Synergistic combination of controlled necrosis inhibitors and N-acetylcysteine

Abstract

The present invention relates to a pharmaceutical composition comprising a combination of N-acetylcysteine ​​and at least one inhibitor of regulated necrotic cell death, such as necroptosis and / or ferroptosis.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising a combination of N-acetylcysteine ​​and at least one inhibitor of regulated necrotic cell death, such as necroptosis and / or ferroptosis.

[0002] Necroptosis, a programmed cell death pathway, is distinct from apoptosis because it does not involve the release of key apoptotic regulators, such as caspases, Bcl-2 family members, or cytochrome c, from mitochondria. "Necroptosis" is a specialized biochemical pathway of programmed necrosis that depends, inter alia, on the serine / threonine kinase activity of RIPK1 (Receptor-Interacting Protein Kinase 1). The groundbreaking discovery that necroptosis is a genetically controlled process led to the hypothesis that this programmed cell death is "druggable," a new breakthrough that has the potential to revolutionize everyday clinical medicine [Linkermann and Green, N. Eng. J. Med. 2014, 370(5), 455-465]. Indeed, molecular targets such as RIPK1 (Receptor Interacting Protein 1), RIPK3 and MLKL (Mixed Lineage Kinase domain-Like) have been convincingly shown to be involved in multiple disorders in which necroptosis has central pathophysiological relevance.

[0003] Necroptosis plays an important role in the pathogenesis of various diseases throughout the body, including neurological, cardiovascular, pulmonary, and gastrointestinal pathologies. Necroptosis also plays a role in infectious and autoimmune diseases. Necroptosis has also been reported to mediate organ rejection, particularly in cardiac and renal allografts (Khoury et al. Am J Pathology, 2020; Jouan-Lanhouet et al. Semin. Cell Dev. Biol. 2014).

[0004] Ferroptosis, a novel type of non-apoptotic regulated cell death first described in 2012, is typically associated with high intracellular levels of free iron and lipid peroxidation. This cell death pathway is directly linked to the cell's ability to regulate internal oxidative stress, particularly through the activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). Failure of glutathione-dependent antioxidant defenses leads to the accumulation of lipid-based reactive oxygen species (ROS), particularly Fe2+-mediated lipid peroxidation via the Fenton reaction, resulting in membrane damage and cell death.

[0005] Recent studies have shown that ferroptosis is involved in the pathophysiology of many human diseases, particularly affecting the heart, brain, nervous system, eyes, gastrointestinal system, liver, skin, kidneys, lungs, intestines, pancreas, or the entire body [Li et al., Cell Death Dis., 2020, 11(88); Tang et al., Cell Research, 2021, 31:107-125; Sun et al., Biomed. Pharmacother., 2020, 127, 110108]. Ferroptosis involves three major metabolic pathways, including thiols, lipids, and iron, leading to iron-dependent lipid peroxidation and ultimately cell death.

[0006] The hallmarks of ferroptosis have been used as key elements to define biomarkers for ferroptosis-related diseases.Ferroptosis is an iron-dependent, controlled tissue necrosis primarily driven by uncontrolled lipid peroxidation and subsequent membrane damage. Changes in the physiological levels of the following polypeptide components have been reported to be associated with ferroptosis: iron, reactive oxygen species, ROS (including lipid ROS such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) as well as oxidized phosphatidylethanolamine (oxPE) species, followed by oxidized phosphatidylserine (oxPS) and oxidized phosphatidylinositol (oxPI) [Wiernicki et al., Cell Death Dis., 2020, 11(922)]), and related peroxide detoxifying molecules (including the thiol-containing compounds glutathione, GSH, or coenzyme Q10, also known as ubiquinone), and long-chain fatty acid-CoA ligase 4 (ACSL4) [Chen X. et al., Front. in Cell and Dev. Biol., 2021, 9(637162)]. These important biochemical ferroptosis biomarkers can be measured and quantified by assays in body fluids (blood, plasma, serum, urine, cerebrospinal fluid) or highlighted by immunohistochemical labeling in biopsies of injured tissue.

[0007] Depending on both the pathology and the injured organ, some of the biomarkers associated with ferroptosis may be altered (increased or decreased) in amount and / or activity compared to normal physiological thresholds. Reference values ​​are listed here only for serum: (1) Iron metabolism (measured by serum iron and ferritin levels) exceeds physiological thresholds (serum iron >180 μg / dl in men and >160 μg / dl in women [Pagana et al., Mosby's Diagnostic and Laboratory Test Reference - Elsevier eBook on VitalSource, 14th Edition, Elsevier, 2019, ISBN: 9780323609678], ferritin >300 ng / ml in men and >200 ng / ml in women [Wang et al., Biochim Biophy. Acta, 2010, 1800(8): 760-769]); (2) glutathione redox status (measured by ELISA of reduced glutathione (GSH) and oxidized glutathione (GSSG) in plasma and glutathione peroxidase activity (GPx)) (GSH < 717 μmol / L, GSSG > 5.32 μmol / L; GSH / GSSG ratio < 156; GPx, men < 20 UI / gHb, women < 26 UI / gHb) [Haleng J. et al., Rev. Med. Liege, 2007]); (3) oxidative stress (measured by plasma total Q10 and reduced and activated Q10 (Q10H2) levels (men: Q10 < 3.44 μmol / l and Q10H2 < 3.04 μmol / l; women: Q10 < 1.88 μmol / l and Q10H2 < 1.64 μmol / l [Kaikkonen et al., Scand J Clin Lab Invest, 1999, 59: 457-466]); (4) Lipid peroxidation (measured by detection of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) adducts) exceeds physiological thresholds (>10 μmol / L for 4-HNE [Chen and Niki, IUBMB Life, 2008, 58(372-373)] and >3 μmol / L for MDA [Banjare et al., J. Sci. Soc., 2017; 44(137-9)] using the thiobarbituric acid method).

[0008] Note that upregulation of ACSL4 enzyme levels in injured organ tissues has also been reported as a putative biomarker of ferroptosis (ACSL4 expression can be monitored by transcriptomic and proteomic approaches).

[0009] Ferroptosis-related pathologies affecting the heart include myocardial ischemia-reperfusion injury, especially after arterial ligation; cardiomyopathies, especially doxorubicin-induced cardiomyopathy [Li et al., 2020]; and cardiovascular diseases, especially aortic dissection [Chen et al., Pharmacol. Res., 2022, 177, 106122] [Li et al., Free Radic. Biol. Med., 2020, 160, 303-318; Qin et al., Biomed. Pharmacother., 2021, 141, 111872].

[0010] Ferroptosis-related pathologies affecting the central nervous system include stroke, especially ischemic stroke [Li et al., 2020] or hemorrhagic stroke [Li et al., JCI Insight, 2017, 2(7):e90777], traumatic brain injury [Xie et al., CNS Neurosci Ther., 2019, 25:465-475], crush spinal cord injury [Zhang et al., Neural Regen. Res., 2019, 14(3):532], epilepsy, including mitochondrial disease-associated epilepsy and intractable epilepsy [Kahn-Kirby et al., PLoS One., 2019, 14(3)], and neurodegenerative diseases, especially chronic neurodegenerative diseases, more specifically Alzheimer's disease [Li et al., 2020] and Huntington's disease [Mi et al. al., Neuromolecular Med., 2019, 21, 110-119], Parkinson's disease [Do Van et al., Neurobiol Dis., 2016, 94: 169-78], amyotrophic lateral sclerosis (Charcot's disease) [Li et al., 2020], multiple sclerosis [Luoqian et al., Cell Mol Immunol., 2022, 19(8), 913-924], Friedreich's ataxia [Cotticelli et al., J Pharmacol Exp Ther., 2019, 369(1): 47-54], periventricular leukomalacia [Skouta et al., J. Am. Chem. Soc., 2014, 136, 4551-4556], and dementias that may be associated with one or more of the above conditions.

[0011] Pathologies associated with ferroptosis that affect the eye include vision loss, particularly due to cataracts [Wei et al., Free Radic Biol Med., 2021, 167, 94-108] and retinal disorders, particularly Stargardt disease and age-related macular degeneration (AMD), especially dry AMD [Sun et al., Invest Ophth Vis Sci., 2018, 59(9), 2482; Chen et al., J. Biol. Chem., 2021, 296, 100187].

[0012] Ferroptosis-related pathologies affecting the liver include chronic liver disease and acute liver injury and failure, including nonalcoholic steatohepatitis (NASH) [Qi et al., Am J Pathol., 2020, 190(1)], chronic infections such as hepatitis B and C [Cappelletti et al., Int J Mol Sci., 2020, 21(14)], and alcoholic cirrhosis [Zhou et al., Hepatol Commun., 2019, 3(5)]. Acute liver failure can be due to, among other things, drug-induced liver injury (DILI) such as acetaminophen (APAP)-induced liver injury [Yamada et al., Cell Death Dis., 2020, 11(2)], ischemia-reperfusion injury induced by septic or hemorrhagic shock [Friedmann Angeli et al., Nat Cell Biol., 2014, 16(12):1180-91], fulminant viral hepatitis, autoimmune causes, or alcohol ingestion.

[0013] Pathologies associated with ferroptosis that affect the skin include inflammatory skin diseases such as psoriasis [Li et al., Cell Death Dis., 2020, 11(88)] and toxic epidermal necrolysis (Lyell's syndrome) [Zhang et al., J Invest Dermatol., 2020, 140(7), S79].

[0014] Ferroptosis-related pathologies affecting the kidney include acute kidney injury (AKI) (also known as acute renal failure), such as crystal (oxalate)-induced AKI, folic acid (FA)-induced AKI [Martin-Sanchez et al., 2017], and cisplatin-induced AKI [Deng et al., J Clin Invest., 2019, 129(11); Mishima et al., J Am Soc Nephrol.,2020, 31(2); Hu et al., Cell Death Dis., 2020, 11(1)], renal ischemia-reperfusion injury [Li et al., 2020], and acute tubular necrosis [Friedmann Angeli et al., 2014].

[0015] Pathologies related to ferroptosis affecting the lung include chronic obstructive pulmonary disease (COPD) [Yoshida et al., Nat Commun., 2019, 10, 3145], bronchial asthma [Tao et al., Oxid Med Cell Longev., 2020], lung injury caused by bacterial infection, particularly Pseudomonas aeruginosa [Dar et al., J Clin Invest., 2018, 128(10), 4639-4653] or Mycobacterium tuberculosis [Amaral et al., J Exp Med., 2019, 216(3): 556-570], and radiation-induced pulmonary fibrosis (RILF) [Li et al., J Inflamm., 2019, 16:11] and pulmonary fibrosis such as paraquat-induced lung injury [Rashidipour et al., Toxicology, 2020, 433-434:152407].

[0016] Pathologies associated with ferroptosis that affect the gastrointestinal tract include necrotizing enterocolitis [Subramanian et al., Acta Physiologica Sinica, 2020, 72(3)] and inflammatory bowel diseases such as Crohn's disease [Mayr et al., Nat Commun., 2020, 11(1)] and ulcerative colitis.

[0017] Pathologies related to ferroptosis that affect the whole body include hemochromatosis [Imoto et al., Transfus Apher Sci., 2018, 57(4), 524-531], β-thalassemia [Sposi, NM, Oxidative Stress and Iron Overload in β-Thalassemia: An Overview, 2019, DOI: 10.5772 / intechopen.90492], hemolytic disorders [Youssef et al., 2019, Ferroptosis in Hemolytic Disorders. In: Tang D. (eds) Ferroptosis in Health and Disease. Springer, Cham.], cytokine storm during viral infection [Edeas et al., Int J Infect Dis., 2020, 97; Yang and Lai, Cell Death Disov., 2020, 6], and radiation-induced necrosis [Wu et al., Front Oncol., 2020, 10], rheumatoid arthritis [Xie et al., Inflammation., 2020, doi: 10.1007 / s10753-020-01338-2], type I diabetes [Bruni et al., Cell Transplant., 2018, 27(6)], obesity-related insulin resistance, and stress-induced premature tissue aging-related pathologies such as atherosclerosis [Bai et al., Free Radic Biol Med., 2020, 160], hypertension [Yang et al., Clin Exp Hypertens., 2020, 42(8)] and type II diabetes [Li et al., Nutrients., 2020, 12(10)].

[0018] Therefore, inhibition of controlled necrotic cell death represents an attractive new therapeutic strategy for diseases associated with necrotic cell death.

[0019] The inventors have previously disclosed two new classes of controlled necrosis inhibitors (also referred to herein as "inhibitors of controlled necrotic cell death"), the first consisting of sibirilin derivatives (WO2017 / 064217, WO2017 / 064216, and WO2022 / 157392), and the second consisting of nigratin derivatives (WO2018 / 073321). [ka]

[0020] The present inventors have now surprisingly discovered that when such a controlled necrosis inhibitor (an inhibitor of controlled necrotic cell death) is combined with N-acetylcysteine ​​(NAC) or a derivative thereof, the combination provides a cytoprotective effect that is more than additive (i.e., synergistic), achieving a much better therapeutic effect than either active ingredient used alone.

[0021] Thus, the present invention relates to a pharmaceutical composition comprising a combination of N-acetylcysteine ​​(NAC) and / or pharmaceutical salts and / or derivatives thereof and at least one inhibitor of controlled necrotic cell death, such as necroptosis and / or ferroptosis.

[0022] N-acetylcysteine ​​(also known as acetylcysteine ​​or N-acetyl-L-cysteine, CAS number 616-91-1) corresponds to the following chemical formula: [ka]

[0023] The main therapeutic uses of NAC based on its pharmacological activity include: In pulmonary medicine, NAC is a mucolytic mucomodulator. It acts on the gel phase of mucus and promotes expectoration, possibly by cleaving disulfide bonds in glycoproteins. -In ophthalmology, NAC is an inhibitor of collagenase, a proteolytic enzyme that is secreted in large amounts during epithelial injury and causes the degradation of polypeptide fibers of corneal collagen. -In toxicology, acetylcysteine ​​is a precursor of glutathione, which can enter cells. This is the main way that it protects liver cells. In fact, glutathione neutralizes the electrophiles produced by the metabolism of paracetamol. In neurology, several early studies have shown that administration of NAC increases glutathione levels in the brain. NAC's usefulness has recently been established as part of the standard treatment for patients with Parkinson's disease. The studies found that it improved dopamine levels, the main neurotransmitter specifically decreased in this disease, as well as improved mental and physical performance in patients [Monti et al., Clin Pharmacol Ther., 2019, 106(4), 884-890].

[0024] Pharmaceutically acceptable salts of NAC or derivatives thereof, such as N-acetylcysteine ​​amide, N-acetylcysteine ​​ethyl ester, and N-acetylcysteine ​​methyl ester, include, but are not limited to, those formed with a free amino group such as those derived from hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, oxalic acid, tartaric acid, etc., and those formed with a carboxyl group such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-(ethylamino)ethanol, histidine, procaine, etc.

[0025] In the context of the present invention, the term "NAC derivative" is intended to mean any compound that is structurally related to NAC and has similar pharmacological activity. For example, the following compound [Sunitha et al., Clin Pharmacol Ther., 2013, 47(5), 884-890], known as N-acetylcysteine ​​amide (also known as NAC amide or N-acetyl-L-cysteine ​​amide or NACA, CAS number 38520-57-9), is a derivative of NAC. [ka]

[0026] In particular, the derivative of NAC in the pharmaceutical composition according to the invention is N-acetylcysteine ​​amide.

[0027] For example, the following compound, known as N-acetylcysteine ​​ethyl ester (also called NAC ethyl ester or N-acetyl-L-cysteine ​​ethyl ester, CAS number 59587-09-6), is a derivative of NAC. [ka]

[0028] In particular, the derivative of NAC in the pharmaceutical composition according to the invention is N-acetylcysteine ​​ethyl ester.

[0029] For example, the following compound, also known as N-acetylcysteine ​​methyl ester (also called NAC methyl ester N-acetyl-L-cysteine ​​methyl ester, CAS number 118398-49-5), is a derivative of NAC: [ka]

[0030] In particular, the derivative of NAC in the pharmaceutical composition according to the invention is N-acetylcysteine ​​methyl ester.

[0031] In particular, the present invention relates to a pharmaceutical composition comprising a combination of N-acetylcysteine ​​(NAC) and / or N-acetylcysteine ​​amide and / or N-acetylcysteine ​​ethyl ester and / or N-acetylcysteine ​​methyl ester and / or pharmaceutical salts thereof with at least one inhibitor of controlled necrotic cell death, such as necroptosis and / or ferroptosis.

[0032] In the present invention, the term "inhibitor of controlled necrotic cell death" refers to a compound that can at least partially save cells from controlled necrosis. In particular, when cells are exposed to a controlled necrotic cell death inducer, treatment with the inhibitor can improve the cell viability, which can be easily confirmed by a person skilled in the art using methods well known in the art, such as those described in the examples herein.

[0033] The inhibitor of controlled necrotic cell death is advantageously a ferroptosis and / or necroptosis inhibitor. In certain embodiments, the inhibitor of controlled necrotic cell death is a ferroptosis inhibitor, preferably a ferroptosis and necroptosis inhibitor.

[0034] Tests for identifying ferroptosis inhibitors are disclosed, for example, on pages 69-81 of WO2022157392 (Experimental Section, Section "II. Biological Activity of the Compounds of the Invention"). A preferred model is the SH-SY5Y human neuroblastoma cell line treated with the ferroptosis inducer RSL3 or erastin. Ferroptosis inhibitors protect cells from cell death in a dose-dependent manner and are characterized, for example, by their ability to reduce lipid peroxidation induced by ferroptosis inducers such as RSL3 or erastin in the SH-SY5Y model.

[0035] A test for identifying necroptosis inhibitors is disclosed, for example, on page 29 of EP3362450B1, in particular in paragraph

[0178] . In this test, necroptosis inhibitors are characterized by their ability to protect cells from cell death induced by a necroptosis inducer in a dose-dependent manner, for example, with an EC50 of 25 μM or less (EC50 is the 50% effective concentration of a drug).

[0036] Examples of known ferroptosis and / or necroptosis inhibitors are resveratrol (CAS No. 501-36-0), ferrostatin 1 (CAS No. 347174-05-4) or liproxstatin (CAS No. 950455-15-9), and NEC1F (described in particular in (Tonnus et al. Nat Commun 12, 4402 (2021), DOI: 10.1038 / s41467-021-24712-6)). In particular, an inhibitor of regulated necrotic cell death is NEC1F.

[0037] The inhibitor of controlled necrotic cell death (hereinafter "inhibitor") of the pharmaceutical composition according to the invention may in particular be sibirilin, nigratin or a derivative thereof.

[0038] Sibiriline and its derivatives In a particular embodiment, the inhibitor of the pharmaceutical composition according to the invention is sibiriline or a derivative thereof, which may correspond to any of the compounds disclosed in WO2017 / 064217, WO2017 / 064216 or WO2022 / 157392.

[0039] In this particular embodiment, the inhibitor is preferably a compound of general formula (I) [ka] or a pharmaceutically acceptable salt and / or solvate thereof; During the ceremony, [ka] teeth, [ka] or [ka] and; (i) [ka] but [ka] then X is N, Y is N(R2) and Z is C(H); (ii) [ka] but [ka] If -X is N(R1) -Y is N or N+(O-) and Z is C(R3), or Y is CH and Z is N, or Y and Z are CH; During the ceremony, R1 and R2 are each independently a hydrogen atom, CN, NO2, OR7, SR8, NRR10, C(O)R11, CO2R12, OC(O)R13, ​​NRC(O)R15, C(O)NR16R17, S(O)RS, SO2RS', (C1-C6)alkyl, (C1-C6)haloalkyl, -(C1-C6)alkyl-[O-(C1-C6)alkyl]m-NRRN1RN2 group (m is in the range of 1 to 6), aryl, aryl-(C1-C6)alkyl represents an aryl, heterocyclyl, or heterocyclyl-(C1-C6)alkyl group, wherein said aryl or heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, CN, NO2, OR18, SR19, NR20R21, C(O)R22, CO2R23, OC(O)R24, NR25C(O)R26, C(O)NR27R28, (C1-C6)alkyl, and (C1-C6)haloalkyl groups; R3, R4, R4b and R5 independently represent a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, C(O)R33, CO2R34, OC(O)R35, NR36C(O)R37, C(O)NR38R39, a (C1-C6)alkyl, a (C1-C6)haloalkyl group, wherein said alkyl or haloalkyl group is OR40, SR41 and NR42R43, an aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl- (C1-C6) alkyl groups, said aryl or heterocyclyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen atoms, CN, NO2, OR44, SR45, NR46R47, C(O)R48, CO2R49, OC(O)R50, NR51C(O)R52, C(O)NR53R54, (C1-C6) alkyl and (C1-C6) haloalkyl groups; R6 represents a hydrogen atom, a (C1-C6)alkyl, an aryl-(C1-C6)alkyl, a heterocyclyl-(C1-C6)alkyl, a -(C1-C6)alkyl-[O-(C1-C6)alkyl]m'-NRN'1RN'2 group (m' is in the range of 1 to 6), or a (C1-C6)alkylcarbonyl group, wherein the (C1-C6)alkyl, aryl-(C1-C6)alkyl, and (C1-C6)alkylcarbonyl groups may optionally be substituted with one or more substituents selected from the group consisting of OH, SH, NH2, (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)alkylamino, and di((C1-C6)alkyl)amino groups; RS and RS', independently of one another, represent a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; R7 to R10, R12, R14 and R16 to R17 are each independently a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; R11, R13 and R15, independently of one another, represent a hydrogen atom, a (C1-C6) alkyl, an aryl, an aryl-(C1-C6) alkyl, a (C1-C6) alkoxy, a (C1-C6) alkylamino or a di((C1-C6) alkyl) amino group; R18 to R28 each independently represent a hydrogen atom, a (C1-C6) alkyl, or an aryl group; R29 to R39 are each independently a hydrogen atom, a (C1-C6)alkyl, a heterocyclyl-(C1-C6)alkyl, an aryl, or an aryl-(C1-C6)alkyl group, wherein the aryl group may optionally be substituted with one or more substituents selected from the group consisting of a halogen atom, CN, NO2, OR55, SR56, NR57R58, C(O)R59, CO2R60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, a (C1-C6)alkyl, and a (C1-C6)haloalkyl group; R40 to R43 each independently represent a hydrogen atom or a (C1-C6) alkyl group; R44 to R54 each independently represent a hydrogen atom, a (C1-C6) alkyl, or an aryl group; R55 to R65 each independently represent a hydrogen atom, a (C1-C6) alkyl group, an aryl-(C1-C6) alkyl group, or an aryl group; RN1, RN'1, RN2 and RN'2 each independently represent a hydrogen atom, a (C1-C6) alkyl group, an aryl-(C1-C6) alkyl group or an aryl group.

[0040] Preferably, in the compounds of the following general formula (I), R1 and R2 are each independently a hydrogen atom, CN, NO2, OR7, SR8, NR9R10, C(O)R11, CO2R12, OC(O)R13, ​​NR14C(O)R15, C(O)NR16R17, S(O)RS, SO2RS', (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or represents a heterocyclyl-(C1-C6)alkyl group, wherein said aryl or heterocyclyl group may be optionally substituted with one or more substituents selected from the group consisting of halogen atoms, CN, NO2, OR18, SR19, NR20R21, C(O)R22, CO2R23, OC(O)R24, NR25C(O)R26, C(O)NR27R28, (C1-C6)alkyl and (C1-C6)haloalkyl groups; R3, R4, R4b and R5 independently represent a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, C(O)R33, CO2R34, OC(O)R35, NR36C(O)R37, C(O)NR38R39, a (C1-C6)alkyl, a (C1-C6)haloalkyl group, wherein said alkyl or haloalkyl group is OR40, SR41 and NR42R43, an aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl- (C1-C6) alkyl groups, said aryl or heterocyclyl groups being optionally substituted with one or more substituents selected from the group consisting of halogen atoms, CN, NO2, OR44, SR45, NR46R47, C(O)R48, CO2R49, OC(O)R50, NR51C(O)R52, C(O)NR53R54, (C1-C6) alkyl and (C1-C6) haloalkyl groups; R6 represents a hydrogen atom, a (C1-C6)alkyl, an aryl-(C1-C6)alkyl or -CH2-CH2-O-CH2-CH2-NH2 group, or a (C1-C6)alkylcarbonyl group optionally substituted with one or more substituents selected from the group consisting of OH, SH, NH2, (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)alkylamino and di((C1-C6)alkyl)amino groups; RS and RS', independently of one another, represent a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; R7 to R10, R12, R14 and R16 to R17 are each independently a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; R11, R13 and R15, independently of one another, represent a hydrogen atom, a (C1-C6) alkyl, an aryl, an aryl-(C1-C6) alkyl, a (C1-C6) alkoxy, a (C1-C6) alkylamino or a di((C1-C6) alkyl) amino group; R18 to R28 each independently represent a hydrogen atom, a (C1-C6) alkyl, or an aryl group; R29 to R39 are each independently a hydrogen atom, a (C1-C6)alkyl, an aryl, or an aryl-(C1-C6)alkyl group, wherein the aryl group may optionally be substituted with one or more substituents selected from the group consisting of a halogen atom, CN, NO2, OR55, SR56, NR57R58, C(O)R59, CO2R60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, a (C1-C6)alkyl, and a (C1-C6)haloalkyl group; R40 to R43 each independently represent a hydrogen atom or a (C1-C6) alkyl group; R44 to R54 each independently represent a hydrogen atom, a (C1-C6) alkyl, or an aryl group; R55 to R65 each independently represent a hydrogen atom, a (C1-C6) alkyl group, or an aryl group.

[0041] In the present invention, the term "pharmaceutically acceptable" is intended to mean something that is useful in the preparation of a pharmaceutical composition and is generally safe and non-toxic for pharmaceutical use.

[0042] The term "pharmaceutically acceptable salts or solvates" is intended, in the framework of the present invention, to mean salts or solvates of compounds which are pharmaceutically acceptable as defined above and which possess the pharmacological activity of the corresponding compounds.

[0043] Pharmaceutically acceptable salts include: (1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid, and (2) Base addition salts formed when an acid proton present in the compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or when an organic or inorganic base is coordinated. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0044] Acceptable solvates include conventional solvates such as those formed during the final steps of the preparation of the compounds due to the presence of solvent.

[0045] The term "halogen" as used herein refers to a fluorine, bromine, chlorine or iodine atom.

[0046] The term "(C1-C6) alkyl," as used herein, refers to a straight or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0047] The term "(C1-C6) haloalkyl" as used herein refers to a (C1-C6) alkyl group as defined above in which some or all of the hydrogen atoms are replaced with halogen atoms as defined above. This means that the (C1-C6) alkyl group is substituted with at least one halogen atom. It can be, for example, a trifluoromethyl group.

[0048] The term "aryl", as used herein, refers to an aromatic hydrocarbon group preferably comprising 6 to 10 carbon atoms and comprising one or more, especially one or two, fused rings, such as, for example, a phenyl or naphthyl group, advantageously a phenyl group.

[0049] The term "heterocyclic", as used herein, refers to a saturated, unsaturated (i.e. non-aromatic) or aromatic monocyclic or bicyclic group comprising two fused, bridged or spiro rings, preferably fused rings, advantageously comprising 5 to 10, especially 5 or 6 atoms in each ring, the ring atoms comprising one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the remainder being carbon atoms.

[0050] Saturated heterocyclic groups are more particularly 5- or 6-membered saturated monocyclic heterocyclic groups such as pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl groups.

[0051] Unsaturated heterocyclic groups are more particularly unsaturated monocyclic or bicyclic heterocyclic groups such as pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, thiazolinyl, isothiazolinyl, oxazolinyl, isoxazolinyl, imidazolinyl, pyrazolinyl, triazolinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydrotriazinyl, tetrahydrotriazinyl, indolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, 1,3-benzodioxolyl, 1,3-benzoxathiolyl, benzoxazolinyl, benzothiazolinyl, benzimidazolinyl, chromanyl or chromenyl groups, each ring comprising 5 or 6 members.

[0052] Aromatic heterocyclic groups, also called heteroaryl groups, are more particularly aromatic monocyclic or bicyclic heterocyclic groups, each ring of which comprises 5 or 6 members, such as pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl (e.g., 1,3,5-triazinyl), indolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl or quinoxalinyl groups.

[0053] The term "aryl-(C1-C6) alkyl" as used herein refers to an aryl group as defined above attached to a molecule via a (C1-C6) alkyl group as defined above. In particular, the -(C1-C6) alkyl-aryl group is a benzyl group.

[0054] The term "heterocyclyl-(C-C)alkyl" as used herein refers to a heterocyclyl group as defined above that is bonded to a molecule via a (C-C)alkyl group as defined above. In particular, a -(C-C)alkyl-heterocyclyl group is a 5- or 6-membered saturated monocyclic heterocyclic group as defined above that is bonded to a molecule via a (C-C)alkyl group as defined above.

[0055] The term "(C1-C6) alkylcarbonyl," as used herein, refers to a (C1-C6) alkyl group as defined above attached to the molecule via a -C(=O)- group, including, but not limited to, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, and the like.

[0056] The term "(C1-C6)alkoxy", as used herein, refers to a (C1-C6)alkyl group as defined above attached to a molecule via an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy, n-pentoxy, n-hexoxy, and the like.

[0057] The term "(C1-C6)thioalkoxy", as used herein, refers to a (C1-C6)alkyl group as defined above attached to a molecule via a sulfur atom, including, but not limited to, thiomethoxy, thioethoxy, n-thiopropoxy, iso-thiopropoxy, n-thiobutoxy, iso-thiobutoxy, sec-thiobutoxy, t-thiobutoxy, n-thiopentoxy, n-thiohexoxy, and the like.

[0058] The term "(C1-C6) alkylamino", as used herein, refers to the group -NHAlk, where Alk represents a (C1-C6) alkyl group as defined above, including, but not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino, iso-butylamino, sec-butylamino, t-butylamino, n-pentylamino, n-hexylamino, and the like.

[0059] The term "di(C1-C6)alkylamino", as used herein, refers to the group -NAlk1Alk2, where Alk1 and Alk2, independently of each other, represent a (C1-C6)alkyl group as defined above, including, but not limited to, dimethylamino, diethylamino, ethylmethylamino, and the like.

[0060] According to a particular embodiment of the invention, R1 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R10, C(O)R11, CO2R12, OC(O)R13, ​​NR14C(O)R15, C(O)NR16R17, S(O)RS, SO2RS', (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, wherein said aryl or heterocyclyl group (aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) The acryl-(C1-C6)alkyl group (which may be part of a C1-C6 alkyl group) may be optionally substituted by one or more substituents, in particular one substituent, selected from the group consisting of a halogen atom, CN, NO2, OR18, SR19, NR20R21, (C1-C6)alkyl and (C1-C6)haloalkyl, in particular a halogen atom, NO2, OR18, (C1-C6)alkyl and (C1-C6)haloalkyl, in particular NO2 and OR18, where R18 to R21 independently represent a hydrogen atom or a (C1-C6)alkyl group.

[0061] According to another particular embodiment of the invention, R1 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R10, C(O)R11, CO2R12, OC(O)R13, ​​NR14C(O)R15, C(O)NR16R17, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group optionally being substituted by one or more substituents as defined above.

[0062] According to yet another particular embodiment of the invention, R1 represents a hydrogen atom, CN, OR7, C(O)R11, CO2R12, OC(O)R13, ​​SO2RS', (C1-C6)alkyl, heterocyclyl or heterocyclyl-(C1-C6)alkyl group, said heterocyclyl group (which may be part of a heterocyclyl-(C1-C6)alkyl group) being selected from the group consisting of halogen atoms, CN, NO2, OR18, SR19, NR20R21, (C1-C6)alkyl and and (C1-C6)haloalkyl groups, in particular halogen atoms, NO2, OR18, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular NO2 and OR18, preferably said heterocyclyl group optionally substituted with NO2, and R18 to R21 independently represent a hydrogen atom or a (C1-C6)alkyl group.

[0063] According to yet another particular embodiment of the invention, R1 represents a hydrogen atom, CN, OR7, C(O)R11, CO2R12, OC(O)R13, ​​a heterocyclyl or heterocyclyl-(C1-C6)alkyl group, said heterocyclyl group optionally being substituted with one or more substituents as defined above.

[0064] In a preferred embodiment, R1 represents a hydrogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom or a (C1-C3) alkyl group, preferably a hydrogen atom.

[0065] In the above embodiments, the (C1-C6) alkyl group, which may be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, is preferably a (C1-C3) alkyl group.

[0066] In the above embodiment, the aryl group which may be part of the aryl-(C1-C6)alkyl group is preferably a phenyl group.

[0067] In the above embodiments, the heterocyclyl group which may be part of the heterocyclyl-(C1-C6)alkyl group is in particular a 5- or 6-membered, saturated, unsaturated (i.e. non-aromatic) or aromatic, in particular saturated or aromatic monocyclic group, such as morpholinyl, pyridinyl or piperazinyl, e.g. a morpholinyl or pyridinyl group, in which the ring atoms comprise one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms.

[0068] In the above embodiments, RS and RS' each independently represent a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, in particular a (C1-C6) alkyl or aryl group, in particular an aryl group such as a phenyl group.

[0069] In the above embodiments, R7 to R10, R12, R14 and R16 to R17 each independently represent a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, and R11, R13 and R15 each independently represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylamino or di((C1-C6) alkyl)amino group, particularly a hydrogen atom, a (C1-C6) alkyl, aryl, (C1-C6) alkylamino or di((C1-C6) alkyl)amino group, particularly a (C1-C3) alkyl, aryl such as phenyl, (C1-C3) alkylamino or di((C1-C3) alkyl)amino group.

[0070] In particular, in the above embodiments, R7 to R17 each independently represent a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, in particular a hydrogen atom, a (C1-C6) alkyl or aryl group, generally a hydrogen atom, a (C1-C3) alkyl or aryl group, and the aryl group which may be part of the aryl-(C1-C6) alkyl group is preferably a phenyl group.

[0071] According to a particular embodiment of the invention, R2 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R10, C(O)R11, CO2R12, OC(O)R13, ​​NR14C(O)R15, C(O)NR16R17, S(O)RS, SO2RS', (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, wherein said aryl or heterocyclyl group (aryl-(C1-C6)alkyl or heterocyclyl- The acryl-(C1-C6)alkyl group (which may be part of a C1-C6 alkyl group) may be optionally substituted by one or more substituents, in particular one substituent, selected from the group consisting of a halogen atom, CN, NO2, OR18, SR19, NR20R21, (C1-C6)alkyl and (C1-C6)haloalkyl, in particular a halogen atom, NO2, OR18, (C1-C6)alkyl and (C1-C6)haloalkyl, in particular NO2 and OR18, where R18 to R21 independently represent a hydrogen atom or a (C1-C6)alkyl group.

[0072] In the above embodiments, RS and RS' each independently represent a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, in particular a (C1-C6) alkyl or aryl group, in particular an aryl group such as a phenyl group.

[0073] According to another particular embodiment of the invention, R2 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R10, C(O)R11, CO2R12, OC(O)R13, ​​NR14C(O)R15, C(O)NR16R17, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group optionally being substituted by one or more substituents as defined above.

[0074] According to yet another particular embodiment of the invention, R2 represents C(O)R11, CO2R12, C(O)NR16R17, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group optionally being substituted with one or more substituents, in particular one substituent, selected from the group consisting of halogen atoms, OR18, SR19, NR20R21, (C1-C6)alkyl and (C1-C6)haloalkyl groups, and R18 to R21 represent, independently of one another, a hydrogen atom or a (C1-C6)alkyl group.

[0075] According to yet another particular embodiment of the invention, R2 represents CO2R12, C(O)NR16R17, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group, in particular CO2R12, C(O)NR16R17 or an aryl-(C1-C6)alkyl group, said aryl group optionally being substituted with one or more substituents, in particular one substituent, selected from the group consisting of halogen atoms, OR18, SR19 and NR20R21, in particular OR18, and R18 to R21, independently of one another, represent a hydrogen atom or a (C1-C6)alkyl group.

[0076] In the above embodiments, the (C1-C6) alkyl group, which may be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, is preferably a (C1-C3) alkyl group.

[0077] In the above embodiment, the aryl group which may be part of the aryl-(C1-C6)alkyl group is preferably a phenyl group.

[0078] In the above embodiments, the heterocyclyl group which may be part of the heterocyclyl-(C1-C6)alkyl group is in particular a 5- or 6-membered, saturated, unsaturated (i.e. non-aromatic) or aromatic, in particular saturated monocyclic group, such as a morpholinyl, pyridinyl or piperazinyl group, in particular a piperazinyl group, in which the ring atoms comprise one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms.

[0079] In the above embodiments, R7 to R10, R12, R14 and R16 to R17 each independently represent a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, and R11, R13 and R15 each independently represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylamino or di((C1-C6) alkyl)amino group, particularly a hydrogen atom, a (C1-C6) alkyl, aryl, (C1-C6) alkylamino or di((C1-C6) alkyl)amino group, particularly a (C1-C3) alkyl, aryl such as phenyl, (C1-C3) alkylamino or di((C1-C3) alkyl)amino group.

[0080] In particular, in the above embodiments, R7 to R17 each independently represent a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, in particular a hydrogen atom, a (C1-C6) alkyl or aryl-(C1-C6) alkyl group, generally a hydrogen atom, a (C1-C3) alkyl or aryl group, and the aryl group which may be part of the aryl-(C1-C6) alkyl group is preferably a phenyl group.

[0081] According to another particular embodiment of the invention, R3 represents a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, CN, OR29, SR30, NR31R32, C(O)R33, CO2R34, OC(O)R35, NR36C(O)R37, C(O)NR38R39, an aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of an atom, OR, SR, NR, R, (C-C) alkyl and (C-C) haloalkyl group, and R to R independently represent a hydrogen atom, a (C-C) alkyl, aryl or aryl-(C-C) alkyl group, in particular a hydrogen atom or a (C-C) alkyl group, generally a hydrogen atom or a (C-C) alkyl group.

[0082] According to another particular embodiment of the invention, R3 represents a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, CN, OR29, SR30, NR31R32, C(O)R33, CO2R34, OC(O)R35, NR36C(O)R37 or C(O)NR38R39, where R29 to R39 independently of one another represent a hydrogen atom, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group, in particular a hydrogen atom or a (C1-C6)alkyl group.

[0083] According to yet another particular embodiment of the invention, R3 represents a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, CN, OR29, SR30, NR31R32, OC(O)R35, NR36C(O)R37, heterocyclyl or heterocyclyl-(C1-C6)alkyl group, said heterocyclyl group optionally being substituted with one or more substituents selected from the group consisting of a halogen atom, OR44, SR45, NR46R47 and a (C1-C6)alkyl group, preferably R3 represents a hydrogen atom, a halogen atom, C N, NR31R32, OC(O)R35, heterocyclyl or heterocyclyl-(C1-C6)alkyl group, said heterocyclyl group being optionally substituted by one or more substituents selected from the group consisting of OR44, SR45 and NR46R47, in particular OR44, and R29 to R37 independently of one another represent a hydrogen atom, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group, in particular a hydrogen atom or a (C1-C6)alkyl group, typically a hydrogen atom or a (C1-C3)alkyl group.

[0084] In the above embodiments, R44 to R47 each independently represent a hydrogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom or a (C1-C3) alkyl group.

[0085] According to yet another particular embodiment of the invention, R3 represents a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, OR29, SR30, NR31R32, C(O)R33, CO2R34, OC(O)R35, NR36C(O)R37 or C(O)NR38R39, preferably a hydrogen atom, a halogen atom, OR29, SR30, NR31R32, OC(O)R35 or NR36C(O)R37, more preferably a hydrogen atom or OC(O)R35, and R29 to R37 independently of one another represent a hydrogen atom, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group, in particular a hydrogen atom or a (C1-C6)alkyl group, typically a hydrogen atom or a (C1-C3)alkyl group.

[0086] In a preferred embodiment, R3 represents a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom, a halogen atom or a (C1-C3) alkyl group, preferably a hydrogen atom or a halogen atom.

[0087] In the above embodiment, the aryl group which may be part of the aryl-(C1-C6)alkyl group is preferably a phenyl group.

[0088] In the above embodiments, the heterocyclyl group which may be part of the heterocyclyl-(C1-C6)alkyl group is in particular a 5- or 6-membered, saturated, unsaturated (i.e. non-aromatic) or aromatic, in particular aromatic, monocyclic group, such as a pyridinyl, pyrimidinyl, pyrazolyl, piperazinyl or piperidinyl group, the ring atoms of which comprise one or more, advantageously 1 to 3, heteroatoms selected from O, S and N, preferably O and N, and the remainder being carbon atoms, e.g. a pyridinyl, pyrimidinyl or pyrazolyl group.

[0089] In the above embodiments, the (C1-C6) alkyl group, which may be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, is preferably a (C1-C3) alkyl group.

[0090] According to a particular embodiment of the invention, R4 represents a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, (C1-C6)alkyl, (C1-C6)haloalkyl group, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group (which may be part of an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) being a halogen atom, CN, NO2, OR44, SR45, NR46R47, C(O)R48, CO2R49, OC(O)R50, NR51C Optionally substituted by one or more substituents, in particular one substituent, selected from the group consisting of (O)R52, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular halogen atoms, OR44, SR45, NR46R47, C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, preferably C(O)R48 and (C1-C6)alkyl groups.

[0091] According to another particular embodiment of the invention, R4 represents a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, a (C1-C6)alkyl, a (C1-C6)haloalkyl group, an aryl, heterocyclyl, an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group optionally being substituted by one or more substituents as defined above.

[0092] According to yet another particular embodiment of the invention, R4 represents a hydrogen atom, a halogen atom, OR29, SR30, NR31R32, (C1-C6)alkyl, aryl or heterocyclyl group, said aryl or heterocyclyl group optionally being substituted by one or more substituents, in particular one substituent, selected from the group consisting of a halogen atom, OR44, SR45, NR46R47, C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, preferably C(O)R48 and (C1-C6)alkyl groups.

[0093] According to yet another particular embodiment of the invention, R4 represents a hydrogen atom, a halogen atom, NR31R32, a (C1-C6)alkyl, an aryl or a heterocyclyl group, said aryl or heterocyclyl group optionally being substituted with one or more substituents, in particular one substituent, selected from the group consisting of C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, preferably C(O)R48 and (C1-C6)alkyl groups.

[0094] In a preferred embodiment, R4 represents a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom or a (C1-C3) alkyl group, preferably a hydrogen atom.

[0095] In the above embodiment, the aryl group which may be part of the aryl-(C1-C6)alkyl group is preferably a phenyl group.

[0096] In the above embodiments, the heterocyclyl group which may be part of the heterocyclyl-(C1-C6)alkyl group is in particular a 5- or 6-membered, saturated, unsaturated (i.e. non-aromatic) or aromatic, in particular saturated monocyclic group, such as a piperazinyl, piperidinyl, pyridinyl, pyrimidinyl or pyrazolyl group, for example a piperazinyl or piperidinyl group, in which the ring atoms comprise one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms.

[0097] In the above embodiments, R29 to R32 represent, independently of one another, a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, the aryl group being preferably phenyl, a halogen atom, CN, NO2, OR55, SR56, NR57R58, C(O)R59, CO2R60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, (C1-C6) alkyl and (C1-C6) haloalkyl groups, advantageously a halogen atom, OR55, SR56, NR57R5 Optionally substituted by one or more substituents, in particular one substituent, selected from the group consisting of 8, C(O)R59, CO2R60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular C(O)R59, CO2R60, C(O)NR64R65, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular C(O)R59, where R55 to R65 independently represent a hydrogen atom, a (C1-C6)alkyl or aryl group, in particular an aryl group, preferably a phenyl group.

[0098] In the above embodiments, R44 to R54 each independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group.

[0099] In the above embodiments, the (C1-C6) alkyl group, which may be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, is preferably a (C1-C3) alkyl group.

[0100] According to a particular embodiment of the invention, R4b represents a hydrogen atom, a halogen atom, OR29, SR30, NR31R32, (C1-C6)alkyl, (C1-C6)haloalkyl group, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group (which may be part of an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) being a halogen atom, CN, NO2, OR44, SR45, NR46R47, C(O)R48, CO2R49, OC(O)R50, NR51C( Optionally substituted by one or more substituents, in particular one substituent, selected from the group consisting of O)R52, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular halogen atoms, OR44, SR45, NR46R47, C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, preferably C(O)R48 and (C1-C6)alkyl groups.

[0101] According to a particular embodiment of the invention, R4b represents a hydrogen atom, a halogen atom, OR29, SR30, NR31R32, (C1-C6)alkyl, aryl or heterocyclyl group, said aryl or heterocyclyl group optionally being substituted by one or more substituents, in particular one substituent, selected from the group consisting of a halogen atom, OR44, SR45, NR46R47, C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, preferably C(O)R48 and (C1-C6)alkyl groups.

[0102] According to yet another particular embodiment of the invention, R4b represents a hydrogen atom, a halogen atom, NR31R32, a (C1-C6)alkyl, an aryl or a heterocyclyl group, said aryl or heterocyclyl group being optionally substituted with one or more substituents, in particular one substituent, selected from the group consisting of C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, preferably C(O)R48 and (C1-C6)alkyl groups.

[0103] According to yet another particular embodiment of the invention, R4b represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, OR29 or NR31R32, preferably a hydrogen atom, a halogen atom, a (C1-C3) alkyl group or OR29, more preferably a hydrogen atom.

[0104] In a preferred embodiment, R4b represents a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom or a (C1-C3) alkyl group, preferably a hydrogen atom.

[0105] In the above embodiment, the aryl group which may be part of the aryl-(C1-C6)alkyl group is preferably a phenyl group.

[0106] In the above embodiments, the heterocyclyl group which may be part of the heterocyclyl-(C1-C6)alkyl group is in particular a 5- or 6-membered, saturated, unsaturated (i.e. non-aromatic) or aromatic, in particular saturated monocyclic group, whose ring atoms comprise one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms.

[0107] In the above embodiments, R29 to R32 represent, independently of one another, a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, the aryl group being preferably phenyl, a halogen atom, CN, NO2, OR55, SR56, NR57R58, C(O)R59, CO2R60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, (C1-C6) alkyl and (C1-C6) haloalkyl groups, advantageously a halogen atom, OR55, SR56, NR57R5 Optionally substituted with one or more substituents, especially one substituent, selected from the group consisting of C(O)R, COR, OC(O)R, NR, C(O)R, C(O)NR, (C-C) alkyl and (C-C) haloalkyl groups, especially C(O)R, COR, C(O)NR, (C-C) alkyl and (C-C) haloalkyl groups, especially C(O)R, where R to R independently represent a hydrogen atom, a (C-C) alkyl or aryl group, especially an aryl group, preferably a phenyl group. Preferably, R to R independently represent a hydrogen atom or a (C-C) alkyl group, especially a hydrogen atom.

[0108] In the above embodiments, R44 to R54 each independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group.

[0109] In the above embodiments, the (C1-C6) alkyl group, which may be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, is preferably a (C1-C3) alkyl group.

[0110] In a particular embodiment of the invention, R4 is as defined above and R4b represents a hydrogen atom, a halogen atom, OR29 or NR31R32, where R29 to R32 independently of one another represent a hydrogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom, preferably R4b represents a hydrogen atom, a halogen atom or OR29, more preferably a hydrogen atom.

[0111] In certain embodiments of the invention, R5 represents a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, (C1-C6)alkyl, (C1-C6)haloalkyl group, said alkyl or haloalkyl group optionally substituted with one or more substituents selected from the group consisting of OR40, SR41 and NR42R43, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group (which may be part of an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) being a halogen atom, CN, NO2, OR44, SR45, NR46R47, C(O)R4 Optionally substituted by one or more substituents, in particular one substituent, selected from the group consisting of 8, CO2R49, OC(O)R50, NR51C(O)R52, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular halogen atoms, OR44, SR45, NR46R47, C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular halogen atoms, OR44, SR45, NR46R47, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular halogen atoms, (C1-C6)alkyl and (C1-C6)haloalkyl groups, preferably (C1-C6)alkyl groups.

[0112] In the above embodiments, R29 to R32 represent, independently of one another, a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group, the aryl group being preferably phenyl, a halogen atom, CN, NO2, OR55, SR56, NR57R58, C(O)R59, CO2R60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, (C1-C6) alkyl and (C1-C6) haloalkyl groups, advantageously a halogen atom, OR55, SR56, NR57R5 Optionally substituted with one or more substituents, especially one substituent, selected from the group consisting of C(O)R, COR, OC(O)R, NR, C(O)R, C(O)NR, (C-C) alkyl and (C-C) haloalkyl groups, especially C(O)R, COR, C(O)NR, (C-C) alkyl and (C-C) haloalkyl groups, especially C(O)R, where R to R independently represent a hydrogen atom, a (C-C) alkyl or aryl group, especially an aryl group, preferably a phenyl group. Preferably, R to R independently represent a hydrogen atom or a (C-C) alkyl group.

[0113] In another particular embodiment of the invention, R5 represents a hydrogen atom, a halogen atom, a (C1-C6)alkyl, a (C1-C6)haloalkyl group, said alkyl or haloalkyl group optionally being substituted by one or more substituents, in particular one substituent, selected from the group consisting of OR40, SR41 and NR42R43, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl groups, said aryl or heterocyclyl group optionally being substituted by one or more substituents selected from the group consisting of halogen atoms, OR44, SR45, NR46R47, (C1-C6)alkyl and (C1-C6)haloalkyl groups, in particular halogen atoms, (C1-C6)alkyl and (C1-C6)haloalkyl groups, preferably (C1-C6)alkyl groups.

[0114] In yet another particular embodiment of the present invention, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl, a (C1-C6) haloalkyl group or a heterocyclyl-(C1-C6) alkyl group, said alkyl or haloalkyl group being optionally substituted with OR40, and said heterocyclyl being optionally substituted with one or more (C1-C6) alkyl groups.

[0115] In a preferred embodiment, R5 represents a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom or a (C1-C3) alkyl group.

[0116] Preferably, R5 represents a hydrogen atom.

[0117] In the above embodiment, the aryl group which may be part of the aryl-(C1-C6)alkyl group is preferably a phenyl group.

[0118] In the above embodiments, the heterocyclyl group which may be part of the heterocyclyl-(C1-C6)alkyl group is in particular a 5- or 6-membered, saturated, unsaturated (i.e. non-aromatic) or aromatic, in particular saturated monocyclic group, such as a piperazinyl group, in which the ring atoms comprise one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms.

[0119] In the above embodiments, R40 to R43 each independently represent a hydrogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom.

[0120] In the above embodiments, R44 to R54 each independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group.

[0121] In the above embodiments, the (C1-C6) alkyl group, which may be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, is preferably a (C1-C3) alkyl group.

[0122] In certain embodiments of the invention, R6 represents a hydrogen atom, a (C1-C3)alkyl, an aryl-(C1-C3)alkyl or -CH2-CH2-O-CH2-CH2-NH2 group, or a (C1-C6)alkylcarbonyl group optionally substituted with one or more substituents selected from the group consisting of OH, SH, NH2, (C1-C3)alkoxy, (C1-C3)thioalkoxy and (C1-C3)alkylamino groups, preferably R6 represents a hydrogen atom, methyl, ethyl, benzyl, -CH2-CH2-O-CH2-CH2-NH2 or a (C1-C6)alkylcarbonyl group optionally substituted with one or more substituents selected from the group consisting of OH, NH2 and SH, in particular R6 represents a hydrogen atom, -CH2-CH2-O-CH2-CH2-NH2 or an ethyl group, in particular an ethyl group.

[0123] In a preferred embodiment, R6 represents a hydrogen atom, a (C1-C3) alkyl or a -CH2-CH2-O-CH2-CH2-NH2 group, in particular a hydrogen atom or a -CH2-CH2-O-CH2-CH2-NH2 group.

[0124] In a first aspect of the present invention, [ka] teeth, [ka] and X is N, Y is N(R2) and Z is C(H), and therefore the inhibitor of the pharmaceutical composition according to the present invention is of the following general formula (Ii): [ka] wherein R2, R4, R4b, R5 and R6 are defined in any one of the above embodiments.

[0125] In particular, R6 represents a hydrogen atom or a (C1-C6) alkyl group, preferably a (C1-C3) alkyl group, in particular a methyl or ethyl group; advantageously, R6 represents an ethyl group.

[0126] In a second aspect of the present invention, [ka] teeth, [ka] and X is N(R1), Y is N and Z is C(R3), and therefore the inhibitor of the pharmaceutical composition according to the invention is of the following general formula (I.ii.a): [ka] wherein R1, R3, R4, R4b, R5 and R6 are defined in any one of the above embodiments.

[0127] In particular, R6 represents a hydrogen atom, a (C1-C3) alkyl such as ethyl, -CH2-CH2-O-CH2-CH2-NH2 or a (C1-C6) alkylcarbonyl group optionally substituted with one or more substituents selected from the group consisting of OH, NH2 and SH, and advantageously R6 represents a hydrogen atom, -CH2-CH2-O-CH2-CH2-NH2 or a (C1-C3) alkyl such as an ethyl group.

[0128] In a third aspect of the present invention, [ka] teeth, [ka] and X is N(R1), Y is N+(O-) and Z is C(R3), and therefore the inhibitor of the pharmaceutical composition according to the present invention is of the following general formula (I.ii.b): [ka] wherein R1, R3, R4, R4b, R5 and R6 are defined in any one of the above embodiments.

[0129] In particular, R6 represents a hydrogen atom or a (C1-C6) alkyl group, preferably a (C1-C3) alkyl group, in particular a methyl or ethyl group; advantageously, R6 represents an ethyl group.

[0130] In a fourth aspect of the present invention, [ka] teeth, [ka] wherein X is N(R1), Y is CH and Z is N, and the inhibitor of the pharmaceutical composition according to the invention is of the following general formula (I.ii.c): [ka] wherein R1, R4, R4b, R5 and R6 are defined in any one of the above embodiments.

[0131] In particular, R6 represents a hydrogen atom or a (C1-C6) alkyl group, preferably a (C1-C3) alkyl group, in particular a methyl or ethyl group; advantageously, R6 represents an ethyl group.

[0132] In a fifth aspect of the present invention, [ka] teeth, [ka] and X is N(R1), Y and Z are CH, and therefore the inhibitor of the pharmaceutical composition according to the invention is of the following general formula (I.ii.d): [ka] wherein R1, R4, R4b, R5 and R6 are defined in any one of the above embodiments.

[0133] In particular, R6 represents a hydrogen atom, a (C1-C6)alkyl group or an aryl-(C1-C6)alkyl group, preferably a hydrogen atom, a (C1-C3)alkyl group or an aryl-(C1-C3)alkyl group, in particular a hydrogen atom, a methyl, ethyl or benzyl group, and advantageously R6 represents a hydrogen atom, a methyl or benzyl group, generally a hydrogen atom.

[0134] In a preferred embodiment, the inhibitor is a compound of the following general formula (I.iii): [ka] wherein R3, R4, R4b, R5 and R6 are defined in any one of the above embodiments, and Y' is N or CH.

[0135] especially, R3, R4, R4b and R5 independently of one another represent a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom, a halogen atom or a (C1-C3) alkyl group, preferably a hydrogen atom or a halogen atom; -R6 represents a hydrogen atom, a (C1-C3) alkyl or a -CH2-CH2-O-CH2-CH2-NH2 group, in particular a hydrogen atom or a -CH2-CH2-O-CH2-CH2-NH2 group.

[0136] The inhibitor of the pharmaceutical composition according to the invention may in particular be selected from the group consisting of compounds 1 to 45 represented below and pharmaceutically acceptable salts and / or solvates thereof. [Table 1] JPEG2025540745000032.jpg206157JPEG2025540745000033.jpg229162JPEG2025540745000034.jpg205164

[0137] In particular, the inhibitor of the pharmaceutical composition according to the invention may be selected from the group consisting of compounds 1, 7, 37, 45 and pharmaceutically acceptable salts and / or solvates thereof.

[0138] Nigratin and its derivatives In certain embodiments, the inhibitor of the pharmaceutical composition according to the present invention is nigratin or a derivative thereof.

[0139] In this particular embodiment, the inhibitor is preferably a compound of the following general formula (II): [ka] or a pharmaceutically acceptable salt and / or solvate thereof, wherein: X1, X2 and X3, independently of one another, represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or OH group, or a group selected from ORX, SRX, SO2RX and NRXRZ, at least one of X1, X2 and X3 represents a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group or a group selected from ORX, SRX, SO2RX and NRXRZ; Rx is a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; RZ is a hydrogen atom or a (C1-C6) alkyl group; The aryl group may be optionally substituted with one or several groups selected from halogen atoms, -OR66, -NR67R68, -SR69, -S(O)R70, -S02R71, -OCOR72, -CO2R73, -CONR74R75, -CO2R76, nitro (-NO2) and cyano (-CN); Y1, Y2 and Y3, independently of one another, represent a hydrogen atom, a (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl or OH group, or a group selected from ORY, SRY, SO2RY and NRYR'Z, at least one of Y1, Y2 and Y3 represents a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group or a group selected from ORY, SRY, SO2RY and NRYR'Z, R-Y is a (C-C) alkyl, aryl, or aryl-(C-C) alkyl group; R'Z is a hydrogen atom or a (C1-C6) alkyl group; The aryl group may be optionally substituted with one or several groups selected from halogen atoms, -OR66, -NR67R68, -SR69, -S(O)R70, -S02R71, -OCOR72, -CO2R73, -CONR74R75, -CO2R76, nitro (-NO2) and cyano (-CN); R66 to R77 are each independently a hydrogen atom or a (C1-C6) alkyl.

[0140] According to a particular embodiment of the invention, X1, X2 and X3 represent, independently of one another, a hydrogen atom or a group selected from ORX, SRX, SO2RX and NRXRZ, wherein at least one of X1, X2 and X3 is not a hydrogen atom.

[0141] In another particular embodiment of the invention, X1, X2 and X3 independently represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl group, OH or an ORX group, and at least one of X1, X2 and X3 represents an ORX group.

[0142] In yet another particular embodiment of the invention, X1, X2 and X3 independently represent a hydrogen atom or an ORX group, and at least one of X1, X2 and X3 represents an ORX group.

[0143] In the above embodiment, R X is preferably a (C 1 -C 6 ) alkyl group, in particular a (C 1 -C 3 ) alkyl group, such as methyl, ethyl, n-propyl, more preferably methyl.

[0144] In the above embodiments, the aryl group may be optionally substituted with one or several groups selected from halogen atoms, —OR66, —NR67R68, —SR69, —S(O)R70, —S02R71, —OCOR72, —CO2R73, —CONR74R75, —CO2R76, nitro (—NO2) and cyano (—CN).

[0145] In another embodiment, X1 represents a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group or a group selected from ORX, SRX, SO2RX and NRXRZ, where Rx is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl groups and Rx is preferably a (C1-C6)alkyl group, in particular a (C1-C3)alkyl group, such as methyl, ethyl, n-propyl, more preferably methyl; X2 and X3 independently of each other represent a hydrogen atom or a (C1-C6)alkyl group, preferably a hydrogen atom.

[0146] In yet another embodiment, X1 represents a group selected from ORX, SRX, SO2RX and NRXRZ, where Rx is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl groups, and Rx is preferably a (C1-C6)alkyl group, in particular a (C1-C3)alkyl group, such as methyl, ethyl, n-propyl, more preferably methyl; and X2 and X3, independently of each other, represent a hydrogen atom or a (C1-C6)alkyl group, preferably a hydrogen atom.

[0147] In a preferred embodiment, X1 represents an ORX group, RX being advantageously a (C1-C6) alkyl group.

[0148] In another preferred embodiment, X2 and X3 each represent a hydrogen atom.

[0149] In yet another preferred embodiment, X1 represents an ORX group, where Rx is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl groups, and Rx is advantageously a (C1-C6)alkyl group, in particular a (C1-C3)alkyl group, such as methyl, ethyl, n-propyl, more advantageously methyl; and X2 and X3, independently of one another, represent a hydrogen atom or a (C1-C6)alkyl group, advantageously a hydrogen atom.

[0150] In the above embodiments, the aryl group may be optionally substituted with one or several groups selected from halogen atoms, —OR66, —NR67R68, —SR69, —S(O)R70, —S02R71, —OCOR72, —CO2R73, —CONR74R75, —CO2R76, nitro (—NO2) and cyano (—CN).

[0151] According to a particular embodiment of the invention, Y1, Y2 and Y3 represent, independently of one another, a hydrogen atom or a group selected from ORY, SRY, SO2RY and NRYR'Z, and at least one of Y1, Y2 and Y3 is not a hydrogen atom.

[0152] In another particular embodiment of the invention, Y1, Y2 and Y3 independently represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl group, OH or an ORY group, and at least one of Y1, Y2 and Y3 represents an ORY group.

[0153] In yet another particular embodiment of the invention, Y1, Y2 and Y3 independently of one another represent a hydrogen atom or an ORY group, and at least one of Y1, Y2 and Y3 represents an ORY group.

[0154] In the above embodiment, RY is preferably a -(C1-C6)alkyl-aryl group, such as benzyl or -CH3-naphthyl, more preferably benzyl.

[0155] In another embodiment, Y1 represents a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group or a group selected from ORY, SRY, SO2RY and NRYR'Z, where RY is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl groups and RY is preferably a -(C1-C6)alkyl-aryl group, such as benzyl or -CH3-naphthyl, more preferably benzyl; Y2 and Y3, independently of each other, represent a hydrogen atom or a (C1-C6)alkyl group, preferably a hydrogen atom.

[0156] In yet another embodiment, Y1 represents a group selected from ORY, SRY, SO2RY and NRYR'Z, where RY is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl groups, RY is preferably a -(C1-C6)alkyl-aryl group, such as benzyl or -CH3-naphthyl, more preferably benzyl, and Y2 and Y3, independently of each other, represent a hydrogen atom or a (C1-C6)alkyl group, preferably a hydrogen atom.

[0157] In a preferred embodiment, Y1 represents an ORY group, where R is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl groups, and R is advantageously a -(C1-C6)alkyl-aryl group, such as benzyl or -CH3-naphthyl, more preferably benzyl; Y2 and Y3, independently of each other, represent a hydrogen atom or a (C1-C6)alkyl group, advantageously a hydrogen atom.

[0158] In the above embodiments, the aryl group may be optionally substituted with one or several groups selected from halogen atoms, —OR66, —NR67R68, —SR69, —S(O)R70, —S02R71, —OCOR72, —CO2R73, —CONR74R75, —CO2R76, nitro (—NO2) and cyano (—CN).

[0159] According to a particular embodiment of the present invention, X1, X2 and X3, independently of one another, represent a hydrogen atom, a (C1-C6) alkyl, an aryl, an aryl-(C1-C6) alkyl or an ORX group, wherein at least one of X1, X2 and X3 is not a hydrogen atom and R X is selected from (C1-C6) alkyl, an aryl and an aryl-(C1-C6) alkyl group; Y1, Y2 and Y3 independently represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl group, an OH or an ORY group, and at least one of Y1, Y2 and Y3 represents a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl group or an ORy group, and RY is selected from a (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl group.

[0160] According to another particular embodiment, X1 represents a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or ORX group, where RX is a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; X2 and X3, independently of one another, represent a hydrogen atom or a (C1-C6) alkyl group; Y1, Y2 and Y3 independently represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, OH or ORY group, and at least one of Y1, Y2 and Y3 represents a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or ORY group, where RY is selected from a (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl group.

[0161] According to yet another particular embodiment, X1 represents an ORX group, where RX is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl groups, and RX is advantageously a (C1-C6)alkyl group, in particular a (C1-C3)alkyl group, such as methyl, ethyl, n-propyl, advantageously methyl; X2 and X3, independently of one another, represent a hydrogen atom or a (C1-C6)alkyl group, advantageously a hydrogen atom; Y1 represents an ORY group, R Y being selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl groups, R Y being advantageously a -(C1-C6)alkyl-aryl group, such as benzyl or -CH3-naphthyl, more preferably benzyl; Y2 and Y3 each, independently of one another, represent a hydrogen atom or a (C1-C6) alkyl group, advantageously a hydrogen atom.

[0162] According to a preferred embodiment, the inhibitor of the pharmaceutical composition according to the invention has the following formula (II.i): [ka] or a pharmaceutically acceptable salt and / or solvate thereof, wherein: Rx represents a (C1-C6) alkyl group, in particular a (C1-C3) alkyl group, such as methyl, ethyl, n-propyl, and more preferably methyl; RY represents an aryl-(C1-C6)alkyl group, such as benzyl or -CH3-naphthyl, more preferably benzyl.

[0163] The inhibitor of the pharmaceutical composition according to the present invention may in particular be selected from the group consisting of compounds 46 to 49 represented below and pharmaceutically acceptable salts and / or solvates thereof. [Table 2]

[0164] In particular, the inhibitor of the pharmaceutical composition according to the invention is compound 46 or a pharmaceutically acceptable salt and / or solvate thereof.

[0165] In particular, the inhibitor of the pharmaceutical composition according to the invention may be selected from the group consisting of compounds 1, 7, 37, 45, 46 and pharmaceutically acceptable salts and / or solvates thereof.

[0166] Pharmaceutical Composition A pharmaceutical composition according to the present invention comprises a combination of N-acetylcysteine ​​(NAC) or a pharmaceutical salt or derivative thereof and at least one inhibitor of controlled necrotic cell death, such as necroptosis and / or ferroptosis.

[0167] In a particular embodiment, the inhibitor of controlled necrotic cell death is a ferroptosis inhibitor, preferably a ferroptosis and necroptosis inhibitor, which may in particular be sibirilin, nigratin or a derivative thereof as defined above.

[0168] In this particular embodiment, the NAC / inhibitor molar ratio is advantageously 500:1 to 1:1, preferably 200:1 to 1:1, in particular 100:1 to 1:1, in particular 50:1 to 1:1, for example 20:1 to 1:1.

[0169] In a preferred embodiment, the inhibitor of controlled necrotic cell death is sibirilin (compound 7) and the weight ratio of NAC / inhibitor is advantageously 100:1 to 1:1, in particular 50:1 to 1:1, in particular 30:1 to 1:1, for example 20:1.

[0170] In a particular embodiment, the molar ratio of N-acetylcysteine ​​amide (NACA) / inhibitor is advantageously 200:1 to 1:1, preferably 100:1 to 1:1, in particular 50:1 to 1:1, in particular 30:1 to 1:1, for example 20:1 to 1:1.

[0171] In a particular embodiment, the molar ratio of N-acetylcysteine ​​ethyl ester (NACET) / inhibitor is advantageously 500:1 to 1:1, preferably 200:1 to 1:1, in particular 100:1 to 1:1, in particular 50:1 to 1:1, for example 20:1 to 1:1.

[0172] The pharmaceutical composition according to the invention may further comprise at least one pharmaceutically acceptable excipient.

[0173] The term "pharmaceutically acceptable excipient" is intended, in the framework of the present invention, to mean a substance that is pharmaceutically acceptable as defined above, that is formulated together with the active ingredient of a pharmaceutical composition, and that is included for long-term stabilization, for increasing the bulk of solid preparations containing small amounts of potent active ingredients, for imparting therapeutic improvements to the active ingredient in the final dosage form (such as enhanced drug absorption, reduced viscosity, or increased solubility), or for improving the taste or appearance of the pharmaceutical composition. Suitable excipients can be easily and judiciously selected by those skilled in the art, taking into account, inter alia, the dosage form and the route of administration.

[0174] The pharmaceutical compositions according to the invention may be formulated in particular for oral administration, topical administration or injection, said compositions being intended for mammals, including humans.

[0175] The pharmaceutical composition may be administered orally in solid or liquid (solution or suspension) form.

[0176] The solid composition can be in the form of tablets, gelatin capsules, powders, granules, etc. When the solid composition is prepared in the form of tablets, the active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. The tablet may be coated with sucrose or other suitable materials, or may be treated to prolong or delay the activity and release a predetermined amount of the active ingredient in a sustained manner. In the case of powders or granules, the active ingredient may be mixed or granulated with dispersing agents, wetting agents, or suspending agents, as well as flavoring or sweetening agents. In the case of gelatin capsules, the active ingredient may be introduced into soft or hard gelatin capsules in the form of powder or granules as described above, or in the form of a liquid composition as described below.

[0177] The liquid composition can contain the active ingredient in a solvent such as water together with a sweetener, flavoring agent, or suitable coloring agent. The liquid composition can also be obtained by suspending or dissolving the powder or granules as described above in a liquid such as water, fruit juice, milk, etc. The liquid composition can be, for example, a syrup or elixir.

[0178] For topical administration, the pharmaceutical composition may be in any form that can be applied to the skin or mucosal surface: cream, gel, ointment, patch, etc.

[0179] For administration by injection, aqueous suspensions, isotonic saline solutions, or sterile injection solutions containing pharmacologically compatible dispersing agents and / or wetting agents are used.

[0180] The inhibitor in the pharmaceutical composition can be used in a dose of 0.01 mg to 2,000 mg per day, administered as a single dose once a day or in divided doses, e.g., twice a day in equal doses. The daily dose is preferably 5 mg to 500 mg, more preferably 10 mg to 200 mg. The effective amount of the inhibitor can be determined by those skilled in the art through routine testing, including assessing the effect of administering the inhibitor on the disorder to be prevented and / or treated by said administration. For example, such testing can be carried out by analyzing both the quantitative and qualitative effects of administering different amounts of the inhibitor on a set of markers (biological and / or clinical) of the disorder, particularly from an individual's biological sample. Furthermore, as is well known to those skilled in the art, the appropriate dose and associated dosing regimen for treating a given disease in a given patient will vary depending on several factors, such as the stage of the disease and the patient's physical and medical condition.

[0181] N-acetylcysteine ​​(NAC), N-acetylcysteine ​​amide, N-acetylcysteine ​​ethyl ester, or N-acetylcysteine ​​methyl ester can be used in a dose ranging from 50 mg to 5,000 mg per day, administered as a single dose once a day or in divided doses several times a day, for example, twice a day in equal amounts. The daily dose is advantageously 100 mg to 2,000 mg, and even more advantageously 500 mg to 1,500 mg.

[0182] Applicable The present invention also relates to a pharmaceutical composition as defined above for the prevention and / or treatment of disorders associated with controlled necrotic cell death, such as necroptosis and / or ferroptosis.

[0183] In certain embodiments, the disorder is associated with ferroptosis, particularly both ferroptosis and necroptosis.

[0184] Disorders associated with ferroptosis include myocardial ischemia-reperfusion injury, particularly that which occurs after myocardial necrosis, particularly in arterial ligation or myocardial infarction; cardiomyopathy, particularly doxorubicin-induced cardiomyopathy; stroke, particularly ischemic stroke or hemorrhagic stroke; cardiovascular diseases such as aortic dissection; traumatic brain injury; crush spinal cord injury; neurodegenerative diseases, particularly chronic neurodegenerative diseases, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease), multiple sclerosis, fibromyalgia ... Riedreich's ataxia and dementia; vision loss, especially due to retinal detachment or cataracts; retinal disorders, especially Stargardt's disease or age-related macular degeneration (AMD), especially dry AMD; chronic liver disease, especially non-alcoholic steatohepatitis (NASH), chronic infections such as hepatitis, and alcoholic cirrhosis; acute liver injury and acute liver failure, especially drug-induced liver injury (DILI) such as acetaminophen (APAP)-induced liver injury, and ischemic relapse induced by septic or hemorrhagic shock. perfusion disorders, fulminant viral hepatitis, those of autoimmune origin or due to alcohol ingestion; skin inflammatory diseases such as psoriasis; toxic epidermal necrolysis (Lyell's syndrome); acute kidney injury (AKI) or acute renal failure, e.g., oxalate-induced, folic acid (FA)-induced and cisplatin-induced AKI, renal ischemia-reperfusion injury and acute tubular necrosis; chronic obstructive pulmonary disease (COPD); bronchial asthma; lung damage caused by bacterial infection, especially with Pseudomonas aeruginosa or Mycobacterium tuberculosis; radiation-induced pulmonary fibrosis (RILF) ) and paraquat-induced lung injury; necrotizing enterocolitis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; hemochromatosis; beta-thalassemia; hemolytic disease; cytokine storm during viral infection; radiation-induced necrosis; rheumatoid arthritis; type I diabetes; obesity-related insulin resistance; epilepsy, including mitochondrial disease-associated epilepsy and intractable epilepsy; and stress-induced premature tissue aging-related pathologies such as atherosclerosis, hypertension, and type II diabetes.

[0185] Preferably, the disorder associated with ferroptosis is myocardial ischemia-reperfusion injury, in particular that which occurs after myocardial necrosis in arterial ligation or myocardial infarction; stroke, in particular ischemic stroke or hemorrhagic stroke; traumatic brain injury; neurodegenerative diseases, in particular chronic neurodegenerative diseases, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease) and multiple sclerosis; vision loss, in particular due to retinal detachment or cataract; retinal disorders, in particular Stargardt's disease or age-related macular degeneration. (AMD), particularly dry AMD; chronic liver disease, particularly non-alcoholic steatohepatitis (NASH); acute liver injury and acute liver failure, particularly due to drug-induced liver injury (DILI) such as acetaminophen (APAP)-induced liver injury, or ischemia-reperfusion injury induced by septic or hemorrhagic shock; and acute kidney injury (AKI) or acute renal failure, such as folic acid (FA)-induced AKI, cisplatin-induced AKI, renal ischemia-reperfusion injury, and acute tubular necrosis.

[0186] In particular, the disorder associated with ferroptosis is selected from the group consisting of neurodegenerative diseases, particularly chronic neurodegenerative diseases, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease) and multiple sclerosis; vision loss, particularly due to retinal detachment or cataract; retinal disorders, particularly Stargardt's disease or age-related macular degeneration (AMD), particularly dry AMD; acute liver injury and acute liver failure, particularly due to drug-induced liver injury (DILI) such as acetaminophen (APAP)-induced liver injury, or ischemia-reperfusion injury induced by septic or hemorrhagic shock; and acute kidney injury (AKI) or acute renal failure, such as folic acid (FA)-induced AKI and cisplatin-induced AKI.

[0187] In particular, disorders associated with controlled necrotic cell death are disorders associated with ferroptosis and necroptosis, and include brain diseases or disorders, including neurodegenerative diseases or disorders (particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease), dementia, Friedreich's ataxia and multiple sclerosis), stroke (particularly ischemic stroke and hemorrhagic stroke), traumatic brain injury, epilepsy; retinopathies, degenerative eye diseases or disorders, such as retinal degenerative diseases or disorders (particularly Stargardt's disease and age-related macular degeneration (AMD)). eye diseases or disorders, including MD); infectious diseases, including diseases caused by viruses or bacteria (including lung damage caused by bacterial infections and cytokine storms during viral infections); autoimmune diseases, including psoriasis and rheumatoid arthritis; chronic liver diseases (especially non-alcoholic steatohepatitis (NASH)), toxic epidermal necrolysis (Lyell's syndrome), bronchial asthma, pulmonary fibrosis, necrotizing enterocolitis, inflammatory bowel disease (Crohn's disease), type I and type II diabetes, hemochromatosis, atherosclerosis, and obesity-related insulin resistance stress-induced premature tissue aging-related pathologies, including age-related disorders such as atherosclerosis, hypertension, and type II diabetes; liver disorders, including acute liver failure (particularly due to drug-induced liver injury (DILI) such as acetaminophen (APAP)-induced liver injury, or ischemia-reperfusion injury induced by septic or hemorrhagic shock) and chronic liver disease; hypertension; hemochromatosis; hemolytic disease; ischemic disorders affecting the heart, brain, or kidneys; acute kidney injury (AKI, also known as acute renal failure (ARF)) the cancer may be selected from the group consisting of liver cancer (particularly hepatocellular carcinoma), eye cancer, gastric cancer, colorectal cancer, pancreatic cancer, brain cancer, lung cancer, adrenocortical carcinoma, kidney cancer (particularly clear cell renal cell carcinoma), kidney damage including folic acid (FA)-induced AKI, cisplatin-induced AKI, renal ischemia-reperfusion injury, acute tubular necrosis, liver fibrosis; myocardial infarction, myocardial ischemia-reperfusion injury, particularly cardiac damage including that occurring after arterial ligation or myocardial necrosis in myocardial infarction; aortic aneurysm; pancreatitis; radiation-induced necrosis; chronic obstructive pulmonary disease, acute respiratory distress disorder; transplant-related disease; and cancer including liver cancer (particularly hepatocellular carcinoma), eye cancer, gastric cancer, colorectal cancer, pancreatic cancer, brain cancer, lung cancer, adrenocortical carcinoma, kidney cancer (particularly clear cell renal cell carcinoma).

[0188] More particularly, the disorder associated with controlled necrotic cell death is a disorder associated with ferroptosis and necroptosis, and may be selected from the group consisting of neurodegenerative diseases or disorders, brain diseases or disorders including stroke, traumatic brain injury, epilepsy; cancer diseases including diseases or disorders including retinopathy, degenerative eye diseases or disorders; infectious diseases; autoimmune diseases; inflammatory diseases; pathologies associated with stress-induced premature tissue aging; liver disorders including acute liver failure and chronic liver disease; hypertension; hemochromatosis; hemolytic diseases; ischemic disorders affecting the heart, brain, or kidney; kidney including acute kidney injury, renal ischemia-reperfusion injury, acute tubular necrosis, and hepatic fibrosis; cardiac injury; aortic aneurysm; pancreatitis; radiation-induced necrosis; chronic obstructive pulmonary disease, acute respiratory distress disorder; transplant-related diseases; and cancer including liver cancer, eye cancer, brain tumor, and kidney cancer.

[0189] In another embodiment, the disorder associated with controlled necrotic cell death is a disorder associated with ferroptosis and necroptosis, and may be selected from the group consisting of neurodegenerative diseases or disorders, brain diseases or disorders including stroke and traumatic brain injury; eye diseases and disorders including retinopathies; liver diseases or disorders including acute liver injury such as acute liver failure; kidney diseases or disorders including acute kidney injury; transplant-related diseases; and cancers including liver cancer (such as hepatocellular carcinoma), eye cancer, and kidney cancer (such as clear cell renal cell carcinoma).

[0190] Disorders associated with both ferroptosis and necroptosis can include acute liver injury and failure, acute renal failure or injury (AKI), acute cerebral tubular necrosis, radiation-induced necrosis, ischemic disorders affecting the heart, brain, or kidneys, rheumatoid arthritis, psoriasis, neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease) and dementia), dry age-related macular degeneration (AMD), hemochromatosis, necrotizing enterocolitis, nonalcoholic steatohepatitis (NASH), Friedreich's ataxia, inflammatory bowel diseases (such as Crohn's disease, toxic epidermal necrolysis (Lyell's syndrome), type I diabetes), and diseases associated with stress-induced premature tissue aging, including age-related disorders such as atherosclerosis, hypertension, and type II diabetes.

[0191] The present invention also relates to a method for inhibiting controlled necrotic cell death, in particular for inhibiting ferroptosis, more particularly for inhibiting both ferroptosis and necroptosis, comprising administering to a person in need thereof an effective dose of a pharmaceutical composition as defined above. In particular, the present invention relates to a method for preventing and / or treating disorders associated with controlled necrotic cell death, such as necroptosis and / or ferroptosis, comprising administering to a person in need thereof an effective dose of a pharmaceutical composition as defined above.

[0192] In a particular embodiment, said disorder is associated with ferroptosis, in particular both ferroptosis and necroptosis, as defined above.

[0193] The present invention also relates to a method for inhibiting lysosomal permeabilization and / or lysosome-dependent cell death, in particular in a subject suffering from a neurodegenerative disease, comprising administering to a person in need thereof an effective dose of a pharmaceutical composition as defined above.The present invention also relates to a method for inhibiting lysosomal permeabilization and / or lysosome-dependent cell death, in particular in a subject suffering from a neurodegenerative disease, comprising administering to a person in need thereof an effective dose of a pharmaceutical composition as defined above.

[0194] The present invention also relates to the use of a pharmaceutical composition as defined above for the manufacture of a medicament, said medicament being intended in particular for the prevention and / or treatment of disorders associated with controlled necrotic cell death, such as necroptosis and / or ferroptosis. In a particular embodiment, said disorder is associated with both ferroptosis and necroptosis and is as defined above.

[0195] The present invention also relates to the use, in particular non-therapeutic use, of a pharmaceutical composition as defined above for the in vitro preservation and / or protection of biological materials such as cells, tissues, body fluids and organs.

[0196] In the context of the present invention, "in vitro" means outside the organism from which the biomaterial is derived.

[0197] As used herein, the expression "preserving and / or protecting a biomaterial" means improving the survival of said biomaterial and enabling its preservation over time. As is clear from the present specification, this improved survival is obtained by preventing ferroptosis-induced cell death in said biomaterial.

[0198] The present invention therefore also relates to the in vitro use of a pharmaceutical composition as defined above as an agent for inhibiting controlled necrotic cell death, such as necroptosis and / or ferroptosis, in biological materials.

[0199] The present invention is also directed to a method for inhibiting controlled necrotic cell death, such as necroptosis and / or ferroptosis, in a biological material, comprising exposing said biological material to a pharmaceutical composition as defined above.

[0200] In the above aspects of the invention, the biological material is preferably a cell sample or a tissue sample.

[0201] The active ingredients of the pharmaceutical composition according to the present invention, i.e. N-acetylcysteine ​​or a pharmaceutical salt or derivative thereof and the inhibitor of controlled necrotic cell death as defined above, in particular a ferroptosis inhibitor, preferably a ferroptosis and necroptosis inhibitor, can be administered simultaneously, separately or sequentially to a person in need thereof, in particular to inhibit controlled necrotic cell death such as necroptosis and / or ferroptosis, more particularly to prevent and / or treat disorders associated with controlled necrotic cell death such as necroptosis and / or ferroptosis.

[0202] Thus, the present invention also provides N-acetylcysteine ​​or its pharmaceutical salts or derivatives at least one inhibitor of controlled necrotic cell death, in particular at least one inhibitor of ferroptosis, preferably at least one inhibitor of ferroptosis and necroptosis as a combined preparation for simultaneous, separate or sequential administration, in particular for inhibiting regulated necrotic cell death such as necroptosis and / or ferroptosis, more particularly for preventing and / or treating disorders associated with regulated necrotic cell death such as necroptosis and / or ferroptosis.

[0203] The present invention also relates to a pharmaceutical composition as defined above for use as a therapeutically active ingredient in a combined or add-on treatment regimen in a person in need thereof, in particular for inhibiting regulated necrotic cell death, such as necroptosis and / or ferroptosis, more particularly for preventing and / or treating disorders associated with regulated necrotic cell death, such as necroptosis and / or ferroptosis. Also provided is the use of a pharmaceutical composition as defined above as a therapeutically active ingredient in a combined or add-on treatment regimen in a patient in need thereof.

[0204] In some embodiments, the pharmaceutical composition of the present invention is administered simultaneously, separately or sequentially with a third active ingredient to a person in need thereof.

[0205] The pharmaceutical composition as defined above may be provided in additional preparations, in particular combination preparations comprising a third active ingredient, intended in particular for simultaneous, separate or sequential administration.

[0206] The third active ingredient is generally one associated with the disorder to be prevented and / or treated.

[0207] The present invention also relates to a kit comprising a pharmaceutical composition as defined above and a delivery device suitable for parenteral administration, enteral administration or topical administration (a device capable of administering said composition). Examples of delivery devices include, but are not limited to, auto-injectors, in particular multi-chamber syringes, transdermal patches, pre-filled syringes or needleless devices. [Brief explanation of the drawings]

[0208] [Figure 1] FIG. 1 shows the maximum viability of ARPE19 cells treated with sodium iodate in the presence of NAC, compound 45, or when co-treated. [Figure 2] FIG. 2 shows the maximum viability of ARPE19 cells treated with sodium iodate in the presence of NAC, compound 46, or when co-treated. [Figure 3] FIG. 3 shows the maximum viability of SH-SY5Y cells treated with erastin in the presence of NAC, compound 46, or when co-treated. [Figure 4] FIG. 4 shows the maximum viability of SH-SY5Y cells treated with erastin in the presence of NAC, Compound 1, or when co-treated. [Figure 5] FIG. 5 shows the maximum viability of HT-22 cells treated with erastin in the presence of NAC, compound 7, or when co-treated. [Figure 6] FIG. 6 shows the maximum viability of HT-22 cells treated with erastin in the presence of NAC, compound 37, or when co-treated. [Figure 7] FIG. 7 shows the maximum viability of HT-22 cells treated with erastin in the presence of NAC, Compound 1, or when co-treated. [Figure 8] FIG. 8 depicts the alanine transferase (ALT) concentrations (UI / L) quantified in mouse plasma for eight groups of mice treated with NAC, increasing doses of Compound 7, or co-treated after APAP intoxication. [Figures 9a-9c]Figures 9a, 9b, and 9c show the synergistic effect of co-treatment of NAC and compound 7 on an in vivo mouse model of APAP intoxication; ALT values ​​are reported as the percentage reduction in maximal ALT obtained in the plasma of mice treated with 400 mg / kg APAP alone; control mice (Ctrl) were mice that did not receive APAP injection. [Figure 10] FIG. 10 shows the maximum viability of LLC-PK1 cells treated with RSL3 in the presence of NAC, compound 7, or when co-treated. [Figure 11] FIG. 11 shows the maximum viability of LLC-PK1 cells treated with RSL3 in the presence of NAC, Compound 1, or when co-treated. [Figure 12] FIG. 12 shows the maximum viability of LLC-PK1 cells treated with RSL3 in the presence of NAC, compound 46, or when co-treated. [Figure 13] FIG. 13 shows the maximum viability of ARPE19 cells treated with sodium iodate in the presence of N-acetylcysteine ​​amide (NACA), compound 46, or when co-treated. [Figure 14] FIG. 14 shows the maximum viability of SHSY5Y cells treated with erastin in the presence of N-acetylcysteine ​​ethyl ester, compound 7, or when co-treated. [Figure 15] FIG. 15 shows the maximum viability of SHSY5Y cells treated with erastin in the presence of N-acetylcysteine ​​ethyl ester, Compound 1, or when co-treated. [Figure 16] FIG. 16 shows the maximum viability of SHSY5Y cells treated with erastin in the presence of N-acetylcysteine ​​ethyl ester, compound 46, or when co-treated. [Example]

[0209] The following abbreviations are commonly used in the art and are used in the examples below. ALT: alanine aminotransferase AMD: Age-related macular degeneration APAP: Acetaminophen CI: calculation index DMEM: Dulbecco's modified Eagle's medium DMSO: dimethyl sulfoxide H&E: Hematoxylin and eosin ip: intraperitoneal MTS: 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxy-phenyl]-2-[4-sulfophenyl]-2H-tetrazolium n: number of experimental replicates NAC: N-acetylcysteine PBS: phosphate buffered saline SD: standard deviation SEM: Standard error of the mean

[0210] I. In vitro cell models of disease The synergistic effect of NAC in combination with a regulated necrosis inhibitor was evaluated in vitro in a cellular model of pathology. Regulated necrosis is involved in several pathologies or dysfunctions in the body, particularly liver injury associated with drug toxicity. Regulated necrosis is also involved in the pathophysiology of degenerative diseases such as retinal degeneration, neurodegenerative diseases such as Parkinson's disease, or neurological disorders associated with excitotoxicity, such as trauma or stroke.

[0211] I.1 Materials and Methods cell culture SH-SY5Y neuronal cells (human neuroblastoma cell line) and HT-22 cells (mouse hippocampal neuronal cell line) were maintained in standard DMEM containing GlutaMAX medium (GIBCO) supplemented with 10% fetal bovine serum (GIBCO) at 37°C in the presence of 5% CO2.

[0212] ARPE-19 cells (human retinal pigment epithelial cell line) were cultured in standard DMEM / F12 medium (GIBCO) supplemented with 10% fetal bovine serum (GIBCO) at 37°C in the presence of 5% CO .

[0213] LLC-PK1 cells (porcine kidney epithelial cells) were cultured in DMEM / F12 (GIBCO) supplemented with 10% fetal bovine serum (GIBCO) at 37°C in the presence of 5% CO .

[0214] Cell viability assay SH-SY5Y, LLC-PK1, ARPE-19, and HT22 cells were seeded in 96-well plates at 10,000 or 5,000 cells per well and incubated overnight. Cells were treated with 10 μM (SH-SY5Y cells) or 0.5 μM (HT22 cells) erastin, 2 μM RSL3 (LLCPK1), or 10 mM sodium iodate (ARPE-19 cells) for 24 hours.

[0215] Elastin and RSL3 were purchased from Selleck Chemical, and sodium iodate was purchased from Sigma-Aldrich. Cell viability was assessed by the MTS assay (CellTiter 96® AQueous Radioactive Cell Proliferation Assay; Promega, Fitchburg, WI, USA) according to the manufacturer's instructions. This assay is based on the reduction of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) by viable cells to form a colored formazan product. After treatment, cells were incubated with MTS at 37°C and 5% CO2 for 3 hours. Absorbance was measured at 490 nm and 630 nm using a microplate reader, and the percentage of viability was calculated by dividing the absorbance of test compound-treated cells by that of DMSO-treated cells (control).

[0216] N-acetylcysteine ​​amide (NACA) was purchased from MedChemExpress (reference: HY-110256).

[0217] N-acetylcysteine ​​ethyl ester was purchased from MedChemExpress (reference: HY-134495).

[0218] Analysis of molecular synergy Cells (HT-22, SHSY-5Y, LLC-PK1 and ARPE 19) were seeded in their respective media in 96-well plates and left overnight. The next day, these cells were treated with NAC, or its derivatives including NACA or N-acetylcysteine ​​ethyl ester (compound A), an inhibitory compound (compound B), or a combination of these two compounds. Analysis of the effect of a relevant combination of compound A (NAC, or its derivatives including NACA and N-acetylcysteine ​​ethyl ester) with another compound B is based on the Bliss independence model. In this approach, the effect of a compound alone (EA or EB) or in combination is expressed as a probability (0≦E≦1). The effect of a compound combination is expressed as: EAB=EA+EB(1-EA) is defined as: where EA and EB represent the effects of compound A and compound B, respectively, and EAB represents the combined effect of A and B (expected effect of the histogram). The calculated index CI is: CI = (EA + EB - EA * EB) / EAB In the formula, CI indicates synergy, antagonism, or additivity when it is less than, greater than, or equal to 1, respectively [Duarte et al., Current Research in Pharmacology and Drug Discovery, 2022].

[0219] I.2. Eye Disease Models Age-related macular degeneration (AMD) is characterized by vision loss caused by the degeneration of the central cells of the retina, called the macula. Oxidative stress has been shown to play a key role in retinal cell loss through the initiation of non-apoptotic cell death, including ferroptosis [Totsuka et al., Exp. Eye Res., 2019, 181-316-324]. One model used to study retinal cell death is the retinal pigment epithelial cell line, human ARPE-19 cells, in the presence of sodium iodate (NaIO3), a strong oxidant [Hanus et al. Cell Death Discov. 2016, 2, 16054] [Chan et al., J. Biomed. Sci., 2019, 26:40].

[0220] Compounds 45 (Figure 1) and 46 (Figure 2) were tested alone and in combination with NAC in this assay. Figures 1 (10 μM compound 45; 100 μM NAC) and 2 (5 μM compound 46; 50 μM NAC) showed significant effects of the tested molecules alone and synergistic effects when combined with NAC (n=2, mean ± SD, *P<0.05, **P<0.01, ***P<0.001).

[0221] Compound 46 (Figure 13) was tested alone and in combination with NACA (N-acetylcysteine ​​amide) in this assay. Figure 13 (10 μM Compound 46; 125 μM NACA) shows significant effects of the test molecule Compound 46 alone and synergistic effects when combined with NACA at the doses tested (n=2, mean ± SD, *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001).

[0222] I.3. Neurotoxicity and Excitotoxicity Models Remarkable biological activity was demonstrated in two neuronal cell lines: (i) the human neuroblastoma cell line SH-SY5Y (Figures 3-4) and (ii) the mouse hippocampal cell line HT22 (Figures 5-7). In both cell lines, erastin induced cell death by ferroptosis [Dixon et al., Cell, 2012, 149(5), 1060-1072]. Elastin is a well-described inducer of ferroptosis and a molecular tool for investigating neuronal pathology [Lewerenz et al., Front. Neurosci., 2018, 12: 214].

[0223] The results obtained, summarized in Figures 3-7, clearly demonstrated the efficacy of the tested compounds against these neurotoxicity models and their synergistic efficacy when combined with NAC.

[0224] Compounds 46 (Figure 3) and 1 (Figure 4) were added to SH-SY5Y cells in the presence of a ferroptosis inducer (erastin), in combination with or without NAC. Figures 3 (25 μM compound 46; 100 μM NAC) and 4 (1 μM compound 1; 100 μM NAC) showed significant effects of the tested molecules alone and synergistic effects when combined with NAC at the doses tested (n=2, mean ± SD, *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001). HT22 cells were treated with compounds 7, 37, or 1 in the presence of a ferroptosis inducer (erastin), in combination with or without NAC (Figures 5, 6, and 7, respectively). Figures 5 (25 μM Compound 7; 100 μM NAC), 6 (50 μM Compound 37; 100 μM NAC), and 7 (5 μM Compound 1; 100 μM NAC) showed significant effects of the tested molecules alone and synergistic effects when combined with NAC at the doses tested (n=2, mean ± SD, *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001).

[0225] Remarkable biological activity was also demonstrated for NAC derivatives in the neuronal cell line SH-SY5Y. The obtained results, summarized in Figures 14-16, clearly demonstrated the efficacy of the tested compounds in this neurotoxicity model and their synergistic efficacy when combined with N-acetylcysteine ​​ethyl ester.

[0226] Compound 7 (Figure 14) was added to SH-SY5Y cells in the presence of a ferroptosis inducer (erastin), with or without N-acetylcysteine ​​ethyl ester. Figure 14 (10 μM Compound 7; 100 μM N-acetylcysteine ​​ethyl ester) showed a significant effect of the test molecule alone and a synergistic effect when combined with NACET (n=2, mean ± SD, *P<0.05, **P<0.01, ***P<0.001).

[0227] Compound 1 (Figure 15) was added to SH-SY5Y cells in the presence of a ferroptosis inducer (erastin), with or without N-acetylcysteine ​​ethyl ester. Figure 15 (2.5 μM Compound 1; 100 μM N-acetylcysteine ​​ethyl ester) showed a significant effect of the test molecule alone and a synergistic effect when combined with N-acetylcysteine ​​ethyl ester (n=2, mean ± SD, *P<0.05, **P<0.01, ***P<0.001).

[0228] Compound 46 (Figure 16) was added to SH-SY5Y cells in the presence of a ferroptosis inducer (erastin), either in combination with or without N-acetylcysteine ​​ethyl ester. Figure 16 (25 μM compound 46; 100 μM N-acetylcysteine ​​ethyl ester) showed a significant effect of the test molecule alone and a synergistic effect when combined with N-acetylcysteine ​​ethyl ester (n=2, mean ± SD, *P<0.05, **P<0.01, ***P<0.001).

[0229] I.4. Pig kidney epithelial cell model In this assay, Compound 7 (Figure 10), Compound 1 (Figure 11), and Compound 46 (Figure 12) were tested alone and in combination with NAC. Figures 10 (2.5 μM Compound 7; 500 μM NAC), 11 (1 μM Compound 1; 500 μM NAC), and 12 (25 μM Compound 46; 500 μM NAC) show significant effects of the tested molecules alone and synergistic effects when combined (n=2, mean ± SD, *P<0.05, **P<0.01, ***P<0.001).

[0230] II. In vivo pathological model II.1. Materials and Methods All animal experiments were performed in compliance with French legislation and institutional guidelines on animal welfare. This project was approved by the "Comite Regional d'Ethique et d'Experimentation Animal" (CREAA) under authorization APAFIS#32246-2021061616397414 v7 granted by the "Ministère de l'Enseignement Superieur de la Recherche et de l'Innovation".

[0231] Nine-week-old C57Bl / 6J male mice were purchased from Janvier Labs (Le Genest-St-Isle, France). After a week of acclimation in the animal house, they were fasted overnight before the experiment. Acetaminophen (APAP) was purchased from Sigma-Aldrich (A70-85-100g, batch #SCLF8273) and diluted to 20 mg / mL in PBS (preheated to 45°C). Acetaminophen intoxication was induced in mice by intraperitoneal (ip) injection of APAP (400 mg / kg). One hour after APAP injection, mice were treated with inhibitors via i.p. injection. N-acetylcysteine ​​(NAC, A9165-25g, Sigma-Aldrich, batch #SLCJ1628), a standard treatment for paracetamol intoxication, was diluted to 40 mg / mL in PBS Tween 80 5% and injected intraperitoneally at a dose of 200 mg / kg. Compound 7 was diluted to 1 mg / ml or 2 mg / ml in PBS Tween 80 5% and injected intraperitoneally at increasing concentrations (2.5, 5, 10 mg / kg) or in combination with NAC (200 mg / kg). Two control groups of mice were administered i.p. with PBS Tween 80 5% (Tween 80 5%), while the APAP-treated group received i.p. with PBS Tween 80 5% (APAP-Tween 80 5%) 1 hour after APAP. Mice were sacrificed 8 hours after APAP injection. Blood and liver samples were collected.

[0232] Biochemical parameters Serum alanine aminotransferase (ALT) plasma levels were measured using an Olympus AU2700 autoanalyzer (Olympus Optical) (Olympus Optical Co., Ltd.) according to the International Federation of Clinical Chemistry and Laboratory Medicine reference method.

[0233] Histological analysis Liver sections were fixed in 4% paraformaldehyde and embedded in paraffin. 4 μm sections were used for hematoxylin and eosin (H&E) staining. All paraffin-embedded liver sections were scanned with a digital slide scanner (Nanozoomer 2.0-RS, Hamamatsu Photonics, Massy, ​​France), and the files were analyzed with NDP Viewer 2.5 software (Hamamatsu Photonics).

[0234] statistical analysis Results are expressed as mean ± SEM. Mean differences between two experimental groups were evaluated using the nonparametric Mann-Whitney U test. All statistical analyses were performed using GraphPad Prism5 software. Calculated P values ​​are integrated into histograms and graphs. Significance was indicated as follows: $P<0.05, $$P<0.01, $$$P<0.001, $$$P<0.0001 (comparison between APAP mice and APAP mice treated with NAC and / or Compound 7); *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001 (comparison between treatment groups).

[0235] II.2. Results Nine groups of mice were tested. Tween80 5%, n=15 ·APAP(400mg / kg)+Tween 80 5%, n=31 ·APAP(400mg / kg)+NAC(200mg / kg), n=15 ·APAP(400mg / kg)+Compound 7(2.5mg / kg), n=23 ·APAP(400mg / kg)+Compound 7(5mg / kg), n=21 ·APAP(400mg / kg)+Compound 7(10mg / kg), n=21 ·APAP(400mg / kg)+Compound 7(2.5mg / kg)+(NAC 200mg / kg), n=9 ·APAP (400mg / kg) + Compound 7 (5mg / kg) + NAC (200mg / kg), n=9 ·APAP (400mg / kg) + Compound 7 (10mg / kg) + NAC (200mg / kg), n=13 Excessive administration of APAP induced liver damage and the release of alanine aminotransferase (ALT) into mouse plasma. Mice treated with APAP (400 mg / kg) for 8 hours showed a significant increase in plasma ALT levels (approximately 3000 IU / L) compared with control mice injected with Tween 80 5% alone (approximately 100 IU / L).

[0236] N-acetylcysteine ​​(NAC) is an effective antidote for limiting liver damage in patients with APAP intoxication. Mice treated with NAC (200 mg / kg) 1 h after APAP (400 mg / kg) injection were partially protected from APAP intoxication, as indicated by a significant reduction in ALT plasma levels (approximately 1300 IU / L) compared with APAP-treated mice (approximately 3000 IU / L). Compound 7 treatment 1 h after APAP administration was also effective in protecting the mouse liver from APAP toxicity by dose-dependently reducing ALT plasma levels, with the maximal effect observed at a dose of compound 7 (10 mg / kg) (approximately 1000 IU / L) (Figure 8).

[0237] Notably, NAC (200 mg / kg) treatment combined with increasing concentrations of compound 7 (2.5, 5, or 10 mg / kg) provided better synergistic protection against APAP toxicity than NAC or compound 7 alone (Figure 9a-c). This protective effect was dose-dependent, with the combination of NAC (200 mg / kg) and compound 7 (10 mg / kg) resulting in nearly complete protection, as ALT plasma levels (approximately 200 IU / L) were similar to those measured in control mice treated with Tween 80 5% alone (approximately 100 IU / L) (Figure 8).

Claims

1. A pharmaceutical composition comprising a combination of N-acetylcysteine ​​and / or pharmaceutical salts and / or derivatives thereof and at least one inhibitor of controlled necrotic cell death, such as necroptosis and / or ferroptosis.

2. 2. The pharmaceutical composition of claim 1, wherein the inhibitor of controlled necrotic cell death is a ferroptosis inhibitor, preferably a ferroptosis and necroptosis inhibitor.

3. The inhibitor of controlled necrotic cell death is (A) A compound of the following general formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt and / or solvate thereof [In the formula, ・ 【Chemistry 2】 teeth, 【Transformation 3】 or 【Chemistry 4】 and (i) 【Transformation 5】 but 【Transformation 6】 where X is N, Y is N(R2) and Z is C(H); (ii) 【Transformation 7】 but 【Transformation 8】 If -X is N(R1), -Y is N or N+(O-) and Z is C(R3), or -Y is CH and Z is N, or Y and Z are CH; During the ceremony, R1 and R2 are, independently of one another, a hydrogen atom, CN, NO2, OR7, SR8, NR9R10, C(O)R11, CO2R12, OC(O)R13, ​​NRC(O)R15, C(O)NR16R17, S(O)RS, SO2RS', (C1-C6)alkyl, (C1-C6)haloalkyl, -(C1-C6)alkyl-[O-(C1-C6)alkyl]m-NRRN1RN2 group (m is in the range of 1 to 6), aryl, aryl-(C1-C6)alkyl represents an aryl, heterocyclyl, or heterocyclyl-(C1-C6)alkyl group, wherein said aryl or heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, CN, NO2, OR18, SR19, NR20R21, C(O)R22, CO2R23, OC(O)R24, NR25C(O)R26, C(O)NR27R28, (C1-C6)alkyl, and (C1-C6)haloalkyl groups; R3, R4, R4b and R5 each independently represent a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, C(O)R33, CO2R34, OC(O)R35, NR36C(O)R37, C(O)NR38R39, a (C1-C6) alkyl, a (C1-C6) haloalkyl group, wherein the alkyl or haloalkyl group is OR40, SR41 and NR42R43, an aryl, heterocyclyl, aryl-(C1-C6) alkyl or heterocyclyl- (C1-C6) alkyl groups, wherein said aryl or heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, CN, NO2, OR44, SR45, NR46R47, C(O)R48, CO2R49, OC(O)R50, NR51C(O)R52, C(O)NR53R54, (C1-C6) alkyl and (C1-C6) haloalkyl groups; R6 represents a hydrogen atom, a (C1-C6)alkyl, an aryl-(C1-C6)alkyl, a heterocyclyl-(C1-C6)alkyl, a -(C1-C6)alkyl-[O-(C1-C6)alkyl]m'-NRN'1RN'2 group, where m' ranges from 1 to 6, or a (C1-C6)alkylcarbonyl group, wherein the (C1-C6)alkyl, aryl-(C1-C6)alkyl, and (C1-C6)alkylcarbonyl groups may optionally be substituted with one or more substituents selected from the group consisting of OH, SH, NH2, (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)alkylamino, and di((C1-C6)alkyl)amino groups; RS and RS' represent, independently of each other, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; R7 to R10, R12, R14 and R16 to R17 are each independently a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; R11, R13 and R15 are each independently a hydrogen atom, a (C1-C6) alkyl, an aryl, an aryl-(C1-C6) alkyl, a (C1-C6) alkoxy, a (C1-C6) alkylamino or a di((C1-C6) alkyl) amino group; R18 to R28 independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group; R29 to R39 are each independently a hydrogen atom, a (C1-C6)alkyl, a heterocyclyl-(C1-C6)alkyl, an aryl or an aryl-(C1-C6)alkyl group, the aryl group optionally being substituted with one or more substituents selected from the group consisting of a halogen atom, CN, NO2, OR55, SR56, NR57R58, C(O)R59, COR60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, a (C1-C6)alkyl and a (C1-C6)haloalkyl group; R40 to R43 each independently represent a hydrogen atom or a (C1-C6) alkyl group; R44 to R54 independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group; R55 to R65 each independently represent a hydrogen atom, a (C1-C6) alkyl, an aryl-(C1-C6) alkyl group, or an aryl group; RN1, RN'1, RN2 and RN'2 each independently represent a hydrogen atom, a (C1-C6) alkyl group, an aryl-(C1-C6) alkyl group or an aryl group; or (B) A compound of the following general formula (II): 【Chemistry 9】 or a pharmaceutically acceptable salt and / or solvate thereof, wherein X1, X2 and X3, independently of one another, represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or OH group, or a group selected from ORX, SRX, SO2RX and NRXRZ, at least one of X1, X2 and X3 represents a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group or a group selected from ORX, SRX, SO2RX and NRXRZ; R X is a (C1-C6) alkyl, aryl, or aryl-(C1-C6) alkyl group; RZ is a hydrogen atom or a (C1-C6) alkyl group; The aryl group may be optionally substituted with one or several groups selected from halogen atoms, —OR66, —NR67R68, —SR69, —S(O)R70, —S02R71, —OCOR72, —CO2R73, —CONR74R75, —CO2R76, nitro (—NO2) and cyano (—CN); Y1, Y2 and Y3, independently of one another, represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or OH group, or a group selected from ORY, SRY, SO2RY and NRYR'Z, at least one of Y1, Y2 and Y3 represents a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group or a group selected from ORY, SRY, SO2RY and NRYR'Z; RY is a (C1-C6) alkyl, aryl, or aryl-(C1-C6) alkyl group; R'Z is a hydrogen atom or a (C1-C6) alkyl group; The aryl group may be optionally substituted with one or more groups selected from halogen atoms, —OR66, —NR67R68, —SR69, —S(O)R70, —S02R71, —OCOR72, —CO2R73, —CONR74R75, —CO2R76, nitro (—NO2), and cyano (—CN); R66 to R77 are each independently a hydrogen atom or a (C1-C6) alkyl group. The pharmaceutical composition according to claim 1 or 2,

4. The inhibitor of controlled necrotic cell death is R1 and R2 are, independently of one another, a hydrogen atom, CN, NO2, OR7, SR8, NR9R10, C(O)R11, CO2R12, OC(O)R13, ​​NRC(O)R15, C(O)NR16R17, S(O)RS, SO2RS', (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1- C6) an alkyl group, wherein said aryl or heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, CN, NO2, OR18, SR19, NR20R21, C(O)R22, CO2R23, OC(O)R24, NR25C(O)R26, C(O)NR27R28, (C1-C6) alkyl, and (C1-C6) haloalkyl groups; R3, R4, R4b and R5 are each independently a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, C(O)R33, CO2R34, OC(O)R35, NR36C(O)R37, C(O)NR38R39, a (C1-C6) alkyl, a (C1-C6) haloalkyl group, wherein the alkyl or haloalkyl group is OR40, SR41 and NR42R43, an aryl, a heterocyclyl, an aryl-(C1-C6) alkyl or a heterocyclyl- (C1-C6) alkyl groups, wherein said aryl or heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, CN, NO2, OR44, SR45, NR46R47, C(O)R48, CO2R49, OC(O)R50, NR51C(O)R52, C(O)NR53R54, (C1-C6) alkyl and (C1-C6) haloalkyl groups; R6 represents a hydrogen atom, a (C1-C6)alkyl, an aryl-(C1-C6)alkyl or a -CH2-CH2-O-CH2-CH2-NH2 group, or a (C1-C6)alkylcarbonyl group optionally substituted by one or more substituents selected from the group consisting of OH, SH, NH2, (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)alkylamino and di((C1-C6)alkyl)amino groups; RS and RS' represent, independently of one another, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; R7 to R10, R12, R14 and R16 to R17 are each independently a hydrogen atom, a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; R11, R13 and R15 are each independently a hydrogen atom, a (C1-C6) alkyl, an aryl, an aryl-(C1-C6) alkyl, a (C1-C6) alkoxy, a (C1-C6) alkylamino or a di((C1-C6) alkyl) amino group; R18 to R28 independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group; R29 to R39 are each independently a hydrogen atom, a (C1-C6) alkyl, an aryl or an aryl-(C1-C6) alkyl group, the aryl group optionally being substituted with one or more substituents selected from the group consisting of a halogen atom, CN, NO2, OR55, SR56, NR57R58, C(O)R59, COR60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, a (C1-C6) alkyl and a (C1-C6) haloalkyl group; R40 to R43 each independently represent a hydrogen atom or a (C1-C6) alkyl group; R44 to R54 independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group; R55 to R65 independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group; 4. The pharmaceutical composition of claim 3, which is a compound of formula (I).

5. The inhibitor of controlled necrotic cell death is R1 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R10, C(O)R11, CO2R12, OC(O)R13, ​​NRC(O)R15, C(O)NR16R17, S(O)RS, SO2RS', (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, the aryl group may be optionally substituted with one substituent selected from the group consisting of a halogen atom, CN, NO, OR, SR, NR, R, (C1-C6) alkyl and (C1-C6) haloalkyl groups, R to R independently represent a hydrogen atom or a (C1-C6) alkyl group, R and R′ independently represent a (C1-C6) alkyl or aryl group, preferably an aryl group; Preferably, R1 represents a hydrogen atom, CN, OR7, C(O)R11, CO2R12, OC(O)R13, ​​SO2RS', (C1-C6)alkyl, heterocyclyl or heterocyclyl-(C1-C6)alkyl group, said heterocyclyl group being optionally substituted by NO2, More preferably, R1 represents a hydrogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom or a (C1-C3) alkyl group, advantageously a hydrogen atom; R2 represents C(O)R11, CO2R12, C(O)NR16R17, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, OR18, SR19, NR20R21, (C1-C6)alkyl and (C1-C6)haloalkyl groups, and R18 to R21 independently represent a hydrogen atom or a (C1-C6)alkyl group, Preferably, R2 represents CO2R12, C(O)NR16R17 or an aryl-(C1-C6)alkyl group, said aryl group being optionally substituted with one or more substituents selected from the group consisting of halogen atoms, OR18, SR19 and NR20R21, in particular OR18; R3 represents a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, CN, OR29, SR30, NR31R32, C(O)R33, CO2R34, OC(O)R35, NR36C(O)R37, C(O)NR38R39, aryl, heterocyclyl, aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group being optionally substituted by one or more substituents selected from the group consisting of a halogen atom, OR44, SR45, NR46R47, (C1-C6)alkyl and (C1-C6)haloalkyl group, R29 to R37 independently represent a hydrogen atom or a (C1-C6)alkyl group, and R44 to R47 independently represent a hydrogen atom or a (C1-C6)alkyl group, Preferably, R3 represents a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, CN, OR29, SR30, NR31R32, OC(O)R35, NR36C(O)R37, heterocyclyl or heterocyclyl-(C1-C6)alkyl group, said heterocyclyl group optionally being substituted by one or more substituents selected from the group consisting of a halogen atom, OR44, SR45, NR46R47 and a (C1-C6)alkyl group, More preferably, R3 represents a hydrogen atom, a halogen atom, a (C1-C6)alkyl group, CN, NR31R32, OC(O)R35, heterocyclyl or heterocyclyl-(C1-C6)alkyl group, said heterocyclyl group being optionally substituted by one or more substituents selected from the group consisting of OR44, SR45 and NR46R47, in particular OR44; Even more preferably, R3 represents a hydrogen atom, a halogen atom or a (C1-C3) alkyl group, advantageously a hydrogen atom or a halogen atom; R4 represents a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, a (C1-C6)alkyl, a (C1-C6)haloalkyl group, an aryl, a heterocyclyl, an aryl-(C1-C6)alkyl or a heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group being optionally substituted by one or more substituents selected from the group consisting of a halogen atom, CN, NO2, OR44, SR45, NR46R47, C(O)R48, COR49, OC(O)R50, NR51C(O)R52, C(O)NR53R54, a (C1-C6)alkyl and a (C1-C6)haloalkyl group, Preferably, R4 represents a hydrogen atom, a halogen atom, OR29, SR30, NR31R32, (C1-C6)alkyl, aryl or heterocyclyl group, said aryl or heterocyclyl group optionally being substituted by one or more substituents selected from the group consisting of halogen atoms, OR44, SR45, NR46R47, C(O)R48, CO2R49, C(O)NR53R54, (C1-C6)alkyl and (C1-C6)haloalkyl groups; More preferably, R4 represents a hydrogen atom, a halogen atom, NR31R32, a (C1-C6) alkyl, aryl or heterocyclyl group, said aryl or heterocyclyl group being optionally substituted with one or more substituents selected from the group consisting of C(O)R48 and a (C1-C6) alkyl group; Even more preferably, R4 represents a hydrogen atom or a (C1-C3) alkyl group, advantageously a hydrogen atom; R4b represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, OR29 or NR31R32, preferably a hydrogen atom, a halogen atom, a (C1-C3) alkyl group or OR29, more preferably a hydrogen atom or a (C1-C3) alkyl group, advantageously a hydrogen atom; In the above definitions of R4 and R4b, R29 to R32 each independently represent a hydrogen atom, a (C1-C6) alkyl, an aryl or an aryl-(C1-C6) alkyl group, wherein the aryl group is selected from the group consisting of a halogen atom, OR55, SR56, NR57R58, C(O)R59, CO2R60, OC(O)R61, NR62C(O)R63, C(O)NR64R65, (C1-C6) alkyl and (C1-C6) haloalkyl groups, in particular C( Optionally substituted with one or more substituents selected from the group consisting of O)R59, CO2R60, C(O)NR64R65, (C1-C6) alkyl and (C1-C6) haloalkyl groups, in particular C(O)R59, R48 represent a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, and R55 to R65 independently represent a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group; R5 represents a hydrogen atom, a halogen atom, CN, OR29, SR30, NR31R32, a (C1-C6) alkyl, a (C1-C6) haloalkyl group, said alkyl or haloalkyl group being optionally substituted with one or more substituents selected from the group consisting of OR40, SR41 and NR42R43, an aryl, heterocyclyl, aryl-(C1-C6) alkyl or heterocyclyl-(C1-C6) alkyl group; wherein the aryl or heterocyclyl group is optionally substituted by one or more substituents selected from the group consisting of a halogen atom, OR, SR, NR, R, (C1-C6) alkyl and (C1-C6) haloalkyl groups, and R to R are, independently of one another, a hydrogen atom or a (C1-C6) alkyl group, and R to R are, independently of one another, a hydrogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom, Preferably, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl, a (C1-C6) haloalkyl group, said alkyl or haloalkyl group optionally being substituted with one or more substituents selected from the group consisting of OR40, SR41 and NR42R43, aryl-(C1-C6) alkyl or heterocyclyl-(C1-C6) alkyl groups, said aryl or heterocyclyl group optionally being substituted with one or more substituents selected from the group consisting of halogen atoms, (C1-C6) alkyl and (C1-C6) haloalkyl groups; More preferably, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl, a (C1-C6) haloalkyl group or a heterocyclyl-(C1-C6) alkyl group, said alkyl or haloalkyl group being optionally substituted by OR40, and said heterocyclyl being optionally substituted by one or more (C1-C6) alkyl groups; Even more preferably, R5 represents a hydrogen atom or a (C1-C3) alkyl group, advantageously a hydrogen atom; R6 represents a hydrogen atom, a (C1-C3) alkyl, an aryl-(C1-C3) alkyl or a -CH2-CH2-O-CH2-CH2-NH2 group, or a (C1-C6) alkylcarbonyl group optionally substituted by one or more substituents selected from the group consisting of OH, SH, NH2, (C1-C3) alkoxy, (C1-C3) thioalkoxy and (C1-C3) alkylamino groups, Preferably, R6 represents a hydrogen atom, methyl, ethyl, benzyl, -CH2-CH2-O-CH2-CH2-NH2 or a (C1-C6) alkylcarbonyl group optionally substituted by one or more substituents selected from the group consisting of OH, NH2 and thiomethyl groups, in particular R6 represents a hydrogen atom or a -CH2-CH2-O-CH2-CH2-NH2 group, 5. The pharmaceutical composition according to claim 3 or 4, which is a compound of formula (I).

6. The inhibitor of controlled necrotic cell death is X1 represents a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or ORX group, where RX is a (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl group; X2 and X3 independently represent a hydrogen atom or a (C1-C6) alkyl group; Y1, Y2 and Y3, independently of one another, represent a hydrogen atom, a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, OH or ORY group, and at least one of Y1, Y2 and Y3 represents a (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or ORY group, RY being selected from a (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl group, The pharmaceutical composition of claim 3, which is a compound of formula (II).

7. X1 represents an ORX group, RX being advantageously a (C1-C6) alkyl group; Y1 represents an ORY group, RY advantageously being an aryl-(C1-C6)alkyl group, and Y2 and Y3 each represent a hydrogen atom; The pharmaceutical composition according to claim 6.

8. The inhibitor of controlled necrotic cell death is (a) a compound of the following general formula (I.iii): 【Chemistry 10】 or a pharmaceutically acceptable salt and / or solvate thereof, wherein R3, R4, R4b and R5 are each independently a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, in particular a hydrogen atom, a halogen atom or a (C1-C3) alkyl group, preferably a hydrogen atom or a halogen atom; R6 represents a hydrogen atom, a (C1-C3) alkyl or a —CH2—CH2—O—CH2—CH2—NH2 group, in particular a hydrogen atom or a —CH2—CH2—O—CH2—CH2—NH2 group, or (b) a compound of the following general formula (II.i): 【Chemistry 11】 or a pharmaceutically acceptable salt and / or solvate thereof, wherein RX represents a (C1-C6)alkyl group, in particular a (C1-C3)alkyl group, such as methyl, ethyl, n-propyl, and more preferably methyl; RY represents an aryl-(C1-C6)alkyl group, such as benzyl or —CH3-naphthyl, more preferably benzyl. The pharmaceutical composition according to claim 3, wherein

9. The inhibitor of controlled necrotic cell death is Table 1 The pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts and / or solvates thereof.

10. The inhibitor of controlled necrotic cell death is Table 2 The pharmaceutical composition according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts and / or solvates thereof.

11. As a combination preparation for simultaneous, separate or sequential administration N-acetylcysteine ​​and / or pharmaceutical salts and / or derivatives thereof at least one inhibitor of regulated necrotic cell death The pharmaceutical composition according to any one of claims 1 to 10, comprising:

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the derivative of N-acetylcysteine ​​is N-acetylcysteine ​​amide, and / or N-acetylcysteine ​​ethyl ester and / or N-acetylcysteine ​​methyl ester, and / or salts thereof.

13. 13. A pharmaceutical composition according to any one of claims 1 to 12 for use in the prevention and / or treatment of diseases associated with controlled necrotic cell death, such as necroptosis and / or ferroptosis.

14. 14. The pharmaceutical composition for use according to claim 13, wherein the disorder is associated with ferroptosis, in particular both ferroptosis and necroptosis.

15. 15. The pharmaceutical composition for use according to claim 13 or 14, wherein the disorder is selected from the group consisting of neurodegenerative diseases or disorders, brain diseases or disorders including stroke, traumatic brain injury, epilepsy; eye diseases or disorders including retinopathy, degenerative eye diseases or disorders; infectious diseases; autoimmune diseases; inflammatory diseases; stress-induced premature tissue aging-related conditions; liver disorders including acute liver failure and chronic liver disease; hypertension; hemochromatosis; hemolytic diseases; ischemic diseases affecting the heart, brain, and kidneys; kidney disorders such as acute kidney injury, renal ischemia-reperfusion injury, acute tubular necrosis, and hepatic fibrosis; cardiac damage; aortic aneurysm; pancreatitis; radiation-induced necrosis; chronic obstructive pulmonary disease, acute respiratory distress disorder; transplant-related diseases; and cancers including liver cancer, eye cancer, brain tumor, and kidney cancer.

16. Use of the pharmaceutical composition according to any one of claims 1 to 12 for the preservation and / or protection of biological materials such as cells, tissues, body fluids and organs in vitro.

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