Soluble guanylate cyclase activator for use in the treatment of heart failure in which the ejection rate in females is maintained

Abstract

The present invention relates to soluble guanylate cyclase (sGC) activators, preferably (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid (luncacyguat) and / or substituted pyrazolopiperidinecarboxylic acids, preferably 1-[1-{4-chloro-4’-[4-(2-methylpropyl)piperazin-1-yl][1,1’-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-{4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-[4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride, 1-{3(R)-1-[4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride hemihydrate or 1-[1-{4-chloro-4’-[4-(2-methylpropyl)piperazin-1-yl][1,1’-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride (enantiomer 1), for the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women, and to their use for the preparation of a medicament for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women.

Description

Technical Field

[0001] The present invention relates to soluble guanylate cyclase (sGC) activators for use in the treatment and / or prevention of heart failure in which the ejection fraction (HFpEF) is maintained in women, preferably (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid (runcaciguat) and / or substituted pyrazolopyridinecarboxylic acids, preferably 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-[4-chloro-4'-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-[4-chloro-4'-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride, 1-{3(R)-1-[4-chloro-4'-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride hemihydrate or 1-[1-{4-chloro-4'-[4-(2-methylpropyl)piperazin-1-yl][1,1'-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride (enantiomer 1), and their use for the preparation of a medicament for use in the treatment and / or prevention of heart failure in which the ejection fraction (HFpEF) is maintained in women.

Background Art

[0002] Suitable sGC activators are known from the following publications (the subject matter disclosed in the following publications also forms part of the subject matter of the disclosure herein): WO 2013 / 157528, WO 2015 / 056663, WO 2009 / 123316, WO 2016 / 001875, WO 2016 / 001876, WO 2016 / 001878, WO 2000 / 02851, WO 2012 / 122340, WO 2013 / 025425, WO 2014 / 039434, WO 2016 / 014463, WO 2009 / 068652, WO 2009 / 071504, WO 2010 / 015652, WO 2010 / 015653, WO 2015 / 033307, WO 2016 / 042536, WO 2009 / 032249, WO 2010 / 099054, WO 2012 / 058132, US 2010 / 0216764, WO 01 / 19776, WO 01 / 19780, WO 01 / 19778, WO 02 / 070459, WO 02 / 070460, WO 02 / 070510, WO 02 / 070462, WO 2007 / 045366, WO 2007 / 045369, WO 2007 / 045433, WO 2007 / 045370, WO 2007 / 045367, WO 2014 / 012935, WO 2014 / 012934, WO 2011 / 141409, WO 2008 / 119457, WO 2008 / 119458, WO 2009 / 127338, WO 2010 / 102717, WO 2011 / 051165, WO 2012 / 076466, WO 2012 / 139888, WO 2013 / 174736.

[0003] The following sGC activators are particularly important: Formula (I)

Chemical formula

[0004] Formula (II)

Chemical formula

[0005] Formula (III)

Chemical formula

[0006] Formula (IV)

Chemical formula

[0007] Formula (V)

Chemical formula

[0008] Formula (VI)

Chemical formula

[0009] One of the most important cell signaling systems in mammalian cells is cyclic guanosine monophosphate (cGMP) signaling. It forms the NO / cGMP system together with nitric oxide (NO), which is released from endothelial cells and transmits hormonal and mechanical signals. Guanylate cyclase catalyzes the biosynthesis of cGMP from guanosine triphosphate (GTP). Representatives of this family that have been identified to date can be divided into two groups according to both structural features and ligand type: particulate guanylate cyclase, which can be stimulated by natriuretic peptides, and soluble guanylate cyclase, which can be stimulated by NO. Soluble guanylate cyclase is composed of two subunits containing one heme per heterodimer, which is part of the regulatory site. The heme domain (H-NOX) is a prerequisite for sGC activation. NO can bind to the iron atom of the heme and thus can significantly increase the activity of the enzyme. Heme-free preparations cannot be stimulated by NO.

[0010] Through the production of cGMP and the regulation of the resulting phosphodiesterases, ion channels, and protein kinases, guanylate cyclase plays an important role in various physiological processes, particularly smooth muscle cell relaxation, platelet aggregation and adhesion, and neuronal signaling, as well as in fibrotic remodeling and inflammation. Under pathophysiological conditions, the NO / cGMP system can be suppressed, which can lead to, for example, hypertension, increased platelet activation, cell proliferation and fibrosis, endothelial dysfunction, atherosclerosis, angina, heart failure, thrombosis, stroke, and myocardial infarction or chronic kidney disease.

[0011] A possible way to treat such disorders, which aim to affect the cGMP signaling pathway in organisms without depending on NO, is a promising approach because it is expected to have high efficiency and few side effects.

[0012] Compounds such as organic nitrates whose effects are based on NO have so far only been used for the therapeutic stimulation of soluble guanylate cyclase. NO is produced by biotransformation and activates soluble guanylate cyclase by binding to the central iron atom of heme. In addition to side effects, the development of resistance is one of the major drawbacks of this treatment method [O. V. Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755].

[0013] Substances that directly stimulate soluble guanylate cyclase, i.e., do not release NO beforehand, have been identified in recent years, and riociguat and vericiguat were approved in 2013 and 2021 [Evgenov et al., ibid., Sandner P, Zimmer DP, Milne GT, Follmann M, Hobbs A, Stasch JP. Soluble Guanylate Cyclase Stimulators and Activators. Handb Exp Pharmacol. 2021;264:355 - 394.

[0014] The common feature of this class of sGC stimulants is the NO-independent and selective activation of heme-containing sGC. Furthermore, sGC stimulants in combination with NO have a synergistic effect on sGC activation based on the stabilization of the nitrosyl-heme complex. The exact binding site of sGC stimulants in sGC is still under discussion, but the heme-free enzyme cannot be stimulated by the above-mentioned sGC stimulants [Evgenov et al., ibid., Sandner et al., 2021].

[0015] However, NO and heme-independent sGC activators (such as BAY 58-2667 as a prototype of this class) have been identified. The general feature of these substances is that they combine with NO and have no additional effect on enzyme activation, and the activation of oxidized or heme-free enzyme is significantly higher than that of heme-containing enzyme [Evgenov et al., ibid.; J.P. Stasch et al., Br. J. Pharmacol. 136 (2002), 773; J.P. Stasch et al., J. Clin. Invest. 116 (2006), 2552, Sandner et al., 2021].

[0016] Here, the compounds described in the present invention can similarly activate soluble guanylate cyclase in its heme-free form. This is also confirmed by the fact that these novel activators, firstly, do not have a synergistic effect with NO in the heme-containing enzyme, and secondly, their action is not blocked by 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a heme-dependent inhibitor of soluble guanylate cyclase, but rather is enhanced by this inhibitor [see O.V. Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755; J.P. Stasch et al., J. Clin. Invest. 116 (2006), 2552]. The sGC activator, lumaciguat (Hahn et al., Drugs Future 43 (2018), 738, International Publication No. WO 2012 / 139888), is under development by BAYER (https: / / www.clinicaltrials.gov / NCT04507061).

[0017] Our understanding of the redox balance of sGC in health and disease remains very limited. Therefore, the therapeutic potential of sGC activators is not yet fully clear. However, since oxidative stress may render the sGC enzyme heme-free, sGC activators may have broad therapeutic potential.

[0018] Heart failure (HF) affects over 40 million people worldwide and can be divided into two major subgroups: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). A reduced heart pump function is the main symptom of HFrEF, while HFpEF (left ventricular ejection fraction ≥50%) is characterized by diastolic filling impairment of the heart due to reduced relaxation ability of the affected myocardium (A.R. Sabbatini, G. Kararigas, J. Am. Coll. Cardiol. 2020;75(9):1074 - 1082). Characteristic pathophysiological changes seen in HFpEF are left ventricular hypertrophy and cardiac fibrosis, leading to diastolic relaxation impairment and increased left ventricular filling pressure (M.R. Zile, C.F. Baicu. J. Cardiovasc. Transl. Res. 2013;6(4):501 - 515), increased myocardial cell stiffness, and systemic inflammation (S.J. Shah et al., Circulation 2016;134(1):73 - 90). HFpEF is often associated with numerous comorbidities such as obesity, renal dysfunction, diabetes, and hypertension (A.R. Sabbatini, G. Kararigas, J. Am. Coll. Cardiol. 2020;75(9):1074 - 1082, review). The annual mortality rate of HFpEF is 10 - 30% (C.W. Yancy et al., J. Am. Coll. Cardiol. 2013;62(16):1495 - 1539). Approximately two - thirds of patients with HFpEF are women (D.C. Scantlebury, B.A. Borlaug, Curr. Opin. Cardiol. 2011;26(6):562 - 568). Since postmenopausal women are mainly affected by HFpEF, it is hypothesized that the decrease in estradiol during this period of life may contribute to the development of left ventricular remodeling, left ventricular hypertrophy, and diastolic dysfunction in HFpEF. Consistent with this, it has been demonstrated that left ventricular hypertrophy (J.P. Singh et al., Am. J. Cardiol. 1999;83(6):1132 - 1134) as well as diastolic dysfunction in postmenopausal women can be improved by postmenopausal hormone therapy.Several pathophysiological mechanisms contributing to the development of HFpEF, such as increased oxidative stress, endothelial dysfunction, arterial hypertension, inflammation, obesity, increased extracellular matrix deposition, and reduced levels of atrial natriuretic peptide and brain peptide, are inhibited by estradiol in premenopausal women and activated during menopause (when estradiol decreases), which may explain why women are more prone to developing HFpEF compared to men (A.R. Sabbatini, G. Kararigas, J. Am. Coll. Cardiol. 2020;75(9):1074-1082, review).

[0019] A variety of drugs with different mechanisms of action have been approved for the treatment of HFrEF, but many outcome trials in HFpEF have failed, and only recently, the first two therapeutic agents: Entresto (a combination of the angiotensin receptor blocker valsartan and neprilysin) and sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) have been approved for HFpEF. The outcome trials of Entresto in HFpEF were overall neutral (S.D. Solomon et al., PARAGON, New Engl. J. Med. 2019; 381(17): 1609-1620). In post hoc analyses, a statistically significant relative risk reduction in the primary composite endpoint was observed in two subpopulations (women and patients with a left ventricular ejection fraction ≤57%). Based on a post hoc analysis combining two outcome trials (one conducted for HFrEF (J.J.V. McMurray et al., PARADIGM, New Engl. J. Med. 2014; 371(11): 993-1004) and the other for HFpEF (S.D. Solomon et al., New Engl. J. Med. 2019; 381: 1609-1620)), the treatment effect of Entresto within a specific range of left ventricular ejection fraction was considered "biologically plausible" (S.D. Solomon et al., New Engl. J. Med. 2019; 381: 1609-1620), but the gender-specific treatment effect observed in PARAGON was ignored. However, these data may suggest that female HfpEF patients may respond differently to chronic heart failure treatment. Given that the disease mainly affects women and considering the high disease burden and mortality in HFpEF patients, there remains a high medical need for new drugs to treat this disease, especially in female patients. The problem underlying the present invention is to provide new medicaments for the treatment of women suffering from HFpEF.

[0020] Formula (I)

Chemical formula

Prior Art Documents

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[0022] [Non-Patent Document 1] O.V. Evgenov et al., Nature Rev. Drug Disc. 5 (2006), 755 [Non-Patent Document 2] Sandner P, Zimmer DP, Milne GT, Follmann M, Hobbs A, Stasch JP. Soluble Guanylate Cyclase Stimulators and Activators. Handb Exp Pharmacol. 2021;264:355 - 394

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Summary of the Invention

Problems to be Solved by the Invention

[0023] Therefore, an object of the present invention is to provide a novel medicament for use in the treatment of heart failure with preserved ejection fraction (HfpEF) in women, which comprises an sGC activator.

Means for Solving the Problems

[0024] Surprisingly, certain substituted pyrazolopiperidine carboxylic acids and their corresponding salts have now been found to be very potent sGC activators with good pharmacokinetic behavior having a good pharmacological activity profile and beneficial physicochemical properties (e.g., solubility). Furthermore, the sGC activator (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid (riociguat) and 1-[1-{4-chloro-4’-[4-(2-methylpropyl)piperazin-1-yl][1,1’-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-{4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-[4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride, 1-{3(R)-1-[4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride hemihydrate or 1-[1-{4-chloro-4’-[4-(2-methylpropyl)piperazin-1-yl][1,1’-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride (enantiomer 1), certain substituted pyrazolopiperidine carboxylic acids selected from the list consisting of are found to be suitable as novel medicaments for use in the treatment of heart failure with preserved ejection fraction (HFpEF) in women while maintaining the ejection rate.

[0025] Accordingly, the present invention consists of the group consisting of the following

Chemical formula

[0026] Accordingly, the present invention provides a group consisting of [Chemical formula] a compound, or a salt thereof, a solvate thereof, or a solvate of a salt thereof, selected for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women while maintaining the ejection rate.

Mode for Carrying Out the Invention

[0027] Preferred with respect to the present invention Salt is a physiologically acceptable salt of the compound according to the present invention. However, the present invention also includes salts which are not themselves suitable for pharmaceutical use but which can be used, for example, for the isolation or purification of the compounds according to the present invention.

[0028] Physiologically acceptable salts of the compounds according to the present invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, such as salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

[0029] Physiologically acceptable salts of the compounds according to the invention are also salts of conventional bases, for example, and preferably alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), as well as ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, for example, and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

[0030] The present invention includes all possible salts of the compounds according to the invention, either as a single salt or as any mixture of said salts in any ratio.

[0031] Regarding the present invention Solvate is described as a form of the compound of the present invention that forms a complex in the solid or liquid state by coordination with solvent molecules. The compounds according to the invention can contain polar solvents, especially water, methanol or ethanol, as structural elements of the crystal lattice of the compound. Hydrates are a specific form of solvates where the coordination is with water. The amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example, hydrates, semi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-solvates or hydrates are possible, respectively. The present invention includes all such hydrates or solvates.

[0032] The compounds of the present invention have beneficial pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.

[0033] The compounds according to the invention are potent activators of soluble guanylate cyclase. They bring about vasorelaxation, inhibition of platelet aggregation, as well as a decrease in blood pressure and an increase in blood flow in the coronary arteries and the kidneys. These effects are mediated via direct heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP.

[0034] In addition, the compounds according to the invention have advantageous pharmacokinetic properties, particularly with regard to their bioavailability and / or duration of action after intravenous or oral administration.

[0035] The compounds according to the invention have an unpredictable spectrum of useful pharmacological activities and good pharmacokinetic behavior, in particular, within a given dosing interval after oral administration, the exposure of such compounds in the blood is sufficient to exceed the minimum effective concentration. Such a profile results in an improved peak-trough ratio (the quotient of the maximum concentration and the minimum concentration) within a given dosing interval, which has the advantage that the compound can be administered less frequently and at a significantly lower dose to achieve the effect. They are compounds that activate soluble guanylate cyclase.

[0036] In the context of the present invention, the terms "treatment" or "treating" include the inhibition, delay, checking, alleviation, attenuation, limitation, reduction, suppression, avoidance or cure of a disease, condition, disorder, injury or health problem or the onset, course or progression of such a condition and / or such a condition. The term "therapy" is understood herein to be synonymous with the term "treatment".

[0037] In the context of the present invention, the terms "prevention", "preventive" and "precluding" are used synonymously and mean the avoidance or reduction of the risk of suffering from, experiencing, or being afflicted with a disease, condition, disorder, injury or health problem, or the onset or progression of such a condition and / or the symptoms of such a condition.

[0038] The treatment or prevention of a disease, condition, disorder, injury or health problem can be partial or complete.

[0039] The compounds according to the invention are particularly suitable for the treatment and / or prevention of cardiovascular and heart diseases, preferably heart failure with preserved ejection fraction (HFpEF) in women.

[0040] Accordingly, the compounds according to the invention can be used in medicaments for the treatment and / or prevention of heart failure, preferably heart failure with preserved ejection fraction (HFpEF) in women.

[0041] For the purposes of the present invention, the term "heart failure" encompasses both acute and chronic forms of heart failure, and further more specific or related types of diseases, such as acute decompensated heart failure, right heart failure, left heart failure, global heart failure, as well as dilated and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), heart failure with mid-range ejection fraction (HFmEF), ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart disease and cardiomyopathy, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, complex heart valve defects, inflammation of the myocardium (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, as well as dilated and systolic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF).

[0042] The inventors tested sGC activators, such as lumaciguat and substituted pyrazolopyridinecarboxylic acids, preferably 1-[1-{4-chloro-4’-[4-(2-methylpropyl)piperazin-1-yl][1,1’-biphenyl]-2-yl}piperidin-3-yl]-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-[4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-{3(R)-1-[4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride, 1-{3(R)-1-[4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride hemihydrate or 1-[1-{4-chloro-4’-[4-(2-methylpropyl)piperazin-1-yl][1,1’-biphenyl]-2-yl}piperidin-3-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid hydrochloride (enantiomer 1), selected from the list consisting of, in a rat model of HFpEF characterized by hypertension, endothelial dysfunction and oxidative stress. These rats have worsening heart and kidney damage and increased mortality. In this model, as in many clinical trials, male rats have been used in the past and the majority of patients are male. The inventors were able to show that sGC activation by lumaciguat (Example 1) and / or 1-{3(R)-1-[4-chloro-4’-(4-isobutylpiperazin-1-yl)[biphenyl]-2-yl]piperidin-3-yl}-5-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (Example 3) has a dose-dependent beneficial effect on both survival and renal function, selected as a very predictive lead-out of HFpEF outcome for the present invention.

[0043] The inventors have surprisingly shown a sex-specific effect in the treatment of HFpEF, providing an effective treatment option for female HFpEF patients.

[0044] The present invention further provides the use of a compound of the invention for the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in which the ejection fraction is maintained in females.

[0045] The present invention further provides the use of a compound according to the invention for the preparation of a medicament for the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in which the ejection fraction is maintained in females.

[0046] The present invention further provides a medicament comprising at least one compound according to the invention for the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in which the ejection fraction is maintained in females.

[0047] The present invention further provides the use of a compound of the invention in a method for the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in which the ejection fraction is maintained in females.

[0048] The present invention further provides a method for the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in which the ejection fraction is maintained in females, using an effective amount of at least one compound according to the invention.

[0049] The present invention further provides a medicament comprising a compound according to the invention and one or more further active compounds.

[0050] The compounds of the present invention can act systemically and / or locally. For this purpose, the compounds can be administered in a suitable manner, for example, orally, parenterally, by inhalation, intranasally, sublingually, on the tongue, buccally, rectally, transdermally, percutaneously, via the conjunctiva or ear, or as an implant or stent.

[0051] For these routes of administration, it is possible to administer the compounds according to the invention in suitable dosage forms.

[0052] For oral administration, the compounds according to the invention can be formulated into dosage forms known in the art for delivery, such as tablets (uncoated or coated tablets, e.g., having an enteric or controlled release coating that dissolves slowly or is insoluble), orally disintegrating tablets, films / wafers, film / freeze-dried products, capsules (e.g., hard gelatin capsules or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions, etc. The compounds according to the invention can be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved forms.

[0053] Parenteral administration can be carried out by avoiding the absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Dosage forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, freeze-dried products or sterile powders.

[0054] Dosage forms suitable for external eye (local) administration function according to the prior art, release the active compound rapidly and / or in a modified or controlled manner, and contain the active compound in crystalline and / or amorphous and / or dissolved forms, such as eye drops, sprays and lotions (e.g., solutions, suspensions, vesicles / colloid systems, emulsions, aerosols), powders for eye drops, sprays and lotions (e.g., ground active compound, mixtures, freeze-dried products, precipitated active compound), semi-solid eye preparations (e.g., hydrogels, in situ hydrogels, creams and ointments), intraocular implants (solid and semi-solid preparations, e.g., bioadhesives, films / wafers, tablets, contact lenses).

[0055] Oral administration is preferred.

[0056] Examples of other suitable routes of administration are pharmaceutical forms for inhalation [in particular powder inhalers, nebulizers], nasal drops, nasal sprays; tablets / films / wafer / capsules for buccal, sublingual, or oral administration; suppositories; eye drops, eye ointments, eye baths, ophthalmic inserts, ear drops, ear sprays, ear powders, ear washes, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (e.g., patches), milks, pastes, foams, dusting powders, implants, or stents.

[0057] The compounds according to the invention can be incorporated into the described dosage forms. This can be done by mixing them with pharmaceutically suitable excipients in a manner known per se. Pharmaceutically suitable excipients include, inter alia, the following: · Fillers and carriers (e.g., cellulose, microcrystalline cellulose (e.g., Avicel®), lactose, mannitol, starch, calcium phosphate (e.g., Di-Cafos®), · Ointment bases (e.g., petrolatum, paraffin, triglycerides, waxes, wool wax, wool wax alcohol, lanolin, hydrophilic ointments, polyethylene glycol), · Suppository bases (e.g., polyethylene glycol, cocoa butter, hard fat), · Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin), · Surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (e.g., Lanette® etc.), sorbitan fatty acid esters (e.g., Span® etc.), polyoxyethylene sorbitan fatty acid esters (e.g., Tween® etc.), polyoxyethylene fatty acid glycerides (e.g., Cremophor® etc.), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (e.g., Pluronic® etc.), · Buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine), · Isotonic agents (e.g., glucose, sodium chloride), · Adsorbents (e.g., highly dispersed silica), · Thickening agents, gel-forming agents, thickeners and / or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomer, polyacrylic acid (e.g., Carbopol® etc.); alginates, gelatin), · Disintegrants (e.g., processed starch, carboxymethylcellulose-sodium, sodium starch glycolate (e.g., Explotab® etc.), crosslinked polyvinylpyrrolidone, croscarmellose-sodium (e.g., AcDiSol® etc.)), · Flow regulators, lubricants, flow promoters and release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersed silica (e.g., Aerosil® etc.)), · Coating materials (e.g., sugar, shellac) and film formers for films or diffusion membranes that dissolve rapidly or in a modified manner (e.g., polyvinylpyrrolidone (e.g., Kollidon® etc.), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polymethacrylate (e.g., Eudragit® etc.)) · Capsule materials (e.g., gelatin, hydroxypropylmethylcellulose), · Synthetic polymers (e.g., polylactide, polyglycolide, polyacrylate, polymethacrylate (e.g., Eudragit® etc.), polyvinylpyrrolidone (e.g., Kollidon® etc.), polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and their copolymers and block copolymers), · Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), · Penetration enhancers, · Stabilizers (e.g., antioxidants, e.g., ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), · Preservatives (e.g., parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), · Colorants (e.g., inorganic pigments, e.g., iron oxide, titanium dioxide), · Flavors, sweeteners, flavor - and / or odor - masking agents.

[0058] The present invention further relates to pharmaceutical compositions comprising at least one compound according to the present invention, together with one or more conventionally pharmaceutically suitable excipients, and to their use according to the present invention.

[0059] One embodiment of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) according to the present invention, preferably together with at least one inert and non-toxic pharmaceutically suitable adjuvant, and the use of these pharmaceutical compositions for the above purposes.

[0060] According to another aspect, the present invention relates to a combination of medicaments, in particular for the treatment and / or prevention of cardiovascular disorders, preferably heart failure with preserved ejection fraction (HFpEF), in particular in women, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular medicaments.

[0061] The term "combination" in the present invention is used as known to those skilled in the art, and said combination can be a fixed combination, a non-fixed combination, or a kit-of-parts.

[0062] The "fixed combination" in the present invention is used as known to those skilled in the art and is defined, for example, as a combination in which a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dose or in one single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the further active ingredient are present in a mixture for simultaneous administration, such as a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and the further active ingredient are present in one unit without being mixed.

[0063] The unfixed combinations or "kits-of-parts" in the present invention are used as known to those skilled in the art and are defined as combinations in which a first active ingredient and further active ingredients are present in two or more units. An example of an unfixed combination or kit-of-parts is a combination in which the first active ingredient and further active ingredients are present separately. The components of the unfixed combination or kit-of-parts can be administered separately, sequentially, simultaneously, concurrently, or with a time-shift in a time series.

[0064] The compounds of the present invention can be used alone or in combination with other active ingredients as required. The present invention further provides a medicament for the treatment and / or prevention of the aforementioned disorders, in particular, comprising at least one compound of the present invention and one or more further active ingredients. Preferred examples of suitable combinations of active ingredients include the following: · Organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; · Compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP), such as inhibitors of phosphodiesterase (PDE) 1, 2, 5, and / or 9, especially PDE5 inhibitors, such as sildenafil, vardenafil, tadalafil, udenafil, desantafil, avanafil, milodenafil, lodenafil or PF-00489791; · Compounds that inhibit the degradation of cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterase (PDE) 3 and 4, especially cilostazol, milrinone, roflumilast, apremilast, or crisaborole; · Hypotensive active ingredients, for example, and preferably, those selected from the group consisting of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors, endothelin antagonists, renin inhibitors, alpha receptor blockers, beta receptor blockers, mineralocorticoid receptor antagonists, rho kinase inhibitors, and diuretics; · Antiarrhythmic drugs, for example, and preferably, those selected from the group consisting of sodium channel blockers, β - receptor blockers, potassium channel blockers, calcium antagonists, If channel blockers, digitalis, parasympathetic blockers (vagolytics), sympathetic stimulants, and other antiarrhythmic drugs such as adenosine, adenosine receptor agonists, and vernakalant; · Positive inotropic agents, for example, cardiac glycosides (digoxin), β - adrenergic and dopaminergic agonists, such as isoprenaline, adrenaline, noradrenaline, dopamine, or dobutamine; · Vasopressin - receptor - antagonists, for example, and preferably, those from the group consisting of conivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, pevavaptan, SR - 121463, RWJ676070, or BAY86 - 8050, and the compounds described in International Publication No. WO 2010 / 105770, International Publication No. WO 2011 / 104322, and International Publication No. WO 2016 / 071212; · Active ingredients that change lipid metabolism, for example, and preferably, those from the group consisting of thyroid receptor agonists, cholesterol synthesis inhibitors, for example, and preferably, HMG - CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR - alpha, PPAR - gamma, and / or PPAR - delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, and lipoprotein(a) antagonists.

[0065] · Bronchodilators, for example, and preferably from the group of β - adrenergic receptor agonists, for example, and preferably, albuterol, isoproterenol, metaproterenol, aricalcitolin, formoterol or salmeterol, or from the group of anticholinergic agonists, for example, and preferably ipratropium bromide; · Anti - inflammatory agents, for example, and preferably from the group of glucocorticoids, for example, and preferably, prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, beclomethasone, betamethasone, flunisolide, budesonide or fluticasone, as well as non - steroidal anti - inflammatory drugs (NSAIDs), for example, and preferably acetylsalicylic acid (aspirin), ibuprofen and naproxen, 5 - aminosalicylic acid derivatives, leukotriene antagonists, TNF - α inhibitors and chemokine receptor antagonists, for example CCR1, 2 and / or 5 inhibitors; · Agents that modulate the immune system, for example immunoglobulins; · Agents that inhibit signal transduction cascades, for example, and preferably from the group of kinase inhibitors, for example, and preferably from the group of tyrosine kinase and / or serine / threonine kinase inhibitors; · Agents that inhibit the degradation and modification of the extracellular matrix, for example, and preferably from the group of inhibitors of matrix - metalloproteinases (MMPs), for example, and preferably inhibitors of chymase, stromelysin, collagenase, gelatinase and aggrecanase (preferably from the group of MMP - 1, MMP - 3, MMP - 8, MMP - 9, MMP - 10, MMP - 11 and MMP - 13), as well as inhibitors of metallo - elastase (MMP - 12) and neutrophil - elastase (HNE), for example sivelestat or DX - 890; · Agents that block the binding of serotonin to its receptor, for example, and preferably, antagonists of the 5 - HT2b receptor; · Organic nitrates and NO donors, such as, and preferably, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; · NO-independent but heme-dependent stimulators of soluble guanylate cyclase, such as, and preferably, the compounds described in WO 00 / 06568, WO 00 / 06569, WO 02 / 42301, WO 03 / 095451, WO 2011 / 147809, WO 2012 / 004258, WO 2012 / 028647 and WO 2012 / 059549; · NO-independent and heme-independent activators of soluble guanylate cyclase, such as, and preferably, the compounds described in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 01 / 19780, WO 02 / 070462 and WO 02 / 070510; · Agents that stimulate the synthesis of cGMP, such as, and preferably, riociguat, cinaciguat, vericiguat or lunciguat; · Prostacyclin analogs, such as, and preferably, iloprost, beraprost, treprostinil or epoprostenol; · Agents that inhibit soluble epoxide hydrolase (sEH), such as, and preferably, N,N'-dicyclohexylurea, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid or 1-adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}-urea; · Agents that interact with glucose metabolism, such as, and preferably, insulin, biguanide, thiazolidinedione, sulfonylurea, acarbose, DPP4 inhibitor, GLP-1 analog or SGLT-2 inhibitor, such as, empagliflozin, dapagliflozin, canagliflozin, sotagliflozin; · Natriuretic peptides, for example, and preferably atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, nesiritide), C-type natriuretic peptide (CNP) or urodilatin; · An activator of cardiac myosin, for example, and preferably omecamtiv mecarbil (CK-1827452); · A calcium sensitizer, for example, preferably levosimendan; · An agent that affects cardiac energy metabolism, for example, and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine, a complete or partial adenosine A1 receptor agonist, for example GS-9667 (previously known as CVT-3619), capadenoson, neradenoson and neradenoson bialanate; · An agent that affects heart rate, for example, and preferably ivabradine; · A cyclooxygenase inhibitor, for example bromfenac and nepafenac; · An inhibitor of the kallikrein-kinin system, for example safotibant and ecallantide; · An inhibitor of the sphingosine 1-phosphate signaling pathway, for example sonidegib mab; · An inhibitor of the complement-C5a receptor, for example eculizumab; · Plasminogen activators (thrombolytics / fibrinolytics) and compounds that promote thrombolysis / fibrinolysis, for example inhibitors of plasminogen activator inhibitors (PAI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitor (TAFI inhibitors), for example tissue plasminogen activator (t-PA, for example Actilyse®), streptokinase, reteplase and urokinase or plasminogen regulators that cause an increase in the formation of plasmin; · Anticoagulants (anticoagulants), for example, heparin (UFH), low molecular weight heparin (LMW), for example, tinzaparin, certoparin, parnaparin, nadroparin, aldeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE5026), adomiparin (M118) and EP-42675 / ORG42675; · Direct thrombin inhibitors (DTIs), for example, Pradaxa (dabigatran), ategacestat (AZD-837), DP-4088, SSR-182289A, argatroban, bivalirudin and tanogitran (BIBT-986 and prodrug BIBT-1011) and hirudin; · Direct factor Xa inhibitors, for example, rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673 / RPR-130673), letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), idraparinux and fondaparinux; · Inhibitors of coagulation factors XI and XIa, for example, FXI ASO-LICA, fesoterodine, BAY121-3790, MAA868, BMS986177, EP-7041 and AB-022; · Substances that inhibit platelet aggregation (platelet aggregation inhibitors, thrombocyte aggregation inhibitors), for example, acetylsalicylic acid (for example, aspirin), P2Y12 antagonists, for example, ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelol and elinogrel, and PAR-1 antagonists, for example, vorapaxar, and PAR-4 antagonists; · Platelet adhesion inhibitors such as GPVI and / or GPIb antagonists, for example, Revacept or Caplacizumab; · Fibrinogen receptor antagonists (glycoprotein-IIb / IIIa antagonists), for example, Abciximab, Eptifibatide, Tirofiban, Lamifiban, Lefradafiban and Fradafiban; · Recombinant human activated protein C, for example, Xigris or recombinant thrombomodulin.

[0066] The antithrombotic agent is preferably understood to mean a compound from the group of platelet aggregation inhibitors, anticoagulants or fibrinolytic promoting substances.

[0067] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a platelet aggregation inhibitor, for example, and preferably, Aspirin, Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine or Dipyridamole.

[0068] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a thrombin inhibitor, for example, and preferably, Ximelagatran, Dabigatran, Melagatran, Bivalirudin or Clexane.

[0069] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a GPIIb / IIIa antagonist, for example, and preferably, Tirofiban or Abciximab.

[0070] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a factor Xa inhibitor, for example, and preferably, rivaroxaban (BAY 59-7939), DU-176b, apixaban, betrixaban, otamixaban, fidaxaban, razaxaban, letaxaban, elixaban, fondaparinux, idraparinux, PMD-3112, darexaban (YM-150), KFA-1982, EMD-503982, MCM-17, MLN-1021, DX9065a, DPC906, JTV803, SSR-126512 or SSR-128428.

[0071] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a factor XI or XIa inhibitor, for example, and preferably, FXI ASO-LICA, fesomersen, BAY121-3790, MAA868, BMS986177, EP-7041 or AB-022.

[0072] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

[0073] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a vitamin K antagonist, for example, and preferably coumarin.

[0074] The antihypertensive agent is preferably understood to mean a compound from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers, mineralocorticoid receptor antagonists, rho kinase inhibitors and diuretics.

[0075] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a calcium antagonist, for example, and preferably, nifedipine, amlodipine, verapamil or diltiazem.

[0076] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an α-1 receptor blocker, by way of example, and preferably prazosin.

[0077] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a beta receptor blocker, by way of example, and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, mecipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

[0078] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an angiotensin AII antagonist, by way of example, and preferably losartan, candesartan, valsartan, telmisartan or embusartanor, a dual angiotensin AII antagonist / neprilysin-inhibitor, by way of example, and preferably LCZ696 (valsartan / sacubitril).

[0079] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an ACE inhibitor, by way of example, and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril, perindopril or trandopril.

[0080] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an endothelin antagonist, by way of example, and preferably bosentan, darusentan, ambrisentan or sitaxsentan.

[0081] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a renin inhibitor, such as, and preferably, aliskiren, SPP-600 or SPP-800.

[0082] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a mineralocorticoid receptor antagonist, such as, and preferably, spironolactone, AZD9977, finerenone or eplerenone.

[0083] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a loop diuretic such as furosemide, torsemide, bumetanide and piretanide, a potassium-sparing diuretic such as amiloride and triamterene, an aldosterone antagonist such as spironolactone, potassium canrenoate and eplerenone, and also a thiazide diuretic such as hydrochlorothiazide, chlorthalidone, xipamide and indapamide.

[0084] The lipid metabolism regulator is preferably understood to mean a compound from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-α, PPAR-γ and / or PPAR-δ agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

[0085] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a CETP inhibitor, such as, and preferably, dalcetrapib, anacetrapib, torcetrapib (CP-529 414), JJT-705 or a CETP vaccine (Avant).

[0086] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a thyroid receptor agonist, such as, and preferably, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS23425 or axitirome (CGS26214).

[0087] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as, and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

[0088] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a squalene synthesis inhibitor, such as, and preferably, BMS-188494 or TAK-475.

[0089] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an ACAT inhibitor, such as, preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

[0090] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an MTP inhibitor, such as, and preferably, implitapide, BMS-201038, R-103757 or JTT-130.

[0091] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a PPAR-gamma agonist, such as, and preferably, pioglitazone or rosiglitazone.

[0092] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a PPAR-delta agonist, such as, and preferably, GW501516 or BAY68-5042.

[0093] In a preferred embodiment of the present invention, the compounds of the present invention are administered, by way of example and preferably, in combination with ezetimibe, ticoeside or pamaqueside.

[0094] In a preferred embodiment of the present invention, the compounds of the present invention are administered, by way of example and preferably, in combination with a lipase inhibitor, orlistat.

[0095] In a preferred embodiment of the present invention, the compounds of the present invention are administered, by way of example and preferably, in combination with a polymeric bile acid sequestrant, cholestyramine, cholestipol, colesolvam, colestagel or cholestimide.

[0096] In a preferred embodiment of the present invention, the compounds of the present invention are administered, by way of example and preferably, in combination with a bile acid reabsorption inhibitor, an ASBT (= IBAT) inhibitor, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

[0097] In a preferred embodiment of the present invention, the compounds of the present invention are administered, by way of example and preferably, in combination with a lipoprotein(a) antagonist, gemcabene calcium (CI-1027) or nicotinic acid.

[0098] In a preferred embodiment of the present invention, the compounds of the present invention are administered, for example and preferably, in combination with a lipoprotein(a) antagonist, gemcabene calcium (CI-1027) or nicotinic acid.

[0099] In a preferred embodiment of the present invention, the compounds of the present invention are administered, by way of example and preferably, in combination with an sGC modulator, riociguat, cinaciguat or vericiguat.

[0100] In a preferred embodiment of the present invention, the compound of the present invention is administered, for example and preferably, in combination with riociguat, cinaciguat or vericiguat.

[0101] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an agent that affects glucose metabolism, for example and preferably, insulin, sulfonylurea, acarbose, DPP4 inhibitor, GLP-1 analog or SGLT-1 inhibitor, empagliflozin, dapagliflozin, canagliflozin, sotagliflozin.

[0102] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a TGFβ antagonist, for example and preferably, pirfenidone or fresolimumab.

[0103] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a CCR2 antagonist, for example and preferably, CCX-140.

[0104] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a TNFα antagonist, for example and preferably, adalimumab.

[0105] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a galectin-3 inhibitor, for example and preferably, GCS-100.

[0106] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an Nrf-2 inhibitor, for example and preferably, bardoxolone.

[0107] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a BMP-7 agonist, for example and preferably, THR-184.

[0108] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a NOX1 / 4 inhibitor, as an example, and preferably, GKT-137831.

[0109] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a medicament that affects vitamin D metabolism, as an example, and preferably, calcitriol, alfacalcidol, doxercalciferol, maxacalcitol, paricalcitol, colecalciferol or paracalcitol.

[0110] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a cell growth inhibitor, as an example, and preferably, cyclophosphamide.

[0111] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an immunosuppressant, as an example, and preferably, cyclosporine.

[0112] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a phosphate binder, as an example, and preferably, cholestyramine, sevelamer hydrochloride and sevelamer carbonate, lanthanum and lanthanum carbonate.

[0113] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a renal proximal tubule sodium-phosphate cotransporter, as an example, and preferably, niacin or nicotinamide.

[0114] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a calcium mimetic for the treatment of hyperparathyroidism.

[0115] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a drug for iron deficiency therapy, as an example, and preferably, an iron product.

[0116] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an agent for the treatment of hyperuricemia, for example, and preferably, allopurinol or rasburicase.

[0117] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a glycoprotein hormone for the treatment of anemia, for example, and preferably, erythropoietin, daprodustat, molidustat, roxadustat, vadadustat, desidustat. In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a biologic for immunotherapy, for example, and preferably, abatacept, rituximab, eculizumab or belimumab.

[0118] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a vasopressin antagonist (the group of vaptans) for the treatment of heart failure, for example, and preferably, tolvaptan, conivaptan, lixivaptan, mozavaptan, satavaptan, pevaptan or relcovaptan.

[0119] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a Jak inhibitor, for example, and preferably, ruxolitinib, tofacitinib, baricitinib, CYT387, GSK2586184, lestaurtinib, pacritinib (SB1518) or TG101348.

[0120] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with a prostacyclin analog for the treatment of microthrombi.

[0121] In a preferred embodiment of the present invention, the compound of the present invention is administered in combination with an alkali therapy, for example, and preferably, sodium bicarbonate.

[0122] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an mTOR inhibitor, such as, and preferably, everolimus or rapamycin.

[0123] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an NHE3 inhibitor, such as, and preferably, AZD1722 or tenapanor.

[0124] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with an eNOS modulator, such as, and preferably, sapropterin.

[0125] In a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a CTGF inhibitor, such as, and preferably, FG-3019.

[0126] The present invention further provides a medicament comprising at least one compound of the present invention, typically together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and its use for the aforementioned purposes.

[0127] The compounds according to the present invention can act systemically and / or locally. For this purpose, they can be administered in a suitable manner, for example, orally, parenterally, by inhalation, nasally, sublingually, on the tongue, buccally, rectally, dermally, transdermally, by the conjunctival, otic route, or as an implant or stent.

[0128] The compounds according to the present invention can be administered in dosage forms suitable for these administration routes.

[0129] Dosage forms suitable for oral administration are dosage forms that act according to the prior art, which rapidly and / or in a modified manner release the compounds according to the invention and contain the compounds according to the invention in crystalline and / or amorphous and / or dissolved forms. For example, tablets (uncoated tablets or coated tablets, e.g., insoluble coatings that control the release of the compounds of the invention, or tablets with gastric juice resistance or delayed solubility), tablets or film / wafer strips that rapidly disintegrate in the mouth, films / freeze-dried products or capsules (e.g., hard gelatin capsules or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0130] Parenteral administration can bypass the absorption process (e.g., intravenous, intraarterial, intracardiac, intraspinal or intraluminal), or can include absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Dosage forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, freeze-dried products or sterile powders.

[0131] For other routes of administration, suitable examples are inhalable pharmaceutical forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films / wafer strips or capsules for buccal, sublingual or oral administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g., patches), milks, pastes, foams, powders for dusting, implants or stents.

[0132] Oral or parenteral administration, particularly oral and intravenous administration, is preferred.

[0133] The compounds of the present invention can be converted into the above-mentioned dosage forms. This can be done by mixing with inert and non-toxic pharmaceutically suitable excipients by methods known per se. These excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxy sorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), dyes (e.g., inorganic pigments, e.g., iron oxide), and flavor and / or odor correctors.

[0134] Generally, in the case of parenteral administration, it has been found advantageous to administer an amount of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight, in order to achieve effective results.

[0135] In the case of oral administration, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg, more preferably about 0.01 to 10 mg / kg, more preferably about 0.01 to 3 mg / kg, still more preferably about 0.03 to 2 mg / kg, still more preferably about 0.03 to 0.7 mg / kg, and still more preferably about 0.3 to 2 mg / kg body weight.

[0136] In the case of oral administration, the oral administration / dosage form contains 0.1 mg to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 120 mg, still more preferably 20 mg to 120 mg, still more preferably 30 mg to 120 mg, still more preferably 2.5 mg to 50 mg, more preferably 2 to 50 mg, more preferably 2 to 40 mg, more preferably 2 to 30 mg, more preferably 2.5 to 40 mg, more preferably 2.5 to 30 mg. Suitable amounts of the active ingredient are, for example, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 m, 90 mg, 100 mg, 120 mg, 125 mg, 150 mg, 175 mg, or 200 mg.

[0137] For the compound of formula (I), suitable amounts for the oral dosage form are, for example, 0.1 mg to 500 mg, preferably 1 mg to 140 mg, preferably 1 mg to 200 mg, more preferably 2.5 mg to 120 mg, still more preferably 20 mg to 120 mg, still more preferably 30 mg to 120 mg. Suitable amounts of the active ingredient of formula (I) are, for example, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 120 mg, 125 mg or 130 mg.

[0138] For the compounds of formula (II), (III), (IV), (V) or (VI), a suitable amount for oral dosage forms is, for example, from 0.1 mg to 500 mg, preferably from 1 mg to 140 mg, more preferably from 2.5 mg to 50 mg, more preferably from 2 mg to 50 mg, more preferably from 2 to 40 mg, more preferably from 2 mg to 30 mg, more preferably from 2.5 mg to 40 mg, more preferably from 2.5 mg to 30 mg. Suitable amounts of the active ingredient of formula (II), (III), (IV), (V) or (VI) are, for example, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg.

[0139] Nevertheless, it may be necessary, in appropriate cases, to deviate from the amounts described, specifically as a function of body weight, route of administration, individual response to the active compound, nature of the preparation, and the time or interval at which administration is carried out. For example, in some cases the minimum amount described above may be sufficient, while in other cases the upper limit mentioned must not be exceeded. In the case of relatively large doses, it may be recommended to divide these into several individual doses over the course of a day.

[0140] The total amount of the active ingredient to be administered is generally in the range of about 0.001 mg / kg to about 200 mg / kg body weight per day, preferably about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg, more preferably about 0.01 to 10 mg / kg, more preferably about 0.01 to 3 mg / kg, still more preferably about 0.03 to 2 mg / kg, still more preferably about 0.03 to 0.7 mg / kg, still more preferably about 0.3 to 2 mg / kg body weight per day. Clinically useful dosing schedules range from once to three times a day to once every four weeks. Further, "drug-free days" during which the patient is not administered the drug for a certain period of time can be beneficial for the overall balance of pharmacological effects and tolerance. The unit dose contains about 0.5 mg to about 1500 mg of the active ingredient and can be administered once or more than once a day or less than once a day. The average daily dose for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and for the use of infusion techniques is preferably 0.01 to 200 mg / kg total body weight. The average daily rectal dosing regimen is preferably 0.01 to 200 mg / kg total body weight. The average daily vaginal dosing regimen is preferably 0.01 to 200 mg / kg total body weight. The average daily topical dosing regimen desirably administers 0.1 to 200 mg one to four times a day. The transdermal concentration is preferably the concentration required to maintain a daily dose of 0.01 to 200 mg / kg. The average daily inhalation dosing regimen is preferably 0.01 to 100 mg / kg total body weight.

[0141] Of course, the specific initial and continuing dosing regimens for each patient will vary according to the nature and severity of the condition being judged by the attending physician, the activity of the specific compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of drug excretion, the drug combination, etc. The desired mode of treatment and the number of administrations of the compounds of the present invention or their pharmaceutically acceptable salts or esters or compositions can be confirmed by those skilled in the art using conventional therapeutic tests.

[0142] Notwithstanding, i.e., it may be necessary to deviate from the amounts described, depending on body weight, route of administration, individual response to the active substance, type of preparation, and the time or interval at which administration takes place. Thus, in some cases it may be sufficient to use less than the minimum amount described above, while in other cases the upper limit described above must not be exceeded. When administering in larger amounts, it may be recommended to distribute these in several individual doses throughout the day.

[0143] According to further embodiments, the compound of formula (I) according to the invention is administered orally once, twice or three times a day. According to further embodiments, the compound of formula (I) according to the invention is administered orally once or twice a day. According to further embodiments, the compound of formula (I) according to the invention is administered orally once a day. For oral administration, immediate release or modified release dosage forms may be used.

[0144] Unless otherwise specified, the percentages in the following tests and examples are by weight and the parts are parts by weight. Solvent ratios, dilution ratios, and concentration data for liquid / liquid solutions are based on volume in each case. "w / v" means "weight / volume". For example, "10% w / v" means that 100 ml of the solution or suspension contains 10 g of the substance.

[0145] Specific examples of the present invention

[0146] 1. For use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women,

Chemical formula

[0147] 2. For use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women, of formula (I) [Chemical formula] is one of the compounds of formula (I), or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

[0148] 3. A compound of formula (II) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women [Chemical formula] is one of the compounds of formula (II), or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

[0149] 4. A compound of formula (III) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women [Chemical formula] is one of the compounds of formula (III), or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

[0150] 5. A compound of formula (IV) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women [Chemical formula] is a compound of formula (IV).

[0151] 6. A compound of formula (V) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women [Chemical formula] is a compound of formula (V).

[0152] 7. A compound of formula (VI) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women [Chemical formula] is a compound of formula (VI).

[0153] 8. Use of a compound according to any one of claims 1 - 7 for the manufacture of a medicament for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women.

[0154] 9. A medicament comprising a compound according to any one of claims 1 - 7 in combination with an inert, non - toxic, pharmaceutically suitable excipient for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women.

[0155] 10. The medicament according to claim 9, comprising an active ingredient in an amount of 0.1 mg to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 120 mg, still more preferably 20 mg to 120 mg, still more preferably 30 mg to 120 mg, still more preferably 2.5 mg to 50 mg, more preferably 2 mg to 50 mg, more preferably 2 mg to 40 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 40 mg, more preferably 2.5 mg to 30 mg.

[0156] 11. The medicament according to claim 10, comprising a compound of formula (I) in an amount of 0.1 mg to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 120 mg, still more preferably 20 mg to 120 mg, still more preferably 30 mg to 120 mg

Chemical formula

[0157] 12. The medicament according to claim 10, comprising a compound of formula (II) in an amount of 0.1 mg to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 50 mg, more preferably 2 mg to 50 mg, more preferably 2 mg to 40 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 40 mg, more preferably 2.5 mg to 30 mg

Chemical formula

[0158] 13. From 0.1 mg to 500 mg, preferably from 1 mg to 140 mg, more preferably from 2.5 mg to 50 mg, more preferably from 2 mg to 50 mg, more preferably from 2 mg to 40 mg, more preferably from 2 mg to 30 mg, more preferably from 2.5 mg to 40 mg, more preferably from 2.5 mg to 30 mg of the compound of formula (III)

Chem.

[0159] 14. From 0.1 to 500 mg, preferably from 1 mg to 140 mg, more preferably from 2.5 mg to 50 mg, more preferably from 2 to 50 mg, more preferably from 2 to 40 mg, more preferably from 2 mg to 30 mg, more preferably from 2.5 mg to 40 mg, more preferably from 2.5 mg to 30 mg of the compound of formula (IV)

Chem.

[0160] 15. From 0.1 to 500 mg, preferably from 1 mg to 140 mg, more preferably from 2.5 mg to 50 mg, more preferably from 2 to 50 mg, more preferably from 2 to 40 mg, more preferably from 2 mg to 30 mg, more preferably from 2.5 mg to 40 mg, more preferably from 2.5 mg to 30 mg of the compound of formula (V)

Chem.

[0161] 16. 0.1 to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 50 mg, more preferably 2 to 50 mg, more preferably 2 to 40 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 40 mg, more preferably 2.5 mg to 30 mg of formula (VI)

Chemical formula

[0162] 17. A method for the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women by administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 7 or a pharmaceutical according to any one of claims 9 to 16.

Example

[0163] Experimental section 1. A. Chemical test compound

[0164] Example 1 Formula (I)

Chemical formula

[0165] Example 2 Formula (II)

Chemical formula

[0166] Example 3 Formula (III)

Chemical formula

[0167] Example 4 Formula (IV)

Chemical formula

[0168] Example 5 Formula (V)

Chemical formula

[0169] Example 6 Formula (VI)

Chem.

[0170] B. Evaluation of pharmacological efficacy and pharmacokinetic profile The following abbreviations are used:

Table 1

[0171] Biological test The test experimental examples described herein are useful for illustrating the present invention, and the present invention is not limited to the given examples.

[0172] The commercial utility of the compounds according to the present invention can be demonstrated using the following assays.

[0173] The examples were tested one or more times in selected biological assays. When tested multiple times, the data are reported as either the mean or the median, where · The mean, also called the arithmetic mean, represents the sum of the obtained values divided by the number of tests, · The median represents the middle number of a group of values when ranked in ascending or descending order. When the number of values in the data set is odd, the median is the middle value. When the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

[0174] The examples were synthesized one or more times. When synthesized multiple times, the data from the biological assays represent the mean calculated using data sets obtained from testing one or more synthesis batches.

[0175] The in vitro activity of the compounds of the present invention can be demonstrated by the following assays.

[0176] The pharmacological effects of the compounds of the present invention can be demonstrated in the following assays:

[0177] B-1. RenTG rat model Ethical statement: All animal experiments were conducted in accordance with current national laws (German Animal Protection Law and EU Directive on the Protection of Animals Used for Scientific Purposes). All tests performed were approved by the local regulatory authority (LANUV NRW in Germany) and the Institutional Animal Care and Use Committee of Bayer AG.

[0178] Test design and results: Eight-week-old male and female renin transgenic rats [TG(mRRen2)27] (RenTG rats) were used. The rats were randomized into groups of 12 - 24 rats / group. Then, all groups were chronically supplemented with L-NAME administered via drinking water (30 - 50 mg / L). L-NAME was dissolved in tap water and stored at room temperature. All groups were treated by forced oral administration with placebo / vehicle consisting of 10% Transcutol, 20% Cremophor and 70% tap water or different doses of each verum. The verum was dissolved in the vehicle and freshly prepared before administration. The test period with concomitant administration of L-NAME and treatment was up to 12 weeks. Baseline blood pressure was measured by the tail-cuff method before the start of treatment and at different time points during the test. Mortality and body weight were evaluated daily. Urine samples were collected using metabolic cages, and urine was collected over 6 hours to quantify proteinuria as a correlation of different urinary biomarkers for renal function and kidney and organ damage. At the end of the test, all animals were kept under deep anesthesia, bled by aortic puncture, euthanized by permanent inhalation of isoflurane, blood was collected to evaluate plasma parameters, and the heart and kidneys were weighed and collected for histopathological evaluation.

[0179] B-1.1 Survival rate evaluation of male rats The survival rate in % of RenTG / L-NAME-supplemented male rats treated with either placebo or lumicasertib (Example 1) at 1, 3, and 10 mg / kg BID was investigated (see Table 1).

[0180] Table 1: Survival rate (%) of RenTG / L-NAME-supplemented male rats [Table 2]

[0181] Example 1 (lumicasertib) was effective in the RenTG rat model and increased the survival rate in a dose-dependent manner (see Figure 2). 58% of the rats died in the placebo-treated control group. In contrast, oral BID treatment with Example 1 (lumicasertib) at 1 mg / kg, 3 mg / kg, and 10 mg / kg decreased the mortality rate to 56%, 39%, and 28%, respectively. The 3 mg / kg treatment with Example 1 (lumicasertib) showed a strong numerical trend, while the 10 mg / kg treatment group reached statistical significance. In summary, the treatment with Example 1 (lumicasertib) decreased the mortality rate in a dose-dependent manner.

[0182] To further confirm the treatment effect of Example 1 (lumicasertib) in RenTG rats, the inventors also evaluated renal function by analysis of proteinuria (urinary protein-to-creatinine ratio, uPCR).

[0183] B-1.2 Renal function evaluation by analysis of proteinuria (urinary protein / creatinine ratio, uPCR) in male rats The urinary protein-to-creatinine ratio was investigated in RenTG / L-NAME-supplemented male rats treated with either placebo (set at 100%) or Example 1 (lumicasertib) at 1, 3, and 10 mg / kg BID (see Table 2).

[0184] Table 2: Urinary protein / creatinine ratio in RenTG / L-NAME-supplemented male rats

[0185]

Table 3

[0186] In summary, Example 1 (lunkacidguanide) was dose-dependently effective in the male RenTG rat model and improved both survival and renal function.

[0187] However, the effect of Example 1 (lunkacidguanide) in female RenTG rats was not known.

[0188] For further evaluation of lunkacidguanide in female RenTG rats, the inventors selected the dose of Example 1 (lunkacidguanide) of 3 mg / kg BID that was effective in male rats. Furthermore, Example 3 at the same dose was used. Similar to male rats, survival rate and renal function were examined.

[0189] B-1.3 Survival rate evaluation of female rats The survival rate in % of RenTG / L-NAME-supplemented female rats treated with either placebo or 3 mg / kg of Example 1 (lunkacidguanide) or 3 mg / kg of Example 3 BID was investigated (see Table 3).

[0190] Table 3: Survival rate (%) of RenTG / L-NAME-supplemented female rats

Table 4

[0191] The effects of Example 1 (lunkacidguanide) and Example 3 were significantly higher in female animals, compared to only 60% in the male group (B1.1 (see Figure 2), all animals (100%) treated with 3 mg / kg of Example 1 (luncacidin guat) survived (see Figure 4). Also, treatment with Example 3 provided a substantial survival benefit, with over 90% of female RenTG rats treated with Example 3 surviving.

[0192] Mortality in the female study trended lower (64% of placebo-treated animals survived in the female control group compared to 42% in the male control group), so the inventors also analyzed mortality in male rats when 64% of male control animals survived. At this point, the survival rate of male rats treated with Example 1 (luncacidin guat) at 3 mg / kg BID was 70%. Again, this is 30% lower than the survival rate of female rats treated with 3 mg / kg BID of Example 1 (luncacidin guat).

[0193] To further validate the inventors' findings, the inventors analyzed proteinuria in female RenTG rats treated with Example 1 (luncacidin guat) and Example 3.

[0194] B-1.4. Renal function evaluation by analysis of proteinuria (urinary protein / creatinine ratio, uPCR) in female rats Urinary protein-to-creatinine ratio in RenTG / L-NAME-supplemented female rats treated with placebo (set at 100%) or either 3 mg / kg of Example 1 BID or Example 3 BID. Data are mean ± SEM.

[0195] Table 4: Urinary protein / creatinine ratio in RenTG / L-NAME-supplemented female rats

Table 5

[0196] Either 3 mg / kg BID of Example 1 (Lumacaftor) or Example 3 was able to significantly reduce proteinuria by 55% and 84% respectively (see Figure 5). This was also more effective compared to male rats treated with 3 mg / kg BID of Example 1 (Lumacaftor) which resulted in a 29% reduction in proteinuria.

[0197] These data confirmed the results of mortality in male RenTG rats versus female RenTG rats, and the sGC activator had a greater effect in females compared to male RenTG rats.

[0198] In summary, these data strongly suggest that sGC activators, particularly Example 1 (Lumacaftor) and Example 3, may represent a novel and very effective treatment option for HFpEF, and will be particularly useful and effective for the treatment of female HFpEF patients.

[0199] The reason for this significantly higher benefit in female HFpEF rats was not understood and was novel to the inventors. To the inventors' knowledge, this has not been studied until now. However, it is speculated that it may be due to the increased oxidative stress and endothelial dysfunction described as important pathophysiological mechanisms in HFpEF (J Am Coll Cardiol 2020;75(9):1074 - 1082, review). The compound class of sGC activators specifically binds to the heme - free sGC and can simulate cGMP synthesis in the absence of NO under conditions of oxidative stress (see Figure 2). Interestingly, women with HFpEF are mostly post - menopausal and have various comorbidities such as diabetes, kidney disease, hypertension, and obesity, which can increase oxidative stress. Therefore, the treatment of female HFpEF patients with sGC activators could be a very effective treatment option and should be further studied and demonstrated by respective clinical studies in the future.

[0200] In B-1.3, the survival evaluation of Example 3 (compounds of formulas (II)-(VI)) was included in female rats. These results suggest a very high efficacy of the sGC activator Example 3 against the survival rate (92.3%) in female rats, but, as in Example 1, did not directly show the male-to-female comparison.

[0201] B-1.5. Survival rate evaluation in male, female, and ovariectomized (OVX) female rats A direct comparison of the sGC activator Example 3 in male rats, female rats, and female rats that had undergone ovariectomy (OVX) in a once-daily administration (OD) regimen showed that the survival rate in male rats was 7% lower than that in female rats. 93% of the male rats survived, while all of the female rats survived in the sGC activator treatment group (100%). The survival rate of female OVX rats was not different compared to non-OVX rats.

[0202] Table 5a-c: Survival rate in % of RenTG / L-NAME supplemented male (a), female (b) and female OVX (c) rats

[0203] Table 5a: Male rats [Table 6]

[0204] Table 5b: Female rats [Table 7]

[0205] Table 5c: Female OVX rats [Table 8]

[0206] B-1.6. Renal function evaluation by analysis of proteinuria (urinary protein to creatinine ratio, uPCR) in male, female and ovariectomized (OVX) female rats The most prominent difference between males and females was seen in proteinuria. In male rats, proteinuria significantly decreased by 57% when treated with sGC activator Example 3. In female rats, these effects were far more prominent, with proteinuria decreasing by 88% and 99% in female rats without OVX and with OVX, respectively. These data clearly show the superiority of sGC activator Example 3 in female rats compared to male rats, and further decreased in OVX rats. These data strongly suggest that postmenopausal female patients can benefit most from treatment with sGC activators.

[0207] Table 6: Urinary protein-to-creatinine ratio in RenTG / L-NAME-supplemented male, female, and female OVX rats

Table 9

[0208] B-2. Clinical trial of HFpEF Women with HFpEF [defined as LVEF ≥ 45% + left ventricular hypertrophy or left atrial hypertrophy and NT-pro BNP level ≥ 300 pg / mL (in the absence of atrial fibrillation) or ≥ 600 pg / mL (in the presence of atrial fibrillation) at randomization] were randomized within 3 months from heart failure decompensation, defined as the need for intravenous diuretic treatment for heart failure with or without hospitalization, to treatment with placebo or one of various doses of sgc activator Example 1 or Example 3 in a double-blind, multi-center trial. The primary readout parameter was the change in 6-minute walk distance (6MWD) 24 weeks after treatment initiation, and the secondary readout parameters were safety and tolerability measured by the number of adverse events caused by the treatment. For example, women who are unable to participate in an aerobic exercise test due to comorbidities that limit exercise, such as chronic obstructive pulmonary disease, interstitial lung disease, intermittent claudication, orthopedic or neurological conditions that interfere with exercise ability, anemia, wheelchair use, walking aids, or nasal oxygen, are excluded from the study. To detect a true delta of at least 30 m increase in 6MWD in the sgc activator group compared to the placebo group, assuming a common standard deviation of 70 meters (5% alpha and 90% power), 116 patients per group are required to obtain a p-value of less than 0.05.

[0209] C. Examples of pharmaceutical compositions The release-modulated (GITS) formulation containing Example 1 is disclosed in International Publication No. WO 2020 / 020789. The compounds of the present invention can be converted into pharmaceutical formulations as follows:

[0210] Tablet: Composition: 100 mg of the compound according to the present invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (natural), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate. Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

[0211] Production: A mixture of the compound of the present invention, lactose, and starch is granulated with a 5% solution (w / w) of PVP in water. The granules are dried and then mixed with magnesium stearate for 5 minutes. This mixture is compressed using a conventional tableting machine (see the above for tablet format). The guide value for pressing is a pressing force of 15 kN.

[0212] Suspension for oral administration: Composition: 1000 mg of the compound of the present invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum, from FMC, Pennsylvania, USA), and 99 g of water. 10 ml of the oral suspension corresponds to a single dose of 100 mg of the compound of the present invention.

[0213] Production: Suspend Rhodigel in ethanol and add the compound of the present invention to the suspension. Add water while stirring. Stir the mixture for about 6 hours until the swelling of Rhodigel is complete.

[0214] Solution for oral administration: Composition: 500 mg of the compound of the present invention, 2.5 g of polysorbate, and 97 g of polyethylene glycol 400. 20 g of the oral solution corresponds to a single dose of 100 mg of the compound of the present invention.

[0215] Production: The compound of the present invention is suspended with stirring in a mixture of polyethylene glycol and polysorbate. The stirring process continues until the compound according to the present invention is completely dissolved.

[0216] Intravenous injection solution: The compound according to the present invention is dissolved at a concentration less than its saturated solubility in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution and / or 30% PEG400 solution). The solution is sterilized by filtration and used to fill a sterile, pyrogen-free injection container.

Brief Description of the Drawings

[0217]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Claims

【Request Item 1】 【Chemistry 1】 【change】 A compound, a salt thereof, a solvate thereof, or a solvate thereof selected from the group consisting of the above, for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women.

2. Formula (I) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women. 【Chemistry 2】 A compound according to claim 1, or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

3. Formula (II) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women. 【Transformation 3】 A compound according to claim 1, or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

4. Formula (III) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women. 【Chemistry 4】 A compound according to claim 1, or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

5. Formula (IV) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women. 【Transformation 5】 The compound according to claim 1.

6. Formula (V) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women. 【Transformation 6】 The compound according to claim 1.

7. Formula (VI) for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women. 【Transformation 7】 The compound according to claim 1.

8. A pharmaceutical product for use in the treatment and / or prevention of heart failure with preserved ejection fraction (HFpEF) in women, comprising a compound according to any one of claims 1 to 7 in combination with an inert, non-toxic, and pharmaceutically suitable excipient.

9. The pharmaceutical product according to claim 8, comprising 0.1 mg to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 120 mg, even more preferably 20 mg to 120 mg, even more preferably 30 mg to 120 mg, even more preferably 2.5 mg to 50 mg, even more preferably 2 mg to 50 mg, even more preferably 2 mg to 40 mg, even more preferably 2 mg to 30 mg, even more preferably 2.5 mg to 40 mg, and even more preferably 2.5 mg to 30 mg of the active ingredient.

10. Formula (I) in amounts of 0.1 mg to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 120 mg, more preferably 20 mg to 120 mg, and more preferably 30 mg to 120 mg. 【Transformation 8】 The pharmaceutical product according to claim 9, comprising the compound.

11. Formula (II) in amounts of 0.1 mg to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 50 mg, more preferably 2 mg to 50 mg, more preferably 2 mg to 40 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 40 mg, and more preferably 2.5 mg to 30 mg. 【Chemistry 9】 The pharmaceutical product according to claim 9, comprising one of the following: a compound thereof, a salt thereof, a solvate thereof, or a solvate of a salt thereof.

12. Formula (III) in amounts of 0.1 mg to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 50 mg, more preferably 2 mg to 50 mg, more preferably 2 mg to 40 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 40 mg, and more preferably 2.5 mg to 30 mg. 【Chemistry 10】 The pharmaceutical product according to claim 9, comprising one of the following: a compound thereof, a salt thereof, a solvate thereof, or a solvate of a salt thereof.

13. Formula (IV) in amounts of 0.1 to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 50 mg, more preferably 2 to 50 mg, more preferably 2 to 40 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 40 mg, and more preferably 2.5 mg to 30 mg. 【Chemistry 11】 The pharmaceutical product according to claim 9, comprising the compound.

14. Formula (VI) in amounts of 0.1 to 500 mg, preferably 1 mg to 140 mg, more preferably 2.5 mg to 50 mg, more preferably 2 to 50 mg, more preferably 2 to 40 mg, more preferably 2 mg to 30 mg, more preferably 2.5 mg to 40 mg, and more preferably 2.5 mg to 30 mg. 【Chemistry 12】 The pharmaceutical product according to claim 9, comprising the compound.

15. Use of at least one compound according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment and / or prevention of heart failure with maintained ejection fraction (HFpEF) in women by administration of a therapeutically effective dose of at least one compound according to any one of claims 1 to 7.

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