WO2021144746A1 - Use of icrf-193 derivatives and pharmaceutical preparations containing thereof for the prevention of chronic cumulative cardiotoxicity caused by therapy with anthracycline anticancer drugs - Google Patents
Use of icrf-193 derivatives and pharmaceutical preparations containing thereof for the prevention of chronic cumulative cardiotoxicity caused by therapy with anthracycline anticancer drugs Download PDFInfo
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- WO2021144746A1 WO2021144746A1 PCT/IB2021/050285 IB2021050285W WO2021144746A1 WO 2021144746 A1 WO2021144746 A1 WO 2021144746A1 IB 2021050285 W IB2021050285 W IB 2021050285W WO 2021144746 A1 WO2021144746 A1 WO 2021144746A1
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- cardiotoxicity
- icrf
- ant
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- cardioprotective
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- ICRF-193 derivatives and pharmaceutical preparations containing thereof for the prevention of chronic cumulative cardiotoxicity caused by therapy with anthracycline anticancer drugs
- the invention relates to the use of ICRF-193 derivatives for the preparation of a medicament for the prevention of chronic cumulative cardiotoxicity caused by repeated administration of anthracyclines within the treatment of various kinds of hematological or solid malignancies.
- Anthracyclines such as doxorubicin, daunombicin (DAU), epirubicin or idarubicin, belong to highly effective and widely used anti-tumor drugs indicated for a number of hematological malignancies as well as solid tumors (Cortes-Funes and Coronado, Role of anthracyclines in the era of targeted therapy. Cardiovasc Toxicol 2007, 7, 56-60; Lenneman and Sawyer, Cardio-Oncology: An Update on Cardiotoxicity of Cancer-Related Treatment. Circulation research 2016, 118, 1008-1020). However, clinical use of these drugs is complicated and frequently also limited by their toxic effects on the myocardium.
- ANT cardiotoxicity With respect to the clinical manifestation, its timing and clinical significance, it is important to distinguish several forms of ANT cardiotoxicity. Acute and subacute forms of ANT cardiotoxicity are manifested several hours or days after administration of ANTs, do not show clear dose dependency and are only rarely clinically significant (Gharib and Burnett, Chemotherapy- induced cardiotoxicity: current practice and prospects of prophylaxis. European journal of heart failure 2002, 4, 235-242; Zamorano et al., 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). European Heart Journal 2016, 37, 2768-2801; Allen, The cardiotoxicity of chemotherapeutic drugs.
- ANT cardiotoxicity Acute forms of ANT cardiotoxicity are most frequently described as transient electrophysiological abnormalities that often occur only subclinically. Their relationship to chronic ANT cardiotoxicity remains unclear as well as their prognostic significance despite the long-term investigations. Subacute forms of ANT cardiotoxicity are considered to be very rare and are mainly associated with the syndrome of toxic myocarditis and/or pericarditis (Gharib and Burnett, Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis. European journal of heart failure 2002, 4, 235-242; Allen, The cardiotoxicity of chemotherapeutic drugs. Seminars in oncology 1992, 19, 529; Kantrowitz and Bristow, Cardiotoxicity of antitumor agents.
- Chronic cardiotoxicity is histopathologically characterized as a loss of myofibrils and vacuolar degeneration of cardiomyocytes (Kantrowitz and Bristow, Cardiotoxicity of antitumor agents. Progress in cardiovascular diseases 1984, 27, 195-200). Severely damaged cardiomyocytes are subsequently subject to unprogrammed and programmed cell death. Chronic ANT cardiotoxicity is considered to be largely irreversible and difficult to treat, which can principally affect morbidity, mortality and quality of life of cancer survivors who received ANTs as a part of cancer therapy. Thus, it is essential to prevent the onset of damage to the myocardium.
- Circulation 2003, 108, 2423-2429 iv) a toxicity towards cardiac progenitor cells (Angelis et al., Anthracycline Cardiomyopathy Is Mediated by Depletion of the Cardiac Stem Cell Pool and Is Rescued by Restoration of Progenitor Cell Function. Circulation 2010, 121, 276-292), or v) pathological signaling from TLR 9 mediated by phosphoinositide 3-kinase g (Li et al., Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth. Circulation 2018, 138, 696-711).
- phosphoinositide 3-kinase g Li et al., Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth. Circulation 2018, 138, 696-711.
- Dexrazoxane (DEX, dextrorotatory enantiomer (+)-(S)-4,4'-(propane-l,2-diyl)bis(piperazine- 2,6-dione, Scheme 1) is historically the first and only drug that has been approved as a cardioprotective drug for clinical use in prevention of chronic cumulative cardiotoxicity caused by ANT therapy (Reichardt el al., Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncology 2018, 14, 2663-2676).
- DEX has been traditionally considered to be a prodrug of the chelating substance named as ADR-925 (or ICRF-198, Scheme 1).
- Clinical use of the dextrorotatory enantiomer is not based on different pharmacodynamics of the optic isomers, but on significantly higher solubility of dextrorotatory enantiomer in an aqueous environment, which turned out to be the essential pharmaceutical limitation of the use of the racemic razoxane.
- the cardioprotective effect of DEX should be related to chelation of iron ions in the myocardium by its metabolite ADR- 925, which should prevent oxidative damage to the myocardium induced by ANTs (Simunek et al., Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron.
- the dose-dependent cardiotoxicity observed during anthracycline administration is due to anthracycline-induced iron-dependent free radical oxidative stress on the relatively unprotected cardiac muscle.
- Dexrazoxane an analogue of EDTA ( ethylene diamine tetra-acetic acid)
- ICRF-187 ethylene diamine tetra-acetic acid
- ICRF-198 are capable of chelating metal ions. It is generally thought that they can provide cardioprotection by scavenging metal ions thus preventing the Fe 3+ -anthracycline complex from redox cycling and forming reactive radicals. ”
- this theory has been questioned several times.
- DEX is, similarly to ANT, an inhibitor of topoisomerase Ila (Top2a), which also explains its certain anticancer a potential.
- Top2a topoisomerase Ila
- bisdioxopiperazine compounds, where DEX belongs were originally studied and developed as anticancer agents and their structure-activity relationships with respect to anticancer effect have been well studied and described (Creighton et al., Antitumour activity in a series of bisdiketopiperazines.
- Toxicology 2009, 255, 72-79 showed than an assessment of the protective potential of bisdioxopiperazine derivatives closely related to DEX in an in vitro model of isolated cardiomyocytes may exhibit false positive results, which were in sharp contrast to results obtained with the use of in vivo models of chronic ANT cardiotoxicity validated with DEX as a positive control. Furthermore, cardioprotective potential of DEX was not found in in vitro experiments with the use of human induced pluripotent stem cells (iPSC) cardiomyocytes (Burridge et al., Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity.
- iPSC human induced pluripotent stem cells
- ICRF-193 was screened for protective effects in an in vivo model of general acute toxicity induced by the administration of a high single dose of ANT (DAU, 25 mg/kg) (Herman et al., Comparison of the protective effect of ICRF-187 and structurally related analogues against acute daunorubicin toxicity in Syrian golden hamsters. Research communications in chemical pathology and pharmacology 1985, 48, 39-55). The authors concluded that unlike DEX, ICRF-193 does not have any protective effects against this massive multi-organ toxicity of ANT discharge no protective activity was found in any pretreatment doses of ICRF-158 /analogue 2/ ICRF-193 /analogue 8/.... “). However, no parameter that might directly or indirectly indicate the potential cardioprotective effect was described in this study.
- the compound ICRF-193 falls within the general formula of the patent GB 2245832 A 1992 (W09200740), which protects roughly tens of thousands of compounds derived from bisdioxopiperazines. This patent generally claimed the ability of these compounds to protect against ANT cardiotoxicity. However, based on more recent data, it is obvious that the bisdioxopiperazine structure by itself is not a carrier of a clinically usable cardioprotective effect. In addition, the structure of ICRF-193 is not explicitly mentioned in this patent as an example and is not described there at all.
- the compound ICRF-193 would have significant cardioprotective effect against chronic cumulative cardiotoxicity induced by repeated ANT administration leading to cardiomyopathy and congestive heart failure, which are principal problems in the clinical practice.
- the protective effect against this type of cardiotoxicity was not evaluated in this patent, the compound ICRF- 193 is not mentioned as an example in the patent and with respect to negative results of close DEX derivatives, even an expert could not predict the cardioprotective potential of compounds of the general formula in this patent against chronic cumulative ANT cardiotoxicity.
- the example presented in the patent concerns toxicity of single dose ANT administration, which is rarely an issue in the clinical practice, and in addition, the observed effect was very weak.
- the substance ICRF-193 also falls within the general formula of the patent application US2008/0275036 Al. This application hypothetically protects thousands of compounds and one of the areas that is claimed is their protective ability against cardiotoxicity of anti-tumor drugs, including ANTs.
- the formula of the compounds ICRF-193 is presented in table 1 on page 30 of the said document, but its characteristic or any pharmacological effect is not explicitly mentioned or described.
- the authors assumed that the cardioprotective effects of DEX stems from the chelating properties of its metabolite and that it will be the case of the other bisdioxopiperazine derivatives.
- ICRF-193 is presented in the patent application W02016/051213 A1 on page 4 and in figure 1 (Fig. 1).
- the entire application is focused on the ability of DEX, its metabolites B and C and DEX derivatives to inhibit formation of poly(ADP-ribose) (PAR) and related potential clinical application of these substances.
- PAR poly(ADP-ribose)
- One of the claimed potential applications of these compounds is protection against ANT toxicity.
- the authors completely rejected the importance of Top2b for the cardioprotective effect of DEX and suggested the interaction with PAR as the main mechanism of the cardioprotection.
- ICRF-193 is mentioned in the patent, no experimental data are provided for this compound as an example (the same is true for other DEX derivatives).
- the compound ICRF-193 is also disclosed in patent application WO2008/157358 Al, which protects methods of treating cancer with a combination of a Top2 inhibitor and Top2 (topoisomerase) poison, including ANT.
- Top2 inhibitors the most well-known representatives of bisdioxopiperazines ICRF-187 (DEX), ICRF-193, ICRF-159 (razoxane) and ICRF-154 are disclosed, together with their unspecified prodrugs and metabolites.
- the use of these compounds (including ICRF-193) as cardioprotective agents is mentioned in the text, but not explicitly claimed.
- the claims only generally stated the use of this combination of drugs but without description of a specific medical intention or purpose (i.e. without particular indication).
- the claim was exemplified by the in vitro reduction of doxorubicin-induced DNA damage detected by the gH2AC marker in proliferating H9c2 cells by DEX and ICRF-193, which is associated with the inhibition and depletion of Top2b.
- pharmacological protection of cardiomyocytes against DNA damage detected as gH2AC is the sole or main prerequisite for effective protection of primary cardiomyocytes in vitro and particularly the heart against chronic cumulative cardiotoxicity caused by ANT therapy in vivo.
- proliferating H9c2 cell line is also of unclear inventive value due to the fact that the cell line used, unlike cardiomyocytes, also expresses the Top2a isoform, which is indeed also significantly affected by studied substances (ANT and DEX/ICRF-193). Moreover, the molecular phenotype of these cells as well as the effects of doxorubicin on them are fundamentally different from primary cardiomyocytes (Lenco J. el al. Proteomic investigation of embryonic rat heart-derived H9c2 cell line sheds new light on the molecular phenotype of the popular cell model. Exp Cell Res. 2015; 339: 174-186). In this patent, no evidence is provided for the ability of ICRF-193 or its prodrug or metabolite to protect either primary cardiomyocytes in vitro or the myocardium from chronic ANT cardiotoxicity in vivo.
- Disclosure of the invention is based on the discovery and unequivocal confirmation of the fact that the compounds of general formula I in the form of an ammonium salt with a pharmaceutically acceptable acid are able to protect primary cardiomyocytes against ANT toxicity in vitro , and, above all, to show excellent efficacy as cardioprotectants at very low doses against chronic cumulative ANT cardiotoxicity induced by repeated (10-week) administration of a clinically relevant dose of daunorubicin (once weekly i.v. at a dose of 3 mg/kg DAU) in a rabbit model.
- This model shows functional, biochemical and morphological similarities to chronic ANT cardiotoxicity observed in the clinical practice. Moreover, the cardioprotective effect of DEX, the approved drug with demonstrated cardioprotective efficacy in the clinical practice, was repeatedly shown in this model (Jirkovsky el al., Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits. Toxicology 2013, 311, 191-204; Popelova el al., Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death. British journal of cancer 2009, 101, 792).
- An object of the invention is the use of the compounds of general formula I in the form of the ammonium salt with a pharmaceutically acceptable acid according to the invention for the manufacture of a medicament for the prevention of chronic cumulative cardiotoxicity (cardiomyopathy and a heart failure) caused by therapy with anthracycline anticancer drugs.
- R H, a C1-C6 alkyl, benzyl or benzyl substituted at positions 2, 3, 4 and 5 with one or more electron-acceptor groups and/or one or more electron-donor groups, a phenyl or phenyl substituted at positions 2, 3, 4 and 5 with one or more electron-acceptor groups and/or one or more electron-donor groups.
- a pharmaceutically acceptable acid refers to such organic and inorganic acids whose anions do not exhibit a toxic effect on the human organism in clinically relevant concentrations. They are especially: chlorides, bromides, iodides, sulfates, nitrates, acetates, maleates, fumarates, methanesulfonates, citrates, succinates, phosphates and/or tartrates, (source: Lemke, Thomas el al. ; (eds.).: Foye's principles of medicinal chemistry. Philadelphia; Baltimore: Lippincott Williams & Wilkins, 2013, 1500 s. ISBN 978-1-4511-7572-1.)
- the compounds of general formula I can be obtained by routine methods of organic synthesis.
- meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione) of formula II the method described in the patent US 5393889A (PCT/JP91/00894) was used (Scheme 2).
- Fig. 1 Protective effects of the compound ICRF-193 against DAU cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
- Fig. 2 Protective effects of the compound lb according to Example 1 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
- FIG. 3 Protective effects of the compound Ic according to Example 2 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
- Fig. 4 Protective effects of the compound Id according to Example 3 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
- Fig. 6 Results of an evaluation of the cardioprotective effects of the compound lb according to Example 1 in a rabbit model of chronic cumulative anthracycline cardiotoxicity.
- the compound meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4, 1-diyl))bis(methylene)-bis(2- aminoacetate) hydrochloride lb is prepared according to Scheme 4 through a reaction of meso- (butane-2, 3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-bis(2-((tert- butoxycarbonyl)amino)acetate) (0.3 mmol) with an excess of hydrogen chloride in 5 ml of acetic acid.
- Example 2 meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-(2S,2'S)- bis(2-aminopropanoate) hydrochloride (Ic)
- the compound meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)- (2S,2'S)-bis(2-aminopropanoate) hydrochloride Ic is prepared according to Scheme 4 through a reaction of meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4, l-diyl))bis(methylene)-(2S,2'S)- bis(2-(( tert-butoxycarbonyl)amino)propanoate) (0.2 g, 0.3 mmol) with an excess of
- Example 3 meso -(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-(2S,2'S)- bis(2-amino-3-phenylpropanoate) hydrochloride (Id)
- the compoundmeso -(butane-2,3-diylbis(2,6-dioxopiperazine-4, l-diyl))bis(methylene)- (2S,2'S)-bis(2-amino-3-phenylpropanoate) hydrochloride Id is prepared according to Scheme 4 through a reaction ofmeso -(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)- (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate) (0.25 g, 0.3 mmol) with an excess of hydrogen chloride in 5 ml of acetic acid.
- the other substances are normally commercially available.
- the startingmeso -(butane-2,3-diylbis(2,6-dioxopiperazine-4, l-diyl))bis(methylene)-(2S,2'S)- bis(2-((tert-butoxycarbonyl)amino)-3-phenylbutanoate) was prepared through a reaction of meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione) with Boc-L-valine according to Scheme 3.
- the other substances are normally commercially available.
- Example 5 Protective effects of ICRF-193 against ANT cytotoxicity in vitro in a model of isolated rat neonatal ventricular cardiomyocytes
- the cell suspension obtained thereby was than enriched with cardiomyocytes through selective adhesion of other cells than myocytes on plastic surface.
- the myocyte-rich cell suspension was then cultivated for three days on plastic wells pre-coated with gelatin, to obtain a culture of spontaneously beating cardiomyocytes. Then, this culture was exposed to ICRF-193, DAU or their combination in serum- free media. In the case of the combination experiment, the culture was first exposed to ICRF-193 for 3 hours, then DAU was added to the cultivation media in the concentration of 1.2 mM for 3 hours, after which both the substances were removed through media replacement.
- the toxic effects of DAU and the protective effect of ICRF-193 were evaluated after 48 hours from the last media replacement by means of determination the activity of lactate dehydrogenase (LDH), an intracellular enzyme that is released into the cultivation media after a cell membrane damage.
- LDH lactate dehydrogenase
- the activity of LDH in the cultivation media was compared to the total LDH activity obtained after lysis of all cells in the sample.
- the LDH activity was determined spectrophotometrically with the use of the lactate and NAD + as the substrates.
- the resulting increase of NADPH was determined by measurement of absorbance at 340 nm using a Tecan Infinite 200M spectrophotometer (Tecan Ltd., Switzerland).
- Fig. 1 The protective effects of the compound ICRF-193 against DAU cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes is shown in Fig. 1.
- DAU induced significant toxicity in the culture of neonatal rat cardiomyocytes as determined by the LDH release. Preincubation with ICRF-193 statistically significantly reduced this damage in the range of the studied concentrations (hatched columns).
- toxicity of DAU (expressed as LDH release into the media) was reduced by approximately 55% as compared to the control.
- Statistically significant differences p ⁇ 0,05, one-way ANOVA) are shown as “c” (significant as compared with the control) and “d” (significant as compared with DAU).
- Example 6 Protective effects of the substance lb according to Example 1 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes The protective effects of the substance lb according to Example 1 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes was determined with the use of the procedure specified in Example 5.
- Fig. 2 The protective effects of the compound lb according to Example 1 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes is shown in Fig. 2.
- DAU induced significant toxicity in the culture of neonatal rat cardiomyocytes as determined by the LDH release. Pre-incubation with the substance lb statistically significantly reduced this damage in the entire range of the used concentrations (hatched columns, i.e. already from 1 mM) while the biggest effect was achieved at 10 mM, where the release of LDH into the media, i.e. the toxicity, was reduced by approximately 59%.
- Statistically significant differences p ⁇ 0,05, one-way ANOVA
- c significant as compared with the control
- d significant as compared with DAU.
- Example 7 Protective effects of the substance Ic according to Example 2 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes
- Example 8 Protective effects of the substance Id according to Example 3 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes
- Example 3 The protective effects of the substance Id according to Example 3 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes was determined with the use of the procedure specified in Example 5.
- Example 9 Protective effects of the substance Ie to Example 4 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes
- Example 4 The protective effects of the substance Ie according to Example 4 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes was determined with the use of the procedure specified in Example 5. Results. Pre-incubation with the substance Ie for 3 hours before three-hour exposure to DAU statistically significantly reduced damage to the culture of isolated neonatal cardiomyocytes 48 hours after the exposure.
- Example 10 Protective effects of the substance lb according to Example 1 against chronic cumulative ANT cardio toxicity in vivo
- the groups 3 and 4 (n 7 in each group): the substance lb according to Example 1 was fully dissolved in the saline (concentration 1 and 5 mg/ml) immediately before drug administration and the solution was filtered through an antibacterial filter.
- the substance lb according to Example 1 was subsequently administered in the doses of 1 and 5 mg/kg via slow i.v. injection (2 min) 30 min before each DAU administration (the same schedule of DAU administration as in the group 1 was adopted).
- the administrations of the compound lb according to Example 1 and DAU were always conducted contralaterally (i.e. each administration was performed into the vein of a different ear).
- LV left ventricle
- LV fractional shortening LVFS
- pentobarbital 30 mg/kg
- a Millar catheter 2.3F, Millar Instruments, USA
- dP/dt max the parameter of systolic function was assessed.
- a necropsy examination was conducted with a focus on signs of circulatory congestion (pleural effusion and effusion in the abdominal cavity), dilatation of heart chambers and macroscopic changes of internal organs.
- Fig. 6A shows the body weight gain at the end of the experiment. In all groups except for the group 1 (DAU), a significant increase of the body weight was observed in the course of the experiment. At the end of the experiment, the body weight gain was significantly higher in all other groups (i.e. including the combination groups with the substance lb according to Example 1), than in the group 1 (DAU). The administration of DAU led to slightly reduced consumption of food and water and slightly reduced motion activity. No other considerable changes of behavior or apparent signs of toxicity were observed in this study. Fig.
- 6B shows signs of blood congestion observed during the necropsy conducted at the end of the experiment or after the premature death.
- the necropsy examination performed in all the animals in this study identified signs of blood congestion in the group 1 (DAU), including pronounced forms of effusions in the thoracic and abdominal cavities with volumes exceeding 5 ml.
- the animal that died in the group 1 (DAU) exhibited very pronounced signs of blood congestion and dilatation of the heart chambers.
- the combination groups 3 and 4 with the substance lb according to Example 1 no effusion in the thoracic cavity and only one case of a mild effusion in the abdominal cavity were found.
- No macroscopically detectable anomalies were found in group 5 with the substance lb according to Example 1 alone or in the both combination groups during the necropsy.
- Fig. 6C shows results of echocardiographic (ECHO) examination of the left ventricle (LV) - fractional shortening (FS) was the evaluated parameter of the systolic function. The last measured values are presented.
- the echocardiographic examination of the LV systolic function revealed a significant decrease of LVFS as compared to the initial values in the group 1 (DAU) whereas in the both combination groups (the groups 3 and 4), the values of this parameter remained unchanged in the course of the experiment.
- the comparison of this parameter between the groups at the end of the experiment confirmed considerably lower values in the group 1 (DAU) as compared to the group 2 (the control group)), but also as compared to the both combination groups with the compound lb according to Example 1 (the groups 3 and 4).
- CTR- control group (group 2), compound Ib_5 - compound lb according to example 1, administered alone in the dose of 5 mg/kg (group 5), DAU - daunorubicin (the group 1), compound Ib_l+DAU - the combination group with the compound lb according to Example 1 administered in the dose of 1 mg/kg before each dose of DAU (the group 3), compound Ib_5+DAU - the combination group with the compound lb according to Example 1 administered in the dose of 5 mg/kg before each dose of DAU (the group 4).
- the results are presented as the means ⁇ S.D.
- This Example demonstrated a very pronounced cardioprotective potential of the substance lb according to Example 1 against chronic cumulative ANT cardiotoxicity in vivo.
- Administration of the substance lb according to Example 1 prevented the DAU-induced premature death of the animals associated with the development of cardiotoxicity and advanced heart failure.
- the substance lb according to Example 1 also effectively prevented DAU-induced blood congestion and systolic dysfunction, as determined by both echocardiographic and catheterization examinations. All these effects were significant already at the dose of 1 mg/kg, which makes this substance currently most effective cardioprotective agent against chronic cumulative cardiotoxicity (DEX is recommended at the dose ratio of 1:10 to 1:20 to ANT, i.e. in our model 30-60 mg/kg).
- Figs. 7A-C show the results of evaluation of the cardioprotective effects of the compound ICRF-239 in the rabbit model of chronic cumulative ANT cardiotoxicity. In the same model, the compound ICRF-239 did not exhibit any protective effect.
- Fig. 7A shows survival of the animals at the end of the experiment.
- Fig. 7B shows the results of echocardiographic (ECHO) examination of the FV systolic function - FV fractional shortening (FVFS). The last measured value is presented.
- Fig. 7C shows the results of FV catheterization examination of the animals surviving until the end of the experiment - the evaluated parameter was the index of the systolic heart function dP/dt max .
- the necropsy signs of circulatory congestion and dilatation of cardiac chambers were observed in the ICRF- 239+DAU combination groups, similarly to the DAU group.
- CTR - the control group the group 2
- DAU - daunorubicin the group 1
- ICRF- 239+DAU the combination group with the compound ICRF-239 administered in the dose of 60 mg/kg before each dose of DAU.
- Statistical significance p > 0.05, SigmaStat 3.5 software) in comparison with: negligence#“ - the control (CTR) group, negligence+“ - the compound ICRF-239 alone (ANOVA).
Abstract
Cardioprotective compounds based on analogues of the compound ICRF-193 of general formula I wherein R1 = H, 2-R2-2-aminoacetoxymethyl wherein R2 is selected from the group consisting of H, a C1-C6 alkyl or a branched alkyl of benzyl. These compounds can be produced by simple syntheses and are characterized with low toxicity and high effectiveness of protection of the heart against chronic cumulative cardiotoxicity caused by anthracycline anticancer therapy. The invention provides also a pharmaceutical preparation comprising the compound of general formula (I) as an active ingredient as well as use of this compound for the manufacture of a medicament for the prevention of chronic cumulative cardiotoxicity caused by therapy with anthracycline anticancer drugs.
Description
Use of ICRF-193 derivatives and pharmaceutical preparations containing thereof for the prevention of chronic cumulative cardiotoxicity caused by therapy with anthracycline anticancer drugs
Field of the Invention
The invention relates to the use of ICRF-193 derivatives for the preparation of a medicament for the prevention of chronic cumulative cardiotoxicity caused by repeated administration of anthracyclines within the treatment of various kinds of hematological or solid malignancies.
Anthracyclines (ANTs), such as doxorubicin, daunombicin (DAU), epirubicin or idarubicin, belong to highly effective and widely used anti-tumor drugs indicated for a number of hematological malignancies as well as solid tumors (Cortes-Funes and Coronado, Role of anthracyclines in the era of targeted therapy. Cardiovasc Toxicol 2007, 7, 56-60; Lenneman and Sawyer, Cardio-Oncology: An Update on Cardiotoxicity of Cancer-Related Treatment. Circulation research 2016, 118, 1008-1020). However, clinical use of these drugs is complicated and frequently also limited by their toxic effects on the myocardium. With respect to the clinical manifestation, its timing and clinical significance, it is important to distinguish several forms of ANT cardiotoxicity. Acute and subacute forms of ANT cardiotoxicity are manifested several hours or days after administration of ANTs, do not show clear dose dependency and are only rarely clinically significant (Gharib and Burnett, Chemotherapy- induced cardiotoxicity: current practice and prospects of prophylaxis. European journal of heart failure 2002, 4, 235-242; Zamorano et al., 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). European Heart Journal 2016, 37, 2768-2801; Allen, The cardiotoxicity of chemotherapeutic drugs. Seminars in oncology 1992, 19, 529). Acute forms of ANT cardiotoxicity are most frequently described as transient electrophysiological abnormalities that often occur only subclinically. Their relationship to chronic ANT cardiotoxicity remains unclear as well as their prognostic significance despite the long-term investigations. Subacute forms of ANT cardiotoxicity are considered to be very rare and are
mainly associated with the syndrome of toxic myocarditis and/or pericarditis (Gharib and Burnett, Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis. European journal of heart failure 2002, 4, 235-242; Allen, The cardiotoxicity of chemotherapeutic drugs. Seminars in oncology 1992, 19, 529; Kantrowitz and Bristow, Cardiotoxicity of antitumor agents. Progress in cardiovascular diseases 1984, 27, 195-200). Histopathological findings are considerably different from chronic cardiotoxicity with typical presence of an inflammatory infiltrate (Kantrowitz and Bristow, Cardiotoxicity of antitumor agents. Progress in cardiovascular diseases 1984, 27, 195-200). Clinically most significant, and therefore also most dreaded, are chronic forms of cardiotoxicity that develop after the administration of multiple chemotherapeutic cycles comprising ANTs (i.e. after repeated exposure of myocardium to ANTs), and the risk primarily depends on the total cumulative dose of ANTs (Gharib and Burnett, Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis. European journal of heart failure 2002, 4, 235-242; Allen, The cardiotoxicity of chemotherapeutic drugs. Seminars in oncology 1992, 19, 529; Kantrowitz and Bristow, Cardiotoxicity of antitumor agents. Progress in cardiovascular diseases 1984, 27, 195-200). Chronic forms of cardiotoxicity are associated with the development of cardiomyopathy (most frequently of the dilatation type) and progressive heart failure. The chronic cardiotoxicity is clinically manifested in the course of months or years after completion of a therapy comprising ANTs (i.e. with an early or delayed onset of toxicity, respectively) ( Bloom et al., Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging. Circulation: Heart Failure 2016, 9, e002661). Chronic cardiotoxicity is histopathologically characterized as a loss of myofibrils and vacuolar degeneration of cardiomyocytes (Kantrowitz and Bristow, Cardiotoxicity of antitumor agents. Progress in cardiovascular diseases 1984, 27, 195-200). Severely damaged cardiomyocytes are subsequently subject to unprogrammed and programmed cell death. Chronic ANT cardiotoxicity is considered to be largely irreversible and difficult to treat, which can principally affect morbidity, mortality and quality of life of cancer survivors who received ANTs as a part of cancer therapy. Thus, it is essential to prevent the onset of damage to the myocardium. This requirement may be particularly urgent in patients with pre-existent major morphological or functional damage to the myocardium (Zamorano et al., 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force
for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). European Heart Journal 2016, 37, 2768-2801).
Effective protection of the myocardium from chronic cumulative ANT cardiotoxicity is hampered by insufficient understanding of its pathophysiological mechanisms. A traditional hypothesis suggests involvement of direct oxidative damage to the myocardium caused by redox active ANTs and their complexes with iron ions (Keizer et al., Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmacology & therapeutics 1990, 47, 219-231; Hasinoff et al., Chemical, biological and clinical aspects of dexrazoxane and other bisdioxopiperazines. Current medicinal chemistry 1998, 5, 1; Simunek et al., Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacological reports 2009, 61, 154-171). More recent theories point to the key importance of interaction of ANTs with topoisomerase IIb (Top2b) in the heart with subsequent DNA damage and number of other events that lead to a toxic damage to the myocardium (Lyu et al., Topoisomerase Pb-mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer research 2007, 67, 8839-8846; Zhang et al., Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature medicine 2012, 18, 1639). Besides, there are numerous other theories that can replace or supplement the above- mentioned mechanisms. Some experts ascribe essential role to retention and specific toxic action of reduced metabolites of ANTs (e.g. doxorubicinol) in the myocardium (source: Menna et al., Anthracycline cardiotoxicity. Expert opinion on drug safety 2012, 11, S21-S36). Other theories assume essential importance of i) induction of accumulation of iron in mitochondria (Ichikawa et al., Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. The Journal of clinical investigation 2014, 124, 617-630), ii) impairment of expression of sarcomeric proteins (Boucek Jr et al., Persistent effects of doxorubicin on cardiac gene expression. Journal of molecular and cellular cardiology 1999, 31, 1435-1446), iii) induction of damage to mitochondrial DNA (Lebrecht et al., Time- dependent and tissue- specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Circulation 2003, 108, 2423-2429), iv) a toxicity towards cardiac progenitor cells (Angelis et al., Anthracycline Cardiomyopathy Is Mediated by Depletion of the Cardiac Stem Cell Pool and Is Rescued by Restoration of Progenitor Cell Function. Circulation 2010, 121, 276-292), or v) pathological signaling from TLR 9 mediated by phosphoinositide 3-kinase g (Li et al., Phosphoinositide 3-Kinase Gamma Inhibition
Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth. Circulation 2018, 138, 696-711). However, universal validity of any of these theories has not been proved so far.
Dexrazoxane (DEX, dextrorotatory enantiomer (+)-(S)-4,4'-(propane-l,2-diyl)bis(piperazine- 2,6-dione, Scheme 1) is historically the first and only drug that has been approved as a cardioprotective drug for clinical use in prevention of chronic cumulative cardiotoxicity caused by ANT therapy (Reichardt el al., Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncology 2018, 14, 2663-2676). Its efficiency has been repeatedly proved in experimental models (with the use of various laboratory animals and also with various ANTs) (Herman et al., A review of the preclinical development of dexrazoxane. Progress in Pediatric Cardiology 2014, 36, 33- 38; Jirkovsky et al., Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits. Toxicology 2013, 311, 191-204) and especially in randomized controlled clinical studies with more than 1000 patients (van Dalen et al., Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database of Systematic Reviews 2011). Though the cardioprotective effect of DEX has been proved beyond all doubt, its clinical use is limited - especially due to concerns about possible negative impact on outcomes of ANT anticancer therapy (Swain et al., Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. Journal of Clinical Oncology 1997, 15, 1318-1332) or about possible increased incidence of secondary malignancies (Tebbi et al., Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. Journal of Clinical Oncology 2007, 25, 493-500). Further studies largely disproved these concerns (Reichardt et al., Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncology 2018, 14, 2663-2676; van Dalen et al., Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database of Systematic Reviews 2011; Kim et al., Risk factor analysis for secondary malignancy in dexrazoxane-treated pediatric cancer patients. Cancer research and treatment: official journal of Korean Cancer Association 2019, 51, 357), but recommendations for clinical use of DEX have been modified only partially (Reichardt et al., Risk-benefit of dexrazoxane for preventing anthracycline-related cardiotoxicity: re-evaluating the European labeling. Future Oncology 2018, 14, 2663-2676).
Scheme 1. Formulae of DEX and its metabolite / decomposition product ADR-925
DEX has been traditionally considered to be a prodrug of the chelating substance named as ADR-925 (or ICRF-198, Scheme 1). Clinical use of the dextrorotatory enantiomer is not based on different pharmacodynamics of the optic isomers, but on significantly higher solubility of dextrorotatory enantiomer in an aqueous environment, which turned out to be the essential pharmaceutical limitation of the use of the racemic razoxane. Thus, the cardioprotective effect of DEX should be related to chelation of iron ions in the myocardium by its metabolite ADR- 925, which should prevent oxidative damage to the myocardium induced by ANTs (Simunek et al., Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacological reports 2009, 61, 154-171; Hasinoff, The interaction of the cardioprotective agent ICRF-187 ((+)-l, 2-bis (3, 5-dioxopiperazinyl-l- yl) propane); its hydrolysis product (ICRF-198); and other chelating agents with the Fe (III) and Cu (II) complexes of adriamycin. Agents and actions 1989, 26, 378-385). A valid Summary of product characteristics of Cardioxane 500 mg powder for solution for infusion says: “The exact mechanism by which dexrazoxane exerts its cardioprotective effect has not been fully elucidated, however based on the available evidence the following mechanism has been suggested. The dose-dependent cardiotoxicity observed during anthracycline administration is due to anthracycline-induced iron-dependent free radical oxidative stress on the relatively unprotected cardiac muscle. Dexrazoxane, an analogue of EDTA ( ethylene diamine tetra-acetic acid), is hydrolyzed in cardiac cells to the ring-opened product ICRF- 198. Both dexrazoxane ( ICRF-187 ) and ICRF-198 are capable of chelating metal ions. It is generally thought that they can provide cardioprotection by scavenging metal ions thus preventing the Fe3+ -anthracycline complex from redox cycling and forming reactive radicals. ” However, this theory has been questioned several times. Various antioxidants and free radical scavengers did exhibit certain protection against ANT toxicity in in vitro models and against acute or subacute toxicity of ANTs in vivo, but none of them was effective in protecting the myocardium from chronic cumulative ANT cardiotoxicity, which represents, as mentioned
above, an essential issue in the clinical practice. In experimental animal models, this type of cardiotoxicity is developed after repeated administration of clinically relevant doses of ANTs in the course of 1-3 months. A few antioxidative substances were studies in small clinical trials, and all of them with negative results (Sterba el al., Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxidants & redox signaling 2013, 18, 899-929). Similar results were obtained with more selective and more effective intracellular iron chelators than ADR-925, which, in addition, form redox inactive complexes with iron ions (unlike ADR-925). E.g. deferoxamine (DFO) protected the myocardium from acute toxicity induced by a high ANT dose in rats (Al-Harbi el al., Prevention of doxorubicin-induced myocardial and haematological toxicities in rats by the iron chelator desferrioxamine. Cancer chemotherapy and pharmacology 1992, 31, 200-204), but did not show any effect against chronic ANT toxicity (Herman et al. , Comparison of the protective effects of desferrioxamine and ICRF-187 against doxorubicin-induced toxicity in spontaneously hypertensive rats. Cancer chemotherapy and pharmacology 1994, 35, 93-100). This finding contrasted with the robust cardioprotective efficiency of DEX in the same model. Although limited penetration of this hydrophilic chelating drug into cardiomyocytes can be used as an argument for failure of DFO as cardioprotectant, similar results were also obtained with a lipophilic selective chelator deferiprone, which easily penetrates directly into cardiomyocytes. Deferiprone has showed some protective effect in vitro in isolated cardiomyocytes (Bamabe el al., Deferiprone protects against doxorubicin-induced myocyte cytotoxicity. Free Radic. Biol. Med. 2002, 33, 266-275), and in vivo in a model of acute cardiotoxicity induced by a high ANT dose in rats (Ammar el al., Amelioration of doxorubicin-induced cardiotoxicity by deferiprone in rats. Canadian Journal of Physiology and Pharmacology 2011, 89, 269-276). However, when assessed in a model of chronic cumulative cardiotoxicity in rabbits, deferiprone did not show any protective effect (Popelova et al., Deferiprone does not protect against chronic anthracycline cardiotoxicity in vivo. J. Pharmacol. Exp. Ther. 2008, 326, 259-269), which was again in contrast to the robust cardioprotective effect of DEX in the same model (Popelova et al., Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death. British journal of cancer 2009, 101, 792). These results indicate the impossibility of reliable prediction of the cardioprotective effects of a drug against chronic cumulative ANT cardiotoxicity based solely on their chelating or antioxidative properties. Furthermore, relatively simple and rapid assessment of drug effects in in vitro or in
vivo on models of acute or subacute ANT toxicity is evidently insufficient. Limitations of in vitro experiments with respect to reliable prediction of the cardioprotective effect in clinical practice have also been discussed elsewhere (Lipshultz el al., The relevance of information generated by in vitro experimental models to clinical doxorubicin cardiotoxicity. Leukemia & lymphoma 2006, 47, 1454-1458).
Recent studies ascribe the cardioprotective effect of DEX to its interaction with Top2b (Lyu el al., Topoisomerase Pb-mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer research 2007, 67, 8839-8846; Lencova-P opel ova el al., Cardioprotective effects of inorganic nitrate/nitrite in chronic anthracycline cardiotoxicity: comparison with dexrazoxane. Journal of molecular and cellular cardiology 2016, 91, 92-103). This hypothesis is in line with the results of experiments with conditional knockout of Top2b in the myocardium (Zhang el al., Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nature medicine 2012, 18, 1639; Vejpongsa and Yeh, Topoisomerase 2b: A Promising Molecular Target for Primary Prevention of Anthracycline-Induced Cardiotoxicity. Clinical Pharmacology & Therapeutics 2014, 95, 45-52). However, no causal relationship between the ability to inhibit or deplete (i.e. to reduce the quantity) of Top2b in the myocardium and cardioprotection against chronic ANT cardiotoxicity has been reliably proved yet. In addition, it is not clear whether both inhibition and depletion of Top2b in the myocardium would be necessary for cardioprotection. It should also be noted that various substances can inhibit Top2b in the myocardium by various mechanisms and it is not clear whether the way of inhibition is also important for the protective effects of DEX against chronic ANT cardiotoxicity. Moreover, there are also other theories explaining the cardioprotective effect of DEX. E.g. McCormack in his recent work (McCormack, The cardioprotective effect of dexrazoxane (Cardioxane) is consistent with sequestration of poly (ADP-ribose) by self-assembly and not depletion of topoisomerase 2B. ecancermedicalscience 2018, 12) completely refuted the importance of interaction of DEX with Top2b for achievement of cardioprotective effects and suggested instead an alternative hypothesis emphasizing the role of inhibition of poly(ADP-ribose) (PAR). Some authors emphasized the importance of direct antioxidative effects of the parent DEX (Junjing et al., Scavenging effects of dexrazoxane on free radicals. Journal of clinical biochemistry and nutrition 2010, 47, 238-245) whereas others highlighted the role of protection of mitochondria from ANT-induced damage to mitochondrial DNA (Lebrecht et al., Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in
chronic doxorubicin cardiomyopathy. Circulation 2003, 108, 2423-2429), or from overloading of mitochondria by iron (Ichikawa et al., Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. The Journal of clinical investigation 2014, 124, 617-630).
Thus, based on current state of knowledge, it is not possible to definitely claim that a compound inhibiting Top2b will be certainly effective against chronic ANT cardiotoxicity in vivo.
Besides the above-mentioned chelating properties, DEX is, similarly to ANT, an inhibitor of topoisomerase Ila (Top2a), which also explains its certain anticancer a potential. Actually, bisdioxopiperazine compounds, where DEX belongs, were originally studied and developed as anticancer agents and their structure-activity relationships with respect to anticancer effect have been well studied and described (Creighton et al., Antitumour activity in a series of bisdiketopiperazines. Nature 1969, 222, 384; Hasinoff et al., A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). Biochemical pharmacology 1995, 50, 953-958; Hellmann and Rhomberg, Razoxane and dexrazoxane-two multifunctional agents - Experimental and clinical results. 2010). During these studies, the cardioprotective effect of DEX was discovered as a byproduct (Hasinoff et al., Chemical, biological and clinical aspects of dexrazoxane and other bisdioxopiperazines. Current medicinal chemistry 1998, 5, 1; Patterson and Willis, Translational Cardiology: Molecular Basis of Cardiac Metabolism, Cardiac Remodeling, Translational Therapies and Imaging Techniques. 2012). However, the structure- activity relationships of bisdioxopiperazines with respect to their cardioprotective effects against chronic ANT cardiotoxicity has not been clearly defined so far. It is mainly due to the unclear molecular mechanism of chronic ANT cardiotoxicity, and correspondingly also uncertain molecular target for the cardioprotective effect. However, even more important factor is a very limited number of experimental studies focusing on this matter with a clear prevalence of negative results and absence of the cardioprotective effects of DEX derivatives (Herman et al., Comparison of the protective effects against chronic doxorubicin cardiotoxicity and the rates of iron (III) displacement reactions of ICRF-187 and other bisdiketopiperazines. Cancer chemotherapy and pharmacology 1997, 40, 400-408; Martin et al., Evaluation of the topoisomerase II- inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin- induced cardiomyopathy. Toxicology 2009, 255, 72-79; Jirkovska-Vavrova et al., Synthesis and analysis of novel analogues of dexrazoxane and its open-ring hydrolysis product for protection against anthracycline cardiotoxicity in vitro and in vivo. Toxicology Research 2015,
4, 1098-1114; Bures et al., Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase Ilbeta but not its iron chelating metabolite. Toxicology 2017, 392, 1-10). Even slight modifications of the structure of DEX (or its racemate razoxane) led to the loss of the cardioprotective effect against chronic ANT cardiotoxicity - e.g. substitution of methyl for ethyl in the aliphatic linker in the compound ICRF-192 (Herman et al., Comparison of the protective effects against chronic doxorubicin cardiotoxicity and the rates of iron (III) displacement reactions of ICRF-187 and other bisdiketopiperazines. Cancer chemotherapy and pharmacology 1997, 40, 400-408), extension the linker with one methylene in ICRF-161, or substitution of one oxo-group in each of the cycles by hydrogen in MK-15 (Jirkovska-Vavrova et al., Synthesis and analysis of novel analogues of dexrazoxane and its open-ring hydrolysis product for protection against anthracycline cardiotoxicity in vitro and in vivo. Toxicology Research 2015, 4, 1098-1114). The methylation of imide nitrogens of bisdioxopiperazines in ICRF-239 did partly reduce the score of chronic damage to the myocardium as compared to ANT alone, but at the same time it reduced the overall survival of the animals, which complicates the interpretation of this finding.
These findings show that structurally similar compounds with bisdioxopiperazine structure may exhibit significantly different protective efficiency against chronic ANT cardiotoxicity. Thus, the bisdioxopiperazine structure is clearly not a guarantee of a clinically usable cardioprotective effect by itself. In addition, a study of Martin et al. (Evaluation of the topoisomerase II- inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin- induced cardiomyopathy. Toxicology 2009, 255, 72-79) showed than an assessment of the protective potential of bisdioxopiperazine derivatives closely related to DEX in an in vitro model of isolated cardiomyocytes may exhibit false positive results, which were in sharp contrast to results obtained with the use of in vivo models of chronic ANT cardiotoxicity validated with DEX as a positive control. Furthermore, cardioprotective potential of DEX was not found in in vitro experiments with the use of human induced pluripotent stem cells (iPSC) cardiomyocytes (Burridge et al., Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced
cardiotoxicity. Nature medicine 2016, 22, 547) However, in this cell model protective potential was observed in N-acetylcystein, whose cardioprotective inactivity in comparison with DEX have been proved in a randomized clinical study in 1983 (Myers et al., A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N- acetylcysteine. Seminars in oncology 1983, 10, 53-55) and also in a chronic dog model (Herman et al., Comparison of the effectiveness of (±)-l, 2-bis (3, 5-dioxopiperazinyl-1-yl) propane (ICRF-187) and N-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles. Cancer research 1985, 45, 276-281). Thus, only data obtained in in vivo models of chronic ANT cardiotoxicity validated with the use of clinically used DEX have principal conclusive importance for the evaluation of the cardioprotective potential of bisdioxopiperazine derivatives closely related to DEX. However, majority of DEX derivatives, including ICRF-193, are difficult to assess in these models due to their very low solubility in water - intravenous administration is frequently impossible and their absorption after intraperitoneal administration is uncertain. One of the previously prepared and studied DEX analogue is ICRF-193 (optically inactive meso-4,4'-(butan-2,3-diyl)bis(piperazine-2,6-dione). This compound was studied with regard to the inhibitory activity against Top2a and became a lead compound for the preparation of further analogues with a potential cytostatic effect. The compound ICRF-193 and its analogues are included and described in several publications and patents, where the anticancer effect of ICRF-193 is described and claimed (e.g. A.M. Creighton et al. Nature, 1969, 222, 384-385; US3941790A, 1976; Kuan-Chun Huang, The Journal Of Biological Chemistry, 2001, 276, 44488-44494; N. Hajji, Mutation Research 2003, 530, 35-46).
ICRF-193 was screened for protective effects in an in vivo model of general acute toxicity induced by the administration of a high single dose of ANT (DAU, 25 mg/kg) (Herman et al., Comparison of the protective effect of ICRF-187 and structurally related analogues against acute daunorubicin toxicity in Syrian golden hamsters. Research communications in chemical pathology and pharmacology 1985, 48, 39-55). The authors concluded that unlike DEX,
ICRF-193 does not have any protective effects against this massive multi-organ toxicity of ANT („ no protective activity was found in any pretreatment doses of ICRF-158 /analogue 2/ ICRF-193 /analogue 8/.... “). However, no parameter that might directly or indirectly indicate the potential cardioprotective effect was described in this study.
The compound ICRF-193 falls within the general formula of the patent GB 2245832 A 1992 (W09200740), which protects roughly tens of thousands of compounds derived from bisdioxopiperazines. This patent generally claimed the ability of these compounds to protect against ANT cardiotoxicity. However, based on more recent data, it is obvious that the bisdioxopiperazine structure by itself is not a carrier of a clinically usable cardioprotective effect. In addition, the structure of ICRF-193 is not explicitly mentioned in this patent as an example and is not described there at all. Conversely, the authors cite the above-mentioned publication (Herman et al., Comparison of the protective effect of ICRF-187 and structurally related analogues against acute daunorubicin toxicity in Syrian golden hamsters. Research communications in chemical pathology and pharmacology 1985, 48, 39-55) in the introduction and remark that unlike DEX, the compound with the formula of ICRF-193 did not show any protective effect against toxicity induced by a single dose of doxorubicin (page 2), which means that they expressed their negative opinion concerning the protective potential of this compound. The only example mentioned in the patent GB 2245832A 1992 is a completely different compound - tran5-1,2-bis(4-methyl-3,5-dioxopiperazin-1-yl)cyclohexane, which was evaluated in a model of cardiotoxicity induced by a single dose of doxorubicin in rats. The key evaluated parameter was cardiac output, which was reduced by doxorubicin. The evaluated bisdioxopiperazine derivative had very low (statistically insignificant) protective effect on the decrease of this parameter after single dose of ANT (decrease by 59% after doxorubicin alone vs. decrease by 47% after a combination with this bisdioxopiperazine derivative) despite the employment of a relatively high dose of the bisdioxopiperazine derivative (100 mg/kg, i.p.). DEX/razoxane was not evaluated in this experiment and there are no reference data validating the use of this unusual experimental model. Moreover, the authors themselves indicate that there were no signs of a congestive heart failure in this model. Thus, no conclusion could be drawn from this example concerning the key ability of the potential cardioprotective agent to prevent the development of an ANT induced heart failure.
/ran.s-1 ,2-bis(4-mcthyl-3,5-dioxopipcrazin-1-yl)cyclohcxanc
Thus, from this example even an expert cannot come to the conclusion that the compound ICRF-193 would have significant cardioprotective effect against chronic cumulative cardiotoxicity induced by repeated ANT administration leading to cardiomyopathy and congestive heart failure, which are principal problems in the clinical practice. The protective effect against this type of cardiotoxicity was not evaluated in this patent, the compound ICRF- 193 is not mentioned as an example in the patent and with respect to negative results of close DEX derivatives, even an expert could not predict the cardioprotective potential of compounds of the general formula in this patent against chronic cumulative ANT cardiotoxicity. The example presented in the patent concerns toxicity of single dose ANT administration, which is rarely an issue in the clinical practice, and in addition, the observed effect was very weak.
The substance ICRF-193 also falls within the general formula of the patent application US2008/0275036 Al. This application hypothetically protects thousands of compounds and one of the areas that is claimed is their protective ability against cardiotoxicity of anti-tumor drugs, including ANTs. The formula of the compounds ICRF-193 is presented in table 1 on page 30 of the said document, but its characteristic or any pharmacological effect is not explicitly mentioned or described. In addition, the authors assumed that the cardioprotective effects of DEX stems from the chelating properties of its metabolite and that it will be the case of the other bisdioxopiperazine derivatives. More recent data show that this assumption is not valid (Sterba el al., Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxidants & redox signaling 2013, 18, 899-929), which also questions the presented inventive step and validity of claiming the cardioprotective effect of bisdioxopiperazine derivatives. The provided evidence always concerned only DEX and did not have any relationship to cumulative chronic ANT cardiotoxicity leading to cardiomyopathy and a heart failure. Only acute effects on electrophysiological parameters were evaluated, including those that were pathologically
modified by supratherapeutic ANT concentrations, in various experimental models (an acute in vivo experiment, an experiment with isolated heart perfused according to Langendorff and with isolated cardiomyocytes in vitro). Even an expert cannot infer any conclusion about cardioprotective potential of ICRF-193 against cumulative chronic ANT cardiotoxicity from these data because this effect was not evaluated here and no data concerning this compound are mentioned.
The compound ICRF-193 is presented in the patent application W02016/051213 A1 on page 4 and in figure 1 (Fig. 1). The entire application is focused on the ability of DEX, its metabolites B and C and DEX derivatives to inhibit formation of poly(ADP-ribose) (PAR) and related potential clinical application of these substances. One of the claimed potential applications of these compounds is protection against ANT toxicity. In this patent application, the authors completely rejected the importance of Top2b for the cardioprotective effect of DEX and suggested the interaction with PAR as the main mechanism of the cardioprotection. Although ICRF-193 is mentioned in the patent, no experimental data are provided for this compound as an example (the same is true for other DEX derivatives). Only data presented therein concerned DEX and its metabolites B and C , and were generated by in silico modelling of interaction of various substances with PAR and inhibition of AIF (Apoptosis Inducing Factor) release from isolated liver mitochondria induced by PAR. The entire patent application does not provide any direct evidence concerning ANT cardiotoxicity or DEX cardioprotection (no data concerning the effects of ANTs on the heart, cardiomyocytes or their organelles are presented here). The presented inventive step and the related attempt to claim the cardioprotective effect of DEX derivatives were based on speculative basis only. The above- presented patent application thus does not provide any evidence for the efficacy of ICRF-193.
The compound ICRF-193 is also disclosed in patent application WO2008/157358 Al, which protects methods of treating cancer with a combination of a Top2 inhibitor and Top2 (topoisomerase) poison, including ANT. As Top2 inhibitors, the most well-known representatives of bisdioxopiperazines ICRF-187 (DEX), ICRF-193, ICRF-159 (razoxane) and ICRF-154 are disclosed, together with their unspecified prodrugs and metabolites. The use of these compounds (including ICRF-193) as cardioprotective agents is mentioned in the text, but not explicitly claimed. The claims only generally stated the use of this combination of drugs but without description of a specific medical intention or purpose (i.e. without particular indication). The claim was exemplified by the in vitro reduction of doxorubicin-induced DNA
damage detected by the gH2AC marker in proliferating H9c2 cells by DEX and ICRF-193, which is associated with the inhibition and depletion of Top2b. However, as mentioned above, no direct evidence has been provided that pharmacological protection of cardiomyocytes against DNA damage detected as gH2AC is the sole or main prerequisite for effective protection of primary cardiomyocytes in vitro and particularly the heart against chronic cumulative cardiotoxicity caused by ANT therapy in vivo. The example performed on proliferating H9c2 cell line is also of unclear inventive value due to the fact that the cell line used, unlike cardiomyocytes, also expresses the Top2a isoform, which is indeed also significantly affected by studied substances (ANT and DEX/ICRF-193). Moreover, the molecular phenotype of these cells as well as the effects of doxorubicin on them are fundamentally different from primary cardiomyocytes (Lenco J. el al. Proteomic investigation of embryonic rat heart-derived H9c2 cell line sheds new light on the molecular phenotype of the popular cell model. Exp Cell Res. 2015; 339: 174-186). In this patent, no evidence is provided for the ability of ICRF-193 or its prodrug or metabolite to protect either primary cardiomyocytes in vitro or the myocardium from chronic ANT cardiotoxicity in vivo.
The recent data from scientific journals and from the patent literature can be summarized as follows. Cardioprotective effects of ICRF-193 against chronic ANT cardiotoxicity have not been directly experimentally evaluated. There is only a negative finding from a study of overall acute toxicity induced by a high ANT dose, where the results of ICRF-193 were substantially different from those of DEX. A structure of ICRF-193 is included in patents protecting an anti-tumor effects of compounds and it is also one of the thousands of substances that can be generated from general formulae of two patents/patent applications (GB 2245832A 1992, US2008/0275036 Al), claiming the cardioprotective effects against ANT toxicity. But ICRF-193 and its potential protective effects against cumulative chronic ANT cardiotoxicity associated with cardiomyopathy and a heart failure is not mentioned as an example in a single case. More recent experimental data show that the cardioprotective effect is not related to chelation and antioxidative properties of metabolites of bixdioxopiperazine derivatives and that even a very small change of the structure of the parent compound DEX may lead to the loss of the effects against chronic ANT cardiotoxicity. Therefore, the inventive step and the related claims presented above with a very general formulae cannot be considered valid without further experimental data concerning a particular compound. There is the patent application W02016/051213 Al, which mentions the compound ICRF-193 (together with a number of other DEX derivatives) as a potential cardioprotective agent against ANT
cardiotoxicity, and its cardioprotective effect against ANT toxicity is claimed herein. In fact, no protective effect of ICRF-193 against any type of ANT toxicity was demonstrated there. Therefore, this inventive step cannot be considered valid in association with chronic ANT cardiotoxicity either. Finally, patent application WO2008/157358 A1 claims the administration of ICRF-193 in combination with Top2 poison in the therapy of cancer, where possible cardioprotective efficacy is derived exclusively from the prevention of ANT-induced DNA damage on the H9c2 cell line in vitro. The inventive value of this work with respect to the prevention of chronic ANT cardiotoxicity is uncertain, as the cell model did not employ cardiomyocytes but a proliferating cell line of markedly different phenotype, and any association between evaluated in vitro protection against ANT-induced DNA damage and real protection against clinically relevant forms of ANT cardiotoxicity in in vivo has not been demonstrated so far. Even in this patent application, the protective effect of ICRF-193 against chronic cumulative cardiotoxicity of ANT is not demonstrated as an example.
Disclosure of the Invention
Firstly, a study of cytoprotective effects of DEX and a library of bisdioxopiperazines against clinically relevant concentrations of ANT was carried out in vitro. The results of this study showed the ability of compound ICRF-193 to protect primary cardiomyocytes against ANT toxicity in vitro at significantly lower concentrations than the parent drug DEX. As mentioned in the background art section, this in vitro test alone cannot reliably predict the cardioprotective potential against chronic cumulative ANT cardiotoxicity in vivo. However, a conclusive in vivo study with ICRF-193 could not be performed because this substance is practically insoluble in water, which hinders both its intravenous (i.v.) administration in to the organism in the required doses and effective absorption in case of different other routes of administration like oral (p.o .), intraperitoneal (i.p. ) etc. This limitation may have influenced the results of evaluation of this substance against the general acute toxicity of DAU in the earlier study (Herman et al., Comparison of the protective effect of ICRF-187 and structurally related analogues against acute daunorubicin toxicity in Syrian golden hamsters. Research communications in chemical pathology and pharmacology 1985, 48, 39-55).
For this reason, derivatives of ICRF-193 of general formula I with higher solubility in water were prepared. These derivatives had been already described in the patent US 5393889A
(PCT/JP91/00894), claiming their use as anti-cancer drugs. The possible effects of compounds of general formula I against any form of ANT cardiotoxicity has not been described or mentioned in the literature yet.
Disclosure of the invention is based on the discovery and unequivocal confirmation of the fact that the compounds of general formula I in the form of an ammonium salt with a pharmaceutically acceptable acid are able to protect primary cardiomyocytes against ANT toxicity in vitro , and, above all, to show excellent efficacy as cardioprotectants at very low doses against chronic cumulative ANT cardiotoxicity induced by repeated (10-week) administration of a clinically relevant dose of daunorubicin (once weekly i.v. at a dose of 3 mg/kg DAU) in a rabbit model.
This model shows functional, biochemical and morphological similarities to chronic ANT cardiotoxicity observed in the clinical practice. Moreover, the cardioprotective effect of DEX, the approved drug with demonstrated cardioprotective efficacy in the clinical practice, was repeatedly shown in this model (Jirkovsky el al., Early and delayed cardioprotective intervention with dexrazoxane each show different potential for prevention of chronic anthracycline cardiotoxicity in rabbits. Toxicology 2013, 311, 191-204; Popelova el al., Dexrazoxane-afforded protection against chronic anthracycline cardiotoxicity in vivo: effective rescue of cardiomyocytes from apoptotic cell death. British journal of cancer 2009, 101, 792). Excellent cardioprotective effects of the compounds of general formula I were observed even with doses 30 times lower than the recommended doses of DEX (the only known and used drug against chronic ANT cardiotoxicity) studied under the same conditions in this model. The significant effect of the compounds of general formula I against chronic ANT cardiotoxicity was noted already at the dose of 1 mg/kg. Compared to known data from scientific literature this means that with respect to the required dose the compounds of general formula I are so far the most potent cardioprotective agents against chronic ANT cardiotoxicity.
An object of the invention is the use of the compounds of general formula I in the form of the ammonium salt with a pharmaceutically acceptable acid according to the invention for the manufacture of a medicament for the prevention of chronic cumulative cardiotoxicity (cardiomyopathy and a heart failure) caused by therapy with anthracycline anticancer drugs.
2
R = H, a C1-C6 alkyl, benzyl or benzyl substituted at positions 2, 3, 4 and 5 with one or more electron-acceptor groups and/or one or more electron-donor groups, a phenyl or phenyl substituted at positions 2, 3, 4 and 5 with one or more electron-acceptor groups and/or one or more electron-donor groups.
A pharmaceutically acceptable acid refers to such organic and inorganic acids whose anions do not exhibit a toxic effect on the human organism in clinically relevant concentrations. They are especially: chlorides, bromides, iodides, sulfates, nitrates, acetates, maleates, fumarates, methanesulfonates, citrates, succinates, phosphates and/or tartrates, (source: Lemke, Thomas el al. ; (eds.).: Foye's principles of medicinal chemistry. Philadelphia; Baltimore: Lippincott Williams & Wilkins, 2013, 1500 s. ISBN 978-1-4511-7572-1.)
Electron-donor groups refer to such substituents that increase the electron density at the phenyl substituent of R2. They are especially: -N¾, -NHAlk, -NA1K2, -OH, -OAlk, -OAr, -NHCOCH3, -NHCOAlk; -NHCOAr; -Aik, -Ar, where Aik = Alkyl, especially having 1 - 4 carbon atoms, Ar = Aryl, where aryl = phenyl or phenyl substituted at positions 2, 3, 4 and 5 with one or more electron-acceptor groups and/or one or more electron-donor groups, naphthyl or pyridyl. Electron-acceptor groups refer to such substituents that reduce the electron density at the phenyl substituent of R2. They are especially: -NO2, -N+Alk3, -CF3, CCI3, -CN, -COOH, -COOAlk, -COOAr, -CHO, -COAlk, -COAr, -F, -Cl, -Br, -I, where Aik = Alkyl, especially having 1 - 4 carbon atoms, Ar = Aryl, where aryl = phenyl or phenyl substituted at positions 2, 3, 4 and 5 with one or more electron-acceptor groups and/or one or more electron-
donor groups, naphthyl or pyridyl. (source: a) John McMurry: Organic Chemistry, Sixth edition, 2004, Brooks/Cole, a Thomson Learning Company; b) L. G. Wade, Jr.: Organic Chemistry, Sixth edition, 2006, Pearson Prentice Hall Inc.; c) J. Clayden et al.,: Organic Chemistry, 2001, Oxford University Press).
The compounds of general formula I can be obtained by routine methods of organic synthesis. For the synthesis of meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione) of formula II, the method described in the patent US 5393889A (PCT/JP91/00894) was used (Scheme 2).
Scheme 2. Synthesis of meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione of formula II (DMF = N, N- dimethylformide)
Suitably protected precursors of the final compounds of general formula I,
were then obtained by esterification of meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl) piperazine-2, 6-dione) of formula II with a suitably protected carboxylic acid with the use of dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine (Scheme 3).
Scheme 3. Synthesis of Boc-protected precursors (of formula Ila) of the final substances of general formula I (DCC = dicyclohexylcarbodiimide; DMAP = 4-(dimethylamino)pyridine, Boc = tert-butyloxycarbonyl) The final products of general formula I in the form of the ammonium salt with a pharmaceutically acceptable acid,
were obtained from the precursors by deprotecting the Boc group with hydrogen chloride (Scheme 4).
Scheme 4. Preparation of the final compounds of general formula I in the form of hydrochlorides (Boc = tert-butyloxycarbonyl)
The simple assumptions made in the previous patent literature about the relationship of the chemical structure and cardioprotective activity of bisdioxopiperazine derivatives were refuted herein. This is demonstrated by an example of structurally very close derivatives of DEX or ICRF-193 not yet evaluated in the literature that were found completely free of any cardioprotective potential against chronic ANT cardiotoxicity in vivo. One of these examples is the N,N' -dimethyl derivative of DEX (ICRF-239, see page 8), mentioned in the background art, which, by substitution on imide nitrogen, is similar to the example in the patent GB 2245832A. The ineffectiveness of N,N' -dimethyl derivative of DEX (ICRF-239) against chronic ANT cardiotoxicity in vivo is demonstrated in example 10. In addition to what is mentioned above, only indirect further comparisons can be made. E.g. compounds of general
formula I show an order of magnitude higher cardioprotective potential than the example of another bisdioxopiperazine evaluated in the acute cardiotoxicity model using single administration of ANT in patent GB 2245832 A (only marginal protective potential was observed at 100 mg/kg, page 20 of the patent).
The repeated administration of the compounds of formula I alone or in the combination with ANT was very well tolerated by animals (no signs of systemic or local toxicity at the site of administration were recorded), further supporting the potential of the compounds of general formula I as clinically appropriate drugs to prevent chronic cumulative cardiotoxicity caused by repeated administration of anthracyclines.
Fig. 1. Protective effects of the compound ICRF-193 against DAU cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
Fig. 2. Protective effects of the compound lb according to Example 1 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
Fig. 3. Protective effects of the compound Ic according to Example 2 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
Fig. 4. Protective effects of the compound Id according to Example 3 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
Fig. 5. Protective effects of the compound Ie according to Example 4 against DAU cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes.
Fig. 6. Results of an evaluation of the cardioprotective effects of the compound lb according to Example 1 in a rabbit model of chronic cumulative anthracycline cardiotoxicity.
Fig. 7. Results of an evaluation of the cardioprotective effects of the compound ICRF-239 in the rabbit model of chronic cumulative anthracycline cardiotoxicity.
Fig. 8. General formula I
Examples In the text below, compounds of general formula I will be introduced
I where the symbols R 1 , R 2 have the above-mentioned meaning.
II
A suspension of the substance ICRF-193 ( meso-4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione, 1 g, 3,54 mmol) in 5 ml of DMF was heated at 130 °C for 10 minutes. Then, an aqueous solution of formaldehyde (37%, 1.48 g, 1.43 ml, 18.23 mmol) was added to the reaction and the reaction was further heated to 130°C for 4 hours. After that, the solvent was evaporated, and 20 ml of ethanol was added. The produced precipitate was filtered and washed on the filter with 5 ml of ethanol and 10 ml of diethyl ether. Yield: 67% (0.26 g) as a white crystalline solid.
The substance ICRF-193 is commercially available. The substance can be prepared with the use of common synthetic procedures according to R.M. Snapka et al., Biochemical Pharmacology, 1996, 52, 543-549. Example 1 : meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,1-diyl))bis(methylene)-bis(2- aminoacetate) hydrochloride (lb)
The compound meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4, 1-diyl))bis(methylene)-bis(2- aminoacetate) hydrochloride lb is prepared according to Scheme 4 through a reaction of meso- (butane-2, 3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-bis(2-((tert- butoxycarbonyl)amino)acetate) (0.3 mmol) with an excess of hydrogen chloride in 5 ml of acetic acid. The reaction was stirred for 2 hours, then 50 ml of diethyl ether was added, and the resulting precipitate was filtered off and dried in a desiccator. Yield: 93% as a white crystalline solid. 1H NMR (500 MH1, DMSO-d6) d 8.51 (t, J = 5.8 Hz, 6H), 5.75 (s, 4H), 3.79 (q, J = 5.7 Hz, 4H), 3.67 (d, J = 16.7 Hz, 4H), 3.59 (d, J = 16.8 Hz, 4H), 2.98 (s, 2H), 0.97 (d, J = 4.1 Hz,
6H). 13C NMR (126 MHz, DMSO-J6) d 169.90, 166.92, 62.61, 59.17, 52.19, 9.75.
The starting meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4, l-diyl))bis(methylene)-bis(2- (( tert-butoxycarbonyl)amino)acetate) was prepared through a reaction of meso-4,4'-(butane- 2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione) with Boc-glycine according to Scheme 3. A solution of dicyclohexylcarbodiimide (0.72 g, 3.45 mmol) in 30 ml of CH2CI2 was added to a suspension of meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione) (0.6 g, 1.75 mmol), Boc-glycine (3.54 mmol) and 4-(dimethylamino)pyridine (6 mg, 0.049 mmol) in 50 ml of CH2CI2 at 0°C under an argon atmosphere. The reaction was stirred for 48 hours. Then, the reaction was filtered, and the filtrate was extracted with 48 ml of a mixture of H2O/CH3COOH (15:1). The organic layer was separated, dried over anhydrous Na2S04 and evaporated. The product was purified using column chromatography (mobile phase: CHCl3/MeOH, 70:1). Yield: 50% as white powder; melting point 195-197 °C. 1H NMR (500
MHz, DMSO-d6) d 7.21 (t, J = 6.2 Hz, 2H), 5.68 - 5.58 (m, 4H), 3.65 (d, J = 6.2 Hz, 4H), 3.58 - 3.51 (m, 4H), 3.48 - 3.41 (m, 4H), 2.84 - 2.76 (m, 2H), 1.37 (s, 18H), 0.90 (d, J = 5.1 Hz, 6H). 13C NMR (126 MHz, DMSO -d6) d 170.52, 169.66, 155.94, 78.49, 62.20, 58.84, 52.29, 41.79, 28.31, 9.70. The other substances are normally commercially available.
Example 2: meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-(2S,2'S)- bis(2-aminopropanoate) hydrochloride (Ic)
The compound meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)- (2S,2'S)-bis(2-aminopropanoate) hydrochloride Ic is prepared according to Scheme 4 through a reaction of meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4, l-diyl))bis(methylene)-(2S,2'S)- bis(2-(( tert-butoxycarbonyl)amino)propanoate) (0.2 g, 0.3 mmol) with an excess of hydrogen chloride in 5 ml of acetic acid. The reaction was stirred for 2 hours, then 50 ml of diethyl ether was added, and the resulting precipitate was filtered off and dried in a desiccator. Yield: 86% as a white crystalline solid. 1H NMR (500 MHz, DMSO-J6) d 8.65 (d, J = 5.5 Hz, 6H), 5.80 (dd, J = 9.8, 3.9 Hz, 2H), 5.71 (dd, J = 9.8, 4.5 Hz, 2H), 4.04 (d, J = 6.4 Hz, 2H), 3.69 (d, J = 16.9 Hz, 4H), 3.61 (d, J = 16.9 Hz, 4H), 2.99 (s, 2H), 1.36 (d, J = 7.2 Hz, 6H), 1.06 - 0.95 (s, 6H). 13C NMR (126 MHz, DMSO -d6) d 169.91, 169.25, 62.74, 59.24, 52.16, 47.85, 15.75, 9.18 The starting meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-bis(2- (tert-butoxycarbonyl)amino)propanoate) was prepared through a reaction of meso- 4,4'- (butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione) with Boc-L-alanine according to Scheme 3. A solution of dicyclohexylcarbodiimide (0.72 g, 3.45 mmol) in 30 ml of CH2CI2 was added to a suspension of meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6- dione) (0.6 g, 1.75 mmol), Boc-L-alanine (3.54 mmol) and 4-(dimethylamino)pyridine (6 mg, 0.049 mmol) in 50 ml of CH2CI2 at 0°C under an argon atmosphere. The reaction was stirred
for 48 hours. Then, the reaction was filtered, and the filtrate was extracted with 48 ml of a mixture of H2O/CH3COOH (15:1). The organic layer was separated, dried over anhydrous Na2S04 and evaporated. The product was purified using column chromatography (mobile phase: CHCl3/McOH, 30:1). Yield: 65% as a white crystalline solid. Melting point 190-192 °C. 1H NMR (500 MHz, DMSO-J6) d 7.29 (d, J = 7.4 Hz, 2H), 5.73 - 5.60 (m, 2H), 5.56 (dd, J = 9.5, 4.5 Hz, 2H), 3.95 (t, J = 7.3 Hz, 2H), 3.55 (d, J = 16.7 Hz, 4H), 3.45 (d, J = 16.8 Hz, 4H), 2.84 - 2.76 (m, 2H), 1.36 (s, 18H), 1.17 (d, J = 7.3 Hz, 6H), 0.90 (d, J = 4.7 Hz, 6H).
The other substances are normally commercially available. Example 3: meso -(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-(2S,2'S)- bis(2-amino-3-phenylpropanoate) hydrochloride (Id)
The compoundmeso -(butane-2,3-diylbis(2,6-dioxopiperazine-4, l-diyl))bis(methylene)- (2S,2'S)-bis(2-amino-3-phenylpropanoate) hydrochloride Id is prepared according to Scheme 4 through a reaction ofmeso -(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)- (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate) (0.25 g, 0.3 mmol) with an excess of hydrogen chloride in 5 ml of acetic acid. The reaction was stirred for 2 hours, then 50 ml of diethyl ether was added, and the resulting precipitate was filtered off and dried in a desiccator. Yield: 86% as a white crystalline solid. *H NMR (500 MHz, DMSO-d6) d 8.76 (d, J = 5.3 Hz, 6H), 7.31 - 7.17 (m, 10H), 5.79 (dd, J = 9.8, 5.9 Hz, 2H), 5.62 (d, J = 9.8 Hz, 2H),
4.29 - 4.23 (m, 2H), 3.77 - 3.40 (m, 8H), 3.19 - 3.03 (m, 4H), 2.98 (s, 2H), 0.97 (d, J = 5.0 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) d 172.15, 169.80, 168.18, 168.15, 134.62, 134.55,
129.68, 128.73, 127.43, 62.74, 59.18, 59.11, 53.16, 53.11, 52.17, 35.73, 35.68, 33.47, 21.27,
9.73. 9.68. The starting meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-(2S,2'S)- bis(2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate) was prepared through a reaction of
meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione) with Boc-L- phenylalanine according to Scheme 3. A solution of dicyclohexylcarbodiimide (0.72 g, 3.45 mmol) in 30 ml of CH2CI2 was added to a suspension ofmeso -4,4'-(butane-2,3-diyl)bis(l- (hydroxymethyl)piperazine-2,6-dione) (0.6 g, 1.75 mmol), Boc-L-phenylalanine (3.54 mmol) and 4-(dimethylamino)pyridine (6 mg, 0.049 mmol) in 50 ml of CH2CI2 at 0°C under an argon atmosphere. The reaction was stirred for 48 hours. Then, the reaction was filtered, and the filtrate was extracted with 48 ml of a mixture of H2O/CH3COOH (15:1). The organic layer was separated, dried over anhydrous Na2S04 and evaporated. The product was purified using column chromatography (mobile phase: CHCl3/MeOH, 100:1). Yield: 30% as a white crystalline solid. Melting point 156-158 °C. 1 H NMR (500 MHz, Chloroform-ri) d 7.34 - 7.20 (m, 6H), 7.20 - 7.12 (m, 4H), 5.82 (t, J= 3.2 Hz, 4H), 4.95 (d, J= 8.4 Hz, 2H), 4.60 (q, J = 6.8 Hz, 2H), 3.58 - 3.49 (m, 4H), 3.47 - 3.39 (m, 4H), 3.16 - 2.95 (m, 4H), 2.67 - 2.59 (m, 2H), 1.41 (s, 18H), 1.07 (d, 7 = 2.1 Hz, 6H).
The other substances are normally commercially available.
Example 4:meso -(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)-(2S,2'S)- bis(2-amino-3-methylbutanoate) hydrochloride (Ie)
The compound meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4, l-diyl))bis(methylene)- (2S,2'S)-bis(2-amino-3-methylbutanoate) hydrochloride Ie is prepared according to Scheme 4 through a reaction of meso-(butane-2,3-diylbis(2,6-dioxopiperazine-4,l-diyl))bis(methylene)- (2S,2'S)-bis(2-((tert-butoxycarbonyl)amino)-3-methylbutanoate) (0.22 g, 0.3 mmol) with an excess of hydrogen chloride in 5 ml of acetic acid. The reaction was stirred for 2 hours, then 50 ml of diethyl ether was added, and the resulting precipitate was filtered off and dried in a desiccator. Yield: 25% as a white crystalline solid. LCMS m/z (ESI+) 541.15 (100, M+H+), 442.04 (25%). 1H NMR (500 MHz, D20) d 6.00 - 5.84 (m, 2H), 5.78 - 5.70 (m, 2H), 3.95 (d, /
= 4.2 Hz, 2H), 3.82 - 3.60 (m, 8H), 2.96 (q, J = 5.7 Hz, 2H), 2.25 - 2.16 (m, 2H), 1.12 - 0.98 (m, 6H), 0.95 - 0.85 (m, 12H).
13C NMR (126 MHz, D20) d 176.59, 170.92, 170.89, 168.43, 63.04, 60.28, 60.19, 58.04, 52.19, 29.25, 17.02, 9.47, 9.42.
The startingmeso -(butane-2,3-diylbis(2,6-dioxopiperazine-4, l-diyl))bis(methylene)-(2S,2'S)- bis(2-((tert-butoxycarbonyl)amino)-3-phenylbutanoate) was prepared through a reaction of meso-4,4'-(butane-2,3-diyl)bis(l-(hydroxymethyl)piperazine-2,6-dione) with Boc-L-valine according to Scheme 3. A solution of dicyclohexylcarbodiimide (0.72 g, 3.45 mmol) in 30 ml of CH2CI2 was added to a suspension of meso-4,4'-(butane-2,3-diyl)bis(l- (hydroxymethyl)piperazine-2,6-dione) (0.6 g, 1.75 mmol), Boc-L-valine (3.54 mmol) and 4- (dimethylamino)pyridine (6 mg, 0.049 mmol) in 50 ml of CH2CI2 at 0°C under an argon atmosphere. The reaction was stirred for 48 hours. Then, the reaction was filtered, and the filtrate was extracted with 48 ml of a mixture of H2O/CH3COOH (15:1). The organic layer was separated, dried over anhydrous Na2SO4 and evaporated. The product was purified using column chromatography (mobile phase: CHCl3/MeOH, 20:1). Yield: 50% as a white crystalline solid. 1H NMR (500 MHz, DMSO -d6) d 7.16 (d, J = 8.1 Hz, 2H), 5.75 (dd, J = 9.7, 6.6 Hz, 2H), 5.55 (dd, J = 9.7, 3.8 Hz, 2H), 3.78 (t, J = 7.1 Hz, 2H), 3.59 - 3.39 (m, 8H), 2.86 - 2.74 (m, 2H), 1.92 (q, J = 6.7 Hz, 2H), 1.41 - 1.28 (m, 18H), 0.93 - 0.77 (m, 18H). 13C NMR (126 MHz, DMSO-d6) d 171.24, 170.44, 155.86, 78.45, 61.88, 60.27, 59.34, 58.79, 52.30, 29.70, 28.34, 18.86, 18.47, 9.61.
The other substances are normally commercially available.
Example 5. Protective effects of ICRF-193 against ANT cytotoxicity in vitro in a model of isolated rat neonatal ventricular cardiomyocytes
Methodology. The protective effects of ICRF-193 were assessed in a model of toxicity induced by administration of DAU into cultivation media of isolated neonatal rat cardiomyocytes. This bioassay was previously validated by DEX (Jirkovska-Vavrova el al., Synthesis and analysis of novel analogues of dexrazoxane and its open-ring hydrolysis product for protection against anthracycline cardiotoxicity in vitro and in vivo. Toxicology Research 2015, 4, 1098-1114). The culture was obtained from heart ventricles of 3-5-day-old Wistar rats
via serial enzymatic digestion of intercellular structures by mixture of collagenase and pancreatin. The cell suspension obtained thereby was than enriched with cardiomyocytes through selective adhesion of other cells than myocytes on plastic surface. The myocyte-rich cell suspension was then cultivated for three days on plastic wells pre-coated with gelatin, to obtain a culture of spontaneously beating cardiomyocytes. Then, this culture was exposed to ICRF-193, DAU or their combination in serum- free media. In the case of the combination experiment, the culture was first exposed to ICRF-193 for 3 hours, then DAU was added to the cultivation media in the concentration of 1.2 mM for 3 hours, after which both the substances were removed through media replacement. The toxic effects of DAU and the protective effect of ICRF-193 were evaluated after 48 hours from the last media replacement by means of determination the activity of lactate dehydrogenase (LDH), an intracellular enzyme that is released into the cultivation media after a cell membrane damage. The activity of LDH in the cultivation media was compared to the total LDH activity obtained after lysis of all cells in the sample. The LDH activity was determined spectrophotometrically with the use of the lactate and NAD+ as the substrates. The resulting increase of NADPH was determined by measurement of absorbance at 340 nm using a Tecan Infinite 200M spectrophotometer (Tecan Ltd., Switzerland).
Results. Pre-incubation with compound ICRF-193 for 3 hours before three-hour exposure to DAU statistically significantly reduced damage to the culture of isolated neonatal cardiomyocytes 48 hours after the exposure.
The protective effects of the compound ICRF-193 against DAU cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes is shown in Fig. 1. DAU induced significant toxicity in the culture of neonatal rat cardiomyocytes as determined by the LDH release. Preincubation with ICRF-193 statistically significantly reduced this damage in the range of the studied concentrations (hatched columns). Already at 10 mM of the agent, toxicity of DAU (expressed as LDH release into the media) was reduced by approximately 55% as compared to the control. Statistically significant differences (p < 0,05, one-way ANOVA) are shown as “c” (significant as compared with the control) and “d” (significant as compared with DAU).
Example 6. Protective effects of the substance lb according to Example 1 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes
The protective effects of the substance lb according to Example 1 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes was determined with the use of the procedure specified in Example 5.
Results. Pre-incubation with the substance lb for 3 hours before three -hour exposure to DAU statistically significantly reduced damage to the culture of isolated neonatal cardiomyocytes 48 hours after the exposure.
The protective effects of the compound lb according to Example 1 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes is shown in Fig. 2. DAU induced significant toxicity in the culture of neonatal rat cardiomyocytes as determined by the LDH release. Pre-incubation with the substance lb statistically significantly reduced this damage in the entire range of the used concentrations (hatched columns, i.e. already from 1 mM) while the biggest effect was achieved at 10 mM, where the release of LDH into the media, i.e. the toxicity, was reduced by approximately 59%. Statistically significant differences (p < 0,05, one-way ANOVA) are shown as “c” (significant as compared with the control) and “d” (significant as compared with DAU).
Example 7. Protective effects of the substance Ic according to Example 2 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes
The protective effects of the substance Ic according to Example 2 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes was determined with the use of the procedure specified in Example 5.
Results. Pre-incubation with the substance Ic for 3 hours before three-hour exposure to DAU statistically significantly reduced damage to the culture of isolated neonatal cardiomyocytes 48 hours after the exposure.
The protective effects of the substance Ic according to Example 2 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes is shown in Fig. 3. DAU induced significant toxicity in the culture of neonatal rat cardiomyocytes as determined by the LDH release. Pre-incubation with the substance Ic (hatched columns) statistically significantly reduced this damage already in the concentration of 3 mM while the biggest effect was
achieved at 10 mM, where the release of LDH into the media, i.e. the toxicity, was reduced by approximately 52%. Statistically significant differences (p < 0,05, one-way ANOVA) are shown as “c” (significant as compared with the control) and “d” (significant as compared with DAU).
Example 8. Protective effects of the substance Id according to Example 3 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes
The protective effects of the substance Id according to Example 3 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes was determined with the use of the procedure specified in Example 5.
Results. Pre-incubation with the substance Id for 3 hours before three-hour exposure to DAU statistically significantly reduced damage to the culture of isolated neonatal cardiomyocytes 48 hours after the exposure.
The protective effects of the substance Id according to Example 3 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes is shown in Fig. 4. DAU induced significant toxicity in the culture of neonatal rat cardiomyocytes as determined by the LDH release. Pre-incubation with the substance Id (hatched columns) statistically significantly reduced this damage already in the concentration of 3 mM while the biggest effect was achieved at 10 mM, where the release of LDH into the media, i.e. the toxicity, was reduced by approximately 42%. Statistically significant differences (p < 0,05, one-way ANOVA) are shown as “c” (significant as compared with the control) and “d” (significant as compared with DAU).
Example 9. Protective effects of the substance Ie to Example 4 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes
The protective effects of the substance Ie according to Example 4 against ANT cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes was determined with the use of the procedure specified in Example 5.
Results. Pre-incubation with the substance Ie for 3 hours before three-hour exposure to DAU statistically significantly reduced damage to the culture of isolated neonatal cardiomyocytes 48 hours after the exposure.
The protective effects of the substance Ie according to Example 4 against DAU cytotoxicity in vitro in a model of isolated neonatal cardiomyocytes is shown in Fig. 5. DAU induced significant toxicity in the culture of neonatal rat cardiomyocytes as determined by the LDH release. Pre-incubation with the substance Ie statistically significantly reduced this damage in the range of the used concentrations (hatched columns) while the biggest effect was achieved at 10 mM, where the release of LDH into the media, i.e. the toxicity, was reduced by approximately 43%. Statistically significant differences (p < 0,05, one-way ANOVA) are shown as “c” (significant as compared with the control) and “d” (significant as compared with DAU).
Example 10. Protective effects of the substance lb according to Example 1 against chronic cumulative ANT cardio toxicity in vivo
Methodology. For the study of cardioprotective effects of the substance lb according to Example 1, the established model of chronic cardiotoxicity in rabbits was used. Adult male New Zealand White rabbits (Velaz, Czech Republic) were housed individually in cages under standard conditions and fed with a standard pelleted diet ad libitum. After acclimatization (2 weeks, weight 3.0-3.5 kg), the rabbits (n = 35) were randomized into 5 groups.
In the group 1 (DAU) (n = 7), chronic anthracycline cardiotoxicity was induced with daunombicin (DAU) administered once a week i.v. into the marginal ear vein in the dose of 3 mg/kg.
The group 2 (control, n = 7) received saline (1 mg/kg) i.v. in the same manner. The groups 3 and 4 (n = 7 in each group): the substance lb according to Example 1 was fully dissolved in the saline (concentration 1 and 5 mg/ml) immediately before drug administration and the solution was filtered through an antibacterial filter. The substance lb according to Example 1 was subsequently administered in the doses of 1 and 5 mg/kg via slow i.v. injection (2 min) 30 min before each DAU administration (the same schedule of DAU administration as in the group 1 was adopted). The administrations of the compound lb according to Example 1 and DAU were always conducted contralaterally (i.e. each administration was performed into the vein of a different ear).
The group 5 (n = 7) - the substance lb according to Example 1 was administered alone in the dose of 5 mg/kg, in the same way as mentioned above in the group 4.
All the studied agents were administered to the rabbits once a week for 10 weeks. The experiment was completed 7 days after the last administration.
The body weight was monitored weekly; behavior changes were evaluated daily. The left ventricle (LV) systolic function was examined by echocardiography (Vivid 4, probe 10.5 MHz) before the beginning of the experiment and weekly from week 8 until the end of experiment. LV fractional shortening (LVFS) as the parameter of the systolic function was determined from the M-mode examination of LV. At the end of the experiment, the LV systolic function was also examined invasively under surgical anesthesia with pentobarbital (30 mg/kg). After preparation of arteria carotis, a Millar catheter (2.3F, Millar Instruments, USA) was introduced into LV and dP/dtmax as the parameter of systolic function was assessed. At the end of the experiment, a necropsy examination was conducted with a focus on signs of circulatory congestion (pleural effusion and effusion in the abdominal cavity), dilatation of heart chambers and macroscopic changes of internal organs.
Results: Chronic ANT cardiotoxicity induced by repeated DAU administration in an experimental rabbit model was associated with one premature death whereas all the animals in the both combination groups with the substance lb according to Example 1 survived until the end of the experiment. Fig. 6A shows the body weight gain at the end of the experiment. In all groups except for the group 1 (DAU), a significant increase of the body weight was observed in the course of the experiment. At the end of the experiment, the body weight gain was significantly higher in all other groups (i.e. including the combination groups with the substance lb according to Example 1), than in the group 1 (DAU). The administration of DAU led to slightly reduced consumption of food and water and slightly reduced motion activity. No other considerable changes of behavior or apparent signs of toxicity were observed in this study. Fig. 6B shows signs of blood congestion observed during the necropsy conducted at the end of the experiment or after the premature death. The necropsy examination performed in all the animals in this study identified signs of blood congestion in the group 1 (DAU), including pronounced forms of effusions in the thoracic and abdominal cavities with volumes exceeding 5 ml. The animal that died in the group 1 (DAU) exhibited very pronounced signs of blood
congestion and dilatation of the heart chambers. Conversely, in the combination groups 3 and 4 with the substance lb according to Example 1, no effusion in the thoracic cavity and only one case of a mild effusion in the abdominal cavity were found. No macroscopically detectable anomalies were found in group 5 with the substance lb according to Example 1 alone or in the both combination groups during the necropsy.
Fig. 6C shows results of echocardiographic (ECHO) examination of the left ventricle (LV) - fractional shortening (FS) was the evaluated parameter of the systolic function. The last measured values are presented. The echocardiographic examination of the LV systolic function revealed a significant decrease of LVFS as compared to the initial values in the group 1 (DAU) whereas in the both combination groups (the groups 3 and 4), the values of this parameter remained unchanged in the course of the experiment. The comparison of this parameter between the groups at the end of the experiment confirmed considerably lower values in the group 1 (DAU) as compared to the group 2 (the control group)), but also as compared to the both combination groups with the compound lb according to Example 1 (the groups 3 and 4). The examination of LV systolic function via LV catheterization (Fig. 6D) showed a significantly lower value of the index dP/dtmax in the group 1 (DAU) as compared to all the other groups, including the both combination groups with the substance lb according to Example 1 (the groups 3 and 4).
CTR- control group (group 2), compound Ib_5 - compound lb according to example 1, administered alone in the dose of 5 mg/kg (group 5), DAU - daunorubicin (the group 1), compound Ib_l+DAU - the combination group with the compound lb according to Example 1 administered in the dose of 1 mg/kg before each dose of DAU (the group 3), compound Ib_5+DAU - the combination group with the compound lb according to Example 1 administered in the dose of 5 mg/kg before each dose of DAU (the group 4). The results are presented as the means ± S.D. Statistical significance (p > 0,05, SigmaStat 3.5 software) in comparison with: “*” - the values at the beginning of the experiment (paired t-test), „Δ“ - with the values in all the other groups (ANOVA, Holm-Sidak post-hoc test).
Conclusions. This Example demonstrated a very pronounced cardioprotective potential of the substance lb according to Example 1 against chronic cumulative ANT cardiotoxicity in vivo. Administration of the substance lb according to Example 1 prevented the DAU-induced premature death of the animals associated with the development of cardiotoxicity and
advanced heart failure. The substance lb according to Example 1 also effectively prevented DAU-induced blood congestion and systolic dysfunction, as determined by both echocardiographic and catheterization examinations. All these effects were significant already at the dose of 1 mg/kg, which makes this substance currently most effective cardioprotective agent against chronic cumulative cardiotoxicity (DEX is recommended at the dose ratio of 1:10 to 1:20 to ANT, i.e. in our model 30-60 mg/kg). The repeated administration of the substance lb according to Example 1 was very well tolerated both when administered alone and in combination with DAU. Figs. 7A-C show the results of evaluation of the cardioprotective effects of the compound ICRF-239 in the rabbit model of chronic cumulative ANT cardiotoxicity. In the same model, the compound ICRF-239 did not exhibit any protective effect.
Fig. 7A shows survival of the animals at the end of the experiment. Fig. 7B shows the results of echocardiographic (ECHO) examination of the FV systolic function - FV fractional shortening (FVFS). The last measured value is presented. Fig. 7C shows the results of FV catheterization examination of the animals surviving until the end of the experiment - the evaluated parameter was the index of the systolic heart function dP/dtmax. During the necropsy, signs of circulatory congestion and dilatation of cardiac chambers were observed in the ICRF- 239+DAU combination groups, similarly to the DAU group. CTR - the control group (the group 2), ICRF-239 - compound ICRF-239 administered alone in the dose of 60 mg/kg, once a week for 10 weeks, DAU - daunorubicin (the group 1), ICRF- 239+DAU - the combination group with the compound ICRF-239 administered in the dose of 60 mg/kg before each dose of DAU. The results are presented as the means ± S.D. (n = 7 in each group). Statistical significance (p > 0.05, SigmaStat 3.5 software) in comparison with: „#“ - the control (CTR) group, „+“ - the compound ICRF-239 alone (ANOVA).
Claims
1. The use of the compounds of general formula I in the form of the ammonium salt with a pharmaceutically acceptable acid for the manufacture of a medicament for the prevention of chronic cumulative cardiotoxicity caused by therapy with anthracycline anticancer drugs
wherein R1 independently refers to hydrogen or the group
2
R is selected from the group consisting of H, a C1-C6 alkyl or branched alkyl, or benzyl.
2. A pharmaceutical preparation for use to prevent chronic cumulative cardiotoxicity caused by therapy with anthracycline anticancer drugs characterized in that it contains the compound of general formula I according to claim 1 as an active ingredient.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ202026A CZ309069B6 (en) | 2020-01-16 | 2020-01-16 | Use of ICRF-193 derivatives to prevent chronic cumulative cardiotoxicity due to anthracycline anticancer therapy |
| CZPV2020-26 | 2020-01-16 |
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|---|---|
| WO2021144746A1 true WO2021144746A1 (en) | 2021-07-22 |
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| PCT/IB2021/050285 WO2021144746A1 (en) | 2020-01-16 | 2021-01-15 | Use of icrf-193 derivatives and pharmaceutical preparations containing thereof for the prevention of chronic cumulative cardiotoxicity caused by therapy with anthracycline anticancer drugs |
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| CZ (1) | CZ309069B6 (en) |
| WO (1) | WO2021144746A1 (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3941790A (en) | 1967-07-03 | 1976-03-02 | National Research Development Corporation | Bis diketopiperazines |
| GB2245832A (en) | 1990-07-13 | 1992-01-15 | Nat Res Dev | Cardioprotective bis-dioxopiperazines |
| US5393889A (en) | 1990-07-04 | 1995-02-28 | Zenyaku Kogyo Kabushiki Kaisha | Water soluble bis-dioxopiperazine derivatives |
| US20080275036A1 (en) | 2007-05-02 | 2008-11-06 | Apt Pharmaceuticals, Inc. | Prevention and treatment of cardiac conditions |
| WO2008157358A1 (en) | 2007-06-15 | 2008-12-24 | University Of Medicine And Dentistry Of New Jersey | Methods for treating neoplasia and for identifying compositions useful in such therapy |
| US20150150843A1 (en) * | 2012-05-21 | 2015-06-04 | Randall T. Peterson | Cardioprotective compounds, their use with chemotherapy, and methods for identifying them |
| WO2016051213A1 (en) | 2014-12-17 | 2016-04-07 | Clinigen Group Plc | Par inhibition |
-
2020
- 2020-01-16 CZ CZ202026A patent/CZ309069B6/en unknown
-
2021
- 2021-01-15 WO PCT/IB2021/050285 patent/WO2021144746A1/en active Application Filing
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3941790A (en) | 1967-07-03 | 1976-03-02 | National Research Development Corporation | Bis diketopiperazines |
| US5393889A (en) | 1990-07-04 | 1995-02-28 | Zenyaku Kogyo Kabushiki Kaisha | Water soluble bis-dioxopiperazine derivatives |
| GB2245832A (en) | 1990-07-13 | 1992-01-15 | Nat Res Dev | Cardioprotective bis-dioxopiperazines |
| WO1992000740A2 (en) | 1990-07-13 | 1992-01-23 | National Research Development Corporation | Bis-dioxopiperazines and their use as protection agents |
| US20080275036A1 (en) | 2007-05-02 | 2008-11-06 | Apt Pharmaceuticals, Inc. | Prevention and treatment of cardiac conditions |
| WO2008157358A1 (en) | 2007-06-15 | 2008-12-24 | University Of Medicine And Dentistry Of New Jersey | Methods for treating neoplasia and for identifying compositions useful in such therapy |
| US20150150843A1 (en) * | 2012-05-21 | 2015-06-04 | Randall T. Peterson | Cardioprotective compounds, their use with chemotherapy, and methods for identifying them |
| WO2016051213A1 (en) | 2014-12-17 | 2016-04-07 | Clinigen Group Plc | Par inhibition |
Non-Patent Citations (58)
Also Published As
| Publication number | Publication date |
|---|---|
| CZ309069B6 (en) | 2022-01-12 |
| CZ202026A3 (en) | 2021-07-28 |
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