EP1587508A1 - Utilisation therapeutique d 'acylglycerols et de leurs analogues azotes et sulfures - Google Patents

Utilisation therapeutique d 'acylglycerols et de leurs analogues azotes et sulfures

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Publication number
EP1587508A1
EP1587508A1 EP04707252A EP04707252A EP1587508A1 EP 1587508 A1 EP1587508 A1 EP 1587508A1 EP 04707252 A EP04707252 A EP 04707252A EP 04707252 A EP04707252 A EP 04707252A EP 1587508 A1 EP1587508 A1 EP 1587508A1
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EP
European Patent Office
Prior art keywords
group
use according
compound
carbon atoms
groups
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP04707252A
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German (de)
English (en)
French (fr)
Inventor
Raphael Darteil
Karine Caumont-Bertrand
Jamila Najib
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Genfit SA
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Genfit SA
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Publication of EP1587508A1 publication Critical patent/EP1587508A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/28—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms

Definitions

  • the present invention relates to the use of acylglycerols and their nitrogen and sulfur analogues in the therapeutic field, in particular for the treatment of cerebral ischemia. It also relates to processes for the preparation of these derivatives. It also relates to new particular compounds of acylglycerols and their nitrogen and sulfur analogues and their preparation methods.
  • the compounds of the invention have advantageous pharmacological, antioxidant and anti-inflammatory properties.
  • the invention also describes the methods of therapeutic treatment using these compounds and pharmaceutical compositions containing them.
  • the compounds of the invention can be used in particular for preventing or treating cerebrovascular accidents.
  • cerebrovascular pathology (150,000 new cases per year) represents the third cause of death and the first cause of disability in adults.
  • Ischemic and hemorrhagic accidents respectively concern 80% and 20% of this pathology.
  • Ischemic strokes are an important therapeutic issue to reduce the morbidity and mortality of this condition.
  • Advances have been made not only in the treatment of the acute phase of ischemia but also in its prevention. It is also important to note that the identification and management of risk factors are essential to the treatment of this pathology.
  • Drug treatments for ischemic strokes are based on different strategies.
  • a first strategy is to prevent the occurrence of ischemic strokes by preventing risk factors (high blood pressure, high cholesterol, diabetes, atrial fibrillation, etc.) or by preventing thrombosis, in particular using anti - platelet aggregators or anticoagulants (Adams 2002).
  • a second strategy is to treat the acute phase of ischemia in order to reduce the long-term consequences (Lutsep and Clark 2001).
  • the penumbra zone the intermediate zone between the heart of the ischemia where the neurons are necrotic and the intact nervous tissue, is the site of a physiopathological cascade which leads to within a few days of neuronal death, if reperfusion is not ensured or if neuroprotection is not effective enough.
  • the first event which occurs within the first few hours, is a massive release of glutamate which results in neuronal depolarization as well as cellular edema.
  • the entry of calcium into the cell induces mitochondrial damage promoting the release of free radicals as well as the induction of enzymes which cause the membrane degradation of neurons.
  • NF- ⁇ B transcription factors
  • This activation induces inflammatory processes such as the induction of adhesion proteins at the endothelial level, the infiltration of the ischemic focus by neutrophils, microglial activation, the induction of enzymes such as nitric oxide (NO) synthase type II or type II cyclooxygenase.
  • NO nitric oxide
  • These inflammatory processes lead to the release of NO or prostanoids which are toxic to the cell. All of these processes result in a phenomenon of apoptosis causing irreversible lesions (Dirnagl, ladecola et al. 1999).
  • prophylactic neuroprotection is based on experimental bases demonstrating resistance to ischemia in animal models. Indeed, various procedures applied prior to the realization of an experimental cerebral ischemia make it possible to make it less severe. Different stimuli make it possible to induce resistance to cerebral ischemia: preconditioning (brief ischemia preceding prolonged ischemia); thermal stress; administration of a low dose of bacterial lipopolysaccharide (Bordet, Deplanque et al. 2000). These stimuli induce resistance mechanisms which activate signals triggering the protective mechanisms. Different triggering mechanisms have been highlighted: cytokines, pathways of inflammation, free radicals, NO, ATP-dependent potassium channels, adenosine.
  • PPARs ( ⁇ , ⁇ , ⁇ ) belong to the family of hormone activated nuclear receptors. When activated by an association with their ligand, they heterodimerize with the Retinoid-X-Receptor (RXR) and then bind to "Peroxisome Proliferator Response Elements" (PPREs) which are localized in the promoter sequence of the target genes. The binding of PPAR to PPRE thus induces the expression of the target gene (Fruchart, Staels et al. 2001).
  • PPARs are distributed in a wide variety of organs, but with a certain specificity for each of them, with the exception of PPAR ⁇ , the expression of which seems ubiquitous.
  • the expression of PPAR ⁇ is particularly important in the liver and along the intestinal wall whereas PPAR ⁇ is mainly expressed in adipose tissue and the spleen.
  • ⁇ , ⁇ , ⁇ the three subtypes ( ⁇ , ⁇ , ⁇ ) are expressed.
  • Cells such as oligodendrocytes as well as astrocytes express more particularly the PPAR ⁇ subtype (Kainu, Wikstrom et al. 1994).
  • the target genes of PPARs control the metabolism of lipids and carbohydrates.
  • PPARs participate in other biological processes.
  • PPARs The activation of PPARs by their ligands induces the change in the transcriptional activity of genes which modulate the inflammatory process, antioxidant enzymes, angiogenesis, cell proliferation and differentiation, apoptosis, the activities of iNOS, MMPases and TIMPs (Smith, Dipreta et al. 2001) (Clark 2002).
  • Free radicals are involved in a very broad spectrum of pathologies such as allergies, cancer initiation and promotion, cardiovascular pathologies (atherosclerosis, ischemia), genetic and metabolic disorders (diabetes), infectious and degenerative diseases (Prion, etc. .) as well as ophthalmic problems (Mates, Perez-Gomez et al. 1999).
  • ROS Reactive oxygen species
  • the management of ROS is done via an antioxidant system which includes an enzymatic and non-enzymatic component.
  • the enzyme system consists of several enzymes, the characteristics of which are as follows: - Superoxide dismutase (SOD) destroys the superoxide radical by converting it into peroxide. The latter is itself supported by a other enzyme system. A low level of SOD is constantly generated by aerobic respiration.
  • SOD Superoxide dismutase
  • Three classes of SOD have been identified in humans, each containing Cu, Zn, Fe, Mn, or Ni as a cofactor.
  • the three forms of human SOD are distributed as follows Cu-Zn SOD which are cytosolic, a mitochondrial Mn-SOD and an extracellular SOD.
  • Catalase is very effective in converting hydrogen peroxide (H 2 0 2 ) into water and into 0 2 . Hydrogen peroxide is catabolized enzymatically in aerobic organisms. Catalase also catalyzes the reduction of a variety of hydroperoxides (ROOH).
  • ROOH hydroperoxides
  • Glutathione peroxidase contains selenium as a cofactor and catalyzes the reduction of hydroperoxides (ROOH and H 2 0 2 ) using glutathione, and thus protects cells against oxidative damage.
  • Non-enzymatic antioxidant cell defenses are made up of molecules that are synthesized or provided by food.
  • antioxidant molecules present in different cellular compartments.
  • Detoxifying enzymes are for example responsible for eliminating free radicals and are essential for the life of the cell.
  • the three most important types of antioxidant compounds are carotenoids, vitamin C and vitamin E (Gilgun-Sherki, Melamed et al. 2001).
  • the inventors have developed compounds capable of preventing the appearance of the risk factors described above and capable of exerting a prophylactic activity in terms of neuroprotection, but also to ensure active neuroprotection in the acute phase of ischemic strokes.
  • the compounds according to the invention have at the same time properties of PPAR activators, antioxidants and anti-inflammatory drugs and, as such, the compounds have a high therapeutic or prophylactic potential for ischemic strokes.
  • the present invention thus provides a family of compounds having advantageous pharmacological properties and usable for the curative or preventive treatment of cerebral ischemia. It also relates to processes for the preparation of these derivatives.
  • G represents an oxygen atom, a sulfur atom or an N- R4 group
  • R4 is a hydrogen atom or a linear or branched alkyl group, saturated or not, optionally substituted, containing from 1 to 5 carbon atoms,
  • R1, R2 and R3, identical or different, represent a hydrogen atom, a CO-R group or a group of formula
  • R is a linear or branched alkyl group, saturated or unsaturated, optionally substituted, the main chain of which contains from 1 to 25 carbon atoms,
  • X is a sulfur atom, a selenium atom, an SO group or an S0 2 group,
  • n is an integer between 0 and 11
  • R ' is a linear or branched alkyl group, saturated or not, optionally substituted, the main chain of which comprises from 2 to 23, preferably 10 to 23, carbon atoms and optionally one or more heterogroups chosen from an oxygen atom , a sulfur atom, a selenium atom, an SO group and an S0 2 group.
  • the group or groups R which are identical or different, preferably represent a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl group, the main chain of which comprises from 1 to 20 carbon atoms, even more preferably from 7 to 17 carbon atoms, even more preferably from 14 to 17 carbon atoms.
  • the group or groups R which are identical or different, can also represent a lower alkyl group comprising from 1 to 6 carbon atoms, such as in particular the methyl, ethyl, propyl radical , isopropyl, butyl, isobutyl, pentyl or hexyl.
  • the compounds of formula (I) are characterized in that one or two of the substituents R1, R2 and R3 is a COCH 3 group.
  • the group or groups R ′ which are identical or different, preferably represent a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl group, the main chain of which comprises from 12 to 23 carbon atoms, even more preferably from 13 to 20 carbon atoms.
  • R ′ represents a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl group, the main chain of which contains from 14 to 17 carbon atoms, even more advantageously 14 carbon atoms.
  • saturated long chain alkyl groups for R or R ′ are in particular the groups C 7 H ⁇ 5 , C ⁇ 0 H 21 , CnH 2 3. C- ⁇ 2 H 25 , C13H27, C 14 H 29 , Ci ⁇ H 3 ⁇ , C ⁇ 6 H 33 , C ⁇ 7 H 35 .
  • chain alkyl groups long unsaturated for R or R ' are in particular the groups C14H25, C ⁇ 4 H 27 , C15H29, C17H2 9 , C ⁇ 7 H 3 ⁇ , C17H33, C19H2 9 , C 19 H 31 , C 2 ⁇ H 3 ⁇ , C21H35, C21H37, C 2 ⁇ H 39 , C23H45, or the alkyl chains of eicosapentaenoic acid (EPA) C20-5 (5, 8, 11, 14, 17) and docosahexaenoic acid (DHA) C 22: 6 (4, 7, 10, 13, 16, 19).
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • the alkyl groups R or R ′ may optionally comprise a cyclic group.
  • cyclic groups are especially cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the alkyl groups R or R ′ may be optionally substituted by one or more substituents, identical or different.
  • This invention also relates to the optical and geometric isomers of these compounds, their racemates, their salts, their hydrates and their mixtures.
  • the compounds of formula (la) are the compounds of formula (I) according to the invention in which only one of the groups R1, R2 or R3 represents a hydrogen atom.
  • the compounds of formula (Ib) are the compounds of formula (I) according to the invention in which two of the groups R1, R2 or R3 represent a hydrogen atom.
  • R1 and R3, identical or different represent a hydrogen atom or, more particularly, a CO-R group.
  • the present invention also includes the prodrugs of the compounds of formula (I), which, after administration in a subject, will transform into compounds of formula (I) and / or the metabolites of the compounds (I) which exhibit therapeutic activities comparable to compounds of formula (I).
  • the present invention thus relates to the use of a compound of formula (I) for the preparation of a pharmaceutical composition intended for treating a cerebrovascular pathology, such as cerebral ischemia or a hemorrhagic stroke.
  • composition comprising, in a pharmaceutically acceptable carrier, a compound of general formula (I) as described above, optionally in combination with another therapeutic active.
  • This composition is in particular intended to treat a cerebrovascular pathology, such as cerebral ischemia or a hemorrhagic stroke.
  • X preferably represents a sulfur or selenium atom and advantageously a sulfur atom.
  • R ′ may comprise one or more heterogroups, preferably 0, 1 or 2, more preferably 0 or 1, chosen from an oxygen atom, a sulfur atom, a selenium atom, an SO group or an SO 2 group.
  • a specific example of group CO- (CH 2 ) 2n + rX-R 'according to the invention is the group CO-CH 2 -S-C ⁇ 4 H 29 .
  • the inventors have developed new compounds of formula (I) having a CO-CH 2 -S-Ci 4 H 2 group .
  • the subject of the present invention is therefore the compounds of formula (I) chosen from: - 1, 3-ditetradecylthioacetyl-2-palmitoylglycerol;
  • R1, R2 and R3 represents a group CO- (CH 2 ) 2n + rX-R ' in which X represents a sulfur or selenium atom, preferably a sulfur atom and / or R 'is a saturated and linear alkyl group comprising from 13 to 17 carbon atoms, preferably from 14 to 16, even more preferably 14 carbon atoms.
  • R2 is a group of formula CO- (CH 2 ) 2n + ⁇ -X-R ', in which X represents a sulfur or selenium atom, preferably a sulfur atom and / or R 'is a group as defined above.
  • R4 preferentially represents an atom of hydrogen or a methyl group.
  • R2 advantageously represents a CO- (CH 2 ) 2n + rX-R 'group as defined above.
  • the particular compounds according to the invention are compounds of general formula (I) in which the group G represents a sulfur atom.
  • R1, R2 and R3, identical or different, preferably identical, represent a group CO- (CH 2 ) 2n + ⁇ -XR 'as defined above before, in which X represents a sulfur or selenium atom and preferably a sulfur atom and / or R 'represents a saturated and linear alkyl group comprising from 13 to 17 carbon atoms, preferably from 14 to 17, even more preferably 14 carbon atoms, in which n is preferably between 0 and 3, and in particular equal to 0. More specifically, other preferred compounds are the compounds of general formula (I) in which R1, R2 and R3 represent CO-CH 2 -S-Ci 4 H 2 g groups.
  • Another subject of the present invention relates to any pharmaceutical composition
  • any pharmaceutical composition comprising in a pharmaceutically acceptable carrier at least one compound of formula (I) as described above, and in particular at least one compound of formula (I) chosen from :.
  • the invention also relates to the use of a compound as defined above for the preparation of a pharmaceutical composition intended for the implementation of a method of treatment or prophylaxis in humans or in animals .
  • the invention also relates to a method of treatment of cerebrovascular pathologies and more particularly of cerebral ischemia, comprising the administration to a subject, in particular human, of an effective dose of a compound of formula (I) or of a pharmaceutical composition as defined above.
  • compositions according to the invention advantageously comprise one or more excipients or vehicles, acceptable from the pharmaceutical point of view. Mention may be made, for example, of saline, physiological, isotonic, buffered solutions, etc., compatible with pharmaceutical use and known to those skilled in the art.
  • the compositions may contain one or more agents or vehicles chosen from dispersants, solubilizers, stabilizers, surfactants, preservatives, etc. Agents or vehicles usable in formulations (liquids and / or injectables and / or solids) are in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, etc.
  • compositions may be formulated in the form of an injectable suspension, gels, oils, tablets, suppositories, powders, capsules, capsules, etc., optionally by means of dosage forms or devices ensuring sustained and / or delayed release.
  • an agent such as cellulose, carbonates or starches is advantageously used.
  • the compounds or compositions according to the invention can be administered in different ways and in different forms.
  • they can for example be administered systemically, orally, parenterally, by inhalation or by injection, such as for example by intravenous, intramuscular, subcutaneous, trans-dermal, intra-arterial, etc.
  • the compounds are generally packaged in the form of liquid suspensions, which can be injected using syringes or infusions, for example.
  • the compounds are generally dissolved in saline, physiological, isotonic, buffered solutions, etc., compatible with pharmaceutical use and known to those skilled in the art.
  • compositions can contain one or more agents or vehicles chosen from dispersants, solubilizers, emulsifiers, stabilizers, surfactants, preservatives, buffers, etc.
  • agents or vehicles which can be used in liquid and / or injectable formulations are in particular methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, liposomes, etc.
  • the compounds can thus be administered in the form of gels, oils, tablets, suppositories, powders, capsules, capsules, aerosols, etc., optionally by means of dosage forms or devices ensuring sustained and / or delayed release.
  • an agent such as cellulose, carbonates or starches is advantageously used.
  • the compounds can be administered orally in which case the agents or vehicles used are preferably chosen from water, gelatin, gums, lactose, starch, magnesium stearate, talc, an oil, polyalkylene glycol, etc. .
  • the compounds are preferably administered in the form of solutions, suspensions or emulsions with in particular water, oil or polyalkylene glycols to which it is possible to add, in addition to preservatives, stabilizers, emulsifiers , etc., salts to adjust the osmotic pressure, buffers, etc.
  • the flow rate and / or the dose injected can be adapted by a person skilled in the art depending on the patient, the pathology concerned, the mode of administration, etc.
  • the compounds are administered in doses which can vary between 1 ⁇ g and 2 g per administration, preferably from 0.1 mg to 1 g per administration.
  • the administrations can be daily or repeated several times a day, if necessary.
  • the compositions according to the invention can also comprise other agents or active principles.
  • the invention also relates to methods of preparing compounds of formula (I) as described above.
  • the compounds of the invention can be prepared from commercial products, using a combination of chemical reactions known to those skilled in the art.
  • the invention also relates to processes for the preparation of the compounds as defined above.
  • the compounds of formula (I) in which G is an oxygen or sulfur atom, R1, R2 and R3 identical or different, represent a CO-R group or a CO- group ( CH 2 ) 2n + rX-R ', are obtained from a compound of formula (I) in which G is respectively an oxygen or sulfur atom, R2 is a hydrogen atom and R1 and R3, identical or different, represent a group CO-R or CO- (CH 2 ) 2n + rX-R ', and of a compound of formula A ° -CO-A in which A is a reactive group chosen for example from OH, Cl, 0-CO-A ° and OR ", R" being an alkyl group, and A ° is the group R or the group (CH 2 ) 2 n + ⁇ -X-R ' I , optionally in the presence of coupling agents or activators known to those skilled in the art.
  • a glycerol molecule is reacted with a compound of formula A ° -CO-A1 in which A1 is a reactive group chosen, for example, from OH, Cl and OR ", R" being an alkyl group, and A ° is the group R or the group (CH 2 ) 2n + ⁇ -X-R '. possibly in the presence of coupling agents or activators known to those skilled in the art.
  • This reaction allows the synthesis of so-called symmetrical compounds, in which R1 and R3 have the same meaning.
  • This reaction can be implemented by adapting the protocols described for example in (Feuge, Gros et al. 1953), (Gangadhar, Subbarao et al. 1989), (Han, Cho et al. 1999) or (Robinson 1960).
  • the compounds of formula (I) according to the invention in which G is an oxygen atom, R2 is a hydrogen atom and R1 and R3, identical or different, represent a CO-R or CO- (CH2) 2 group n + ⁇ -X-R ', can also be obtained from a compound of formula (I) according to the invention in which G is an oxygen atom, R2 and R3 represent a hydrogen atom and R1 is a group CO-R or CO- (CH 2 ) 2n + rX-R '(this particular form of compounds of formula (I) being called compounds of formula IV), and of a compound of formula A ° -CO-A2 in which A2 is a reactive group chosen, for example, from OH and Cl, and A ° is the group R or the group (CH 2 ) 2n + rX-R ' .
  • A2 is a reactive group chosen, for example, from OH and CI
  • a ° is the group R or the group optionally in the presence of coupling agents or activators known to those skilled in the art to give a compound of general formula (III)
  • R1 represents a CO-R or CO- (CH2) 2n + ⁇ -XR 'group
  • the compounds of formula (I) in which G is an oxygen atom, R3 is a hydrogen atom and R1 and R2, identical or different, represent a CO-R or CO group - (CH 2 ) 2n + rX-R ', can be obtained from a compound of formula (I) according to the invention in which G is an oxygen atom, R2 and R3 represent a hydrogen atom and R1 is a CO-R or CO- (CH 2 ) 2n + ⁇ -XR 'group (compounds IV), according to the following steps:
  • the reaction can advantageously be carried out by adapting the protocol described by (Gaffney and Reese 1997) in which PxE can represent the compound 9-phenylxanthene-9-ol or 9-chloro-9-phenylxanthene
  • A2 is a reactive group chosen, for example, from OH and Cl
  • a ° is the group R or the group (CH 2 ) 2n + ⁇ -X-R'- in the presence, optionally, of coupling agents or activators known to those skilled in the art to give a compound of general formula (VI), in which R1 and R2, identical or different, represent a group
  • CO-R or CO- (CH 2 ) 2n + rX-R 'and Px is a protective group
  • R2 identical or different, represent a group CO-R or CO-
  • the compounds of general formula (I) in which G is an oxygen atom, R1 and R3 represent a hydrogen atom and R2 represents a CO-R or CO- (CH 2 ) 2n + ⁇ -X-R ', are obtained by a process comprising:
  • A2 is a reactive group chosen, for example, from OH and Cl, and A ° is the group R or the group (CH 2 ) 2n + rX-R ', optionally in the presence coupling agents or activators known to those skilled in the art to give a compound of general formula (VIII)
  • R2 represents a CO-R or CO- (CH 2 ) 2n + ⁇ -XR 'group
  • the compound of formula (IX) can be prepared by a process comprising:
  • step e) with a compound of formula A ° -CO-A2 in which A2 is a reactive group chosen, for example, from OH and Cl, and A ° is the group R or the group (CH2) 2n + ⁇ -X-R'- optionally in the presence of coupling agents or activators known to those skilled in the art.
  • A2 is a reactive group chosen, for example, from OH and Cl
  • a ° is the group R or the group (CH2) 2n + ⁇ -X-R'- optionally in the presence of coupling agents or activators known to those skilled in the art.
  • the compounds of formula (I) according to the invention in which G is an N- R4 group and in which R1 and R2 represent a CO-R or CO- (CH 2 ) 2n + ⁇ -X- R 'group, and R3 is a hydrogen atom can be obtained by reaction of a compound XI and a compound of formula A ° -CO-A2 in which A2 is a reactive group chosen for example between OH and Cl, and A ° is the group R or the group (CH 2 ) 2n + ⁇ -XR 'in stoichiometric amount, optionally in the presence of coupling agents or activators known to those skilled in the art.
  • a molecule of 2-aminopropane-1, 3-diol is reacted with a compound of formula A ° -CO-A in which A is a reactive group chosen for example from OH, 0-CO-A ° , OR "and Cl, and A ° is the group R or the group (CH 2 ) 2 n + ⁇ -XR ', optionally in the presence of coupling agents or activators known to those skilled in the art.
  • FIG. 1A Structure of acylglycerols according to the invention (Examples 2a, 2c, 4a-r).
  • Figure 1B Structure of particular compounds according to the invention (examples 5a-b, 6-c).
  • Figure 3 Evaluation of the properties of PPAR ⁇ agonists of compounds according to the invention with the Gal4 / PPAR ⁇ transactivation system.
  • Figure 4 Evaluation of the neuroprotective effect of compounds according to the invention.
  • Example 4g the compounds according to the invention used in the examples for measuring or evaluating activity will be abbreviated as "Ex 4g” to denote the compound according to the invention, the preparation of which is described in example 4g.
  • Thin layer chromatographies were carried out on MERCOF 6OF 254 silica gel plates 0.2 mm thick.
  • the abbreviation Rf is used to denote the retention factor.
  • the column chromatographies were carried out on silica gel 60 with a particle size 40-63 ⁇ m (reference 9385-5000 MERCK).
  • the melting points (PF) were measured using a BUCHI B 540 device by the capillary method.
  • the infrared (IR) spectra were performed on a Fourier transform spectrometer BRUKER (Vector 22).
  • the nuclear magnetic resonance (NMR) spectra were recorded on a BRUKER AC 300 spectrometer (300 MHz).
  • Each signal is identified by its chemical displacement, its intensity, its multiplicity (noted s for singlet, if for broad singlet, d for doublet, dd for split doublet, t for triplet, td for split triplet, quint for quintuplet and m for multiplet ) and its coupling constant (J).
  • Mass spectra (SM) were carried out on a PERKIN-ELMER SCIEX API 1 spectrometer (ESI-MS for ElectroSpray lonization Mass Spectrometry) or on an APPLIED BIOSYSTEMS Voyager DE-STR spectrometer of MALDI-TOF type (Matrix-Assisted Laser Desorption / lonization - Time Of Flight).
  • Decanethiol (4.57 g; 25 mmol) and 4-bromobutyric acid (5 g; 25 mmol) are stirred at room temperature under an inert atmosphere.
  • the tetradecylthioacetic acid (example 1 a) (5 g; 17.4 mmol) is dissolved in a methanol / dichloromethane mixture (160 ml / 80 ml). The reaction mixture was stirred and cooled in an ice bath before adding slowly oxone ® (12.8 g; 21 mmol) dissolved in water (160 ml). The reaction mixture is stirred at room temperature for 3 hours. The solvents are evaporated in vacuo. The precipitate formed in the residual aqueous phase is drained, washed several times with water and dried.
  • EXAMPLE 1g Preparation of tetradecylsulfonylacetic acid Tetradecylthioacetic acid (Example 1a) (5 g; 17.4 mmol) is dissolved in a methanol / dichloromethane mixture (160 ml / 80 ml). The reaction mixture is stirred and cooled in an ice bath before adding slowly oxone ® (21.8 g; 35 mmol) dissolved in water (160 ml). The reaction mixture is stirred at room temperature for 3 hours. The solvents are evaporated in vacuo. The precipitate formed in the residual aqueous phase is drained, washed several times with water and dried. Efficiency 89%
  • the tetradecylthioacetic acid (example 1a) (4 g, 13.86 mmol) is dissolved in tetrahydrofuran (100 ml) before adding the EDCI (2,658 g, 13.86 mmol), the dimethylaminopyridine (1.694 g, 13.86 mmol) then the solketal (1.72 ml, 13.86 mmol) in this order.
  • the reaction mixture is left under stirring at room temperature for 4 days.
  • the solvent is evaporated in vacuo.
  • This compound is synthesized according to the procedure previously described (Example 2a) from solketal and palmitic acid.
  • EXAMPLE 3d Preparation of 1,3-dioleoylglvcerol This compound is obtained according to the procedure previously described (Example 3a) from glycerol and oleic acid. The product is obtained in the form of a colorless oil.
  • 1-palmitoylglycerol (example 2b) (5.516 g; 17 mmol) is dissolved in dichloromethane (500 ml) before adding dicyclohexylcarbodiimide (5.165 g; 25 mmol), dimethylaminopyridine (3.058 g; 25 mmol) and oleic acid (4,714 g; 17 mmol).
  • the reaction mixture is stirred at room temperature for 24 hours.
  • the precipitate of dicyclohexyluree is filtered, rinsed with dichloromethane and the filtrate is evaporated in vacuo.
  • the residue obtained is purified by chromatography on silica gel (eluent dichloromethane) and allows the desired compound to be obtained in the form of a white solid.
  • the glycerol (30 g; 0.326 mol) is dissolved in dichloromethane (300 ml) before adding the pyridine (79 ml; 0.977 mol) then drop by drop the acetic anhydride (61.5 ml; 0.651 mol).
  • the reaction mixture is kept under stirring at ambient temperature for 48 hours.
  • the medium is taken up in dichloromethane.
  • the organic phase is washed with 1N hydrochloric acid and then with a 10% potassium carbonate solution, then with water saturated with salt, dried over magnesium sulfate, filtered and brought to dryness to provide a colorless oil which is used without further purification.
  • EXAMPLE 4c Preparation of 1,2,3-tri- (6-decylthio) hexanoylglycerol This compound is obtained according to the procedure described above (Example 4a) from 6- (decylthio) hexanoic acid (Example 1c) and glycerol.
  • 1,3-dipalmitoylglycerol (example 3a) (5.64 g; 9.9 mmol; 1eq), tetradecylthioacetic acid (example 1a) (5.74 g; 19.8 mmol; 2eq), dicyclohexylcarbodiimide (4.1 g; 19.8 mmol; 2eq) and dimethylaminopyridine (2.42 g; 19.8 mmol; 2eq) are dissolved in dichloromethane.
  • the reaction mixture is left under stirring at room temperature for 3 days.
  • the dicyclohexyluree formed is filtered and washed several times with dichloromethane.
  • the filtrate is brought to dryness.
  • the residual product is purified by chromatography on silica gel (eluent: dichloromethane / cyclohexane 4/6). Efficiency: 80%
  • EXAMPLE 4i Preparation of 1,3-oleoyl-2-tetradecylthioacetylglvcerol This compound is obtained according to the procedure described above (Example 4g) from 1,3-dioleoylglycerol (compound 3d) and tetradecylthioacetic acid (compound 1a). The product is obtained in the form of a colorless viscous oil. Yield: 32%
  • 1-oleoyl-3-palmitoylglycerol (example 3g) (2 g; 3 mmol) is dissolved in dichloromethane (150 ml) before adding dicyclohexylcarbodiimide (1.040 g; 5 mmol), dimethylaminopyridine (0.616 g; 5 mmol ) and tetradecylthioacetic acid (Example 1a) (1.455 g; 5 mmol).
  • the mixture is left stirring at room temperature for 24 hours, the precipitate of dicyclohexyluree is filtered, rinsed with dichloromethane and the filtrate is concentrated.
  • the residue obtained is purified by chromatography on silica gel (eluent dichloromethane-cyclohexane 4-6) and allows the desired compound to be obtained in the form of an oil. Yield 49%
  • EXAMPLE 4o Preparation of 1,3-ditetradecylthioacetyl-2-palmitoylglvcerol The product is prepared according to the procedure described (example 4g) from 1, 3-ditetradecylthioacetylglycerol (example 3f) and palmitic acid.
  • EXAMPLE 4p Preparation of 1,3-diacetyl-2-tetradecylthioacetylqlvcerol The product is prepared according to the procedure described (example 4g) from 1, 3-diacetylglycerol (example 3h) and tetradecylthioacetic acid (example 1a). Yield: 10% Rf (ethyl acetate-cyclohexane 3-7): 0.47
  • 1, 3-propanediol (1 g; 11 mmol) are placed in a flask and heated 190 ° C for 1 hour. After cooling to room temperature, the medium is taken up in chloroform and washed with water. The organic phase is dried over magnesium sulfate, filtered and then evaporated to provide an ocher solid residue.
  • 2-tetradecylthioacetylaminopropan-1,3-diol (example 5a) (1 g; 2.77 mmol) is dissolved in dichloromethane (180 ml) then dicyclohexycarbodiimide (1.427 g; 6.91 mmol), dimethylaminopyridine (0.845 g; 6.91 mmol) and tetradecylthioacetic acid (Example 1a) (1.995 g; 6.91 mmol) are added in this order. The reaction mixture is left under stirring at room temperature for 48 hours. The precipitate of dicyclohexyluree is filtered and washed with dichloromethane and the filtrate is concentrated.
  • Triphenylmethylthiol (9.58 g; 35 mmol) is dissolved in dichloromethane before adding dicyclohexylcarbodiimide (7.15 g; 35 mmol), dimethylaminopyridine (4.24 g; 35 mmol) and tetradecylthioacetic acid (Example 1a) (10 g; 35 mmol).
  • the reaction mixture is left under stirring at room temperature for 24 hours.
  • Dicyclohexylcarbodiimide is filtered and rinsed with dichloromethane. The filtrate is brought to dryness. The residue is purified by chromatography on silica gel (eluent dichloromethane / cyclohexane 1/9).
  • EXAMPLE 6c Preparation of 1.3-ditetradecylthioacetoxy-2- (2- tetradecylthio) methylcarbonylthiopropane 2-iodo-1, 3-ditetradecylthioacetoxypropane (example 6b) (200 mg; 0.27 mmol) and 2- (tetradecylthio) thiolacetic acid (example 6a) (82 mg; 0.27 mmol) are dissolved in distilled tetrahydrofuran (30 ml). The reaction mixture is cooled in an ice bath before adding the sodium hydride (22 mg; 0.54 mmol). The medium is left stirring at room temperature.
  • the compounds according to the invention were prepared in the form of an emulsion as described below.
  • the emulsion comprising a compound according to the invention and phosphatidylcholine (PC) is prepared according to the protocol of Spooner et al. (Spooner, Clark et al. 1988).
  • the compound according to the invention is mixed with the PC in a 4: 1 ratio (w / w) in chloroform, the mixture is dried under nitrogen, then evaporated overnight under vacuum, the resulting powder is taken up by 0 , 16 M of KCI containing 0.01 M of EDTA then the lipid particles are dispersed by ultrasound for 30 minutes at 37 ° C.
  • the liposomes formed are then separated by ultracentrifugation (XL 80 ultracentrifuge, Beckman Coulter, Villepinte, France) at 25,000 rpm for 45 minutes to recover the liposomes whose size is greater than 100 nm and approaches that of chylomicrons.
  • Liposomes consisting solely of PC are prepared in parallel to serve as a negative control.
  • composition of the liposomes in compound according to the invention is estimated using the enzymocolorimetric assay kit for triglycerides.
  • the assay is carried out against a standard range, prepared using the CFAS lipid calibrator Ref. No. 759350 (Boehringer Mannheim GmbH, Germany).
  • the standard range was built from 16 to 500 ⁇ g / ml. 100 ⁇ l of each sample or standard range dilution are deposited per well of a titration plate (96 wells). Then 200 ⁇ l of triglyceride reagents Ref. 701912 (Boehringer Mannheim GmbH, Germany) are added to each well, and the entire plate is incubated for 30 min. at 37 ° C.
  • the optical densities (OD) are read at 492 nm on the spectrophotometer.
  • liposomes containing the compounds according to the invention, thus prepared are used in the in vitro experiments described in Examples 9, 10 and 11.
  • the LDLs are prepared according to the method described by Lebeau et al. (The beautiful,
  • test compounds are prepared at 10 "2 M in ethanol and diluted in PBS to have final concentrations ranging from 0.1 to 100 ⁇ M for a total ethanol concentration of 1% (v / v ).
  • EDTA is removed from the LDL preparation by dialysis.
  • the oxidation then takes place at 30 ° C. by adding 100 ⁇ l of a solution with 16.6 ⁇ M of CuSO 4 or of 2 mM of AAPH with 800 ⁇ L of LDL (125 ⁇ g of proteins / ml) and 100 ⁇ l of a solution of the compound to be tested.
  • the formation of dienes, the species to be observed, is measured by optical density at 234 nm in samples treated with the compounds in the presence or absence of copper (or AAPH). The measurement of the optical density at 234 nm is carried out every 10 minutes for 8 hours using a thermostated spectrophotometer (Kontron Uvikon 930).
  • the analyzes are carried out in triplicate. We consider that the compounds have an antioxidant activity when they induce a phase shift compared to the control sample. The inventors demonstrate that the compounds according to the invention delay the oxidation of LDL (induced by copper), this indicating that the compounds according to the invention have an intrinsic antioxidant character. An example of results obtained with compounds according to the invention is presented in FIG. 2.
  • the delay in the formation of conjugated dienes is characteristic of the antioxidant products. 4g and 4a are those which have the most significant intrinsic antioxidant properties
  • Figure 2-b shows that the incubation of the compounds according to the invention with LDL in the presence of copper slows down the rate of formation of conjugated dienes.
  • formation of conjugated dienes is 3 nmol / min / mg LDL with copper alone, this speed is reduced to 1 nmol / min / mg LDL with compound Ex 4a at 10 "4 M, which corresponds to a decrease in 66% of the oxidation rate.
  • the compounds according to the invention Ex 4h and Ex 4g also slow down the oxidation rate of LDL which is then respectively 2.5 and 1.8 nmol / min / mg of LDL.
  • Figure 2-c shows that the incubation of LDL with copper leads to the formation of 496 nmol / mg LDL of conjugated dienes.
  • Incubation with the compound Ex 4a (10 "4 M) causes a reduction of 60% in the maximum amount of conjugated dienes formed.
  • Compounds Ex 4g and 4h (10 " 4 M) also limit the formation of conjugated dienes. Incubating LDL with these compounds decreases the maximum amount of dienes formed by 31 and 24% respectively.
  • the compounds according to the invention tested are the compounds whose preparation is described in the examples described above.
  • LDL oxidation is measured by the TBARS method. According to the same principle as that described above, the LDLs are oxidized with CuS04 and the lipid peroxidation is determined as follows:
  • TBARS are measured using a spectrophotometric method; lipid hydroperoxidation is measured using peroxide-lipid oxidation dependent on iodide iodine. The results are expressed in nmol of malonodialdehyde (MDA) or in nmol of hydroperoxide / mg of proteins. The results obtained previously, by measuring the inhibition of the formation of conjugated dienes, are confirmed by the experiments of measurement of lipid peroxidation of LDL.
  • the compounds according to the invention therefore also effectively protect LDL against lipid peroxidation induced by copper (oxidizing agent).
  • Example 9 Measurement of the antioxidant properties of the compounds according to the invention on cell cultures
  • the cell lines used for this type of experiment are of the neuronal, neuroblastoma (human) and PC12 (rat) cells type.
  • PC12 cells were prepared from a rat pheochromocytoma and are characterized by Greene and Tischler (Greene and Tischler 1976). These cells are commonly used for studies of neuronal differentiation, signal transduction and neuronal death.
  • the PC12 cells are cultured as previously described (Farinelli, Park et al. 1996), in complete RPMI medium (Invitrogen) supplemented with 10% horse serum and 5% fetal calf serum.
  • the mRNAs are extracted from the cells in culture treated or not with the compounds according to the invention. The extraction is carried out using reagents from the Absolutely RNA RT-PCR miniprep Kit (Stratagene, France) according to the supplier's instructions. The mRNAs are then assayed by spectrometry and quantified by quantitative RT-PCR using the Light Cycler Fast start DNA Master Sybr Green I kit (Roche) on a Light Cycler System device (Roche, France). Primer pairs specific for Super Oxide Dismutase (SOD), Catalase and Glutathione Peroxidase (GPx) genes, antioxidant enzymes, are used as probes.
  • SOD Super Oxide Dismutase
  • GPx Glutathione Peroxidase
  • Primer pairs specific for the b-actin and cyclophilin genes are used as control probes.
  • the increase in the expression of mRNAs, measured by quantitative RT-PCR, of the genes of the antioxidant enzymes is demonstrated in the different cell types used, when the cells are treated with the compounds according to the invention.
  • the antioxidant properties of the compounds are also evaluated using a fluorescent indicator, the oxidation of which is followed by the appearance of a signal. fluorescent.
  • the decrease in intensity of the fluorescent signal emitted is measured in the cells treated with the compounds in the following manner: the PC12 cells cultured as previously described (black plate 96 wells transparent background, Falcon) are incubated with increasing doses of H 2 0 2 (0.25 mM - 1 mM) in serum-free medium for 2 and 24 hours. After the incubation, the medium is removed and the cells are incubated with a solution of dichlorodihydrofluorescein diacetate (DCFDA, Molecular Probes, Eu subconscious, USA) 10 ⁇ M in PBS for 30 min at 37 ° C.
  • DCFDA dichlorodihydrofluorescein diacetate
  • the cells are then rinsed with PBS.
  • the detection of the fluorescence emitted by the oxidation indicator is measured using a fluorimeter (Tecan Ultra 384) at an excitation wavelength of 495 nm and an emission wavelength 535 nm.
  • the results are expressed as a percentage of protection relative to the oxidized control.
  • the fluorescence intensity is lower in the cells incubated with the compounds according to the invention than in the untreated cells.
  • the different cell lines (cell models mentioned above) as well as the cells in primary culture are treated as above.
  • the cell supernatant is recovered after the treatment and the cells are lysed and recovered for the determination of the protein concentration.
  • the detection of lipid peroxidation is determined as follows: lipid peroxidation is measured using thiobarbituric acid (TBA) which reacts with lipoperoxidation of aldehydes such as malonodialdehyde (MDA).
  • TSA thiobarbituric acid
  • MDA malonodialdehyde
  • the cell supernatant is collected (900 ⁇ l) and 90 ⁇ l of butyl hydroxytoluene are added thereto (Morliere, Moysan et al. 1991).
  • the compounds according to the invention advantageously have intrinsic antioxidant properties which make it possible to slow down and / or inhibit the effects of oxidative stress.
  • the inventors also show that the compounds according to the invention are capable of inducing the expression of the genes of antioxidant enzymes. These particular characteristics of the compounds according to the invention allow the cells to fight more effectively against oxidative stress and therefore to be protected from damage induced by free radicals.
  • Example 10 Evaluation of the activation of PPARs in vitro by the compounds according to the invention
  • the nuclear receptors belonging to the PPAR subfamily which are activated by two major classes of pharmaceutical compounds, fibrates and glitazones, which are widely used in human clinics for the treatment of dyslipidemias and diabetes, play an important role in homeostasis lipid and carbohydrate.
  • the following experimental data show that the compounds according to the invention activate PPAR ⁇ in vitro.
  • PPARs The activation of PPARs is evaluated in vitro in lines of fibroblastic type RK13 or in a hepatocyte line HepG2, by measuring the transcriptional activity of chimeras consisting of the DNA binding domain of the yeast transcription factor Gal4 and of the binding domain of ligand of the different PPARs.
  • the example presented below is given for HepG2 cells.
  • the HepG2 cells come from ECACC (Porton Down, UK) and are cultured in DMEM medium supplemented with 10% vol / vol fetal calf serum, 100 U / ml penicillin (Gibco, Paisley, UK ) and 2 mM L-Glutamine (Gibco, Paisley, UK).
  • the culture medium is changed every two days.
  • the cells are stored at 37 ° C. in a humid atmosphere containing 5% of CO 2 and 95% of air.
  • the plasmids pG5TkpGL3, pRL-CMV, pGal4-hPPAR ⁇ , pGal4-hPPAR ⁇ and pGal4-f have been described by Raspe et al. (Raspe, Madsen et al. 1999).
  • the constructs pGal4-mPPAR ⁇ and pGal4-hPPAR ⁇ were obtained by cloning into the vector pGal4-f DNA fragments amplified by PCR corresponding to the DEF domains of the mouse PPAR ⁇ and human PPAR ⁇ nuclear receptors respectively.
  • the HepG2 cells are seeded in 24-well culture dishes at a rate of 5 ⁇ 10 4 cells / well and are transfected for 2 hours with the reporter plasmid pG5TkpGL3 (50 ng / well), the expression vectors pGal4-f, pGal4- mPPAR ⁇ , pGal4-hPPAR ⁇ , pGal4-hPPAR ⁇ , pGal4-hPPAR ⁇ (100 ng / well) and the transfection efficiency control vector pRL-CMV (1 ng / well) according to the protocol described above (Raspe, Madsen et al . 1999) and incubated for 36 hours with the test compounds.
  • the cells are lysed (Gibco, Paisley, UK) and the luciferase activities are determined using the D ⁇ al-Luciferase TM Reporter Assay System assay kit (Promega, Madison, Wl, USA) according to the supplier's instructions.
  • the protein content of the cell extracts is then evaluated using the Bio-Rad Protein Assay (Bio-Rad, M ⁇ nchen, Germany) according to the supplier's instructions.
  • FIG. 3 An example of results obtained with compounds according to the invention is presented in FIG. 3.
  • FIG. 3 the HepG2 cells, transfected with the plasmids of the Gal4 / PPAR ⁇ system, are incubated with different concentrations of the compounds according to the invention (5, 15, 50 and 100 ⁇ M) for 24 hours as well as with different vehicle concentrations (PC).
  • the results are represented by the induction factor (luminescent signal compared to the untreated cells) according to the different treatments.
  • the compound according to the invention Ex 4a also induces an increase in the induction factor with a dose effect of 41 to 100 ⁇ M, 30 to 50 ⁇ M, 18 to 15 ⁇ M and 9 to 5 ⁇ M.
  • the compound according to the invention Ex 4p also induces an increase in the luminescent signal, revealing an activity on the nuclear receptor PPAR ⁇ .
  • the induction factors for the compound Ex 4p are 35 to 100 ⁇ M, 44 to 50 ⁇ M, 36 to 15 ⁇ M and 24 to 5 ⁇ M.
  • the vehicle PC liposome
  • cytokines and free radicals The inflammatory response appears in many neurological disorders, such as cerebral ischemia.
  • inflammation is one of the important factors of neurodegeneration.
  • One of the first reactions of glia cells to stroke is to release cytokines and free radicals.
  • cytokines and free radicals The consequence of this release of cytokines and free radicals is an inflammatory response in the brain and which can lead to the death of neurons (Rothwell 1997).
  • Cell lines and primary cells are grown as described above.
  • LPS Lipopolysaccharide
  • TNF- ⁇ is an important factor in the inflammatory response to stress (oxidant for example).
  • the culture medium of the stimulated cells is removed and the amount of TNF- ⁇ is evaluated with an ELISA-TNF- ⁇ kit (Immunotech, France ).
  • the samples are diluted 50 times in order to be in line with the standard range (Chang, Hudson et al. 2000).
  • the anti-inflammatory property of the compounds is characterized in the following way: the culture medium of the cells is completely changed and the cells are incubated with the compounds to be tested for 2 hours. After this incubation, LPS is added to the culture medium at a final concentration of 1 ⁇ g / ml.
  • the cell supernatant is recovered and stored at -80 ° C when it is not treated directly.
  • the cells are lysed and the amount of protein is measured, using the Bio-Rad Protein Assay assay kit (Bio-Rad, M ⁇ nchen, Germany) according to the supplier's instructions.
  • the measurement of the decrease in TNF- ⁇ secretion favored by the treatment with the test compounds is expressed in pg / ml / ⁇ g of protein and reported as a percentage relative to the control.
  • Example 12 Evaluation of the neuroprotective effects of the compounds according to the invention in a model of cerebral ischemia-reperfusion
  • A- / Prophylactic model 1 / Treatment of animals
  • Wistar rats weighing 200 to 350 g were used for this experiment.
  • the animals are kept under a 12 hour light / dark cycle at a temperature of 20 +/- 3 ° C. Animals have free access to water and food. Food gain and weight gain are recorded.
  • the animals are treated by gavage with the compounds according to the invention (600 mg / kg / day) suspended in a vehicle ((carboxymethylcellulose 0.5% (CMC) and Tween 0.1%) or treated with the aforementioned vehicle, for 14 days before the induction of ischemia by occlusion of the middle cerebral artery
  • CMC carboxymethylcellulose 0.5%
  • Tween Polyoxyethylenesorbitan Monooleate
  • the animals were anesthetized using an intraperitoneal injection of 300 mg / kg of chloral hydrate.
  • a rectal probe is placed and the body temperature is maintained at 37 +/- 0.5 ° C. Blood pressure is measured during the whole experiment.
  • the right carotid is updated using a medial cervical incision.
  • the pterygopalatine artery was ligated at its origin and an arteriotomy is performed in the external carotid artery in order to slide a nylon monofilament into it.
  • This filament is then gently advanced into the common carotid artery and then into the internal carotid artery in order to block the origin of the middle cerebral artery. After 1 hour, the filament is removed to allow reperfusion.
  • Brains are quickly frozen and sectioned.
  • the sections are colored in Cresyl purple.
  • the non-colored areas of the brain sections were considered to be injured by the infarction.
  • Analysis of the brain sections of animals treated with the compounds according to the invention reveals a marked reduction in the volume of the infarction compared to the untreated animals.
  • the compounds according to the invention are administered to animals before ischemia (prophylactic effect), they are capable of inducing neuroprotection.
  • the results of the figure 4-a indicate that the corrected volume of the total infarction (size of the lesion after ischemia) is 186 mm 3 .
  • the compound Ex 4a compound according to the invention described in example 4a
  • the size of the lesion is reduced by 22% (145 mm 3 ) compared to that of the control animals.
  • B- / Curative model or treatment of the acute phase 1 / Induction of ischemia-reperfusion by intraluminal occlusion of the cerebral middle artery.
  • Animals as described above are used for this experiment.
  • the animals are anesthetized using an intraperitoneal injection of 300 mg / kg of chloral hydrate.
  • a rectal probe is placed and the body temperature is maintained at 37 +/- 0.5 ° C. Blood pressure is measured during the whole experiment.
  • the right carotid is updated using a medial cervical incision.
  • the pterygopalatine artery was ligated at its origin and an arteriotomy is performed in the external carotid artery in order to slide a nylon monofilament into it.
  • This filament is then gently advanced into the common carotid artery and then into the internal carotid artery in order to close off the origin of the middle cerebral artery. After 1 hour, the filament is removed to allow reperfusion. 2 / Treatment of animals:
  • Animals having undergone prior ischemia-reperfusion are treated with the compounds according to the invention by the oral route (as already described in a CMC + Tween vehicle) one or more times after the reperfusion (600 mg / kg / d or 2 administrations 300 mg / kg / day).
  • the animals previously treated or not treated with the compounds according to the invention are killed by an overdose of pentobarbital.
  • Brains are quickly frozen and sectioned.
  • the sections are colored in Cresyl purple.
  • the non-colored areas of the brain sections were considered to be injured by the infarction.
  • a curative treatment treatment of the acute phase
  • the animals treated with the compounds according to the invention have damage to the brain level reduced compared to the untreated animals.
  • the volume of the infarction is reduced when the compounds according to the invention are administered one or more times after ischemia-reperfusion.
  • FIGS An example of results obtained with a compound according to the invention is presented in FIGS.
  • FIG. 4-c show that the animals treated (600 mg / kg / day), with the compound according to the invention Ex 4a, for 24 hours after ischemia develop lesions whose size is reduced by 27% compared to the control animals (volume of the infarction 132 mm 3 for the treated versus 180 mm 3 for the controls).
  • results of FIG. 4-d representing uncorrected infarctions indicate that the curative and neuroprotective nature of the compound according to the invention Ex 4a observed at the level of total infarction is composed of a neuroprotective effect at the level of cortical infarction (25% reduction in lesions) but without effect at the level of striatal infarction (no significant reduction in lesions).
  • the results of FIG. 4-e show that the animals treated (600 mg / kg / day), with the compound according to the invention Ex 4a, for 72 hours after ischemia develop lesions whose size is reduced by 40% compared to the control animals (volume of the corrected infarction: 110 mm 3 for the treated versus 180 mm 3 for the controls).
  • volume of the corrected infarction 110 mm 3 for the treated versus 180 mm 3 for the controls.
  • the use of the compounds according to the invention in various experimental models, shows that these compounds have an intrinsic antioxidant activity, capable of delaying and reducing the effects of oxidative stress. In addition, they induce the expression of the genes of antioxidant enzymes, which associated with their antioxidant nature makes it possible to strengthen anti-radical protections. Furthermore, the compounds according to the invention have an anti-inflammatory power and the property of activating the nuclear receptor PPAR ⁇ . Finally, the use of the compounds according to the invention in an ischemia reperfusion model in animals shows the beneficial effect on neuroprotection both with preventive and curative treatment.
  • Spooner P. J., S. B. Clark, et al. (1988). "The ionization and distribution behavior of oleic acid in chylomicrons and chylomicron-like emulsion particles and the influence of serum albumin.” J Biol Chem 263 (3): 1444-53. Spooner, R. J., A. Delides, et al. (nineteen eighty one). "Heat stability and kinetic properties of human serum glutathione reductase activity in various disease states.”

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JP2006517954A (ja) 2006-08-03
CA2514301A1 (fr) 2004-08-19
WO2004069241A1 (fr) 2004-08-19
US20060252827A1 (en) 2006-11-09
FR2850650B1 (fr) 2005-03-25
FR2850650A1 (fr) 2004-08-06

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