WO2018153900A1

WO2018153900A1 - Selective partial adenosine a1 receptor agonists in combination with sglt-2 inhibitors

Info

Publication number: WO2018153900A1
Application number: PCT/EP2018/054246
Authority: WO
Inventors: Barbara ALBRECHT-KÜPPER; Stephan Vettel
Original assignee: Bayer Aktiengesellschaft
Priority date: 2017-02-22
Filing date: 2018-02-21
Publication date: 2018-08-30

Abstract

The present invention relates to selective partial adenosine A1 receptor agonists in combination with SGLT-2 (sodium dependent glucose transporter) inhibitors, 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 SGLT-2 inhibitors

The present invention relates to selective partial adenosine A1 receptor agonists in combination with SGLT-2 (sodium dependent glucose transporter) inhibitors 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 in 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 by 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 bind selectively 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 are the activation of adenosine A1 receptors: bradycardia, negative inotropy, protection of the heart from ischemia ("preconditioning") and improvement of energy production and utilization Receptors affect diuresis and protect 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 However, they usually have the disadvantage that after oral administration they are only very weak or very short-acting or have undesirable side effects on, 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 drug (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 effect profile, the design of the prodrug residue as well as the desired release mechanism must be very precisely matched to the individual active ingredient, 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.

SGLT-2 (sodium dependent glucose transporter) inhibitors are used to treat type 2 diabetes mellitus. SGLT-2 (sodium-glucose linked transporter 2) is a secondary active carrier protein that resorbs glucose and sodium in the kidney in the proximal tubule from the primary urine. If this protein is not functional due to a hereditary disorder, high levels of sugar are found in the urine in affected individuals, without this being caused by high blood sugar levels.

SGLT-2 inhibitors mimic this effect and inhibit the renal sodium-dependent glucose transporter type 2 (SGLT-2) in the renal tubules. This promotes the concentration-dependent urinary excretion of glucose. This leads to both a lowering of the blood sugar concentration and to a calorie loss, without, however, causing a hypoglycemia. This mechanism of lowering blood sugar is independent of insulin action and secretion as well as of insulin resistance or lack of insulin production by the beta cells of the pancreas. In clinical studies, SGLT-2 inhibitors have been shown to significantly reduce cardiovascular mortality in patients with heart failure (see New Engl. J. Med. 2015, 373, 21 17-28). The mechanism behind the cardiovascular benefits of SGLT-2 inhibitors is multifunctional and involves changes in arterial stiffness, cardiac function, cardiac oxygen demand, and cardiac-renal effects, such as reduction albuminuria, lowering uric acid and effects on hyperglycemia, body weight and blood pressure.

The object of the present invention is therefore to provide combinations of pharmaceutical agents for the treatment of cardiovascular diseases, in particular also cardiac insufficiency, which reduce the mortality and / or morbidity in patients and show an additional benefit to the pure lowering of the heart rate, without the Mean arterial blood pressure or heart rate significantly further 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 SGLT-2 inhibitors, a combination of both drugs is possible and is expected to further reduce 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 a SGLT-2 inhibitor.

The combination of selective partial adenosine A1 receptor agonists with a SGLT-2 inhibitor 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.

Suitable SGLT-2 inhibitors include dapagliflozin, empagliflozin, canagliflozin, ipragliflozin and toulafloxin. Dapagliflozin is the compound (1S) -1,5-anhydro-1- [4-chloro-3- (4-ethoxybenzyl) phenyl] -D-glucitol of the formula (A)

(A) Empagliflozin is the compound (1S) -1,5-anhydro-1- (4-chloro-3- {4 - [(3S) -tetrahydrofuran-3-yloxy] -benzyl} phenyl) -D-glucitol of the formula ( B)

Canagliflozin is the compound (1S) -1,5-anhydro-1- (3 - {[5- (4-fluorophenyl) -2-thienyl] methyl} -4-methylphenyl) -D-glucitol of the formula (C)

Ipragliflozin is the compound (1S) -1,5-anhydro-1- [3- (1-benzothiophen-2-ylmethyl) -4-fluorophenyl] -D-glucitol of the formula (D)

Tofogliflozin is the compound (1 S _! 3'R _! 4'S _! 5'S _! 6'R) -6- (4-ethylbenzyl) -6 '- (hydroxymethyl) -3' _! 4 ' _! 5 ', 6'-tetrahydro-3H-spiro [2-benzofuran-1, 2'-pyran] -3', 4 ', 5'-triol of the formula (E)

(E) or its hydrate.

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 A1 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 describes various alkylamino-substituted dicyanopyridines and their amino acid ester prodrugs and, in addition to the primary use in cardiovascular diseases, inter alia, also their use in kidney diseases.

Preferred selective adenosine A1 receptor agonists in the context of the present invention combinations 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] -6- (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- (pyrrolidine-1-pyridine) 4-yl] phenoxy} ethyl L-ornithinate bis (trifluoroacetate) (known from WO 2010/086101) of the formula 6)

2- {4- [2-amino-6 - _({[2- (4-chloφhenyl) -1 3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyanopyridine-4-yl] - 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) -pyri - din-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) pyrr 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) -yl] phenoxy} ethyl-L-lysyl-L alaninate dihydrochloride (known from WO 2009/01581 1) of formula 11)

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-alanyl-L-alaninate hydrochloride (known from WO 2010/086101, also known as Neladenoson bialanat the formula (12)

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-argyl-L-alaninate dihydrochloride (known from WO 2010/086101) of the formula (13)

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)

(15) • 2- {4- [2-Amino-6 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) - ^

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 a SGLT-2 inhibitor 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 a SGLT-2 inhibitor and their use for the treatment of cardiovascular diseases such as heart failure with received ejection fraction or heart failure with reduced ejection fraction and renal diseases as well as other manifestations of the disease (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 an SGLT-2 inhibitor, such as by way of example and preferably dapagliflozin, empagliflozin, canagliflozin, ipragliflozin and tofogliflozin.

Preferred subject matter of the present invention are combinations containing the compound of formula (4) and dapagliflozin.

Preferred subject matter of the present invention are combinations containing the compound of formula (4) and empagliflozin.

Preferred subject of the present invention are combinations containing the compound of formula (4) and canagliflozin.

Preferred subject of the present invention are combinations containing the compound of formula (4) and Ipragliflozin.

Preferred subject matter of the present invention are combinations containing the compound of formula (4) and tofogliflozin.

Preferred subject of the present invention are combinations containing the compound of formula (12) and dapagliflozin.

Preferred subject matter of the present invention are combinations containing the compound of formula (12) and empagliflozin.

Preferred subject matter of the present invention are combinations containing the compound of formula (12) and canagliflozin.

Preferred subject of the present invention are combinations containing the compound of formula (12) and Ipragliflozin.

Preferred subject matter of the present invention are combinations containing the compound of formula (12) and tofogliflozin.

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 the SGLT-2 inhibitor once 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) and 10-100g of the SGLT-2 inhibitor 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) once daily and the SGLT-2 inhibitor once 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) and 10-100 mg of the SGLT-2 inhibitor are administered.

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 ACE inhibitors, 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 Her- zens and metabolic and renal diseases in humans and animals using at least one combination according to the invention.

The invention also relates to the combination of separate pharmaceutical compositions in kit form. This is a kit comprising two separate entities: a pharmaceutical composition of a selective partial adenosine A1 receptor agonist and a pharmaceutical SGLT-2 inhibitor composition.

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 dapagliflozin.

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 empagliflozin.

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 canagliflozin.

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 ipragliflozin.

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 tofogliflozin.

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 dapagliflozin.

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 empagliflozin.

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 canagliflozin.

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 ipragliflozin. 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 tofogliflozin.

The kit form is particularly advantageous when the separate components must be administered in different dosage forms or administered at different dose intervals.

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, 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 of thromboembolic disorders and ischaemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiovascular diseases, spasms 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 damage, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, for the prevention of restenosis such as after thrombolytic therapy, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasty ien (PTCA), heart transplants and bypass operations, as well as micro- and macrovascular lesions (vasculitis), increased levels of fibrinogen and low-density LDL as well as elevated levels of plasminogen activator inhibitor 1 (PAI-1), and for treatment and / or Prophylaxis of male erectile dysfunction and female sexual dysfunction are used.

For the purposes of the present invention, the term cardiac insufficiency includes both acute and chronic manifestations of heart failure, as well as more specific or related Forms of the disease such as acute congestive heart failure, right heart failure, left ventricular insufficiency, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart failure heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, nalklappenstenose aortic regurgitation, tricuspid stenosis, tricuspid insufficiency, Pulmo, Pulmonalklappeninsuffizienz , combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure, and acute worsening heart failure episodes.

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 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 such as glutamylsynthetase, altered urinosmolarity or urine level, increased microalbuminuria, macroalbuminuria, lesions on glomerula and arterioles, tubular dilatation, hyperphosphatemia and / or the need for dialysis can. 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 disorders (eg, hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.

Furthermore, the combinations of the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, lung diseases such. Pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell disease, thromboembolism (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory syndrome (ARDS), acute lung injury (A-Ll), 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 regulating cerebral perfusion 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 treating development 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 intestinal inflammation (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, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic diseases, systemic sclerosis, scleroderma , digital ulcerations, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).

Furthermore, the combinations according to the invention are suitable for combatting postoperative scar formation, e.g. as a result of glaucoma surgery.

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. Examples of suitable combination active ingredients are as follows: the active substances lowering the blood pressure, by way of example and preferably from the group of angiotensin II receptor antagonists, ACE inhibitors, calcium antagonists, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and 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 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 by preference, 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 rivaroxaban, 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, ACE inhibitors, 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 preferably fedipin, 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 by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Caroteneol, 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 angiotensin all-antagonist, such as by way of example and preferably losartan, valsartan, candesartan, embusartan, olmesartan, olmesartan-medoxomil, eprosartan, azilsartan or telmisartan.

In a preferred embodiment of the invention, the combinations according to the invention are administered in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril. 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 preferably 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, for 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 of 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 e.g. 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 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 administration forms.

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-release or insoluble coatings, which control the release of the compounds on which the combinations according to the invention are based), tablets or films rapidly breaking down in the oral cavity, films / lyophilisates, capsules ( hard or soft gelatin capsules, for example), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Preferred forms of administration include tablet form (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compounds on which the combinations according to the invention are based), tablets or films rapidly disintegrating in the oral cavity. Wafers, and particularly preferred forms of administration, are tablet form (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings which control the release of components underlying the combinations of the invention), tablets or films / wafers rapidly disintegrating in the oral cavity. The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For the Renteral administration are suitable as forms of application, inter alia, 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 dodecyl sulfate, 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 invention, the components can be administered together or sequentially 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, each containing 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, in oral administration, the dosage of the SGLT-2 inhibitor is about 10-100 mg od.

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 the SGLT-2 inhibitor about 10 mg OD, also preferred is the dosage of the selective partial adenosine A1 receptor agonist about 5-40 mg od, the dosage of SGLT-2 inhibitor about 20 mg OD.

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 comprising a selective partial adenosine A1 receptor agonist, a SGLT-2 inhibitor and in each case the salts, solvates and solvates of the salts thereof.

2. Combinations according to claim 1 containing a selective partial adenosine A1 receptor agonist, a SGLT-2 inhibitor from the list Dapagliflozin, Empagliflozin, Canagliflozin, Ipragliflozin and Tofogliflozin and in each case the salts, solvates and solvates of the salts thereof.

3. A combination according to any one of claims 1 and 2, wherein the selective partial adenosine A1 prescription agonist is selected from the list Capadenoson (1), 2 - ({[2- (4-chlorophenyl) -1,3-thiazol-4 -yl] methyl} sulfanyl) -6- (diethylamino) -4- [4- (2-hydroxyethoxy) phenyl] pyridine-3,5-dicarbonitrile (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- (pyrrolidine-1) yl) pyridine-3,5-dicarbonitrile (4), 2 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -4- [4- (2-hydroxyeth - oxy) phenyl] -6- (piperidin-1-yl) pyridine-3,5-dicarbonitrile (5), 2- {4- [2- ({[2- (4-chlorophenyl) -1, 3-thiazole -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-or nithinate dihydrochloride (7), 2- {4- [2 - ({[2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyan-6-one ( 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 at-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-alaninate dihydrochloride (14), 2- {4- [2- ({[2- (4-chlorophenyl) -1, 3-thiazol-4-yl] methyl} sulfanyl) -3,5-dicyan-6- (pyrrolidin-1-yl) pyridin-4-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-dicyanopyridin-4-yl] phenoxy} ethyl-L-histidyl -L-alanine dihydrochloride (16).

A combination according to claim 3, 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).

5. Combinations according to one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of cardiovascular and renal diseases.

6. A pharmaceutical composition comprising a combination according to any one of claims 1 to 4 in combination with an inert, non-toxic, pharmaceutically suitable excipient.

7. Medicaments containing a combination according to any one of claims 1 to 4 for the treatment and / or prophylaxis of cardiovascular and renal diseases.

8. A method for the treatment and / or prophylaxis of cardiovascular and renal diseases in humans and animals using combinations according to claims 1 to 4 or a medicament according to claims 6 to 7.

A kit comprising a pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing a SGLT-2 inhibitor.

A kit according to claim 9 comprising a pharmaceutical composition containing a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing ivabradine.