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WO2018153897A1 - Agonistes partiels sélectifs du récepteur a1 de l'adénosine en combinaison avec des inhibiteurs des canaux hcn - Google Patents

Agonistes partiels sélectifs du récepteur a1 de l'adénosine en combinaison avec des inhibiteurs des canaux hcn Download PDF

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Publication number
WO2018153897A1
WO2018153897A1 PCT/EP2018/054241 EP2018054241W WO2018153897A1 WO 2018153897 A1 WO2018153897 A1 WO 2018153897A1 EP 2018054241 W EP2018054241 W EP 2018054241W WO 2018153897 A1 WO2018153897 A1 WO 2018153897A1
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sulfanyl
methyl
thiazol
chlorophenyl
phenoxy
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PCT/EP2018/054241
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German (de)
English (en)
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Barbara ALBRECHT-KÜPPER
Stephan Vettel
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Bayer Pharma Aktiengesellschaft
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Publication of WO2018153897A1 publication Critical patent/WO2018153897A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to selective partial adenosine A1 receptor agonists in combination with HCN channel inhibitors and their use for the treatment and / or prophylaxis of cardiovascular and renal diseases.
  • Adenosine a purine nucleoside
  • Adenosine is present in all cells and is released from a variety of physiological and pathophysiological stimuli.
  • Adenosine is produced intracellularly 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.
  • AMP adenosine 5'-monophosphate
  • S-adenosyl homocysteine as an intermediate, but can be released from the cell and then functions as a hormone-like substance or neurotransmitter by binding to specific receptors.
  • adenosine increases the perfusion of the coronary arteries and has a cardioprotective effect. It also affects blood pressure, heart rate, neurotransmitter release and lymphocyte differentiation. In the kidney, it has a renopro- tective effect. In adipocytes, adenosine is able to inhibit lipolysis and thus reduce the concentration of free fatty acids and triglycerides in the blood.
  • adenosine 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.
  • 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).
  • adenosine receptors are mediated intracellularly by the messenger cAMP.
  • inhibition of the adenylate cyclase causes a decrease in the intracellular cAMP content.
  • adenosine A1 receptors 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.
  • preconditioning 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 ,
  • 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.
  • A1 receptors In adipocytes, activation of A1 receptors causes inhibition of lipolysis.
  • 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).
  • 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.
  • 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.
  • 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.
  • ivabradine is preferably used as the HCN channel inhibitor.
  • 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.
  • 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:
  • the combinations according to the invention allow an effective treatment of cardiovascular diseases, in particular also cardiac insufficiency, whereby the mortality and / or morbidity in patients is further reduced without significantly influencing the mean arterial blood pressure or heart rate.
  • cardiovascular diseases in particular also cardiac insufficiency
  • the 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.
  • 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).
  • 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.
  • 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.
  • diseases of the cardiovascular system cardiovascular diseases
  • the invention also relates to the combination of separate pharmaceutical compositions in kit form.
  • kit form This is a kit comprising two separate entities: a pharmaceutical 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.
  • 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 intervention system
  • HFpEF cardiac insufficiency with preserved ejection fraction
  • 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.
  • myocarditis myocarditis
  • chronic myocarditis chronic myocarditis
  • acute myocarditis acute myocarditis
  • viral myocarditis viral myocarditis
  • diabetic cardiac insufficiency diabetic cardiac insufficiency
  • the combinations according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier disease, obesity (obesity) and obesity combined hyperlipidaemias and the metabolic syndrome, as well as type 1 diabetes
  • the combinations according to the invention can be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, cladidatio, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, Gangren, CREST syndrome , Erythematosis, onychomycosis, rheumatic diseases and to promote wound healing.
  • the combinations according to the invention are also suitable for treatment of muscular dystrophy, such as muscular dystrophy Becker-Kiener (BMD) and Duchenne muscular dystrophy (DMD).
  • the combinations according to the invention are suitable for the treatment and / or prophylaxis of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS) Feiines urological syndrome (FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (Ul) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI , OUI), pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorder
  • LUTS lower urinary tract syndromes
  • Feiines urological syndrome Feiines urological syndrome
  • diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC
  • kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
  • renal insufficiency encompasses both acute and chronic manifestations of 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, hypertens
  • 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.
  • 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.
  • 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).
  • 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).
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory tract syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • pulmonary fibrosis pulmonary emphysema (eg, cigarette smoke-induced Pulmonary emphysema) and cystic fibrosis (CF).
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory tract syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • pulmonary fibrosis pulmonary emphysema
  • CF cystic fibrosis
  • the mentioned combinations according to the invention can be used as bronchodilators.
  • 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.
  • 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.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic intestinal inflammation
  • Crohn 's Disease UC
  • Pancreatitis peritonitis
  • rheumatoid diseases inflammatory skin diseases as well as inflammatory eye diseases.
  • combinations according to the invention can likewise be used for the treatment and / or prophylaxis of autoimmune diseases.
  • 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.
  • 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).
  • 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.
  • 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;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Lipid metabolism-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.
  • 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
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the combinations according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the combinations according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by preference, ximaglagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • the combinations according to the invention are administered in combination with a GPIIb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the combinations according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-31 12, YM- 150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • 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
  • the combinations according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • the combinations according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin II receptor antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid Receptor antagonists and diuretics understood.
  • the combinations according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the combinations according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the combinations according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or Bucindo- lol, administered.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol, pindolo
  • 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.
  • an angiotensin all-antagonist such as by way of example and preferably losartan, valsartan, candesartan, embusartan, olmesartan, olmesartan-medoxomil, eprosartan, azilsartan or telmisartan.
  • 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.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the combinations according to the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the combinations according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the combinations 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.
  • a loop diuretic such as furosemide, torasemide, bumetanide and piretanide
  • potassium-sparing diuretics such as amiloride and triamterene
  • aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone
  • thiazide diuretics such as hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha PPAR alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile
  • the combinations according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor such as, for example and preferably, dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the combinations according to the invention are administered in combination with a thyroid receptor agonist, such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
  • a thyroid receptor agonist such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,
  • the combinations according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the combinations according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the combinations according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimbe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimbe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the combinations according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • 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.
  • the combinations according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the combinations according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the combinations according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the combinations according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • the combinations according to the invention are administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • the combinations according to the invention are administered in combination with a SGLT2 inhibitor (sodium dependent glucose transporter), such as, for example, dapagliflozin, empagliflozin, canagliflozin, ipragliflozin and toofogliflozin.
  • SGLT2 inhibitor sodium dependent glucose transporter
  • the combinations according to the invention are administered in combination with a myosin activator, such as, for example, Omecamtiv mercabil.
  • the components can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the combinations according to the invention can be administered in suitable administration forms.
  • 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.
  • 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
  • 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).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • 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.
  • oral or parenteral administration with oral administration being more preferred.
  • 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.
  • 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.
  • Carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulf
  • 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.
  • the components may be in a so-called sustained-release formulation, in which the release of the components according to the invention takes place at different times.
  • a tablet having delayed-dissolving coatings which in each case contains one or more components of the combinations according to the invention.
  • the dosage of the selective partial adenosine A1 receptor agonist when dosed orally, is about 5-40 mg.
  • the dosage of ivabradine when dosed orally, is about 2.5-7.5 mg bid, 5-7.5 mg bid, or 5 mg bid.
  • 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.
  • 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.
  • dosages described above may be formulated within the scope of the invention as a fixed-dose combination, wherein the preferred unitary forms may be tablets or capsules.
  • the dosage of the selective partial adenosine A1 receptor agonist is about 5-40 mg od, the dosage of 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.

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Abstract

La présente invention concerne des agonistes partiels sélectifs du récepteur A1 de l'adénosine en combinaison avec des inhibiteurs des canaux HCN et leur utilisation pour le traitement et/ou la prévention des maladie cardiovasculaire et rénales.
PCT/EP2018/054241 2017-02-22 2018-02-21 Agonistes partiels sélectifs du récepteur a1 de l'adénosine en combinaison avec des inhibiteurs des canaux hcn WO2018153897A1 (fr)

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