WO2017029261A1 - Combination drug comprising finerenone and an nep-inhibitor (sacubitril) - Google Patents

Combination drug comprising finerenone and an nep-inhibitor (sacubitril) Download PDF

Info

Publication number
WO2017029261A1
WO2017029261A1 PCT/EP2016/069336 EP2016069336W WO2017029261A1 WO 2017029261 A1 WO2017029261 A1 WO 2017029261A1 EP 2016069336 W EP2016069336 W EP 2016069336W WO 2017029261 A1 WO2017029261 A1 WO 2017029261A1
Authority
WO
WIPO (PCT)
Prior art keywords
diseases
treatment
prophylaxis
combination preparation
preparation according
Prior art date
Application number
PCT/EP2016/069336
Other languages
German (de)
French (fr)
Inventor
Peter Kolkhof
Peter Sandner
Christina NOWAK
Original Assignee
Bayer Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Publication of WO2017029261A1 publication Critical patent/WO2017029261A1/en

Links

Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to the use of the mineralocorticoid receptor antagonist Finerenone in combination with an inhibitor of neutral endopeptidase (NEP), for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, 5 and for the treatment and / or Prophylaxis of fibrotic diseases.
  • NEP neutral endopeptidase
  • renin-angiotensin-aldosterone system One of these essential control systems is the so-called renin-angiotensin-aldosterone system
  • RAAS RAAS 20
  • Renin cleaves the liver-formed angiotensinogen into angiotensin I while the angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II.
  • ACE angiotensin-converting enzyme
  • Angiotensin II has potent 25 vasoconstrictive and thus hypertensive effects and stimulates the formation of the steroid hormone aldosterone in the adrenal cortex. Aldosterone promotes the recovery of sodium from the urine into the blood, increasing blood volume.
  • angiotensin II The specific effects of angiotensin II are mediated via corresponding extracellular receptors (angiotensin receptor, AT-R), which expresses 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
  • angiotensin 11 and aldosterone have direct pro-inflammatory and fibrotic properties.
  • Both hormones play an important role, in particular during remodeling ('remodeling') in the heart, kidneys and blood vessels, which are induced by a myocardial infarction or acute renal failure, for example Aldosterone the deposit of collagen proteins in the heart muscle, which can lead to increased stiffness and thus in the long term to a reduced functionality.
  • cGMP cyclic guanosine monophosphate
  • NO nitric oxide
  • cGMP / O have a vasodilating effect and thus an antihypertensive effect.
  • Certain enzymes, so-called guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP).
  • GTP guanosine triphosphate
  • the known members of this family can be divided into structural groups as well as the type of ligands in two groups: the particulate, by so-called natriuretic peptides stimulable guanylate cyclases (pGC) and the soluble, stimulable by NO guanylate cyclases (sGC).
  • the particulate membranous guanylate cyclases consist of the cytosolic catalytic domain, a transmembrane region and the extracellular ligand-binding domain.
  • the binding of natriuretic peptides to the extracellular ligand-binding domain leads to the activation of the catalytic domain and the biosynthesis of cGMP from GTP.
  • the enzyme neprilysin inactivates natriuretic peptides by proteolytic cleavage and consequently has an inhibitory effect on the particulate guanylate cyclase.
  • Natriuretic peptides such as e.g.
  • natriuretic peptides function functionally as antagonists of RAAS.
  • Aldosterone and angiotensin 11 form a classic, feed-forward 'regulatory circuit: in addition to potassium, angiotensin 11 is the main stimulus for the release of aldosterone from the adrenal glands, and conversely, aldosterone in heart tissue and vessels stimulates the production of ACE, the enzyme that precedes the precursor - angiotensin which generates angiotensin 11.
  • MR antagonists such as the steroidal compounds spironolactone, canrenone / canrenoate and eplerenone, as well as newer non-steroidal MR antagonists such as MT-3995, CS-3150, LY2623091, PF-03882845 and finerenone (BAY 94-8862)), aldosterone-mediated sodium retention in the kidneys (natriuretic effect).
  • 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.
  • MR MR antagonists
  • v. A 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 in proximal tubule sections occurs.
  • LCZ696 is an AR! (Angiotensin receptor neprilysin inhibitor) and thus a dual agent consisting of the AT-R antagonist valsartan and the neprilysin inhibitor sacubitril.
  • neprilysin inhibition one achieves a diminished degradation of natriuretic peptides.
  • diuretic and natriuretic through its vasodilator effect on pre-glomerular vessels.
  • they may also inhibit sodium reabsorption in proximal tubule sections.
  • AT-R blockade and neprilysin inhibition by LCZ696 have recently been evaluated in clinical trials (Phase III) in patients with heart failure and resulted in a reduction in death and hospitalization risks (McMurray et al 2014 NEJM).
  • Phase III clinical trials
  • NEJM NEP inhibitor sacubitril
  • compensatory increases in renin and angiotensin were measured with LCZ696 both in healthy volunteers and in hypertensive patients. Concerning. however, additional compensatory, feed-back or feed-forward regulations would require long-term data.
  • the invention provides a combination preparation containing finerenones with N- (3-carboxy-1-oxopropyl) -
  • the combination preparation shows acute and especially chronic use, positive effects on sodium excretion, end-organ protection of the heart and kidneys and reduction of morbidity and morality under experimental conditions.
  • These experimental conditions consist on the one hand of healthy animals or animals with hypertension, cardiac and / or renal insufficiency (eg transgenic renin rats).
  • non-steroidal MR antagonist Finerenone in combination with N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid or an ester of of N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid for the treatment of cardiovascular diseases such as Cardiac insufficiency with retained fraction or congestive heart failure with reduced fraction of ejaculation, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, renal diseases, e.g.
  • cardiovascular diseases such as Cardiac insufficiency with retained fraction or congestive heart failure with reduced fraction of ejaculation, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, renal diseases, e.g.
  • An object of the present invention is a combination preparation comprising the mineralocorticoid receptor selective antagonist Finerenone and the NEP inhibitor N- (3).
  • Finerenone is the non-steroidal mineralocorticoid receptor selective antagonist (5) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxamide of the formula (I)
  • the NEP inhibitor of the present invention is N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or an ester of the acid, or each salt, solvate or Solvate of salts of acid or ester.
  • Acid and esters of the NEP inhibitor of the invention are described in EP 0 555 175 A1.
  • N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid is the ethyl ester
  • preferred salts include the sodium salt, the triethanolamine salt and the tris (hydroxymethyl) aminomethane salt.
  • 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 molar ratio of finerenone to NEP inhibitor of the invention in the combination preparation according to the invention is for example 0.01-10: 1, preferably 0.05-5: 1 and most preferred is a molar ratio of 0.1-1: 1.
  • the combination preparation according to the invention is 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, for example, Cardiac insufficiency with retained fraction or congestive heart failure with reduced fraction of ejaculation, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, renal diseases, e.g. chronic renal failure or diabetic nephropathy, pulmonary diseases, central nervous system disorders, for the treatment and / or prophylaxis of fibrotic disorders, as well as other manifestations of disease (e.g., end-organ damage affecting the brain, kidney, or heart).
  • cardiovascular diseases such as, for example, Cardiac insufficiency with retained fraction or congestive heart failure with reduced fraction of ejaculation, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, renal diseases, e.g. chronic renal failure
  • the combined preparation according to the invention is 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, glomerular sclerosis, proteinuria secondary to renal disease, renal vascular hypertension, diabetic and non-diabetic retinopathy, migraine, peripheral vascular disease,
  • Another object of the present invention is the use of the combination preparation of 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.
  • the combination preparation 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 the inventive combination preparation and one or more other 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:
  • Hypotensive agents by way of example and preferably from the group of calcium antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-relaxers, beta-receptor B-relaxers and rho-kinase inhibitors;
  • Diuretics especially loop diuretics and thiazides and thiazide-like diuretics
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • fat 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 S qualensynthese inhibitors, the 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 S qualensynthese inhibitors, the 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, nitroglycerine, 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 dobutamine;
  • positive inotropic compounds such as cardiac glycosides (digoxin), beta adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and dobutamine;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • 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
  • Calcium sensitizers such as by way of example and preferably levosimendan
  • Myosin activators by way of example and preferably Omecamtiv mecarbil;
  • HNE Human neutrophil elastase inhibitors
  • 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 preparation 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, methylcidothiazide, 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, methylcidothiazide, polythiazide, trich
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-relaxer, beta-receptor B-lover, Rho-kinase inhibitors and diuretics Understood.
  • the combination preparation 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 combination preparation according to the invention is used in combination with an ACE inhibitor, by way of example and by way of example Enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor by way of example and by way of example Enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the combination preparation according to the invention is administered in combination with an endothelin antagonist, such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the combination preparation according to the invention is administered in combination with a renin inhibitor such as, for example and preferably, aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.
  • a renin inhibitor such as, for example and preferably, aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.
  • the combination preparation 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 preparation according to the invention is used in combination with a beta-receptor blocker such as, for 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 blocker such as, for example and preferably, propranolol, atenolol, timolo
  • the combination preparation according to the invention is used in combination with a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI -23095 or BA-1049.
  • a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI -23095 or BA-1049.
  • Antithrombotic agents are preferably understood as meaning compositions from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the combination preparation according to the invention is administered in combination with a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the combination preparation 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 preparation 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 preparation according to the invention is used 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
  • the combination preparation according to the invention is administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the combination preparation 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, the 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.
  • the combination preparation according to the invention is admixed 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). administered.
  • 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). administered.
  • the combination preparation according to the invention is used 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), administered.
  • 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), administered.
  • the combination preparation according to the invention is combined with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravasatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin administered.
  • statins such as, for example and preferably, lovastatin, simvastatin, pravasatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin administered.
  • the combination preparation 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 preparation according to the invention is administered in combination with an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the combination preparation according to the invention is used in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038, R! 03757 or JTT-130. Administered.
  • the combination preparation 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-gamma agonist such as by way of example and preferably pioglitazone or rosiglitazone.
  • the combination preparation according to the invention is administered with a PPAR-delta agonist such as, for example and preferably, GW-501516 or BAY 68-5042.
  • a PPAR-delta agonist such as, for example and preferably, GW-501516 or BAY 68-5042.
  • the combination preparation according to the invention is administered with a cholesterol absorption inhibitor, such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
  • the combination preparation according to the invention is administered with a lipase inhibitor, such as, by way of example and by way of preference, quistlate.
  • a lipase inhibitor such as, by way of example and by way of preference, quistlate.
  • the combination preparation according to the invention is administered in combination with a polymeric bile acid adsorbent, such as, for example and preferably, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, for example and preferably, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • AS BT IB AT
  • the combination preparation according to the invention is administered in combination with a lipoprotein (a) antagonist, such as, for example and preferably, gemcabene calcium (CT 1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, for example and preferably, gemcabene calcium (CT 1027) or nicotinic acid.
  • the compounds 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 compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms, the compounds of the invention in crystalline and / or amorphized 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 compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules ( hard or soft gelatin capsules, for example), 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 compound of the invention
  • Preferred forms of administration are tablet form (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound according to the invention), tablets rapidly disintegrating 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.
  • Inhalant medicines 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, shaking 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 compounds of 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 sodium
  • the components may be used together or sequentially or separately in a combined dosage form or in two separate 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.
  • finerenone and NEP inhibitor may be provided as a capsule or tablet, respectively.
  • the dosage of finerenone is about 1 to 100 mg od, preferably about 2.5 to 50 mg od and most preferably 10 to 20 mg od.
  • dosages of finerenone on oral administration of 1.25 mg od, 2.5 mg od, 5 mg od, 7.5 mg od, 15 mg od or 20 mg od.
  • the dosage of the NEP inhibitor is about 1 to 1000 mg bid, preferably about 10 to 500 mg bid and most preferably 24 to 97 mg bid.
  • the dosage of Finerenone is about 1 to 100 mg od and the dosage of NEP inhibitor is about 1 to 1000 mg bid, preferably the dosage of Finerenone is about 2.5 to 50 mg od and the dosage of NEP Inhibitors about 10 to 500 mg bid and most preferably the dosage of finerenone is about 10-20 mg od and the dosage of the NEP inhibitor about 24 to 97 mg bid.
  • 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 Finerenone composition and a pharmaceutical NEP inhibitor composition.
  • the invention also relates to a preferred kit form comprising two units: A pharmaceutical composition comprising finerenones and NEP inhibitor and a pharmaceutical composition comprising NEP inhibitor.
  • the kit is particularly advantageous when the separate components must 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:
  • Finerenone Composition 1 1:
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • 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 250-350 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 approximately 24 hours in metabolic cages suitable for rats of this weight class (Tecniplast GmbH, D-823 3 Hohenpeissenberg) with free access to salt-reduced food 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 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).
  • the coronary artery of the left ventricle is punctured with a occlusion thread (PROLENE 1 metric 5-0 ETHICON1H) just below its origin (below the left atrium) and permanently ligated.
  • the occurrence of myocardial infarction is monitored by an ECG measurement (AD Instruments Power Lab 8/30).
  • the lungs are inflated by briefly disconnecting the exhalation tube.
  • the thorax is closed again and the muscle layers are sutured with ETHIBOND excel 1 metric 5/0 6951H and the epidermis with ETHIBOND excel 3/0 65 Sil.
  • the surgical suture is covered with silver powder (eg Fissan) and then the anesthesia is terminated.
  • a "sham” group in which only the surgical procedure but not the LA D occlusion was carried out, was taken 24 hours after the infarction, and retroorbital blood (Li Hep plasma) was taken for the troponin determination.
  • the animals were randomized at surgery and divided into individual treatment groups as well as into a control group without substance treatment.
  • the substance treatment takes place once or twice daily for 8 weeks p.o. 2ml / kg (the first treatment is 24h after surgery), or by adding the test substances in the feed or drinking water.
  • the animals are again anesthetized (2% isoflurane) and a pressure catheter (Miliar SPR-320 2F) for 2 minutes in the carotid artery and then introduced for 2 minutes in the left ventricle. It records heart rate, left ventricular pressure (LVP), left ventricular end-diastolic pressure (L VII DP), contractility (dp / dt), and relaxation rate (tau) using the Powerlab system (AD Instruments, Power Lab 3/80) and the Chart7 software and evaluated. Subsequently, blood samples for analysis of certain parameters, e.g. BNP, angiotensin or aldosterone were removed and the animals were killed. Heart, lungs and kidney are removed and weighed. The tissue samples can be used for further histological examinations as well as for gene expression analyzes. 3.) DOCA / salt model
  • 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 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]
  • Biomarkers eg ANP, Atrial Natriuretic Peptides, and BNP, Brain Natriuretic Peptides, 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to the use of the mineralocorticoid receptor antagonist finerenone combined with an inhibitor of the neutral endopeptidase (NEP), for treating and/or preventing cardiovascular diseases, renal diseases, lung disorders, and for treating and/or prophylaxis of fibrotic diseases.

Description

KOMBINATIONSPRÄPARAT UMFASSEND FINERENONE UND EINEN NEP-INHIBITOR (SACUBITRIL)  COMBINATION PREPARATION COMPRISING FERNERENONE AND A NEP INHIBITOR (SACUBITRIL)
Die vorliegende Erfindung betrifft die Verwendung des Mineralocorticoid-Rezeptor- Antagonisten Finerenone in Kombination mit einem Inhibitor der Neutralen Endopeptidase (NEP), zur Behandlung und/oder Prophylaxe von Herz-Kreislauf-Erkrankungen, renalen Erkrankungen, Lungenerkrankungen, 5 sowie zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen. The present invention relates to the use of the mineralocorticoid receptor antagonist Finerenone in combination with an inhibitor of neutral endopeptidase (NEP), for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, 5 and for the treatment and / or Prophylaxis of fibrotic diseases.
Die gesamte Κο βΓ&ηΙίΙϊοη 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 The entire Κο βΓ & ηΙίΙϊοη 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
10 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 Vorwärtskopp lungs - (,feed-forward') Mechanismen ausgeglichen werden. Eine kurzfristige10 of the body, but also external influences such. Climate, stress, nutritional components including medications have a direct influence on these regulatory circuits. This diminished or excessive activities of individual components of these cascades and control systems can be compensated by countermeasure by means of so-called "feed-back" or also feed-forward mechanisms. A short-term
15 Gegensteuerung, z.B. durch eine kompensatorische Freisetzung eines bestimmten körpereigenen Hormons ist somit für die Aufrechterhaltung der Κό ετίυϊΐΜϊοη in Notsituationen (z.B. bei Verletzungen) lebenswichtig. Allerdings kann auch eine permanente kompensatorische Gegenregulation langfristig fatale Folgen für den Gesamtorganismus haben. 15 counter-control, e.g. by a compensatory release of a certain endogenous hormone is thus vital for the maintenance of Κό ετίυϊΐΜϊοη in emergency situations (for example, in injuries). However, a permanent compensatory counterregulation can have fatal consequences for the entire organism in the long term.
Eines dieser essentiellen Regelsysteme ist das sogenannte Renin- Angiotensin-Aldosteron-System One of these essential control systems is the so-called renin-angiotensin-aldosterone system
20 (RAAS). Es ist ein zentrales Kaskadensystem von Hormonen und Enzymen, die den Salz- und20 (RAAS). It is a central cascade system of hormones and enzymes affecting the salt and water
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 11 umwandelt. Angiotensin 11 besitzt potente 25 gefäßverengende und damit blutdrucksteigernde Wirkungen und stimuliert die Bildung des Steroidhormons Aldosteron in der Nebennierenrinde. Aldosteron fördert die Rückaufnahme von Natrium aus dem Urin ins Blut, wodurch das Blutvolumen steigt. Water balance and thus control the blood pressure of the body. Due to lack of salt and fluid or blood pressure drops, the hormone renin is formed and released in special kidney cells. 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 25 vasoconstrictive and thus hypertensive effects and stimulates the formation of the steroid hormone aldosterone in the adrenal cortex. Aldosterone promotes the recovery of sodium from the urine into the blood, increasing blood volume.
Die spezifischen Effekte von Angiotensin 11 werden über entsprechende extrazelluläre Rezeptoren (Angiotensin-Rezeptor, AT-R) vermittelt, die auf Zielzellen des kardiovaskulären Systems exprimiert The specific effects of angiotensin II are mediated via corresponding extracellular receptors (angiotensin receptor, AT-R), which expresses on target cells of the cardiovascular system
30 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 11 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 35 oder ein akutes Nierenversagen induziert werden, eine wesentliche Rolle: So stimuliert z.B. Aldosteron die Einlagerang von Kollagenproteinen im Herzmuskel, was zu einer erhöhten Steifigkeit und damit langfristig zu einer verminderten Funktionalität führen kann. 30 will be. 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 11 and aldosterone have direct pro-inflammatory and fibrotic properties. Both hormones play an important role, in particular during remodeling ('remodeling') in the heart, kidneys and blood vessels, which are induced by a myocardial infarction or acute renal failure, for example Aldosterone the deposit of collagen proteins in the heart muscle, which can lead to increased stiffness and thus in the long term to a reduced functionality.
Ein weiteres wichtiges Regelsystem ist das cyclische Guanosinmonophosphat (cGMP)- Stickstoffmonoxid (NO) System. cGMP/ O wirken gefäßdilatierend und damit blutdrucksenkend. Bestimmte Enzyme, sogenannte Guanylatzyklasen katalysieren die Biosynthese von cGMP aus Guanosintriphosphat (GTP). Die bisher bekannten Vertreter dieser Familie lassen sich sowohl nach strukturellen Merkmalen als auch nach der Art der Liganden in zwei Gruppen aufteilen: Die partikulären, durch sogenannte natriuretische Peptide stimulierbaren Guanylatzyklasen (pGC) und die löslichen, durch NO stimulierbaren Guanylatzyklasen (sGC). Die partikulären, membranständigen Guanylatzyklasen bestehen aus der zytosolischen katalytischen Domäne, einer Transmembranregion und der extrazellulären Liganden-bindenden Domäne. Die Bindung natriuretischer Peptide an die extrazelluläre Liganden-bindenden Domäne führt zur Aktivierung der katalytischen Domäne und die Biosynthese von cGMP aus GTP. Das Enzym Neprilysin inaktiviert natriuretische Peptide durch proteolytische Spaltung und wirkt folglich inhibierend auf die partikuläre Guanylatzyklase. Natriuretische Peptide wie z.B. das , Atrial Natriuretic Peptide' (ANP), das v.a. aus dem Vorhof (Atrium) des Herzens freigesetzt wird, wirken vasodilatorisch und führen in der Niere in sehr kurzer Zeit zu einer erhöhten Natriumausscheidung und wirken renal somit wie Aldosteron/Mineralocorticoid-Rezeptor- Antagonisten. Darüber hinaus vermindern sie die Bildung und/oder Freisetzung von Renin, Aldosteron und Vasopressin. Somit wirken natriuretische Peptide funktionell als Antagonisten des RAAS.  Another important control system is the cyclic guanosine monophosphate (cGMP) nitric oxide (NO) system. cGMP / O have a vasodilating effect and thus an antihypertensive effect. Certain enzymes, so-called guanylate cyclases, catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP). The known members of this family can be divided into structural groups as well as the type of ligands in two groups: the particulate, by so-called natriuretic peptides stimulable guanylate cyclases (pGC) and the soluble, stimulable by NO guanylate cyclases (sGC). The particulate membranous guanylate cyclases consist of the cytosolic catalytic domain, a transmembrane region and the extracellular ligand-binding domain. The binding of natriuretic peptides to the extracellular ligand-binding domain leads to the activation of the catalytic domain and the biosynthesis of cGMP from GTP. The enzyme neprilysin inactivates natriuretic peptides by proteolytic cleavage and consequently has an inhibitory effect on the particulate guanylate cyclase. Natriuretic peptides such as e.g. the 'Atrial Natriuretic Peptide' (ANP), the is released from the atrium of the heart, act vasodilatory and lead in the kidney in a very short time to increased sodium excretion and thus renal aldosterone / mineralocorticoid receptor antagonists. In addition, they reduce the formation and / or release of renin, aldosterone and vasopressin. Thus, natriuretic peptides function functionally as antagonists of RAAS.
Aldosteron und Angiotensin 11 bilden einen klassischen ,feed-forward' Regelkreis: Neben Kalium ist Angiotensin 11 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 11 generiert.  Aldosterone and angiotensin 11 form a classic, feed-forward 'regulatory circuit: in addition to potassium, angiotensin 11 is the main stimulus for the release of aldosterone from the adrenal glands, and conversely, aldosterone in heart tissue and vessels stimulates the production of ACE, the enzyme that precedes the precursor - angiotensin which generates angiotensin 11.
Die pathopysiologischen Wirkungen von Angiotensin I I 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 11 führt. The pathophysiological effects of angiotensin I and aldosterone can be diminished by corresponding 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 results in 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. 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 both single ACE or AT-R blockade, as well as dual ACE AT-R blockade, aldosterone plasma levels in patients with heart failure, 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 Antagonisten (wie z.B. die steroidalen Verbindungen Spironolactone, Canrenone/ Canrenoat und Eplerenone, sowie neuere nicht-steroidale MR Antagonisten wie z.B. MT-3995, CS-3150, LY2623091, PF-03882845 und Finerenone (BAY 94-8862)) 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 Natriums ekretion und - rückresorption in proximalen Tubulusabschnitten abläuft. MR antagonists (such as the steroidal compounds spironolactone, canrenone / canrenoate and eplerenone, as well as newer non-steroidal MR antagonists such as MT-3995, CS-3150, LY2623091, PF-03882845 and finerenone (BAY 94-8862)), aldosterone-mediated sodium retention in the kidneys (natriuretic effect). 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 v. A. 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 in proximal tubule sections occurs.
LCZ696 ist ein AR ! (Angiotensin-Rezeptor-Neprilysin-Inhibitor) und somit ein dualer Wirkstoff, der aus dem AT-R Antagonisten Valsartan und dem Neprilysin-Inhibitor Sacubitril besteht. Durch die Neprilysin Inhibition erreicht man eine verminderte Degradation von natriuretischen Peptiden. Diese wirken v.a. diuretisch und natriuretisch durch ihre gefäßdilatierende Wirkung auf präglomeruläre Gefäße. Darüber hinaus können sie auch die Natriumrückresorption in proximalen Tubulusabschnitten inhibieren.  LCZ696 is an AR! (Angiotensin receptor neprilysin inhibitor) and thus a dual agent consisting of the AT-R antagonist valsartan and the neprilysin inhibitor sacubitril. By the neprilysin inhibition one achieves a diminished degradation of natriuretic peptides. These act v.a. diuretic and natriuretic through its vasodilator effect on pre-glomerular vessels. In addition, they may also inhibit sodium reabsorption in proximal tubule sections.
Die Kombination von AT-R Blockade und Neprilysin Inhibition durch LCZ696 (einer Kombination des AT-R Antagonisten Valsartan und des NEP -Inhibitors Sacubitril) wurde kürzlich in der klinischen Erprobung (Phase III) bei Patienten mit Herzinsuffizienz untersucht und führte zu einer Reduktion des Todes- und Hospitalisierungsrisikos (McMurray et al 2014 NEJM). Außer der gewünschten ANP- und cGMP-Erhöhung wurde unter LCZ696 Gabe sowohl in gesunden Probanden als auch in hypertensiven Patienten ein kompensatorischer Anstieg von Renin und Angiotensin gemessen. Bzgl. weiterer kompensatorischer ,feed-back' oder ,feed-forward' Regulationen müssten allerdings Langzeitdaten abgewartet werden.  The combination of AT-R blockade and neprilysin inhibition by LCZ696 (a combination of the AT-R antagonist valsartan and the NEP inhibitor sacubitril) has recently been evaluated in clinical trials (Phase III) in patients with heart failure and resulted in a reduction in death and hospitalization risks (McMurray et al 2014 NEJM). In addition to the desired increase in ANP and cGMP, compensatory increases in renin and angiotensin were measured with LCZ696 both in healthy volunteers and in hypertensive patients. Concerning. however, additional compensatory, feed-back or feed-forward regulations would require long-term data.
Die Erfindung stellt ein Kombinationspräparat bereit, das Finerenone mit N-(3 -Carboxy- 1 -oxopropyl)-The invention provides a combination preparation containing finerenones with N- (3-carboxy-1-oxopropyl) -
(4S)-(p-phenylphenyl-methyl)-4-amino-2R-methylbutansäure oder einem Ester von der N-(3- Carboxy-1 -oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-2R-methylbutansäure kombiniert. Das Kombinationspräparat zeigt unter akutem und insbesondere unter chronischem Einsatz, positive Effekte bzgl. Natriumausscheidung, Endorganschutz von Herzen und Nieren und Verminderung von Morbidität und Moralität 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). (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or an ester of the N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4- amino-2R-methylbutanoic acid combined. The combination preparation shows acute and especially chronic use, positive effects on sodium excretion, end-organ protection of the heart and kidneys and reduction of morbidity and morality under experimental conditions. These experimental conditions consist on the one hand of healthy animals or animals with hypertension, cardiac and / or renal insufficiency (eg transgenic renin rats).
Die gleichzeitige Blockade der Bindung von Aldosteron an MR und die Blockade von Neprilysm durch das erfindungsgemäße Kombinationspräparat, führt zu überadditiven Effekten bzgl. Natriumausscheidung, Endorgan-Schutz und Verminderung von Morbidität und Mortalität.  Simultaneous blockade of aldosterone binding to MR and blockade of neprilysm by the combination preparation of the invention result in over-additive effects on sodium excretion, end organ protection, and reduction of morbidity and mortality.
Hier beanspruchen wir die Anwendung des nicht-steroidalen MR Antagonisten Finerenone in Kombination mit N-(3 -Carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-2R- methylbutansäure oder einem Ester von der N-(3-Carboxy-l-oxopropyl)-(4S)-(p-phenylphenyl- methyl)-4-amino-2R-methylbutansäure zur Behandlung von Herz-Kreislauf-Erkrankungen wie z.B. Herzinsuffizienz mit erhaltener Ej ektionsfraktion oder Herzinsuffizienz mit reduzierter Ej ektionsfraktion, Behandlung und/oder Prophylaxe von Vorhofflimmern, Schlaganfall oder Atherosklerose, renalen Erkrankungen wie z.B. chronisches Nierenversagen oder diabetische Nephropathie, Lungenerkrankungen, Erkrankungen des Zentra lnervensystems , zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen sowie anderen Krankheitserscheinungen (z.B. Endorganschäden, die Hirn, Niere oder Herz betreffen).  Here we claim the use of the non-steroidal MR antagonist Finerenone in combination with N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid or an ester of of N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid for the treatment of cardiovascular diseases such as Cardiac insufficiency with retained fraction or congestive heart failure with reduced fraction of ejaculation, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, renal diseases, e.g. chronic renal failure or diabetic nephropathy, pulmonary diseases, diseases of the central nervous system, for the treatment and / or prophylaxis of fibrotic diseases and other manifestations of disease (e.g., end-organ damage affecting the brain, kidney or heart).
Ein Gegenstand der vorliegenden Erfindung ist ein Kombinationspräparat umfassend den Mineralocorticoid-Rezeptor selektiven Antagonisten Finerenone und den NEP-Inhibitor N-(3- An object of the present invention is a combination preparation comprising the mineralocorticoid receptor selective antagonist Finerenone and the NEP inhibitor N- (3).
Carboxy-l-oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-2R-methylbutansäure oder einen Ester davon, sowie die Salze, Solvate und Solvate der Salze von Finerenone. Carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or an ester thereof, as well as the salts, solvates and solvates of the salts of Finerenone.
Finerenone ist der non-steroidale Mineralocorticoid-Rezeptor selektive Antagonist (5) -4-(4 -Cy ano-2 - methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridin-3-carboxamid der Formel (I)  Finerenone is the non-steroidal mineralocorticoid receptor selective antagonist (5) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxamide of the formula (I)
Figure imgf000005_0001
Figure imgf000005_0001
Formel (I)  Formula (I)
oder ein Salz, Solvat oder Solvat der Salze davon und ist in DE 10 2007009494 AI und WO 2008 104 306 A2 beschrieben.  or a salt, solvate or solvate of the salts thereof and is described in DE 10 2007009494 Al and WO 2008 104 306 A2.
Der NEP-Inhibitor der vorliegenden Erfindung ist N-(3 -Carboxy- 1 -oxopropyl)-(4S)-(p- phenylphenylmethyl)-4-amino-2R-methylbutansäure oder ein Ester der Säure oder j eweils ein Salz, Solvat oder Solvat der Salze der Säure oder des Esters. Säure und Ester des NEP-Inhibitors der Erfindung sind in EP 0 555 175 AI beschrieben. Eine bevorzugte Form der N-(3 -Carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R- methylbutansäure ist der Ethylester, N-(3-Carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-2R-methylbutan-säureethylester der Formel (II). The NEP inhibitor of the present invention is N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or an ester of the acid, or each salt, solvate or Solvate of salts of acid or ester. Acid and esters of the NEP inhibitor of the invention are described in EP 0 555 175 A1. A preferred form of N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid is the ethyl ester, N- (3-carboxy-1-oxopropyl) - ( 4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid ethyl ester of the formula (II).
Figure imgf000006_0001
Formel (II)
Figure imgf000006_0001
Formula (II)
In Bezug auf N-(3-Carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutan- säureethylester umfassen bevorzugte Salze das Natriumsalz, das Triethanolaminsalz und das Tris(hydroxymethyl)aminomethansalz.  With respect to ethyl N- (3-carboxy-l-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoate, preferred salts include the sodium salt, the triethanolamine salt and the tris (hydroxymethyl) aminomethane salt.
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.
Das molare Verhältnis von Finerenone zu NEP -Inhibitor der Erfindung in dem erfindungsgemäßen Kombinationspräparat ist beispielsweise 0,01-10: 1, vorzugsweise 0,05-5: 1 und am meisten bevorzugt ist ein molares Verhältnis von 0,1-1 : 1.  The molar ratio of finerenone to NEP inhibitor of the invention in the combination preparation according to the invention is for example 0.01-10: 1, preferably 0.05-5: 1 and most preferred is a molar ratio of 0.1-1: 1.
Das erfindungsgemäße Kombinationspräparat ist geeignet für die Prophylaxe und/oder Behandlung von verschiedenen Erkrankungen und krankheitsbedingten Zuständen, insbesondere zur Behandlung und/oder Prophylaxe von Herz-Kreislauf-Erkrankungen wie z.B. Herzinsuffizienz mit erhaltener Ej ektionsfraktion oder Herzinsuffizienz mit reduzierter Ej ektionsfraktion, Behandlung und/oder Prophylaxe von Vorhofflimmern, Schlaganfall oder Atherosklerose, renalen Erkrankungen wie z.B. chronisches Nierenversagen oder diabetische Nephropathie, Lungen erkrankungen, Erkrankungen des Zentralnervensystems, zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen sowie anderen Krankheitserscheinungen (z.B. Endorganschäden, die Hirn. Niere oder Herz betreffen).  The combination preparation according to the invention is 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, for example, Cardiac insufficiency with retained fraction or congestive heart failure with reduced fraction of ejaculation, treatment and / or prophylaxis of atrial fibrillation, stroke or atherosclerosis, renal diseases, e.g. chronic renal failure or diabetic nephropathy, pulmonary diseases, central nervous system disorders, for the treatment and / or prophylaxis of fibrotic disorders, as well as other manifestations of disease (e.g., end-organ damage affecting the brain, kidney, or heart).
Weiterhin ist das erfindungsgemäße Kombinationspräparat 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, glomulerärer Sklerose, Proteinurie als Folge einer primären Nierenkrankheit, renaler vaskulärer Hypertonie, diabetischer und nicht-diabetischer Retinopathie, Migräne, periphärer Gefäß krankheit, Raynaud-Krankheit, luminaler Hyperplasie, kognitiver Dysfunktion, Glaukom und Schlaganfall. Furthermore, the combined preparation according to the invention is 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, glomerular sclerosis, proteinuria secondary to renal disease, renal vascular hypertension, diabetic and non-diabetic retinopathy, migraine, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, cognitive dysfunction, glaucoma and stroke.
Weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung des erfindungsgemäßen Kombinationspräparats 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 combination preparation of 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.
Das erfindungsgemäße Kombinationspräparat kann allein oder bei Bedarf in Kombination mit anderen Wirkstoffen eingesetzt werden. Weiterer Gegenstand der vorliegenden Erfindung sind Arzneimittel, enthaltend das erfindungsgemäß e Kombinationspräparat 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 combination preparation 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 the inventive combination preparation and one or more other 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, ACE-Hemmer, Endothelin-Antagonisten, Renin-Inhibitoren, alpha-Rezeptoren- B locker, beta-Rezeptoren-B locker und Rho-Kinase-Inhibitoren; Hypotensive agents, by way of example and preferably from the group of calcium antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-relaxers, beta-receptor B-relaxers and rho-kinase inhibitors;
• Diuretika, insbesondere Schleifendiuretika sowie Thiazide und Thiazid-ähnliche Diuretika;  • Diuretics, especially loop diuretics and thiazides and thiazide-like diuretics;
• 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 S qualensynthese-Inhibitoren, der ACAT-Inhibitoren, CETP- Inhibitoren, MTP -Inhibitoren, PPAR-alpha-, PPAR-gamma- und/oder PPAR-delta-Agonisten, Cholesterin- Abso tionshemmer, Lipase-Inhibitoren, polymeren Gallensäureadsorber, Gallensäure-• fat 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 S qualensynthese inhibitors, the 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, Iso sorbiddinitrat, Molsidomin oder SIN- 1. sowie inhalatives NO; positiv-inotrop wirksame Verbindungen, wie beispielsweise Herzglycoside (Digoxin), beta- adrenerge und dopaminerge Agonisten wie Isoproterenol, Adrenalin, Noradrenalin, Dopamin und Dobutamin; Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerine, 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 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;
Calcium-Sensitizer, wie beispielhaft und vorzugsweise Levosimendan;  Calcium sensitizers, such as by way of example and preferably levosimendan;
If-Kanal-B locker, wie beispielhaft und vorzugsweise Ivabradin;  If-channel B loosely as exemplified and preferably ivabradine;
Myosin Aktivatoren, wie beispielhaft und vorzugsweise Omecamtiv mecarbil;  Myosin activators, by way of example and preferably Omecamtiv mecarbil;
NO-unabhängige, jedoch Häm-abhängige Stimulatoren der Guanylatcyclase und/oder NO- und Häm-unabhängige Aktivatoren der Guanylatcyclase, wie insbesondere die in WO03/097063, WO03/09545, WO04/009589, WO03/004503, WO02/070462, WO2007/045366, WO2007/045369, WO2007/045370, WO2007/045433, WO2007/045367, WO2007/124854, WO2007/128454, WO2008/031513, WO2008/061657, WO2008/119457, WO2008/119458, WO2009/127338, WO2010/079120, WO2010/102717, WO2011/051165, WO2011/147809, WO2011/141409, WO2014/012935, WO2012/059549, WO2012/004259, WO2012/004258, WO2012/059548, WO2012/028647, WO2012/152630, WO 2012/076466, WO2014/068099, WO2014/068104, WO2012/143510, WO2012/139888, WO2012/152629, WO2013/004785, WO2013/104598, WO2013/104597, WO2013/030288, WO2013/104703, WO2013/131923, WO2013/174736, WO2014/012934, WO2014/068095, WO2014/195333, WO2014/128109, WO2014/131760, WO2014/131741, WO2015/018808, W02015/004105, WO2015/018814, W098/16223, WO98/16507, W098/23619, WO00/06569, WO01/19776, WO01/19780, WOOl/19778, WO02/042299, WO02/092596, WO02/042300, WO02/042301, WO02/036120, WO02/042302, WO02/070459, WO02/070460, WO02/070461, WO02/070510, WO2012/165399, WO2014/084312, WO2011115804, WO2012003405, WO2012064559, WO2014/047111, WO2014/047325, WO2011/149921, WO2010/065275, WO2011/119518, WO 2015/08885, WO2015/08886, WO2014/144100 offenbarten Verbindungen und besonders bevorzugt:  NO-independent, but heme-dependent guanylate cyclase stimulators and / or NO and heme-independent activators of guanylate cyclase, in particular those described in WO03 / 097063, WO03 / 09545, WO04 / 009589, WO03 / 004503, WO02 / 070462, WO2007 / 045366, WO2007 / 045369, WO2007 / 045370, WO2007 / 045433, WO2007 / 045367, WO2007 / 124854, WO2007 / 128454, WO2008 / 031513, WO2008 / 061657, WO2008 / 119457, WO2008 / 119458, WO2009 / 127338, WO2010 / 079120, WO2010 / 102717, WO2011 / 051165, WO2011 / 147809, WO2011 / 141409, WO2014 / 012935, WO2012 / 059549, WO2012 / 004259, WO2012 / 004258, WO2012 / 059548, WO2012 / 028647, WO2012 / 152630, WO 2012/076466, WO2014 / 068099, WO2014 / 068104, WO2012 / 143510, WO2012 / 139888, WO2012 / 152629, WO2013 / 004785, WO2013 / 104598, WO2013 / 104597, WO2013 / 030288, WO2013 / 104703, WO2013 / 131923, WO2013 / 174736, WO2014 / 012934 WO2014 / 068095, WO2014 / 195333, WO2014 / 128109, WO2014 / 131760, WO2014 / 131741, WO2015 / 018808, WO2015 / 004105, WO2015 / 018814, WO98 / 16223, WO98 / 16507, WO98 / 23619, WO00 / 06569, WO01 / 19776, WO 01/19780, WO 01/1997 78, WO02 / 042299, WO02 / 092596, WO02 / 042300, WO02 / 042301, WO02 / 036120, WO02 / 042302, WO02 / 070459, WO02 / 070460, WO02 / 070461, WO02 / 070510, WO2012 / 165399, WO2014 / 084312, WO2011115804, WO2012003405, WO2012064559, WO2014 / 047111, WO2014 / 047325, WO2011 / 149921, WO2010 / 065275, WO2011 / 119518, WO2015 / 08885, WO2015 / 08886, WO2014 / 144100 and particularly preferred:
2-[i-(2-Fluorbenzyl)-lH-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-morpholinyl)-4,6-pyrimidindiamin, offenbart als Beispiel 16 in WO 00/06569,  2- [i- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridino-3-yl] -5- (4-morpholinyl) -4,6-pyrimidinediamine disclosed as Example 16 in WO 00 / 06569,
2-[l-(2-Fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-yl]-5-(4-pyridinyl)-4-pyrimidin amin, offenbart als Beispiel 1 in WO 02/42301, 2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridin-3-yl] -5- (4-pyridinyl) -4-pyrimidine amine, disclosed as Example 1 in WO 02/42301,
Methyl-4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]^  Methyl-4,6-diamino-2- [l- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] ^
(methyl)carbamat, offenbart als Beispiel 8 in WO 03/095451, (methyl) carbamate, disclosed as Example 8 in WO 03/095451,
Methyl-4,6-diamino-2-[i-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrim  Methyl-4,6-diamino-2- [i- (2-fluorobenzyl) -lH-pyrazolo [3,4-b] pyridin-3-yl] -5-pyrim
carbamat, offenbart als Beispiel 5 in WO 03/095451 carbamate, disclosed as Example 5 in WO 03/095451
4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl) carbonsäure, offenbart als Beispiel 8a in WO 01/019780,  4 - ({(4-carboxybutyl) [2- (2 - {[4- (2-phenylethyl) benzyl] oxy} phenyl) ethyl] amino} methyl) carboxylic acid, disclosed as Example 8a in WO 01/019780,
Methyl- {4,6-diamino-2-[5-fluoro-l-(2-fluorbenzyl)-lH-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-5- yl} carbamat, Methyl- {4,6-diamino-2-[5-fluoro-l-(2-fluorbenzyl)-lH-pyrazolo[3,4-b]pyridine-3- yl]pyrimidin-5-yl}methylcarbamat, Methyl- {4,6-diamino-2-[5 -fluoro-1 -(2-fluorbenzyl)-l H- pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}(2,2,2-trifluorethyl)carbarnat, offenbart in WO 2011/147809, 5-Chloro-2-(5-chlorothiophene-2-sulfonylanlino-N-(4-(mo holine-4-sulfonyl)- phenyl)-benzamid als Natriumsalz, offenbart in WOOO/02851,  Methyl {4,6-diamino-2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} carbamate, methyl {4,6-diamino-2- [5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridine-3-yl] pyrimidin-5-yl} methylcarbamate, methyl {4 , 6-diamino-2- [5-fluoro-1 - (2-fluorobenzyl) -1H-pyrazolo [3,4- b] pyridin-3-yl] pyrimidin-5-yl} (2,2,2-) trifluoroethyl) carbarnate, disclosed in WO 2011/147809, 5-chloro-2- (5-chlorothiophene-2-sulfonylanilino-N- (4- (mono-holine-4-sulfonyl) -phenyl) -benzamide as the sodium salt, disclosed in WO00 / 02851,
2-(4-Chloro-phenylsulfonylamino)-4,5-dimetho y-N-(4-(thiomo holin-4-sulfonyl)-phenyl)- benzamid, offenbart in WO00/02851 ,  2- (4-Chlorophenylsulfonylamino) -4,5-dimethoxy-N- (4- (thiomholin-4-sulfonyl) -phenyl) -benzamide disclosed in WO00 / 02851,
l-{6-[5-Chloro-2-({4-trans-4-}trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5- (trifluoromethyl)- 1 H-pyrazol-4-carbonsäure, offenbart in WO 2009/032249, 1- {6- [5-chloro-2 - ({4-trans-4-trifluoromethyl) cyclohexyl] benzyl} oxy) phenyl] pyridin-2-yl} -5- (trifluoromethyl) -1H-pyrazole-4 carboxylic acid disclosed in WO 2009/032249,
l-[6-(2-(2-Methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazol-4-carbonsäure, offenbart in WO 2009/071504, 1- [6- (2- (2-Methyl-4- (4-trifluoromethoxyphenyl) benzyloxy) -phenyl) pyridin-2-yl] -5-trifluoromethyl-pyrazole-4-carboxylic acid disclosed in WO 2009/071504,
l-[6-(3,4-dichlorophenyl)-2-pyridinyl-5-(trifluoromethyl)-lH-pyrazole-4-cabonsäure, offenbart in1- [6- (3,4-Dichlorophenyl) -2-pyridinyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid disclosed in US-A-5,648,347
WO 2009/068652, WO 2009/068652,
1 -( {2 -[3 -Chlor-5 -(trifluoromethyl)phenyl] -5 -methyl- 1 ,3 -thiazol-4-yl } methyl) - 1 H-pyra/ol-4- carbonsäure, 4-({2-[3-(Trifluoromethyl)phenyl]-l,3-thiazol-4-yl}methyl)benzoesäure und l-({2-[2- Fluoro-3-(trifluoromethyl)phenyl]-5-methyl-l,3-thiazol-4-yl}methyl)-lH-pyrazol-4-carbonsäure offenbart in WO 2009/123316,  1 - ({2 - [3-Chloro-5 - (trifluoromethyl) -phenyl] -5-methyl-1, 3-thiazol-4-yl} -methyl) -1 H -pyra-ol-4-carboxylic acid, 4- ( {2- [3- (trifluoromethyl) phenyl] -1,3-thiazol-4-yl} methyl) benzoic acid and 1- ({2- [2-fluoro-3- (trifluoromethyl) phenyl] -5-methyl-1 , 3-thiazol-4-yl} methyl) -1H-pyrazole-4-carboxylic acid disclosed in WO 2009/123316,
4-Amino-2-[5-chloro-3(3,3,3-trifluoro ropyl)-iH-indazoί-lyl]-5,5-dimethyl-5,7-dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-on, 4-Amino-2[5-chloro-3-(2,3,6-trifluorbenzyl)-lH-indazol-lyl]-5,5- dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on, 4-Amino-5,5-dimethyl-2-[3-(2,3,6- trifluorbenzyl)lH-thieno[3,4-c]pyrazol-l-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on, 4- Amino-5,5-dimethyl-2-[3-(2,3,6-trifluorbenzyl)-lH-thieno[2,3-d]pyrazol-l-yl]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on, 4-Amino-5,5-dimethyl-2-[7-(2,3,6- trifluorobenzyl)imidazo[l,5-b]pyridazin-5-yl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on, 4- Amino-2-[6-chloro-3-(2,3,6-trifluorobenzyle)imidazo[i,5-a]pyridin-l-yl]]-5,5-dimethyl-5,7- dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-on , 4-Amino-2-[6-fluoro-3-(2,3,6- trifluorobenzyl)imidazo[l,5-a]pyridin-l-yl]]-5,5-dm 4-Amino-2- [5-chloro-3 (3,3,3-trifluoro-ropyl) -iH-indazolyl] -5,5-dimethyl-5,7-dihydro-6H-pyrrolo [2,3- d] pyrimidin-6-one, 4-amino-2 [5-chloro-3- (2,3,6-trifluorobenzyl) -1H-indazolyl] -5,5-dimethyl-5,7-dihydro-6H -pyrrolo [2,3-d] pyrimidin-6-one, 4-amino-5,5-dimethyl-2- [3- (2,3,6-trifluorobenzyl) -1H-thieno [3,4-c] pyrazole -l-yl] -5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one, 4-amino-5,5-dimethyl-2- [3- (2,3,6-) trifluorobenzyl) -1H-thieno [2,3-d] pyrazol-1-yl] -5,5-dimethyl-5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one, 4- Amino-5,5-dimethyl-2- [7- (2,3,6-trifluorobenzyl) imidazo [l, 5-b] pyridazin-5-yl] -5,7-dihydro-6H-pyrrolo [2,3 -d] pyrimidin-6-one, 4-amino-2- [6-chloro-3- (2,3,6-trifluorobenzyl) imidazo [i, 5-a] pyridin-1-yl]] - 5,5 -dimethyl-5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidin-6-one, 4-amino-2- [6-fluoro-3- (2,3,6-) Trifluorobenzyl) imidazo [l, 5-a] pyridin-l-yl]] - 5,5-dm
d]pyrimidin-6-on , 4-Amino-2-[6-fluoro-3-(2,3,6-trifluorobenzyl)6-fluoroimidazo[l,5-a]pyridin-l- yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrirnidin-6-on , 4-Amino-5,5-dimethyl-2-[3- (2,4,6-trifluorobenzyle)imidazo[l,5-a]pyridin^  d] pyrimidin-6-one, 4-amino-2- [6-fluoro-3- (2,3,6-trifluorobenzyl) -6-fluoroimidazo [l, 5-a] pyridin-1-yl] -5,5 -dimethyl-5,7-dihydro-6H-pyrrolo [2,3-d] pyrirnidin-6-one, 4-amino-5,5-dimethyl-2- [3- (2,4,6-trifluorobenzyl) imidazo [l, 5-a] pyridin ^
4-Amino-2-[3-(2-cyclopentylethyl)imidazo[l,5-a]pyridm^  4-Amino-2- [3- (2-cyclopentylethyl) imidazo [l, 5-a] pyridm ^
pyrrolo[2,3-d]pyrimidin-6-on, offenbart in WO 2010/065275,  pyrrolo [2,3-d] pyrimidin-6-one, disclosed in WO 2010/065275,
3-(4-Amino-5-cyclopropylpyrimidin-2-yl)-i-(2-fluorobenzyl)-l/ -pyrazolo[3,4-£']pyridine bekannt als BAY 41-2272 offenbart als Beispiel 1 in WO 00/06568,  3- (4-Amino-5-cyclopropylpyrimidin-2-yl) -i- (2-fluorobenzyl) -l / -pyrazolo [3,4- ''] pyridines known as BAY 41-2272 disclosed as Example 1 in WO 00 / 06568,
2- {5-Fluor-l-[(3-fluorpyridin-2-yl)memyl]-lH-pyrazolo[3,4-b]pyridin-3-yl}-5-niethyl-5- (trifluormethyl)-4-[(3,3,3-trifluo ropyl)amino]-5,7-dihydro-6H-pyrrolo[2,3  2- {5-Fluoro-l - [(3-fluoropyridin-2-yl) -methyl] -1H-pyrazolo [3,4-b] pyridin-3-yl} -5-niethyl-5- (trifluoromethyl) -4 - [(3,3,3-trifluoroproyl) amino] -5,7-dihydro-6H-pyrrolo [2,3
offenbart als Beispiel 1 in WO 2014/131760  disclosed as Example 1 in WO 2014/131760
3- (4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3- methy lbutanoy 1] amino } pheny 1) -3 - cyclopropylpropansäure offenbart als Beispiel 22 in WO 2012/139888.  3- (4-chloro-3 - {[(2S, 3R) -2- (4-chlorophenyl) -4,4,4-trifluoro-3-methylbutanoyl] amino} phenyl 1) -3-cyclopropylpropanoic acid disclosed as Example 22 in WO 2012/139888.
* Inhibitoren der humanen neutrophilen Elastase (HNE), wie beispielsweise Sivelestat oder DX-890 (Reltran);  Human neutrophil elastase inhibitors (HNE), such as Sivelestat or DX-890 (Reltran);
» die Signaltransduktionskaskade inhibierende Verbindungen, wie beispielsweise Tyrosinkinase- Inhibitoren, insbesondere Sorafenib, Imatinib, Gefitinib und Erlotinib; und/oder  The signal transduction cascade inhibiting compounds, such as tyrosine kinase inhibitors, especially sorafenib, imatinib, gefitinib and erlotinib; and or
• den Energiestoffwechsel des Herzens beeinflussende Verbindungen, wie beispielhaft und vorzugsweise Etomoxir, Dichloracetat, Ranolazine oder Trimetazidine.  • the energy metabolism of the heart affecting compounds, such as by way of example and preferably etomoxir, dichloroacetate, ranolazines or trimetazidines.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat in Kombination mit einem Diuretikum, wie beispielhaft und vorzugsweise Furosemid, Bumetanid, Torsemid, Bendroflumethiazid, Chlorthiazid, Hydrochlorthiazid, Hydroflumethiazid, Methy c lothiazid, 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 preparation 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, methylcidothiazide, 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, 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, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-relaxer, beta-receptor B-lover, Rho-kinase inhibitors and diuretics Understood.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäße Kombinationspräparat 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 preparation 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 Aus führungs form der Erfindung wird das erfindungsgemäße Kombinationspräparat 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 preparation according to the invention is used in combination with an ACE inhibitor, by way of example and by way of example Enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
Bei einer bevorzugten Aus ffihrungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat in Kombination mit einem Endothelin- Antagonisten, wie beispielhaft und vorzugsweise Bosentan, Darusentan, Ambrisentan oder Sitaxsentan, verabreicht.  In a preferred embodiment of the invention, the combination preparation according to the invention is administered in combination with an endothelin antagonist, such as, for example and preferably, bosentan, darusentan, ambrisentan or sitaxsentan.
Bei einer bevorzugten Aus ffihrungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat 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 preparation according to the invention is administered in combination with a renin inhibitor such as, for example and preferably, aliskiren, SPP-600, SPP-635, SPP-676, SPP-800 or SPP-1148.
Bei einer bevorzugten Aus ffihrungs form der Erfindung wird das erfindungsgemäße Kombinationspräparat in Kombination mit einem alpha- 1 -Rezeptoren-Blocker, wie beispielhaft und vorzugsweise Prazosin, verabreicht.  In a preferred embodiment of the invention, the combination preparation 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 Aus ffihrungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat in Kombination mit einem beta-Rezeptoren-Blocker, 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 preparation according to the invention is used in combination with a beta-receptor blocker such as, for 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 Aus ffihrungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat 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 preparation according to the invention is used in combination with a rho-kinase inhibitor such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI -23095 or BA-1049.
Unter antithrombotis ch wirkenden Mitteln (Antithrombotika) werden vorzugsweise Zusammensetzungen aus der Gruppe der Thrombozytenaggregationshemmer, der Antikoagulantien oder der profibrinolytischen Substanzen verstanden.  Antithrombotic agents (antithrombotics) are preferably understood as meaning compositions from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
Bei einer bevorzugten Ausführungsform der Erfindung wird das erfindungsgemäß e Kombinationspräparat in Kombination mit einem Thrombozytenaggregationshemmer, wie beispielhaft und vorzugsweise Aspirin, Clopidogrel, Ticlopidin oder Dipyridamol, verabreicht. In a preferred embodiment of the invention, the combination preparation according to the invention is administered in combination with a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
Bei einer bevorzugten Aus ffihrungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat 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 preparation 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 Aus ffihrungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat in Kombination mit einem GPIIb/IIIa- Antagonisten, wie beispielhaft und vorzugsweise Tirofiban oder Abciximab, verabreicht. Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat 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. In a preferred embodiment of the invention, the combination preparation 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. In a preferred embodiment of the invention, the combination preparation according to the invention is used 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.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat in Kombination mit Heparin oder einem low molecular weight (LMW)- Heparin-Derivat verabreicht.  In a preferred embodiment of the invention, the combination preparation 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 das erfindungsgemäße Kombinationspräparat in Kombination mit einem Vitamin K- Antagonisten, wie beispielhaft und vorzugsweise Coumarin, verabreicht.  In a preferred embodiment of the invention, the combination preparation 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- Abso tionshemmer, 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, the 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 Aus führungs form der Erfindung wird das erfindungsgemäße Kombinationspräparat 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 preparation according to the invention is admixed 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). administered.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat 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 preparation according to the invention is used 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), administered.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat in Kombination mit einem HMG-CoA-Reduktase-Inhibitor aus der Klasse der Statine, wie beispielhaft und vorzugsweise Lovastatin, Simvastatin, Pravas tatin, Fluvastatin, Atorvastatin, Rosuvastatin, Cerivastatin oder Pitavastatin, verabreicht. In a preferred embodiment of the invention, the combination preparation according to the invention is combined with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravasatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin administered.
Bei einer bevorzugten Aus führun gs form der Erfindung wird das erfindungsgemäße Kombinationspräparat 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 preparation 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 Aus führungs form der Erfindung wird das erfindungsgemäße Kombinationspräparat in Kombination mit einem ACAT-Inhibitor, wie beispielhaft und vorzugsweise Avasimibe, Melinamide, Pactimibe, Eflucimibe oder SMP-797, verabreicht. Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäße Kombinationspräparat in Kombination mit einem MTP-Inhibitor, wie beispielhaft und vorzugsweise Implitapide, BMS-201038, R- ! 03757 oder JTT- 130. verabreicht. In a preferred embodiment of the invention, the combination preparation according to the invention is administered in combination with an ACAT inhibitor such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797. In a preferred embodiment of the invention, the combination preparation according to the invention is used in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038, R! 03757 or JTT-130. Administered.
Bei einer bevorzugten Ausführungsform der Erfindung wird das erfindungsgemäße Kombinationspräparat in Kombination mit einem PPAR-gamma-Agonisten, wie beispielhaft und vorzugsweise Pioglitazone oder Rosiglitazone, verabreicht.  In a preferred embodiment of the invention, the combination preparation according to the invention is administered in combination with a PPAR-gamma agonist, such as by way of example and preferably pioglitazone or rosiglitazone.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat 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 preparation according to the invention is administered with a PPAR-delta agonist such as, for example and preferably, GW-501516 or BAY 68-5042.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat mit einem Cholesterin- Abso tionshemmer, wie beispielhaft und vorzugsweise Ezetimibe, Tiqueside oder Pamaqueside, verabreicht. In a preferred embodiment of the invention, the combination preparation according to the invention is administered with a cholesterol absorption inhibitor, such as, for example and preferably, ezetimibe, tiqueside or pamaqueside.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat mit einem Lipase-Inhibitor, wie beispielhaft und vorzugsweise Qrlistat, verabreicht.  In a preferred embodiment of the invention, the combination preparation according to the invention is administered with a lipase inhibitor, such as, by way of example and by way of preference, quistlate.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat 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 preparation according to the invention is administered in combination with a polymeric bile acid adsorbent, such as, for example and preferably, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäß e Kombinationspräparat in Kombination mit einem Gallensäure-Reabso tionshemmer, wie beispielhaft und vorzugsweise AS BT (= IB AT) -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 preparation according to the invention is used in combination with a bile acid reab tion inhibitor, such as by way of example and preferably AS BT (= IB AT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC -635.
Bei einer bevorzugten Aus führungs form der Erfindung wird das erfindungsgemäße Kombinationspräparat in Kombination mit einem Lipoprotein(a)-Antagonisten, wie beispielhaft und vorzugsweise Gemcabene calcium (CT 1027) oder Nicotinsäure, verabreicht.  In a preferred embodiment of the invention, the combination preparation according to the invention is administered in combination with a lipoprotein (a) antagonist, such as, for example and preferably, gemcabene calcium (CT 1027) or nicotinic acid.
Die erfindungsgemäßen Verbindungen 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 compounds 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 Verbindungen in geeigneten Applikationsformen verabreicht werden. For these administration routes, the compounds 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 Verbindungen 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 Verbindung 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 the oral administration are according to the prior art functioning, the compounds of the invention rapidly and / or modified donating application forms, the compounds of the invention in crystalline and / or amorphized 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 compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules ( hard or soft gelatin capsules, for example), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
Als bevorzugte Applikationsformen sind zu nennen Tabletten form (nicht-überzogene oder überzogene Tabletten, beispielsweise mit magensaftresistenten oder sich verzögert auflösenden oder unlöslichen Überzügen, die die Freisetzung der erfindungsgemäß en Verbindung kontrollieren), in der Mundhöhle schnell zerfallende Tabletten oder Filme/Oblaten.  Preferred forms of administration are tablet form (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound according to the invention), tablets rapidly disintegrating 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 Infusions Zubereitungen 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. Inhalations arzneiformen (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, S chüttelmixtur en) , 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 Inhalant medicines (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, shaking 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 Verbindungen können in die angeführten Applikations formen 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 compounds of 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 dem erfindungsgemäßen Kombinationspräparat können die Komponenten zusammen oder nacheinander oder getrennt in einer kombinierten Emheitsdosierungsform oder in zwei getrennten Einheitsdo sierangs formen verabreicht werden. Die Einheitsdosierungsform kann auch eine fixierte Kombination sein. In the combination preparation according to the invention, the components may be used together or sequentially or separately in a combined dosage form or in two separate Unit dosage forms are administered. The unit dosage form may also be a fixed combination.
Eine therapeutisch wirksame Menge jeder Komponente der erfindungsgemäß en Kombination kann simultan oder sequenziell in j eder 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 Einheitsdo sierungs formen verabreicht werden, können Finerenone und NEP-Inhibitor beispielsweise jeweils als Kapsel oder Tablette bereitgestellt werden.  In the event that the components of the combination of the invention are administered in separate unit dosage forms, for example, finerenone and NEP inhibitor may be provided as a capsule or tablet, respectively.
Bei oraler Applikation beträgt die Dosierung von Finerenone etwa 1 bis 100 mg od, vorzugsweise etwa 2,5 bis 50 mg od und ganz besonders bevorzugt 10 bis 20 mg od.  When administered orally, the dosage of finerenone is about 1 to 100 mg od, preferably about 2.5 to 50 mg od and most preferably 10 to 20 mg od.
Besonders bevorzugt sind Dosierungen von Finerenone bei oraler Applikation von 1,25 mg od, 2,5 mg od, 5 mg od, 7,5 mg od, 15 mg od oder 20 mg od.  Especially preferred are dosages of finerenone on oral administration of 1.25 mg od, 2.5 mg od, 5 mg od, 7.5 mg od, 15 mg od or 20 mg od.
Die Dosierung des NEP-Inhibitors beträgt etwa 1 bis 1000 mg bid, vorzugsweise etwa 10 bis 500 mg bid und ganz besonders bevorzugt 24 bis 97 mg bid.  The dosage of the NEP inhibitor is about 1 to 1000 mg bid, preferably about 10 to 500 mg bid and most preferably 24 to 97 mg bid.
Bei einer bevorzugten Ausführungsform der Erfindung beträgt die Dosierung von Finerenone etwa 1 bis 100 mg od und die Dosierung des NEP-Inhibitors etwa 1 bis 1000 mg bid, vorzugsweise beträgt die Dosierung von Finerenone etwa 2,5 bis 50 mg od und die Dosierung des NEP-Inhibitors etwa 10 bis 500 mg bid und ganz besonders bevorzugt beträgt die Dosierung von Finerenone etwa 10-20 mg od und die Dosierung des NEP-Inhibitors etwa 24 bis 97 mg bid.  In a preferred embodiment of the invention, the dosage of Finerenone is about 1 to 100 mg od and the dosage of NEP inhibitor is about 1 to 1000 mg bid, preferably the dosage of Finerenone is about 2.5 to 50 mg od and the dosage of NEP Inhibitors about 10 to 500 mg bid and most preferably the dosage of finerenone is about 10-20 mg od and the dosage of the NEP inhibitor about 24 to 97 mg bid.
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 Finerenonezusammensetzung und eine pharmazeutis che NEP-Inhibitorzusammensetzung. Die Erfindung betrifft außerdem eine bevorzugte Kitform, die zwei Einheiten umfasst: Eine pharmazeutische Zusammensetzung umfassend Finerenone und NEP-Inhibitor und eine pharmazeutische Zusammensetzung umfassend NEP-Inhibitor. The invention also relates to the combination of separate pharmaceutical compositions in kit form. This is a kit comprising two separate entities: a pharmaceutical Finerenone composition and a pharmaceutical NEP inhibitor composition. The invention also relates to a preferred kit form comprising two units: A pharmaceutical composition comprising finerenones and NEP inhibitor and a pharmaceutical composition comprising NEP inhibitor.
Der 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 must 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:  The compounds according to the invention can be converted into pharmaceutical preparations as follows:
Tablette: Tablet:
Finerenone Zusammensetzung 1 :  Finerenone Composition 1:
100 mg Finerenone, 50 mg Lactose (Monohydrat), 50 mg Maisstärke (nativ), 10 mg Polyvinylpyrrolidon (PVP 25) (Fa. BASF, Ludwigshafen, Deutschland) und 2 mg Magnesiumstearat. 100 mg finerenone, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinyl pyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
Tablettengewicht 212 mg. Durchmesser 8 mm, Wölbungsradius 12 mm. Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.
Herstellung: production:
Die Mischung aus erfindungsgemäßer Verbindung, Lactose und Stärke wird mit einer 5% -igen Lösung (m/m) des PVPs in Wasser granuliert. Das Granulat wird nach dem Trocknen mit dem Magnesiumstearat 5 Minuten gemischt. Diese Mischung wird mit einer üblichen Tablettenpresse verpresst (Format der Tablette siehe oben). Als Richtwert für die Verpressung wird eine Presskraft von 15 kN verwendet.  The mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.
Kapseini  Kapseini
1000 Kapseln mit jeweils 50 mg Wirkstoff  1000 capsules each with 50 mg active ingredient
N-(3-Carboxv-l -oxopropvl)-(4S)-(p-phenvlphenvl-methvl)-4-amino-2R-methvlbutan-säureethylester Zusammensetzung:  Ethyl N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenvl-phen-4-methyl-4-amino-2R-methvlbutanoate) Composition:
50 g N-(3-Carboxy-l-oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-2R-methylbutan- säureethylester Natrium Salz, 187 g Lactose, 80 g modifizierte Stärke und 3 g Magnesium-stearat.50 g of ethyl N- (3-carboxy-l-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoate sodium salt, 187 g of lactose, 80 g of modified starch and 3 g of magnesium stearate.
Herstellung: production:
Alle Pulver werden durch ein Sieb mit Sieböffnungen von 0,6 mm gesiebt. Der Wirkstoff wird in einen geeigneten Mischer gegeben und dann erst mit Magnesiumstearat und später mit Lactose und Stärke gemischt bis eine homogene Mischung entsteht. Hartgelatinekapseln werden jeweils mit 300 mg der Mischung gefüllt. Finerenone Zusammensetzung 2: All powders are sieved through a sieve with sieve openings of 0.6 mm. The active ingredient is placed in a suitable mixer and then mixed first with magnesium stearate and later with lactose and starch until a homogeneous mixture is obtained. Hard gelatin capsules are each filled with 300 mg of the mixture. Finerenone Composition 2:
Es wurde eine Granulatlösung Finerenone in kristalliner Form und mikronisierter Form, Hypromellose 5 cP, Natriumlaurilsufat in gereinigtem Wasser hergestellt.  A granulated solution Finerenone in crystalline form and micronized form, Hypromellose 5 cP, Natriumlaurilsufat was prepared in purified water.
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 Rotations tablettenpresse 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 I I b Ph I I b Ph IIb Ph I I b Ph I I b Ph I I b Ph I I b Composition Ph I Ib Ph I Ib Ph IIb Ph I Ib Ph I Ib Ph I Ib Ph I Ib
[mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg] [mg]
Finerenone 1.25 2.50 5.00 7.50 10.00 15.00 20.00Finerenone 1.25 2.50 5.00 7.50 10.00 15.00 20.00
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 P 4.50 4.50 4.50 4.50 4.50 4.50 4.50 Hypromellose 5 P 4.50 4.50 4.50 4.50 4.50 4.50 4.50
Lactose lactose
45.00 45.00 45.00 45.00 45.00 42.50 40.00 monohydrate  45.00 45.00 45.00 45.00 45.00 42.50 40.00 monohydrate
Magnesium stearate 0.90 0.90 0.90 0.90 0.90 0.90 0.90 Magnesium 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 0.0324 Eisenoxid rot 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072 Gewicht (film- 6.000Ü 6.0000 6.0000 6.0000 6.0000 6.0000 6.0000 coatin«) Iron oxide yellow 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 Red iron oxide 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072 Weight (film- 6.000Ü 6.0000 6.0000 6.0000 6.0000 6.0000 6.0000 coatin «)
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) Tablet)
Bewertung der physiologischen Wirksamkeit Evaluation of physiological activity
Die Eignung der erfindungsgemäß en Verbindungen zur Behandlung von kardiovaskulären Erkrankungen kann in folgenden Assaysystemen gezeigt werden:  The suitability of the compounds according to the invention for the treatment of cardiovascular diseases can be demonstrated 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 (250-350 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- 823 3 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 Substanzdosis gruppen 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 j edes 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 (250-350 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 approximately 24 hours in metabolic cages suitable for rats of this weight class (Tecniplast Deutschland GmbH, D-823 3 Hohenpeissenberg) with free access to salt-reduced food 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. For each animal, the urine volume per unit of time is determined separately 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.) Chronisches Myokardinfarktmodell an der Ratte 2.) Chronic myocardial infarction model in the rat
Männliche Wistar Han Ratten (Charles River, 280-300g) werden mit Rompun 2% und Ketavet 1:5 narkotisiert, inhibiert, an eine Beatmungspumpe (ugo basile 7025 rodent, 50 Hübe pro min, 7 ml) angeschlossen und mit Druckluft/Sauerstoffgemisch 1:2 beatmet. Die Körpertemperatur wird durch eine Wärmematte auf 37-38°C gehalten. Als Schmerzmittel werden 0.05 mg/kg lml/kg (1 :10) subkutan Temgesic gegeben. Der Brustkorb wird zwischen der dritten und vierten Rippe seitlich geöffnet und das Herz freigelegt. Die Herzkranzarterie des linken Ventrikels (LAD) wird mit einem Okklusionsfaden (PROLENE 1 metric 5-0 ETHICON1H) kurz unterhalb ihres Ursprungs (unterhalb des linken Atriums) unterstochen und permanent abgebunden. Das Auftreten eines Myokardinfarkts wird durch eine EKG Messung (AD Instruments Power Lab 8/30) überwacht. Die Lunge wird durch kurzes Abklemmen des Ausatemschlauches aufgeblasen. Der Thorax wird wieder geschlossen und die Muskelschichten mit ETHIBOND excel 1 metric 5/0 6951H und die Oberhaut mit ETHIBOND excel 3/0 65 Sil zugenäht. Die OP-Naht wird mit Silberpuder bedeckt (z.B.Fissan) und anschließend die Narkose beendet. Als weitere Kontrolle wird eine„sham" Gruppe, bei der nur der Operationsvorgang, nicht aber die LA D Okklusion durchgeführt wurde, mitgeführt. 24 Stunden nach dem Infarkt wir retroorbital Blut (Li Hep Plasma) für die Troponinbestimmung abgenommen. Male Wistar Han rats (Charles River, 280-300g) are anesthetized with Rompun 2% and Ketavet 1: 5, inhibited, connected to a ventilation pump (ugo basile 7025 rodent, 50 strokes per minute, 7 ml) and compressed air / oxygen mixture 1 : 2 ventilated. The body temperature is maintained at 37-38 ° C by a heat mat. As analgesic 0.05 mg / kg lml / kg (1:10) given subcutaneously temgesic. The thorax is opened laterally between the third and fourth ribs and the heart is exposed. The coronary artery of the left ventricle (LAD) is punctured with a occlusion thread (PROLENE 1 metric 5-0 ETHICON1H) just below its origin (below the left atrium) and permanently ligated. The occurrence of myocardial infarction is monitored by an ECG measurement (AD Instruments Power Lab 8/30). The lungs are inflated by briefly disconnecting the exhalation tube. The thorax is closed again and the muscle layers are sutured with ETHIBOND excel 1 metric 5/0 6951H and the epidermis with ETHIBOND excel 3/0 65 Sil. The surgical suture is covered with silver powder (eg Fissan) and then the anesthesia is terminated. As a further control, a "sham" group, in which only the surgical procedure but not the LA D occlusion was carried out, was taken 24 hours after the infarction, and retroorbital blood (Li Hep plasma) was taken for the troponin determination.
Die Tiere wurden bei der OP randomisiert und in einzelne Behandlungsgruppen, sowie in eine Kontrollgruppe ohne Substanzbehandlung aufgeteilt. Die Substanzbehandlung erfolgt 1 oder 2 Mal täglich über 8 Wochen p.o. 2ml/kg (die erste Behandlung erfolgt 24h nach der OP), oder durch Zusatz der Testsubstanzen im Futter oder Trinkwasser.  The animals were randomized at surgery and divided into individual treatment groups as well as into a control group without substance treatment. The substance treatment takes place once or twice daily for 8 weeks p.o. 2ml / kg (the first treatment is 24h after surgery), or by adding the test substances in the feed or drinking water.
Acht Wochen nach der Okklusion werden die Tiere erneut narkotisiert (2% Isofluran) und ein Druckkatheter (Miliar SPR-320 2F) für 2 Minuten in die A. carotis und dann für 2 Minuten in den linken Ventrikel eingeführt. Dort werden Herzfrequenz, linksventrikulärer Druck (LVP), linksventrikulärer enddiastolischer Druck ( L VII DP), Kontraktilität (dp/dt) und Relaxationsgeschwindigkeit (tau) mit Hilfe des Powerlab Systems (AD Instruments, Power Lab 3/80) und der Chart7 Software erfasst und ausgewertet. Anschließend werden Blutproben für Analysen bestimmter Parameter, wie z.B. BNP, Angiotensin oder Aldosteron entnommen und die Tiere abgetötet. Herz, Lunge und die Niere werden entnommen und gewogen. Die Gewebeproben können für weitere histologische Untersuchungen, sowie für Genexpressionsanalysen herangezogen werden. 3.) DOCA/Salz-Modell  Eight weeks after occlusion, the animals are again anesthetized (2% isoflurane) and a pressure catheter (Miliar SPR-320 2F) for 2 minutes in the carotid artery and then introduced for 2 minutes in the left ventricle. It records heart rate, left ventricular pressure (LVP), left ventricular end-diastolic pressure (L VII DP), contractility (dp / dt), and relaxation rate (tau) using the Powerlab system (AD Instruments, Power Lab 3/80) and the Chart7 software and evaluated. Subsequently, blood samples for analysis of certain parameters, e.g. BNP, angiotensin or aldosterone were removed and the animals were killed. Heart, lungs and kidney are removed and weighed. The tissue samples can be used for further histological examinations as well as for gene expression analyzes. 3.) 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. Da/u 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 anaesthetized 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=10, zugeordnet. Während des gesamten Versuches steht den Tieren Trinkwasser und Futter ad libitum zur Verfügung. Die Substanzen 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 = 10. Throughout the experiment, the animals have access to drinking water and food ad libitum. The substances 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 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 Genexpression von Biomarkern (z.B. ANP, Atrial Natriuretic Peptide, und BNP, Brain Natriuretic Peptide, 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]) are measured and the weights of heart, kidney and lung are determined, protein excretion and gene expression of Biomarkers (eg ANP, Atrial Natriuretic Peptides, and BNP, Brain Natriuretic Peptides, Angiotensin and Aldosterone) by RIA. ELISA or RT / TaqMan PCR after RNA isolation from cardiac and renal tissues.
4.) L-NAME behandelte, transgene Renin-Ratte (TGR(mRen2)27)  4.) 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. verschiedenen er pharmakologischer B ehandlungsgrupp en, 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 S chwanzmans chette (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, the determination of systolic blood pressure by S chwanzmans chette (tail cuff), as well as the determination of proteinuria and urine electrolyte composition by urine collection in metabolic cages, are carried out at regular intervals. 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.

Claims

Patentansprüche claims
1. Kombinationspräparat umfassend:  1. Combination preparation comprising:
Finerenone und N-(3-Carboxy- 1 -oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-2R- methylbutans äure oder die Ester davon, sowie jeweils die Salze, Solvate und Solvate der Salze von Finerenone und N-(3-Carboxy-l -oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-2R- methylbutansäure oder den Ester davon.  Finerenones and N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid or the esters thereof, and in each case the salts, solvates and solvates of the salts of Finerenones and N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R-methylbutanoic acid or the ester thereof.
2. Das Kombinationspräparat gemäß Anspruch 1 zur Behandlung und/oder Prophylaxe von Krankheiten.  2. The combination preparation according to claim 1 for the treatment and / or prophylaxis of diseases.
3. Das Kombinationspräparat gemäß einem der Ansprüche 1 oder 2 zur Verwendung in einem Verfahren zur Behandlung und/oder Prophylaxe von Herz-Kreislauf-Erkrankungen, renalen Erkrankungen, Lungenerkrankungen, sowie zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen.  3. The combination preparation according to any one of claims 1 or 2 for use in a method for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, and for the treatment and / or prophylaxis of fibrotic diseases.
4. Das Kombinationspräparat gemäß einem der Ansprüche 1 bis 3, in dem das molare Verhältnis von Finerenone zu N-(3-Carboxy-l -oxopropyl)-(4S)-(p-phenylphenyl-methyl)-4-amino-2R- methylbutansäure oder den Estern davon 0,1-1 : 1 ist.  4. The combination preparation according to any one of claims 1 to 3, wherein the molar ratio of finerenone to N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenyl-methyl) -4-amino-2R- methylbutanoic acid or the esters thereof is 0.1-1: 1.
5. Verwendung eines Kombinationspräparats gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von Herz-Kreislauf-Erkrankungen, renalen Erkrankungen, Lungenerkrankungen, sowie zur Behandlung und/oder Prophylaxe von fibrotischen Erkrankungen.  5. Use of a combination preparation according to claim 1 for the manufacture of a medicament 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.
6. Arzneimittel enthaltend ein Kombinationspräparat gemäß einem der Ansprüche 1 bis 5 in Kombination mit einem inerten, nicht-toxischen, pharmazeutisch geeigneten Hilfsstoff.  6. A pharmaceutical composition comprising a combination preparation according to any one of claims 1 to 5 in combination with an inert, non-toxic, pharmaceutically suitable excipient.
7. Arzneimittel enthaltend ein Kombinationspräparat gemäß einem der Ansprüche 1 bis 5, in Kombination mit einem oder mehreren weiteren Wirkstoffen ausgewählt aus der Gruppe bestehend aus ACE-Inhibitoren, Beta-Blocker, Acetylsalicylsäure, Diuretika, Ir Kanal- Blocker ( Ivabradin), Calcium- Antagonisten, Statine, Digitalis (Digoxin)-Derivate, Calcium- Sensitizer, Nitrate sowie Antithrombotika.  7. A medicament comprising a combination preparation according to any one of claims 1 to 5, in combination with one or more further active ingredients selected from the group consisting of ACE inhibitors, beta-blockers, acetylsalicylic acid, diuretics, Ir channel blocker (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, Lungen erkrankungen, 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 eines Kombinationspräparats gemäß einem der Ansprüche 1 bis 5, oder eines Arzneimittels gemäß einem der Ansprüche 6 bis 8. Das Kombinationspräparat gemäß einem der Ansprüche 1 bis 4 zur Behandlung und/oder Prophylaxe von Krankheiten, wobei Finerenone einmal täglich verabreicht wird und N-(3- Carboxy-l-oxopropyl)-(4S)-(p-phenylphenylme-thyl)-4-amino-2R-methylbutansäure oder Ester davon zweimal täglich verabreicht wird. 9. A method for the treatment and / or prophylaxis of cardiovascular diseases, renal diseases, lung diseases, and for the treatment and / or prophylaxis of fibrotic diseases in humans and animals using a combination preparation according to any one of claims 1 to 5, or a medicament according to one of claims 6 to 8. The combination preparation according to any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases wherein Finerenone is administered once a day and N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4 amino-2R-methylbutanoic acid or ester thereof is administered twice a day.
Das Kombinationspräparat gemäß einem der Ansprüche 1 bis 4 und 10 zur Behandlung und/oder Prophylaxe von Krankheiten, wobei 10 bis 20 mg Finerenone und 24 bis 97 mg N- (3-Carboxy- 1 -oxopropyl) - (4S ) -(p -phenylpheny lmethy 1) -4 -amino -2R-methy lbutans äure oder die Ester davon verabreicht werden.  The combination preparation according to any one of claims 1 to 4 and 10 for the treatment and / or prophylaxis of diseases, wherein 10 to 20 mg of finerenone and 24 to 97 mg of N- (3-carboxy-1-oxopropyl) - (4S) - (p -) phenylphenylmethy1) -4-amino-2R-methylbutanoic acid or the esters thereof.
Ein Kit umfassend eine pharmazeutische Zusammensetzung umfassend Finerenone und N-(3- Carboxy-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutan-säure oder die Ester davon und eine pharmazeutische Zusammensetzung umfassend N-(3 -Carboxy- 1 - oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutansäure oder die Ester davon.  A kit comprising a pharmaceutical composition comprising finerenones and N- (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or the esters thereof and a pharmaceutical composition comprising N - (3-carboxy-1-oxopropyl) - (4S) - (p-phenylphenylmethyl) -4-amino-2R-methylbutanoic acid or the esters thereof.
PCT/EP2016/069336 2015-08-19 2016-08-15 Combination drug comprising finerenone and an nep-inhibitor (sacubitril) WO2017029261A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15181581 2015-08-19
EP15181581.8 2015-08-19

Publications (1)

Publication Number Publication Date
WO2017029261A1 true WO2017029261A1 (en) 2017-02-23

Family

ID=53879434

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/069336 WO2017029261A1 (en) 2015-08-19 2016-08-15 Combination drug comprising finerenone and an nep-inhibitor (sacubitril)

Country Status (1)

Country Link
WO (1) WO2017029261A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3566704A1 (en) * 2018-05-11 2019-11-13 Bayer Aktiengesellschaft The use of non-steroidal mineralocorticoid receptor antagonists alone or in combination for the treatment of muscular or neuromuscular diseases
CN119185304A (en) * 2024-10-15 2024-12-27 武汉人福创新药物研发中心有限公司 Finerenone pharmaceutical composition and preparation method and use thereof
CN119488498A (en) * 2024-12-18 2025-02-21 平光制药股份有限公司 Finerenone oral sustained-release dry suspension and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217996A (en) * 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
US20040192584A1 (en) * 2003-03-18 2004-09-30 Pharmacia Corporation Combination of an aldosterone receptor antagonist and a neutral endopeptidase inhibitor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217996A (en) * 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
US20040192584A1 (en) * 2003-03-18 2004-09-30 Pharmacia Corporation Combination of an aldosterone receptor antagonist and a neutral endopeptidase inhibitor

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ADIS MEDICAL WRITERS: "Consider mineralocorticoid receptor antagonists as add-on therapy in treatment-resistant hypertension", DRUGS AND THERAPY PERSPECTIVES, ADIS INTERNATIONAL, AUCKLAND, NZ, vol. 31, no. 10, 21 July 2015 (2015-07-21), pages 345 - 349, XP009191544, ISSN: 1172-0360, DOI: 10.1007/S40267-015-0229-6 *
FRANCESCO ORSO ET AL: "Newest additions to heart failure treatment", EXPERT OPINION ON PHARMACOTHERAPY, vol. 15, no. 13, 1 September 2014 (2014-09-01), LONDON, UK, pages 1849 - 1861, XP055306645, ISSN: 1465-6566, DOI: 10.1517/14656566.2014.934812 *
JOHN J.V. MCMURRAY ET AL: "Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure", NEW ENGLAND JOURNAL OF MEDICINE, vol. 371, no. 11, 11 September 2014 (2014-09-11), pages 993 - 1004, XP055175908, ISSN: 0028-4793, DOI: 10.1056/NEJMoa1409077 *
LARS BÄRFACKER ET AL: "Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases", CHEMMEDCHEM, vol. 7, no. 8, 12 August 2012 (2012-08-12), pages 1385 - 1403, XP055213619, ISSN: 1860-7179, DOI: 10.1002/cmdc.201200081 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3566704A1 (en) * 2018-05-11 2019-11-13 Bayer Aktiengesellschaft The use of non-steroidal mineralocorticoid receptor antagonists alone or in combination for the treatment of muscular or neuromuscular diseases
WO2019215317A1 (en) * 2018-05-11 2019-11-14 Bayer Aktiengesellschaft The use of non-steroidal mineralocorticoid receptor antagonists alone or in combination for the treatment of muscular or neuromuscular diseases
US11439628B2 (en) 2018-05-11 2022-09-13 Bayer Aktiengesellschaft Use of non-steroidal mineralocorticoid receptor antagonists alone or in combination for the treatment of muscular or neuromuscular diseases
CN119185304A (en) * 2024-10-15 2024-12-27 武汉人福创新药物研发中心有限公司 Finerenone pharmaceutical composition and preparation method and use thereof
CN119488498A (en) * 2024-12-18 2025-02-21 平光制药股份有限公司 Finerenone oral sustained-release dry suspension and preparation method thereof

Similar Documents

Publication Publication Date Title
EP3525779B1 (en) Combination containing the sgc stimulator vericuguat and the mineralcorticoid receptor antagonist finerenone
US11331308B2 (en) Combination containing sGC activators and mineralocorticoid receptor antagonists
EP3325013B1 (en) Stimulators / activators of soluble guanylat cyclase in combination with a nep-inhibitor and/or an angiotensin aii-antagonist and the use thereof
WO2017029261A1 (en) Combination drug comprising finerenone and an nep-inhibitor (sacubitril)
EP4536205A1 (en) Soluble guanylate cyclase activators for use in the treatment of heart failure with preserved ejection fraction in women
US20110178137A1 (en) Diaryl urea for treating heart failure
WO2017029258A1 (en) Combination drug comprising finernone and valsartan
WO2018153899A1 (en) Selective partial adenosine a1 receptor agonists in combination with soluble guanylyl cyclase (sgc) stimulators and/or activators
DE102017008472A1 (en) Combination containing PDE5 inhibitors and mineralocorticoid receptor antagonists
WO2018153898A1 (en) Selective partial adenosine a1 receptor agonists in combination with mineralocorticoid receptor antagonists
WO2018153900A1 (en) Selective partial adenosine a1 receptor agonists in combination with sglt-2 inhibitors
WO2018153897A1 (en) Selective partial adenosine a1 receptor agonists in combination with hcn channel blockers
WO2018153895A1 (en) Selective partial adenosine a1 receptor agonists in combination with a neutral endopeptidase inhibitor and/or an angiotensin ii receptor antagonist
DE102012200351A1 (en) New substituted annellated pyrimidine compounds are guanylate cyclase stimulators useful to treat and/or prevent heart failure, hypertension, ischemia, vascular disease, renal failure, thromboembolic disorders and fibrotic diseases

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16750870

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16750870

Country of ref document: EP

Kind code of ref document: A1