisch wirksamen Verbindungen wie beispielhaft und vorzugsweise Cyclophosphamide, Methotrexate, Rapamycin, Azathioproin, Tocilizumab, Infliximab, Rituximab, Adalimumab, Belimumab, Abatacept, SARI 00842 oder Thalidomide Derivate verabreicht.  In the preferred embodiment of the invention, the combination according to the invention is administered in combination with anti-inflammatory compounds such as by way of example and preferably cyclophosphamide, methotrexate, rapamycin, azathioproin, tocilizumab, infliximab, rituximab, adalimumab, belimumab, abatacept, SARI 00842 or thalidomide derivatives.
Die erfindungsgemäßen Kombinationen können systemisch und/oder lokal wirken. Zu diesem Zweck können sie auf geeignete Weise appliziert werden, wie z.B. oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otisch oder als Implantat bzw. Stent.  The combinations according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
Für diese Applikationswege können die erfindungsgemäßen Kombinationen in geeigneten Applikationsformen verabreicht werden.  For these administration routes, the combinations according to the invention can be administered in suitable administration forms.
Für die orale Applikation eignen sich nach dem Stand der Technik funktionierende, die erfindungsgemäßen Kombinationen schnell und/oder modifiziert abgebende Applikationsformen, die die erfindungsgemäßen Verbindungen in kristalliner und/oder amorphisierter und/oder gelöster Form enthalten, wie z.B. Tabletten (nicht-überzogene oder überzogene Tabletten, beispielsweise mit magensaftresistenten oder sich verzögert auflösenden oder unlöslichen Überzügen, die die Freisetzung der erfindungsgemäßen Kombinationen kontrollieren), in der Mundhöhle schnell zerfallende Tabletten oder Filme/Oblaten, Filme/Lyophylisate, Kapseln (beispielsweise Hart- oder Weichgelatinekapseln), Dragees, Granulate, Pellets, Pulver, Emulsionen, Suspensionen, Aerosole oder Lösungen. For oral administration are according to the prior art working, the inventive combinations rapidly and / or modified donating application forms, the contain the compounds of the invention in crystalline and / or amorphous and / or dissolved form, such as tablets (uncoated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings, which control the release of the combinations of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
Als bevorzugte Applikationsformen sind zu nennen Tablettenform (nicht-überzogene oder überzogene Tabletten, beispielsweise mit magensaftresistenten oder sich verzögert auflösenden oder unlöslichen Überzügen, die die Freisetzung der erfindungsgemäßen Kombinationen kontrollieren), in der Mundhöhle schnell zerfallende Tabletten oder Filme/Oblaten.  Preferred forms of application include tablet form (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the combinations of the invention), tablets disintegrating rapidly in the oral cavity or films / wafers.
Die parenterale Applikation kann unter Umgehung eines Resorptionsschrittes geschehen (z.B. intravenös, intraarteriell, intrakardial, intraspinal oder intralumbal) oder unter Einschaltung einer Resorption (z.B. intramuskulär, subcutan, intracutan, percutan oder intraperitoneal). Für die parenterale Applikation eignen sich als Applikationsformen u.a. Injektions- und Infusionszubereitungen in Form von Lösungen, Suspensionen, Emulsionen, Lyophilisaten oder sterilen Pulvern.  Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
Für die sonstigen Applikationswege eignen sich z.B. Inhalationsarzneiformen (u.a. Pulverinhalatoren, Nebulizer), Nasentropfen, -lösungen oder -sprays, lingual, sublingual oder buccal zu applizierende Tabletten, Filme/Oblaten oder Kapseln, Suppositorien, Ohren- oder Augenpräparationen, Vaginalkapseln, wässrige Suspensionen (Lotionen, Schüttelmixturen), lipophile Suspensionen, Salben, Cremes, transdermale therapeutische Systeme (z.B. Pflaster), Milch, Pasten, Schäume, Streupuder, Implantate oder Stents.  For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions , Ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
Bevorzugt sind die orale oder parenterale Applikation, wobei die orale Applikation bevorzugter ist. Insbesondere bevorzugt ist die orale Applikation mittels Tablettenform.  Preferred are oral or parenteral administration, with oral administration being more preferred. Especially preferred is oral administration by means of tablet form.
Die erfindungsgemäßen Kombinationen können in die angeführten Applikationsformen überführt werden. Dies kann in an sich bekannter Weise durch Mischen mit inerten, nichttoxischen, pharmazeutisch geeigneten Hilfsstoffen geschehen. Zu diesen Hilfsstoffen zählen u.a. Trägerstoffe (beispielsweise mikrokristalline Cellulose, Lactose, Mannitol), Lösungsmittel (z.B. flüssige Polyethylenglycole), Emulgatoren und Dispergier- oder Netzmittel (beispielsweise Natriumdodecylsulfat, Polyoxysorbitanoleat), Bindemittel (beispielsweise Polyvinylpyrrolidon), synthetische und natürliche Polymere (beispielsweise Albumin), Stabilisatoren (z.B. Antioxidantien wie beispielsweise Ascorbinsäure), Farbstoffe (z.B. anorganische Pigmente wie beispielsweise Eisenoxide) und Geschmacks- und/oder Geruchskorrigentien. The combinations according to the invention can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Carrier materials (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and flavor and / or odor remedies.
In den erfindungsgemäßen Kombinationen können die Komponenten zusammen oder nacheinander oder getrennt in einer kombinierten Einheitsdosierungsform oder in zwei getrennten Einheitsdosierungsformen verabreicht werden. Die Einheitsdosierungsform kann auch eine fixierte Kombination sein. In the combinations according to the invention, the components may be used together or sequentially or separately in a combined unit dosage form or in two separate ones Unit dosage forms are administered. The unit dosage form may also be a fixed combination.
Eine therapeutisch wirksame Menge jeder Komponente der erfindungsgemäßen Kombination kann simultan oder sequenziell in jeder Reihenfolge verabreicht werden.  A therapeutically effective amount of each component of the combination of the invention may be administered simultaneously or sequentially in any order.
In einer Ausführungsform können die Komponenten in einer sogenannten Retard-formulierung vorliegen, in der die Freisetzung der erfindungsgemäßen Komponenten zu unterschiedlichen Zeitpunkten stattfindet. Beispielsweise genannt sei eine Tablette mit sich verzögert auflösenden Überzügen, die jeweils eine oder mehrere der erfindungsgemäßen Komponenten enthält. In one embodiment, the components may be in a so-called sustained-release formulation in which the release of the components according to the invention takes place at different times. For example, mention may be made of a tablet having delayed-dissolving coatings, each containing one or more of the components according to the invention.
Für den Fall, dass die Komponenten der erfindungsgemäßen Kombination in getrennten Emheitsdosierungsformen verabreicht werden, können die MR Antagonisten und sGC Aktivatoren beispielsweise jeweils als Kapsel oder Tablette bereitgestellt werden.  For example, in the case where the components of the combination of the invention are administered in separate dosage forms, the MR antagonists and sGC activators may each be provided as a capsule or tablet.
Bei oraler Applikation beträgt beispielsweise die Dosierung von Finerenone gemäß der Verbindung der Formel (IV) etwa 1 bis 100 mg od, vorzugsweise etwa 2,5 bis 50 mg od und ganz besonders bevorzugt 10 bis 40 mg od.  For oral administration, for example, the dosage of finerenone according to the compound of formula (IV) is about 1 to 100 mg od, preferably about 2.5 to 50 mg od and most preferably 10 to 40 mg od.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit von Körpergewicht, Applikationsweg, individuellem Verhalten gegenüber dem Wirkstoff, Art der Zubereitung und Zeitpunkt bzw. Intervall, zu welchem die Applikation erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muss. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen. Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.
Die Erfindung betrifft auch die Kombination von getrennten pharmazeutischen Zusammensetzungen in Kitform. Dies ist ein Kit, der zwei getrennte Einheiten umfasst: Eine pharmazeutische Zusammensetzung von mindestens einem MR Antagoinst und eine pharmazeutische Zusammensetzung von mindestens einem sGC Aktivator.  The invention also relates to the combination of separate pharmaceutical compositions in kit form. This is a kit comprising two separate entities: a pharmaceutical composition of at least one MR antagoinst and a pharmaceutical composition of at least one sGC activator.
Die Erfindung betrifft außerdem eine bevorzugte Kitform, die zwei Einheiten umfasst: Eine pharmazeutische Zusammensetzung enthaltend mindestens einen MR Antagonisten und eine pharmazeutische Zusammensetzung enthaltend mindestens einen sGC Aktivator.  The invention also relates to a preferred kit form comprising two units: A pharmaceutical composition containing at least one MR antagonist and a pharmaceutical composition containing at least one sGC activator.
Das Kit ist insbesondere vorteilhaft, wenn die getrennten Komponenten in unterschiedlichen Dosisformen verabreicht werden müssen oder in unterschiedlichen Dosisintervallen verabreicht werden.  The kit is particularly advantageous when the separate components have to be administered in different dosage forms or administered at different dose intervals.
Ausführungsbeispiele für pharmazeutische Zusammensetzungen  Exemplary embodiments of pharmaceutical compositions
Die erfindungsgemäßen Verbindungen können folgendermaßen in pharmazeutische Zubereitungen überführt werden: Tablette: The compounds according to the invention can be converted into pharmaceutical preparations as follows: Tablet:
Pharmazeutische Formulierung von Finerenone (4S)- 4-(4-Cvano-2-methoxyphenyl)-5-ethoxy- 2,8-dimethyl-l,4-dihvdro-l,6-naphthyridin-3-carbox-amid der Formel (IV)  Pharmaceutical formulation of finerenone (4S) - 4- (4-cano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula ( IV)
Es wurde eine Granulatlösung der Verbindung der Formel (IV) in kristalliner Form in mikronisierter Form, Hypromellose 5 cP, Natriumlaurilsufat in gereinigtem Wasser hergestellt.  A granular solution of the compound of formula (IV) in crystalline form in micronised form, hypromellose 5 cP, sodium lauric sulfate in purified water was prepared.
Cellulose microcrystalline, lactose monohydrate and croscarmellose sodium wurden in einem Behälter oder einem fluidized bed granulator gemischt (premix).  Cellulose microcrystalline, lactose monohydrate and croscarmellose sodium were mixed in a container or a fluidized bed granulator (premix).
Der premix und die Granulatlösung wurden in dem fluid-bed granulator granuliert.  The premix and the granule solution were granulated in the fluid-bed granulator.
Das Lubricant Magnesium Stearat wurde hinzugegeben, nachdem das Granulat getrocknet und gesiebt wurde. Damit wurde eine pressfertige Mischung hergestellt.  The Lubricant Magnesium Stearate was added after the granules were dried and sieved. Thus, a press-ready mixture was prepared.
Unter Verwendung einer Rotationstablettenpresse wurde die pressfertige Mischung zu Tabletten gepresst.  Using a rotary tablet press, the press-ready mixture was pressed into tablets.
Eine homogene coating Suspension wurde aus hypromellose, talc, titanium dioxid, Eisenoxid gelb, Eisenoxid rot und gereinigten Wasser hergestellt. In einer geeigneten coating Vorrichtung wurde die coating Suspension auf die Tabletten gesprüht. A homogeneous coating suspension was made from hypromellose, talc, titanium dioxide, yellow iron oxide, red iron oxide and purified water. In a suitable coating device, the coating suspension was sprayed onto the tablets.
Zusammensetzung Ph llb Ph llb Ph llb Ph llb Ph llb Ph llb Ph llbComposition Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb
Verbindung [mg] [mg] [mg] [mg] [mg] [mg] [mg] der Formel (IV) in der Compound [mg] [mg] [mg] [mg] [mg] [mg] [mg] of formula (IV) in the
1.25 2.50 5.00 7.50 10.00 15.00 20.00 mikronisiert  1.25 2.50 5.00 7.50 10.00 15.00 20.00 micronised
Excipients Excipients
Cellulose  cellulose
73.80 72.50 69.90 67.30 64.70 62.00 59.30 microcrystalline  73.80 72.50 69.90 67.30 64.70 62.00 59.30 microcrystalline
Croscarmellose  croscarmellose
4.50 4.50 4.50 4.50 4.50 4.50 4.50 sodium  4.50 4.50 4.50 4.50 4.50 4.50 4.50 sodium
Hypromellose 5 cP 4.50 4.50 4.50 4.50 4.50 4.50 4.50 Hypromellose 5 cP 4.50 4.50 4.50 4.50 4.50 4.50 4.50
Lactose monohydrate 45.00 45.00 45.00 45.00 45.00 42.50 40.00Lactose monohydrate 45.00 45.00 45.00 45.00 45.00 42.50 40.00
Magnesium stearate 0.90 0.90 0.90 0.90 0.90 0.90 0.90Magnesium stearate 0.90 0.90 0.90 0.90 0.90 0.90 0.90
Sodium laurilsulfate 0.05 0.10 0.20 0.30 0.40 0.60 0.80Sodium lauryl sulphate 0.05 0.10 0.20 0.30 0.40 0.60 0.80
Gewicht Weight
(unbeschichtete 130.00 130.00 130.00 130.00 130.00 130.00 130.00 (uncoated 130.00 130.00 130.00 130.00 130.00 130.00 130.00
Tablette) Tablet)
Film-coating  Film-coating
Hypromellose 5 cP 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336 Hypromellose 5 cP 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336
Titanium dioxid 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196Titanium dioxide 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196
Talcum 0.6072 0.6072 0.6072 0.6072 0.6072 0.6072 0.6072Talcum 0.6072 0.6072 0.6072 0.6072 0.6072 0.6072 0.6072
Eisenoxid gelb 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324Iron oxide yellow 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324
Eisenoxid rot 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072Red iron oxide 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072
Gewicht (film-Weight (film
6.0000 6.0000 6.0000 6.0000 6.0000 6.0000 6.0000 coating) 6.0000 6.0000 6.0000 6.0000 6.0000 6.0000 6.0000 coating)
Gewicht  Weight
(beschichtete 136.00 136.00 136.00 136.00 136.00 136.00 136.00 (coated 136.00 136.00 136.00 136.00 136.00 136.00 136.00
Tablette) Bewertung der physiologischen Wirksamkeit Tablet) Evaluation of physiological activity
Die Eignung der erfindungsgemäßen Kombinationen zur Behandlung von Herz- und Herz- Kreislauferkrankungen sowie Nieren- und kardio-renalen Erkrankungen und anderen in der Anmeldung beschriebenen Erkrankungen kann in folgenden Assaysystemen gezeigt werden:  The suitability of the combinations according to the invention for the treatment of heart and cardiovascular diseases as well as kidney and cardio-renal diseases and other diseases described in the application can be shown in the following assay systems:
1.) In vivo-Test zum Nachweis von natriuretischer Wirksamkeit an wachen Ratten in Stoffwechselkäfigen 1.) In vivo test for the detection of natriuretic activity in conscious rats in metabolic cages
Wistar Ratten (250-450 g Körpergewicht) werden mit freiem Zugang zu Futter (Altromin) und Trinkwasser gehalten. Ab ca. 72 Stunden vor Versuchsbeginn erhalten die Tiere anstelle des normalen Futters ausschließlich Kochsalz-reduziertes Futter mit einem Gehalt von 0.02% Natrium-Chlorid (ssniff R/M-H, 10mm mit 0,02% Na, S0602-E081, ssniff Spezialdiäten GmbH, D-59494 Soest). Während des Versuches werden die Tiere für ca. 24 Stunden einzeln in für Ratten dieser Gewichtsklasse geeigneten Stoffwechselkäfigen (Tecniplast Deutschland GmbH, D-82383 Hohenpeißenberg) mit freiem Zugang zu Kochsalz-reduziertem Futter und Trinkwasser gehalten. Am Versuchsbeginn wird den Tieren die zu prüfende Substanz in einem Volumen von 0,5 ml/kg Körpergewicht eines geeigneten Lösemittels mittels einer Schlundsonde in den Magen verabreicht. Als Kontrolle dienende Tiere erhalten nur Lösemittel. Kontrollen und Substanztestungen werden am selben Tag parallel durchgeführt. Kontrollgruppen und Substanzdosisgruppen bestehen aus jeweils 6 bis 8 Tieren. Während des Versuchs wird der von den Tieren ausgeschiedene Urin kontinuierlich in einem Auffangbehälter am Käfigboden gesammelt. Für jedes Tier wird gesondert das Urinvolumen pro Zeiteinheit bestimmt und die Konzentration der im Urin ausgeschiedenen Natrium- bzw. Kalium- Ionen mittels flammenphotometrischer Standardmethoden gemessen. Die Messintervalle betragen typischerweise den Zeitraum bis zu 8 Stunden nach Versuchsbeginn (Tagintervall) und den Zeitraum von 8 bis 24 Stunden nach Versuchsbeginn (Nachtintervall).  Wistar rats (250-450 g body weight) are kept with free access to feed (Altromin) and drinking water. Starting approx. 72 hours before the start of the experiment, instead of the normal diet, the animals are given only salt-reduced food with a content of 0.02% sodium chloride (ssniff R / MH, 10 mm with 0.02% Na, S0602-E081, ssniff Spezialdiäten GmbH). D-59494 Soest). During the experiment, the animals are kept individually for about 24 hours in suitable for rats of this weight category metabolic cages (Tecniplast Germany GmbH, D-82383 Hohenpeissenberg) with free access to salt-reduced feed and drinking water. At the beginning of the test, the substance to be tested is administered to the animals in a volume of 0.5 ml / kg body weight of a suitable solvent in the stomach by means of a gavage. Control animals receive only solvents. Controls and substance testing are done in parallel on the same day. Control groups and substance dose groups each consist of 6 to 8 animals. During the experiment, the urine excreted by the animals is continuously collected in a container on the floor of the cage. The urine volume per unit of time is determined separately for each animal, and the concentration of the sodium or potassium ions excreted in the urine is measured by standard flame photometric methods. The measuring intervals are typically the period up to 8 hours after the start of the test (day interval) and the period from 8 to 24 hours after the start of the test (night interval).
2.) DOCA/Salz-Modell  2.) DOCA / salt model
Die Verabreichung von Desoxycorticosteronacetat (DOCA) in Kombination mit einer Hochsalzdiät und einseitiger Nierenentfernung bei der Ratte induziert einen Hypertonus, der durch relativ niedrige Reninspiegel charakterisiert ist. Als Folge dieser endokrinen Hypertonie (DOCA ist eine direkte Vorstufe von Aldosteron) kommt es, abhängig von der gewählten DOCA-Konzentration, zu einer Hypertrophie des Herzens und weiteren Endorganschäden, z.B. der Niere, die u.a. durch Proteinurie und Glomerulosklerosis charakterisiert sind. In diesem Rattenmodell lassen sich somit Testsubstanzen auf vorhandene antihypertrophe und endorganschützende Wirkung hin untersuchen. Administration of desoxycorticosterone acetate (DOCA) in combination with a high salt diet and unilateral renal clearance in the rat induces hypertension characterized by relatively low renin levels. As a result of this endocrine hypertension (DOCA is a direct precursor of aldosterone), depending on the DOCA concentration chosen, cardiac hypertrophy and other end organ damage, e.g. the kidney, the u.a. characterized by proteinuria and glomerulosclerosis. In this rat model, test substances can thus be tested for the presence of antihypertrophic and endorphin protective effects.
Etwa 8 Wochen alte (Körpergewicht zwischen 250 und 300 Gramm), männliche Sprague Dawley (SD-) Ratten werden linksseitig uninephrektomiert. Dazu werden die Ratten mit 1.5-2%>igem Isofluran in einer Mischung aus 66%> N2O und 33%> O2 anästhesiert und die Niere wird über einen Flankenschnitt entfernt. Als spätere Kontrolltiere dienen sogenannte sham operierte Tiere, denen keine Niere entfernt wird. About 8 weeks old (body weight between 250 and 300 grams), male Sprague Dawley (SD) rats are left uninephrectomized. The rats are anesthetized with 1.5-2% isoflurane in a mixture of 66%> N2O and 33%> O2 and the kidney is anesthetized Flank cut removed. As a later control animals serve so-called sham operated animals, which no kidney is removed.
Uninephrektomierte SD-Ratten erhalten 1% Natriumchlorid im Trinkwasser und einmal wöchentlich eine subkutane Injektion DOCA (Firma SIGMA, gelöst in Sesamöl; Hochdosis: 100 mg/kg/wk s.c; Normaldosis: 30 mg/kg/wk s.c.) zwischen die Schulterblätter gespritzt.  Uninephrectomized SD rats receive 1% sodium chloride in drinking water and once weekly a subcutaneous injection of DOCA (company SIGMA, dissolved in sesame oil, high dose: 100 mg / kg / wk s.c., normal dose: 30 mg / kg / wk s.c.) injected between the shoulder blades.
Die Substanzen, die auf ihre protektive Wirkung in vivo untersucht werden sollen, werden per Gavage oder per Futter verabreicht (Ssniff, Germany). Die Tiere werden einen Tag vor Versuchsbeginn randomisiert und Gruppen mit gleicher Tierzahl, in der Regel n=8-15, zugeordnet. Während des gesamten Versuches steht den Tieren Trinkwasser und Futter ad libitum zur Verfügung. Die Substanzen (Kombinationen) werden einmal täglich 4-12 Wochen lang per Gavage oder per Futter verabreicht. Als Plazebogruppe dienen Tiere, die genauso behandelt werden, aber entweder nur das Lösungsmittel oder das Futter ohne Testsubstanz erhalten.  The substances to be tested for their protective effect in vivo are administered by gavage or by food (Ssniff, Germany). The animals are randomized one day before the start of the experiment and assigned to groups with the same number of animals, usually n = 8-15. Throughout the experiment, the animals have access to drinking water and food ad libitum. The substances (combinations) are administered once a day for 4-12 weeks by gavage or by food. The placebo group used is animals that are treated in exactly the same way, but receive either only the solvent or the feed without the test substance.
Am Versuchsende können hämodynamische Parameter (Blutdruck, Herzfrequenz, Inotropie [dp/dt], Relaxationszeit [tau], maximaler linksventrikulärer Druck, linksventrikulärer enddiastolischer Druck [LVEDP]) gemessen werden, sowie die Gewichte von Herz, Niere und Lunge, Proteinausscheidung und Genexpression von Biomarkern (z.B. BNP, Brain Natriuretic Peptide, Plasma Renin Aktivität, Angiotensin und Aldosteron) mittels RIA, ELISA oder RT/TaqMan PCR nach RNA Isolation aus kardialem und renalen Gewebe bestimmt.  Hemodynamic parameters (blood pressure, heart rate, inotropy [dp / dt], relaxation time [tau], maximal left ventricular pressure, left ventricular enddiastolic pressure [LVEDP]), heart, kidney and lung weights, protein excretion and gene expression of Biomarkers (eg BNP, brain natriuretic peptides, plasma renin activity, angiotensin and aldosterone) are determined by RIA, ELISA or RT / TaqMan PCR after RNA isolation from cardiac and renal tissue.
3.) L-NAME behandelte, transgene Renin-Ratte (TGR(mRen2)27)  3.) L-NAME Treated Renal Transgenic Rat (TGR (mRen2) 27)
Die transgene Renin-Ratte ,TGR(mRen2)27' ist eine, von Mullins und Ganten entwickelte hypertensive Rattenlinie, die das Ren-2-Gen der Maus überexprimiert. Durch zusätzliche Gabe des Stickstoffmonoxid-Synthase-Inhibitors L-NAME induziert man eine endotheliale Dysfunktion, die Morbidität und Mortalität in diesem Modell erhöht. Homozygote Tiere versterben an sekundären Komplikationen wie Herz- und Niereninsuffizienz, oder Schlaganfall, sofern sie keiner lebenslangen, antihypertensiven Therapie unterzogen werden. The transgenic renin rat, TGR (mRen2) 27 'is a hypertensive rat line developed by Mullins and Ganten that overexpresses the mouse Ren-2 gene. Additional administration of the nitric oxide synthase inhibitor L-NAME induces endothelial dysfunction, which increases morbidity and mortality in this model. Homozygous animals die of secondary complications, such as heart and kidney failure, or stroke, unless they undergo lifelong, antihypertensive therapy.
Männliche TGR(mRen2)27 Renin-Ratten im Alter von 10 bis 20 Wochen werden bzgl. verschiedenener pharmakologischer Behandlungsgruppen, sowie einer Plazebo-Gruppe randomisiert. Zusätzlich erfolgt die Gabe des Inhibitors der Stickstoffmonoxid-Synthase, L-NAME über das Trinkwasser in einer Konzentration von 30 bis 100 mg/1. Während des gesamten Versuches steht den Tieren Trinkwasser und Futter ad libitum zur Verfügung. Die Substanzen werden täglich 4-10 Wochen lang per Gavage oder per Futter verabreicht. Als Plazebogruppe dienen Tiere, die genauso behandelt werden, aber entweder nur das Lösungsmittel oder das Futter ohne Testsubstanz erhalten. Während des Versuchs erfolgt in regelmäßigen Abständen die Bestimmung des systolischen Blutdrucks per Schwanzmanschette (tail cuff), sowie die Bestimmung von Proteinurie und Urinelektrolytzusammensetzung durch Urinsammlung in metabolischen Käfigen. Am Versuchsende werden hämodynamische Parameter (Blutdruck, Herzfrequenz, Inotropie [dp/dt], Relaxationszeit [tau], maximaler linksventrikulärer Druck, linksventrikulärer enddiastolischer Druck [LVEDP]) gemessen, sowie die Gewichte von Herz, Niere und Lunge bestimmt, Proteinausscheidung und Biomarker (z.B. ANP, RIA Kit RK 005-24, Phoenix Pharmaceuticals, Inc., USA, cGMP, RIA Kit RE29075, IBL International GmbH, Hamburg, Renin, Angiotensin I, RIA Kit CA-1533, DiaSorin S.p.A., Italy, und Aldosterone, P2714, DiaSorin S.p.A., Italy), sowie Genexpression von Biomarkern mittels RT/TaqMan PCR nach RNA Isolation aus kardialem und renalen Gewebe bestimmt. Male TGR (mRen2) Twenty-seven renin rats aged 10 to 20 weeks are randomized to various pharmacological treatment groups and a placebo group. In addition, the nitric oxide synthase inhibitor, L-NAME, is administered via the drinking water at a concentration of 30 to 100 mg / l. Throughout the experiment, the animals have access to drinking water and food ad libitum. The substances are administered daily for 4-10 weeks by gavage or by food. The placebo group used is animals that are treated in exactly the same way, but receive either only the solvent or the feed without the test substance. During the trial, tail cuff systolic blood pressure is measured at regular intervals, as well as the determination of proteinuria and urinary electrolyte composition by urine collection in metabolic cages. At the end of the experiment Hemodynamic parameters (blood pressure, heart rate, inotropy [dp / dt], relaxation time [tau], maximal left ventricular pressure, left ventricular enddiastolic pressure [LVEDP]) are measured, weights of heart, kidney and lung are determined, protein excretion and biomarkers (eg ANP , RIA Kit RK 005-24, Phoenix Pharmaceuticals, Inc., USA, cGMP, RIA Kit RE29075, IBL International GmbH, Hamburg, Renin, Angiotensin I, RIA Kit CA-1533, DiaSorin SpA, Italy, and Aldosterone, P2714, DiaSorin SpA, Italy), as well as gene expression of biomarkers by RT / TaqMan PCR after RNA isolation from cardiac and renal tissue.
Beispiele  Examples
Herz- und Herzkreislauferkrankungen wie auch Nieren und kardiorenale Erkrankungen sind von einer hohen Morbidität der Patienten aber auch von einer hohen Mortalität gekennzeichnet. Diese Morbidität und Mortalität zusammen mit verschiedenen Risikofaktoren wie z.B. Bluthochdruck, lässt sich sehr gut im bereits beschriebenen Tiermodell der mit L-NAME behandelten Renin transgenen Ratte abbilden. Daher wurde z.B. dieses Tiermodell verwendet um MR-Antagonisten wie z.B. Finerenone gemäß der Verbindung der Formel (IV) und sGC Aktivatoren, wie z.B. die Verbindung der Formel (X) und Kombinationen aus Beiden zu untersuchen:  Heart and cardiovascular diseases as well as kidney and cardiorenal diseases are characterized by a high morbidity of the patients but also by a high mortality. This morbidity and mortality together with various risk factors, e.g. High blood pressure can be mapped very well in the previously described animal model of the L-NAME-treated renin transgenic rat. Therefore, e.g. this animal model uses MR antagonists, e.g. Finerenones according to the compound of formula (IV) and sGC activators, e.g. to study the compound of formula (X) and combinations of both:
Z.B. wurden der MR-Antagonist Finerenone entsprechend der Verbindung der Formel (IV) und der sGC Aktivator entsprechend der Verbindung der Formel (X) alleine und in Kombinationen in TGR(mRen2)27 Renin-Ratten im Alter von 10 bis 20 Wochen getestet. Zusätzlich erfolgte die Gabe des Inhibitors der Stickstoffmonoxid-Synthase, L-NAME über das Trinkwasser in einer Konzentration von 30 bis 100 mg/1. Während des gesamten Versuches standen den Tieren Trinkwasser und Futter ad libitum zur Verfügung. Die Substanzen wurden täglich 4-10 Wochen lang per Gavage verabreicht. Als Plazebogruppe dienten Tiere, die genauso behandelt wurden, aber nur das Lösungsmittel für die Testsubstanz erhalten haben. In der Versuchsserie wurde neben Placebo (Gruppe A), der MR- Antagonist Finerenone (10mg/kg od) (Gruppe B) und der sGC Aktivator entsprechend der Verbindung der Formel (X) (1 mg/kg bid) (Gruppe C) alleine, und eine Kombination aus Finerenone (10mg/kg od) + die Verbindung der Formel (X) (1 mg/kg bid) (Gruppe D) verabreicht. Pro Gruppe (A, B, C, D,) wurden in dieser Studie 15 Tiere eingesetzt (Tabelle 1):  For example, For example, the MR antagonist finerenone corresponding to the compound of formula (IV) and the sGC activator corresponding to the compound of formula (X) were tested alone and in combinations in TGR (mRen2) 27 renin rats at 10 to 20 weeks of age. In addition, the administration of the inhibitor of nitric oxide synthase, L-NAME via the drinking water in a concentration of 30 to 100 mg / 1. Throughout the experiment, the animals were given drinking water and food ad libitum. The substances were administered daily for 4-10 weeks by gavage. The placebo group used were animals that were treated in the same way, but only received the solvent for the test substance. In the experimental series, in addition to placebo (group A), the MR antagonist Finerenone (10 mg / kg od) (group B) and the sGC activator corresponding to the compound of formula (X) (1 mg / kg bid) (group C) alone , and a combination of Finerenone (10 mg / kg od) + the compound of formula (X) (1 mg / kg bid) (Group D). Per group (A, B, C, D,) 15 animals were used in this study (Table 1):
Gruppenbezeichnung Behandlung Dosis Gruppengröße [n] Group name Treatment Dose Group size [n]
Gruppe A Placebo 15 Group A Placebo 15
Gruppe B Finerenone, (Verbindung der 10 mg/kg od 15  Group B Finerenone, (compound of 10 mg / kg od 15
Formel (IV))  Formula (IV))
Gruppe C Verbindung der Formel (X) 1 mg/kg bid 15  Group C compound of formula (X) 1 mg / kg bid 15
Gruppe D Finerenone (Verbindung der 10 mg/kg od 15  Group D Finerenone (compound of 10 mg / kg od 15
Formel (IV)) + +  Formula (IV)) + +
Verbindung der Formel (X)  Compound of the formula (X)
1 mg/kg bid Tabelle 1 : Gruppeneinteilung, Behandlung, eingesetzte Dosierung und Applikationsschema (od/once daily = einmal täglich; bid/bidaily = zweimal täglich) und Gruppengröße der mit L-NAME behandelten Renin transgenen Ratten. 1 mg / kg bid Table 1: Grouping, treatment, dosage used and schedule of application (od / once daily = once daily, bid / bidaily = twice daily) and group size of L-NAME-treated renin transgenic rats.
Mortalität:  Mortality:
Nachdem 40% der Placebotiere verstorben waren - der Studienabbruch erfolgte in der Regel wenn 40- 50% der mit Placebo behandelten Tiere verstorben sind was einer Überlebensrate von 60-50%> entspricht - wurde die Studie abgebrochen und die Überlebensraten in den einzelnen Behandlungsgruppen miteinander verglichen. Es zeigte sich, dass mit einer Behandlung von Finerenone (10 mg/kg od) alleine bzw. der sGC Aktivator entsprechend der Verbindung der Formel (X) (1 mg/kg bid) alleine, nur 20%> bzw. 27%> der Tiere im Studienzeitraum verstarben was Überlebensraten von 80%> bzw. 73%> entspricht. Allerdings verhinderte eine Kombination aus Finerenone (10 mg/kg od) + Verbindung der Formel (X) (1 mg/kg bid) alle Todesfälle über den Studienzeitraum hinweg und führte zu eine signifikanten höheren Überleben mit einer Überlebensrate vonl00%> im Studienzeitraum (Tabelle 2):  After 40% of the placebo animals had died - the dropout usually occurred when 40-50% of the placebo-treated animals died, which corresponds to a survival rate of 60-50% - the study was discontinued and the survival rates in the individual treatment groups compared , It was found that with a treatment of finerenone (10 mg / kg od) alone or the sGC activator corresponding to the compound of formula (X) (1 mg / kg bid) alone, only 20%> or 27%> Animals in the study period died which corresponds to survival rates of 80%> or 73%>. However, a combination of finerenone (10 mg / kg od) + compound of formula (X) (1 mg / kg bid) prevented all deaths over the study period and resulted in significantly higher survival with a survival rate of 100%> over the study period (Table 2):
behandelten Renin transgenen Ratten.  treated renin transgenic rats.
Parallel zu der kompletten Verhinderung der kardiovaskulären und kardio-renalen Mortalität verbesserten sich auch andere Parameter für Herz-, Herz-Kreislauf und Nierenfunktion. Diese wurden z.B. durch die Bestimmung der Proteinausscheidung über die Niere oder über die BNP-Produktion (Brain Natriuretic Peptide) im Herzen durch Bestimmung der Plasma BNP Spiegel quantifiziert.  Parallel to the complete prevention of cardiovascular and cardio-renal mortality, other parameters for cardiac, cardiovascular and renal function also improved. These were e.g. quantified by determining the protein excretion via the kidney or via the BNP production (Brain Natriuretic Peptide) in the heart by determining the plasma BNP levels.
Proteinurie; Protein/Kreatinin Quotient im Urin:  proteinuria; Protein / creatinine Quotient in urine:
Beim Patienten wird häufig für die Bestimmung des Nierenschadens die Proteinausscheidung in der Niere - die bei Patienten deutlich gesteigert ist - herangezogen. Hierbei wird der Quotient aus dem im Urin ausgeschiedenen Protein und dem im Urin ausgeschiedenen Kreatinin, der sogenannte Protein/Kreatinin Quotient bestimmt, der als quantitatives Maß für den Nierenschaden herangezogen werden kann. Auch in den durchgeführten Tierexperimenten wurde z.B. die Proteniurie, gemessen als Protein/Kreatininquotient im Urin, unter der Behandlung mit Finerenone (10 mg/kg od) alleine bzw. mit dem sGC Aktivator entsprechend der Verbindung der Formel (X) (1 mg/kg bid) alleine, bereits signifikant um 58%> bzw. 8%> gesenkt. Auch hier führte aber die Kombination von Finerenone (10 mg/kg od) + Verbindung der Formel (X) (1 mg/kg bid) zu einer deutlich stärkeren, hochsignifikanten Senkung der Proteinurie insgesamt um 85% (Tabelle 3): Patients often use protein secretion in the kidney - which is significantly increased in patients - to determine renal damage. Here, the quotient of the excreted in the urine protein and excreted in the urine creatinine, the so-called protein / creatinine quotient is determined, which can be used as a quantitative measure of the kidney damage. Also in the animal experiments carried out, for example, the protenuria, measured as protein / Kreatininquotient in urine, under treatment with finerenone (10 mg / kg od) alone or with the sGC activator corresponding to the compound of formula (X) (1 mg / kg alone), already significantly reduced by 58%> or 8%>. Again, however, the combination of Finerenone (10 mg / kg od) + compound of formula (X) (1 mg / kg bid) to a significantly stronger, highly significant lowering of proteinuria total by 85% (Table 3):
behandelten Renin transgenen Ratten. Daten als Mittelwert + SEM; */**/***/**** = signifikant mit p<0.05/0.01/0.001/0.0001 (einseitiger ANOVA + post hoc Analyse).  treated renin transgenic rats. Data as mean + SEM; * / ** / *** / **** = significant with p <0.05 / 0.01 / 0.001 / 0.0001 (unilateral ANOVA + post hoc analysis).

Claims

Patentansprüche claims
1. Kombinationen, die mindestens einen sGC Aktivator und mindestens einen nicht-steroidalen MR Antagonisten enthalten.  1. Combinations containing at least one sGC activator and at least one non-steroidal MR antagonist.
2. Kombination gemäß Anspruch 1, die den sGC Aktivator (3S)-3-(4-Chlor-3- {[(2S,3R)-2-(4- chlorphenyl)-4,4,4-trifluor-3 -methylbutanoyl] amino } phenyl)-3 -cyclopropylpropansäure der Formel (X) A combination according to claim 1 which contains the sGC activator (3S) -3- (4-chloro-3- {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3 - methylbutanoyl] amino} phenyl) -3-cyclopropylpropanoic acid of the formula (X)
und (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridin- 3-carboxamid der Formel (IV)  and (S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (IV)
enthält.  contains.
3. Kombination gemäß Anspruch 1 zur Behandlung und/oder Prophylaxe von Krankheiten.3. Combination according to claim 1 for the treatment and / or prophylaxis of diseases.
4. Kombination gemäß Anspruch 1 zur Verwendung in einem Verfahren zur Behandlung und/oder Prophylaxe von Herz-, Herz-Kreislauf-Erkrankungen, Nieren-, kardio-renalen Erkrankungen, Lungen- und kardio-pulmonären Erkrankungen, sowie zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen. 4. A combination according to claim 1 for use in a method for the treatment and / or prophylaxis of cardiac, cardiovascular diseases, renal, cardio-renal diseases, pulmonary and cardio-pulmonary diseases, and for the treatment and / or prophylaxis of fibrotic diseases.
5. Verwendung von Kombinationen gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von Herz- und Herz-Kreislauf-Erkrankungen, Nieren- und kardio-renalen Erkrankungen, Lungen- und kardio-pulmonären Erkrankungen, sowie zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen. 5. Use of combinations according to claim 1 for the manufacture of a medicament for the treatment and / or prophylaxis of cardiovascular diseases, renal and cardio-renal diseases, pulmonary and cardio-pulmonary diseases, and for the treatment and / or Prophylaxis of fibrotic diseases.
6. Arzneimittel enthaltend mindestens eine Kombination gemäß Anspruch 1 in Kombination mit einem inerten, nicht-toxischen, pharmazeutisch geeigneten Hilfsstoff.  6. Medicament containing at least one combination according to claim 1 in combination with an inert, non-toxic, pharmaceutically suitable excipient.
7. Arzneimittel enthaltend mindestens eine Kombination gemäß Anspruch 1, in Kombination mit einem oder mehreren weiteren Wirkstoffen ausgewählt aus der Gruppe bestehend aus ACE- Inhibitoren, Angiotensin Rezeptor Blockern, Kombination von Angiotensin Rezeptor Blockern und NEP-Inhibitoren (ARNIs), Antidiabetika, Beta-Blocker, Acetylsalicylsäure, Diuretika, If-Kanal-Blocker ( Ivabradin), Calcium-Antagonisten, Statine, Digitalis (Digoxin)- Derivate, Calcium-Sensitizer, Nitrate sowie Antithrombotika.  7. A medicament containing at least one combination according to claim 1, in combination with one or more further active compounds selected from the group consisting of ACE inhibitors, angiotensin receptor blockers, combination of angiotensin receptor blockers and NEP inhibitors (ARNIs), antidiabetics, beta Blockers, acetylsalicylic acid, diuretics, if-channel blockers (ivabradine), calcium antagonists, statins, digitalis (digoxin) derivatives, calcium sensitizers, nitrates and antithrombotics.
8. Arzneimittel gemäß Anspruch 6 oder 7 zur Behandlung und/oder Prophylaxe von Herz- Kreislauf-Erkrankungen, renalen Erkrankungen, Lungenerkrankungen, sowie zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen.  8. Medicament according to claim 6 or 7 for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, as well as for the treatment and / or prophylaxis of fibrotic diseases.
9. Verfahren zur Behandlung und/oder Prophylaxe von Herz-Kreislauf-Erkrankungen, renalen Erkrankungen, Lungenerkrankungen, sowie zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen in Menschen und Tieren unter Verwendung einer Kombination gemäß Anspruch 1, oder eines Arzneimittels gemäß einem der Ansprüche 6 bis 8.  9. A method for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, as well as for the treatment and / or prophylaxis of fibrotic diseases in humans and animals using a combination according to claim 1, or a medicament according to one of the claims 6 to 8.
10. Kombinationen gemäß Anspruch 1 und 7 zur Behandlung und/oder Prophylaxe von Krankheiten, wobei 10 bis 40 mg Finerenone verabreicht werden.  10. Combinations according to claim 1 and 7 for the treatment and / or prophylaxis of diseases, wherein 10 to 40 mg Finerenone be administered.
11. Ein Kit umfassend eine pharmazeutische Zusammensetzung umfassend Finerenone und die Verbindung der Formel (X).  11. A kit comprising a pharmaceutical composition comprising finerenones and the compound of formula (X).
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