WO2018153895A1 - Selective partial adenosine a1 receptor agonists in combination with a neutral endopeptidase inhibitor and/or an angiotensin ii receptor antagonist - Google Patents

Abstract

The present invention relates to selective partial adenosine A1 receptor agonists in combination with a neutral endopeptidase inhibitor and/or an angiotensin II receptor antagonist, and the use thereof for the treatment and/or prophylaxis of cardiovascular and renal diseases.

Description

 Selective partial adenosine A1 receptor agonists in combination with an inhibitor of neutral endopeptidase and / or an angiotensin II receptor antagonist

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, 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.

Under normoxic conditions, the concentration of free adenosine in the extracellular space is very low. However, the extracellular concentration of adenosine in the affected organs increases dramatically under both ischemic and hypoxic conditions. It is known, for example, that 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. These effects of adenosine aim to increase the supply of oxygen in the affected organs, to make the energy production more efficient or to reduce the metabolism of these organs in order to achieve an adaptation of the organ metabolism to the organ perfusion under ischemic or hypoxic conditions.

The effect of adenosine is mediated via specific receptors. So far, the subtypes A1, A2a, A2b and A3 are known. According to the invention, "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).

The effects of these adenosine receptors are mediated intracellularly by the messenger cAMP. In the case of A1 receptors, inhibition of adenylate cyclase causes a decrease in intracellular cAMP content. In the cardiovascular system, 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 In the kidney, activation of A1 receptors has an effect on diuresis and protects kidney function in kidney disease and ischaemia.

The cardioprotective effect of 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. However, 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. In adipocytes, 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. For example, the central nervous system (CNS) (see Curr Topics Med. Chem. 2003, 3, 369-385; Exp. Opin. Invest. Drugs 2008, 17, 1901-1910). Therefore, they are mainly used only for experimental purposes. In the treatment of cardiovascular and renal diseases, 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). In order to achieve an optimal action profile, the design of the prodride residue as well as the desired release mechanism must be tailored very precisely to the individual drug, the indication, the site of action and the route of administration. A large number of drugs are administered as prodrugs which have improved bioavailability over the underlying drug, for example, by improving physicochemical profile, especially solubility, active or passive absorption properties, or tissue specific distribution. 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). 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 combination of angiotensin receptor blockade and neprilysine inhibition by LCZ696 has been recently investigated in clinical trials (Phase III) in patients with heart failure and has resulted in a reduction in the risk of death and hospitalization (N. Engl. J. Med. 2014, 371, 993-1004). 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 (J. Clin Pharmacol., 2010, 50, 401-414).

Despite the reduction in mortality and morbidity in heart failure patients, there is still a medical need for further improvement of these endpoints. Since the positive effect of LCZ696 in heart failure is associated with a reduction in blood pressure and the If cardiac insufficiency almost exclusively includes drugs with a hypotensive effect, such as ACE inhibitors / AT1 blockers and beta-blockers, the administration of additional drugs with a hypotensive effect is associated with risks.

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.

To solve this problem, selective partial adenosine A1 receptor agonists have been synthesized which show no effect on blood pressure and heart rate in human-relevant preclinical models, but have a cardioprotective effect. Since the mechanism of protective activity of partial A1 receptor agonists is independent of the mode of action of LCZ696, a combination of both drugs is possible and is expected to result in further reduction of mortality and / or morbidity without additional hemodynamic effects.

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 )

or a salt, solvate or solvate of the salts thereof and is described in US Pat. No. 5,399,578 (see Example 16 there).

Neprilysin inhibitors of the present combinations according to the invention are exemplary and preferably sacubitril, sacubitrilate, omapatrilate or ecadotril, in particular sacubitril.

The NEP inhibitor of the present invention combinations is (2R, 4S) -4- (3-carboxypropanoylamino) -2-methyl-5- (4-phenylphenyl) pentanoic acid of the formula (B)

or an ester of the acid or each a salt, solvate or solvate of the salts of the acid or the ester. Acid and esters of the NEP inhibitor of the present combinations according to the invention are described in EP 0 555 175 A1. The compound of formula (B) is also known as sacubitrilate.

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)

or a salt, solvate or solvate of the salts. 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. In the combinations of the invention, 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 The 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] -hemi- pentahydrate complex is also known as LCZ696 (see WO 2007/056546 and EP-B 1 948 158).

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. In 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)

2 - ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -6- (diethylamino) -4- [4- (2-hydroxy-ethoxy) -phenyl] -pyridine 3,5-dicarbonitrile (known from WO 2010/086101) of the formula (2)

2 - ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -4- [4- (2-hydroxyethoxy) -phenyl] -6- (3-methoxyazetidine-1) yl) pyridine-3,5-dicarbonitrile (known from WO 2010/086101) of the formula (3)

2 - ({[2- (4-Chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -4- [4- (2-hydroxyethoxy) phenyl] (pyrrolidin-1-yl) pyridine-3 , 5-dicarbonitrile (known from WO 2010/086101, also known as neladenosone) of the formula (4)

2 - ({[2- (4-chlorophenyl) -1, 3-thiazol-4-yl] methyl} sulfanyl) -4- [4- (2-hydroxyethoxy) phenyl] -6- (piperidin-1-yl) pyridine-3,5-dicarbonitrile (known from WO 2010/086101) of the formula (5)

2- {4- [2 - ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) - pyridin-4-yl] phenoxy} ethyl L-ornithinate bis (trifluoroacetate) (known from WO 2010/086101) of the formula (6)

• 2- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyanopy

 Phenox ethyl-L-ornithinate dihydrochloride (known from WO 2009/015812) of the formula (7)

2- {4- [2 - ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-N - [(2S) -2,4-diaminobutanoyl] -L-alaninate dihydrochloride (known from WO 2010/086101) of the formula (8)

2- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -yl] phenoxy} ethyl-N - [(2S ) -2,4-diaminobutanoyl] -L-alaninate dihydrochloride (known from WO 2009/01581 1 of the formula (9)

2- {4- [2 - ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) -pyri - din-4-yl] phenoxy} ethyl-L-lysyl-L-alaninate dihydrochloride (known from WO 2010/086101) of the formula 10)

2- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridin-4-yl] -phenoxy} ethyl-L-lysyl-L-alaninate dihydrochloride (known from WO 2009/01581 1) of the formula (11)

2- {4- [2 - ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano-6- (pyrrole

din-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate hydrochloride (known from WO 2010/086101, also known as neladenoson bialanate of the formula (12)

2- {4- [2- ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) pyrr din-4-yl] phenoxy} ethyl L-argyl-L-alaninate dihydrochloride (known from WO 2010/086101) of the formula (13)

2- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) - ^

yl] phenoxy} ethyl-L-argyl-L-alaninate dihydrochloride (known from WO 2009/01581 1) of the formula 14)

2- {4- [2- ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) -pyridine 4-yl] phenoxy} ethyl-L-histidyl-L-alaninate dihydrochloride (known from WO 2010/086101 of the formula (15)

2- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridin-4-yl] -phenoxy} -ethyl L-histidyl-L-alaninate dihydrochloride (known from WO 2009/01581 1) of the formula (16)

Preferred within the scope of the combinations according to the invention are selective partial adenosine A1 receptor agonists of the formulas (4), (12), (1) and (11).

Particularly preferred within the scope of the combinations according to the invention are the selective partial adenosine A1 receptor agonists of the formulas (4) and (12).

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. Thus, 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.

In addition, the combinations according to the invention are expected to result in an unpredictable, valuable pharmacological and pharmacokinetic activity spectrum. 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.

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 ejektionsfraktion 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.

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.

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.

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.

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.

The invention also relates to the combination of separate pharmaceutical compositions in kit form. This is a kit 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.

Another object of the present invention is a kit 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.

The combinations according to the invention can therefore be stable in medicaments for the treatment and / or prophylaxis of 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, acute coronary artery disease autoimmune heart disease (pericarditis, endocarditis, valvolitis, aortitis, cardiomyopathy), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysms, premature ventricular contraction (PVC), for treatment and / or prophylaxis thromboembolic disorders and ischaemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular disease, spasm of the coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or cardiac insufficiency-related edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA) , Heart transplants and bypass operations, as well as micro- and macrovascular damage (vasculitis), increased levels of fibrinogen and low-density LDL and elevated levels of plasminogen activator inhibitor 1 (PAI-1), as well as for the treatment and / or prophylaxis of male erectile Dysfunction and female sexual dysfunction are used. For the purposes of the present invention, the term 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.

In addition, 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

In addition, 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). Furthermore, 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.

Furthermore, the combinations according to the invention are suitable for the treatment and / or prophylaxis of kidney diseases, in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure. For the purposes of the present invention, the term 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, hypertensive nephrosclerosis and nephrotic syndrome, which are diagnosed by, for example, abnormally decreased creatinine and / or water excretion, abnormally elevated blood levels, v on urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes, e.g. Glutamyl synthetase, altered urinary or urine output, increased microalbuminuria, macroalbuminuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia, and / or the need for dialysis. 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.

Furthermore, 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). In addition, the abovementioned combinations according to the invention can be used as bronchodilators. Furthermore, 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. Likewise, the combinations according to the invention can be used to combat pain and tinnitus.

In addition, 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.

Furthermore, the combinations according to the invention can likewise be used for the treatment and / or prophylaxis of autoimmune diseases. Furthermore, the combinations according to the invention for the treatment and / or prophylaxis of fibrotic diseases of the internal organs, such as the lung, heart, kidney, skin, bone marrow and especially the liver, as well as dermatological fibroses and fibrotic diseases of the eye suitable. For the purposes of the present invention, the term 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).

Furthermore, 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. As 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;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP), for example inhibitors of phosphodiesterases (PDE) 1, 2, 5 and / or 9, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil;

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.

• Compounds that improve type 2 diabetes exemplarily and preferably from the group of SGLT2 (sodium dependent glucose transporter) inhibitors.

• compounds that can directly activate myosin.

• compounds that can inhibit the HCN channel.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances. In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, the combinations according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the combinations according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.

Among the 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. In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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 or bucindolol.

In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

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 lipoprotein (a) antagonists understood.

In a preferred embodiment of the invention, 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).

In a preferred embodiment of the invention, 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). In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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-475.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the combinations according to the invention are administered in combination with a lipase inhibitor, such as by way of example and preferably orlistat.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, the combinations according to the invention are used in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably AS BT (= IBAT) inhibitors such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, 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.

In a preferred embodiment of the invention, 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. In a preferred embodiment of the invention, the combinations according to the invention are administered in combination with a myosin activator, such as, for example, Omecamtiv mercabil.

In a preferred embodiment of the invention, the combinations according to the invention are administered in combination with an HCN channel inhibitor, such as, for example, ivabradine. In the combinations according to the invention, 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.

For these administration routes, the combinations according to the invention can be administered in suitable forms of administration.

For oral administration are according to the prior art functioning, 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). For the parenteral administration, suitable application forms are i.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicaments (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or 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.

Preferred is oral or parenteral administration, with oral administration being more preferred. Especially preferred is oral administration by means of tablet form. In the combinations according to the invention, 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) and flavor and / or odoriferous.

In the combinations of the present invention, 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.

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, which in each case contains one or more components of the combinations according to the invention.

In one embodiment of the invention, when dosed orally, the dosage of the selective partial adenosine A1 receptor agonist 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.

In one embodiment of the invention, the dosage of the NEP inhibitor is about 20-100 mg bid, about 20-50 mg bid or 50-100 mg bid.

In one embodiment of the invention, the dosage of LCZ696 is about 40-400 mg, 50-200 mg bid, 50-100 mg bid or 100-200 mg bid.

In one embodiment of the invention, 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. Preferably, 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. Preferably, a q.d. or b.i.d. Administration for heart failure.

In one embodiment of the invention, 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. In a preferred embodiment of the invention, 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 and 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.

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.

Claims

claims

1. Combinations containing a selective partial adenosine A1 receptor agonist, a neprilysin inhibitor and / or an angiotensin all receptor antagonist and in each case the salts, solvates and solvates of the salts thereof.

2. Combinations according to claim 1 comprising a selective partial adenosine A1 receptor agonist, sacubitril or sacubitrilate and / or valsartan and in each case the salts, solvates and solvates of the salts thereof.

3. A combination according to claim 1 containing a selective partial adenosine A1 receptor agonist 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 and in each case the salts, solvates and solvates of the salts thereof.

4. A combination according to any one of claims 1 to 3, wherein the selective partial adenosine A1 prescription agonist is selected from the list Capadenoson (1), 2 - ({[2- (4-chlorophenyl) -1, 3-thiazole-4 -yl] methyl} sulfanyl) -6- (diethylamino) -4- [4- (2-hydroxyethoxy) phenyl] pyridine-3,5-dodecarbonitrile (2), 2 - ({[2- (4-chlorophenyl ) -1, 3-thiazol-4-yl] methyl} sulfanyl) -4- [4- (2-hydroxyethoxy) phenyl] -6- (3-methoxyazetidin-1-yl) pyridine-3,5-dicarbonitrile ( 3), 2 - ({[2- (4-chlorophenyl) -1, 3-thiazol-4-yl] methyl} sulfanyl) -4- [4- (2-hydroxyethoxy) phenyl] -6- (pyrrolidin-1 -yl) pyridine-3,5-dicarbonitrile (4), 2 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -4- [4- (2- hydroxyethoxy) phenyl] -6- (piperidin-1-yl) pyridine-3,5-dicarbonitrile (5), 2- {4- [2- ({[2- (4-chlorophenyl) -1, 3- thiazol-4-yl] methyl} sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl L-ornithine-bis (trifluoroacetate) (6), 2- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} -sulfanyl) -3,5-dicyanopyridin-4-yl] -phenoxy } ethyl-L-orn ithinate dihydrochloride (7), 2- {4- [2- ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyano-6- ( pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl N - [(2S) -2,4-diaminobutanoyl] -L-alaninate dihydrochloride (8), 2- {4- [2-amino -6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridin-4-yl] phenoxy} ethyl-N- [(2S) - 2,4-diaminobutanoyl] -L-alaninate dihydrochloride (9), 2- {4- [2- ({[2- (4-chlorophenyl) -1, 3-thiazol-4-yl] methyl} sulfanyl) - 3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] -phenoxy} -ethyl-L-lysyl-L-alaninate dihydrochloride (10), 2- {4- [2-amino-6- ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyanopyridin-4-yl] -phenoxy} -ethyl-L-lysyl-L-alaninate dihydrochloride (11), 2- {4- [2- ({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano-6- (pyrrolidin-1 -yl) pyridin-4-yl] phenoxy} ethyl-L-alanyl-L-alaninate hydrochloride (12), 2- {4- [2- ({[2- (4-chlorophenyl) -1, 3-thiazole -4-yl] methyl} sulfanyl) -3,5-dicyan-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} ethyl-L-argyl-L-alanine t-Dihydrochloride (13), 2- {4- [2-amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} - sulfanyl) -3,5-dicyanopyridin-4-yl] phenoxy} ethyl-L-argyl-L-alanine ^^ (14), 2- {4- [2-

({[2- (4-Chloro-phenyl) -1,3-thiazol-4-yl] -methyl} -sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) -py-yl] -phenoxy} -ethyl-L- histidyl-L-alaninate dihydrochloride (15), 2- {4- [2-amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4-yl] phenoxy} ethyl-Lh ^

 natdihydrochloride (16).

A combination according to claim 4, wherein the selective partial adenosine A1 receptor agonist is selected from the list 2 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -4 - [4- (2-hydroxyethoxy) phenyl] -6- (pyrrolidin-1-yl) pyridine-3,5-dicarbonitrile (4) and 2- {4- [2- ({[2- (4-chloro) phenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyan-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy} -ethyl-L-alanyl-L- alaninate hydrochloride (12).

6. Combinations according to one of claims 1 to 5 for the manufacture of a medicament for the treatment and / or prophylaxis of cardiovascular and renal diseases.

7. A pharmaceutical composition comprising a combination according to any one of claims 1 to 5 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

8. Medicaments containing a combination according to any one of claims 1 to 5 for the treatment and / or prophylaxis of cardiovascular and renal diseases.

9. A method for the treatment and / or prophylaxis of cardiovascular and renal diseases in humans and animals using combinations according to claims 1 to 5 or a medicament according to claims 7 to 8.

A kit comprising a pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing a neprilysin inhibitor and an angiotensin all receptor antagonist.

A kit according to claim 10 comprising a pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing sacubitril and valsartan.

12. A kit according to claim 10 comprising a pharmaceutical composition comprising a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing 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.