Classifications

• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • 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
  • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
  • C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
  • C07C53/16—Halogenated acetic acids
  • C07C53/18—Halogenated acetic acids containing fluorine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• Adenosine AI agonists as a drug for kidney disease
• the present application relates to selective partial adenosine AI receptor agonists of the formula (I) and their use for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, preferably for the treatment and / or prevention of acute and / or chronic kidney disease (primary and secondary disease) with and without concomitant acute and / or chronic heart disease.
• the present application relates to selective partial adenosine AI agonists of the formula (I) and their use for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, preferably for the treatment and / or prevention of Chronic kidney disease with and without concomitant acute and / or chronic heart disease.
• the kidneys provide in the body an important regulatory system for detoxification (excretion of urinary metabolic waste products, including creatinine, urea and uric acid), electrolyte balance (such as sodium, calcium, potassium and phosphorus), regulation of blood pH and fluid balance, regulation of blood pressure (inter alia Volume regulation, modulation of the renin-angiotensin-aldosterone system), for hormone production (eg erythropoietin and vitamin D) and for bone metabolism.
• a kidney failure thus has far-reaching consequences for the entire organism.
• Kidney failure or kidney disease can be differentiated into acute, reversible and chronic, irreversible forms, regardless of whether it is a primary or secondary form of the disease (co-morbidity). Depending on the trigger, duration and severity of acute renal failure or acute kidney disease, a manifestation of chronic kidney failure or chronic kidney disease is likely.
• the most common trigger for acute renal failure or renal disease is a reduced blood flow in the kidneys, e.g. due to an acute volume loss (including blood loss, lack of fluid), a drop in blood pressure with reduced renal perfusion pressure (eg in the context of acute and / or decompensated heart failure) and / or occlusion of the renal vessels (including stenoses and / or thrombi and / or embolisms in the Renal arteries and / or veins).
• inflammatory diseases glomerulonephritis
• high-dose drugs and / or duration such as antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and cytotoxic drugs, but also heavy metals, alcohol and X-ray contrast media lead to acute renal damage.
• the most common triggers for chronic kidney failure or kidney disease are in addition to acute renal failure or acute kidney disease, including long-standing diabetes mellitus, high blood pressure (arterial hypertension), kidney inflammation (glomerulonephritis), repeated pyelonephritis (pyelonephritis), povolemia, renal artery stenosis, hepatorenal syndrome and / or heart failure.
• GFR glomerular filtration rate
• Myogenic mesangial cells in the matrix of the glomerulus are in direct contact with the glomerular basement membrane and, via their contraction or relaxation, influence the capillary bed of the glomerulus and thus the GFR.
• mesangial cells not only play a physiological role in the regulation of the capillary bed but also play an essential role in the pathophysiology of kidney disease, as their dysfunction accompanies the release of pro-inflammatory, pro-proliferative and pro-fibrotic factors, depending on the species, Duration and extent can have a decisive influence on the development of a functional and / or structural, reversible and / or irreversible damage to the kidney, such as in the case of glomerulonephritis and / or glomerulosclerosis.
• 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.
• the effect of adenosine is mediated via specific receptors. So far, the subtypes AI, A2a, A2b and A3 are known.
• adenosine receptor-selective ligands are those substances which bind selectively to one or more subtypes of the adenosine receptors and either mimic the action of adenosine (adenosine receptor agonists) or block its action (adenosine receptor antagonists).
• adenosine receptors are mediated intracellularly by the messenger cAMP
• an activation of the membrane-bound adenylate cyclase leads to an increase in the intracellular cAMP concentration, while the binding of adenosine
• activation of AI receptors by specific Al agonists results in a frequency-dependent decrease in heart rate, negative inotropy, and protection of the adenylate cyclase Heart before ischemia (" pre-conditioning ") without having any influence on the systemic blood pressure.
• selective agonists may be useful, inter alia, for the treatment of angina pectoris and atrial fibrillation (see review article, I. Giorgi, P. Nieri, Expert Opinion Ther. Patents 2008, 18: 677-691) and, by virtue of suppl - cardioprotective properties, for treatment and organ protection in acute myocardial infarction, acute coronary syndrome, heart failure, bypass surgery, cardiac catheterization and organ transplantation Zimmermann et al., Clin Res Cardiol 2011, 100 (Suppl 1) P1692, B. Albrecht- Kupper et al., Purinergic Signaling 2012, (Suppl 1): S91-S99).
• AI receptors are also expressed in the kidney, in particular in the renal cortex, in the renal cortex, kidney marrow and in the inner renal medulla (Vizthum et al., Kidney Internat. 2004, 65, 1180-1190) and here regulate the preglomerular vasoconstriction (Afferens afferens), the tubulo- glomerular feedback (TGF), the release of renin, erythropoietin and catecholamines from sympathetic nerve endings, as well as the sodium reabsorption and the release of aldosterone.
• Afferens afferens the tubulo- glomerular feedback
• renin renin
• erythropoietin catecholamines
• adenosine is that under normoxic conditions, the concentration of free adenosine in the extracellular space is very low, while areas with low oxygen supply higher content to have adenosine. This is especially true in the kidney, where the renal medulla is significantly less oxygenated than the renal cortex. Thus, even under physiological conditions, the adenosine concentration in the renal medulla per se is 3-4 times higher than the adenosine concentration in the renal cortex.
• Physiologically e.g., in the renal medulla
• pathophysiologically e.g., in the renal cortex under ischemic / hypoxic conditions
• adenosine is to increase the oxygen supply of the affected areas or to reduce the metabolism of these areas in order to achieve an adaptation under ischemic or hypoxic conditions.
• the reduced blood flow to the external renal cortex region is accompanied by a reduced diuresis and natriuresis, as well as a reduced creatinine clearance, ie with a reduced GFR, based on these parameters thus nominally with a reduction in renal function.
• stimulation of AI receptors in the kidney also inhibits renin and aldosterone release, as well as increasing the release of erythropoietin.
• an agonism is given with intrinsic activity, with values between 0 and 1. While a full agonist is characterized by a maximum intrinsic activity of 1 and a full antagonist by a lack of intrinsic activity, ie 0, the intrinsic activity of a partial Agonists between> 0 and ⁇ 1. While agonists with intrinsic activity shift receptor balance so that nearly all receptors adopt an active conformation, a full (neutral) antagonist with intrinsic activity of 0 does not alter the basal receptor equilibrium. A partial agonist, on the other hand, shifts only part of the receptors into the active conformation according to its intrinsic activity between> 0 and ⁇ 1. However, the actual profile of action of a partial agonist is not only in the reduced potency, but rather in that it acts as an antagonist in the presence of a full agonist.
• a partial AI receptor agonist when transferred to the kidney, a partial AI receptor agonist, with functional and structural acute and / or chronic renal injury associated with circulatory disorders and / or ischemia and / or hypoxia, would be weaker at the same time but spatially separated depending on endogenous adenosine concentration Agonist and / or behave as an antagonist.
• adenosine receptor-specific ligands known from the prior art are predominantly derivatives based on natural adenosine [S.A. Poulsen and RJ Quinn, "Adenosine receptors: new opportunities for future drugs", Bioorganic and Medicinal Chemistry 6 (1998), pages 619-641].
• these adenosine ligands known from the prior art usually have the disadvantage that they are not really receptor-specific, are less effective than the natural adenosine, are only very weakly active after oral administration or have undesirable side effects on the central nervous system (CNS) (AK Dhalla et al., Curr. Topics in Med. Chem. 2003, 3, 369-385; E. Elzein, J. Zablocki, Exp. Opin. Invest. Drugs 2008, 17 (12), 1901-1910). Therefore, they are mainly used only for experimental purposes. In clinical development compounds of this type are so far only for intravenous administration.
• Prodrugs are derivatives of an active substance which undergo a one-stage or multistage biotransformation of an enzymatic and / or chemical nature in vivo before the actual active ingredient is released.
• a prodrug residue is usually used to improve the property profile of the underlying drug [P. Ettmayer et al., J. Med. Chem. 47, 2393-2404 (2004)].
• the design of the prodrug residue as well as the desired release mechanism must be tailored very precisely to the individual drug, the indication, the site of action and the route of administration.
• prodrugs which have improved bioavailability relative to the underlying drug, for example achieved by an improvement in the physicochemical profile, especially solubility, active or passive absorption properties, or tissue specific distribution.
• An example of the extensive literature on prodrugs is: H. Bundgaard (Ed.), Design of Prodrugs: Bioreversible Derivatives for Various Functional Groups and Chemical Entities, Elsevier Science Publishers BV, 1985.
• An Overview of Prodrug Derivatives Based on Carboxylic Esters and possible properties of such compounds is described, for example, in K. Beaumont et al., Curr. Drug Metab. 4, 461-485 (2003).
• dipeptide prodrugs of acyclovir for the treatment of herpetic eye infections are known (Anand, BS, et al., Curr. Eye Res. 26, No. 3-4, 151-163 (2003)), which discloses the oligopeptide transporter of the cornea to increase the bioavailability of acyclovir in the eye.
• WO 01/25210, WO 02/070484, WO 02/070485, WO 2002/070520, WO 03/053441, WO 2008/028590, WO 2008/064789, WO 2009/100827, WO 2009/015776, WO 2009/015812 , WO 2009/112155 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 phenylamino-nothiazoles
• WO 2008/064788 describes cyclically substituted 3,5-dicyanopyridines
• WO 2009/080197 discloses substituted azabicyclic adensonin receptor ligands
• WO 2009/015811, 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 disclose selective AI receptor agonists of the 2-thio-3,5-dicyano-4-phenyl-6-aminopyridine type in combination with aminoglycosides to protect renal cells from antibiotic-induced Renal cell damage described.
• WO2009 / 015811 discloses prodrug derivatives of 2-aro-ino-6 - ( ⁇ [2- (4-chloro-phenyl) -l, 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, among others, also their use in kidney diseases.
• cardiovascular diseases among others
• kidney diseases neither specific kidney diseases are named, nor are results reported on their potential effectiveness.
• partial agonists of the formula (I) can bring about protection of the kidney in acute and / or chronic kidney diseases, as listed below, without adversely affecting kidney function.
• a further object of the present invention is therefore the provision and targeted selection of potent and selective, partial AI receptor agonists which have an advantageous therapeutic and / or pharmacologically dual-action profile, and as such for the treatment and / or prevention of chronic functional and / or structural kidney disease (primary and secondary disease) are suitable.
• the suitability for the treatment and / or prophylaxis of acute kidney diseases in particular in the suitability for the treatment and / or prophylaxis of acute renal insufficiency, as well as acute renal failure (primary disease and secondary disease) to understand.
• the suitability for the treatment and / or prophylaxis of chronic kidney diseases in particular in the suitability for the treatment and / or prophylaxis of chronic renal failure, as well as chronic renal failure (primary disease and secondary disease) to understand.
• the term acute renal insufficiency includes acute manifestations of kidney disease, renal failure and / or renal insufficiency with and without dialysis, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, volume depletion (eg dehydration, blood loss), shock, acute glomerulonephritis, hemolytic anemic syndrome (HUS), vascular catastrophe (arterial or venous thrombosis or embolism), cholesterol embolism, acute Bence Jones kidney in plasmocytoma, acute supravesical or subvesical drainage disorders, immunological renal diseases such as renal transplant rejection, immune complex-induced kidney disease , tubular dilatation, hyperphosphatemia and / or acute renal disease, which may be characterized by the need for dialysis.
• renal hypoperfusion intradialytic hypotension
• volume depletion eg dehydration, blood loss
• shock acute glomerulonephritis
• hemolytic anemic syndrome HUS
• vascular catastrophe artificial or venous thro
• kidney resections dehydration by forced diuresis, uncontrolled blood pressure increase with malignant hypertension, urinary obstruction and infection and amyloidosis and systemic diseases with glomerular involvement, such as rheumatologic-immunological systemic diseases such as lupus erythematosus, renal arterial thrombosis, renal vein thrombosis, Analgesic nephropathy and renal tubular acidosis, as well as x-ray contrast agent and drug-induced acute interstitial kidney disease.
• rheumatologic-immunological systemic diseases such as lupus erythematosus, renal arterial thrombosis, renal vein thrombosis, Analgesic nephropathy and renal tubular acidosis, as well as x-ray contrast agent and drug-induced acute interstitial kidney disease.
• chronic renal insufficiency includes chronic manifestations of kidney disease, renal failure and / or renal insufficiency with and without dialysis, as well as underlying or related renal diseases such as renal hypoperfusion, intradiovenous lytic hypotension, obstructive uropathy, glomerulopathies, glomerular and tubular proteinuria, renal edema, hematuria, primary, secondary and chronic glomerulonephritis, membranous and membranoproliferative glomerulonephritis, Alport syndrome, glomerulosclerosis, tubulointerstitial diseases, nephropathic disorders such as primary and congenital kidney disease, nephritis immunologic kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis and ne
• renal diseases such as renal hypoper
• kidney failure in renal cell carcinoma partial renal dissection, forced diuresis dehydration, uncontrolled hypertensive hypertension, urinary obstruction and infection and amyloidosis and systemic disorders with glomerular involvement, such as rheumatologic-immunological systemic disorders such as lupus erythematosus, and renal artery stenosis.
• Renal artery thrombosis, renal vein thrombosis, analgesic nephropathy, and renal tubal acidosis Furthermore, chronic renal insufficiency based on radiographic contrast agent and drug-induced chronic interstitial kidney disease, metabolic syndrome and dyslipidemia.
• the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
• sequelae of renal insufficiency such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
• diseases of the cardiovascular system or cardiovascular diseases include the following diseases: hypertension, peripheral and cardiac vascular diseases, coronary heart disease, coronary restenosis such as restenosis after balloon dilatation of peripheral blood vessels, myocardial infarction, acute coronary syndrome, acute Coronary syndrome with ST elevation, acute coronary syndrome without ST elevation, stable and unstable angina, cardiac insufficiency, Prinzmetal angina, persistent ischemic dysfunction (hibernating myocardium), transient postischemic dysfunction (stunned myocardium), heart failure, tachycardia, atrial tachycardia, arrhythmias , Atrial and ventricular fibrillation, persistent atrial fibrillation, permanent atrial fibrillation, atrial fibrillation with normal left ventricular function, atrial fibrillation with impaired left ventricular function, Wolff-Parkinson-White syndrome, periphe circulatory disorders, increased levels of fibrinogen and low density LDL, as well as elevated levels of plasminogen activator inhibitor 1
• cardiac failure encompasses both acute and chronic manifestations of heart failure, 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, congenital heart defects, valvular heart failure, heart failure.
• heart valve defects mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic cardiac insufficiency, alcoholic cardiomyopathy, cardiac storage disorders, diastolic and systolic heart failure (ie heart failure with preserved ejection farction (HFpEF) or heart failure with reduced ejection fraction (HFrEF)).
• HFpEF preserved ejection farction
• HFrEF heart failure with reduced ejection fraction
• R 1 is hydrogen or (C 1 -C 4 ) -alkyl
• R 2 is hydrogen or (C 1 -C 4 ) -alkyl
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain another heteroatom from the series N, O and S,
• 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, trifluoromethoxy and (C 1 -C 4 -alkoxy)
• R 3 is hydrogen
• R 4 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or
• R 9 is hydrogen
• R o i o r is hydrogen or methyl
• R 11 is hydrogen or the side group of a natural a-amino acid or its homologs or isomers
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• R 1 is (C 1 -C 4 ) -alkyl
• R 2 is (C 1 -C 4 ) -alkyl
• R 1 and R 2 are each hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle which may contain another heteroatom from the series N, O and S,
• 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, trifluoromethoxy and (C 1 -C 4 -alkoxy)
• R 3 is hydrogen or a group of the formula
• R 4 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or
• R 9 is hydrogen
• R i o fo r is hydrogen or methyl
• R 11 is hydrogen or the side group of a natural a-amino acid or its homologues or isomers
• R 12 is hydrogen
• R 13 is hydrogen
• Compounds according to the invention are the compounds of the formula (I) and their N-oxides, salts, solvates, salts of N-oxides and solvates of the salts and N-oxides, the compounds of the formulas below and their salts encompassed by formula (I), Solvates and solvates of the salts and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the following compounds mentioned not already salts, solvates and solvates of the salts.
• the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
• the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
• the present invention encompasses all tautomeric forms.
• Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable, but can be used for example for the isolation or purification of the compounds of the invention.
• Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
• Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
• Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
• customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
• solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
• the present invention also includes prodrugs of the compounds of the invention.
• prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted into compounds of the invention (for example metabolically or hydrolytically).
• alkyl is a linear or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.
• Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 4 carbon atoms and one double bond.
• alkenyl radical having 2 to 4 carbon atoms and one double bond.
• Alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond.
• Alkanediyl in the context of the invention is a linear or branched divalent alkyl radical having 2 to 6 carbon atoms.
• Cycloalkyl in the context of the invention is a monocyclic, saturated carbocycle having 3 to 7 or 5 to 6 ring carbon atoms. Examples which may be mentioned are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 or 1 to 4 or 2 to 4 carbon atoms. Preference is given to a linear or branched alkoxy radical having 1 to 4 or 2 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.
• Cycloalkoxy in the context of the invention is a monocyclic, saturated carbocycle having 3 to 7 carbon atoms, which is bonded via an oxygen atom.
• the following may be mentioned by way of example and preferably: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.
• Alkylsulfanyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms, which is bonded via a sulfanyl group.
• Alkylsulfonyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms, which is bonded via a sulfonyl group.
• Heterocycle in the context of the invention is a saturated heterocycle having a total of 4 to 7 ring atoms, which contains one or two ring heteroatoms from the series N, O and / or S and is linked via a ring carbon atom or optionally a ring nitrogen atom.
• Examples which may be mentioned are: azetidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.
• azetidinyl Preferred are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl. Particularly preferred are azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.
• the side group of an ⁇ -amino acid in the meaning of R 3 includes both the side groups of the naturally occurring oc-amino acids and the side groups of homologues and isomers of these oc-amino acids.
• the oc-amino acid can be present here both in the L and in the D configuration or else as a mixture of the L and D form.
• side groups are exemplified: methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine) Butan-1-yl (norleucine), tert-butyl (2-tert-butylglycine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl ( Tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2- Hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (5-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamo
• Preferred ⁇ -amino acid side groups in the meaning of R 3 are methyl (alanine), propan-2-yl (valine), 2-methylpropan-1-yl (leucine), benzyl (phenylalanine), imidazol-4-ylmethyl (histidine ), Hydroxymethyl (serine), 1-hydroxyethyl (threonine), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric acid), aminomethyl (2 , 3-diaminopropionic acid), 3-guanidinopropan-1-yl (arginine).
• the L configuration is preferred in each case.
• An oxo group is in the context of the invention for an oxygen atom which is bonded via a double bond to a carbon atom.
• radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Most preferably, the substitution with one or two identical or different substituents.
• R 1 is hydrogen or (C 1 -C 3 ) -alkyl
• R 2 is hydrogen or (C 1 -C 3 ) -alkyl
• (C 1 -C 3) -alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl, or
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N, O and S,
• 4- to 6-membered heterocycle may be substituted with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, (Ci-C alkyl, trifluoromethoxy, methoxy and ethoxy,
• R 3 is hydrogen
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is methyl
• R 9 is hydrogen
• R 10 is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-yl-methyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is (C 1 -C 3 ) -alkyl
• R 2 is (C 1 -C 3 ) -alkyl
• R 1 and R 2 are each hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N, O and S,
• 4- to 6-membered heterocycle may be substituted with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, (Ci-C alkyl, trifluoromethoxy, methoxy and ethoxy,
• R 3 is hydrogen
• R 4 is 3-aminopropan-1-yl
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is methyl
• R 9 is hydrogen
• R i ou r is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen or ethyl
• R 2 is hydrogen or ethyl
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N, O and S,
• R 3 is hydrogen
• R 4 is 3-aminopropan-1-yl
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is methyl
• R 9 is hydrogen
• R o i o r is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is ethyl
• R 2 is ethyl
• R 1 and R 2 are each hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N, O and S,
• R 3 is hydrogen
• R 4 is 3 -aminopropan-1-yl
• R ? stands for hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is methyl
• R 9 is hydrogen
• R o i o r is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-yl-methyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen or ethyl
• R 2 is hydrogen or ethyl
• R 1 and R 2 together with the nitrogen atom to which they are attached, an azetidinyl, pyrrolidinyl or
• R 3 is hydrogen or a group of the formula
• R 4 is 3 -aminopropan-1-yl
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is methyl
• R 9 is hydrogen
• R 10 is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is ethyl
• R 2 is ethyl
• R 1 and R 2 are hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached, an azetidinyl, pyrrolidinyl or
• R 3 is hydrogen or a group of the formula
• R 4 is 3 -aminopropan-1-yl
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is methyl
• R 9 is hydrogen
• R 10 is hydrogen, R u is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen
• R 2 is hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidinyl ring
• R 3 represents a group of the formula
• R 4 is 3-aminopropan-1-yl
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• R 8 is methyl
• R 9 is hydrogen
• R 10 is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen or ethyl
• R 2 is hydrogen or ethyl
• R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
• R 3 is a group of the formula
• R 4 is 3-aminopropan-1-yl
• R ⁇ is hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is ethyl
• R 2 is ethyl
• R 1 and R 2 are hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
• R 3 is a group of the formula
• R 4 is 3-aminopropan-1-yl
• R ⁇ is hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 2 is hydrogen or ethyl
• R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
• R 3 is a group of the formula
• R 8 is methyl
• R 9 is hydrogen
• R o i o r is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is ethyl
• R 2 is ethyl
• R 1 and R 2 are hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
• R 3 is a group of the formula
• R 8 is methyl
• R 9 is hydrogen
• R o i o r is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen or ethyl
• R 2 is hydrogen or ethyl
• R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
• R 3 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is ethyl
• R 2 is ethyl
• R 1 and R 2 are hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
• R 3 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 3 is hydrogen or a group of the formula
• R 4 is 3 -aminopropan-1-yl
• R 5 represents hydrogen
• R 6 represents hydrogen
• R 7 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 3 is hydrogen or a group
• R 8 is methyl
• R 9 is hydrogen
• R i o fo r is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen or methyl
• R 14 is hydrogen or methyl
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen or (C 1 -C 3 ) -alkyl
• R 2 is hydrogen or (C 1 -C 3 ) -alkyl
• (C 1 -C 3) -alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl, or
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N, O and S, wherein the 4- to 6-membered heterocycle may be substituted with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, methoxy and ethoxy, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is (C 1 -C 3 ) -alkyl
• R 2 is (C 1 -C 3 ) -alkyl
• (C 1 -C 3) -alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl, or
• R 1 and R 2 are hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N, O and S,
• 4- to 6-membered heterocycle may be substituted with 1 or 2 substituents independently selected from the group fluorine, trifluoromethyl, methyl, ethyl, methoxy and ethoxy, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 3 is a group of the formula
• R 8 is methyl
• R 9 is hydrogen
• R o i o r is hydrogen
• R 11 is methyl, 2-aminoeth-1-yl, 4-aminobut-1-yl, 3-guanidinopropan-1-yl or imidazol-4-ylmethyl,
• R 12 is hydrogen
• R 13 is hydrogen
• R 14 is hydrogen
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen
• R 2 is hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
• azetidinyl, pyrrolidinyl or piperidinyl ring having 1 or 2 substituents independently of one another can be substituted from the group fluorine, trifluoromethyl, methyl, ethyl, methoxy and ethoxy,
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen
• R 2 is hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• R 1 is hydrogen
• R 2 is hydrogen
• R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts are examples of N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
• the compounds of the invention show an unpredictable, valuable spectrum of pharmacological activity and are therefore particularly suitable for the prevention and / or treatment of diseases, in particular of acute and / or chronic kidney diseases.
• the compounds of the invention show an advantageous therapeutic and / or pharmacological profile of action.
• adenosine AI selective receptor ligands refers to those adenosine receptor ligands in which, on the one hand, a marked effect on the Al adenosine receptor subtype and, on the other hand, no or a significantly weaker effect (factor 10 or higher) on A2a , A2b and A3 adenosine receptor subtypes, reference being made to the test methods for the selectivity of action (see Methods Bl.).
• the compounds of the invention may function as full or as partial adenosine receptor agonists, depending on their particular structure.
• Partial adenosine receptor agonists are defined herein as receptor ligands that elicit a functional response to adenosine receptors that is lower than full agonists (such as adenosine itself). As a result, partial agonists are less effective in receptor activation than full agonists.
• Partial adenosine AI agonists can also be used in diseases of the kidney in conjunction with other diseases, such as. of the cardiovascular system.
• the partial AI agonites according to the invention are suitable for the prevention and / or the treatment of acute kidney diseases with and without accompanying acute and / or chronic heart diseases.
• the partial AI agonists according to the invention are suitable for the prevention and / or the treatment of chronic kidney diseases with and without accompanying acute and / or chronic heart diseases.
• Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
• Another object of the present invention is the use of partial AI agonists for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
• Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the partial AI agonists.
• Another object of the present invention are the partial AI agonists for use in a method for the treatment and / or prophylaxis of acute kidney diseases.
• Another object of the present invention are the partial AI agonists for use in a method for the treatment and / or prophylaxis of chronic kidney disease.
• the present invention further provides the partial AI agonists for use in a method for the treatment and / or prophylaxis of acute kidney diseases in combination with coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction and atrial fibrillation.
• the present invention further provides the partial AI agonists for use in a method for the treatment and / or prophylaxis of chronic kidney diseases in combination with coronary heart disease, acute coronary syndrome, angina pectoris, heart failure, myocardial infarction and atrial fibrillation.
• Another object of the present invention are the partial AI agonists for use in a method for the treatment and / or prophylaxis of chronic kidney disease in combination with diabetes, metabolic syndrome and dyslipidemias.
• the partial AI agonists may be used alone or as needed in combination with other agents.
• Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
• Suitable combination active ingredients are lipid metabolism-altering active substances, antidiabetics, hypotensives, circulation-promoting and / or antithrombotic agents, antioxidants, chemokine receptor antagonists, p38 kinase inhibitors, NPY agonists, orexin agonists.
• the present invention relates, in particular, to combinations of at least one of the partial AI agonists with at least one lipid metabolism-altering active ingredient, an antidiabetic agent, a hypotensive agent and / or an antithrombotic agent.
• Lipid metabolism-altering agents such as, for example and preferably, from the group of HMG-CoA reductase inhibitors, inhibitors of HMG-CoA reductase expression, squalene synthesis inhibitors, ACAT inhibitors, LDL receptor inducers, cholesterol Abso ⁇ tionhemmer, polymeric Bile acid adsorbers, bile acid reabsorption inhibitors, MTP inhibitors, lipase inhibitors, LpL activators, Fibrates, niacin, CETP inhibitors, PPAR-a, PPAR- ⁇ and / or PPAR-8 agonists, RXR modulators, FXR modulators, LXR modulators, thyroid hormones and / or thyroid mimetics, ATP citrate ly
• Hypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin II ATI receptor antagonists, ACE inhibitors, renin inhibitors, beta-B receptors, alpha-receptors-B relaxers, aldosterone antagonists, mineralocorticoid Receptor antagonists, ECE inhibitors, ACE / NEP inhibitors and the vasopeptidase inhibitors,
• Antithrombotic agents by way of example and with preference from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances, factor Xa inhibitors or vitamin K antagonists,
• Antiinflammatory agents by way of example and preferably from the group of glucocorticosteroids, non-steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs,
• Diuretics such as by way of example and preferably loop diuretics, thiazides, potassium-sparing diuretics, or carbonic anhydrase inhibitors,
• Organic nitrates and NO donors such as, for example, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO,
• cGMP cyclic guanosine monophosphate
• cAMP cyclic adenosine monophosphate
• PDE phosphodiesterases
• Positive inotropic agents such as digitoxin, digoxin, epinephrine, norepinephrine, dobutamine and dopamine,
• Antiproliferative agents such as multikinase inhibitors and preferably sorafenib, imatinib, gefitinib and erlotinib
• Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin; Agonists of the prostacyclin receptor (IP receptor), such as iloprost, beraprost, cicaprost;
• Agonists of the prostacyclin receptor (IP receptor) such as iloprost, beraprost, cicaprost
• RXFP-1 relaxin receptor-1
• Inhibitors of the If (funny channel) channel such as Ivabradine
• Calcium sensitizers such as by way of example and preferably levosimendan; • potassium supplements;
• NO-independent, but heme-dependent guanylate cyclase stimulators in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
• Guanylate cyclase NO- and heme-independent activators in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
• HNE human neutrophil elastase
• the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and or
• the compounds of the invention are administered in combination with a CETP inhibitor such as, by way of example, and preferably dalcetrapib, BAY 60-5521, anacetrapib, torcetrapib, JTT-705 or CETP vaccine (CETi-1).
• a CETP inhibitor such as, by way of example, and preferably dalcetrapib, BAY 60-5521, anacetrapib, torcetrapib, JTT-705 or CETP vaccine (CETi-1).
• the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
• a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
• the compounds 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, cerivastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin ,
• statins such as by way of example and preferably lovastatin, cerivastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin ,
• the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494, RPR 107393 or TAK-475.
• a squalene synthesis inhibitor such as by way of example and preferably BMS-188494, RPR 107393 or TAK-475.
• the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe, lecimibid, CP-113818 or SMP-797.
• an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe, lecimibid, CP-113818 or SMP-797.
• the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757, CP-346086, AEGR-733, LAB678 or JTT-130.
• an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757, CP-346086, AEGR-733, LAB678 or JTT-130.
• the compounds according to the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone, ciglitazone or rosiglitazone.
• a PPAR delta agonist such as by way of example and preferably GW 501516 or BAY 68-5042.
• the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside, pamaqueside or colesevelam.
• a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside, pamaqueside or colesevelam.
• the compounds 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 compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
• ASBT IBAT
• the compounds 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 compounds according to the invention are used in combination with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, nitrendipine, felodipine, lercanidipine, nimodipine, nicardipine, lacidipine, isradipine, nisoldipine, nilvadipine, manidipine, verapamil or Diltiazem administered.
• a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, nitrendipine, felodipine, lercanidipine, nimodipine, nicardipine, lacidipine, isradipine, nisoldipine, nilvadipine, manidipine, verapamil or Diltiazem administered.
• the compounds of the invention are administered in combination with an alpha-1 receptor blocker such as, by way of example and by way of, prazosin, terazosin, doxazosin, trimazosin and the first generation unselective blockers phentolamine and phenoxybenzamine.
• an alpha-1 receptor blocker such as, by way of example and by way of, prazosin, terazosin, doxazosin, trimazosin and the first generation unselective blockers phentolamine and phenoxybenzamine.
• the compounds according to the invention are used in combination with a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol, acebutolol, betaxolol, pindolol, levibunolol or bucindolol
• the compounds according to the invention are administered in combination with an angiotensin AT-1 receptor antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan, irbesartan, eprosartan, olmesartan or embursatan.
• an ACE inhibitor such as, for example and preferably, enalapril, captopril, lisinopril, spirapril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
• the compounds 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, attresentan, ambrisentan or sitaxsentan.
• an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, attresentan, ambrisentan or sitaxsentan.
• the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600, SPP-800, SPP-1148, VTP-27999 or MK-8141.
• a renin inhibitor such as by way of example and preferably aliskiren, SPP-600, SPP-800, SPP-1148, VTP-27999 or MK-8141.
• the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
• the compounds according to the invention are used in combination with a loop diuretic, such as by way of example and preferably bumetanide, ethacrynic acid, gate semid or furosemide; in combination with thiazides, such as, by way of example and by way of illustration, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, metyclothiazide, metolazone or polythiazide; in combination with potassium-sparing diuretics, such as and preferably amiloride, eplerenone, spironolactone or triamterene, and / or in combination with carboanhydrase inhibitors, such as and preferably acetazolamide, dichlorophenamide or methazolamide.
• the compounds according to the invention are administered in combination with a vasopressin receptor antagonist, such as by way of example and
• the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as by way of example and preferably aspirin, clopidogrel, ticlopidine, prasugrel, tirofiban or dipyridamole.
• a platelet aggregation inhibitor such as by way of example and preferably aspirin, clopidogrel, ticlopidine, prasugrel, tirofiban or dipyridamole.
• the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, dabigatran, melagatran, argatroban, bivalirudin, hirudin, lepirudin, desirudin or Clexane.
• the compounds according to the invention are administered in combination with a GPiib / IIaa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
• a GPiib / IIaa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
• the compounds of the invention are used in combination with a factor Xa inhibitor such as, by way of example, rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, edoxaban, enoxaparin, fondaparinux, idraparinux, PMD-3112, 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, rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, edoxaban, enoxaparin, fondaparinux, idraparinux, PMD-3112, YM -150, KFA-1982, EMD
• the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
• LMW low molecular weight
• the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, by way of example and by way of preference, warfarin, coumarin, acenocoumarol, phenprocoumone or dicumarol.
• compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and their use for the purposes mentioned above.
• the compounds according to the invention 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 compounds according to the invention can be administered in suitable administration forms.
• the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
• Tablets uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings which control the release of the compound of the invention
• tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (for example Hart - or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• Parenteral administration may be by circumvention of an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
• an absorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
• absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
• parenteral administration are suitable as application forms u.a. Injection and mfusionszurungen 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 ophthalmic 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.
• the compounds according to the invention 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.
• excipients include excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (For example, albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
• excipients for example microcrystalline cellulose, lactose, mannitol
• solvents for example liquid polyethylene glycols
• emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
• binders for example polyvinylpyrrolidone
• synthetic and natural polymers for example, albumin
• the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described WO 2009/015812.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2010/086101.
• the compound was prepared as described in WO 2009/015811.
• the luciferase test is optimized with the aim of high sensitivity and reproducibility, low variance and good suitability for implementation on a robotic system by varying several test parameters, such as cell density, duration of the culture phase and the test incubation, forskolin concentration and medium composition.
• test parameters such as cell density, duration of the culture phase and the test incubation, forskolin concentration and medium composition.
• the stock cultures are grown in DMEM / Fl 2 medium with 10% FCS (fetal calf serum) at 37 ° C under 5% CO 2 and split 1:10 each after 2-3 days.
• Test cultures are seeded at 2,000 cells per well in 384-well plates and grown at 37 ° C for approximately 48 hours. Then the medium is replaced with a physiological saline solution (130 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 20 mM HEPES, 1 mM magnesium chloride hexahydrate, 5 mM sodium bicarbonate, pH 7.4).
• DMSO substances to be tested are in a dilution series of 5 x 10 "11 M to 3 x 10" 6 M (final concentration) to the test cultures pipetted (maximum DMSO final concentration in test mixture: 0.5%). Ten minutes later, forskolin is added to the AI cells and then all cultures are incubated for four hours at 37 ° C.
• the reference compound used in these experiments is the adenosine-analogous compound NECA (5-N-ethylcarboxamido-adenosine), which binds with high affinity to all adenosine receptor subtypes and has an agonistic activity [Klotz, KN, Hessling, J. , Hegler, J., Owman, C, Kuli, B., Fredholm, BB, Lohse, MJ, "Comparative pharmacology of human adenosine receptor subtypes - characterization of stably transfected receptors in CHO cells", Naunyn Schmiedebergs Arch. Pharmacol. 357, 1-9 (1998)].
• NECA adenosine-analogous compound
• the receptor selectivity and the partiality can be determined by the action of the substances on cell lines which express the respective receptor subtypes after stable transfection with the corresponding cDNA (see in this regard the document ME Olah, H. Ren, J. Ostrowski, KA Jacobson, GL Stiles, "Cloning, expression, and characterization of the unique bovine AI adenosine receptor.” Studies on the ligand binding site by site-directed mutagenesis, "Biol. Chem. 267 (1992), pages 10764- 10770, the disclosure of which is hereby incorporated by reference in its entirety).
• the effect of the substances on such cell lines can be detected by biochemical measurement of the intracellular messenger cAMP (see the document KN Klotz, J. Hessling, J.
• Glycerol-induced hemolysis in rats is an established animal model for the study of haemolysis-induced acute renal failure with a reduction in single-infhrone filtrate and a rapid increase in urine-requiring substances such as creatinine and urea.
• Haemolytic uremia leads to acute blockage of the tubules by protein deposits ("luminal casts") and ultimately to degeneration / necrosis of the tubules, and curative therapy, i.e., an anti-degenerative therapy of structural kidney damage, is not yet known.
• Lipocalin-2 [rel. 114,787,204
• the model is characterized by progressive proteinuria, impaired tubular electrolyte transport, reduced glomerular filtration rate, an increase in urine output, interstitial fibrosis with reactive lymphocyte infiltrates, glomerulosclerosis and tubulus atrophy.
• the level of proteinuria is a specific index of renal function prognosis: the higher the proteinuria, the greater is the functional and structural kidney damage and thus the progression from chronic to terminal renal insufficiency (uremia).
• uremia chronic to terminal renal insufficiency
• the course of proteinuria indicates the functional and structural response to therapy and thus the renal function prognosis.
• Kidney damage marker gene expression
• Creatinine 36 *** 39 *** 386 ⁇ 57 39 **
• EXAMPLE 1 and EXAMPLE 4 on left ventricular diastolic dysfunction measured as hyperresponsive left ventricular pressure decrease per time (in mmHg / s) due to isoprenaline infusion [ng / kg body weight], in 5/6 -tel nephrectomy rat model compared to enalapril as a reference therapy
• the SHR developed overt hypertensive damage to the glomeruli in the remaining kidney, from which time the rats were treated for a further four weeks according to the groups indicated above.
• the following samples were obtained / measured: eight-hour urine collection, invasive measurement of systolic and diastolic left heart function, and TaqMan analyzes of renal damage markers in the renal cortex.
• Kidney damage marker gene expression
• Heart rate beats per minute 318 + 10 352 ⁇ 10 353 ⁇ 7 295 + 11 *** 326 ⁇ 9
• B-fifth Determination of pharmacokinetic parameters after intravenous and oral administration The substance to be tested is administered intravenously to animals (for example mouse, rat, dog) as a solution, and the oral administration is carried out as a solution or suspension by gavage. After substance administration, the animals are bled at fixed times. This is heparinized, followed by plasma by centrifugation. The substance is analytically quantified in the plasma via LC / MS-MS. Pharmacokinetic parameters such as AUC (area under the concentration-time curve), Cmax (maximum plasma concentration), Tl / 2 (half-life) and CL (clearance) are determined from the plasma concentration-time curves thus determined by means of a validated pharmacokinetic calculation program calculated.
• the dissolved test substance is pipetted into suspensions of transil / buffer and transil / plasma. After these incubations, the transil is separated from the respective phase by centrifugation at 1800 g. The substance concentrations before centrifugation and in the supernatant after centrifugation are determined. The free fraction is calculated as the ratio of membrane affinity in plasma (MApiasma) and in buffer (MAp U ff er ).
• test substances Possible effects of a single oral administration of a test substance on behavioral parameters, open field test and body temperature are studied in rats.
• the test substances are administered orally in increasing doses.
• Control animals receive only the vehicle (ethanol / solutol / water (10:40:50, v / v / v).)
• Each treatment group consists of 6 male rats and the animals respond to behavioral changes and changes in body temperature to 0.5, 1 After about 0.5 and 7 hours, the animals are also examined for possible substance-dependent changes in their movement activity in the "open field test.” Plasma concentrations of the test substances are determined in satellite groups.
• the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
• the granules are mixed after drying with the magnesium stearate for 5 minutes.
• This mixture is compressed with a conventional tablet press (for the tablet format see above).
• a pressing force of 15 kN is used as a guideline for the compression.
• a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
• the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
• the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention. iv solution:
• the compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution and / or PEG 400 solution 30%).
• a physiologically acceptable solvent e.g., isotonic saline, 5% glucose solution and / or PEG 400 solution 30%.
• the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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