WO2018153897A1

WO2018153897A1 - Selective partial adenosine a1 receptor agonists in combination with hcn channel blockers

Info

Publication number: WO2018153897A1
Application number: PCT/EP2018/054241
Authority: WO
Inventors: Barbara ALBRECHT-KÜPPER; Stephan Vettel
Original assignee: Bayer Pharma 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 HCN channel blockers, 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 HCN channel

inhibitors

The present invention relates to selective partial adenosine A1 receptor agonists in combination with HCN channel 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 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 the A1 receptors, inhibition of the adenylate cyclase causes a decrease in the intracellular cAMP content.

In the cardiovascular system, the main effects are the activation of adenosine A1 receptors: bradycardia, negative inotropia, protection of the heart from ischemia ("preconditioning") and improve energy production and use. 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 the A1 receptors in the heart can be exploited, inter alia, by the activation of these A1 receptors by specific A1 agonists for the treatment and organ protection in acute myocardial infarction, acute coronary syndrome, heart failure, bypass operations, cardiac catheter examinations and organ transplants , 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 they are only very weak or very short-term effective after oral administration or have undesirable side effects on, for example, the central nervous system (CNS). ben (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 relative to the underlying drug, for example achieved by an improvement in physicochemical profile, especially solubility, active or passive absorption properties or tissue specific distribution.

Ivabradin selectively and specifically inhibits the HCN ion current, which, as an intrinsic pacemaker in the heart, controls spontaneous diastolic depolarization in the sinus node, thereby regulating cardiac output. The cardiac effects are specific to the sinus node and have no effect on intra-atrial, atrioventricular or intraventricular conduction, nor on myocardial contractility or ventricular repolarization, i. the conduction system, the muscle power of the heart or the blood pressure are not affected. Ivabradine is used to treat chronic stable angina pectoris and chronic heart failure. Despite the reduction in mortality and mainly morbidity in patients with heart failure, there is still a medical need for further improvement of these endpoints. Since the positive effect of ivabradine in heart failure is exclusively due to the lowering of the heart rate without further haemodynamic effects, the effect can be potentiated by a combination with drugs that adhere to further cardioprotective mechanisms without leading to a greater reduction in heart rate ,

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 middle ar significantly affect blood pressure or heart rate.

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 the protective effect of the partial A1 receptor agonists is independent of the mode of action of ivabradine, a combination of both drugs is possible and should lead to a further reduction of mortality and / or morbidity, without additional haemodynamic 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 an HCN channel inhibitor.

The combination of selective partial adenosine A1 receptor agonists with an HCN channel 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.

As the HCN channel inhibitor, ivabradine is preferably used.

Ivabradine is the HCN channel inhibitor 3- {3 - [{[(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl} (methyl) amino ] propyl} -7,8-dimethoxy-1,3,5,5-tetrahydro-2H-3-benzazepin-2-one of the formula (A)

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 / No. 100827, WO 2009/015776, WO 2009/015812, WO 2009/112155 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 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 - ({[2- (4-Chlorophenyl) -1,3-thiazol-4-yl] methyl} sulfanyl) -4- [4- (2-hydroxyeth-methoxyazetidin-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- (pyrrolidin-1-yl) - pyridin-4-yl] phenoxy} ethyl L-ornithinate bis (trifluoroacetate) (known from WO 2010/086101) of formula 6)

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

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) -3,5-dicyanopyridin-4-yl] - phenoxy} ethyl-N - [(2S) -2,4-diaminobutanoyl] -L-alaninate dihydrochloride (known

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) -3,5-dicyanopyridin-4-yl] -phenoxy} -ethyl -L-lysyl-L-alaninate dihydrochloride (known from WO 2009/01581 1) of the formula (11)

NH-x 2 HCl 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) -3,5-dicyanopyridin-4-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- (py

yl) pyridin-4-yl] phenoxy} ethyl-L-histidyl-L-alaninate dihydrochloride (known from WO

2010/086101 of 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 2009/015811) 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 an HCN channel 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 an HCN channel inhibitor and their use for the treatment of cardiovascular diseases, e.g. Cardiac insufficiency with preserved ejection fraction or heart failure with reduced ejection fraction and renal diseases as well as other disease manifestations (e.g., 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 HCN channel inhibitor, such as by way of example and preferably ivabradine.

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

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

The components to be combined may be present as salts. Salts used 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) is administered once daily and ivabradine 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) and 2.5-7.5 mg of ivabradine 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 daily and ivabradine 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) and 2.5-7.5 mg ivabradine 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 substances 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 heart as well as metabolic and renal diseases in humans and animals using at least a 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 HCN channel 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 ivabradine.

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 ivabradine.

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, cardiac insufficiency 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 tachyarrhythmia, torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV junctional extrasystoles, sick sinus syndrome, syncope, AV node reentrant tachycardia, Wolff-Parkinson-White syndrome, of acute coronary artery syndrome (ACS), 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 diseases and ischaemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transitory and ischemic attacks, preeclampsia, inflammatory cardiac ovarian disease, spasm of the coronary arteries and peripheral arteries, edema formation such as pulmonary edema, cerebral edema, renal edema or heart failure edema, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction, to prevent restenosis such as after thrombolytic therapy , percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass surgery, as well as microvascular and macrovascular lesions (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.

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. heart failure nalklappenstenose with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic regurgitation, tricuspid stenosis, tricuspid insufficiency, Pulmo, Pulmonalklappeninsuffizienz, combined heart valve defects, heart muscle inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcohol-toxic cardiomyopathy, cardiac storage diseases, diastolic heart failure as well as systolic heart failure and acute phases de w worsening of 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 treatment of muscular dystrophy, such as muscular dystrophy Becker-Kiener (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 kidney insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial diseases, Nephropathic disorders such as primary and congenital kidney disease, nephritis, renal immunological disorders such as renal transplant rejection, immune complex-induced renal disease, nephropathy induced by toxic substances, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and nephrotic Syndrome, which is diagnosed by, for example, abnormally decreased creatinine and / or water excretion, abnormally elevated blood levels of H substance, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as e.g. Glutamyl synthetase, altered urinary or urinary 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 according to the invention for the treatment and / or prophylaxis of secondary effects of renal insufficiency, such as, for example, pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (eg hypercalemia, hyponatremia) and disorders in the 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 (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced Pulmonary emphysema) and cystic fibrosis (CF). In addition, the mentioned combinations according to the invention can be used as bronchodilators.

Furthermore, the combinations according to the invention are also suitable for regulating 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 (apoplexy 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 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, morphaea, 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 disorders. As suitable combination active ingredients may be mentioned by way of example and preferably:

Hypotensive agents, by way of example and by way of preference 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, nitroglycerine, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP), such as 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-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors 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.

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 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, 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 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 Bucindo- lol, administered.

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 according to 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 the 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 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 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 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 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 (for example hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Preferred forms of application are tablet form (uncoated or overprinted). coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compounds on which the combination according to the invention is based), tablets or films / wafers rapidly breaking down in the oral cavity and particularly preferred forms of administration are tablet form (non-coated or non-coated) coated tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the components underlying the combinations of the invention), tablets or films / wafers rapidly disintegrating 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 parenteral administration are suitable as application forms u.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 medicines (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 patches), 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. Carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers ( For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or 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, 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, when dosed orally, the dosage of ivabradine is about 2.5-7.5 mg bid, 5-7.5 mg bid, or 5 mg bid.

In one embodiment of the invention, ivabradine is provided orally as a tablet and comprises an effective amount of, for example, 2.5 to 7.5 mg of ivabradine, which can be administered to patients. The administration of the active ingredient may take place twice a day starting, for example, from a daily dose of 10 mg or 15 mg of ivabradine. Preferably, ivabradine is given twice daily at a dose of 5 mg each. After two weeks of use, the dose is adjusted so that the patient has a resting heart rate between 50 and 60 beats per minute.

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 ivabradine about 10 mg bid, also preferably the dosage of the selective partial adenosine A1 receptor agonist about 5-40 mg od, the dosage of ivabradine about 15 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 comprising a selective partial adenosine A1 receptor agonist, a HCN channel inhibitor 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, ivabradine 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 comprising a selective partial adenosine A1 receptor agonist and a pharmaceutical composition containing an HCN channel 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.