Purine derivatives as medicaments for the treatment of neonatal hypoxic-ischemic brain damage and related diseases

Abstract

The present invention relates to compounds of formula (I) and to the addition salts thereof with a pharmaceutically acceptable acid, for the treatment of non-traumatic acquired brain injury, wherein M represents NR 1 R 2 group, OR 1 group or SR 1 group, A represents NR 4 R 5 group, OR 10 group or a hydrogen atom, R 3 is (C1-C6)alkyl, (C1-C6)cycloalkyl, aryl, -CH2-aryl, CH2-(C1-C6)cycloalkyl or -CH2-heteroaryl. The present invention further relates to compounds of formula (I) wherein R 5 is (C1-C8)alkyl or (C1-C6)cycloalkyl, said alkyl and cycloalkyl being substituted by one, two or three -OCOR a groups.

Description

TECHNICAL FIELD

[0001] The present invention aims at providing purine derivatives which are Aftins for use in the treatment of non-traumatic acquired brain injury (ABI), in particular in the treatment of hypoxic injury, and more particularly in the treatment of neonatal hypoxic-ischemic (HI) and hypoxic-ischemic encephalopathy (HIE). BACKGROUND

[0003] Acquired brain injury (ABI) is defined as brain injury caused by events occurring before or after birth, i.e. non-hereditary, congenital, degenerative or induced by birth-related injuries. Brain injuries usually included in said definition are non-progressive brain pathologies, typically resulting from ischemic, hypoxic, hemorrhagic, infectious events and non-malignant tumors. ABI can result in cognitive, physical, emotional, or behavioral impairments, which lead to permanent or temporary changes, such as changes in physical effects, thinking or learning abilities, behavior or emotional management. Recovery from ABI usually takes time. While the greatest improvement usually occurs within the first few months after injury, recovery can continue over the following years.

[0004] As a more specific type of non-traumatic ABI, as will be developed hereafter, one can cite neonatal brain injuries. They are one of the main causes of infant mortality and long-term neurological disabilities, such as developmental disabilities, including mental retardation and cerebral palsy, causing a great burden to society, highlighting the urgent need for effective neuroprotective strategies to reduce the prevalence of brain injuries.

[0005] In particular, hypoxic-ischemic (HI) and hypoxic-ischemic encephalopathy (HIE) represent common causes of neurological injury in preterm and term infants with birth-related complications.

[0006] There is currently no pharmacological treatment that provides protection against brain injury in the newborn. Hypothermia is the only approved treatment for HIE, but it can only be used to treat full-term infants and is only partially protective (Buonocore, G., et al., New Pharmacological Approaches in Infants with Hypoxic-Ischemic Encephalopathy, Current Pharmaceutical Design, 2012. 18(21): p. 3086-3100; Shankaran, S., Childhood Outcomes after Hypothermia for Neonatal Encephalopathy, New England Journal of Medicine, 2012. 366(22): p. 2085-2092). In fact, almost half of the infants treated with hypothermia still die or suffer from long-term neurological impairment.

[0007] Thus, there is an urgent need for new therapeutic options to treat non-traumatic ABI, and in particular to treat HI and HIE.

[0008] In addition, a large number of in vitro and in vivo studies have demonstrated an increase in BBB (blood-brain barrier) permeability and changes in the expression and localization of key tight junction (TJ) components after HI in the newborn (Mark, K.S. and T.P. Davis, Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation, American Journal of Physiology-Heart and Circulatory Physiology, 2002. 282(4): p. H1485-H1494. 21; Chen, X., et al., Ischemia-reperfusion impairs blood-brain barrier function and alters tight junction protein expression in the ovine fetus, Neuroscience, 2012. 226: p. 89-100).

[0009] The BBB is a cellular structure that separates the brain parenchyma from the blood stream. The endothelium has very special properties that enable it to regulate the exchange between blood and brain parenchyma. The BBB is composed of a specialized monolayer of brain endothelial cells, pericytes and astrocytic "end feet". At an early stage of development, well-formed tight junctions (TJs) between brain endothelial cells have been shown to constitute the physical basis of the effective barrier mechanism(s) and are essential for establishing a stable brain environment required for proper brain maturation. Most of the changes in the BBB are observed at an early stage (hours to days) after exposure to HI injury. HI-induced opening of the BBB significantly promotes neuronal cell death.

[0010] Therefore, the inventors identified the BBB as an important potential target for reducing and / or repairing brain damage after HI injury.

[0011] Aftins are a family of chemically synthesized trisubstituted purines. This family of compounds was originally designed for non-therapeutic methods as disclosed in EP 2 664 619 and is now known from WO 2018 / 189122 to be useful in the treatment of neurodegenerative disorders, such as Alzheimer’s disease (AD). As disclosed in WO 2018 / 189122, in murine in vivo models of AD and ex vivo hippocampal organotypic cultures, neurotrophic markers are increased and pro-inflammatory cytokine expression is decreased after Aftin administration. Improvements in cognitive tests were also demonstrated in adult mouse models of neuroinflammation.

[0012] However, to the best of the inventors’ knowledge, it has never been suggested or demonstrated in the prior art that Aftins can repair and / or reduce brain damage lesions, in particular in patients suffering from acquired brain injury (ABI). SUMMARY

[0014] It has now been found that Aftin compounds, and in particular compounds of formula (I) as defined hereinafter, are useful for the treatment of acquired brain injury (ABI), in particular brain injury caused by hypoxia, and even more particularly hypoxic injury, such as neonatal encephalopathy, including neonatal hypoxic-ischemic and neonatal hypoxic-ischemic encephalopathy.

[0015] The present invention thus relates to a compound of formula (I) as defined below, for use in the treatment of non-traumatic acquired brain injury (ABI), in particular brain injury caused by hypoxia, and even more particularly hypoxic injury, such as neonatal encephalopathy, including neonatal hypoxic-ischemic and neonatal hypoxic-ischemic encephalopathy.

[0016] The present invention further relates to a subclass of novel compounds of formula (I) as defined below. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1A with Figure 1B : Ability of Aftin to reduce infarct volume in the ipsilateral hemisphere following HI (hypoxia-ischemia) injury in the Rice Vannucci model.

[0018] Figure 1A : Representative images of brain sections stained with cresyl violet 3 days after HI brain injury. Top row: brain sections from male rats; bottom row: brain sections from female rats.

[0019] From left to right: sham group (untreated control), HI + PL group (induced HI injury + no active agent given), and HI + Compound 13 (induced HI injury + Compound 13 given).

[0020] Figure 1B : Infarct volume (%) measured for each study group. y-axis: infarct volume (%); x-axis (from left to right): sham group, HI + PL group, and HI + Compound 13 group.

[0021] From left to right: graphical results for male + female, graphical results for male only, and graphical results for female only.

[0022] Sham group: male n = 5, female n = 10;

[0023] HI + PL: male n = 8, female n = 8;

[0024] HI + Compound 13: male n = 7, female n = 6.

[0025] Figure 2A with Figure 2B : Ability of Aftin to reverse BBB leakage under inflammatory stress in vitro

[0026] Figure 2A : Permeability of radiolabeled sucrose (osmotic marker) was investigated on a primary rat cell-based BBB (blood brain barrier) model following a lipopolysaccharide (LPS) challenge.

[0027] First graph (left): y-axis: 14 C- Sucrose permeability through BBB (10 -6 cm.s -1 ); x-axis (from left to right): BBB control (negative control); BBB + LPS (10 ng / mL) (positive control); BBB + Compound 13 (0.1 μΜ); BBB + LPS + Compound 13 (0.1 μΜ); BBB + Compound 13 (1 μΜ); BBB + LPS + Compound 13 (1 μΜ).

[0028] Second graph (right): y-axis: 14 C- Sucrose permeability through BBB (10-6 cm.s -1 ) ; x-axis (from left to right) : BBB control (negative control) ; BBB + LPS (10 ng / mL) (positive control) ; BBB + Aftin-5 (0.1 mM) ; BBB + LPS + Aftin-5 (0.1 mM) ; BBB + Aftin-5 (1 mM) ; BBB + LPS + Aftin-5 (1 mM).

[0029] Figure 2B : Schematic representation of the BBB model based on primary rat cells after LPS challenge.

[0030] DEFINITIONS

[0031] As used herein, the term "individual" refers to an animal, such as a valuable animal for breeding, companion or preservation purposes, or preferably a human or human child, suffering from or likely to suffer from one or more of the diseases and conditions described herein.

[0032] In particular, as used in the present application, the term "individual" refers to a mammal, such as a rodent, a cat, a dog, a primate or a human, preferably the subject is a human.

[0033] The determination of those individuals in need of treatment of the diseases and conditions described herein is well within the capabilities and knowledge of the person skilled in the art. By using clinical tests, physical examinations, medical / family history or biological and diagnostic tests, the veterinarian or physician of the art can easily determine those individuals in need of such treatment.

[0034] As used herein, the term "infant" refers to a human child, preferably 2 years old or less, in particular 1 year old or less, and more particularly 8 months old or less. Even more particularly, an infant can refer to a "newborn" or "neonate" of an infant within the first 28 days after birth.

[0035] The term "therapeutically effective amount" refers to a concentration of a compound effective to treat the relevant disease or to individually stimulate the desired outcome, i.e. to alleviate or eradicate the symptoms of the encompassed disorder.

[0036] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, excipients, compositions, or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0037] Within the scope of the present application, the term "treatment" refers to an intervention aimed at partially or completely relieving at least one symptom associated with an acquired brain injury (ABI), and more particularly with a hypoxic injury, and more particularly with neonatal hypoxic-ischemic (HI) and neonatal hypoxic-ischemic encephalopathy (HIE), as defined more below. In said case, the individual can be from a specific group of individuals diagnosed with an acquired brain injury (ABI), or presenting at least one symptom of an acquired brain injury (ABI), such as for example an indication of BBB permeability abnormalities, as described more in detail below.

[0038] According to a preferred embodiment, the individual to be treated according to the present application is an individual suffering from a non-traumatic acquired brain injury (ABI), in particular a hypoxic injury, and more particularly neonatal hypoxic-ischemic (HI) or neonatal hypoxic-ischemic encephalopathy (HIE). In a preferred embodiment, said individual is an infant. Preferably, said infant is a neonate. DETAILED DESCRIPTION

[0040] Surprisingly, the inventors demonstrated the role of compounds of formula (I) in reducing brain injury lesions. The following examples show, through in vivo and in vitro models, said new biological role of compounds of formula (I) as defined below. Namely, in a well-characterized Rice-Vannucci neonatal HI model, the inventors demonstrated a sustained reduction of brain injury lesions Figure 1A with Figure 1B an increase of neurotrophic markers in the brain, after administration of Aftin compounds. Moreover, they showed that compounds of formula (I) as defined below are able to reverse BBB leakage Figure 2A with Figure 2B under inflammatory stress.

[0041] Indeed, the inventors have surprisingly demonstrated that Aftin compounds of formula (I) are able to reduce infarct volume in male and female neonatal rats exposed to HI, conducting a proof of concept that administration of Aftin compounds promotes the regeneration of neural tissue, thus repairing the damage induced by brain lesions. The pharmacological action is associated with the restoration of BBB integrity.

[0042] According to a first aspect, the subject-matter of the present application relates to a compound of formula (I) for use in the treatment of a non-traumatic acquired brain injury (ABI),

[0043]

[0044] wherein

[0045] M represents NR 1 R 2 group, OR 1 group or SR 1 group,

[0046] A represents NR 4 R 5 group, OR 10 group or a hydrogen atom,

[0047] R 1 is an aryl group, a heteroaryl group, a -CH2-aryl group or a -CH2-heteroaryl group, said aryl and heteroaryl groups being optionally substituted with one or more substituents independently selected from a halogen atom, a CF3 group, a hydroxyl group, an OR 6 group, a SR 6 group, a NR 6 R 7 group, a CN group, a CONR 6 R 7 group, a SOR 6 group, a SO2R 6 group, an azido group (-N3), an aryl group, a heteroaryl group and a (C1-C6)alkyl group,

[0048] R 2 is a (C1-C6)alkyl group or a (C1-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted with one or more substituents independently selected from a halogen atom, a hydroxyl group and a NH2 group,

[0049] or R 1 and R 2 form, together with the nitrogen atom which bears them, a heterobicycle, 1 and R 2 form, together with the nitrogen atom which bears them, a heterobicycle,

[0050] R 6 and R 7 independently of one another represent a hydrogen atom or a (C1-C6)alkyl group,

[0051] R 3 is a (C1-C6)alkyl group, a (C1-C6)cycloalkyl group, an aryl group, a -CH2-aryl group, a CH2-(C1-C6)cycloalkyl group or a -CH2-heteroaryl group, said alkyl, cycloalkyl, aryl and heteroaryl groups being optionally substituted with one or more substituents independently selected from a halogen atom, a hydroxyl group and a NH2 group,

[0052] R 4 is a hydrogen atom, a (C1-C6)alkyl group, a (C1-C6)cycloalkyl group, an aryl group or a heteroaryl group, said alkyl and cycloalkyl groups being optionally substituted with one or more substituents independently selected from a halogen atom, a hydroxyl group and a NH2 group, said aryl and heteroaryl groups being optionally substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a NH2 group and a NH-R 9 group,

[0053] R9 is a heteroaryl group optionally substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a NH2group and a heteroaryl group,

[0054] R 5 is a hydrogen atom, a (Ci-C8)alkyl group or a (Ci-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted with one or more substituents independently selected from a halogen atom, a hydroxyl group, an azido group, a -OCOR a group and a NR 6 R 7 group, one or more of the carbon atoms of said alkyl or cycloalkyl groups being optionally replaced with a nitrogen atom,

[0055] R a represents a (Ci-C6)alkyl group, said alkyl group being optionally substituted with an amino group,

[0056] or alternatively, R4and R5may form, with the nitrogen atom that bears them, a (C3-C6)heterocycloalkyl group, said (C3-C6)heterocycloalkyl group being optionally substituted with one or more substituents independently selected from a (Ci-C4)alkyl group, a NR 6 R 7 group and a halogen atom,

[0057] R 10 is a hydrogen atom, a (Ci-C6)alkyl group, a (Ci-C6)cycloalkyl group, an aryl group, a heteroaryl group, a -CH2-aryl group or a -CH2-heteroaryl group, said aryl group being optionally substituted with one or more substituents selected from a halogen atom, a hydroxyl group, an OR 6 group, a SR 6 group, a NR 6 R 7 group, a CN group, a CONR 6 R 7 group, a SO2NR 6 R 7 group, a SOR 6 group, a SO2R 6 group and an azido group (N3),

[0058] as well as the addition salts thereof with a pharmaceutically acceptable acid.

[0059] In the context of the present invention, the term "halogen" is understood to mean a chlorine (CI), fluorine (F), bromine (Br) or iodine (I).

[0060] As used herein, the term "alkyl" refers to a straight chain or branched saturated aliphatic hydrocarbon group. For example, a (Ci-C6)alkyl group represents a straight chain or branched carbon chain of 1 to 6 carbon atoms. Examples are, but are not limited to, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methylbutyl group.

[0061] The term "cycloalkyl" means a cyclic alkyl group which can be substituted by one or more (Ci-C6)alkyl groups. Examples are, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopropyl, methylcyclobutyl.

[0062] The term "(C3-C6)heterocycloalkyl" means a (C3-C6)cycloalkyl group wherein one or two of the carbon atoms are replaced by a heteroatom such as oxygen or nitrogen. Examples are, but are not limited to, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl and homopiperazinyl.

[0063] The term "aryl" means a monocyclic or polycyclic aromatic hydrocarbon radical of 6-20 atoms derived by the removal of one hydrogen from a carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, 1 ring or 2 or 3 rings fused together. The group is typically derived from a ring selected from benzene, naphthalene, anthracene and the like. "Aryl" preferably means a group such as phenyl.

[0064] The term "heteroaryl" denotes a 5- or 6-membered aromatic ring containing 1 or 2 heteroatoms or a bicyclic or tricyclic aromatic core containing 1 to 4 heteroatoms and wherein at least one of these rings has 6 ring members, the other fused rings having 5 or 6 ring members. Examples are, but are not limited to, pyridyl, pyrrolyl, thienyl, thiazolyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl and pyridazinyl.

[0065] The term "heteroatom" is to be understood as meaning nitrogen (N), oxygen (O) or sulfur (S).

[0066] Preferably, the heteroaryl group comprises at least one nitrogen atom. In particular, the heteroaryl group does not comprise an oxygen atom. Finally, very preferably, the heteroaryl group comprises only nitrogen as heteroatom(s). Thus, advantageously, the heteroaryl group comprises 1 to 4 nitrogen atoms.

[0067] One can more particularly mention pyridyl, pyrrolyl, thiazolyl, pyrazolyl and triazolyl, and even more particularly pyridyl and pyrrolyl.

[0068] In the context of the present application, the terms "aromatic ring", "aryl" and "heteroaryl" include all positional isomers.

[0069] The term "heterobicyclic" means an 8- to 14-membered bicyclic group comprising at least one heteroatom. Preferably, one ring from the heterobicyclic is aromatic. In particular, the heterobicyclic comprises only nitrogen as heteroatom(s). Finally, very particularly the heterobicyclic can be selected from these 2 groups:

[0070]

[0071] The M group, when NR 1 R 2may in particular be chosen from the following groups (1) to (89):

[0072]

[0073]

[0074]

[0075] A group, when NR 4 R 5 may in particular be chosen from the following groups (1’) to (19’):

[0076]

[0077]

[0078] R 3 may in particular be chosen from the following groups (1”) to (14”):

[0079]

[0080] Among the compounds of general formula (I) for said use according to the application, a first subgroup of compounds consists of the compounds in which M represents NR 1 R 2 group, OR 1 group or SR 1 group,

[0081] R 1 is an aryl, -CH2-aryl, heteroaryl or CH2-heteroaryl group, said aryl and heteroaryl groups being optionally substituted with one or more substituents chosen independently from a halogen atom, a CF3 group, a hydroxyl group, an OR 6 group, a CONR 6 R 7 group, an azido group (-N3), an aryl group, a heteroaryl group and a (C1-C6)alkyl group,

[0082] R 2 is a (C1-C6)alkyl group,

[0083] or R 1 and R 2 form, together with the nitrogen atom bearing them, a heterobicycle, 1 and R 2 form, together with the nitrogen atom bearing them, a heterobicycle,

[0084] R 6 and R 7 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group.

[0085] In the compounds of general formula (I) according to the invention for the stated purpose, the second subgroup of the compounds is formed by the following compounds: wherein M represents NR. 1 R 2 Group, OR 1 Group or SR 1 Group;

[0086] R 1 It is an aryl, -CH2-aryl, heteroaryl, or CH2-heteroaryl group, wherein the aryl group is optionally surrounded by one or more atoms selected from halogen atoms, CF3 groups, OR groups, etc. 6 Group, CONR 6 R 7 Substitution of groups, aryl, heteroaryl, and (C1-C6) alkyl groups,

[0087] R 2 It is a (C1-C6) alkyl group.

[0088] Or R 1 With R 2 and with carrying R 1 and R 2 The nitrogen atoms together form a heterobicyclic ring.

[0089] R 6 and R 7 Each can be represented independently as a hydrogen atom or a (C1-C6) alkyl group.

[0090] In the compounds of general formula (I) according to the invention for the stated purpose, the third subgroup of the compounds is formed by the following compounds: wherein M represents NR. 1 R 2 Group, OR 1 Group or SR 1 Group;

[0091] R 1 It is phenyl, benzyl, pyridyl, –CH2-pyridyl, pyrroleyl, or –CH2-pyrroleyl, said group optionally surrounded by a group selected from fluorine, chlorine, CF3, or OR. 6 Group, CONR 6 R 7 Substitution of groups, phenyl, pyridyl and methyl groups,

[0092] R 2 It is methyl, ethyl, n-propyl, or isopropyl.

[0093] Or R 1 With R 2 and with carrying R 1 and R 2 The nitrogen atoms together form a heterobicycle selected from the following two groups:

[0094]

[0095] R 6 and R 7 independently of one another represent a hydrogen atom or a methyl group.

[0096] Among the compounds of general formula (I) for said use according to the application, a fourth sub-group of compounds is formed by the compounds in which A represents NR 4 R 5 a group, OR 10 a group or a hydrogen atom;

[0097] R 4 is a hydrogen atom or a (Ci-C6)alkyl group, said alkyl group being optionally substituted with one hydroxyl group,

[0098] R 5 is a hydrogen atom, a (Ci-C8)alkyl group or a (Ci-C6)cycloalkyl group, said alkyl group being optionally substituted with one or two hydroxyl groups or -OCOR a groups, one of the carbon atoms of said alkyl or cycloalkyl group being optionally replaced with a nitrogen atom,

[0099] R a represents a (Ci-C6)alkyl group, said alkyl group being optionally substituted with an amino group,

[0100] or alternatively, R 4 and R 5 may form, with the nitrogen atom which bears them, a (C3-C6)heterocycloalkyl group, said (C3-C6)heterocycloalkyl group being optionally substituted with one or more substituents independently selected from a (Ci-C4)alkyl group, a NR 6 R 7 group and a halogen atom,

[0101] R 10 is -CH2-aryl.

[0102] Among the compounds of general formula (I) for said use according to the application, a fifth sub-group of compounds is formed by the compounds in which A represents NR 4 R 5 a group, OR 10 a group or a hydrogen atom;

[0103] R 4 is a hydrogen atom or a 2-hydroxyethyl group,

[0104] R 5is a hydrogen atom, a 1-hydroxybutan-2-yl group, a 1-hydroxy-3-methylbutan-2-yl group, a 1,2-dihydroxypropan-3-yl group, a N-ditehylaminoeth-2-yl group, a piperidin-4-yl group, a 2-hydroxyethyl group, or any one of groups (12') to (21') as defined above,

[0105] or alternatively, R 4 and R 5 may form, with the nitrogen atom that bears them, a morpholinyl group, a piperazinyl group, a pyrrolidinyl group, a piperidinyl group, said groups being optionally substituted with one or more substituents independently selected from a (Ci-C4)alkyl group, a NR 6 R 7 a group and a halogen atom, and for example from any one of groups (5') to (1 1 ') as defined above,

[0106] R 6 and R 7 independently of one another represent a hydrogen atom or a methyl group,

[0107] R 10 is a benzyl group.

[0108] Among the compounds of general formula (I) for said use according to the application, a sixth sub-group of compounds is formed by the compounds of general formula (I) in which R 3 represents a (Ci-C6)alkyl group, a (Ci-C6)cycloalkyl group or a -CH2-aryl group, said aryl group being optionally substituted with one or more substituents independently selected from a halogen atom.

[0109] Among the compounds of general formula (I) for said use according to the application, a seventh sub-group of compounds is formed by the compounds of general formula (I) in which R 3 represents any one of groups (1 ") to (14") as defined above, and more particularly a cyclopentyl group, an isopropyl group or a benzyl group.

[0110] Among the compounds of general formula (I) for said use according to the application, an eighth sub-group of compounds is formed by the compounds of general formula (I) in which simultaneously A and / or M and / or R 3 are as defined in the above sub-groups.

[0111] Among the compounds of general formula (I) for said use according to the application, a ninth sub-group of compounds is formed by the compounds of general formula (I) in which M represents NR 1 R 2 a group,

[0112] R 2represents a (C1-C6)alkyl or (C1-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted with one or more substituents selected from a halogen atom, a hydroxyl and NH2 group, and

[0113] R 1 , A and R 3 as defined above, wherein R 3 is preferably isopropyl, benzyl or cyclopentyl.

[0114] According to said particular embodiment, M is preferably a group (1), (2), (15), (17), (25), (43) or (44) as defined herein above, and even more preferably a group (1), (43) or (44) as defined herein above.

[0115] Compounds 13, 15, 18, 20, 22 and 23 as defined hereafter in Table 1, and pharmaceutically acceptable salts thereof, are particularly encompassed within the scope of said particular embodiment.

[0116] Among the compounds of general formula (I) for said use according to the application, a tenth sub-group of compounds is formed by the compounds of general formula (I) in which M represents NR 1 R 2 group,

[0117] R 3 is a (C1-C6)cycloalkyl, aryl, -CH2-aryl or -CH2-heteroaryl group, said cycloalkyl, aryl and heteroaryl groups being optionally substituted with one or more substituents selected from a halogen atom, a hydroxyl and NH2 group, R 3 is preferably benzyl or cyclopentyl,

[0118] R 1 , A and R 2 as defined above.

[0119] According to said particular embodiment, M is preferably a group (1), (2), (15), (17), (25), (43) or (44) as defined herein above, and even more preferably a group (1) or (2).

[0120] Compounds 14, 15, 18 and 22 as defined hereafter in Table 1, and pharmaceutically acceptable salts thereof, are particularly encompassed within the scope of said particular embodiment.

[0121] Among the compounds of general formula (I) for said use according to the application, an eleventh sub-group of compounds is formed by the compounds in which M represents NR 1 R 2 group, OR 1 group or SR1 group,

[0122] A represents a group NR 4 R 5 group, and

[0123] R 1 , R 2 and R 3 as defined above, wherein R 3 is preferably isopropyl, benzyl or cyclopentyl.

[0124] According to said specific embodiment, R 1 is aryl, heteroaryl, -CH2-aryl or -CH2-heteroaryl, said aryl and heteroaryl groups being optionally substituted with one substituent chosen among a halogen atom, a CF3group, a hydroxyl group, an OR 6 group, a SR 6 group, a NR 6 R 7 group, a CN group, a CONR 6 R 7 group, a SOR 6 group, a SO2R 6 group, an azido group (-N3) and a (C1-C6)alkyl group.

[0125] According to said specific embodiment, M is preferably a group (1), (2), (15), (17), (25), (43) or (44) as defined herein above, and even more preferably a group (1), (2) or (17).

[0126] Compounds 13, 14, 15, 18, 20, 22, 23, 26, 38 and Aftin-5, as defined hereafter in Table 1, and pharmaceutically acceptable salts thereof, are particularly encompassed within the scope of said specific embodiment.

[0127] A subfamily of compounds of formula (I) is also reported hereafter, still in accordance with EP 2 664 619, which can also be used as a medicament. Thus, said compounds of formula (la), (lb), (lc), (Id), (le) for use as a medicament are an additional subject forming part of the present application.

[0128] Compounds of formula (Ia)

[0129] They are defined as follows:

[0130]

[0131] wherein

[0132] A represents NR4 R 5 group or OR 10 group,

[0133] R 1 , R 5 and R 10 as defined above,

[0134] R 3 is a (C1-C6)alkyl, (C1-C6)cycloalkyl, aryl, -CH2-aryl or -CH2-heteroaryl group, said alkyl, cycloalkyl, aryl and heteroaryl groups being optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a NH2group,

[0135] R 4 is a hydrogen atom, a (C1-C6)alkyl or (C1-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group and a NH2group.

[0136] According to a particular embodiment, the present application relates to compounds of formula (Ia) as defined above, for the use according to the application, wherein,

[0137] A represents NR 4 R 5 group or OR 10 group,

[0138] R 1 is a -CH2-aryl group, preferably a benzyl group,

[0139] R 3 is a (C1-C6)alkyl or (C1-C6)cycloalkyl group, preferably a methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl or isopropyl group, in particular an isopropyl group,

[0140] R 4 is a hydrogen atom,

[0141] R 5 is a (C1-C6)alkyl or (C1-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one hydroxyl group, preferably R 5 is a methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl or 1-hydroxybut-2-yl group, in particular a 1-hydroxybut-2-yl group,

[0142] R 10 is a -CH2-aryl group, preferably a benzyl group,

[0143] and the addition salts thereof with a pharmaceutically acceptable acid.

[0144] Aftin-3 is encompassed within the scope of said formula (Ia) as shown hereafter.

[0145]

[0146] Compound Aftin-3 is disclosed in Tang et al. (J. Biol. Chem. 2005; 280, 31220-21229) as a negative control in a kinase activity test.

[0147] Compounds 31, 32 and 46, as defined hereafter in Table 1, and pharmaceutically acceptable salts thereof are particularly encompassed within the scope of formula (Ia).

[0148] Compounds of formula (Ib)

[0149] They are defined as follows:

[0150]

[0151] wherein

[0152] R 1 , R 2 and R 5 are as defined above,

[0153] R 3 is a (Ci-C6)alkyl, (Ci-C6)cycloalkyl, aryl, -CH2-aryl or -CH2-heteroaryl group, said alkyl, cycloalkyl, aryl and heteroaryl groups being optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl and a NH2group,

[0154] R 4 is a hydrogen atom, a (Ci-C6)alkyl or (Ci-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl and a NH2group,

[0155] and the addition salts thereof with a pharmaceutically acceptable acid.

[0156] Compounds 13, 14, 15, 18, 20, 22, 23, 26 and 38, as defined hereafter in Table 1, and pharmaceutically acceptable salts thereof are particularly encompassed within the scope of formula (Ib).

[0157]

[0158] Aftin-4 is encompassed within the scope of said formula (Ib). Compound Aftin-4 is disclosed in Tang et al. (J. Biol. Chem. 2005; 280, 31220-21229) as a negative control in a kinase activity test.

[0159] As shown below, Aftin-5 is also encompassed within the scope of the formula (lb).

[0160]

[0161] Aftin-5 is disclosed and included in EP 2 664 619.

[0162] According to a specific embodiment, the present application relates to a compound of formula (lb) as defined above, for use according to the application, wherein

[0163] NR 1 R 2 is selected from the group consisting of the groups (1) to (89) as defined above.

[0164] According to an even more specific embodiment, the present application relates to a compound of formula (lb) as defined above, for use according to the application, wherein

[0165] NR 1 R 2 is selected from the group consisting of the groups (1) to (89) as defined above. 1 R 2 is selected from the group consisting of the groups (1), (2), (11), (15), (17), (25), (32), (34) and (43) to (51) as defined above, and more particularly from the groups of formulae (1), (2), (15), (17), (25), (43) and (44), and even more particularly from the groups of formulae (1), (2) and (17).

[0166] R 3 is a (C1-C6)alkyl, (C1-C6)cycloalkyl or -CH2-aryl, CH2-(C1-C6)cycloalkyl group, preferably R 3 is a methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, isopropyl, cyclopentyl or benzyl group, particularly R 3 is an isopropyl, cyclopentyl or benzyl group,

[0167] R 4 is a hydrogen atom, (C1-C6)alkyl or (C1-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one or more hydroxyl groups, preferably R 4 is a methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl or 2-hydroxyethyl group or a hydrogen atom, particularly R 4 is a 2-hydroxyethyl group or a hydrogen atom,

[0168] R 5is a hydrogen atom, a (Ci-C6)alkyl group or a (Ci-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted with one or more hydroxyl groups or -OCOR a groups, one or more of the carbon atoms of said alkyl and cycloalkyl groups being optionally replaced with a nitrogen atom, wherein R a represents a (Ci-C6)alkyl group, said alkyl group being optionally substituted with an amino group.

[0169] Preferably, R 5 is a methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, 1 -hydroxybut-2-yl, 1 -hydroxy-3-methylbut-2-yl, 1,2-dihydroxypropan-3-yl, N-diethylaminoeth-2-yl, piperidin-4-yl or 2-hydroxyethyl group, or a hydrogen atom or an L-valyl ester of [(2R)-2-butyl], in particular R 5 is a 1 -hydroxybut-2-yl, 1 -hydroxy-3-methylbut-2-yl, 1,2-dihydroxypropan-3-yl, N-diethylaminoeth-2-yl, piperidin-4-yl or 2-hydroxyethyl group or a hydrogen atom,

[0170] and the addition salts thereof with a pharmaceutically acceptable acid.

[0171] Compounds of formula (Ic)

[0172] They are defined as follows:

[0173]

[0174] wherein,

[0175] R 3 is a (Ci-C6)alkyl group, a (Ci-C6)cycloalkyl group, -CH2-aryl or -CH2-heteroaryl, preferably R 3 is a methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, isopropyl, cyclopentyl or benzyl group, in particular R 3 is an isopropyl, cyclopentyl or benzyl group,

[0176] R 4 is a hydrogen atom,

[0177] R 5 is a hydrogen atom, a (Ci-C6)alkyl group or a (Ci-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted with one or more hydroxyl groups or -OCOR a groups, one or more of the carbon atoms of said cycloalkyl groups being optionally replaced with a nitrogen atom, preferably R 5is a L-valyl ester of methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, 1-hydroxybutan-2-yl, 1,2-dihydroxypropan-3-yl or piperidin-4-yl, [(2R)-2-butyl] or a hydrogen atom, in particular R 5 is a L-valyl ester of methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, 1-hydroxybutan-2-yl, 1,2-dihydroxypropan-3-yl or piperidin-4-yl, [(2R)-2-butyl] or a hydrogen atom, in particular R

[0178] R a represents (Ci-C6)alkyl, said alkyl being optionally substituted by amino,

[0179] R 11 is selected from halogen or a hydrogen atom, OR 6 group, CONR 6 R 7 group, aryl and heteroaryl, preferably R 11 is OR 6 , CONR 6 R 7 , pyridyl, phenyl, or a fluorine or hydrogen atom,

[0180] R 6 and R 7 independently of one another represent a hydrogen atom or a (Ci-C6)alkyl group,

[0181] and the addition salts thereof with a pharmaceutically acceptable acid.

[0182] Compounds 14 and 38, as defined hereafter in Table 1, and the pharmaceutically acceptable salts thereof are in particular encompassed within the scope of formula (Ic).

[0183] Compounds of formula (Id)

[0184] They are defined as follows:

[0185]

[0186] wherein,

[0187] R 3 is (Ci-C6)alkyl, CH2-aryl, -CH2-heteroaryl or (Ci-C6)cycloalkyl, preferably R 3 is methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl, isopropyl or cyclopentyl, in particular R 3 is isopropyl or cyclopentyl,

[0188] R 4 is a hydrogen atom, a (Ci-C6)alkyl group or a (Ci-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one or more hydroxyl groups, preferably R 4is a methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl or 2-hydroxyethyl group or a hydrogen atom, in particular R 4 is a 2-hydroxyethyl group or a hydrogen atom,

[0189] R 5 is a (Ci-C6)alkyl or (Ci-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one or more hydroxyl or -OCOR a groups, preferably R 5 is a methyl, ethyl, cyclopropyl, cyclobutyl, methylcyclopropyl, methylcyclobutyl or [(2R)-2-butyl] L-valyl ester, 1-hydroxybutan-2-yl or 2-hydroxyethyl group, in particular R 5 is a 1-hydroxybutan-2-yl or 2-hydroxyethyl group,

[0190] R a represents a (Ci-C6)alkyl group, said alkyl group being optionally substituted by an amino group,

[0191] R 12 is selected from a halogen, a CF3group or a hydrogen atom, an OR 6 group and a (Ci-C6)alkyl group, preferably R 12 is a hydrogen, a CF3group, a fluorine or chlorine atom, or an OR 6 or a methyl group,

[0192] R 6 is a (Ci-C6)alkyl group, preferably R 6 is a methyl group,

[0193] and the addition salts thereof with a pharmaceutically acceptable acid.

[0194] The compounds 26 and Aftin-5, as defined hereafter in Table 1, and the pharmaceutically acceptable salts thereof are in particular encompassed within the scope of formula (Id).

[0195] Compounds of formula (Ie)

[0196] They are defined as follows:

[0197]

[0198] wherein

[0199] R 1 and R 5 are as defined above,

[0200] R 3is a (C1-C6)alkyl, (C1-C6)cycloalkyl, aryl, -CH2-aryl or -CH2-heteroaryl group, said alkyl, cycloalkyl, aryl and heteroaryl groups being optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl and a NH2group,

[0201] R 4 is a hydrogen atom, a (C1-C6)alkyl or (C1-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl and a NH2group,

[0202] and the addition salts thereof with a pharmaceutically acceptable acid.

[0203] According to a particular embodiment, the present application relates to a compound of formula (Ie) as defined above, for use according to the application, wherein,

[0204] R 1 is a -CH2-aryl group, preferably a benzyl group,

[0205] R 3 is a (C1-C6)alkyl group, preferably an isopropyl group,

[0206] R 4 is a hydrogen atom,

[0207] R 5 is a (C1-C6)alkyl group optionally substituted by one or more hydroxyl groups, preferably R 5 is a 1-hydroxybutan-2-yl group,

[0208] and the addition salts thereof with a pharmaceutically acceptable acid.

[0209] The compound 47, as defined hereafter in Table 1, and the pharmaceutically acceptable salts thereof are particularly encompassed within the scope of formula (Ie).

[0210] The compounds of formula (I), (Ia), (Ib), (Ic), (Id) and (Ie) can contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, form part of the present application.

[0211] The pharmaceutically acceptable salts of the compounds of formula (I), (Ia), (Ib), (Ic), (Id) and (Ie) include the addition salts with a pharmaceutically acceptable acid, such as mineral acids, for instance hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, and organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid, benzoic acid, toluene-sulphonic acid, methanesulphonic acid, stearic acid and lactic acid.

[0212] The compounds of formula (I), (la), (lb), (Ic), (Id) and (le) or salts thereof can form solvates (i.e. hydrates); the present application includes such solvates.

[0213] The present application therefore additionally relates to the compounds of formula (I) according to the application as disclosed herein, wherein

[0214] M represents NR 1 R 2 group or OR 1 group,

[0215] R 1 is an aryl, heteroaryl, -CH2-aryl or -CH2-heteroaryl group, said aryl and heteroaryl groups being optionally substituted by one or more substituents independently selected from a halogen atom, a CF3 group, a hydroxyl group, an OR 6 group, a SR 6 group, a NR 6 R 7 group, a CN group, a CONR 6 R 7 group, a SOR 6 group, a SO2R 6 group, an azido group (-N3), an aryl group, a heteroaryl group and a (C1-C6)alkyl group, and preferably R 1 is an aryl, heteroaryl, -CH2-aryl or -CH2-heteroaryl group, said aryl and heteroaryl groups being optionally substituted by one halogen atom or CF3 group,

[0216] R 6 and R 7 independently of each other represent a hydrogen atom or a (C1-C6)alkyl group, and

[0217] R 2 is a (C1-C6)alkyl or (C1-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one or more substituents independently selected from a halogen atom, a hydroxyl group and a NH2 group, and preferably R 2 is a (C1-C6)alkyl group,

[0218] and the addition salts thereof with a pharmaceutically acceptable acid, for use according to the application.

[0219] In some embodiments, M represents NR 1 R 2 group, and said NR 1 R 2 group is selected from the following groups:

[0220]

[0221] and the addition salts thereof with pharmaceutically acceptable acids, for the use according to the application.

[0222] In some embodiments, the compound of formula (I) can be characterized in that:

[0223] A represents NR 4 R 5 group,

[0224] R 4 is a hydrogen atom,

[0225] R 5 is a (Ci-C8)alkyl group, said alkyl group being optionally substituted with one or more substituents independently selected from a halogen atom, a hydroxyl group, a -OCOR a group and a NR 6 R 7 group, one or more carbon atoms of said alkyl group being optionally replaced with a nitrogen atom, R 5 is preferably a (Ci-C6)alkyl group, said alkyl group being optionally substituted with one hydroxyl group, and one of the carbon atoms of said alkyl group being optionally replaced with a nitrogen atom,

[0226] R a represents a (Ci-C6)alkyl group, said alkyl group being optionally substituted with an amino group,

[0227] or alternatively, R 4 and R 5 may form, with the nitrogen atom that bears them, a (C3-C6)heterocycloalkyl group, said (C3-C6)heterocycloalkyl group being optionally substituted with one or more substituents independently selected from a (Ci-C4)alkyl group, a NR 6 R 7 group and a halogen atom, and

[0228] R 6 and R 7 independently of each other represent a hydrogen atom or a (Ci-C6)alkyl group,

[0229] and the addition salts thereof with pharmaceutically acceptable acids.

[0230] In some embodiments, A represents a group NR 4 R 5 group:

[0231]

[0232] In some embodiments, the compound of formula (I) can be characterized in that:

[0233] R 3is a (C1-C6)alkyl, (C1-C6)cycloalkyl, aryl or -CH2-aryl group, said alkyl, cycloalkyl and aryl groups being optionally substituted with one or more substituents independently selected from a halogen atom, a hydroxyl and a NH2group, and preferably R 3 represents a cyclopentyl, isopropyl or benzyl group.

[0234] More specific compounds are summarized in the following table, which can be used in the framework of the present application.

[0235] Table 1

[0236]

[0237]

[0238]

[0239]

[0240] According to a preferred embodiment of the present application, the compound of formula (I) for use according to the present application is selected from those disclosed in Table 1 above herein, and in particular from the compounds 13, 14, 15, 18, 20, 22, 23, 26, 31, 38 and Aftin-5, and more particularly Aftin-5 and compound 13.

[0241] Illustratively, the compound of formula (I) for use according to the present application is selected from the compounds of the following formulae:

[0242]

[0243] The compounds of formula (I) can be prepared according to any suitable method from the prior art, for example the preparation procedures described in EP 2 664 619 and variations of these procedures, which can be implemented starting from the knowledge of the person skilled in the art.

[0244] Novel compounds of formula (I)

[0245] The present application further relates to the new sub-classes of compounds of formula (I) as defined hereinafter.

[0246] The present application more particularly relates to the compounds of formula (I)

[0247]

[0248] wherein

[0249] M represents NR 1 R 2 group, OR 1 group or SR1 group,

[0250] A represents NR 4 R 5 group,

[0251] R 1 is an aryl, heteroaryl, -CH2-aryl or -CH2-heteroaryl group, said aryl and heteroaryl groups being optionally substituted by one or more substituents independently selected from a halogen atom, a CF3 group, a hydroxyl group, an OR 6 group, a SR 6 group, a NR 6 R 7 group, a CN group, a CONR 6 R 7 group, a SOR 6 group, a SO2R 6 group, an azido group (-N3), an aryl group, a heteroaryl group and a (C1-C6)alkyl group,

[0252] R 2 is a (C1-C6)alkyl or (C1-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted by one or more substituents independently selected from a halogen atom, a hydroxyl group and a NH2 group,

[0253] or R 1 and R 2 form, together with the nitrogen atom which bears them, a heterobicycle, 1 and R 2 form, together with the nitrogen atom which bears them, a heterobicycle,

[0254] R 6 and R 7 independently of one another represent a hydrogen atom or a (C1-C6)alkyl group,

[0255] R 3 is a (C1-C6)alkyl, (C1-C6)cycloalkyl, aryl, -CH2-aryl, CH2-(C1-C6)cycloalkyl or -CH2-heteroaryl group, said alkyl, cycloalkyl, aryl and heteroaryl groups being optionally substituted by one or more substituents independently selected from a halogen atom, a hydroxyl group and a NH2 group,

[0256] R 4 is a hydrogen atom, a (C1-C6)alkyl, (C1-C6)cycloalkyl, aryl or heteroaryl group, said alkyl and cycloalkyl groups being optionally substituted by one or more substituents independently selected from a halogen atom, a hydroxyl group and a NH2 group, said aryl and heteroaryl groups being optionally substituted by one or more substituents selected from a halogen atom, a hydroxyl group, a NH2 group and a NH-R 9 group,

[0257] R 9is a heteroaryl group optionally substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a NH2 group and a heteroaryl group,

[0258] R 5 is a (Ci-C8)alkyl group or a (Ci-C6)cycloalkyl group, said alkyl and cycloalkyl groups being optionally substituted with one, two or three -OCOR a groups, or with one, two or three -OP(O)(OH)OR a groups, one or more of the carbon atoms of said alkyl or cycloalkyl groups being optionally replaced with a nitrogen atom,

[0259] R a represents a (Ci-C6)alkyl group, said alkyl group being optionally substituted with an amino group,

[0260] R 10 is a hydrogen atom, a (Ci-C6)alkyl group, a (Ci-C6)cycloalkyl group, an aryl group, a heteroaryl group, -CH2-aryl or -CH2-heteroaryl, said aryl group being optionally substituted with one or more substituents selected from a halogen atom, a hydroxyl group, an OR 6 group, an SR 6 group, an NR 6 R 7 group, a CN group, a CONR 6 R 7 group, a SO2NR 6 R 7 group, a SOR 6 group, a SO2R 6 group and an azido group (N3),

[0261] as well as the addition salts thereof with a pharmaceutically acceptable acid.

[0262] In other words, the R 5 group must include an ester, which can be derived from a natural or unnatural amino acid.

[0263] According to a particular embodiment, the present application relates to the new compounds of formula (I) as defined above, wherein R 5 is a (Ci-C8)alkyl group substituted with one -OCOR a group, one or more of the carbon atoms of said alkyl group being optionally replaced with a nitrogen atom,

[0264] R a represents a (Ci-C6)alkyl group, said alkyl group being optionally substituted with an amino group,

[0265] as well as the addition salts thereof with a pharmaceutically acceptable acid.

[0266] According to an even more specific embodiment, the present application relates to compounds of formula (I) selected from

[0267]

[0268] and the addition salts thereof with a pharmaceutically acceptable acid, such as mineral acids, for example hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, and organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid, benzoic acid, toluene- sulfonic acid, methanesulfonic acid, stearic acid and lactic acid.

[0269] Typically, the new compounds of formula (I) carrying a -OCOR a group can be synthesized starting from compounds of formula (I) carrying an OH group in their R 5 group according to conventional practice well known to the person skilled in the art via an esterification step. Examples 3 and 4 hereafter illustrate these new compounds.

[0270] Such compounds of formula (I) can be prodrugs forming active or inactive metabolites when administered to a patient.

[0271] Use

[0272] The compounds of formula (I), any of the other sub-formulae as defined above, or any of the pharmaceutically acceptable salts thereof can be used in the treatment of acquired brain injury (ABI).

[0273] Acquired brain injury (ABI) is a damage to the brain that is not genetic, congenital, degenerative, or induced by birth trauma. In essence, this type of brain injury is a brain injury that has occurred after birth. The injury results in a change in the neuronal activity of the brain, which affects the physical integrity, metabolic activity, or functional ability of the nerve cells in the brain.

[0274] In other words, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and more particularly Alzheimer's disease, are clearly not encompassed within the scope of the present application.

[0275] There are two types of ABI as defined by the Brain Injury Association: traumatic brain injury (TBI) and non-traumatic brain injury.

[0276] Traumatic brain injury (TBI) is defined as a change in brain function, or other evidence of brain pathology, caused by an external force. Traumatic impact injuries can be defined as either closed (or non-penetrating) or open (penetrating). They are usually caused by a mechanical impact or acceleration-deceleration injury, which results in skull fractures, compression of brain tissue and lacerations of white and grey matter and subsequent hemorrhage (Bramlett et al., Journal of Cerebral Blood Flow & Metabolism, 24: 133-150, 2004).

[0277] There are two main mechanisms of TBI: those involving an impact to the head (traumatic impact) and those involving an inertial force affecting the brain (traumatic inertial). Examples of TBI include falls, assaults, motor vehicle accidents and sports injuries. Different forms of lesions can result from TBI in all contusive, compressive, diffuse axonal injuries and hemorrhagic pathologies.

[0278] Non-traumatic brain injuries are changes in brain function or pathology caused by internal forces. These can be caused by stroke (hemorrhage, blood clots), infectious diseases (meningitis, encephalitis), seizures, electric shock, tumors, toxic exposures, metabolic disorders, neurotoxic poisoning (carbon monoxide, lead exposure), hypoxia (drowning, asphyxiation, hypoxic / anoxic injury), or drug overdose.

[0279] According to one embodiment, the present application focuses primarily on non-traumatic brain injuries, and in particular on hypoxic injuries, and more particularly on neonatal hypoxic-ischemic (HI) and neonatal hypoxic-ischemic encephalopathy (HIE).

[0280] These conditions are usually caused by birth asphyxia, which results in a severe reduction of cerebral blood flow (CBF) and leads to a lack of oxygen and glucose delivery, and potentially the accumulation of toxic substances.

[0281] Typically, non-traumatic acquired brain injuries (ABI) are caused by stroke (i.e. embolism, thrombosis, aneurysm), tumors, brain hemorrhage (intracranial surgery, hemorrhage, hematoma), infectious diseases affecting the brain (i.e. meningitis), toxic exposures (carbon monoxide poisoning, inhalation of toxic chemicals, solvent inhalation, excessive and long-term use of drugs and / or alcohol) or lack of oxygen supply to the brain (i.e. heart attack, near-drowning, anoxia / hypoxia, drug overdose).

[0282] In one embodiment, the non-traumatic acquired brain injury (ABI) is caused by brain tumors, metabolic disorders, exposure to toxins, arteriovenous malformations in the cerebral vasculature, cerebral hemorrhage, status epilepticus, diabetes, alcohol and / or drug intake, hypoxic brain injury / anoxic brain injury, hypoxia-ischemia, hypoxic-ischemic encephalopathy, diffuse brain hypoxia, focal brain ischemia, cerebral infarction, global cerebral ischemia and cerebral encephalopathy.

[0283] In one embodiment, the non-traumatic acquired brain injury (ABI) can typically be caused by pressure from a tumor, hypoxia or exposure to at least one toxin.

[0284] According to another embodiment, the use according to the application relates to the treatment of acquired brain injury caused by hypoxia.

[0285] According to a particular embodiment, the non-traumatic acquired brain injury is a hypoxic injury.

[0286] According to another particular embodiment, the non-traumatic acquired brain injury is neonatal encephalopathy, including neonatal hypoxic-ischemic (HI) and neonatal hypoxic-ischemic encephalopathy (HIE).

[0287] HIE injury is the result of insufficient blood flow to the brain combined with a lower than normal oxygen concentration in the arterial blood. This event can lead to significant mortality and long-term neurological deficits, such as cerebral palsy, epilepsy, severe learning and mental impairment, cognitive development problems, and motor and behavioral problems in the developing and developing brain.

[0288] It has been observed that the BBB permeability is affected following brain injury caused in particular by hypoxia.

[0289] That is, BBB permeability abnormalities after HI are multifactorial and involve factors such as energy expenditure, release of reactive oxygen species (ROS) and local inflammation (Riljak, V., et al., Pathophysiology of Perinatal Hypoxic-Ischemic Encephalopathy - Biomarkers, Animal Models and Treatment Perspectives, Physiological Research, 2016, 65: pp. S533-S545; del Zoppo, G.J., Inflammation and the neurovascular unit in the setting of focal cerebral ischemia, Neuroscience, 2009, 158(3): pp. 972-982.). These lesions are observed early after HI injury (hours to days).

[0290] Based on the biological activity shown in the experimental data below, the compounds of formula (I) can be used in the treatment of any of the disorders as mentioned above.

[0291] Aftin compounds were previously disclosed in WO2018 / 189122 as having a positive effect on some markers associated with Alzheimer’s disease (AD) and thus can be used in the treatment of neurodegenerative and / or neuroinflammatory disorders.

[0292] The inventors have now surprisingly demonstrated that said Aftin compounds present the ability to reduce and / or repair brain injury lesions. This was never disclosed before. Indeed, WO2018 / 189122 only demonstrated that Aftin-5 is able to cross the BBB but did not disclose or suggest a repairing effect on the brain. As will be presented by the ‘Examples’ section below, the experimental data provide a consolidated evidence in favor of the use of compounds of formula (I) such as, for example, Aftin-5 and compound 13 to effectively repair and / or reduce brain injury lesions, in particular brain injury lesions caused by hypoxia.

[0293] According to one embodiment, the present application relates to a compound of formula (I) for use in the treatment of a brain injury lesion, in particular a brain injury lesion caused by hypoxia, as defined above.

[0294] According to a preferred embodiment of the application, a compound of formula (I), or one of its pharmaceutically acceptable salts, in particular a compound selected from compounds 13, 14, 15, 18, 20, 22, 23, 26, 31, 38 and Aftin-5, and more particularly Aftin-5 and compound 13, selected from those disclosed in Table 1 above, is used for the treatment of neonatal encephalopathy, including hypoxic-ischemic (HI) and hypoxic-ischemic encephalopathy (HIE).

[0295] Surprisingly, in the well-characterized Rice-Vannucci neonatal HI model, the inventors demonstrated a sustained reduction in brain injury lesions (Figure 1) and an increase in neurotrophic markers in the brain after administration of Aftin compounds. They demonstrated that Aftin helps to reduce neurovascular changes and brain injury and can prevent long-term negative outcomes. In addition, in vitro studies on rodent blood brain barrier (BBB) models showed that this family of molecules is able to cross the BBB, distribute to the brain parenchyma and reverse BBB leakage under inflammatory stress (Figure 2).

[0296] In one aspect, the present application further relates to the use of at least one compound of formula (I), any of the other sub-formulae, or any of its pharmaceutically acceptable salts, as defined above, for the manufacture of a pharmaceutical composition intended for the treatment of non-traumatic acquired brain injury (ABI), in particular for the treatment of hypoxic injury, and more particularly for the treatment of hypoxic-ischemic (HI) and hypoxic-ischemic encephalopathy (HIE).

[0297] In another aspect, the present application relates to a method for the treatment of non-traumatic acquired brain injury (ABI), in particular for the treatment of hypoxic injury, and more particularly for the treatment of hypoxic-ischemic (HI) and hypoxic-ischemic encephalopathy (HIE) in an individual in need thereof, comprising the administration of an effective amount of a compound of formula (I), any of the other sub-formulae, or any of its pharmaceutically acceptable salts, as defined above, optionally in a pharmaceutically acceptable vehicle.

[0298] In particular, the individual in need is an individual suffering from non-traumatic acquired brain injury (ABI), in particular from hypoxic injury, and more particularly from hypoxic-ischemic (HI) or hypoxic-ischemic encephalopathy (HIE). In a particular embodiment, the individual is an infant. Preferably, the infant is a neonate.

[0299] The compound of formula (I) can be implemented in any type of pharmaceutical composition.

[0300] Formulations of the pharmaceutical compositions according to the present application comprising at least one compound of formula (I) or any of the sub-formulae as defined above can be prepared according to procedures known in the art and techniques applicable.

[0301] In some embodiments, suitable pharmaceutically acceptable vehicles according to the present application include any and all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.

[0302] In certain embodiments, suitable pharmaceutically acceptable vehicles can include water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and combinations thereof.

[0303] In some embodiments, the pharmaceutically acceptable vehicle can further comprise a minor amount of auxiliary substances or excipients such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the active ingredient. The preparation and use of pharmaceutically acceptable vehicles is well known in the art. The aforementioned excipients are selected according to the dosage form and the desired mode of administration.

[0304] The use of any and all conventionally known media or agents which are incompatible with the active ingredient are excluded from the pharmaceutical compositions of the present application.

[0305] In some embodiments, the active agent, e.g., in the form of a pharmaceutical composition, can be administered by any suitable route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical, mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation and / or inhalation; and / or as oral, nasal, and / or aerosol spray.

[0306] In some embodiments, the active agent is administered by oral administration or systemic intravenous administration.

[0307] In certain embodiments, the administration of the pharmaceutical composition by injection can be performed directly in the target tissue of interest, in particular in order to avoid the diffusion of the active ingredient in the pharmaceutical composition.

[0308] Other modes of administration employ pulmonary formulations, suppositories, and transdermal application.

[0309] In some embodiments, oral formulations according to the present application include conventional excipients such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.

[0310] In some embodiments, an effective amount of the compound is administered to the individual in need thereof.

[0311] It is within the knowledge of the skilled person to determine an effective amount of a compound of formula (I) as active ingredient to observe a desired result.

[0312] Within the scope of the application, the effective amount of the compound to be administered can be determined by a physician or skilled person and can be adjusted appropriately over the course of therapy.

[0313] In certain embodiments, the effective amount to be administered can depend on a variety of parameters including the substance chosen for administration, whether the administration is in single or multiple doses, and individual parameters (including age, physical condition, size, weight, sex) as well as the severity of the disorder to be treated.

[0314] In certain embodiments, the effective amount of active agent can range from about 0.001 mg to about 3000 mg per dosage unit, preferably from about 0.05 mg to about 100 mg per dosage unit.

[0315] Within the scope of the present application, about 0.001 mg to about 3000 mg includes about 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, and 2950 mg per dosage unit.

[0316] In certain embodiments, the active agent can be administered at a dosage level sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg of body weight of the subject per day.

[0317] In certain embodiments, each dosage unit can be administered three times per day, twice per day, once per day, every other day, every third day, weekly, every two weeks, every three weeks, or every four weeks.

[0318] In certain embodiments, the therapeutic treatment encompasses administration of multiple dosage units, including two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations.

[0319] In certain embodiments, the treatment of the disorders encompassed can include administration of a compound of Formula (I) or any of the other subformulae as defined above in combination with another compound, in particular a compound known in the art to be beneficial to a subject in need thereof in respect of the disorder, to a subject in need thereof.

[0320] The present application will be better understood by reference to the following examples and figures, which are provided merely for illustrative purposes and should not be construed as limiting the present application in any way. Examples

[0321] Example 1

[0322] Scheme

[0323] The study was approved by the Institutional Animal Care and Use Committees of the Alpert Medical School of Brown University and the Women & Infants Hospital of Rhode Island and was in compliance with the National Institutes of Health Guidelines for the use of laboratory animals.

[0324] The subjects were Wistar rats born from time-mated dams obtained from Charles River Laboratory (Wilmington, Maine, USA).

[0325] The rats at postnatal day 7 (P7) (CNS maturation corresponding to human gestational age 32-34 weeks) were divided into 3 groups: sham-operated group, HI+PL or HI+Compound 13.

[0326] In the sham-operated group, hypoxia-ischemia was not induced in the rats. This group was used as a control group.

[0327] In the HI+PL group (where PL stands for placebo), hypoxia-ischemia was induced in the rats. The rats were then further administered with a saline vehicle used as a placebo.

[0328] In the HI + Compound 13 group, hypoxia-ischemia was induced in the rats. The rats were then further administered a dose of Compound 13, which is a compound of Formula (I) according to the present application.

[0329] HI injury was induced in the HI + PL and HI + Compound 13 groups using the Rice-Vanucci method (Rice JE et al., 1981).

[0330] In summary, each animal in all three groups was anesthetized using 3-4% isoflurane and verified to be completely free of leg withdrawal reflex prior to surgery.

[0331] A midline ventral incision was made in the neck. The right common carotid artery (RCCA) was located and ligated with a 5-0 silk suture in the HI + PL and HI + Compound 13 groups. Sham subjects followed the same procedure except there was no RCCA ligation.

[0332] The neck incision was sutured using a 5-0 silk suture. During the surgical procedure, the body temperature was maintained at 36°C using an isothermal heating pad, as reduced temperature has been shown to provide some degree of neuroprotection in human and animal models (Marks K et al., 2010; Mishima K et al., 2004; Reinboth BS et al., 2016; Silveira RC and Procianoy RS, 2015).

[0333] Postoperatively, all rats were returned to their dams for recovery during 1.5-3h prior to hypoxia.

[0334] HI subjects from the HI + PL and HI + Compound 13 groups were placed in a hypoxic chamber with 8% humidified oxygen (equilibrated with nitrogen) for 90 min, where the chamber temperature was maintained between 35-36°C. Sham subjects were exposed to room air for 90 min.

[0335] These conditions resulted in a reproducible amount of brain injury in rats at postnatal day 10 (P10), 72h post-surgery, whose brain maturation is equivalent to a term neonate.

[0336] Immediately after hypoxia induction, all rats from the HI + PL and HI + Compound 13 groups received an intraperitoneal (IP) injection of 30mg / kg of Compound 13 (HI + Compound 13 group) or an equal volume of vehicle (DMSO / PEG / saline) (HI + PL group).

[0337] All rats were then returned to their dams until the second and third 30mg / kg IP treatment doses of Compound 13 or vehicle were administered at 24h and 48h post-surgery.

[0338] 72 hours after HI injury (P10), rats were euthanized, and their brains and blood were collected for RT-qPCR, Western blot immunoassay, and bioplex analysis. Some young rats were perfused with saline via the heart, followed by perfusion with 10% paraformaldehyde (PFA).

[0339] The fixed tissue sections were then mounted on a glass slide, stained with cresol violet, and treated for infarct volume measurement. Figure 1B ) and immunohistochemical analysis ( Figure 1A ).

[0340] Infarction is calculated as a percentage of the volume of the lesion to the total volume of the contralateral hemisphere after adjusting for hemispheric edema, according to the following formula: Infarction (%) = [1 - (total volume of the ipsilateral hemisphere - volume of the infarction) / total volume of the contralateral hemisphere)] × 100%.

[0341] Results

[0342] The inventors noted that, compared with the HI+PL hemisphere, in the HI+compound group 13, the infarct area in males (apical row) and females (basal row) was statistically reduced after treatment with the compound of formula (I) (statistical analysis by one-way ANOVA and Bonferroni post-hoc test, *P<0.05; **P<0.01; ***P<0.001).

[0343] Example 2

[0344] Scheme

[0345] Studying radiolabeled sucrose ( ) in a primary rat cell-based BBB (blood-brain barrier) model. 14 The permeability of C-sucrose (a permeability marker). At 10 -6 cm.s -1 Measure permeability. 14 C-sucrose is a small molecular weight marker of 342 Da, which tends to reflect cellular bypass disruption.

[0346] To induce increased BBB permeability, lipopolysaccharide (LPS) was injected. LPS induces increased BBB permeability by stimulating the formation and release of cytokines and other molecules.

[0347] In this embodiment, two different Aftin compounds were tested: Aftin-5 ( Figure 2A (left side) and compound 13 ( Figure 2A (Right side).

[0348] In both cases, the permeability of the BBB untreated was used as a positive control, i.e. as a representation of the permeability of the BBB when it is not affected by non-traumatic ABI.

[0349] Injection of 10 ng / mL of LPS was used to represent the permeability of the BBB after inflammatory damage, such as that induced by non-traumatic ABI.

[0350] Aftin-5 or Compound 13 was administered in two different doses, with or without LPS: 0.1 μΜ and 1 μΜ.

[0351] Results

[0352] The permeability test shows that the administration of Aftin compounds of formula (I) according to the present application, such as Aftin-5 or Compound 13, statistically restores the permeability of the BBB under inflammatory stress conditions (statistical analysis by one-way ANOVA and Dunnett post-hoc test, *P < 0.05; **P < 0.01; ***P < 0.001).

[0353] The Aftin family of molecules is able to cross the BBB to distribute to the brain parenchyma and reverse BBB leakage under inflammatory stress.

[0354] Conclusion

[0355] These preliminary results show that Aftins represent an important new class of molecules for the treatment of HIE in newborns.

[0356] In fact, these results provide new insights on the way Aftins can restore or attenuate BBB dysfunction, improve brain metabolism and thus restore neuronal function after HI injury in newborns.

[0357] This therapeutic strategy can potentially represent an important adjuvant agent for the treatment of hypothermia for HIE in infants and prove effective for the treatment of premature babies, for which there are currently no treatments available other than supportive care.

[0358] Example 3

[0359] Preparation of Compound 50: (2S)-2-amino-3-methyl-butyric acid [(2R)-2-[[6-[benzyl(ethyl)amino]-9-isopropyl-purin-2-yl]amino]butyl] ester hydrochloride or L-valyl ester hydrochloride of (2R)-2-[[6-[benzyl(ethyl)amino]-9-isopropyl-purin-2-yl]amino]butan-1-ol.

[0360] Compound (50) was obtained as depicted in the following scheme by reacting compound 13 with an excess of Boc-valine HOBt ester to give 50a. In the second step, the Boc protecting group was removed by using anhydrous HC1.

[0361]

[0362] Reagents and conditions. a: Boc-valine, DCC, HOBt. b: compound 13, c: HC1, Et20.

[0363] (2S)-2-(tert-Butoxycarbonylamino)-3-methyl-butyric acid [(2R)-2-[[6-[benzyl(ethyl)amino]- 9-isopropyl-purin-2-yl]amino]butyl] ester (compound 50a)

[0364] Dicyclohexyl carbodiimide (DCC) (2.44 g) was added to a solution of tert-butoxycarbonyl valine, Boc-valine (4.57 g) and 1-hydroxybenzotriazole - HOBt (2.49 g) in 150 mL of THF-AcOEt (2:1) at 5°C. The cooling bath was removed after 5 min of stirring and stirring was continued at 20°C for 3 h. The suspension was filtered on a Buchner funnel and the precipitate (DCU) was washed twice with 20 mL of AcOEt. The combined filtrate was added to a mixture of compound 13 (6.4 g) and NEt3(4 mL) in THF 100 mL. Stirring was continued for 3 days. The mixture was washed with 200 mL of 1 M Na2C03, then with 100 mL of H20 and 100 mL of brine. The solution was concentrated under vacuum below 40°C. The ester 50a was isolated on a silica gel column chromatography using AcOEt-cyclohexane (1 :1) as eluent. Yield: 45%. NMR (DMSO d6) δ: 0.75 (3H, t J = 6.5 Hz); 1.12 (m, 3H); 1.38 (d, 6H), 1.54 (m, 17H); 1.95 (m, 1H); 3.65 (m, 1H); 4.05 (m, 4H); 4.55 (1H, Hept, J = 6.5 Hz); 5.05 and 5.45 (2 br s, 2H); 6.25 (br s, 1H); 7.25 (m, 5H); 7.80 (s, 1H).

[0365] (2S)-2-Amino-3-methyl-butyric acid [(2R)-2-[[6-[benzyl(ethyl)amino]-9-isopropyl- purin-2-yl]amino]butyl] ester hydrochloride or L-valyl ester hydrochloride of (2R)-2-[[6- [benzyl(ethyl)amino]-9-isopropyl-purin-2-yl]amino]butan-1-ol (compound 50).

[0366] Dissolve ester 50a in anhydrous 50 mL Et20. Add 2M HC1 in Et20 and stir at 20 °C for 24 h. Decant the solvent and triturate the solid with Et20 (3 x 20 mL). Then dry the precipitate under vacuum (P205) for 48 h to give 40. Yield: 43%. NMR (DMSO d6) δ: 0.75 (m, 3H); 1.15 (m, 3H); 1.45 (m 6H), 1.64 (m, 8H); 2.35 (m, 1H); 3.75 (m, 1H); 4.12 (m, 4H); 4.55 (m, 1H); 4.95 and 5.45 (2 br s, 2H); 6.25 (br s, 1H); 7.25 (m, 5H); 8.20 (br s, 1H). 8.45 (m, 3H).

[0367] Preparation of compound 49: (2S)-2-amino-3-methyl-butyric acid [(2R)-2-[[9-isopropyl-6-(N- methylanilino)purin-2-yl]amino]butyl] ester hydrochloride or L-valyl ester hydrochloride of (2R)-2-[[9-isopropyl-6-(N-methylanilino)purin-2-yl]amino]butan-1-ol

[0368] Compound (49) was prepared from Aftin 5 by the same procedure as compound 50. The synthesis of compound 49 is depicted in the following scheme.

[0369]

[0370] Reagents and conditions. a: Boc-valine, DCC, HOBt. b: Aftin 5, c: HC1, Et20.

[0371] (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butyric acid [(2R)-2-[[9-isopropyl-6-(N- methylanilino)purin-2-yl]amino]butyl] ester (compound 49a).

[0372] NMR (DMSO d6) δ: 0.85 (3H, t J = 6.5 Hz); 1.35 (d, 6H), 1.45 (m, 15H); 1.92 (m, 1H); 3.73 (s, 3H); 3.75 (m, 1H); 4.05 (m, 3H); 4.55 (1H, Hept, J = 6.5 Hz); 6.35 (br s, 1H); 7.28 (m, 5H); 7.75 (s, 1H).

[0373] (2S)-2-Amino-3-methyl-butyric acid [(2R)-2-[[9-isopropyl-6-(N- methylaminyl)purin-2-yl]amino]butyl] ester hydrochloride or the L-valyl ester hydrochloride of (2R)-2-[[9-isopropyl-6-(N-methylaminyl)purin-2-yl]amino]butan-1-ol (Compound 49).

[0374] NMR (DMSO d6) δ: 0.95 (3H, t J = 6.5 Hz); 1.10 (d, 6H), 1.55 (2d, 6H); 2.20 (m, IH); 3.75 (s, 3H); 3.85 (m, IH); 4.25 (m, 3H); 4.65 (m, IH); 6.35 (br s, IH); 7.45 (m, 5H); 8.20 (br s, IH). 8.55 (br s, 3H).

Claims

1. A compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid. in M represents NR 1 R 2 Group, A represents NR 4 R 5 Group, R 1 It is a phenyl or -CH2-phenyl group, wherein the phenyl group is optionally substituted by a substituent selected from the following: halogen atom, CF3 group, OR 6 Groups and (C1-C6) alkyl groups, R 2 It is a (C1-C6) alkyl group. R 6 Indicates a hydrogen atom or a (C1-C6) alkyl group. R 3 It is a (C1-C6) alkyl group. R 4 It is a hydrogen atom. R 5 It is a (C1-C8) alkyl group, wherein the alkyl group is separated by a -OCOR a Group substitution, R a The alkyl group represents (C1-C6) alkyl groups, wherein the alkyl group is replaced by an amino group.

2. The compound of formula (I) according to claim 1, wherein the compound is selected from... And its addition salt with a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; and the organic acid is selected from acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid, benzoic acid, toluenesulfonic acid, methanesulfonic acid, stearic acid and lactic acid.

3. Use of a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid in the preparation of a medicament for the treatment of non-traumatic acquired brain injury. in M represents NR 1 R 2 Group, A represents NR 4 R 5 Group, R 1 It is a phenyl or -CH2-phenyl group, wherein the phenyl group is optionally substituted by a substituent selected from the following: halogen atom, CF3 group, OR 6 Groups and (C1-C6) alkyl groups, R 2 It is a (C1-C6) alkyl group. R 6 Indicates a hydrogen atom or a (C1-C6) alkyl group. R 3 It is a (C1-C6) alkyl group. R 4 It is a hydrogen atom. R 5 It is a (C1-C8) alkyl group, wherein the alkyl group is separated by a radical selected from hydroxyl and -OCOR. a Substitution of groups, R a The alkyl group represents (C1-C6) alkyl groups, wherein the alkyl group is replaced by an amino group.

4. The use according to claim 3, wherein M represents NR 1 R 2 Group, and the NR 1 R 2 The group is selected from the following groups:

5. The use according to claim 3, wherein A represents NR selected from the following groups. 4 R 5 Group 6. The use according to claim 3, wherein the compound is selected from compounds 13, 20, 23, 26, 38 and Aftin-5 as defined below.

7. The use according to claim 3, wherein the non-traumatic acquired brain injury is caused by brain tumors, metabolic disorders, toxic exposure, arteriovenous malformations in the cerebral vascular system, cerebral hemorrhage, status epilepticus, diabetes, alcohol and / or drug intake, hypoxic-ischemic brain injury, hypoxia-ischemia, hypoxic-ischemic encephalopathy, diffuse cerebral hypoxia, focal cerebral ischemia, cerebral infarction, global cerebral ischemia, and cerebrovascular encephalopathy.

8. The use according to claim 3, wherein the non-traumatic acquired brain injury is caused by hypoxia.

9. The use according to claim 8, wherein the non-traumatic acquired brain injury is hypoxic injury.

10. The use according to claim 9, wherein the non-traumatic acquired brain injury is neonatal encephalopathy, including neonatal hypoxic-ischemic encephalopathy and neonatal hypoxic-ischemic encephalopathy.

11. The use according to claim 3, wherein the compound of formula (I) reduces and / or repairs the brain injury lesion.

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