Chromanol compounds for the treatment of heart failure

Abstract

The present invention relates to certain chromanol, quinone, or hydroquinone compounds and their derivatives for treating heart failure with reduced ejection fraction (HFrEF). Specifically, the present invention relates to chromanol compounds selected from S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone and S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone, and pharmaceutically acceptable salts thereof.

Description

Detailed Description of the Invention

[0001] I. FIELD OF THE INVENTION The present invention relates to chromanol compounds and derivatives thereof for the treatment or prevention of heart failure with reduced ejection fraction (HFrEF).

[0002] II. Description of the Background Art Heart failure is a clinical diagnosis characterized by symptoms and signs, including shortness of breath, fatigue, and elevated venous pressure, caused by overt cardiac dysfunction (Pearse and Cowie 2014).

[0003] There are various types of heart failure, which are generally classified as heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and congestive heart failure. Generally, these conditions are treated differently, and medications suitable for one type of heart failure are generally not suitable for treating other types of heart failure.

[0004] HFrEF is typically quantified with reference to left ventricular ejection fraction (LVEF), obtained from echocardiography, with values ​​above 50–60% considered normal. Patients with heart failure with preserved ejection fraction also exhibit values ​​≥ 50%. Values ​​below 40% are considered reduced LVEF (HFrEF), while patients with an LVEF in the 40–49% range represent the “intermediate zone,” defined as heart failure with a mildly reduced ejection fraction (HFmrEF). Patients with HFmrEF are most likely to have primarily mild systolic dysfunction but also have features of diastolic dysfunction.

[0005] Differentiation of patients with HF based on LVEF is important because underlying etiologies, demographics, comorbidities, and response to treatment differ.

[0006] Asymptomatic structural or functional cardiac abnormalities (e.g., systolic or diastolic left ventricular (LV) dysfunction) are precursors to heart failure. However, valvular, pericardial, endocardial, cardiac rhythm, and conduction abnormalities can also cause heart failure (often two or more abnormalities are present).

[0007] Patients with heart failure with reduced ejection fraction also have left ventricular systolic dysfunction, which is commonly combined with a component of diastolic dysfunction. (Yancy et al. JACC Vol. 62, No. 16, 2013)

[0008] Identification of the cardiac disorder underlying heart failure is crucial for therapeutic reasons, as the exact pathology determines the specific treatment used (e.g., valve repair or replacement for valvular disease, specific drug therapy for HF with reduced EF, heart rate reduction in tachycardial cardiomyopathy, etc.) (ESC Guidelines 2016).

[0009] WO 2020 / 096862 describes a cardiac device for remodeling a cardiac ventricle as a percutaneous treatment of heart failure with reduced ejection fraction, the device comprising: a force distribution means configured to extend from a first ventricular wall to a second ventricular wall; and a first plurality of anchoring means configured to secure the force distribution means to a first region of tissue in the first ventricular wall.

[0010] Russian Patent Application Publication No. 2422136 discloses a method for treating chronic heart failure with reduced left ventricular ejection fraction using a beta-blocker, a diuretic, a recombinant human interleukin and an ACE inhibitor.

[0011] Despite the availability of such methods, there remains a need for new methods or compounds for the treatment of heart failure with reduced ejection fraction.

[0012] It is an object of the present invention to provide compounds for the treatment or prevention of heart failure with reduced ejection fraction (HFmrEF or HFrEF).

[0013] III. Summary of the Invention The above objectives are met by providing certain chromanol, quinone or hydroquinone compounds for use in such treatment.

[0014] The above objects are met by the present invention by providing a compound according to Formula (I), (II), a hydroquinone analogue of Formula (II), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of heart failure with reduced ejection fraction.

[0015] [ka] wherein R1 represents hydrogen or a prodrug moiety that can be removed in biological tissue; -One of the following: R2 and R3, together with the N atom to which they are attached, form a saturated or unsaturated non-aromatic optionally substituted 5-8 membered ring having 1-4 N, O or S atoms, and R2 and R3, together, containing 3-12 carbon atoms; or R2 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R3 is an alkyl group optionally substituted with nitrogen or oxygen, the alkyl group containing 3 to 12 carbon atoms, the alkyl group of R3 containing one or more non-aromatic cyclic structures which may contain nitrogen or oxygen atoms in the ring and which may contain linear and / or branched substituted groups, and one or more ethylenic unsaturations.

[0016] In the context of the present invention, compounds according to formula (II) include hydrogenated quinone (ie, hydroquinone) analogs, although quinone derivatives are preferred from the standpoint of stability.

[0017] The compound of formula II is one of the metabolites of the compound according to formula I. Thus, the compound of formula I is a prodrug of the compound of formula II,

[0018] In preferred embodiments, the nitrogen may be an amine, quaternary amine, guanidine, or imine, the oxygen is a hydroxyl, carbonyl, or carboxylic acid; and / or the oxygen and nitrogen may together form an amide, urea, or carbamate group.

[0019] In a preferred embodiment, R1 in formula (I) is hydrogen or together with the 6-oxygen forms an ester group having 2 to 6 carbon atoms.

[0020] In a preferred embodiment of a compound of either Formula (I) or Formula (II), R2 and R3, together with the N atom to which they are attached, form a saturated ring incorporating an additional N atom, which ring is unsubstituted or substituted with an alcohol or alkanol group having 1 to 4 carbon atoms (e.g., ethylol).

[0021] In another preferred embodiment, R2 is a hydrogen atom and R3 comprises a saturated ring structure having 4 to 7 carbon atoms and 1 nitrogen atom, which ring is optionally substituted with an alkyl group, an alcohol group, or a group having 1 to 4 carbon atoms which may include oxygen, a carboxylic acid, or an amine group.

[0022] In another preferred embodiment, the compound is a compound according to Formula II, wherein R2 is a hydrogen atom and R3 comprises a ring structure having 4 to 6 carbon atoms and 1 nitrogen atom, the ring being unsubstituted or substituted with an alcohol or alkanol group having 1 to 4 carbon atoms (e.g., ethylol), preferably substituted with methyl, ethyl, or alcohol-substituted methyl or ethyl, as appropriate.

[0023] In another preferred embodiment, the compound is a compound according to Formula I, wherein R2 is a hydrogen atom and R3 comprises a saturated cyclic structure having 4 to 7 carbon atoms and 1 nitrogen atom, the ring being unsubstituted or substituted with an alcohol or alkanol group having 1 to 4 carbon atoms (e.g., ethylol), preferably optionally substituted with methyl, ethyl, or alcohol-substituted methyl or ethyl.

[0024] According to yet another preferred embodiment, the compound is either (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-121), ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride (SUL-13), or (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-109), as a racemic mixture or as one of its enantiomers, or a pharmaceutically acceptable salt thereof.

[0025] In the most preferred embodiment, the compound is the (2R)-enantiomer of SUL-121, i.e., (2R)-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-150) or a pharmaceutically acceptable salt thereof, although the S enantiomer is effective, and the R enantiomer is believed to be even more effective.

[0026] In a preferred embodiment according to the present invention, the compound according to either formula (I) or formula (II) has a molecular weight of less than 500 Da.

[0027] In a preferred embodiment according to the present invention, the compound according to either formula (I) or formula (II) is for use in the treatment or prevention of heart failure with reduced ejection fraction (HFmrEF), where the ejection fraction is reduced to 50% or less, and even more preferably, the compound according to either formula (I) or formula (II) is for use in the treatment or prevention of heart failure with reduced ejection fraction (HFrEF), where the ejection fraction is reduced to 40% or less. [Brief explanation of the drawings]

[0028] IV. Brief Description of the Drawings [Figure 1] These results show that SUL-150 administration prevents, at least to some extent, the development of heart failure with reduced ejection fraction. Long-term administration of doxorubicin to rats leads to heart failure with reduced ejection fraction, characterized by decreases in (A) heart rate, (B) ejection fraction, (C) stroke work, and (D) cardiac output. Oral administration of SUL-150, either prophylactically or therapeutically, prevents at least some of these changes in cardiac function. *p<0.05 vs. Sham, †p<0.05 vs. doxorubicin / vehicle. [Figure 2] EGFP synthesis correlates with cell size and protein synthesis in H9C2 cardiomyocytes. (A) Phenylephrine dose-dependently increases H9C2 cardiomyocyte cell surface area and (B) EGFP expression. (C) H9C2 cardiomyocyte surface area correlates with EGFP expression. (D) Phenylephrine dose-dependently increases H9C2 cardiomyocyte protein synthesis. (E) H9C2 cardiomyocyte protein synthesis correlates with EGFP expression. (F) Phenylephrine induces EGFP expression in H9C2 cardiomyocytes compared to vehicle-treated control cardiomyocytes. The protein synthesis inhibitor brefeldin A reduces EGFP expression in H9C2 cardiomyocytes. [Figure 3]SUL compounds inhibit phenylephrine-induced hypertrophy in rat H9C2 cardiomyocytes. Phenylephrine induces EGFP expression in H9C2 cardiomyocytes in a dose-dependent manner (gray lines, Figures A-H). Preincubation with 30 μM of (A) SUL-11, (B) SUL-99, (C) SUL-127, (D) SUL-13, (E) SUL-138, or (F) SUL-138M2, the primary metabolite of SUL-138, (G) SUL-150, or (H) SUL-151 reduced EGFP expression by cardiomyocytes. [Figure 4] We demonstrate that SUL-150 administration prevents doxorubicin-induced cardiac fibrogenesis. Chronic administration of doxorubicin to rats leads to fibrogenesis characterized by increased collagen deposition between cardiomyocytes. Oral administration of SUL-150, either preventively or therapeutically, prevents cardiac fibrogenesis and reduces collagen content in cardiac tissue. [Figure 5] These results demonstrate that SUL-150 administration reduces cardiac oxidative stress. Chronic doxorubicin administration induces cardiac oxidative stress, as indicated by an increase in lipid peroxidation products (TBARS, A). Oral SUL-150 administration, either as a prophylactic or therapeutic regimen, prevents the induction of cardiac oxidative stress and maintains lipid peroxidation product levels at baseline (A). Because oxidative stress can result from increased radical production or decreased radical scavenging activity, cardiac radical scavenging was investigated (B). Neither doxorubicin nor SUL-150 administration altered cardiac radical scavenging activity. [Figure 6]These results demonstrate that SUL-150 administration maintains cardiac energy levels and mitochondrial copy number. Chronic doxorubicin administration depletes cardiac ATP levels (normalized to ADP), suggesting mitochondrial dysfunction (A). SUL-150 administration, either as a preventative or therapeutic regimen, attenuates cardiac energy loss. Chronic doxorubicin administration reduces cardiac mtDNA copy number (B), which is thought to be due to ATP loss. SUL-150 attenuates the decrease in mtDNA copy number. In doxorubicin-treated rats, mtDNA copy number is associated with cardiac ejection fraction (EF), suggesting that maintenance of cardiac mitochondrial mass underlies improved myocardial contractility (C). [Figure 7] We demonstrate that SUL-150 maintains the activity of respiratory complex IV under doxorubicin stress. H9C2 cardiomyoblasts were exposed to doxorubicin (1 μM) for 24 hours, after which their mitochondria were isolated and assessed for complex IV activity. Doxorubicin exposure reduced complex IV activity, which was alleviated by co-treatment of H9C2 cardiomyoblasts with SUL-150.

[0029] V. Detailed Description of the Invention The object of the present invention to provide a compound for the treatment or prevention of heart failure with reduced ejection fraction (HFrEF) is met by providing a compound according to formula (I) or (II) as shown above, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of HFrEF.

[0030] Treatment or prevention with chromanol, quinone or hydroquinone compounds according to the invention is preferably part of a combination therapy with one or more other common means for treating heart failure.

[0031] R1 may be a substituent that is easily removed in the human body so that the compound is a prodrug. R1 may be, for example, an amino acid derivative or an ester derivative, and generally has a molecular weight of less than 100 daltons.

[0032] In a preferred embodiment, R1 in formula (I) is hydrogen or, together with the 6-oxygen, forms an ester group having 2 to 6 carbon atoms. The ester may contain one or more ether or alcohol groups. Suitable esters include acetate, butyrate, 3-hydroxybutyrate, etc.

[0033] In a preferred embodiment of a compound of either Formula (I) or Formula (II), R2 and R3 together with the N atom to which they are attached form a saturated ring having 3 to 6 carbon atoms and incorporating one additional N atom, which ring is optionally substituted with 1 to 4 carbon atoms which may contain oxygen, carboxylic acid, or amine groups.

[0034] More preferably, R2 and R3 together with the N atom to which they are attached form a 5- to 7-membered ring containing one additional amine group, which ring is optionally substituted with methyl, ethyl, or alcohol-substituted methyl or ethyl.

[0035] In another preferred embodiment, R2 is a hydrogen atom and R3 comprises a ring structure having 3 to 6 carbon atoms and 1 nitrogen atom.

[0036] More preferably, R2 is a hydrogen atom and R3 comprises a 5- to 7-membered ring containing one additional amine group attached to the amide nitrogen, the ring optionally being substituted with methyl, ethyl, or alcohol-substituted methyl or ethyl.

[0037] In either case, the ring (the cyclic structure formed by R2 and R3, or the cyclic structure of R3 alone) may be unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms, an alcohol, or an alkanol group having 1 to 4 carbon atoms (e.g., ethylol).

[0038] In a preferred embodiment according to the present invention, the compound according to either formula (I) or formula (II) has a molecular weight of less than 500 Da.

[0039] In a preferred embodiment, the compound for use according to the invention is a chromanol compound according to formula I.

[0040] Certain chromanol compounds are described in WO 2014 / 098586. The compounds described in detail have the abbreviation SUL-XXX (XXX is a two- or three-digit number). Many of these compounds are racemic mixtures, but several enantiomers have also been tested. Suitable methods for preparing the chromanol compounds according to the present invention are described in WO 2014 / 098586 or WO 2014 / 011047.

[0041] WO 2017 / 060432 discloses amide derivatives of 2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid and methods for preparing such compounds.

[0042] Hydrogenated quinone derivatives can be easily prepared by hydrogenation of the quinone structure.

[0043] According to yet another preferred embodiment, the compound is either (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-121), ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride (SUL-13), or (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-109), as a racemic mixture or as one of its enantiomers, or a pharmaceutically acceptable salt thereof.

[0044] In the most preferred embodiment, the compound is the R-enantiomer of SUL-121, namely R-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-150) or a pharmaceutically acceptable salt thereof.

[0045] The counter ion in pharmaceutically acceptable salt can be any counter ion known in the art.Preferably, the compound has at least one basic nitrogen that can be protonated, amine.The counter ion is preferably halogen, such as chloride, sulfate, citrate, formate, etc., and most preferably chloride.

[0046] These compounds are available as racemic mixtures or in substantially pure enantiomeric form.The compounds have one or more chiral centers, typically one or two chiral centers.

[0047] Preferably, the compound is substantially enantiomerically pure. Substantially enantiomerically pure means an enantiomeric excess of about 95% or greater, more preferably about 98% or greater, and most preferably about 99% or greater. These amounts also apply when the compound contains two or more chiral centers.

[0048] The compounds are preferably used in an amount effective to achieve treatment or prevention of HFrEF.HFrEF, where the ejection fraction is about 40% or less.

[0049] The term treatment or prevention includes ameliorating the symptoms of heart failure and / or inhibiting the progression of heart failure, including improving cardiac function such as heart rate and cardiac output.

[0050] Preferably, the compounds according to the invention are for use in the treatment or prevention of HFrEF in a mammalian organism, the mammal being preferably a human.

[0051] HFrEF is typically quantified with reference to left ventricular ejection fraction (LVEF), obtained from echocardiography, with values ​​above 50–60% considered normal. Patients with heart failure with preserved ejection fraction also exhibit values ​​≥ 50%. Values ​​below 40% are considered reduced LVEF (HFrEF), while patients with an LVEF in the 40–49% range represent the “intermediate zone,” defined as heart failure with a mildly reduced ejection fraction (HFmrEF). Patients with HFmrEF are most likely to have primarily mild systolic dysfunction but also have features of diastolic dysfunction.

[0052] The present invention provides compounds for use in the treatment of HFrEF with a preserved ejection fraction of 50% or less (HFmrEF) and about 40% or less (HFrEF). Preferably, the compounds for use in treatment are for treating HFrEF with a preserved ejection fraction of about 40% or less.

[0053] The effect is generally observed at a dose of about 1 μM in body fluids, although higher doses are preferably used. Preferred amounts are concentrations of about 10 μM or more, more preferably about 20 μM or more, in vivo or in vitro. Generally, a concentration of about 200 μM or less in humans should be sufficient and safe.

[0054] For human use, this means a dosage of about 10 mg or greater, assuming a volume of distribution of 30 L, 100% availability, and a concentration of about 1 μM. Preferred amounts result in a concentration of about 10 μM, with dosages of about 100 mg or greater being appropriate. Thus, preferably, dosage forms of about 20 mg or greater, preferably 50 mg or greater, and preferably 100 mg or greater are appropriate.

[0055] Generally, solid oral dosage forms contain up to about 500 mg, preferably about 450 mg or less of the compound, taking into account excipients.

[0056] For parenteral administration, for example intravenously (iv), or other liquid forms, larger amounts can be administered.

[0057] An example of a dosage that can be used is an effective amount of the compound of the present invention in a dosage of 0.2 mg / kg or more, for example, preferably in the range of about 1 mg / kg to about 100 mg / kg, or in the range of about 2 mg / kg to about 40 mg / kg body weight, or in the range of about 3 mg / kg to about 30 mg / kg body weight, or in the range of about 4 mg / kg to about 15 mg / kg body weight. The compound of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times daily.

[0058] The compounds described herein can be formulated as pharmaceutical compositions by formulating them with excipients such as pharmaceutically or physiologically acceptable pharmaceutical excipients, carriers, and vehicles.

[0059] Suitable pharmaceutically or physiologically acceptable excipients, carriers, and vehicles include, for example, processing agents and drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, cyclodextran, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low-melting waxes, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients include "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991).

[0060] The pharmaceutical composition preferably comprises a unit dose formulation, the unit dose being sufficient to have a therapeutic effect. The unit dose may be a dose administered periodically during the course of treating or suppressing a disease.

[0061] The compounds of the present invention can be administered enterally, orally, parenterally, sublingually, by inhalation (e.g., as a mist or spray), rectally, or topically in dosage unit formulations containing conventional non-toxic pharmaceutically or physiologically acceptable carriers, adjuvants, and excipients as desired. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intratarsal injection, or infusion techniques. The compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and excipients appropriate for the desired administration route.

[0062] Generally, oral administration is the preferred route of administration, and formulations suitable for oral administration are the preferred formulations.

[0063] The compounds described for use herein can be administered in solid, liquid, or aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injections, creams, solutions, suppositories, enemas, colonic washes, emulsions, dispersions, food premixes, and other suitable forms. The compounds can also be administered in liposomal formulations.

[0064] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in propylene glycol. Acceptable excipients and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils have traditionally been used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0065] Suppositories for rectal administration of drugs can be prepared by mixing the drug with suitable non-irritating pharmaceutical excipients such as cocoa butter and polyethylene glycol, which are solid at room temperature but liquid at rectal temperature and therefore melt in the rectum to release the drug.

[0066] Oral solid dosage forms can include capsules, tablets, pills, powders and granules.In such solid dosage forms, active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch.Such dosage forms can also contain other materials other than inert diluents, such as lubricants such as magnesium stearate.In the case of capsules, tablets and pills, dosage forms can also contain buffering agents.Tablets and pills can also be prepared with enteric coating.

[0067] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also contain adjuvants (e.g., wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents).

[0068] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the host to which the active ingredient is administered and the specific mode of administration.The selected unit dose is usually prepared and administered to provide a specified final concentration of drug in blood, tissue, organ, or other target area of ​​the body.The effective amount for a given situation can be easily determined by routine experimentation and is within the skill and judgment of an ordinary clinician or person skilled in the art.

[0069] The invention will now be further described by way of the following examples, in which reference is made to the drawings.

[0070] VI. Working Examples Example 1 The efficacy of the compounds of the present invention for the treatment or prevention of HFrEF was tested in vivo in rats.Doxorubicin, an anthracycline antibiotic used in cancer chemotherapy, was used to induce heart failure with reduced ejection fraction in a preclinical rat model (Christiansen et al. (2006) Eur. J. Cardiothorac. Surg. 30:611-616; Ertunc et al. (2009) Pharmacology 84:240-248; Hayward et al. (2007) J. Am. Ass. Lab. Animal Sci. 46:20-32).

[0071] experiment SUL-150 (250 mg) was dissolved in 100% EtOH (1.02 mL) and further diluted with distilled water (68.7 mL) to obtain a clear 10 mM solution. The SUL-150 solution was sprayed evenly onto standard food pellets (1.25 kg). The food pellets were air-dried overnight. Food pellets were prepared fresh weekly. Since the food pellets contained 200 mg of SUL-150, which approximates a daily food intake of 25 g for a 350 g rat, the daily dose of SUL-150 was approximately 5 mg / day.

[0072] Male outbred Wistar rats (10-12 weeks old) weighing 250-300 grams were housed under a 12-hour light / dark cycle and provided with ad libitum access to standard chow containing distilled water. Thirty rats were administered doxorubicin (2 mg / kg) by intraperitoneal injection weekly for 9 consecutive weeks and were either left untreated (standard chow diet, 10 rats) or fed a diet supplemented with SUL-150 as prophylaxis (before the first doxorubicin administration, 10 rats) or treatment (starting after the sixth doxorubicin administration, 10 rats). Sham control rats (8 rats) were administered saline by intraperitoneal injection weekly for 9 consecutive weeks and were fed a standard chow diet. All rats underwent cardiac function evaluation 12 weeks after the first doxorubicin administration.

[0073] Cardiac function tests (PV loop assessment) were performed under anesthesia (isoflurane in O (100% FiO)) followed by orotracheal intubation. Rats were placed on a mechanical rodent ventilator (Harvard Apparatus, Holliston, MA) at a tidal volume of 10 mL / kg and 70 breaths per minute. A small window was made below the sternum, and a 2F microtip pressure conductance catheter (SPR-838; Millar Instruments, Houston, TX) was inserted through a small incision directly into the left ventricle (LV) via the apex of the heart. After stabilization, signals were recorded with a pressure-volume conductance system (MPVSSUL Ultra, Millar Instruments, Houston, TX) connected to a data acquisition system (PowerLab, AD Instruments, Colorado Springs, CO).

[0074] Mean arterial pressure (MAP), LV stroke work (LVSW), stroke volume (SV), LV end-diastolic volume (LVEDV), LV end-systolic pressure (LVESP), ratio of mean arterial pressure to LV end-systolic pressure (MAP LVESP), LV ejection fraction (LVEF), heart rate (HR), maximum slope of LV systolic pressure increment (dP / dt max), and time constant of LV pressure decay (tau) were obtained under steady-state conditions.

[0075] For preload maneuvers, the inferior vena cava was compressed and data were collected to assess preload recruitment stroke work (PRSW), dP / dt-end-diastolic volume relationship (dP / dt EDV), and the slopes of the end-systolic and end-diastolic PV relationships (ESPVR and EDPVR).

[0076] Volume calibration was performed using fresh, heparinized, warm blood from each animal, and 50 mL of 7.5% hypertonic saline was injected at the end of each experiment for parallel conductance volume calibration.

[0077] Data were analyzed using GraphPad Prism 8.0 (GraphPad Software Inc., CA). All results are expressed as mean ± SD (standard deviation) or median and interquartile interval. Differences between groups were assessed by ANOVA followed by pairwise comparisons to the sham and vehicle-treated groups, with p-values ​​adjusted for multiple comparisons using the FDR correction.

[0078] result Figure 1 shows that chronic administration of doxorubicin to rats leads to the development of heart failure as indicated by a decrease in heart rate, ejection fraction, and stroke work, ultimately resulting in a severe decrease in cardiac output ( * indicates p<0.05 vs. sham). Figure 1 further shows that administration of SUL-150 via food pellets prior to doxorubicin administration (prophylactic group) substantially preserved cardiac function, with significant preservation of ejection fraction and cardiac output († indicates p<0.05 vs. doxorubicin-treated group). Administration of SUL-150 via food pellets after six cumulative doxorubicin doses (treatment group) substantially improved cardiac function compared to the untreated group (p<0.05 vs. doxorubicin-treated group), with parameters not different from those obtained for the prophylactic group, demonstrating that SUL-150 is a therapeutic agent for heart failure.

[0079] Table 1 shows that doxorubicin-induced heart failure manifests as heart failure with reduced ejection fraction (HFrEF), characterized by a decrease in both contractile and relaxing capacity, indicating remodeling or fibrosis within cardiac tissue.

[0080] Administration of SUL-150, either as a prophylactic or therapeutic regimen, preserves contractile capacity (i.e., dP / dTmax, contractile efficiency) and relaxation capacity (i.e., ), suggesting, without wishing to be bound by theory, that SUL-150 inhibits cardiac fibrosis or increases the energy of contraction.

[0081] conclusion Doxorubicin-induced heart failure is characterized by a decrease in cardiac contractility and therefore cardiac output. Treatment with 6-chromanol SUL-150 substantially improves cardiac contractile function and therefore cardiac output.

[0082] [Table 1]

[0083] Example 2 Example 2 shows that in in vitro experiments, several different compounds according to the invention have improved efficacy compared to Trolox not according to the invention and several other Trolox derivatives.

[0084] Ventricular hypertrophy portends worsening hemodynamically stressful conditions such as hypertension and valvular disease, which are directly associated with heart failure with reduced ejection fraction (HFrEF).

[0085] Ventricular hypertrophy in heart failure results from increased cardiac mass and asymmetric interventricular septal thickening. Histological features include increased cardiomyocyte size (i.e., cardiomyocyte hypertrophy), disorganized myocyte arrangement (myofibril disarray), and both perivascular and interstitial fibrosis, a common phenotype in many cardiomyopathies.

[0086] Pathological cardiomyocyte hypertrophy is characterized by a shift in gene expression profile, including upregulation of fetal cardiac myosin heavy chain beta (MHC-β) instead of the predominant adult α isoform (MHC-α), skeletal muscle α-actin (SKA), and atrial natriuretic factor (ANF) genes. Furthermore, cardiomyocytes switch to a carbohydrate-dependent energy mechanism instead of fatty acid oxidation, which itself requires changes in the expression levels of metabolic genes. Interestingly, both pathophysiological adaptations are associated with increased transcriptional activity downstream of CREB, JNK, NFκB, and NFAT.

[0087] In vitro assays to investigate cardiomyocyte hypertrophy and screen for putative small molecule inhibitors of cardiomyocyte hypertrophy utilize well-characterized inducers of hypertrophy (e.g., phenylephrine or IL-6) combined with transcriptome screening of typical genes upregulated during cardiomyocyte hypertrophy and quantification of cardiomyocyte surface area. However, these assays are laborious and time-consuming, making them unacceptable for rapid screening of larger small molecule compounds.

[0088] An alternative method to indirectly quantify protein synthesis and cardiomyocyte size is quantification of enhanced green fluorescent protein (EGFP) expression under the control of the canonical cytomegalovirus (CMV) enhancer / promoter element [Vettel, 2012]. The CMV promoter contains multiple functional binding sites for CREB, NFκB, and NFAT. Therefore, in vitro expression of EGFP by cardiomyocytes inhibits cardiomyocyte hypertrophy [Vettel, 2012] and can be used as a high-throughput platform to screen small molecules that may have clinical efficacy in treating heart failure.

[0089] The following compounds were tested (Table 2):

[0090] [Table 2]

[0091] Experimental design Culture and differentiation of H9C2 cardiomyocytes Rat H9C2 cardiomyoblasts (ATCC CRL-1446) were maintained in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution (Sigma-Aldrich) and passaged when the cultures reached 70% confluency. Prior to the experiments, H9C2 myoblasts were differentiated into cardiomyocytes by serum depletion (to 1%) and stimulation with 20 nM retinoic acid for 5 days. Differentiated H9C2 cardiomyocytes were cultured at 0.6-10% CO for all experiments. 5 cells / cm2 The seeds were sown in.

[0092] Cell size determination H9C2 cardiomyocytes were serum-starved for 24 h and then treated with different concentrations of phenylephrine (dose range 2·10 -5 ~1·10 -11 M) for an additional 24 hours. Cells were washed with ice-cold PBS and fixed with 2% paraformaldehyde in PBS for 10 minutes at room temperature. Fixed cells were incubated with 5 μM rhodamine-conjugated phalloidin (ThermoFisher Scientific) and washed extensively with PBS. Fluorescent photographs were taken randomly using a Zeiss AxioObserver Z1 microscope, and cell size was analyzed using CellProfiler software [McQuin, 2018].

[0093] Quantification of EGFP synthesis as a proxy for cell size. H9C2 cardiomyocytes (0.6·10 5 cells / cm 2 ) were infected with CMV-copGPF (MOI 10) in serum-free culture medium for 24 h. H9C2 cardiomyocytes were preincubated with 30 μM SUL compounds under standard culture conditions for 30 min, followed by phenylephrine (dose range 2·10 -5 ~1·10 -11 The cells were stimulated with 100 μl of 25 mM Tris, 2 mM dithiothreitol, 2 mM EDTA, and 1% Triton X-100 for an additional 24 hours. The H9C2 cardiomyocytes were then lysed in 100 μl of soft lysis buffer (25 mM Tris, 2 mM dithiothreitol, 2 mM EDTA, and 1% Triton X-100, pH 7.4). The fluorescence intensity per well of the resulting supernatant was recorded using a CLARIOStar Plus plate reader (BMG Labtech) equipped with a FITC filter set (excitation at 488 nm with a 10 nm bandwidth; emission at 515 nm with a 20 nm bandwidth).

[0094] Statistical evaluation All experiments were performed in triplicate per condition and averaged. Data from two individual experiments were used for evaluation in GraphPad Prism 8.0 (GraphPad Software Inc., CA). Mean H9C2 cardiomyocyte size was related to mean EGFP levels using linear regression. Phenylephrine-induced EGFP synthesis was normalized using baseline levels as 0% and maximum EGFP recording as 100%. All data sets were normalized to vehicle controls. Four-parameter nonlinear regression was used to determine the efficacy of phenylephrine to induce GFP synthesis. The efficacy of SUL compounds in inhibiting phenylephrine-induced EGFP synthesis was calculated as 100%-E max where Emax is the maximum effect induced by phenylephrine.

[0095] result EGFP synthesis is associated with H9C2 cardiomyocyte hypertrophy. H9C2 cardiomyoblasts were differentiated into cardiomyocytes according to established protocols and treated with increasing doses of phenylephrine:(1·10 -11 ~2·10 -5 M) for 24 hours. Phenylephrine increased cardiomyocyte hypertrophy in a dose-dependent manner (EC 50 is 7.4 10 -10 ) compared the cell surface area of ​​H9C2 cardiomyocytes to 791 ± 263 μm in vehicle-treated control cardiomyocytes. 2 From 2·10 -5 M 3278 ± 296 μm in cardiomyocytes exposed to phenylephrine 2 Similarly, phenylephrine increased EGFP fluorescence in a dose-dependent manner in H9C2 cardiomyocytes transduced with CMV-EGFP lentiviral particles (EC 50 is 5.2 10 -9 M) (Figure 2B). Increased H9C2 cardiomyocyte surface area (R) associated with EGFP expression. 2 (EC 0.5601, p < 0.001; Figure 2C). Similar to the increase in cell surface area, phenylephrine dose-dependently increased protein synthesis by H9C2 cardiomyocytes (EC 50 is 5.5 10-10 ; Fig. 2D), which was also associated with an increase in EGFP fluorescence (R 2 (Equation 2E is 0.5734, p<0.0001; Figure 2E). Addition of the broadly effective protein synthesis inhibitor brefeldin A inhibited the phenylephrine-induced increase in EGFP fluorescence (Figure 2F), suggesting that EGFP is newly synthesized upon phenylephrine stimulation, thereby validating our experimental setup.

[0096] Sul compounds inhibit the H9C2 cardiomyocyte hypertrophic response. Phenylephrine induces EGFP expression in H9C2 cardiomyocytes in a dose-dependent manner (Figures 3A–H, gray lines). Preincubation of H9C2 cardiomyocytes with 30 μM of either SUL-11, -99, -127, -13, -138, -138M2, -150, or -151 reduced phenylephrine-induced EGFP expression. However, compounds according to the present invention (SUL-13, -138, -150, or -151) clearly showed increased potency and efficacy (Table 2). Notably, SUL-138M2, a primary metabolite of SUL-138, exhibited greater potency in inhibiting EGFP expression than SUL-138, suggesting that SUL-138 may act as a prodrug in this experiment. Furthermore, the R- and S-enantiomers of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone, SUL-150 and SUL-151, respectively, were equally potent in inhibiting EGFP expression by H9C2 cardiomyocytes (Fig. 2G and H, respectively).

[0097] The results are further summarized in Table 3.

[0098] [Table 3]

[0099] Example 3 The following experiment was designed after discovering the unexpected results of Example 1. The following findings may be useful in understanding why the SUL-type compounds of the present invention are effective in treating heart failure with reduced ejection fraction.

[0100] This Example 3 shows that DOX-induced heart failure is accompanied by cardiac fibrosis (increased collagen deposition) and oxidative stress (increased lipid peroxidation), which may result from mitochondrial dysfunction (decreased cardiac mtDNA copy number and ATP production).

[0101] SUL-150 attenuated these pathological processes and maintained cardiac mitochondrial function at homeostatic levels in either preventive or therapeutic models. In isolated mitochondria, SUL-150 attenuated the DOX-induced decline in respiratory complex IV activity, suggesting this may be the mechanism underlying the observed therapeutic effects.

[0102] Experimental design Preparation of SUL-150 food pellets SUL-150 (250 mg) was dissolved in 100% EtOH (1.02 mL) and further diluted with distilled water (68.7 mL) to obtain a clear 10 mM solution. The SUL-150 solution was sprayed evenly onto standard food pellets (1.25 kg). The food pellets were air-dried overnight. Food pellets were prepared fresh weekly. Since the food pellets contained 200 mg of SUL-150, which approximates a daily food intake of 25 g for a 350 g rat, the daily dose of SUL-150 was approximately 5 mg / day.

[0103] Animal procedures Male outbred Wistar rats (10-12 weeks old) weighing 250-300 grams were housed under a 12-hour light / dark cycle and provided with ad libitum access to standard chow containing distilled water. Thirty rats were administered doxorubicin (2 mg / kg) by intraperitoneal injection weekly for 9 consecutive weeks and were either left untreated (standard chow diet, 10 rats) or fed a diet supplemented with SUL-150 as prophylaxis (before the first doxorubicin administration, 10 rats) or treatment (starting after the sixth doxorubicin administration, 10 rats). Sham control rats (8 rats) were administered saline by intraperitoneal injection weekly for 9 consecutive weeks and were fed a standard chow diet. All rats underwent cardiac function evaluation 12 weeks after the first doxorubicin administration.

[0104] Experimental protocol For the results of cardiac function testing (PV loop assessment), see Example 1 above.

[0105] Myocardial fibrosis Cardiac tissue samples for histopathology were fixed in 3.6% formalin and embedded in paraffin. Four-μm-thick cardiac tissue sections were prepared and stained with picrosirius red and counterstained with Weighert's hematoxylin (both Sigma-Aldrich, St. Louis, MO) according to the manufacturer's instructions. Samples were imaged with a NanoZoomer S60 digital slide scanner (Hammamatsu Photonics), and left ventricular interstitial fibrosis (i.e., non-perivascular fibrosis) was quantified using an Aperio ImageScope (Leica Biosystems, Nussloch, Germany).

[0106] Cardiac oxidative stress Heart tissue samples were homogenized in ddH2O using a TissueRuptor II (Qiagen, Hilden, Germany), followed by 3 x 1 min sonication at 20 kHz (Sonopuls 2000, Bandelin, Berlin, Germany) and centrifugation at 14,000 g to pellet insoluble proteins. Supernatants were used to assess radical scavenging activity by ABTS radical decolorization as described by Re et al.

[14] and lipid peroxidation by assessing reactivity to thiobarbituric acid according to Ohkawa et al.

[15] .

[0107] Cardiac mitochondrial copy number Heart tissue samples were diluted with 50 U ml -1 of RNase I and 100 U ml -1 The cells were homogenized in lysis buffer (100 mM NaCl, 10 mM EDTA, 0.5% SDS in 20 mM Tris-HCl (pH 7.4)) containing 100 mM proteinase K (both from ThermoFisher, Waltham, MA). After overnight incubation at 55°C, total DNA was precipitated with 2-propanol. Aliquots of 5 ng of total DNA were amplified using iTaq Universal SYBR Green Supermix (Bio-Rad, Hercules, CA) and primers specific for mitochondrial DNA (MT-ND1; sense 5'-CCTCCTAATAAGCGGCTCCT-3', antisense 5'-GGCGGGGATTAATAGTCAGA-3') or nuclear DNA (NDUFA1; sense 5'-ATGGCCCGAACCAAGCAGACC-3', antisense 5'-TTAAGCTCTCTCCCCCCGTATCCG-3') on a ViiA7 real-time PCR system (ThermoFisher, Waltham, MA). mtDNA copy number was calculated as mtDNA = 2 × 2. Cq(NDUFA1)-Cq(MT-ND1 It was calculated as:

[0108] Cardiac ATP / ADP ratio Cardiac tissue samples were homogenized in Tris-saturated phenol (pH 7.4) using a TissueRuptor II (Qiagen, Hilden, Germany) to extract adenosine, which was then separated with chloroform. Water (1:1 v / v) was added by centrifugation. Nucleotide separation and measurement of ATP and ADP concentrations were performed by HPLC. Separation was performed by injecting 100 μL of the sample onto a reversed-phase chromatography C18 column. The column temperature was maintained at 25°C. The mobile phase was 70% acetonitrile: 30% 75 mmol / L KH2PO4 (v / v), and the flow rate was 1 mL / min. Eluted nucleotides were detected at a wavelength of 260 nm. The nucleotide concentrations of the eluate were calculated using a calibration curve for each standard nucleotide peak area. ATP concentrations were normalized to the ADP concentration in each sample.

[0109] Respiratory complex IV activity H9C2 cardiomyoblasts were exposed to 1 μM DOX for 24 hours under standard cell culture conditions in the presence or absence of 1 μM SUL-150. Mitochondria were isolated using density gradient centrifugation using the MitoCheck® Mitochondria Isolation Kit (Cayman Chemical #701010, Ann Arbor, MI) according to the manufacturer's instructions, and mitochondrial complex IV activity (cytochrome c oxidase) was assessed by measuring the rate of cytochrome c oxidation, as reflected by the increase in absorbance at 550 nm (Cayman Chemical #700990, Ann Arbor, MI).

[0110] Statistical evaluation Data were analyzed using GraphPad Prism 8.0 (GraphPad Software Inc., CA). All results are expressed as mean ± SD or median and interquartile intervals. Differences between groups were assessed by ANOVA, followed by pairwise comparisons to sham and vehicle-treated groups, with p-values ​​adjusted for multiple comparisons using the FDR correction.

[0111] result SUL-150 administration appears to reduce cardiac fibrosis in a rat model of doxorubicin-induced heart failure. Chronic doxorubicin administration to rats leads to the development of heart failure, as indicated by decreases in heart rate, ejection fraction, and stroke work, ultimately resulting in a severe reduction in cardiac output. Furthermore, chronic doxorubicin administration induces a fibrogenic response in the left ventricular interstitium, as indicated by increased collagen deposition (Figure 4). Administration of SUL-150 via food pellets either before doxorubicin administration (prophylactic group) or after six cumulative doxorubicin doses (treatment group) preserves cardiac function (as shown above) and blocks this fibrogenic response (Figure 4).

[0112] SUL-150 administration appears to reduce cardiac oxidative stress without affecting cardiac antioxidant capacity. Heart failure is associated with increased oxidative stress in cardiac tissue, which may result from an imbalance between oxidative radical scavenging capacity and oxidative radical production. Cardiac oxidative stress was evident after chronic doxorubicin administration, as indicated by an increase in lipid peroxidation products (TBARS, Figure 5A). Administration of SUL-150, either as a preventive or therapeutic regimen, attenuated cardiac lipid peroxidation (Figure 5A), suggesting a reduction in cardiac oxidative stress.

[0113] Cardiac radical scavenging activity remained unchanged by chronic doxorubicin administration (Fig. 5B) or by prophylactic or therapeutic administration of SUL-150 (Fig. 5B), suggesting that increased radical production, rather than decreased scavenging capacity, underlies the observed increase in oxidative stress.

[0114] SUL-150 administration preserves cardiac mitochondrial copy number and normalizes cardiac energy status. Heart failure is associated with cardiac energy loss, the development of mitochondrial dysfunction, and the loss of mitochondrial mass through mitophagy, leading to contractile dysfunction. Indeed, chronic doxorubicin administration reduced cardiac ATP content available for contraction (Figure 6A), which was attenuated by prophylactic or therapeutic administration of SUL-150.

[0115] Mitochondrial DNA (mtDNA) copy number can be used as a surrogate marker of mitochondrial mass, and a decrease in mitochondrial mass is thought to underlie the energy depletion that occurs after long-term doxorubicin administration. Long-term doxorubicin administration reduces cardiac mtDNA copy number (Figure 6B), which is prevented by administration of SUL-150. Notably, in doxorubicin-treated animals, mtDNA copy number was positively associated with cardiac ejection fraction (r 2 = 0.454, p = 0.033; Figure 6C), suggesting that higher mitochondrial load corresponds to better contractility of the heart.

[0116] SUL-150 attenuates doxorubicin-induced decline in respiratory complex IV activity in isolated cardiac mitochondria. SUL compounds have been shown to increase mitochondrial function through the activation of respiratory complex IV, which can be inhibited by doxorubicin. Indeed, exposure of H9C2 cardiomyoblasts to doxorubicin (1 μM, 24 h) significantly reduced respiratory complex IV activity (Figure 7). Co-incubation of H9C2 cardiomyoblasts with doxorubicin and SUL-150 (both at 1 μM for 24 h) maintained complex IV activity, which may explain the enhanced ATP production observed in SUL-150-treated rats. Interestingly, administration of SUL-150 (1 μM, 24 h) did not alter respiratory complex IV activity in untreated control H9C2 cardiomyoblasts.

[0117] conclusion The chemotherapy agent doxorubicin is known for its cardiotoxic effects, leading to heart failure with reduced ejection fraction (HFrEF).

[0118] Example 1 shows that 6-chromanol SUL-150 (administered either prophylactically or therapeutically) preserves cardiac contractile function and therefore cardiac output despite administration of doxorubicin.

[0119] Example 2 shows that the claimed analogs of SUL-150 are also effective in preventing ventricular hypertrophy, particularly more effective than other Trolox-type compounds not according to the invention, indicating that these claimed compounds can also be used to treat HFrEF.

[0120] Example 3 shows that doxorubicin-induced heart failure is accompanied by increased cardiac oxidative stress, energy depletion, and loss of mitochondrial mass. SUL-150 administration, either prophylactically or therapeutically, unexpectedly prevents these pathological changes, potentially through the maintenance of respiratory complex IV activity.

Claims

1. A pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of heart failure with reduced ejection fraction. 【Chemical 1】 wherein R1 is hydrogen or forms, together with the oxy group at the 6-position of the benztetrahydropyran, an ester group having 2 to 6 carbon atoms; - One of the following: R2 and R3 together with the N atom to which they are attached form a saturated or unsaturated non-aromatic, optionally substituted 5-8 membered ring having 1-4 N, O or S atoms, and R2 and R3 together containing 3-12 carbon atoms; Alternatively, R2 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R3 is an alkyl group optionally substituted with nitrogen or oxygen, said alkyl group containing 3 to 12 carbon atoms, and the alkyl group of R3 contains one or more non-aromatic cyclic structures which may contain a nitrogen or oxygen atom in the ring and which may contain linear and / or branched substituted groups.

2. The pharmaceutical composition of claim 1, wherein the nitrogen in R2 and / or R3 can be an amine, quaternary amine, guanidine, or imine, the oxygen in R2 and / or R3 can be a hydroxyl, carbonyl, or carboxylic acid; and / or the oxygen and nitrogen in R2 and / or R3 can together form an amide, urea, or carbamate group.

3. A pharmaceutical composition described in claim 1 or 2, wherein R2 and R3 together with the N atom to which they are attached form a saturated ring incorporating a further N atom, and this ring is unsubstituted or substituted with an alcohol or alkanol group having 1 to 4 carbon atoms.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the compound is a compound according to formula I.

5. 5. The pharmaceutical composition of claim 4, wherein R2 and R3 together with the N atom to which they are attached form a 5- to 7-membered ring containing one additional amine group, the ring being optionally substituted with methyl, ethyl, or alcohol-substituted methyl or ethyl.

6. 3. The pharmaceutical composition of claim 1, wherein R2 is a hydrogen atom and R3 comprises a saturated cyclic structure having 4 to 7 carbon atoms and 1 nitrogen atom, the ring being optionally substituted with an alkyl group, an alcohol group, or a group having 1 to 4 carbon atoms which may include oxygen, a carboxylic acid, or an amine group.

7. 2. The pharmaceutical composition of claim 1, wherein the compound is (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-121), ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride (SUL-13), or (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-109), as a racemic mixture or as one of its enantiomers, or a pharmaceutically acceptable salt thereof.

8. 8. The pharmaceutical composition of claim 7, wherein the compound is the 2R-enantiomer of SUL-121: (2R)-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-150) or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to any one of claims 1 to 6, wherein the compound according to formula (I) has a molecular weight of less than 500 Da.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the treatment or prevention is carried out in combination therapy with one or more conventional means for treating heart failure.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the patient with heart failure with reduced ejection fraction has a preserved ejection fraction (HFmrEF) of 50% or less.

12. 12. The pharmaceutical composition of claim 11, wherein the patient with heart failure with reduced ejection fraction has a preserved ejection fraction (HFrEF) of about 40% or less.

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