Synergistic combinations of regulatory necrosis inhibitors and n-acetylcysteine

Abstract

The present invention relates to a pharmaceutical composition comprising N-acetylcysteine in combination with at least one inhibitor of regulatory 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). Background Art

[0002] Necroptosis is a programmed cell death pathway that is distinct from apoptosis in that it does not involve key apoptotic regulators such as caspases, Bcl-2 family members, or cytochrome c released from mitochondria. "Necroptosis" is a specific programmed necrosis biochemical pathway that mainly depends on the serine / threonine kinase activity of RIPK1 (receptor-interacting protein kinase 1). The breakthrough discovery that necroptosis is a gene-controlled process has led to the hypothesis that this programmed cell death is "druggable", and this emerging breakthrough is expected to revolutionize daily clinical medicine [Linkermann and Green, N. Engl. J. Med. 2014, 370(5), 455-465]. In fact, molecular targets including RIPK1 (receptor-interacting protein 1), RIPK3, and MLKL (mixed lineage kinase domain-like) have been convincingly shown to contribute to a variety of diseases in which necroptosis has a core pathophysiological significance.

[0003] Necroptosis plays an important role in the pathogenesis of various diseases throughout the body, including disorders of the nervous, cardiovascular, pulmonary, and gastrointestinal systems. Necroptosis also plays a role in infectious and autoimmune diseases. It has been reported that necroptosis also mediates organ rejection, particularly in heart and kidney transplantation (Khoury et al., Am J Pathol., 2020; Jouan-Lanhouet et al., Semin. Cell Dev. Biol., 2014).

[0004] Ferroptosis is a novel non-apoptotic regulated cell death first described in 2012 and generally involves high intracellular levels of free iron and lipid peroxidation. This death pathway is directly related to the cell's ability to regulate its internal oxidative stress, particularly via the activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). Failure of the glutathione-dependent antioxidant defense mechanism leads to the accumulation of lipid-based reactive oxygen species (ROS), resulting in membrane damage and cell death, and the reactive oxygen species mainly originate from Fe 2+ Lipid peroxidation via the Fenton reaction.

[0005] Recent studies have shown that ferroptosis is associated with the pathophysiology of many human diseases [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], particularly affecting the heart, brain, nervous system, eyes, gastrointestinal system, liver, skin, kidneys, lungs, intestine, pancreas, or the whole body. Ferroptosis involves three major metabolisms, including thiols, lipids, and iron, leading to the generation of iron-dependent lipid peroxidation, ultimately resulting in cell death.

[0006] The characteristics of ferroptosis are used as key elements in defining biomarkers related to ferroptosis-associated diseases. Ferroptosis is an iron-dependent regulated tissue necrosis, mainly caused by unrestricted lipid peroxidation and subsequent membrane damage. Alterations in the physiological levels of the following 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), and 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 compound 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 key biochemical ferroptosis biomarkers can be measured and quantified by assays of body fluids (blood, plasma, serum, urine, cerebrospinal fluid), or highlighted by immunohistochemical labeling of biopsies of damaged tissues.

[0007] Depending on the pathology and the affected organ, the quantity and / or activity of some ferroptosis-related biomarkers may change (increase > or decrease <) relative to the normal physiological threshold. Here we only describe the reference values for serum:

[0008] (1) Iron metabolism (by measuring the levels of iron and ferritin in serum) exceeds the 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 Biophys Acta, 2010, 1800(8):760 - 769]);

[0009] (2) Glutathione redox status (by measuring the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) in plasma and the activity of glutathione peroxidase (GPx) using ELISA) (GSH < 717 μmol / L, GSSG > 5.32 μmol / L; GSH / GSSG ratio < 156; GPx, <20 UI / gHb in men and <26 UI / gHb in women), [Haleng J. et al., Rev. Med. Liege, 2007]);

[0010] (3) Oxidative stress (by measuring the levels of total Q10, reduced and active Q10 (Q10H2) in plasma) (Q10 < 3.44 μmol / l in men, Q10H2 < 3.04 μmol / l; Q10 < 1.88 μmol / l in women, Q10H2 < 1.64 μmol / l, [Kaikkonen et al., Scand J Clin Lab Invest, 1999, 59:457 - 466]);

[0011] (4) Lipid peroxidation (measured by detecting 4 - hydroxy - 2 - nonenal (4 - HNE) and malondialdehyde (MDA) adducts) exceeds the physiological thresholds (4 - HNE > 10 μmol / L [Chen and Niki, IUBMB Life, 2008, 58(372 - 373)], MDA > 3 μmol / L, using the thiobarbituric acid method [Banjare et al., J. Sci. Soc., 2017; 44(137 - 9)]).

[0012] Note that the up - regulation of the ACSL4 enzyme level in damaged organ tissues has also been reported as a putative biomarker of ferroptosis (ACSL4 expression can be monitored by transcriptomic and proteomic methods).

[0013] Pathologies associated with ferroptosis affecting the heart include myocardial ischemia-reperfusion injury (especially after arterial ligation), cardiomyopathy (especially doxorubicin-induced cardiomyopathy) [Li et al., 2020] and cardiovascular diseases (especially aortic dissection) [Chen et al., Pharmacol. Res., 2022, 177, 106122], etc. [Li et al., Free Radic. Biol. Med., 2020, 160, 303-318; Qin et al., Biomed. Pharmacother., 2021, 141, 111872].

[0014] Pathologies associated with ferroptosis 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], contusive spinal cord injury [Zhang et al., Neural Regen. Res., 2019, 14(3):532], epilepsy (including epilepsy associated with mitochondrial diseases and refractory epilepsy [Kahn-Kirby et al., PLoS One., 2019, 14(3)]), and neurodegenerative diseases, especially chronic neurodegenerative diseases, more particularly Alzheimer's disease [Li et al., 2020], Huntington's disease [Mi et 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 dementia, which may be related to one or more prior pathologies.

[0015] Pathologies associated with ferroptosis affecting the eye include vision loss (especially due to cataracts [Wei et al., Free Radic Biol Med., 2021, 167, 94 - 108]), and retinal diseases, especially Stargardt disease and age-related macular degeneration (AMD), particularly dry AMD [Sun et al., Invest Ophth Vis Sci., 2018, 59(9), 2482; Chen et al., J. Biol. Chem., 2021, 296, 100187].

[0016] Pathologies associated with ferroptosis affecting the liver include chronic liver diseases as well as acute liver injury and acute liver failure. Among chronic liver diseases, non-alcoholic 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)] are worth mentioning. Acute liver failure may especially be caused by drug-induced liver injury (DILI), such as liver injury caused by acetaminophen (APAP) [Yamada et al., Cell Death Dis., 2020, 11(2)], ischemia-reperfusion injury induced by sepsis or hemorrhagic shock [Friedmann Angeli et al., Nat Cell Biol., 2014, 16(12):1180 - 91], fulminant viral hepatitis, autoimmunity, or alcohol intake.

[0017] Pathologies associated with ferroptosis affecting the skin include skin inflammatory diseases, such as psoriasis [Li et al., Cell Death Dis., 2020, 11(88)] and toxic epidermal necrolysis (Lyell syndrome) [Zhang et al., J Invest Dermatol., 2020, 140(7), S79].

[0018] Pathologies associated with ferroptosis affecting the kidney include acute kidney injury (AKI) (also known as acute renal failure), such as AKI caused by crystals (oxalate), folic acid (FA) [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].

[0019] Pathologies associated with 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 (especially 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 pulmonary fibrosis, such as radiation-induced lung fibrosis (RILF) [Li et al., J Inflamm., 2019, 16:11] and paraquat-induced lung injury [Rashidipour et al., Toxicology, 2020, 433-434:152407].

[0020] Pathologies associated with ferroptosis affecting the intestine include necrotizing enterocolitis [Subramanian et al., Acta Physiologica Sinica, 2020, 72(3)] and inflammatory bowel disease, such as Crohn's disease [Mayr et al., Nat Commun., 2020, 11(1)] and ulcerative colitis.

[0021] Pathologies associated with systemic ferroptosis include hemochromatosis [Imoto et al., Transfus Apher Sci., 2018, 57(4), 524-531], β-thalassemia [Sposi, N.M., Oxidative Stress and Iron Overload in β-Thalassemia: An Overview, 2019, DOI: 10.5772 / intechopen.90492], hemolytic diseases [Youssef et al., 2019, Ferroptosis in Hemolytic Disorders. In: Tang D. (eds) Ferroptosis in Health and Disease. Springer, Cham.], cytokine storms during viral infections [Edeas et al., Int J Infect Dis., 2020, 97; Yang and Lai, Cell Death Discov., 2020, 6], 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 pathologies associated with stress-induced premature tissue aging, 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)].

[0022] Therefore, inhibiting regulated necrotic cell death is a novel and attractive therapeutic strategy for diseases associated therewith.

[0023] The present inventors have previously disclosed two classes of novel inhibitors of regulated necrosis (also referred to herein as "inhibitors of regulated necrotic cell death"), the first class consisting of sibiriline derivatives (WO 2017 / 064217, WO 2017 / 064216, and WO 2022 / 157392), and the second class consisting of nigratine derivatives (WO 2018 / 073321).

[0024]

[0025] Now, the inventors unexpectedly found that when such inhibitors of regulated necrosis (inhibitors of regulated necrotic cell death) are combined with N-acetylcysteine (NAC) or its derivatives, the combination produces a cytoprotective effect with superadditivity (i.e., synergy), achieving a much better therapeutic efficacy than when each active ingredient is used alone. SUMMARY OF THE INVENTION

[0026] Accordingly, the present invention relates to a pharmaceutical composition comprising a combination of N-acetylcysteine (NAC) and / or its pharmaceutically acceptable salts and / or derivatives with at least one inhibitor of regulated necrotic cell death (such as necroptosis and / or ferroptosis).

[0027] N-acetylcysteine (also known as acetylcysteine or N-acetyl-L-cysteine, CAS number 616-91-1) corresponds to the following chemical formula:

[0028]

[0029] N-acetylcysteine, according to its pharmacological activity, the main therapeutic applications of NAC are as follows:

[0030] - In pulmonology, NAC is a mucolytic mucoregulator. It acts on the gel phase of mucus, presumably by disrupting the disulfide bonds of glycoproteins, thereby promoting expectoration.

[0031] - In ophthalmology, NAC is an inhibitor of collagenase, a proteolytic enzyme that is secreted in large amounts when the epithelium is damaged and causes degradation of the polypeptide fibers of corneal collagen.

[0032] - In toxicology, acetylcysteine is a precursor of glutathione and can enter cells. This is the main way it protects hepatocytes. In fact, glutathione neutralizes the electrophiles produced by the metabolism of paracetamol.

[0033] - In the field of neurology, several preliminary studies have shown that the administration of NAC can increase the level of glutathione in the brain. The benefits of NAC as part of the standard treatment for patients with Parkinson's disease have recently been confirmed. It has been found that the levels of dopamine (the main neurotransmitter that is significantly reduced in this disease) in patients have increased, and mental and physical functions have also improved [Monti et al., Clin Pharmacol Ther., 2019, 106(4), 884-890].

[0034] Pharmaceutically acceptable salts of NAC or its derivatives (such as N-acetylcysteine amide, N-acetylcysteine ethyl ester, N-acetylcysteine methyl ester) include, but are not limited to, salts formed with free amino groups (such as salts derived from hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, oxalic acid, tartaric acid, etc.), and salts formed with free carboxyl groups (such as salts derived from sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, iron hydroxide, isopropylamine, triethylamine, 2-(ethylamino)ethanol, histidine, procaine, etc.).

[0035] Within the framework of the present invention, the term "NAC derivative" is intended to refer to any compound that is structurally related to NAC and has similar pharmacological activity. For example, the following compound, called N-acetylcysteine amide (also known as NAC amide or N-acetyl-L-cysteine amide or NACA, CAS number 38520-57-9) [Sunitha et al., Clin Pharmacol Ther., 2013, 47(5), 884-890], is a derivative of NAC:

[0036]

[0037] N-acetylcysteine amide, in particular, the NAC derivative of the pharmaceutical composition according to the present invention is N-acetylcysteine amide.

[0038] For example, the following compound, called N-acetylcysteine ethyl ester (also known as NAC ethyl ester or N-acetyl-L-cysteine ethyl ester, CAS number 59587-09-6), is a derivative of NAC:

[0039]

[0040]

[0041] In particular, the NAC derivative of the pharmaceutical composition according to the present invention is N-acetylcysteine ethyl ester.

[0042] For example, the following compound, called N-acetylcysteine methyl ester (also known as NAC methyl ester, N-acetyl-L-cysteine methyl ester, CAS number 118398-49-5), is a derivative of NAC:

[0043]

[0044] In particular, the NAC derivative of the pharmaceutical composition according to the present invention is N-acetylcysteine methyl ester.

[0045] In particular, the present invention relates to a pharmaceutical composition comprising N-acetylcysteine (NAC) and / or N-acetylcysteine amide and / or N-acetylcysteine ethyl ester and / or N-acetylcysteine methyl ester and / or a pharmaceutically acceptable salt thereof in combination with at least one inhibitor of regulated necrotic cell death (such as necroptosis and / or ferroptosis).

[0046] For the purposes of the present invention, the term "inhibitor of regulated necrotic cell death" refers to a compound capable of at least partially protecting cells from regulated necrotic death. In particular, when cells are exposed to an inducer of regulated necrotic cell death, treatment with this inhibitor can increase cell viability, which can be readily verified by those skilled in the art using methods well known in the art (such as the methods described in the examples of this specification).

[0047] The inhibitor of regulated necrotic cell death is advantageously an inhibitor of ferroptosis and / or necroptosis. In a particular embodiment, the inhibitor of regulated necrotic cell death is a ferroptosis inhibitor, preferably an inhibitor of ferroptosis and necroptosis.

[0048] Assays for identifying ferroptosis inhibitors are disclosed, for example, on pages 69 to 81 of WO2022157392 (experimental section, "II. Biological activity of the compounds of the present invention" section). A preferred model is the SH-SY5Y human neuroblastoma cell line treated with the ferroptosis inducer RSL3 or erastin. Ferroptosis inhibitors are characterized in that, in a model such as the SH-SY5Y model, they can protect cells from cell death in a dose-dependent manner and reduce lipid peroxidation induced by a ferroptosis inducer (such as RSL3 or erastin).

[0049] Assays for identifying necroptosis inhibitors are disclosed, for example, on page 29 of EP3362450B1, particularly paragraph

[178] . Necroptosis inhibitors are characterized in that in this assay, they can protect cells from cell death induced by a necroptosis inducer in a dose-dependent manner, where the EC 50 is, for example, 25 μM or lower (the EC 50 being the half-maximal effective concentration of the drug).

[0050] Examples of known ferroptosis and / or necroptosis inhibitors are resveratrol (CAS number 501-36-0), Ferrostatin 1 (CAS number: 347174-05-4) or Liproxstatin (CAS number 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, the inhibitor of regulated necrotic cell death is NEC1F.

[0051] The inhibitor of regulated necrotic cell death of the pharmaceutical composition according to the invention (hereinafter referred to as "inhibitor") can in particular be silybin, nigralin or a derivative thereof.

[0052] Sibelium and its derivatives

[0053] In a particular embodiment, the inhibitor of the pharmaceutical composition according to the invention is silybin or a derivative thereof. Thus, the inhibitor can correspond to any of the compounds disclosed in WO 2017 / 064217, WO 2017 / 064216 or WO 2022 / 157392.

[0054] In this particular embodiment, the inhibitor is preferably a compound of general formula (I)

[0055]

[0056] or a pharmaceutically acceptable salt and / or solvate thereof,

[0057] wherein:

[0058] ■ is

[0059] (i) when is then

[0060] X is N, Y is N(R2) and Z is C(H);

[0061] (ii) when is then

[0062] -X is N(R1), and

[0063] -Y is N or N + (O - ) and Z is C(R3), or

[0064] Y is CH and Z is N, or

[0065] Y and Z are CH;

[0066] and in which:

[0067] ■ R1 and R2 each independently represent a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 , C(O)R 11 , CO2R 12 , OC(O)R 13 , NR 14 C(O)R 15 , C(O)NR 16 R 17 , S(O)R S , SO2R S ’, (C1-C6)alkyl, (C1-C6)haloalkyl, -(C1-C6)alkyl-[O-(C1-C6)alkyl] where m is from 1 to 6 m -NR N1 R N2 group, aryl, aryl-(C1-C6)alkyl, heterocyclic group or heterocyclic group-(C1-C6)alkyl, where the aryl or heterocyclic group is optionally substituted by one or more substituents selected from halogen atom, CN, NO2, OR 18 , SR 19 , NR 20 R 21 , C(O)R 22 , CO2R 23 , OC(O)R 24 , NR 25 C(O)R 26 , C(O)NR 27 R 28 , (C1-C6)alkyl and (C1-C6)haloalkyl;

[0068] ■ R3, R4, R 4b and R5 each independently represent a hydrogen atom, halogen atom, CN, OR 29 , SR 30 , NR 31 R 32 , C(O)R 33 , CO2R 34 , OC(O)R 35 , NR 36 C(O)R 37 , C(O)NR 38 R 39, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, heterocyclic group, aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl, wherein said alkyl or haloalkyl is optionally substituted by one or more substituents selected from OR 40 、SR 41 and NR 42 R 43 , and the aryl or heterocyclic group is optionally substituted by one or more substituents selected from halogen atom, CN, NO2, OR 44 、SR 45 、NR 46 R 47 、C(O)R 48 、CO2R 49 、OC(O)R 50 、NR 51 C(O)R 52 、C(O)NR 53 R 54 、(C1-C6) alkyl and one or more substituents of (C1-C6) haloalkyl;

[0069] ■ R6 represents a hydrogen atom, (C1-C6) alkyl, aryl-(C1-C6) alkyl, heterocyclic group-(C1-C6) alkyl, -(C1-C6) alkyl-[O-(C1-C6) alkyl] where m' is 1 to 6 m’ -NR N’1 R N’2 group or (C1-C6) alkylcarbonyl, and the (C1-C6) alkyl, aryl-(C1-C6) alkyl and (C1-C6) alkylcarbonyl are optionally substituted by one or more substituents selected from OH, SH, NH2, (C1-C6) alkoxy, (C1-C6) thioalkoxy, (C1-C6) alkylamino and bis((C1-C6) alkyl)amino;

[0070] ■ R S and R S ' each independently represent (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl;

[0071] ■ R7-R 10 、R 12 、R 14 and R 16 -R 17 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl;

[0072] ■ R 11 、R 13 and R 15Each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group, an aryl-(C1-C6) alkyl group, a (C1-C6) alkoxy group, a (C1-C6) alkylamino group, or a di((C1-C6) alkyl)amino group;

[0073] ■R 18 to R 28 Each independently represents a hydrogen atom, a (C1-C6) alkyl group, or an aryl group;

[0074] ■R 29 to R 39 Each independently represents a hydrogen atom, a (C1-C6) alkyl group, a heterocyclic-(C1-C6) alkyl group, an aryl group, or an aryl-(C1-C6) alkyl group, and the aryl group is optionally substituted with one or more substituents selected from a halogen atom, CN, NO2, OR 55 、SR 56 、NR 57 R 58 、C(O)R 59 、CO2R 60 、OC(O)R 61 、NR 62 C(O)R 63 、C(O)NR 64 R 65 、(C1-C6) alkyl group and (C1-C6) haloalkyl group;

[0075] ■R 40 to R 43 Each independently represents a hydrogen atom or a (C1-C6) alkyl group;

[0076] ■R 44 to R 54 Each independently represents a hydrogen atom, a (C1-C6) alkyl group, or an aryl group;

[0077] ■R 55 to R 65 Each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl-(C1-C6) alkyl group, or an aryl group; and

[0078] R N1 、R N ’1、R N2 and R N ’2 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl-(C1-C6) alkyl group, or an aryl group.

[0079] ■ Preferably, in the compound of the following general formula (I), wherein: R1 and R2 each independently represent a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 、C(O)R 11 、CO2R12 、 OC(O)R 13 、 NR 14 C(O)R 15 、 C(O)NR 16 R 17 、 S(O)R S 、 SO2R S ’、 (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, heterocyclic group, aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl, wherein the aryl or heterocyclic group is optionally selected from halogen atom, CN, NO2, OR 18 、 SR 19 、 NR 20 R 21 、 C(O)R 22 、 CO2R 23 、 OC(O)R 24 、 NR 25 C(O)R 26 、 C(O)NR 27 R 28 、 substituted by one or more substituents of (C1-C6) alkyl and (C1-C6) haloalkyl;

[0080] ■ R3, R4, R 4b and R5 each independently represent a hydrogen atom, a halogen atom, CN, OR 29 、 SR 30 、 NR 31 R 32 、 C(O)R 33 、 CO2R 34 、 OC(O)R 35 、 NR 36 C(O)R 37 、 C(O)NR 38 R 39 、 (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, heterocyclic group, aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl, wherein the alkyl or haloalkyl is optionally selected from OR 40 、 SR 41 and NR 42 R 43 of one or more substituents, and the aryl or heterocyclic group is optionally selected from halogen atom, CN, NO2, OR 44 、 SR 45 、 NR 46 R 47 、 C(O)R 48 、 CO2R 49 、 OC(O)R 50 、 NR 51C(O)R 52 、C(O)NR 53 R 54 、 substituted with one or more substituents selected from (C1-C6) alkyl and (C1-C6) haloalkyl;

[0081] ■ R6 represents a hydrogen atom, (C1-C6) alkyl, aryl-(C1-C6) alkyl or -CH2-CH2-O-CH2-CH2-NH2 group, or (C1-C6) alkylcarbonyl optionally substituted with one or more substituents selected from OH, SH, NH2, (C1-C6) alkoxy, (C1-C6) thioalkoxy, (C1-C6) alkylamino and di((C1-C6) alkyl) amino;

[0082] ■ R S and R S ’ each independently represent (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl;

[0083] ■ R7-R 10 、R 12 、R 14 and R 16 -R 17 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl;

[0084] ■ R 11 、R 13 and R 15 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkylamino or di((C1-C6) alkyl) amino;

[0085] ■ R 18 to R 28 each independently represent a hydrogen atom, (C1-C6) alkyl or aryl;

[0086] ■ R 29 to R 39 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, wherein the aryl is optionally selected from halogen atom, CN, NO2, OR 55 、SR 56 、NR 57 R 58 、C(O)R 59 、CO2R 60 、OC(O)R 61 、NR 62 C(O)R 63 、C(O)NR64 R 65 substituted by one or more substituents selected from (C1-C6) alkyl and (C1-C6) haloalkyl;

[0087] ■R 40 to R 43 each independently represents a hydrogen atom or (C1-C6) alkyl;

[0088] ■R 44 to R 54 each independently represents a hydrogen atom, (C1-C6) alkyl or aryl; and

[0089] ■R 55 to R 65 each independently represents a hydrogen atom, (C1-C6) alkyl or aryl.

[0090] For the purposes of the present invention, the term "pharmaceutically acceptable" is intended to mean useful for the preparation of pharmaceutical compositions and generally safe and non-toxic for pharmaceutical use.

[0091] Within the framework of the present invention, the term "pharmaceutically acceptable salt or solvate" is intended to mean a salt or solvate of a pharmaceutically acceptable compound as defined above, which has the pharmacological activity of the corresponding compound.

[0092] Pharmaceutically acceptable salts include:

[0093] (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, etc.; or with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxy naphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid and trifluoroacetic acid, etc., and

[0094] (2) base addition salts formed by replacing the acidic proton present in the compound with a metal ion (such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion), or by coordinating with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

[0095] Acceptable solvates include conventional solvates, such as those formed in the final step of compound preparation due to the presence of a solvent.

[0096] As used in the present invention, the term "halogen" refers to a fluorine, bromine, chlorine or iodine atom.

[0097] As used in the present invention, the term "(C1-C6)alkyl" refers to a straight or branched chain saturated hydrocarbon chain containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0098] As used in the present invention, the term "(C1-C6)haloalkyl" refers to a (C1-C6)alkyl as defined above, wherein some or all of the hydrogen atoms are replaced by a halogen atom as defined above. This means that the (C1-C6)alkyl is substituted by at least one halogen atom. For example, it can be trifluoromethyl.

[0099] As used in the present invention, the term "aryl" refers to an aromatic hydrocarbon group preferably containing 6 to 10 carbon atoms and containing one or more (especially 1 or 2) fused rings, such as phenyl or naphthyl, advantageously phenyl.

[0100] As used in the present invention, the term "heterocycle" refers to a saturated, unsaturated (i.e., non-aromatic) or aromatic monocyclic or bicyclic group containing two fused rings, bridged rings or spiro rings, preferably a bicyclic group with fused rings, advantageously each ring containing 5 to 10, especially 5 or 6 atoms, wherein the atoms of the ring contain one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the rest are carbon atoms.

[0101] The saturated heterocyclic group is more particularly a 5- or 6-membered saturated monocyclic heterocyclic group, such as pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, triazolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl.

[0102] The unsaturated heterocyclic group is more particularly an unsaturated monocyclic or bicyclic heterocyclic group, each ring containing 5 or 6 members, such as pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, thiazolinyl, isothiazolinyl, oxazolinyl, isoxazolinyl, imidazolinyl, pyrazolinyl, triazolinyl, dihydropyridyl, tetrahydropyridyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydro pyrazinyl, tetrahydropyrazinyl, dihydrotriazinyl, tetrahydrotriazinyl, indolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, 1,3-benzodioxolyl, 1,3-benzoxathiolyl, benzoxazolinyl, benzothiazolinyl, benzimidazolinyl, chromanyl or chromenyl.

[0103] An aromatic heterocyclic group is also referred to as a heteroaryl group, and more particularly as an aromatic monocyclic or bicyclic heterocyclic group, each ring containing 5 or 6 members, such as pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl (e.g., 1,3,5-triazinyl), indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl or quinoxalinyl.

[0104] As used in the present invention, the term "aryl-(C1-C6)alkyl" refers to an aryl group as defined above attached to the molecule via a (C1-C6)alkyl group as defined above. In particular, -(C1-C6)alkyl-aryl is benzyl.

[0105] As used in the present invention, the term "heterocyclic-(C1-C6)alkyl" refers to a heterocyclic group as defined above attached to the molecule via a (C1-C6)alkyl group as defined above. In particular, -(C1-C6)alkyl-heterocyclic is a 5- or 6-membered saturated monocyclic heterocyclic group as defined above attached to the molecule via a (C1-C6)alkyl group as defined above.

[0106] As used in the present invention, the term "(C1-C6)alkylcarbonyl" 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, butyryl, valeryl, hexanoyl, etc.

[0107] As used in the present invention, the term "(C1-C6)alkoxy" refers to a (C1-C6)alkyl group as defined above attached to the molecule via an oxygen atom, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, etc.

[0108] As used in the present invention, the term "(C1-C6)thioalkoxy" refers to a (C1-C6)alkyl group as defined above attached to the molecule via a sulfur atom, including but not limited to thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, isothiobutoxy, sec-thiobutoxy, tert-thiobutoxy, n-thiopentyloxy, n-thiohexyloxy, etc.

[0109] As used in the present invention, the term "(C1-C6)alkylamino" refers to an -NHAlk group, where Alk represents a (C1-C6)alkyl group as defined above, including but not limited to methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, n-hexylamino, etc.

[0110] As used in the present invention, the term "di(C1-C6)alkylamino" refers to the -NAlk1Alk2 group, where Alk1 and Alk2 each independently represent a (C1-C6)alkyl as defined above, including but not limited to dimethylamino, diethylamino, ethylmethylamino, etc.

[0111] According to a particular embodiment of the present invention, R1 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 , C(O)R 11 , CO2R 12 , OC(O)R 13 , NR 14 C(O)R 15 , C(O)NR 16 R 17 , S(O)R S , SO2R S ’, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group (which may be part of an aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl) is optionally substituted by one or more, especially one, substituents selected from halogen atoms, CN, NO2, OR 18 , SR 19 , NR 20 R 21 , (C1-C6)alkyl and (C1-C6)haloalkyl, especially halogen atoms, NO2, OR 18 , (C1-C6)alkyl and (C1-C6)haloalkyl, especially NO2 and OR 18 , where R 18 to R 21 each independently represent a hydrogen atom or a (C1-C6)alkyl.

[0112] According to another particular embodiment of the present invention, R1 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 , C(O)R 11 , CO2R 12 , OC(O)R 13 , NR 14 C(O)R 15 , C(O)NR 16 R 17 , (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group is optionally substituted by one or more substituents as defined above.

[0113] According to another particular embodiment of the present invention, R1 represents a hydrogen atom, CN, OR7, C(O)R 11 , CO2R 12 , OC(O)R 13 , SO2R S ’, (C1-C6)alkyl, heterocyclic group or heterocyclic group-(C1-C6)alkyl, wherein said heterocyclic group (which may be part of the heterocyclic group-(C1-C6)alkyl) is optionally substituted by one or more, especially one, substituents selected from halogen atoms, CN, NO2, OR 18 , SR 19 , NR 20 R 21 , (C1-C6)alkyl and (C1-C6)haloalkyl, especially halogen atoms, NO2, OR 18 , (C1-C6)alkyl and (C1-C6)haloalkyl, especially NO2 and OR 18 , and wherein R 18 to R 21 each independently represents a hydrogen atom or (C1-C6)alkyl.

[0114] According to another particular embodiment of the present invention, R1 represents a hydrogen atom, CN, OR7, C(O)R 11 , CO2R 12 , OC(O)R 13 , heterocyclic group or heterocyclic group-(C1-C6)alkyl, wherein said heterocyclic group is optionally substituted by one or more substituents as defined above.

[0115] In a preferred embodiment, R1 represents a hydrogen atom or (C1-C6)alkyl, especially a hydrogen atom or (C1-C3)alkyl, preferably a hydrogen atom.

[0116] In the above embodiments, (C1-C6)alkyl (which may be part of aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl) is preferably (C1-C3)alkyl.

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

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

[0119] In the above embodiments, R S and R S ’ each independently represent a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl, especially a (C1-C6)alkyl or aryl, particularly an aryl, such as phenyl.

[0120] In the above embodiments, R7-R 10 , R 12 , R 14 and R 16 -R 17 each independently represent a hydrogen atom, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl, R 11 , R 13 and R 15 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, especially a hydrogen atom, a (C1-C6)alkyl, aryl, (C1-C6)alkylamino or di((C1-C6)alkyl)amino, particularly a (C1-C3)alkyl, aryl such as phenyl, (C1-C3)alkylamino or di((C1-C3)alkyl)amino.

[0121] In particular, in the above embodiments, R7 to R 17 each independently represent a hydrogen atom, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl, especially a hydrogen atom, a (C1-C6)alkyl or aryl, typically a hydrogen atom, a (C1-C3)alkyl or aryl, wherein the aryl (which may be part of an aryl-(C1-C6)alkyl) is preferably phenyl.

[0122] According to a particular embodiment of the invention, R2 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 , C(O)R 11 , CO2R 12 , OC(O)R 13 , NR 14 C(O)R 15 , C(O)NR 16 R17 、 S(O)R S 、 SO2R S ’, (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, heterocyclic group, aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl, wherein the aryl or heterocyclic group (which may be part of aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl) is optionally substituted by one or more substituents especially selected from halogen atom, CN, NO2, OR 18 、 SR 19 、 NR 20 R 21 、 (C1-C6) alkyl and (C1-C6) haloalkyl, especially halogen atom, NO2, OR 18 、 (C1-C6) alkyl and (C1-C6) haloalkyl, particularly NO2 and OR 18 of substituents, wherein R 18 to R 21 each independently represents a hydrogen atom or (C1-C6) alkyl.

[0123] In the above embodiments, R S and R S ’ each independently represents (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, especially (C1-C6) alkyl or aryl, particularly aryl, such as phenyl.

[0124] According to another particular embodiment of the present invention, R2 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 、 C(O)R 11 、 CO2R 12 、 OC(O)R 13 、 NR 14 C(O)R 15 、 C(O)NR 16 R 17 、 (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, heterocyclic group, aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl, wherein the aryl or heterocyclic group is optionally substituted by one or more substituents as defined above.

[0125] According to another particular embodiment of the present invention, R2 represents C(O)R 11 、 CO2R 12 、 C(O)NR 16 R 17, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group is optionally substituted by one or more, especially one selected from halogen atoms, OR 18 , SR 19 , NR 20 R 21 , (C1-C6)alkyl and (C1-C6)haloalkyl substituents, where R 18 to R 21 each independently represents a hydrogen atom or (C1-C6)alkyl.

[0126] According to another particular embodiment of the present invention, R2 represents CO2R 12 , C(O)NR 16 R 17 , (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl, especially CO2R 12 , C(O)NR 16 R 17 or aryl-(C1-C6)alkyl, wherein the aryl is optionally substituted by one or more, especially one selected from halogen atoms, OR 18 , SR 19 and NR 20 R 21 , especially OR 18 , where R 18 to R 21 each independently represents a hydrogen atom or (C1-C6)alkyl.

[0127] In the above embodiments, the (C1-C6)alkyl (which can be part of an aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl) is preferably (C1-C3)alkyl.

[0128] In the above embodiments, the aryl (which can be part of an aryl-(C1-C6)alkyl) is preferably phenyl.

[0129] In the above embodiments, the heterocyclic group (which can be part of a heterocyclic group-(C1-C6)alkyl) is particularly 5- or 6-membered, saturated, unsaturated (i.e., non-aromatic) or aromatic, especially a saturated monocyclic group, where the atoms of the ring contain one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the rest are carbon atoms, such as morpholinyl, pyridyl or piperazinyl, especially piperazinyl.

[0130] In the above embodiments, R7-R 10 , R 12 , R 14 and R16 -R 17 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, R 11 , R 13 and R 15 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group, an aryl-(C1-C6) alkyl group, a (C1-C6) alkoxy group, a (C1-C6) alkylamino group or a bis((C1-C6) alkyl)amino group, especially a hydrogen atom, a (C1-C6) alkyl group, an aryl group, a (C1-C6) alkylamino group or a bis((C1-C6) alkyl)amino group, particularly a (C1-C3) alkyl group, an aryl group such as a phenyl group, a (C1-C3) alkylamino group or a bis((C1-C3) alkyl)amino group.

[0131] In particular, in the above embodiments, R7 to R 17 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, especially a hydrogen atom, a (C1-C6) alkyl group or an aryl-(C1-C6) alkyl group, typically a hydrogen atom, a (C1-C3) alkyl group or an aryl group, wherein the aryl group (which may be part of an aryl-(C1-C6) alkyl group) is preferably a phenyl group.

[0132] According to another particular embodiment of the present invention, R3 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, CN, OR 29 , SR 30 , NR 31 R 32 , C(O)R 33 , CO2R 34 , OC(O)R 35 , NR 36 C(O)R 37 , C(O)NR 38 R 39 , an aryl group, a heterocyclic group, an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group, wherein the aryl group or heterocyclic group is optionally substituted with one or more substituents selected from halogen atoms, OR 44 , SR 45 , NR 46 R 47 , a (C1-C6) alkyl group and a (C1-C6) haloalkyl group, wherein R 29 to R 39 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, especially a hydrogen atom or a (C1-C6) alkyl group, typically a hydrogen atom or a (C1-C3) alkyl group.

[0133] According to another particular embodiment of the present invention, R3 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, CN, OR 29 、SR 30 、NR 31 R 32 、C(O)R 33 、CO2R 34 、OC(O)R 35 、NR 36 C(O)R 37 or C(O)NR 38 R 39 wherein R 29 to R 39 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, especially a hydrogen atom or a (C1-C6) alkyl group.

[0134] According to another particular embodiment of the present invention, R3 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, CN, OR 29 、SR 30 、NR 31 R 32 、OC(O)R 35 、NR 36 C(O)R 37 、a heterocyclic group or a heterocyclic-(C1-C6) alkyl group, wherein the heterocyclic group is optionally substituted with one or more substituents selected from a halogen atom, OR 44 、SR 45 、NR 46 R 47 and (C1-C6) alkyl groups, preferably, R3 represents a hydrogen atom, a halogen atom, CN, NR 31 R 32 、OC(O)R 35 、a heterocyclic group or a heterocyclic-(C1-C6) alkyl group, wherein the heterocyclic group is optionally substituted with one or more substituents selected from OR 44 、SR 45 and NR 46 R 47 especially substituted with OR 44 wherein R 29 to R 37 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, especially a hydrogen atom or a (C1-C6) alkyl group, typically a hydrogen atom or a (C1-C3) alkyl group.

[0135] In the above embodiments, R 44 to R 47Each independently represents a hydrogen atom or a (C1-C6) alkyl group, especially a hydrogen atom or a (C1-C3) alkyl group.

[0136] According to another particular embodiment of the present invention, R3 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, OR 29 , SR 30 , NR 31 R 32 , C(O)R 33 , CO2R 34 , OC(O)R 35 , NR 36 C(O)R 37 or C(O)NR 38 R 39 , preferably a hydrogen atom, a halogen atom, OR 29 , SR 30 , NR 31 R 32 , OC(O)R 35 or NR 36 C(O)R 37 , more preferably a hydrogen atom or OC(O)R 35 , where R 29 to R 37 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, especially a hydrogen atom or a (C1-C6) alkyl group, typically a hydrogen atom or a (C1-C3) alkyl group.

[0137] In a preferred embodiment, R3 represents a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, especially a hydrogen atom, a halogen atom or a (C1-C3) alkyl group, preferably a hydrogen atom or a halogen atom.

[0138] In the above embodiments, the aryl group (which may be part of an aryl-(C1-C6) alkyl group) is preferably phenyl.

[0139] In the above embodiments, the heterocyclic group (which may be part of a heterocyclic-(C1-C6) alkyl group) is particularly 5- or 6-membered, saturated, unsaturated (i.e., non-aromatic) or aromatic, especially an aromatic monocyclic group, where the atoms of the ring contain one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the remaining are carbon atoms, such as pyridyl, pyrimidinyl, pyrazolyl, piperazinyl or piperidinyl, such as pyridyl, pyrimidinyl or pyrazolyl.

[0140] In the above embodiments, the (C1-C6) alkyl group (which may be part of an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group) is preferably a (C1-C3) alkyl group.

[0141] According to a particular embodiment of the present invention, R4 represents a hydrogen atom, a halogen atom, CN, OR 29 、SR 30 、NR 31 R 32 、(C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group (which may be part of the aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl) is optionally substituted by one or more, in particular one, substituents selected from halogen atoms, CN, NO2, OR 44 、SR 45 、NR 46 R 47 、C(O)R 48 、CO2R 49 、OC(O)R 50 、NR 51 C(O)R 52 、C(O)NR 53 R 54 、(C1-C6)alkyl and (C1-C6)haloalkyl, in particular halogen atoms, OR 44 、SR 45 、NR 46 R 47 、C(O)R 48 、CO2R 49 、C(O)NR 53 R 54 、(C1-C6)alkyl and (C1-C6)haloalkyl, especially C(O)R 48 、CO2R 49 、C(O)NR 53 R 54 、(C1-C6)alkyl and (C1-C6)haloalkyl, preferably C(O)R 48 and substituents of (C1-C6)alkyl.

[0142] According to another particular embodiment of the present invention, R4 represents a hydrogen atom, a halogen atom, CN, OR 29 、SR 30 、NR 31 R 32 、(C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group is optionally substituted by one or more substituents as defined above.

[0143] According to another particular embodiment of the present invention, R4 represents a hydrogen atom, a halogen atom, OR 29 、SR 30 、NR 31 R 32 、(C1-C6)alkyl, aryl or heterocyclic group, wherein said aryl or heterocyclic group is optionally substituted by one or more, especially one selected from halogen atom, OR 44 、SR 45 、NR 46 R 47 、C(O)R 48 、CO2R 49 、C(O)NR 53 R 54 、(C1-C6)alkyl and (C1-C6)haloalkyl, especially C(O)R 48 、CO2R 49 、C(O)NR 53 R 54 、(C1-C6)alkyl and (C1-C6)haloalkyl, preferably substituted by the substituents of C(O)R 48 and (C1-C6)alkyl.

[0144] According to another particular embodiment of the present invention, R4 represents a hydrogen atom, a halogen atom, NR 31 R 32 、(C1-C6)alkyl, aryl or heterocyclic group, wherein said aryl or heterocyclic group is optionally substituted by one or more, especially one selected from C(O)R 48 、CO2R 49 、C(O)NR 53 R 54 、(C1-C6)alkyl and (C1-C6)haloalkyl, preferably substituted by the substituents of C(O)R 48 and (C1-C6)alkyl.

[0145] In a preferred embodiment, R4 represents a hydrogen atom, a halogen atom or (C1-C6)alkyl, especially a hydrogen atom or (C1-C3)alkyl, preferably a hydrogen atom.

[0146] In the above embodiments, the aryl (which may be part of an aryl-(C1-C6)alkyl) is preferably phenyl.

[0147] In the above embodiments, the heterocyclic group (which may be part of a heterocyclic group-(C1-C6)alkyl) is in particular a 5- or 6-membered, saturated, unsaturated (i.e. non-aromatic) or aromatic, especially saturated monocyclic group, where the atoms of the ring contain one or more, advantageously 1 to 3, heteroatoms selected from O, S and N, preferably O and N, and the rest are carbon atoms, such as piperazinyl, piperidinyl, pyridyl, pyrimidinyl or pyrazolyl, such as piperazinyl or piperidinyl.

[0148] In the above embodiments, R 29 to R 32 each independently represents a hydrogen atom, (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl, said aryl (which may be part of an aryl-(C1-C6)alkyl) is preferably phenyl and is optionally substituted by one or more, especially one, substituent selected from halogen atoms, CN, NO2, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6)alkyl and (C1-C6)haloalkyl, advantageously halogen atoms, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6)alkyl and (C1-C6)haloalkyl, especially C(O)R 59 , CO2R 60 , C(O)NR 64 R 65 , (C1-C6)alkyl and (C1-C6)haloalkyl, particularly C(O)R 59 , where R 55 to R 65 each independently represents a hydrogen atom, (C1-C6)alkyl or aryl, especially aryl, preferably phenyl.

[0149] In the above embodiments, R 44 to R 54Each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group, especially an aryl group, preferably a phenyl group.

[0150] In the above embodiments, the (C1-C6) alkyl group (which may be part of an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group) is preferably a (C1-C3) alkyl group.

[0151] According to a particular embodiment of the present invention, R 4b represents a hydrogen atom, a halogen atom, OR 29 、SR 30 、NR 31 R 32 、a (C1-C6) alkyl group, a (C1-C6) haloalkyl group, an aryl group, a heterocyclic group, an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group, wherein the aryl or heterocyclic group (which may be part of an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group) is optionally substituted by one or more, especially one, selected from halogen atoms, CN, NO2, OR 44 、SR 45 、NR 46 R 47 、C(O)R 48 、CO2R 49 、OC(O)R 50 、NR 51 C(O)R 52 、C(O)NR 53 R 54 、(C1-C6) alkyl groups and (C1-C6) haloalkyl groups, especially halogen atoms, OR 44 、SR 45 、NR 46 R 47 、C(O)R 48 、CO2R 49 、C(O)NR 53 R 54 、(C1-C6) alkyl groups and (C1-C6) haloalkyl groups, especially C(O)R 48 、CO2R 49 、C(O)NR 53 R 54 、(C1-C6) alkyl groups and (C1-C6) haloalkyl groups, preferably C(O)R 48 and substituents of (C1-C6) alkyl groups.

[0152] According to a particular embodiment of the present invention, R 4b represents a hydrogen atom, a halogen atom, OR 29 、SR 30 、NR 31R 32 、 a (C1-C6) alkyl, aryl or heterocyclic group, wherein said aryl or heterocyclic group is optionally substituted by one or more, especially one selected from halogen atoms, OR 44 、 SR 45 、 NR 46 R 47 、 C(O)R 48 、 CO2R 49 、 C(O)NR 53 R 54 、 (C1-C6) alkyl and (C1-C6) haloalkyl, especially C(O)R 48 、 CO2R 49 、 C(O)NR 53 R 54 、 (C1-C6) alkyl and (C1-C6) haloalkyl, preferably substituted by substituents of C(O)R 48 and (C1-C6) alkyl.

[0153] According to another particular embodiment of the present invention, R 4b represents a hydrogen atom, a halogen atom, NR 31 R 32 、 a (C1-C6) alkyl, aryl or heterocyclic group, wherein said aryl or heterocyclic group is optionally substituted by one or more, especially one selected from C(O)R 48 、 CO2R 49 、 C(O)NR 53 R 54 、 (C1-C6) alkyl and (C1-C6) haloalkyl, preferably substituted by substituents of C(O)R 48 and (C1-C6) alkyl.

[0154] According to another particular embodiment of the present invention, R 4b represents a hydrogen atom, a halogen atom, (C1-C6) alkyl, OR 29 or NR 31 R 32 , preferably a hydrogen atom, a halogen atom, (C1-C3) alkyl or OR 29 , more preferably a hydrogen atom.

[0155] In a preferred embodiment, R 4b represents a hydrogen atom, a halogen atom or (C1-C6) alkyl, especially a hydrogen atom or (C1-C3) alkyl, preferably a hydrogen atom.

[0156] In the above embodiments, the aryl (which may be part of an aryl-(C1-C6) alkyl) is preferably phenyl.

[0157] In the above embodiments, the heterocyclic group (which may be part of a heterocyclic group-(C1-C6)alkyl) is in particular a 5- or 6-membered, saturated, unsaturated (i.e. non-aromatic) or aromatic, especially saturated monocyclic group, where the atoms of the ring contain one or more, advantageously 1 to 3, heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms.

[0158] In the above embodiments, R 29 to R 32 each independently represents a hydrogen atom, (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl, the aryl (which may be part of the aryl-(C1-C6)alkyl) is preferably phenyl and is optionally substituted by one or more, especially one, substituent selected from halogen atoms, CN, NO2, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6)alkyl and (C1-C6)haloalkyl, advantageously halogen atoms, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6)alkyl and (C1-C6)haloalkyl, especially C(O)R 59 , CO2R 60 , C(O)NR 64 R 65 , (C1-C6)alkyl and (C1-C6)haloalkyl, especially C(O)R 59 , where R 55 to R 65 each independently represents a hydrogen atom, (C1-C6)alkyl or aryl, especially aryl, preferably phenyl. Preferably, R 29 to R 32 each independently represents a hydrogen atom or (C1-C6)alkyl, especially a hydrogen atom.

[0159] In the above embodiments, R44 to R 54 each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group, especially an aryl group, preferably a phenyl group.

[0160] In the above embodiment, the (C1-C6) alkyl group (which may be part of an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group) is preferably a (C1-C3) alkyl group.

[0161] In a particular embodiment of the present invention, R4 is as defined above, and R 4b represents a hydrogen atom, a halogen atom, OR 29 or NR 31 R 32 , where R 29 to R 32 each independently represents a hydrogen atom or a (C1-C6) alkyl group, especially a hydrogen atom, preferably R 4b represents a hydrogen atom, a halogen atom or OR 29 , more preferably a hydrogen atom.

[0162] In a particular embodiment of the present invention, R5 represents a hydrogen atom, a halogen atom, CN, OR 29 , SR 30 , NR 31 R 32 , a (C1-C6) alkyl group, a (C1-C6) haloalkyl group, an aryl group, a heterocyclic group, an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group, wherein the alkyl or haloalkyl group is optionally substituted with one or more substituents selected from OR 40 , SR 41 and NR 42 R 43 , and the aryl or heterocyclic group (which may be part of an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group) is optionally substituted with one or more, especially one, substituents selected from a halogen atom, CN, NO2, OR 44 , SR 45 , NR 46 R 47 , C(O)R 48 , CO2R 49 , OC(O)R 50 , NR 51 C(O)R 52 , C(O)NR 53 R 54 , a (C1-C6) alkyl group and a (C1-C6) haloalkyl group, especially a halogen atom, OR 44 , SR 45 , NR 46 R 47, C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl and (C1-C6) haloalkyl, especially a halogen atom, OR 44 , SR 45 , NR 46 R 47 , (C1-C6) alkyl and (C1-C6) haloalkyl, especially a halogen atom, (C1-C6) alkyl and (C1-C6) haloalkyl, preferably substituted by substituents of (C1-C6) alkyl.

[0163] In the above embodiments, R 29 to R 32 each independently represents a hydrogen atom, (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, the aryl (which may be part of aryl-(C1-C6) alkyl) is preferably phenyl, and optionally substituted by one or more, especially one selected from a halogen atom, CN, NO2, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl, advantageously a halogen atom, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl, especially C(O)R 59 , CO2R 60 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl, especially substituted by substituents of C(O)R 59 , where R 55 to R 65Each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group, especially an aryl group, preferably a phenyl group. Preferably, R 29 to R 32 each independently represents a hydrogen atom or a (C1-C6) alkyl group.

[0164] In another particular embodiment of the present invention, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, a (C1-C6) haloalkyl group, an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group, wherein the alkyl or haloalkyl group is optionally substituted by one or more, especially one selected from OR 40 、SR 41 and NR 42 R 43 substituents, and the aryl or heterocyclic group is optionally substituted by one or more selected from halogen atoms, OR 44 、SR 45 、NR 46 R 47 、(C1-C6) alkyl groups and (C1-C6) haloalkyl groups, especially halogen atoms, (C1-C6) alkyl groups and (C1-C6) haloalkyl groups, preferably (C1-C6) alkyl group substituents.

[0165] In another particular embodiment of the present invention, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, a (C1-C6) haloalkyl group or a heterocyclic-(C1-C6) alkyl group, the alkyl or haloalkyl group is optionally substituted by OR 40 , and the heterocyclic group is optionally substituted by one or more (C1-C6) alkyl groups.

[0166] In a preferred embodiment, R5 represents a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, especially a hydrogen atom or a (C1-C3) alkyl group.

[0167] Preferably, R5 represents a hydrogen atom.

[0168] In the above embodiments, the aryl group (which may be part of an aryl-(C1-C6) alkyl group) is preferably a phenyl group.

[0169] In the above embodiments, the heterocyclic group (which may be part of a heterocyclic-(C1-C6) alkyl group) is particularly 5- or 6-membered, saturated, unsaturated (i.e., non-aromatic) or aromatic, especially a saturated monocyclic group, wherein the atoms of the ring contain one or more, advantageously 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the rest are carbon atoms, such as a piperazinyl group.

[0170] In the above embodiments, R 40 to R 43Each independently represents a hydrogen atom or a (C1-C6) alkyl group, especially a hydrogen atom.

[0171] In the above embodiments, R 44 to R 54 Each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group, especially an aryl group, preferably a phenyl group.

[0172] In the above embodiments, the (C1-C6) alkyl group (which may be part of an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group) is preferably a (C1-C3) alkyl group.

[0173] In a particular embodiment of the present invention, R6 represents a hydrogen atom, a (C1-C3) alkyl group, an aryl-(C1-C3) alkyl group or a -CH2-CH2-O-CH2-CH2-NH2 group, or a (C1-C6) alkylcarbonyl group optionally substituted by one or more substituents selected from OH, SH, NH2, (C1-C3) alkoxy, (C1-C3) thioalkoxy and (C1-C3) alkylamino. Preferably, R6 represents a hydrogen atom, a methyl group, an ethyl group, a benzyl group, a -CH2-CH2-O-CH2-CH2-NH2 group or a (C1-C6) alkylcarbonyl group optionally substituted by one or more substituents selected from OH, NH2 and SH. In particular, R6 represents a hydrogen atom, a -CH2-CH2-O-CH2-CH2-NH2 group or an ethyl group, especially an ethyl group.

[0174] In a preferred embodiment, R6 represents a hydrogen atom, a (C1-C3) alkyl group or a -CH2-CH2-O-CH2-CH2-NH2 group, especially a hydrogen atom or a -CH2-CH2-O-CH2-CH2-NH2 group.

[0175] In the first aspect of the present invention, is X is N, Y is N(R2), Z is C(H), and thus, the inhibitor of the pharmaceutical composition according to the present invention is of the following general formula (I.i):

[0176]

[0177] wherein R2, R4, R 4b , R5 and R6 are as defined in any of the above embodiments.

[0178] In particular, R6 represents a hydrogen atom or a (C1-C6) alkyl group, preferably a (C1-C3) alkyl group, especially a methyl group or an ethyl group. Advantageously, R6 represents an ethyl group.

[0179] In the second aspect of the present invention, is X is N(R1), Y is N, Z is C(R3), thus, the inhibitor of the pharmaceutical composition according to the present invention is of the following general formula (I.ii.a):

[0180]

[0181] wherein R1, R3, R4, R 4b , R5 and R6 are as defined in any of the above embodiments.

[0182] In particular, R6 represents a hydrogen atom, (C1-C3) alkyl (such as ethyl), -CH2-CH2-O-CH2-CH2-NH2 or (C1-C6) alkylcarbonyl optionally substituted with one or more substituents selected from OH, NH2 and SH. Advantageously, R6 represents a hydrogen atom, -CH2-CH2-O-CH2-CH2-NH2 or (C1-C3) alkyl (such as ethyl).

[0183] In the third aspect of the present invention, for X is N(R1), Y is N + (O - ), Z is C(R3), thus, the inhibitor of the pharmaceutical composition according to the present invention is of the following general formula (I.ii.b):

[0184]

[0185] wherein R1, R3, R4, R 4b , R5 and R6 are as defined in any of the above embodiments.

[0186] In particular, R6 represents a hydrogen atom or (C1-C6) alkyl, preferably (C1-C3) alkyl, especially methyl or ethyl. Advantageously, R6 represents ethyl.

[0187] In the fourth aspect of the present invention, for X is N(R1), Y is CH, Z is N, thus, the inhibitor of the pharmaceutical composition according to the present invention is of the following general formula (I.ii.c):

[0188]

[0189] wherein R1, R4, R 4b , R5 and R6 are as defined in any of the above embodiments.

[0190] In particular, R6 represents a hydrogen atom or (C1-C6) alkyl, preferably (C1-C3) alkyl, especially methyl or ethyl. Advantageously, R6 represents ethyl.

[0191] In the fifth aspect of the present invention, For X is N(R1), Y and Z are CH, and thus the inhibitor of the pharmaceutical composition according to the present invention is of the following general formula (I.ii.d):

[0192]

[0193] wherein R1, R4, R 4b , R5 and R6 are as defined in any of the above embodiments.

[0194] In particular, R6 represents a hydrogen atom, (C1-C6) alkyl or aryl-(C1-C6) alkyl, preferably a hydrogen atom, (C1-C3) alkyl or aryl-(C1-C3) alkyl, especially a hydrogen atom, methyl, ethyl or benzyl, advantageously R6 represents a hydrogen atom, methyl or benzyl, typically a hydrogen atom.

[0195] In a preferred embodiment, the inhibitor is a compound of the following general formula (I.iii):

[0196]

[0197] wherein R3, R4, R 4b , R5 and R6 are as defined in any of the above embodiments, and wherein Y' is N or CH.

[0198] In particular:

[0199] - R3, R4, R 4b and R5 each independently represent a hydrogen atom, a halogen atom or (C1-C6) alkyl, especially a hydrogen atom, a halogen atom or (C1-C3) alkyl, preferably a hydrogen atom or a halogen atom, and

[0200] - R6 represents a hydrogen atom, (C1-C3) alkyl or -CH2-CH2-O-CH2-CH2-NH2 group, especially a hydrogen atom or -CH2-CH2-O-CH2-CH2-NH2 group.

[0201] The inhibitor of the pharmaceutical composition according to the present invention may in particular be selected from compounds 1 to 45 shown below and their pharmaceutically acceptable salts and / or solvates.

[0202]

[0203]

[0204]

[0205]

[0206] In particular, the inhibitor of the pharmaceutical composition according to the present invention may be selected from Compound 1, 7, 37, 45 and their pharmaceutically acceptable salts and / or solvates.

[0207] Nigraline and its derivatives

[0208] In a particular embodiment, the inhibitor of the pharmaceutical composition according to the present invention is nigratine or its derivative.

[0209] In this particular embodiment, the inhibitor is preferably a compound of the following general formula (II):

[0210]

[0211] or its pharmaceutically acceptable salts and / or solvates, wherein:

[0212] ■ X1, X2 and X3 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or OH group, or a group selected from OR X , SR X , SO2R X and NR X R Z groups,

[0213] wherein at least one of X1, X2 and X3 represents (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, or a group selected from OR X , SR X , SO2R X and NR X R Z groups, wherein

[0214] R X is (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl,

[0215] R Z is a hydrogen atom or (C1-C6) alkyl, and

[0216] aryl is optionally substituted with one or more substituents selected from halogen atoms, -OR 66 , -NR 67 R 68 , -SR 69 , -S(O)R 70 , -SO2R 71 , -OCOR 72 , -CO2R 73 , -CONR 74 R 75 , -CO2R 76, substitution with groups of nitro (-NO2) and cyano (-CN);

[0217] ■ Y1, Y2 and Y3 each independently represent a hydrogen atom, a (C1-C6) alkyl group, an aryl group, an aryl-(C1-C6) alkyl group or an OH group, or are selected from OR Y , SR Y , SO2R Y and NR Y R' Z groups,

[0218] wherein at least one of Y1, Y2 and Y3 represents a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, or is selected from OR Y , SR Y , SO2R Y and NR Y R’ Z groups, where

[0219] R Y is a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group,

[0220] R’ Z is a hydrogen atom or a (C1-C6) alkyl group, and

[0221] the aryl group is optionally substituted with one or more groups selected from a halogen atom, -OR 66 , -NR 67 R 68 , -SR 69 , -S(O)R 70 , -SO2R 71 , -OCOR 72 , -CO2R 73 , -CONR 74 R 75 , -CO2R 76 , nitro (-NO2) and cyano (-CN);

[0222] and

[0223] ■ R 66 to R 77 each independently is a hydrogen atom or a (C1-C6) alkyl group.

[0224] According to a particular embodiment of the present invention, X1, X2 and X3 each independently represent a hydrogen atom, or are selected from OR X , SR X , SO2R X and NR X R Z groups, wherein at least one of X1, X2 and X3 is not a hydrogen atom.

[0225] In another particular embodiment of the present invention, X1, X2 and X3 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, OH or OR X group, where at least one of X1, X2 and X3 represents OR X group.

[0226] In another particular embodiment of the present invention, X1, X2 and X3 each independently represent a hydrogen atom or OR X group, where at least one of X1, X2 and X3 represents OR X group.

[0227] In the above embodiment, R X is preferably (C1-C6) alkyl, especially (C1-C3) alkyl, such as methyl, ethyl, n-propyl, and more preferably methyl.

[0228] In the above embodiment, the aryl is optionally substituted with one or more groups selected from a halogen atom, -OR 66 , -NR 67 R 68 , -SR 69 , -S(O)R 70 , -SO2R 71 , -OCOR 72 , -CO2R 73 , -CONR 74 R 75 , -CO2R 76 , nitro (-NO2) and cyano (-CN).

[0229] In another embodiment, X1 represents (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, or a group selected from OR X , SR X , SO2R X and NR X R Z where R X is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl, R X is preferably (C1-C6) alkyl, especially (C1-C3) alkyl, such as methyl, ethyl, n-propyl, and more preferably methyl; and X2 and X3 each independently represent a hydrogen atom or (C1-C6) alkyl, preferably a hydrogen atom.

[0230] In another embodiment, X1 represents a group selected from OR X , SR X , SO2R Xand NR X R Z group, wherein R X is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl, and R X is preferably (C1-C6) alkyl, especially (C1-C3) alkyl, such as methyl, ethyl, n-propyl, more preferably methyl; and X2 and X3 each independently represent a hydrogen atom or (C1-C6) alkyl, preferably a hydrogen atom.

[0231] In a preferred embodiment, X1 represents OR X group, and R X is advantageously (C1-C6) alkyl.

[0232] In another preferred embodiment, X2 and X3 each represent a hydrogen atom.

[0233] In another preferred embodiment, X1 represents OR X group, wherein R X is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl, R X is advantageously (C1-C6) alkyl, especially (C1-C3) alkyl, such as methyl, ethyl, n-propyl, more advantageously methyl; and X2 and X3 each independently represent a hydrogen atom or (C1-C6) alkyl, advantageously represent a hydrogen atom.

[0234] In the above embodiments, the aryl is optionally substituted with one or more groups selected from halogen atoms, -OR 66 , -NR 67 R 68 , -SR 69 , -S(O)R 70 , -SO2R 71 , -OCOR 72 , -CO2R 73 , -CONR 74 R 75 , -CO2R 76 , nitro (-NO2) and cyano (-CN).

[0235] According to a particular embodiment of the present invention, Y1, Y2 and Y3 each independently represent a hydrogen atom, or are selected from OR Y , SR Y , SO2R Y and NR Y R’ Z group, wherein at least one of Y1, Y2 and Y3 is not a hydrogen atom.

[0236] In another particular embodiment of the present invention, Y1, Y2 and Y3 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, OH or OR Y group, where at least one of Y1, Y2 and Y3 represents OR Y group.

[0237] In another particular embodiment of the present invention, Y1, Y2 and Y3 each independently represent a hydrogen atom or OR Y group, where at least one of Y1, Y2 and Y3 represents OR Y group.

[0238] In the above embodiments, R Y is preferably -(C1-C6) alkyl-aryl, such as benzyl or -CH3-naphthyl, more preferably benzyl.

[0239] In another embodiment, Y1 represents (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, or is selected from OR Y , SR Y , SO2R Y and NR Y R’ Z groups, where R Y is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl, R Y is preferably -(C1-C6) alkyl-aryl, such as benzyl or -CH3-naphthyl, more preferably benzyl; and Y2 and Y3 each independently represent a hydrogen atom or (C1-C6) alkyl, preferably a hydrogen atom.

[0240] In another embodiment, Y1 represents a group selected from OR Y , SR Y , SO2R Y and NR Y R’ Z groups, where R Y is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl, R Y is preferably -(C1-C6) alkyl-aryl, such as benzyl or -CH3-naphthyl, more preferably benzyl; and Y2 and Y3 each independently represent a hydrogen atom or (C1-C6) alkyl, preferably a hydrogen atom.

[0241] In a preferred embodiment, Y1 represents OR Y group, where R Y is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl, R YAdvantageously, it is -(C1-C6)alkyl-aryl, such as benzyl or -CH3-naphthyl, more preferably benzyl; and Y2 and Y3 each independently represent a hydrogen atom or (C1-C6)alkyl, advantageously represent a hydrogen atom.

[0242] In the above embodiment, the aryl is optionally substituted with one or more groups selected from a halogen atom, -OR 66 , -NR 67 R 68 , -SR 69 , -S(O)R 70 , -SO2R 71 , -OCOR 72 , -CO2R 73 , -CONR 74 R 75 , -CO2R 76 , nitro (-NO2) and cyano (-CN).

[0243] According to a particular embodiment of the invention:

[0244] ■ X1, X2 and X3 each independently represent a hydrogen atom, (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl or OR X group, where at least one of X1, X2 and X3 is not a hydrogen atom, and where R X is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl; and

[0245] ■ Y1, Y2 and Y3 each independently represent a hydrogen atom, (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl, OH or OR Y group, where at least one of Y1, Y2 and Y3 represents (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl or OR y group, where R Y is selected from (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl.

[0246] According to another particular embodiment:

[0247] ■ X1 represents (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl or OR X group, where R X is (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl;

[0248] ■ X2 and X3 each independently represent a hydrogen atom or (C1-C6)alkyl; and

[0249] ■ Y1, Y2 and Y3 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, OH or OR Y group, wherein at least one of Y1, Y2 and Y3 represents (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or OR Y group, wherein R Y is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl.

[0250] According to another particular embodiment:

[0251] ■ X1 represents OR X group, wherein R X is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl, R X is preferably (C1-C6) alkyl, especially (C1-C3) alkyl, such as methyl, ethyl, n-propyl, more preferably methyl;

[0252] ■ X2 and X3 each independently represent a hydrogen atom or (C1-C6) alkyl, preferably represent a hydrogen atom;

[0253] ■ Y1 represents OR Y group, wherein R Y is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl, R Y is preferably -(C1-C6) alkyl-aryl, such as benzyl or -CH3-naphthyl, more preferably benzyl; and

[0254] ■ Y2 and Y3 each independently represent a hydrogen atom or (C1-C6) alkyl, preferably represent a hydrogen atom.

[0255] According to a preferred embodiment, the inhibitor of the pharmaceutical composition according to the present invention is of the following formula (II.i):

[0256]

[0257] or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

[0258] R X represents (C1-C6) alkyl, especially (C1-C3) alkyl, such as methyl, ethyl, n-propyl, more preferably represents methyl, and

[0259] R Y represents aryl-(C1-C6) alkyl, such as benzyl or -CH3-naphthyl, more preferably benzyl.

[0260] The inhibitor of the pharmaceutical composition according to the present invention may be particularly selected from compounds 46 to 49 represented below, and their pharmaceutically acceptable salts and / or solvates.

[0261]

[0262] In particular, the inhibitor of the pharmaceutical composition according to the present invention is compound 46 or its pharmaceutically acceptable salt and / or solvate.

[0263] In particular, the inhibitor of the pharmaceutical composition according to the present invention may be selected from compounds 1, 7, 37, 45, 46 and their pharmaceutically acceptable salts and / or solvates.

[0264] Pharmaceutical composition

[0265] The pharmaceutical composition according to the present invention comprises a combination of N-acetylcysteine (NAC) or its medicinal salt or derivative and at least one inhibitor of regulated necrotic cell death (such as necroptosis and / or ferroptosis).

[0266] In a particular embodiment, the inhibitor of regulated necrotic cell death is a ferroptosis inhibitor, preferably an inhibitor of ferroptosis and necroptosis. The inhibitor may particularly be silybin, nigralutin or their derivatives, as defined above.

[0267] In this particular embodiment, the NAC / inhibitor molar ratio is advantageously from 500:1 to 1:1, preferably from 200:1 to 1:1, especially from 100:1 to 1:1, particularly from 50:1 to 1:1, for example from 20:1 to 1:1.

[0268] In a preferred embodiment, the inhibitor of regulated necrotic cell death is silybin (compound 7), and the NAC / inhibitor weight ratio is advantageously from 100:1 to 1:1, especially from 50:1 to 1:1, particularly from 30:1 to 1:1, for example 20:1.

[0269] In a particular embodiment, the N-acetylcysteine amide (NACA) / inhibitor molar ratio is advantageously from 200:1 to 1:1, preferably from 100:1 to 1:1, especially from 50:1 to 1:1, particularly from 30:1 to 1:1, for example from 20:1 to 1:1.

[0270] In a particular embodiment, the N-acetylcysteine ethyl ester (NACET) / inhibitor molar ratio is advantageously from 500:1 to 1:1, preferably from 200:1 to 1:1, especially from 100:1 to 1:1, particularly from 50:1 to 1:1, for example from 20:1 to 1:1.

[0271] The pharmaceutical composition according to the invention may further comprise at least one pharmaceutically acceptable excipient.

[0272] Within the framework of the present invention, the term "pharmaceutically acceptable excipient" is intended to mean a pharmaceutically acceptable substance as defined above, which is formulated together with the active ingredient of the pharmaceutical composition for the purposes of long-term stability, bulking up solid dosage forms containing a small amount of active ingredient, improving the therapeutic effect of the active ingredient in the final dosage form (such as promoting drug absorption, reducing viscosity or enhancing solubility), or enhancing the taste or appearance of the pharmaceutical composition. A person skilled in the art can readily and advisedly select a suitable excipient, particularly taking into account the dosage form and the route of administration.

[0273] The pharmaceutical composition according to the invention may be formulated for oral administration, topical administration or injection in particular, wherein the composition is intended for mammals, including humans.

[0274] The pharmaceutical composition may be administered orally in solid or liquid (solution or suspension) form.

[0275] The solid composition may be in the form of tablets, gelatin capsules, powders, granules, etc. When preparing the solid composition in tablet form, the active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. The tablets may be coated with sucrose or other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity and that they continuously release a predetermined amount of the active ingredient. In powders or granules, the active ingredient may be mixed or granulated with a dispersing agent, wetting agent or suspending agent and a flavoring or sweetening agent. In gelatin capsules, the active ingredient may be introduced into soft or hard gelatin capsules in the form of a powder or granules (as mentioned above) or in the form of a liquid composition (as mentioned below).

[0276] The liquid composition may contain the active ingredient in a solvent such as water, as well as a sweetening agent, flavor enhancer or suitable coloring agent. The liquid composition may also be obtained by suspending or dissolving powders or granules as described above in a liquid such as water, fruit juice, milk, etc. It may be, for example, a syrup or an elixir.

[0277] For topical administration, the pharmaceutical composition may be in any form capable of being applied to the skin or mucous membrane surface: creams, gels, ointments, patches, etc.

[0278] For administration by injection, an aqueous suspension, an isotonic saline solution or a sterile injection solution containing a pharmacologically compatible dispersing agent and / or wetting agent is used.

[0279] The inhibitor of the pharmaceutical composition can be used at a dose of 0.01 mg to 2,000 mg per day, administered once a day as a single dose or in multiple doses throughout the day, for example, twice a day at equal doses. The dose administered per day is advantageously 5 mg to 500 mg, even more advantageously 10 mg to 200 mg. The effective dose of the inhibitor can be determined by those skilled in the art through routine tests, including evaluating the effect of the administration of the inhibitor on the disease for which prevention and / or treatment is sought by said administration. For example, these tests can be carried out by analyzing the quantitative and qualitative effects of administering different amounts of the inhibitor on a set of marker (biological and / or clinical) characteristics of the disease, particularly biological samples from humans. In addition, as is well known to those skilled in the art, the appropriate dose and related dosing regimen for treating a given disease in a given patient will depend on a variety of other factors, such as the stage of the disease and the physical and medical condition of the patient.

[0280] N-acetylcysteine (NAC), N-acetylcysteine amide, or N-acetylcysteine ethyl ester or N-acetylcysteine methyl ester can be used in a daily dose range of 50 mg to 5,000 mg, administered once a day as a single dose or in multiple doses throughout the day, for example, twice or three times a day at equal doses. The dose administered daily is advantageously 100 mg to 2,000 mg, even more advantageously 500 mg to 1,500 mg.

[0281] Application

[0282] The present invention also relates to a pharmaceutical composition as defined above for preventing and / or treating diseases associated with the regulation of necrotic cell death (such as necroptosis and / or ferroptosis).

[0283] In a particular embodiment, the disease is associated with ferroptosis, especially with ferroptosis and necroptosis.

[0284] Diseases associated with ferroptosis can be myocardial ischemia-reperfusion injury, especially after myocardial necrosis occurring in arterial ligation or myocardial infarction; cardiomyopathy, especially doxorubicin-induced cardiomyopathy; stroke, especially ischemic stroke or hemorrhagic stroke; cardiovascular diseases such as aortic dissection; traumatic brain injury; spinal cord contusion; neurodegenerative diseases, especially chronic neurodegenerative diseases, more especially Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease), multiple sclerosis, Friedreich's ataxia, and dementia; vision loss, especially vision loss due to retinal detachment or cataract; retinal diseases, especially Stargardt's disease or age-related macular degeneration (AMD), especially dry AMD; chronic liver diseases, especially non-alcoholic steatohepatitis (NASH), chronic infections such as hepatitis and alcoholic liver disease; acute liver injury and acute liver failure, especially caused by drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, caused by ischemia-reperfusion injury induced by sepsis or hemorrhagic shock, caused by fulminant viral hepatitis, caused by autoimmunity, or caused by alcohol intake; skin inflammatory diseases such as psoriasis; toxic epidermal necrolysis (Lyell syndrome); acute kidney injury (AKI) or acute renal failure, such as oxalate, folic acid (FA), and cisplatin-induced AKI, renal ischemia-reperfusion injury, and acute tubular necrosis; chronic obstructive pulmonary disease (COPD); bronchial asthma; lung injury caused by bacterial infection, especially caused by Pseudomonas aeruginosa or Mycobacterium tuberculosis infection; pulmonary fibrosis, such as radiation-induced lung fibrosis (RILF) and paraquat-induced lung injury; necrotizing enterocolitis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; hemochromatosis; β-thalassemia; hemolytic diseases; cytokine storm during viral infection; radiation-induced necrosis; rheumatoid arthritis; type I diabetes; obesity-related insulin resistance; epilepsy, including epilepsy associated with mitochondrial diseases and refractory epilepsy; and pathologies associated with stress-induced premature tissue aging, such as atherosclerosis, hypertension, and type II diabetes.

[0285] Preferably, the ferroptosis-related diseases are selected from myocardial ischemia-reperfusion injury, especially myocardial necrosis occurring during arterial ligation or myocardial infarction; stroke, especially ischemic stroke or hemorrhagic stroke; traumatic brain injury; neurodegenerative diseases, especially chronic neurodegenerative diseases, more especially Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease) and multiple sclerosis; vision loss, especially vision loss due to retinal detachment or cataract; retinal diseases, especially Stargardt's disease or age-related macular degeneration (AMD), especially dry AMD; chronic liver diseases, especially non-alcoholic steatohepatitis (NASH); acute liver injury and acute liver failure, especially caused by drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or ischemic reperfusion injury induced by sepsis or hemorrhagic shock; and acute kidney injury (AKI) or acute renal failure, such as folic acid (FA)-induced AKI, cisplatin-induced AKI, renal ischemic reperfusion injury and acute tubular necrosis.

[0286] In particular, the ferroptosis-related diseases are selected from neurodegenerative diseases, especially chronic neurodegenerative diseases, more especially Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease) and multiple sclerosis; vision loss, especially vision loss due to retinal detachment or cataract; retinal diseases, especially Stargardt's disease or age-related macular degeneration (AMD), especially dry AMD; acute liver injury and acute liver failure, especially caused by drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or ischemic reperfusion injury induced by sepsis or hemorrhagic shock; and acute kidney injury (AKI) or acute renal failure, such as folic acid (FA)-induced AKI and cisplatin-induced AKI.

[0287] In particular, the diseases associated with regulated necrotic cell death are diseases associated with ferroptosis and necroptosis, and may be selected from: brain diseases or disorders, including neurodegenerative diseases or disorders (especially Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease), dementia, Friedreich's ataxia, and multiple sclerosis), stroke (especially ischemic stroke and hemorrhagic stroke), traumatic brain injury, epilepsy; eye diseases or disorders, including retinopathy, degenerative eye diseases or disorders, such as retinal degenerative diseases or disorders (especially Stargardt's disease and age-related macular degeneration (AMD)); infectious diseases, including diseases caused by viruses or bacteria (including lung injury caused by bacterial infection, cytokine storm during viral infection); autoimmune diseases, including psoriasis and rheumatoid arthritis; inflammatory diseases, including chronic liver disease (especially non-alcoholic steatohepatitis (NASH)), toxic epidermal necrolysis (Lyell syndrome), bronchial asthma, pulmonary fibrosis, necrotizing enterocolitis, inflammatory bowel disease (such as Crohn's disease), type I and type II diabetes, hemochromatosis, atherosclerosis, obesity-related insulin resistance; pathologies associated with stress-induced premature tissue aging, including age-related diseases, such as atherosclerosis, hypertension, and type II diabetes; liver injury, including acute liver failure (especially caused by drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or ischemic reperfusion injury induced by sepsis or hemorrhagic shock) and chronic liver disease; hypertension; hemochromatosis; hemolytic diseases; ischemic diseases affecting the heart, brain, or kidneys; kidney injury, including acute kidney injury (AKI, also known as acute renal failure (ARF)), such as folic acid (FA)-induced AKI, cisplatin-induced AKI, renal ischemic reperfusion injury, acute tubular necrosis, liver fibrosis; heart injury, including myocardial infarction, myocardial ischemic reperfusion injury, especially occurring after myocardial necrosis during arterial ligation or myocardial infarction; aortic aneurysm; pancreatitis; radiation-induced necrosis; chronic obstructive pulmonary disease, acute respiratory distress disorder; transplantation-related diseases; cancer, including liver cancer (especially hepatocellular carcinoma), eye cancer, gastric cancer, colorectal cancer, pancreatic cancer, brain cancer, lung cancer, adrenocortical carcinoma, kidney cancer (especially clear cell renal cell carcinoma).

[0288] More particularly, the diseases associated with regulated necrotic cell death are diseases associated with ferroptosis and necroptosis, and may be selected from: brain diseases or disorders, including neurodegenerative diseases or disorders, stroke, traumatic brain injury, epilepsy; eye 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 injury, including acute liver failure and chronic liver disease; hypertension; hemochromatosis; hemolytic diseases; ischemic diseases affecting the heart, brain or kidneys; kidney injury, including acute kidney injury, renal ischemia-reperfusion injury, acute tubular necrosis, liver fibrosis; heart injury; aortic aneurysm; pancreatitis; radiation-induced necrosis; chronic obstructive pulmonary disease, acute respiratory distress disorder; diseases associated with transplantation; cancer, including liver cancer, eye cancer, brain cancer, kidney cancer.

[0289] In another embodiment, the diseases associated with regulated necrotic cell death are diseases associated with ferroptosis and necroptosis, and may be selected from: brain diseases or disorders, including neurodegenerative diseases or disorders, stroke, traumatic brain injury; eye diseases or disorders, including retinopathy; liver diseases or disorders, including acute liver injury, such as acute liver failure; kidney diseases or disorders, including acute kidney injury; diseases associated with transplantation; cancer, including liver cancer (such as hepatocellular carcinoma), eye cancer, kidney cancer (such as clear cell renal cell carcinoma).

[0290] The diseases associated with ferroptosis and necroptosis may be acute liver injury and acute liver failure, acute renal failure or acute kidney injury (AKI), acute tubular necrosis, radiation-induced necrosis, ischemic diseases 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 (atrophic) age-related macular degeneration (AMD), hemochromatosis, necrotizing enterocolitis, non-alcoholic steatohepatitis (NASH), Friedreich's ataxia, inflammatory bowel diseases such as Crohn's disease, toxic epidermal necrolysis (Lyell syndrome), type I diabetes and diseases associated with stress-induced premature tissue aging, including age-related diseases such as atherosclerosis, hypertension and type II diabetes.

[0291] The present invention also relates to a method for inhibiting regulated necrotic cell death, particularly for inhibiting ferroptosis, more particularly for inhibiting ferroptosis and necroptosis, which comprises administering to a human in need an effective dose of a pharmaceutical composition as defined above. In particular, the present invention relates to a method for preventing and / or treating diseases associated with regulated necrotic cell death such as necroptosis and / or ferroptosis, which comprises administering to a human in need an effective dose of a pharmaceutical composition as defined above.

[0292] In a particular embodiment, the disease is associated with ferroptosis, in particular with ferroptosis and necroptosis, and is as defined above.

[0293] The invention also relates to a method for inhibiting lysosomal permeabilization and / or lysosome-dependent cell death, particularly in a subject suffering from a neurodegenerative disease, which comprises administering to a person in need an effective dose of a pharmaceutical composition as defined above.

[0294] The invention also relates to the use of a pharmaceutical composition as defined above in the preparation of a medicament, said medicament being particularly useful for the prevention and / or treatment of diseases associated with regulated necrotic cell death such as necroptosis and / or ferroptosis. In a particular embodiment, the disease is associated with ferroptosis, in particular with ferroptosis and necroptosis, and is as defined above.

[0295] The invention also relates to the use of a pharmaceutical composition as defined above for the ex vivo preservation and / or protection of biomaterials, such as cells, tissues, body fluids and organs, particularly for non-therapeutic use.

[0296] In the context of the present invention, "ex vivo" means outside the organism from which the biomaterial is derived.

[0297] As used herein, the expression "preserving and / or protecting a biomaterial" means increasing the survival rate of said biomaterial such that it can be stored for a long time. It will be clear from the present specification that this increase in survival rate is achieved by preventing ferroptosis-induced cell death in said biomaterial.

[0298] Thus, the invention also relates to the ex vivo use of a pharmaceutical composition as defined above as an agent for inhibiting regulated necrotic cell death such as necroptosis and / or ferroptosis in a biomaterial.

[0299] The invention also relates to a method for inhibiting regulated necrotic cell death such as necroptosis and / or ferroptosis in a biomaterial, which comprises exposing said biomaterial to a pharmaceutical composition as defined above.

[0300] In the above aspects of the present invention, the biomaterial is preferably a cell sample or a tissue sample.

[0301] The active ingredients of the pharmaceutical composition according to the invention, namely N-acetylcysteine or a pharmaceutically acceptable salt or derivative thereof as defined above and an inhibitor of regulated necrotic cell death, particularly an inhibitor of ferroptosis, preferably an inhibitor of ferroptosis and necroptosis, can be administered to a person in need simultaneously, separately or sequentially, particularly for inhibiting regulated necrotic cell death, such as necroptosis and / or ferroptosis, more particularly for the prevention and / or treatment of diseases associated with regulated necrotic cell death such as necroptosis and / or ferroptosis.

[0302] Accordingly, the present invention also relates to a pharmaceutical composition comprising:

[0303] - N-acetylcysteine or a pharmaceutically acceptable salt or derivative thereof, and

[0304] - at least one inhibitor of regulated necrotic cell death, in particular at least one ferroptosis inhibitor, preferably at least one ferroptosis and necroptosis inhibitor,

[0305] as a combined product for simultaneous, separate or sequential administration, in particular for inhibiting regulated necrotic cell death, such as necroptosis and / or ferroptosis, and more particularly for preventing and / or treating diseases associated with regulated necrotic cell death, such as necroptosis and / or ferroptosis.

[0306] The present invention also relates to the use of a pharmaceutical composition as defined above as a therapeutically active ingredient in a combined therapy or an additional treatment regimen for a person in need, in particular for inhibiting regulated necrotic cell death, such as necroptosis and / or ferroptosis, and more particularly for preventing and / or treating diseases associated with regulated necrotic cell death, such as necroptosis and / or ferroptosis. The use of a pharmaceutical composition as defined above as a therapeutically active ingredient in a combined therapy or an additional treatment regimen for a patient in need is also provided.

[0307] In some embodiments, the pharmaceutical composition of the present invention is administered to a person in need simultaneously, separately or sequentially with a third active ingredient.

[0308] The pharmaceutical composition as defined above may be provided in the form of a combined product comprising an additional product, in particular a third active ingredient, particularly for simultaneous, separate or sequential administration.

[0309] The third active ingredient is generally related to the disease to be prevented and / or treated.

[0310] The present invention also relates to a kit comprising a pharmaceutical composition as defined above and a delivery device (a device for administering the composition), particularly suitable for parenteral administration, enteral administration or topical administration. Examples of delivery devices include, but are not limited to, autoinjectors, in particular multi-chamber syringes, transdermal patches, prefilled syringes or needleless devices. BRIEF DESCRIPTION OF THE DRAWINGS

[0311] Figure 1 Represents the maximum viability of ARPE19 cells treated with sodium iodate in the presence of NAC, compound 45, or under combined treatment.

[0312] Figure 2Represents the maximum viability of ARPE19 cells treated with sodium iodate in the presence of NAC, compound 46, or in combination.

[0313] Figure 3 Represents the maximum viability of SH-SY5Y cells treated with erastin in the presence of NAC, compound 46, or in combination.

[0314] Figure 4 Represents the maximum viability of SH-SY5Y cells treated with erastin in the presence of NAC, compound 1, or in combination.

[0315] Figure 5 Represents the maximum viability of HT-22 cells treated with erastin in the presence of NAC, compound 7, or in combination.

[0316] Figure 6 Represents the maximum viability of HT-22 cells treated with erastin in the presence of NAC, compound 37, or in combination.

[0317] Figure 7 Represents the maximum viability of HT-22 cells treated with erastin in the presence of NAC, compound 1, or in combination.

[0318] Figure 8 Shows the quantified alanine transferase (ALT) concentration (UI / L) in mouse plasma of 8 groups of mice treated with NAC, increasing doses of Compound 7, or a combination after APAP intoxication.

[0319] Figure 9a , Figure 9b and Figure 9c The synergistic effect of combined treatment of NAC and compound 7 on the in vivo mouse model of APAP intoxication is shown; ALT values ​​are reported as the percentage of the maximum ALT reduction obtained in the plasma of mice treated with 400 mg / kg APAP alone; control mice (Ctrl) were mice not injected with APAP.

[0320] Figure 10 Represents the maximum viability of LLC-PK1 cells treated with RSL3 in the presence of NAC, compound 7, or in combination.

[0321] Figure 11 Represents the maximum viability of LLC-PK1 cells treated with RSL3 in the presence of NAC, compound 1, or in combination.

[0322] Figure 12 Represents the maximum viability of LLC-PK1 cells treated with RSL3 in the presence of NAC, compound 46, or in combination.

[0323] Figure 13 Represents the maximum viability of ARPE19 cells treated with sodium iodate in the presence of N-acetylcysteine amide (NACA), compound 46, or under combined treatment.

[0324] Figure 14 Represents the maximum viability of SH-SY5Y cells treated with erastin in the presence of N-acetylcysteine ethyl ester, compound 7, or under combined treatment.

[0325] Figure 15 Represents the maximum viability of SH-SY5Y cells treated with erastin in the presence of N-acetylcysteine ethyl ester, compound 1, or under combined treatment.

[0326] Figure 16 Represents the maximum viability of SH-SY5Y cells treated with erastin in the presence of N-acetylcysteine ethyl ester, compound 46, or under combined treatment. Detailed implementation mode

[0327] Examples

[0328] The following abbreviations commonly used in the art were used in the following examples:

[0329]

[0330]

[0331] I. In vitro cell model of disease

[0332] The synergistic effect of the combination of NAC and a regulated necrosis inhibitor was evaluated in vitro in a cytopathology model. Regulated necrosis is associated with various organism pathologies or dysfunctions, especially liver injury related to drug toxicity. Regulated necrosis is also associated with the pathophysiology of degenerative diseases (such as retinal degeneration) or neurodegenerative diseases (such as Parkinson's disease), and is also associated with nervous system diseases related to excitotoxicity (such as trauma or stroke).

[0333] I.1. Materials and methods

[0334] - Cell culture

[0335] SH-SY5Y neuronal cells (human neuroblastoma cell line) and HT-22 cells (mouse hippocampal neuronal cell line) were maintained in standard DMEM (GIBCO) supplemented with GlutaMAX medium containing 10% fetal bovine serum (GIBCO) in the presence of 37 °C and 5% CO2.

[0336] ARPE-19 cells (human retinal pigment epithelial cell line) were cultured in standard DMEM / F12 medium (GIBCO) supplemented with 10% fetal bovine serum (GIBCO) in the presence of 37 °C and 5% CO2.

[0337] LLC-PK1 cells (porcine kidney epithelial cells) were cultured in DMEM / F12 (GIBCO) supplemented with 10% fetal bovine serum (GIBCO) in the presence of 37 °C and 5% CO2.

[0338] - Cell viability assay

[0339] SH-SY5Y, LLC-PK1, ARPE-19, and HT22 cells were seeded into 96-well plates at a density of 10,000 or 5,000 cells per well, respectively, and then incubated overnight. The cells were treated with 10 μM (for SH-SY5Y cells) or 0.5 μM (for HT22 cells) erastin or 2 μM of RSL3 (for LLC-PK1) or 10 mM sodium iodate (for ARPE-19 cells) for 24 hours.

[0340] Erastin and RSL3 were purchased from Selleck Chemical, and sodium iodate was purchased from Sigma Aldrich. Cell viability was evaluated by the MTS assay (CellTiter AQueous Non-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 live cells to form a colored formazan product. After treatment, the cells were incubated with MTS at 37 °C and 5% CO2 for 3 hours. Absorbance was measured at 490 and 630 nm using a microplate reader, and the percentage of viability was calculated by dividing the absorbance of the test compound by the absorbance of DMSO-treated cells (control).

[0341] N-acetylcysteine amide (NACA) was purchased from MedChemExpress (reference number: HY-110256).

[0342] N-acetylcysteine ethyl ester was purchased from MedChemExpress (reference number: HY-134495).

[0343] - Analysis of molecular synergy

[0344] Cells (HT-22, SHSY-5Y, LLC-PK1, and ARPE 19) were seeded in 96-well plates in their respective media overnight. On the next day, the cells were treated with NAC or its derivatives (including NACA or N-ethyl cysteine acetate (Compound A)), inhibitor compound (Compound B), or a combination of the two compounds. The analysis of the effect of the combination of Compound A (NAC or its derivatives (including NACA and N-ethyl cysteine acetate)) and another Compound B was based on the Bliss independence model. In this method, the effects of the compounds alone (EA or EB) or in combination are expressed as probabilities (0 ≤ E ≤ 1). The combined effect of the compounds is defined as:

[0345] EAB = EA + EB(1 - EA)

[0346] where EA and EB represent the effects of Compound A and Compound B, respectively, and EAB represents the combined effect of the combination of A and B (the expected effect on the histogram). The calculation index CI is calculated as follows: CI = (EA + EB – EA*EB) / EAB

[0347] where, when CI is below, above, or equal to 1, CI has a synergistic, antagonistic, or additive effect, respectively [Duarte et al., Current Research in Pharmacology and Drug Discovery, 2022].

[0348] I.2. Models of Ocular Diseases

[0349] Age-related macular degeneration or AMD is characterized by vision loss due to the degeneration of central retinal cells (called the macula). Oxidative stress has been shown to play an important role in retinal cell loss by initiating 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 human ARPE-19 cells (a retinal pigment epithelial cell line) 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].

[0350] This experiment tested Compound 45 ( Figure 1 ) and Compound 46 ( Figure 2 ) alone and their combination with NAC. Figure 1 (10 μM Compound 45; 100 μM NAC) and Figure 2(5 μM Compound 46; 50 μM NAC) showed a significant effect of the test molecule alone and a synergistic effect when combined with NAC (n = 2, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001).

[0351] This experiment tested Compound 46 alone ( Figure 13 ) and its combination with NACA (N-acetylcysteine amide). Figure 13 (10 μM Compound 46; 125 μM NACA) showed a significant effect of the test molecule Compound 46 alone and a synergistic effect when combined with NACA at the tested dose combination (n = 2, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001).

[0352] I.3. Neurotoxicity and Excitotoxicity Models

[0353] The target bioactivity was confirmed in the following two neuronal cell lines: (i) SH-SY5Y, a human neuroblastoma cell line ( Figures 3 - 4 ) and (ii) HT22, a mouse hippocampal cell line ( Figures 5 - 7 ). Erastin induced ferroptosis in both cell lines [Dixon et al., Cell, 2012, 149(5), 1060 - 1072]. Erastin is a well-characterized ferroptosis inducer and a molecular tool for studying neuronal pathology [Lewerenz et al., Front. Neurosci., 2018, 12:214].

[0354] Figures 3 to 7 The results summarized in

[0355] clearly showed the efficacy of the test compounds against these neurotoxicity models and their synergistic efficacy when combined with NAC. Figure 3 In the presence of the ferroptosis inducer (erastin), Compound 46 ( Figure 4 ) and 1 ( Figure 3 (25 μM Compound 46; 100 μM NAC) and Figure 4 (1 μM Compound 1; 100 μM NAC) showed a significant effect of the test molecule alone and a synergistic effect when combined with NAC at the tested dose (n = 2, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001). In the presence of the ferroptosis inducer (erastin), Compound 7, 37, or 1 ( Figure 5 、Figure 6 and Figure 7 ) Treat HT22 cells with or without combination with NAC. Figure 5 (25 μM compound 7; 100 μM NAC), Figure 6 (50 μM compound 37; 100 μM NAC) and Figure 7 (5 μM compound 1; 100 μM NAC) showed significant effects of the individual test molecules and their synergistic effects when combined with NAC at the tested doses (n = 2, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001).

[0356] The target biological activities of NAC derivatives were also confirmed in the neuronal cell line SH-SY5Y. Figures 14 to 16 The obtained results summarized in

[0357] showed clearly the efficacy of the test compounds in this neurotoxicity model and their synergistic efficacy when combined with ethyl N-acetylcysteine. Figure 14 ) with or without combination with ethyl N-acetylcysteine was added to SH-SY5Y cells in the presence of the ferroptosis inducer (erastin). Figure 14 (10 μM compound 7; 100 μM ethyl N-acetylcysteine) showed significant effects of the individual test molecule and its synergistic effect when combined with NACET (n = 2, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001).

[0358] In the presence of the ferroptosis inducer (erastin), compound 1 ( Figure 15 ) with or without combination with ethyl N-acetylcysteine was added to SH-SY5Y cells. Figure 15 (2.5 μM compound 1; 100 μM ethyl N-acetylcysteine) showed significant effects of the individual test molecule and its synergistic effect when combined with ethyl N-acetylcysteine (n = 2, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001).

[0359] In the presence of the ferroptosis inducer (erastin), compound 46 ( Figure 16 ) with or without combination with ethyl N-acetylcysteine was added to SH-SY5Y cells. Figure 16 (25 μM compound 46; 100 μM ethyl N-acetylcysteine) showed significant effects of the individual test molecule and its synergistic effect when combined with ethyl N-acetylcysteine (n = 2, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001).

[0360] I.4. Porcine Kidney Epithelial Cell Model

[0361] This experiment tested compound 7 alone ( Figure 10 ), compound 1 ( Figure 11 ), and compound 46 ( Figure 12 ) and their combinations with NAC. Figure 10 (2.5 μM compound 7; 500 μM NAC), Figure 11 (1 μM compound 1; 500 μM NAC), and Figure 12 (25 μM compound 46; 500 μM NAC) showed significant effects of the individual test molecules and their synergistic effects when combined with NAC (n = 2, mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001).

[0362] II. In vivo pathological model

[0363] II.1. Materials and Methods

[0364] All animal experiments were conducted in accordance with French law and the animal welfare guidelines of the institution. This project was approved by the "Regional Ethics and Animal Experimentation Committee" (Comité Régional d’Ethique et d’Expérimentation Animal, CREAA), authorization APAFIS#32246 - 2021061616397414v7, granted by the "Ministry of Higher Education, Research and Innovation" (Ministère de l’Enseignement Supérieur de la Recherche et de l’Innovation).

[0365] Nine-week-old C57Bl / 6J male mice were purchased from Janvier Labs (Le Genest St Isle, France). After one week of acclimation in the animal house, the mice were fasted overnight before the experiment. Acetaminophen (APAP) was purchased from Sigma-Aldrich (A70-85-100g, lot #SCLF8273) and diluted to 20 mg / mL in PBS (pre-warmed to 45 °C). Acetaminophen toxicity was induced in the mice by intraperitoneal (i.p.) injection of APAP (400 mg / kg). One hour after the injection of APAP, the mice were treated by intraperitoneal injection of inhibitors. N-acetylcysteine (NAC, A9165-25g, Sigma-Aldrich, lot #SLCJ1628, reference treatment for acetaminophen toxicity) 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 or 10 mg / kg) or in combination with NAC (200 mg / kg). Two groups of control mice were set up: the first group was injected with PBS Tween 80 5% (Tween 80 5%) via the i.p. route, and the second group was treated with APAP and PBS Tween 80 5% (APAP-Tween 80 5%) was administered i.p. one hour after APAP treatment. The mice were sacrificed eight hours after the injection of APAP. Blood and liver were collected.

[0366] - Biochemical parameters

[0367] The plasma level of serum alanine aminotransferase (ALT) was measured using an Olympus AU2700 automated analyzer (Olympus Optical) according to the main reference procedure of the International Federation of Clinical Chemistry and Laboratory Medicine.

[0368] - Histological analysis

[0369] Liver tissue fragments were fixed with 4% paraformaldehyde and embedded in paraffin. 4-μm sections were taken for hematoxylin-eosin (H&E) staining. All paraffin-embedded liver tissue sections were scanned using a digital slide scanner (Nanozoomer 2.0-RS, Hamamatsu Photonics, Massy, France) and the files were analyzed using NDPviewer 2.5 software (Hamamatsu).

[0370] -Statistical analysis

[0371] Results are expressed as mean ± SEM. The mean differences between the two experimental groups were evaluated using the non-parametric Mann-Whitney U test. All statistical analyses were performed using GraphPad Prism5 software. The calculated P values were integrated on the histograms and graphs. Significance was shown as follows: $P < 0.05$, $$P < 0.01$, $$$P < 0.001 and $$$$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).

[0372] II.2. Results

[0373] Nine groups of mice were studied:

[0374] - Tween 80 5%, n = 15

[0375] - APAP (400 mg / kg) + Tween 80 5%, n = 31

[0376] - APAP (400 mg / kg) + NAC (200 mg / kg), n = 15

[0377] - APAP (400 mg / kg) + compound 7 (2.5 mg / kg), n = 23

[0378] - APAP (400 mg / kg) + compound 7 (5 mg / kg), n = 21

[0379] - APAP (400 mg / kg) + compound 7 (10 mg / kg), n = 21

[0380] - APAP (400 mg / kg) + compound 7 (2.5 mg / kg) + (NAC 200 mg / kg), n = 9

[0381] - APAP (400 mg / kg) + compound 7 (5 mg / kg) + NAC (200 mg / kg), n = 9

[0382] - APAP (400 mg / kg) + compound 7 (10 mg / kg) + NAC (200 mg / kg), n = 13

[0383] APAP overdose leads to liver injury and the release of alanine aminotransferase (ALT) in mouse plasma. Mice treated with APAP (400 mg / kg) for 8 hours showed significantly elevated plasma ALT levels (about 3000 IU / L) compared to control mice injected with only 5% Tween 80 (about 100 IU / L).

[0384] N-acetylcysteine (NAC) is an effective antidote for reducing liver injury in patients poisoned with APAP. Mice treated with NAC (200 mg / kg) one hour after injection of APAP (400 mg / kg) partially alleviated APAP toxicity compared to mice treated with APAP (about 3000 IU / L), as shown by a significant decrease in plasma ALT levels (about 1300 IU / L). Treatment with compound 7 one hour after APAP was also effective in protecting the mouse liver from APAP toxicity, which decreased plasma ALT levels in a dose-dependent manner, with the best effect at a dose of compound 7 (10 mg / kg) (about 1000 IU / L)( Figure 8 ).

[0385] Notably, treatment with a combination of NAC (200 mg / kg) and increasing concentrations of compound 7 (2.5, 5, or 10 mg / kg) had a better synergistic protective effect against APAP toxicity compared to treatment with either NAC alone or compound 7 alone( Figures 9a - 9c ). This protective effect depends on the dose of compound 7. The combination of NAC (200 mg / kg) and compound 7 (10 mg / kg) had an almost complete protective effect, as the plasma ALT level was similar to that measured in control mice treated with only 5% Tween 80 (about 100 IU / L) (about 200 IU / L)( Figure 8 ).

Claims

1. A pharmaceutical composition comprising a combination of N-acetylcysteine and / or its pharmaceutically acceptable salts and / or derivatives with at least one inhibitor of regulated necrotic cell death such as necroptosis and / or ferroptosis.

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

3. The pharmaceutical composition according to claim 1 or 2, wherein the inhibitor of regulated necrotic cell death is: (A) A compound of the following general formula (I): or its pharmaceutically acceptable salts and / or solvates, wherein: ■ For (i) When is , X is N, Y is N(R2) and Z is C(H); (ii) When is , -X is N(R1), and -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; and wherein: ■R1 and R2 each independently represent a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 、C(O)R 11 、CO2R 12 、OC(O)R 13 、NR 14 C(O)R 15 、C(O)NR 16 R 17 、S(O)R S 、SO2R S ’, (C1-C6)alkyl, (C1-C6)haloalkyl, -(C1-C6)alkyl-[O-(C1-C6)alkyl] where m is from 1 to 6 m -NR N1 R N2 group, aryl, aryl-(C1-C6)alkyl, heterocyclic group or heterocyclic group-(C1-C6)alkyl, where the aryl or heterocyclic group is optionally substituted by one or more substituents selected from halogen atom, CN, NO2, OR 18 、SR 19 、NR 20 R 21 、C(O)R 22 、CO2R 23 、OC(O)R 24 、NR 25 C(O)R 26 、C(O)NR 27 R 28 、substituted by substituents of (C1-C6)alkyl and (C1-C6)haloalkyl; ■R3, R4, R 4b and R5 each independently represent a hydrogen atom, a halogen atom, CN, OR 29 , SR 30 , NR 31 R 32 , C(O)R 33 , CO2R 34 , OC(O)R 35 , NR 36 C(O)R 37 , C(O)NR 38 R 39 , (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, heterocyclic group, aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl, wherein the alkyl or haloalkyl is optionally substituted with one or more substituents selected from OR 40 , SR 41 and NR 42 R 43 , and the aryl or heterocyclic group is optionally substituted with one or more substituents selected from halogen atom, CN, NO2, OR 44 , SR 45 , NR 46 R 47 , C(O)R 48 , CO2R 49 , OC(O)R 50 , NR 51 C(O)R 52 , C(O)NR 53 R 54 , and one or more substituents of (C1-C6) alkyl and (C1-C6) haloalkyl; ■R6 represents a hydrogen atom, (C1-C6) alkyl, aryl-(C1-C6) alkyl, heterocyclic-(C1-C6) alkyl, -(C1-C6) alkyl-[O-(C1-C6) alkyl] where m' is from 1 to 6 m’ -NR N’1 R N’2 group or (C1-C6) alkylcarbonyl, and the (C1-C6) alkyl, aryl-(C1-C6) alkyl and (C1-C6) alkylcarbonyl are optionally substituted by one or more substituents selected from OH, SH, NH2, (C1-C6) alkoxy, (C1-C6) thioalkoxy, (C1-C6) alkylamino and bis((C1-C6) alkyl) amino; ■R S and R S each independently represents (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl; R7-R 10 , R 12 , R 14 and R 16 -R 17 Each independently represents a hydrogen atom, a (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group; ■R 11 , R 13 and R 15 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group, an aryl-(C1-C6) alkyl group, a (C1-C6) alkoxy group, a (C1-C6) alkylamino group or a di((C1-C6) alkyl)amino group; ■R 18 to R 28 each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group; ■R 29 to R 39 each independently represents a hydrogen atom, (C1-C6)alkyl, heterocyclic-(C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl, said aryl being optionally substituted with one or more substituents selected from halogen atom, CN, NO2, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 , and one or more substituents of (C1-C6)alkyl and (C1-C6)haloalkyl; ■R 40 to R 43 each independently represents a hydrogen atom or a (C1-C6) alkyl group; ■R 44 to R 54 each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group; ■R 55 to R 65 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl-(C1-C6) alkyl group or an aryl group; and R N1 、R N’1 、R N2 and R N’2 each independently represents 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): or its pharmaceutically acceptable salts and / or solvates, wherein: ■ X1, X2 and X3 each independently represent a hydrogen atom, a (C1-C6) alkyl group, an aryl group, an aryl-(C1-C6) alkyl group or an OH group, or a group selected from OR X , SR X , SO2R X and NR X R Z groups, wherein at least one of X1, X2 and X3 represents (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl, or is selected from OR X , SR X , SO2R X and NR X R Z groups, wherein R X is (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, R Z is a hydrogen atom or a (C1-C6) alkyl group, and The aryl group is optionally substituted by one or more groups selected from a halogen atom, -OR 66 , -NR 67 R 68 , -SR 69 , -S(O)R 70 , -SO2R 71 , -OCOR 72 , -CO2R 73 , -CONR 74 R 75 , -CO2R 76 , nitro (-NO2) and cyano (-CN); ■ Y1, Y2 and Y3 each independently represent a hydrogen atom, a (C1-C6) alkyl group, an aryl group, an aryl-(C1-C6) alkyl group or an OH group, or are selected from OR Y , SR Y , SO2R Y and NR Y R' Z groups, At least one of Y1, Y2 and Y3 represents (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, or is selected from OR Y , SR Y , SO2R Y and NR Y R’ Z groups, where R Y is (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl, R’ Z is a hydrogen atom or a (C1-C6) alkyl group, and The aryl group is optionally substituted by one or more groups selected from a halogen atom, -OR 66 , -NR 67 R 68 , -SR 69 , -S(O)R 70 , -SO2R 71 , -OCOR 72 , -CO2R 73 , -CONR 74 R 75 , -CO2R 76 , nitro (-NO2) and cyano (-CN); and ■R 66 to R 77 Each independently is a hydrogen atom or a (C1-C6) alkyl group.

4. The pharmaceutical composition according to claim 3, wherein the inhibitor of regulated necrotic cell death is a compound of formula (I), wherein: ■R1 and R2 each independently represent a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 、C(O)R 11 、CO2R 12 、OC(O)R 13 、NR 14 C(O)R 15 、C(O)NR 16 R 17 、S(O)R S 、SO2R S ’, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group is optionally substituted by one or more substituents selected from a halogen atom, CN, NO2, OR 18 、SR 19 、NR 20 R 21 、C(O)R 22 、CO2R 23 、OC(O)R 24 、NR 25 C(O)R 26 、C(O)NR 27 R 28 、(C1-C6)alkyl and one or more substituents of (C1-C6)haloalkyl; ■R3, R4, R 4b and R5 each independently represent a hydrogen atom, a halogen atom, CN, OR 29 , SR 30 , NR 31 R 32 , C(O)R 33 , CO2R 34 , OC(O)R 35 , NR 36 C(O)R 37 , C(O)NR 38 R 39 , (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, heterocyclic group, aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl, wherein the alkyl or haloalkyl is optionally substituted with one or more substituents selected from OR 40 , SR 41 and NR 42 R 43 , and the aryl or heterocyclic group is optionally substituted with one or more substituents selected from halogen atom, CN, NO2, OR 44 , SR 45 , NR 46 R 47 , C(O)R 48 , CO2R 49 , OC(O)R 50 , NR 51 C(O)R 52 , C(O)NR 53 R 54 , and one or more substituents of (C1-C6) alkyl and (C1-C6) haloalkyl; ■ R6 represents a hydrogen atom, (C1-C6) alkyl, aryl-(C1-C6) alkyl or -CH2-CH2-O-CH2-CH2-NH2 group, or (C1-C6) alkylcarbonyl optionally substituted with one or more substituents selected from OH, SH, NH2, (C1-C6) alkoxy, (C1-C6) thioalkoxy, (C1-C6) alkylamino and bis((C1-C6) alkyl) amino; ■R S and R S each independently represents (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl; ■R7-R 10 、R 12 、R 14 and R 16 -R 17 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group; ■R 11 , R 13 and R 15 Each independently represents a hydrogen atom, a (C1-C6)alkyl group, an aryl group, an aryl-(C1-C6)alkyl group, a (C1-C6)alkoxy group, a (C1-C6)alkylamino group or a di((C1-C6)alkyl)amino group; ■R 18 to R 28 each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group; ■R 29 to R 39 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, and the aryl group is optionally selected from a halogen atom, CN, NO2, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 and is substituted by one or more substituents of a (C1-C6) alkyl group and a (C1-C6) haloalkyl group; ■R 40 to R 43 each independently represents a hydrogen atom or a (C1-C6) alkyl group; ■R 44 to R 54 each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group; and ■R 55 to R 65 Each independently represents a hydrogen atom, a (C1-C6) alkyl group, or an aryl group.

5. The pharmaceutical composition according to claim 3 or 4, wherein the inhibitor of regulated necrotic cell death is a compound of formula (I), wherein: ■R1 represents a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 , C(O)R 11 , CO2R 12 , OC(O)R 13 , NR 14 C(O)R 15 , C(O)NR 16 R 17 , S(O)R S , SO2R S ’, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group is optionally substituted with a substituent selected from a halogen atom, CN, NO2, OR 18 , SR 19 , NR 20 R 21 , (C1-C6)alkyl and (C1-C6)haloalkyl, wherein R 18 to R 21 each independently represents a hydrogen atom or (C1-C6)alkyl, R S and R S ’ each independently represents (C1-C6)alkyl or aryl, preferably aryl, Preferably, R1 represents a hydrogen atom, CN, OR7, C(O)R 11 , CO2R 12 , OC(O)R 13 , SO2R S ’, (C1-C6)alkyl, heterocyclic group or heterocyclic group-(C1-C6)alkyl, wherein the heterocyclic group is optionally substituted by NO2, More preferably, R1 represents a hydrogen atom or (C1-C6) alkyl, especially a hydrogen atom or (C1-C3) alkyl, advantageously a hydrogen atom; ■R2 represents C(O)R 11 , CO2R 12 , C(O)NR 16 R 17 , (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group is optionally substituted with one or more substituents selected from halogen atom, OR 18 , SR 19 , NR 20 R 21 , (C1-C6)alkyl and (C1-C6)haloalkyl, where R 18 to R 21 each independently represents a hydrogen atom or (C1-C6)alkyl, Preferably, R2 represents CO2R 12 , C(O)NR 16 R 17 or aryl-(C1-C6)alkyl, wherein the aryl is optionally substituted with one or more substituents selected from halogen atoms, OR 18 , SR 19 and NR 20 R 21 , especially substituted with OR 18 ; ■R3 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, CN, OR 29 、SR 30 、NR 31 R 32 、C(O)R 33 、CO2R 34 、OC(O)R 35 、NR 36 C(O)R 37 、C(O)NR 38 R 39 、an aryl group, a heterocyclic group, an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group, wherein the aryl group or the heterocyclic group is optionally substituted with one or more substituents selected from a halogen atom, OR 44 、SR 45 、NR 46 R 47 、a (C1-C6) alkyl group and a (C1-C6) haloalkyl group, wherein R 29 to R 37 each independently represents a hydrogen atom or a (C1-C6) alkyl group, R 44 to R 47 each independently represents a hydrogen atom or a (C1-C6) alkyl group, Preferably, R3 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, CN, OR 29 , SR 30 , NR 31 R 32 , OC(O)R 35 , NR 36 C(O)R 37 , a heterocyclic group or a heterocyclic group-(C1-C6) alkyl group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from a halogen atom, OR 44 , SR 45 , NR 46 R 47 and a (C1-C6) alkyl group, More preferably, R3 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, CN, NR 31 R 32 , OC(O)R 35 , a heterocyclic group or a heterocyclic group-(C1-C6) alkyl group, wherein the heterocyclic group is optionally substituted with one or more substituents selected from OR 44 , SR 45 and NR 46 R 47 , especially substituted with OR 44 substituted, Even more preferably, R3 represents a hydrogen atom, a halogen atom or (C1-C3) alkyl, advantageously a hydrogen atom or a halogen atom; ■R4 represents a hydrogen atom, a halogen atom, CN, OR 29 , SR 30 , NR 31 R 32 , (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclic group, aryl-(C1-C6)alkyl or heterocyclic group-(C1-C6)alkyl, wherein the aryl or heterocyclic group is optionally substituted by one or more substituents selected from halogen atom, CN, NO2, OR 44 , SR 45 , NR 46 R 47 , C(O)R 48 , CO2R 49 , OC(O)R 50 , NR 51 C(O)R 52 , C(O)NR 53 R 54 , and substituted by one or more substituents of (C1-C6)alkyl and (C1-C6)haloalkyl Preferably, R4 represents a hydrogen atom, a halogen atom, OR 29 , SR 30 , NR 31 R 32 , (C1-C6)alkyl, aryl or heterocyclic group, wherein the aryl or heterocyclic group is optionally substituted by one or more substituents selected from halogen atom, OR 44 , SR 45 , NR 46 R 47 , C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6)alkyl and (C1-C6)haloalkyl, More preferably, R4 represents a hydrogen atom, a halogen atom, NR 31 R 32 , a (C1-C6) alkyl group, an aryl group or a heterocyclic group, wherein the aryl group or the heterocyclic group is optionally substituted by one or more substituents selected from C(O)R 48 and (C1-C6) alkyl groups, Even more preferably, R4 represents a hydrogen atom or (C1-C3) alkyl, advantageously a hydrogen atom, R 4b represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, OR 29 or NR 31 R 32 , preferably a hydrogen atom, a halogen atom, a (C1-C3) alkyl group or OR 29 , more preferably a hydrogen atom or a (C1-C3) alkyl group, and advantageously represents a hydrogen atom Among them, in the definitions of R4 and R above 4b , R 29 to R 32 each independently represents a hydrogen atom, a (C1-C6) alkyl group, an aryl group or an aryl-(C1-C6) alkyl group, and the aryl group is optionally selected from a halogen atom, OR 55 , SR 56 , NR 57 R 58 , C(O)R 59 , CO2R 60 , OC(O)R 61 , NR 62 C(O)R 63 , C(O)NR 64 R 65 , and is substituted by one or more substituents selected from (C1-C6) alkyl groups and (C1-C6) haloalkyl groups, especially by one or more substituents selected from C(O)R 59 , CO2R 60 , C(O)NR 64 R 65 , (C1-C6) alkyl groups and (C1-C6) haloalkyl groups, particularly substituted by C(O)R 59 , and R 48 represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group, especially an aryl group, and R 55 to R 65 each independently represents a hydrogen atom, a (C1-C6) alkyl group or an aryl group, especially an aryl group; ■R5 represents a hydrogen atom, a halogen atom, CN, OR 29 , SR 30 , NR 31 R 32 , (C1-C6) alkyl, (C1-C6) haloalkyl, aryl, heterocyclic group, aryl-(C1-C6) alkyl or heterocyclic group-(C1-C6) alkyl, wherein the alkyl or haloalkyl is optionally substituted by one or more substituents selected from OR 40 , SR 41 and NR 42 R 43 , the aryl or heterocyclic group is optionally substituted by one or more substituents selected from halogen atom, OR 44 , SR 45 , NR 46 R 47 , (C1-C6) alkyl and (C1-C6) haloalkyl, wherein R 29 to R 32 each independently represents a hydrogen atom or (C1-C6) alkyl, R 40 to R 43 each independently represents a hydrogen atom or (C1-C6) alkyl, especially a hydrogen atom Preferably, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, a (C1-C6) haloalkyl group, an aryl-(C1-C6) alkyl group or a heterocyclic-(C1-C6) alkyl group, wherein the alkyl or haloalkyl group is optionally substituted with one or more substituents selected from OR 40 , SR 41 and NR 42 R 43 and the aryl or heterocyclic group is optionally substituted with one or more substituents selected from a halogen atom, a (C1-C6) alkyl group and a (C1-C6) haloalkyl group, More preferably, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl group, a (C1-C6) haloalkyl group or a heterocyclic group-(C1-C6) alkyl group, wherein the alkyl group or haloalkyl group is optionally substituted by OR 40 substituted, and the heterocyclic group is optionally substituted by one or more (C1-C6) alkyl groups, Even more preferably, R5 represents a hydrogen atom or (C1-C3) alkyl, advantageously a hydrogen atom; and ■ R6 represents a hydrogen atom, (C1-C3) alkyl, aryl-(C1-C3) alkyl or -CH2-CH2-O-CH2-CH2-NH2 group, or (C1-C6) alkylcarbonyl optionally substituted with one or more substituents selected from OH, SH, NH2, (C1-C3) alkoxy, (C1-C3) thioalkoxy and (C1-C3) alkylamino, Preferably, R6 represents a hydrogen atom, methyl, ethyl, benzyl, -CH2-CH2-O-CH2-CH2-NH2 or (C1-C6) alkylcarbonyl optionally substituted with one or more substituents selected from OH, NH2 and thiomethyl, particularly R6 represents a hydrogen atom or -CH2-CH2-O-CH2-CH2-NH2 group.

6. The pharmaceutical composition according to claim 3, wherein the inhibitor of regulated necrotic cell death is a compound of formula (II), wherein: ■X1 represents (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or OR X group, where R X is (C1-C6) alkyl, aryl or aryl-(C1-C6) alkyl; ■ X2 and X3 each independently represent a hydrogen atom or a (C1-C6) alkyl group; and ■Y1, Y2 and Y3 each independently represent a hydrogen atom, (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl, OH or OR Y group, wherein at least one of Y1, Y2 and Y3 represents (C1-C6) alkyl, aryl, aryl-(C1-C6) alkyl or OR Y group, wherein R Y is selected from (C1-C6) alkyl, aryl and aryl-(C1-C6) alkyl.

7. The pharmaceutical composition according to claim 6, wherein: ■X1 represents OR X group, R X is preferably (C1-C6) alkyl; ■Y1 represents OR Y group, R Y is advantageously aryl-(C1-C6)alkyl, and Y2 and Y3 each represent a hydrogen atom.

8. The pharmaceutical composition according to claim 3, wherein the inhibitor of regulated necrotic cell death is: (a) A compound of the following general formula (I.iii): or a pharmaceutically acceptable salt and / or solvate thereof, wherein: -R3, R4, R 4b and R5 each independently represent a hydrogen atom, a halogen atom or a (C1-C6) alkyl group, especially a hydrogen atom, a halogen atom or a (C1-C3) alkyl group, preferably a hydrogen atom or a halogen atom, and - R6 represents a hydrogen atom, a (C1-C3) alkyl group or a -CH2-CH2-O-CH2-CH2-NH2 group, particularly a hydrogen atom or a -CH2-CH2-O-CH2-CH2-NH2 group; or (b) A compound of the following general formula (II.i): or a pharmaceutically acceptable salt and / or solvate thereof, wherein: -R X represents a (C1-C6) alkyl group, especially a (C1-C3) alkyl group, such as methyl, ethyl, n-propyl, more preferably represents methyl, and -R Y represents aryl-(C1-C6)alkyl, such as benzyl or -CH3-naphthyl, more preferably benzyl.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the inhibitor of regulated necrotic cell death is selected from: and its pharmaceutically acceptable salt and / or solvate.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the inhibitor of regulated necrotic cell death is selected from: and its pharmaceutically acceptable salt and / or solvate.

11. The pharmaceutical composition according to any one of claims 1 to 10, which comprises: - N-acetylcysteine and / or its medicinal salt and / or derivative, and - at least one inhibitor of regulated necrotic cell death as a combined product for simultaneous, separate or sequential administration.

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 its salt.

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

14. The pharmaceutical composition for the use according to claim 13, wherein the disease is associated with ferroptosis, particularly associated with ferroptosis and necroptosis.

15. A pharmaceutical composition for use according to claim 13 or 14, wherein the disease is selected from brain diseases or disorders, including neurodegenerative diseases or disorders, stroke, traumatic brain injury, epilepsy; eye 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 injury, including acute liver failure and chronic liver diseases; hypertension; hemochromatosis; hemolytic diseases; Ischemic diseases affecting the heart, brain or kidneys; kidney injury, including acute kidney injury, renal ischemia-reperfusion injury, acute tubular necrosis, liver fibrosis; heart injury; Aortic aneurysm; Pancreatitis; radiation-induced necrosis; chronic obstructive pulmonary disease, acute respiratory distress disorder; diseases associated with transplantation; cancer, including liver cancer, eye cancer, brain cancer, kidney cancer.

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

Images