WO2018153895A1 - Agonistes partiels sélectifs du récepteur a1 de l'adénosine en combinaison avec un inhibiteur de l'endopeptidase neutre et/ou un antagoniste du récepteur de l'angiotensine ii - Google Patents

Agonistes partiels sélectifs du récepteur a1 de l'adénosine en combinaison avec un inhibiteur de l'endopeptidase neutre et/ou un antagoniste du récepteur de l'angiotensine ii Download PDF

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WO2018153895A1
WO2018153895A1 PCT/EP2018/054238 EP2018054238W WO2018153895A1 WO 2018153895 A1 WO2018153895 A1 WO 2018153895A1 EP 2018054238 W EP2018054238 W EP 2018054238W WO 2018153895 A1 WO2018153895 A1 WO 2018153895A1
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methyl
sulfanyl
thiazol
chlorophenyl
phenoxy
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PCT/EP2018/054238
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German (de)
English (en)
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Barbara ALBRECHT-KÜPPER
Stephan Vettel
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Bayer Pharma Aktiengesellschaft
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to selective partial adenosine A1 receptor agonists in combination with an inhibitor of neutral endopeptidase and / or angiotensin II receptor antagonists and their use for the treatment and / or prophylaxis of cardiovascular and renal diseases.
  • Adenosine a purine nucleoside
  • Adenosine is present in all cells and is released from a variety of physiological and pathophysiological stimuli.
  • Adenosine is produced intracellularly by the degradation of adenosine 5'-monophosphate (AMP) and S-adenosyl homocysteine as an intermediate, but can be released from the cell and then functions as a hormone-like substance or neurotransmitter through binding to specific receptors.
  • AMP adenosine 5'-monophosphate
  • S-adenosyl homocysteine as an intermediate, but can be released from the cell and then functions as a hormone-like substance or neurotransmitter through binding to specific receptors.
  • adenosine increases the perfusion of the coronary arteries and has a cardioprotective effect. It also affects blood pressure, heart rate, neurotransmitter release and lymphocyte differentiation. In the kidney, it has a renopro- tective effect. In adipocytes, adenosine is able to inhibit lipolysis and thus reduce the concentration of free fatty acids and triglycerides in the blood.
  • adenosine receptor-selective ligands are those substances which selectively bind to one or more subtypes of the adenosine receptors and either mimic the action of adenosine (adenosine agonists) or block its action (adenosine antagonists).
  • adenosine receptors are mediated intracellularly by the messenger cAMP.
  • A1 receptors inhibition of adenylate cyclase causes a decrease in intracellular cAMP content.
  • the main effects of the activation of adenosine A1 receptors are: bradycardia, negative inotropy, protection of the heart from ischemia ("preconditioning") and improvement of energy production and utilization
  • activation of A1 receptors has an effect on diuresis and protects kidney function in kidney disease and ischaemia.
  • A1 receptors in the heart can be exploited, inter alia, by activation of these A1 receptors by specific A1 agonists for treatment and organ protection in acute myocardial infarction, acute coronary syndrome, heart failure, bypass surgery, cardiac catheterization and organ transplantation.
  • full A1 receptor agonists have the disadvantage that it can also lead to the induction of unwanted physiological effects, such as bradycardia to AV block and central CNS effects. This can be circumvented by partial A1 receptor agonists.
  • Partial A1 receptor agonists have a lower efficiency at the A1 receptor than full receptors and result in a selective activation of physiological effects with a high receptor reserve. They cause cardioprotection and economization of energy in damaged cardiomyocytes in humans in the heart without having a significant effect on heart rate or blood pressure.
  • the protective effect of partial A1 receptor agonists in the kidney can be used for the treatment and organ protection of chronic kidney disease.
  • activation of A1 receptors causes inhibition of lipolysis.
  • the effect of partial A1 receptor agonists on lipid metabolism leads to a decrease in free fatty acids.
  • Lowering lipids in turn, can reduce insulin resistance and improve symptoms in patients with metabolic syndrome and diabetics.
  • the aforementioned selectivity on the A1 receptor can be determined by the effect of the substances on cell lines expressing the A1 receptor after stable transfection with the corresponding cDNA (see J. Biol. Chem. 1992, 267, 10764-10770).
  • the effect of the substances on such cell lines can be detected by biochemical measurement of the intracellular messenger cAMP (see Naunyn Schmiedebergs Arch. Pharmacol., 1998, 357, 1-9).
  • the degree of partiality can be evaluated by a GTP shift assay (see J. Med. Chem. 1995, 38, 4000-4006).
  • the "adenosine receptor-specific" ligands known from the prior art are predominantly derivatives based on natural adenosine (see Bioorg.Med.Chem 1998, 6, 619-641) . These known adenosine ligands have however usually the disadvantage that they are only very weak or very short-term effective after oral administration or unwanted side effects on z.
  • the central nervous system CNS
  • A1 R agonists have so far played no role and there are no drugs in the clinic that address this mechanism.
  • Prodrugs are derivatives of an active substance which undergo a single or multistage biotransformation of enzymatic and / or chemical nature in vivo before the actual active substance is released.
  • a prodrug residue is usually used to improve the property profile of the underlying active ingredient (J. Med. Chem. 2004, 47, 2393-2404, H. Bundgaard (Ed.), Design of Prodrugs: Bioreversible Derivatives for various functional groups and chemical entities, Elsevier Science Publishers BV, 1985, Curr Drug Metab., 2003, 4, 461-485; Curr. Eye Res., 2004, 26, 151-163).
  • LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI) and thus a dual agent consisting of the angiotensin II receptor antagonist valsartan and the neprilysine inhibitor sabocitrile (see also below).
  • ARNI angiotensin receptor neprilysin inhibitor
  • neprilysin inhibition 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.
  • the object of the present invention is accordingly to provide combinations of pharmaceutical active substances for the treatment of cardiovascular diseases, in particular also cardiac insufficiency, which reduce mortality and / or morbidity in patients without significantly increasing the mean arterial blood pressure or the heart rate influence.
  • the solution of the above object and the subject of the present invention are the following combinations of selective partial adenosine A1 receptor agonists with neprilysin inhibitors and / or angiotensin II receptor antagonists.
  • the combination of selective partial adenosine A1 receptor agonists with a neprilysin inhibitor and / or an angiotensin II receptor antagonist results in further cardioprotection without additional haemodynamic effects on blood pressure and heart rate.
  • the combination is therefore suitable for the treatment and / or prophylaxis of diseases, preferably of cardiovascular diseases, in particular for the treatment and / or prophylaxis of cardiac insufficiency with preserved ejection fraction or cardiac insufficiency with reduced ejection fraction and renal diseases.
  • Angiotensin II receptor antagonists of the present combinations according to the invention are exemplary and preferably valsartan, losartan, candesartan, telmisartan, irbesartan, olmesartan, olmesartan-medoxomil, eprosartan or azilsartan, in particular valsartan.
  • Valsartan is the angiotensin II receptor antagonist (2S) -3-methyl-2- [pentanoyl - [[4- [2- (2H-tetrazol-5-yl) phenyl] phenyl] methyl] amino] butanoic acid of the formula (A )
  • Neprilysin inhibitors of the present combinations according to the invention are exemplary and preferably sacubitril, sacubitrilate, omapatrilate or ecadotril, in particular sacubitril.
  • NEP inhibitor of the present invention combinations is (2R, 4S) -4- (3-carboxypropanoylamino) -2-methyl-5- (4-phenylphenyl) pentanoic acid of the formula (B)
  • Sacubitril is the NEP inhibitor 4 - [[(1S, 3R) -4-ethoxy-3-methyl-4-oxo-1 - [(4-phenylphenyl) methyl] -butyl] amino] -4-oxo-butanoic acid of the formula (C)
  • Sacubitril is also known from EP-A 0 555 175.
  • Preferred salts of sacubitril are the sodium salt, the triethanolamine salt and the tris (hydroxymethyl) aminomethane salt.
  • valsartan and sacubitril may be used individually or as trisodium [3 - ((1S, 3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) -propionate (S)-3'-methyl -2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate
  • Selective partial adenosine A1 receptor agonists are already known: in WO 01/25210, WO 02/070484, WO 02/070485, WO 2002/070520, WO 03/053441, WO 2008/028590, WO 2008/064789, WO 2009 / 100827, WO 2009/015776, WO 2009/015812, WO 2009/1 12155 and WO 2009/143992 disclose various substituted 3,5-dicyano-6-aminopyridines as adenosine receptor ligands for the treatment of cardiovascular diseases.
  • WO 2006/027142 describes substituted phenylaminothiazoles
  • WO 2008/064788 describes cyclically substituted 3,5-dicyanopyridines
  • WO 2009/080197 discloses substituted azabicyclic adenosine receptor ligands
  • WO 2009/01581 1, WO 2009/015812, WO 2010/072314 and WO 2010/072315 describe amino acid ester prodrugs of 3,5-dicyano-6-aminopyridines.
  • WO2010 / 086101 discloses other adenosine receptor ligands for the treatment of cardiovascular diseases.
  • WO 03/053441 and WO 07/073855 (A1), selective AI receptor agonists of the type 2-thio-3,5-dicyano-4-phenyl-6-aminopyridine in combination with aminoglycosides are used to protect renal cells from antibiotic-induced Renal cell damage described.
  • WO2009 / 01581 1 discloses prodrug derivatives of 2-amino-6 - ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ thio) -4- [4- (2-hydroxyethoxy ) Phenyl] pyridine-3,5-dicarbonitrile and, inter alia, its use in acute renal failure and nephropathy.
  • WO 10/086101 discloses various alkylamino-substituted dicyanopyridines and their amino acid ester prodrugs and in addition to the primary use in cardiovascular diseases, among other things, their use in kidney diseases described.
  • Preferred selective partial adenosine A1 receptor agonists in the context of the present combinations according to the invention are: 2-amino-6 - ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ sulfanyl) -4 [4- (2-hydroxyethoxy) phenyl] pyridine-3,5-dicarbonitrile (known from WO 03/053441, also known as capadenosone) of the formula (1)
  • the combinations according to the invention allow an effective treatment of cardiovascular diseases, in particular also cardiac insufficiency, whereby the mortality and / or morbidity in patients is further reduced without significantly influencing the mean arterial blood pressure or heart rate.
  • cardiovascular diseases in particular also cardiac insufficiency
  • the above-described disadvantages of the forms of therapy known in the prior art such as the still high demand for a further reduction in morbidity and / or mortality without additional hemodynamic effect, could be further addressed.
  • Another object of the present invention is the use of selective partial adenosine A1 receptor agonists in combination with neprilysin inhibitors and / or angiotensin II receptor antagonists for the treatment of cardiovascular diseases, e.g. Cardiac insufficiency with preserved ejection fraction or cardiac insufficiency with reduced ejection fraction and renal diseases as well as other disease manifestations (e.g., end-organ damage affecting the heart and kidney.
  • cardiovascular diseases e.g. Cardiac insufficiency with preserved ejection fraction or cardiac insufficiency with reduced ejection fraction and renal diseases as well as other disease manifestations (e.g., end-organ damage affecting the heart and kidney.
  • Another object of the present invention are selective partial adenosine A1 receptor agonists in combination with angiotensin II receptor antagonists and their use for the treatment of cardiovascular diseases such as heart failure with preserved ejekomsfr sept or heart failure with reduced ejection fraction and renal diseases and others Disease symptoms (eg end organ damage affecting the heart and kidney.
  • Preferred subject matter of the invention are selective partial adenosine A1 receptor agonists in combination with a neprilysin inhibitor, such as, for example and preferably, sacubitril and / or an angiotensin II receptor antagonist, such as, for example and preferably, valsartan, losartan, candesartan, telmisartan, irbesartan, Olmesartan, olmesartan-medoxomil, eprosartan or azilsartan.
  • a neprilysin inhibitor such as, for example and preferably, sacubitril and / or an angiotensin II receptor antagonist, such as, for example and preferably, valsartan, losartan, candesartan, telmisartan, irbesartan, Olmesartan, olmesartan-medoxomil, eprosartan or azilsartan.
  • Preferred subject matter of the present invention are combinations comprising a selective partial adenosine A1 receptor agonist, sacubitrilate or an ester thereof and / or valsartan and in each case the salts, solvates and solvates of the salts of a selective partial adenosine A1 receptor agonist sacubitrilate or an ester thereof and / or valsartan.
  • Another preferred subject matter of the present invention are combinations comprising a selective partial adenosine A1 receptor agonist and LCZ696 and in each case the salts, solvates and solvates of the salts thereof.
  • a particularly preferred subject matter of the present invention are combinations comprising a selective partial adenosine A1 receptor agonist, sacubitril and / or an angiotensin II receptor antagonist and in each case the salts, solvates and solvates of the salts thereof.
  • Particularly preferred subject of the present invention are combinations containing the compound of formula (4), sacubitrilate or an ester thereof and / or valsartan, and in each case the salts, solvates and solvates of the salts of the compound of formula (6) and sacubitrilate or a Esters thereof and / or valsartan.
  • Another particularly preferred subject of the present invention are combinations comprising the compound of the formula (4) and LCZ696 and in each case the salts, solvates and solvates of the salts thereof.
  • Particularly preferred subject of the present invention are combinations containing the compound of formula (12), sacubitrilate or an ester thereof and / or Vals artan, and in each case the salts, solvates and solvates of the salts of the compound of formula (6) and sacubitrilate or an ester thereof and / or valsartan.
  • Another particularly preferred subject of the present invention are combinations comprising the compound of the formula (12) and LCZ696 and in each case the salts, solvates and solvates of the salts thereof.
  • a further subject of the present invention are combinations comprising a selective partial adenosine A1 receptor agonist and valsartan, and in each case the salts, sol and solvates of the salts of a selective partial adenosine A1 receptor agonist and Va- isartan.
  • Another object of the present invention are combinations comprising the compound of formula (4) and valsartan, and in each case the salts, solvates and solvates of the salts of the compound of formula (4) and valsartan.
  • Another object of the present invention are combinations containing the compound of formula (12) and valsartan, and in each case the salts, solvates and solvates of the salts of the compound of formula (12) and valsartan.
  • 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.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein the compound of formula (4) once daily and valsartan and sacubitril or sacubitrilate or an ester thereof are administered twice daily.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (4), 20-200 mg valsartan and 20-200 mg sacubitrilate or an ester thereof are administered.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (4) and 20-200 mg sacubitrilate or an ester thereof are administered.
  • a further subject of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of the formula (4) and 20-200 mg of sacubitrile are administered.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (4) and 20-200 mg valsartan are administered
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein the compound of formula (4) is administered once daily and trisodium [3 - ((1S, 3R) -1-biphenyl-4- ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate (S) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] Hemipentahydrate is administered twice a day.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (4) and 40-400 mg trisodium [3 - ((1 S, 3R) -1- biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate (S) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'- ylmethyl ⁇ amino) butyrate] - hemipentahydrate.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein the compound of formula (12) are administered once daily and valsartan and sacubitril or sacubitrilate or an ester thereof twice daily.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (12), 20-200 mg valsartan and 20-200 mg sacubitrilate or an ester thereof are administered.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (12) and 20-200 mg sacubitrilate or an ester thereof are administered.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (12) and 20-200 mg Sacubitril be administered.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (12) and 20-200 mg valsartan are administered
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein the compound of formula (12) is administered once a day and trisodium [3 - ((1S, 3R) -1-biphenyl-4- ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate (S) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] Hemipentahydrate is administered twice a day.
  • Another object of the present invention are combinations according to the invention for the treatment and / or prophylaxis of diseases, wherein 5-40 mg of the compound of formula (12) and 40-400 mg trisodium [3 - ((1 S, 3R) -1-biphenyl 4-ylmethyl-3-ethoxycarbonyl-1-butyl-carbamoyl) -propionate- (S) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) -biphenyl-4'-ylmethyl ⁇ amino) - butyrate] hemipentahydrate.
  • Another object of the present invention are the combinations according to the invention for the treatment and / or prophylaxis of diseases.
  • the compounds according to the invention are suitable alone or in combination with one or more other active substances for the prevention and / or treatment of various diseases, for example diseases of the cardiovascular system (cardiovascular diseases), for cardioprotection after damage to the heart as well as metabolic and renal diseases.
  • diseases of the cardiovascular system cardiovascular diseases
  • cardioprotection after damage to the heart as well as metabolic and renal diseases.
  • Another object of the present invention is a medicament containing at least one combination according to the invention in combination with an inert, non-toxic, pharmaceutically suitable excipient.
  • Another object of the present invention is a medicament containing at least one combination according to the invention in combination with one or more further active ingredients selected from the group consisting of renin inhibitors, beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis (digoxin) Derivatives, calcium sensitizers, nitrates and antithrombotics.
  • one or more further active ingredients selected from the group consisting of renin inhibitors, beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis (digoxin) Derivatives, calcium sensitizers, nitrates and antithrombotics.
  • Another object of the present invention is a medicament containing at least one combination of the invention for the treatment of various diseases, such as diseases of the cardiovascular system (cardiovascular diseases), for cardioprotection after damage to the heart as well as metabolic and renal diseases.
  • diseases of the cardiovascular system cardiovascular diseases
  • cardioprotection after damage to the heart as well as metabolic and renal diseases.
  • Another object of the present invention is methods for the treatment and / or prophylaxis of various diseases, such as diseases of the cardiovascular system (cardiovascular diseases), for cardioprotection after damage to the heart as well as metabolic and renal diseases in humans and animals using at least one inventive Combination.
  • diseases of the cardiovascular system cardiovascular diseases
  • cardioprotection after damage to the heart as well as metabolic and renal diseases in humans and animals using at least one inventive Combination.
  • kits comprising two or three separate units: A pharmaceutical composition of a selective partial adenosine A1 receptor agonist, a pharmaceutical N EP inhibitor composition and / or a pharmaceutical Valsartan composition.
  • the invention also relates to a preferred kit form comprising two units: A pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing a NEP inhibitor and / or valsartan.
  • the invention also relates to a preferred kit form comprising two units: A pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing LCZ696.
  • the invention also relates to a preferred kit form comprising two units: A pharmaceutical composition comprising the compound of formula (4) and a pharmaceutical composition comprising LCZ696.
  • the invention also relates to a preferred kit form comprising two units: A pharmaceutical composition comprising the compound of formula (12) and a pharmaceutical composition comprising LCZ696.
  • the kit form is particularly advantageous when the separate components must be administered in different dosage forms or administered at different dose intervals.
  • a further subject of the present invention is a kit comprising a pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing an angiotensin II receptor antagonist and sacubitrilate or the esters thereof.
  • a further subject of the present invention is a kit comprising a pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing valsartan and sacubitrilate or the esters thereof.
  • a further subject of the present invention is a kit comprising a pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing tetrasodium [3 - ((1S, 3R) -1-biphenyl-4-ylmethyl-3-ethoxycar -bonyl-1-butylcarbamoyl) propionate (S) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ amino) butyrate] hemipentahydrate.
  • a further subject of the present invention is a kit comprising a pharmaceutical composition containing the compound of the formula (4) and a pharmaceutical composition containing valsartan and sacubitrilate or the esters thereof.
  • kits comprising a pharmaceutical see composition containing the compound of formula (4) and a pharmaceutical composition containing trisodium [3 - ((1 S, 3R) -1-biphenyl-4-ylmethyl-3 -ethoxycarbonyl-1-butylcarbamoyl) propionate (S) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ -amino) butyrate] -hemipentahydrate ,
  • Another object of the present invention is a kit comprising a pharmaceutical see composition containing the compound of formula (12) and a pharmaceutical composition containing valsartan and sacubitrilate or the esters thereof.
  • a further subject of the present invention is a kit comprising a pharmaceutical composition comprising the compound of formula (12) and a pharmaceutical composition containing trisodium [3 - ((1S, 3R) -1-biphenyl-4-ylmethyl-3-ethoxycar -bonyl-1-butylcarbamoyl) propionate- (S) -3'-methyl-2 '- (pentanoyl ⁇ 2 "- (tetrazol-5-ylate) biphenyl-4'-ylmethyl ⁇ -amino) butyrate] -hemipentahydrate.
  • cardiovascular diseases such as hypertension, resistant hypertension, acute and chronic heart failure, heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) coronary heart disease and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial and ventricular arrhythmias and conduction disorders such as atrio-ventricular blockade grade l-lll (AB block l-lll), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular fibrillation ternary ventricular tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, atrioventricular extrasystoles, sick sinus syndrome, syncope, AV node reentrant tachycardia, Wolff-Parkinson-White syndrome,
  • cardiac failure includes both acute and chronic manifestations of cardiac insufficiency, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects.
  • Cardiac insufficiency in cardiac valve defects mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac disease, dystolic heart failure and systolic heart failure and acute phase n worsening of existing chronic heart failure.
  • the combinations according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier disease, obesity (obesity) and obesity combined hyperlipidaemias and the metabolic syndrome, as well as type 1 diabetes
  • the combinations according to the invention can be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, cladidatio, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangren, CREST syndrome, erythematosis , Onychomycosis, rheumatic diseases and to promote wound healing.
  • the combinations according to the invention are also suitable for the treatment of muscular dystrophy, such as Becker-Kiener muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD).
  • the combinations according to the invention are suitable for the treatment and / or prophylaxis of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS) Feiines urological syndrome (FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (Ul) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI , OUI), pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorder
  • LUTS lower urinary tract syndromes
  • Feiines urological syndrome Feiines urological syndrome
  • diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC
  • kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
  • renal insufficiency encompasses both acute and chronic manifestations of renal insufficiency, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hyper
  • the present invention also encompasses the use of the combinations of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte imbalances (e.g., hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.
  • the combinations according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, lung diseases such as pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis , COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (A- LI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced pulmonary emphysema) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory tract syndrome
  • A- LI acute lung injury
  • AATD alpha-1-antitrypsin defic
  • the abovementioned combinations according to the invention can be used as bronchodilators.
  • the combinations according to the invention are also suitable for the regulation of cerebral blood flow and are, for example, effective agents for controlling vascular cerebral dementia and migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma. Furthermore, they are also suitable for the treatment of various forms of epilepsy.
  • the combinations according to the invention can be used to combat pain and tinnitus.
  • the combinations according to the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic inflammatory bowel disease (IBD, Crohn 's Disease). UC), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases as well as inflammatory eye diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • inflammatory diseases of the kidney chronic inflammatory bowel disease
  • IBD chronic inflammatory bowel disease
  • Crohn 's Disease Crohn 's Disease
  • UC chronic inflammatory bowel disease
  • pancreatitis peritonitis
  • rheumatoid diseases inflammatory skin diseases as well as inflammatory eye diseases.
  • the combinations according to the invention can likewise be used for the treatment and / or prophylaxis of autoimmune diseases.
  • fibrotic disorders includes in particular the following terms: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic disorders, systemic sclerosis, scleroderma, digital ulcerations, morphea, keloids, hypertrophic scarring (also after surgery), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
  • the combinations according to the invention are suitable for combating postoperative scar formation, for example as a consequence of glaucoma operations.
  • the combinations according to the invention can be used alone or as needed in combination with other active ingredients.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the combinations according to the invention and one or more further active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • the blood pressure lowering agents by way of example and preferably from the group of angiotensin II receptor antagonists, calcium antagonists, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blocker, mineralocorticoid receptor antagonists and the diuretics;
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Lipid metabolism-modifying agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as, for example, and HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.
  • cholesterol synthesis inhibitors such as, for example, and HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as, for example, and HMG-CoA reductase or squalene synthesis inhibitors
  • CETP inhibitors such as, for example, and HMG-CoA reductase or squalene synthesis inhibitors
  • CETP inhibitors such as, for example, and H
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the combinations according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the combinations according to the invention are administered in combination with a thrombin inhibitor, such as by way of example and preferably ximaglagatran, dabigatran, melagatran, bivalirudin or clexane.
  • a thrombin inhibitor such as by way of example and preferably ximaglagatran, dabigatran, melagatran, bivalirudin or clexane.
  • the combinations according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • the combinations according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-31 12, YM- 150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the combinations according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the combinations according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin II receptor antagonists, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics Understood.
  • the combinations according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the combinations according to the invention are administered in combination with an alpha-1 receptor blocker, such as by way of example and preferably prazosin.
  • the combinations according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol
  • the combinations according to the invention are administered in combination with an endothelin antagonist, such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the combinations according to the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the combinations according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the combinations of the invention are used in combination with a loop diuretic such as furosemide, torasemide, bumetanide and piretanide with potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.
  • a loop diuretic such as furosemide, torasemide, bumetanide and piretanide
  • potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics
  • Hydrochlorothiazide chlorthalidone
  • xipamide xipamide
  • indapamide indapamide
  • 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 lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha PPAR alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid
  • the combinations according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the combinations according to the invention are administered in combination with a thyroid receptor agonist, such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the combinations according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the combinations according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK
  • the combinations according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimbe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimbe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the combinations according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • the combinations according to the invention are administered in combination with a PPAR-gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the combinations according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the combinations according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the combinations according to the invention are administered in combination with a lipase inhibitor, such as by way of example and preferably orlistat.
  • the combinations according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • the combinations according to the invention are administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • the combinations according to the invention are administered in combination with a SGLT2 inhibitor (sodium dependent glucose transporter), such as, for example, dapagliflozin, empagliflozin, canagliflozin, ipragliflozin and toofogliflozin.
  • a SGLT2 inhibitor sodium dependent glucose transporter
  • the combinations according to the invention are administered in combination with a myosin activator, such as, for example, Omecamtiv mercabil.
  • the combinations according to the invention are administered in combination with an HCN channel inhibitor, such as, for example, ivabradine.
  • an HCN channel inhibitor such as, for example, ivabradine.
  • the components 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.
  • the combinations according to the invention can be administered in suitable forms of administration.
  • the inventive combinations rapidly and / or modified donating application forms containing the compounds which are part of the combination in crystalline and / or amorphous and / or dissolved form, such as eg tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compounds of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (For example, hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Preferred forms of application include tablet form (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which inhibits the release of the combinations according to the invention. control the underlying compounds), rapidly disintegrating tablets or films / wafers in the oral cavity and particularly preferred forms of administration are tablet form (uncoated or coated tablets, for example with enteric or delayed dissolving or insoluble coatings, which are the basis of the release of the combinations according to the invention Control components), rapidly disintegrating tablets or films / wafers in the oral cavity.
  • 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.
  • suitable application forms are i.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • 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 components can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecylsulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecylsulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascor
  • the components can be administered together or separately or separately in a combined unit dosage form, in two separate unit dosage forms, or in three separate unit dosage forms.
  • 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 tablet having delayed-dissolving coatings which in each case contains one or more components of the combinations according to the invention.
  • the dosage of the selective partial adenosine A1 receptor agonist when dosed orally, is about 5-40 mg. In one embodiment of the invention, the dosage of valsartan is about 20-1 10 mg bid, 20-50 mg bid, or 50-1 10 mg bid.
  • the dosage of the NEP inhibitor is about 20-100 mg bid, about 20-50 mg bid or 50-100 mg bid.
  • the dosage of LCZ696 is about 40-400 mg, 50-200 mg bid, 50-100 mg bid or 100-200 mg bid.
  • valsartan is provided in the form of a suitable unit dosage form, for example a capsule or tablet, and comprises a therapeutically effective amount, for example, of from 20 to 320 mg of valsartan, which can be administered to patients.
  • Administration of the active substance may take place three times a day starting, for example, from a daily dose of 20 mg or 40 mg of valsartan, which rises above 80 mg daily and further to 160 mg daily to 320 mg daily.
  • valsartan is administered once a day or twice a day in patients with heart failure at a dose of 80 mg or 160 mg each. Corresponding doses can be taken for example in the morning, at noon or in the evening.
  • the NEP inhibitor is administered in unit forms, for example, tablets or capsules comprising, for example, 20 mg to 800 mg, preferably 50 mg to 700 mg, more preferably 100 mg to 600 mg, and even more preferably 100 mg to 300 mg, once be administered during the day.
  • the dosages described above may be formulated within the scope of the invention as a fixed-dose combination, wherein the preferred unitary forms may be tablets or capsules.
  • the dosage of the selective partial adenosine A1 receptor agonist is about 5-40 mg od
  • the dosage of valsartan about 25 mg bid and the dosage of NEP inhibitor is about 25 mg bid
  • also preferred is the dosage of the selective partial adenosine A1 receptor agonist is about 5-40 mg od
  • the dosage of valsartan about 50 mg bid and the dosage of the NEP inhibitor is about 50 mg bid
  • also preferred is the dosage of the selective partial adenosine A1 receptor agonist about 5-40 mg od
  • the dosage of valsartan about 100 mg bid and the dosage of the NEP inhibitor is about 100 mg bid.

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Abstract

La présente invention concerne des agonistes partiels sélectifs du récepteur A1 de l'adénosine en combinaison avec un inhibiteur de l'endopeptidase neutre et/ou un antagoniste du récepteur de l'angiotensine II, et leur utilisation pour le traitement et la prévention des maladies cardiovasculaires et rénales.
PCT/EP2018/054238 2017-02-22 2018-02-21 Agonistes partiels sélectifs du récepteur a1 de l'adénosine en combinaison avec un inhibiteur de l'endopeptidase neutre et/ou un antagoniste du récepteur de l'angiotensine ii WO2018153895A1 (fr)

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