EP1999138A1 - Novel amphiphilic derivatives of alpha-c-phenyl-n-tert-butylnitrone - Google Patents
Novel amphiphilic derivatives of alpha-c-phenyl-n-tert-butylnitroneInfo
- Publication number
- EP1999138A1 EP1999138A1 EP07731140A EP07731140A EP1999138A1 EP 1999138 A1 EP1999138 A1 EP 1999138A1 EP 07731140 A EP07731140 A EP 07731140A EP 07731140 A EP07731140 A EP 07731140A EP 1999138 A1 EP1999138 A1 EP 1999138A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- group
- chosen
- group chosen
- 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.)
- Withdrawn
Links
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- 238000000034 method Methods 0.000 claims abstract description 17
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 5
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- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
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- 230000000694 effects Effects 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 6
- 230000007170 pathology Effects 0.000 claims description 6
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 5
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- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical group C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 claims description 4
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical compound OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 2
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- 229910019142 PO4 Inorganic materials 0.000 claims description 2
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- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
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- 229960004203 carnitine Drugs 0.000 claims description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical group C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
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- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 238000007348 radical reaction Methods 0.000 claims description 2
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- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- IYSYLWYGCWTJSG-XFXZXTDPSA-N n-tert-butyl-1-phenylmethanimine oxide Chemical compound CC(C)(C)[N+](\[O-])=C\C1=CC=CC=C1 IYSYLWYGCWTJSG-XFXZXTDPSA-N 0.000 description 11
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- A61P39/06—Free radical scavengers or antioxidants
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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Definitions
- the invention relates to novel compounds derived from ⁇ -C-phenyl-N- ⁇ -butyl nitrone, a process for their preparation and their use for the preparation of medicaments for preventing or treating diseases related to oxidative stress.
- pathologies of this type are cited in this list which includes in particular immune and inflammatory diseases, ischemia-reperfusion syndrome, atherosclerosis, Alzheimer's and Parkinson's diseases, lesions due to UV and ionizing radiation, some forms of chemical carcinogenesis as well as cellular aging.
- Oxygen and nitrogen free radical species are produced naturally in the body and their regulation is ensured by certain specialized enzymes such as Super Oxyde Dismutase soluble (SODs).
- SODs Super Oxyde Dismutase soluble
- the trapping of these extremely reactive radical species is vital because they cause irreversible damage in the cell. If the normal production of these radical species is easily regulated by the cell, an overproduction of free radicals linked to external oxidative stress (inflammatory shock, ischemia-reperfusion syndrome, ...) or a genetic deficiency (mitochondrial anomaly in particular) causes rapid cell degradation. The management of this important flow of radicals by the human or animal body becomes impossible.
- Soluble SOD is responsible for converting the superoxide radical into hydrogen peroxide, which is then supported by catalases or glutathione peroxidases.
- ⁇ -tocopherol and ⁇ -carotene are the main examples of lipid antioxidants.
- spin trap these highly reactive free radicals via molecules called “spin trap”, among which nitrones appear as the most effective.
- PBN P ⁇ -C-phenyl-N-tert-butyl nitrone
- nitrones the most known and most effective are the ⁇ -C-phenyl-N-tert-butyl nitrone (PBN), the 5,5-dimethylpyrrolidine-IV-oxide (DMPO) and molecules discovered more recently: the IV benzylidene-1-diethoxyphosphoryl-I- methylethylamine N-oxide (PBNP) and 5-diethylphosphono-5-methylpyrroline-N-oxide (DEPMPO).
- PBN ⁇ -C-phenyl-N-tert-butyl nitrone
- DMPO 5,5-dimethylpyrrolidine-IV-oxide
- PBNP the IV benzylidene-1-diethoxyphosphoryl-I- methylethylamine N-oxide
- DEPMPO 5-diethylphosphono-5-methylpyrroline-N-oxide
- the Applicant has set itself the objective of designing and manufacturing new molecules, having a spin trap activity, having an increased bioavailability compared to the molecules of the prior art and whose preparation is simple and allows to envisage a production on an industrial scale.
- X represents a hydrophilic group chosen from a mono or a polysaccharide, as well as the amine derivatives of mono- and polysaccharides, an ethylene oxide chain, a peptide chain, an ionic polar group chosen from a quaternary ammonium, an amine oxide, , a carnitine group, a group
- n represents an integer of 1, 2 or 3;
- Y represents a spacer arm or a bond for connecting the hydrophilic X substituents to the rest of the molecule; Y is chosen from ester, amide, urea, urethane, ether, thioether, amine or C 1 -C 6 hydrocarbon chains optionally interrupted by one or more ester, amide, urea, urethane and one or more several ether bridges, aminated
- - OC 9-NH- p is t ether -O-, a thio-ether bridge -S-; one or more amino acids, serinol.
- n is an integer of 0, 1 or 2;
- m 1 represents an integer of 1 or 2;
- X ' represents a hydrogen atom or a C 4 -C 14 alkyl chain optionally substituted by one or more fluorine atoms.
- the substituent (X ') m ' -Y- (CH 2) n -, placed on the aromatic ring, may be in the ortho, meta or para position.
- monosaccharides that can be used in the present invention, mention may be made of: glucose, lactose, fructose, mannose, galactose, ribose, maltose, sucrose.
- Amino derivatives of sugars include glucosamine and galactosamine.
- polysaccharides that may be used in the present invention there may be mentioned chains consisting of several monosaccharide units, for example: sucrose, maltose and lactobionic acid.
- hydrophilic part X of the molecule of formula (I) is a polyethylene oxide chain, it advantageously comprises from 30 to 100 ethylene oxide units, preferably from 50 to 60 units.
- the peptide chain consists of natural amino acids such as alanine, arginine, rasparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine.
- natural amino acids such as alanine, arginine, rasparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine.
- the spacer arm Y Depending on the mono or the multifunctionality of the spacer arm Y, it is substituted once or twice by the group X.
- the group X 1 may for example be chosen from the following radicals:
- hydrocarbon radicals n-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-butyl; decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl ... fluorinated hydrocarbon radicals: mention may be made of those corresponding to the formula - (CH 2 ) r (CF 2 ) r F, in which r and t represent two integers with: 14> r + t> 4, such as, for example:
- X represents a lactobionamide, carnitine or a polyoxyethylene chain; m is 1; m 'is 1 or 2 n is 1;
- X ' is selected from octyl, heptyl, octyl, decyl, dodecyl, CF 3 (CF 2 ) r CH 2 CH 2 -, with 8>r> 6
- the invention also relates to a process for the preparation of the compounds corresponding to formula (I), this process being characterized in that an aldehyde corresponding to formula (II) is reacted with a hydroxylamine corresponding to the formula ( III) according to diagram 2 below:
- the hydrophilic portion is synthesized from 2-methyl-2-nitro propanol.
- the alcohol function is converted to amine by tosylation followed by substitution with sodium azide.
- Staudinger the alkyl azide is converted into amine in the presence of triphenyl phosphine and sodium hydroxide.
- This amine can react with lactobionolactone, this reaction makes it possible to graft the polar head by an amide bond.
- nitro function is then reduced to hydroxylamine by means of 4 equivalents of zinc in a THF-water mixture in the presence of ammonium chloride.
- Derivative 2 is obtained from 3-vinylbenzaldehyde by direct condensation in basic medium of the aliphatic thiol.
- Compound 3 is synthesized from A-cyanobenzaldehyde. The aldehyde function is protected by acetalization and the nitrile function reduced to amine. On this one is condensed the acid function of the aliphatic chain.
- Product 4 is obtained by condensation of the isocyanate of the aliphatic chain on this amine in toluene. The aldehyde function of these two compounds is deprotected by transacetalization in acetaldehyde.
- Derivatives 5, 6 and 7 are synthesized from 4-carboxybenzaldehyde whose aldehyde function is previously protected by acetalization.
- Compound 5 is obtained after having obtained the acyl azide by treatment with diphenylphosphorylazide. The azide is converted to isocyanate by heating in toluene. The aliphatic alcohol is condensed in the presence of DABCO to obtain, after transacetalization, the compound 5.
- the compound 6 is obtained from the acid by coupling in the presence of a peptide coupling agent, the dicyclohexylcarbodiimide of the aliphatic amine and deprotection. of the aldehyde by heating in an acidic medium in acetaldehyde.
- Figure 3 illustrates the synthesis of the double-stranded hydrophobic portion from serinol.
- Compound 7 is obtained from 4-carboxybenzaldehyde. " The aldehyde function is protected by acetalization Serinol is condensed on the acid function after it has been activated by coupling of N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide. Aliphatic chains are condensed by condensation of alkyl isocyanates in toluene The compound 8 is obtained after transacetalization in acetaldehyde d-Obtaining mono and double-chain amphiphilic nitrones derived from lactobionolactone (FIG.
- the various amphiphilic nitrones are obtained by coupling the aldehyde function of the various hydrophobic synthons on the hydroxylamine group of the hydrophilic lactobionamide part.
- the coupling reaction is carried out under argon in a THF / acetic acid mixture for 24 hours. All nitrones were purified by reverse phase HPLC (Cl 8 column / methanol-water eluent).
- the invention further relates to the use of compounds of formula (I) as defined above as an anti-free radical agent.
- the products of the invention can be used for the prevention and / or treatment of pathologies related to oxidative stress and to the formation of oxygen radical species.
- the invention therefore relates to pharmaceutical compositions comprising a compound according to the invention in a pharmaceutically acceptable carrier. It relates to the use of a compound according to the invention for the preparation of a medicament for preventing and / or treating the effects of free radicals.
- It also relates to the use of a compound of the invention for the preparation of a pharmaceutical composition for preventing and / or treating pathologies related to oxidative stress and the formation of oxygen radical species, including immune diseases and inflammatory, ischemia-reperfusion syndrome, atherosclerosis, Alzeimer's disease, Parkinson's disease, Huntington's disease, UV radiation and ionizing radiation, cancers, cellular aging.
- pathologies related to oxidative stress and the formation of oxygen radical species including immune diseases and inflammatory, ischemia-reperfusion syndrome, atherosclerosis, Alzeimer's disease, Parkinson's disease, Huntington's disease, UV radiation and ionizing radiation, cancers, cellular aging.
- the products of the invention may be administered by any route known to those skilled in the art, in particular by intravenous or intramuscular injection, by oral or dermal administration. They can be used alone or in combination with other assets. Their dosage and the quantity administered daily are adapted according to the activity measured for the molecule concerned and according to the weight of the patient.
- the compounds of the invention may be used for preventing and / or treating the effects of aging as well as the effects of solar radiation.
- the invention therefore also relates to a cosmetic composition
- a cosmetic composition comprising a compound of the invention in a cosmetically acceptable carrier.
- Said composition may be intended for application on the skin or on the integuments (nails, hair). It may be in the form of an aqueous or oily solution, a water-in-oil or oil-in-water emulsion, a triple emulsion, an ointment.
- the compounds of the invention can be introduced into any cosmetic composition for which an antiradical activity is sought: a skin care cream, a sunscreen product, a makeup remover, a mask for the skin or hair, a shampoo, a product make-up such as a lipstick, a make-up, a foundation, a nail polish, etc.
- the compounds of the invention can be used as free radical scavengers in radical reactions.
- the compounds of the invention are easy to implement and can be used under a wide variety of conditions.
- the precursor compound 1 of the polar head can be easily prepared from 2-methyl-2-nitropropanol according to a method already described in WO 2004/043982: 2-methyl-2-nitropropanol is converted into 2-methyl-2- nitro-propylamine by a sequence of 3 steps consisting of: 1- activating the alcohol function to form a sulphonic ester of tosyl chloride, 2-substituting this sulphonyl ester with an azido group, 3- selectively reducing the azido group to aminated by the reaction of Staudinger. 2-methyl-2-nitropropylamine is condensed on lactobionolactone in methoxyethanol in basic medium at 60 ° C.
- Compound 1 is then easily purified by chromatography on silica gel (eluent: AcOEt / cyclohexane, 8: 2, v / v) to give a white powder with 25% yield from 2-methyl-2-nitropropanol.
- Compound 3 carrying the hydrocarbon chain can be easily prepared from 4-cyanobenzaldehyde according to a method already described in WO 2004/043982: 4-cyanobenzaldehyde is converted into 4- (1,3-dioxacyclopent-2-yl) benzylamine by a sequence of 2 steps consisting of: 1- protecting the aldehyde function in the form of dioxolane, 2- reducing the cyano group to amine.
- the 4- (1,3-dioxacyclopent-2-yl) benzylamine is condensed on octanoic acid in dichloromethane in the presence of a peptide coupling system consisting of DCC and HOBt according to a method already described (Ouari, O Polidori, A., Pucci, B., Tordo, P., Chalier, FJ Org Chem 1999, 64, 3554-3556) then the dioxolane protecting group is removed by treatment in a mixture of acetic acid / water 1 : 1 v / v.
- Compound 3 is then purified by chromatography on silica gel (eluent: Cyclohexane / AcOEt, 6: 4 v / v) to give a white powder with 40% yield from 4-cyanobenzaldehyde.
- the compound 10 is obtained by condensation of the compound 1 with the compound 3 according to a method already described in WO 2004/043982: the hydroxylamine 1 and the benzaldehyde derivative 3 are dissolved in a stoichiometric amount in anhydrous THF under an argon atmosphere and in the presence of molecular sieve 4A.
- the reaction medium is brought to 60 ° C away from light.
- the hydroxylamine is added sequentially every 24 hours per fraction of 0.20 equivalent until the benzaldehyde derivative is consumed.
- acetic acid as a co-solvent considerably increases the kinetics of reaction, as already been demonstrated.
- nitrone formed is purified by chromatography on silica gel (Eluent: AcOEt / Cyclohexane, 7: 3 v / v) and then by size exclusion chromatography on Sephadex LH-20 resin (eluent: Dichloromethane / Methanol, 1: 1). / v).
- acetyl groups of the polar head are removed by the Zemplen method by transesterification in methanol in the presence of a catalytic amount of sodium methanolate.
- Compound 10 is purified by size exclusion chromatography on Sephadex LH-20 resin (eluent: methanol) to yield a white powder with 70% yield.
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Abstract
Compounds derived from a-C-phenyl-N-tert-butylnitrone, a process for the preparation thereof and use thereof for the preparation of medicaments for use in preventing or treating oxidative stress-related diseases.
Description
NOUVEAUX DERIVES AMPHIPHILES DE L'α-C-PHENYL-iV-tert-BUTYL NOVEL AMPHIPHILIC DERIVATIVES OF α-C-PHENYL-IV-tert-BUTYL
NITRONE.NITRONE.
L'invention a pour objet de nouveaux composés, dérivés de l'α-C- phényl-iV-/ert-butyl nitrone, un procédé pour leur préparation et leur utilisation pour la préparation de médicaments destinés à prévenir ou traiter les maladies liées au stress oxydatif.The invention relates to novel compounds derived from α-C-phenyl-N-β-butyl nitrone, a process for their preparation and their use for the preparation of medicaments for preventing or treating diseases related to oxidative stress.
Les pathologies liées au stress oxydatif et à la formation des espèces radicalaires oxygénées ont été répertoriées par Croos CE., Arch. Intern. Med. (1987) 107, 526-545 et par Anderson K.M., Elis G., Bonomi P., Harris J.E., Médical Hypothèses (1999) 52, 53-57.The pathologies related to oxidative stress and the formation of oxygen radical species have been listed by Croos CE., Arch. Intern. Med. (1987) 107, 526-545 and by Anderson K.M., Elis G., Bonomi P., Harris J.E., Medical Hypotheses (1999) 52, 53-57.
Elles sont nombreuses : plus de 70 pathologies de ce type sont citées dans cette liste qui inclut notamment les maladies immunitaires et inflammatoires, le syndrome d'ischémie-reperfusion, l'athérosclérose, les maladies d'Alzheimer et de Parkinson, les lésions dues aux radiations UV et ionisantes, certaines formes de carcinogenèse chimique ainsi que le vieillissement cellulaire.They are numerous: more than 70 pathologies of this type are cited in this list which includes in particular immune and inflammatory diseases, ischemia-reperfusion syndrome, atherosclerosis, Alzheimer's and Parkinson's diseases, lesions due to UV and ionizing radiation, some forms of chemical carcinogenesis as well as cellular aging.
Les espèces radicalaires oxygénées et nitrogénées (ROS et RNS) sont produites naturellement dans l'organisme et leur régulation est assurée par certaines enzymes spécialisées comme la Super Oxyde Dismutase soluble (SODs). Le piégeage de ces espèces radicalaires extrêmement réactives est vital car elles occasionnent des dégâts irréversibles dans la cellule. Si la production normale de ces espèces radicalaires est régulée facilement par la cellule, une surproduction de radicaux libres liée à un stress oxydatif externe (choc inflammatoire, syndrome d'ischémie-reperfusion, ...) ou une déficience génétique (anomalie mitochondriale notamment) entraîne une dégradation cellulaire rapide. La prise en charge de cet important flux de radicaux par l'organisme humain ou animal devient dès lors impossible.Oxygen and nitrogen free radical species (ROS and RNS) are produced naturally in the body and their regulation is ensured by certain specialized enzymes such as Super Oxyde Dismutase soluble (SODs). The trapping of these extremely reactive radical species is vital because they cause irreversible damage in the cell. If the normal production of these radical species is easily regulated by the cell, an overproduction of free radicals linked to external oxidative stress (inflammatory shock, ischemia-reperfusion syndrome, ...) or a genetic deficiency (mitochondrial anomaly in particular) causes rapid cell degradation. The management of this important flow of radicals by the human or animal body becomes impossible.
Il existe plusieurs mécanismes de défense contre le stress oxydatif de la cellule susceptibles de s'exercer à différents niveaux de la cascade oxydative. Celle-ci est initiée généralement par la surproduction de radicaux superoxyde liée à une réduction partielle de l'oxygène moléculaire dans la mitochondrie (syndrome typique de l'ischémie- reperfusion). Ce radical superoxyde peut se dismuter en eau oxygénée. Ces deux espèces, par l'intermédiaire de la réaction de Fenton, en présence de fer ferreux, peuvent donner des radicaux hydroxyle qui ont la particularité de réagir très rapidement et de manière non spécifique avec n'importe lequel des composants de la cellule comme les lipides, l'ADN ou les protéines, causant des dommages irréversibles parmi ceux-ci, comme cela a été décrit par Stadtman H.R., Berlett B.S. J. Biol. Chem. (1991) 266, 17201-17211 ; Floyd R.A. Carcinogenesis (1990) 11, 1447-1450 ; Gille J.J., Van Berkel C.G., Joenge H. Carcinogenesis (1994) 15, 2695-2699 ; Halliwell B. Mutât. Res. (1999) 443, 37-52.
Ces espèces radicalaires en activant certains gènes suicides (gènes Bel ou p53) par l'intermédiaire du facteur NF-kB sont également à l'origine du phénomène d'apoptose cellulaire qui a été décrit par Siebenlist U., Franzoso G., Brown K. Annu. Rev. CeIl Biol. (1994) 10, 405-455.There are several defense mechanisms against the oxidative stress of the cell that can be exerted on different levels of the oxidative cascade. This is generally initiated by the overproduction of superoxide radicals linked to a partial reduction of molecular oxygen in the mitochondria (typical ischemia-reperfusion syndrome). This superoxide radical can be disproportionated in hydrogen peroxide. These two species, via the Fenton reaction, in the presence of ferrous iron, can give hydroxyl radicals which have the particularity of reacting very quickly and nonspecifically with any of the components of the cell such as lipids, DNA or proteins, causing irreversible damage among them, as described by Stadtman HR, Berlett BSJ Biol. Chem. (1991) 266, 17201-17211; Floyd RA Carcinogenesis (1990) 11, 1447-1450; Gille JJ, Van Berkel CG, Joenge H. Carcinogenesis (1994) 15, 2695-2699; Halliwell B. Mutat. Res. (1999) 443, 37-52. These radical species by activating certain suicide genes (Bel or p53 genes) via the factor NF-kB are also at the origin of the phenomenon of cellular apoptosis which has been described by Siebenlist U., Franzoso G., Brown K. Annu. Rev. This Biol. (1994) 10, 405-455.
La SOD soluble est chargée de convertir le radical superoxyde en eau oxygénée, celle-ci étant ensuite prise en charge par des catalases ou des peroxydases glutathion dépendantes.Soluble SOD is responsible for converting the superoxide radical into hydrogen peroxide, which is then supported by catalases or glutathione peroxidases.
Il existe d'autres niveaux de protection cellulaires contre les oxydants, notamment au niveau de la membrane, qui permettent de limiter l'oxydation des phospholipides membranaires insaturés. L'α-tocophérol et le β-carotène sont les principaux exemples d' antioxydants lipidiques.There are other levels of cellular protection against oxidants, particularly at the membrane, which limit the oxidation of unsaturated membrane phospholipids. Α-tocopherol and β-carotene are the main examples of lipid antioxidants.
La stratégie la plus prometteuse, dans la recherche d'une thérapie destinée à prévenir ou traiter les maladies liées au stress oxydatif, consiste à intervenir le plus en amont possible de cette cascade oxydative, afin de prévenir très tôt les dommages liés à la très forte réactivité des espèces radicalaires.The most promising strategy, in the search for a therapy intended to prevent or treat diseases related to oxidative stress, is to intervene as far upstream as possible in this oxidative cascade, in order to prevent very early the damage related to the very strong reactivity of radical species.
Pour cela on a cherché à piéger ces radicaux libres hautement réactifs par l'intermédiaire de molécules dites « piège à spin », parmi lesquelles les nitrones apparaissent comme les plus efficaces.For this we sought to trap these highly reactive free radicals via molecules called "spin trap", among which nitrones appear as the most effective.
L'effet thérapeutique des nitrones dans la réduction et la prévention des dommages causés par les radicaux libres dans les systèmes biologiques a été mis en évidence en 1990 par Oliver C, Starke-Read P., Stadman E., Liu G., Carney J., Floyd R. Proc. Natl. Acad. Sci. USA (1990) 87, 5144-5147.The therapeutic effect of nitrones in reducing and preventing free radical damage in biological systems was highlighted in 1990 by Oliver C, Starke-Read P., Stadman E., Liu G., Carney J. ., Floyd R. Proc. Natl. Acad. Sci. USA (1990) 87, 5144-5147.
Ces auteurs ont pu démontrer une diminution des dommages causés par une ischémie cérébrale après injection de Pα-C-phényl-iV-tert-butyl nitrone (PBN) chez les gerbilles. Les ischémies cérébrales sont accompagnées d'une forte augmentation de la production de radicaux libres qui ont été piégés par la PBN pour former des adduits de spin bien plus stables donc moins réactifs et toxiques. La PBN est le piège à spin qui a fait l'objet du plus grand nombre d'études biologiques.These authors were able to demonstrate a decrease in damage caused by cerebral ischemia after injection of Pα-C-phenyl-N-tert-butyl nitrone (PBN) in gerbils. Cerebral ischemia is accompanied by a sharp increase in the production of free radicals that have been trapped by PBN to form spin adducts that are much more stable and thus less reactive and toxic. PBN is the spin trap that has been the subject of the greatest number of biological studies.
On peut par exemple se reporter à Hensley K., Carney J.M., Stewart C.A., Tabatabaie T., Pye Q.N., Floyd R. A. Int. Rev. Neurobiol. (1997) 40, 229-317.For example, see Hensley K., Carney J.M., Stewart C. A., Tabatabaie T., Pye Q.N., Floyd R. A. Int. Rev. Neurobiol. (1997) 40, 229-317.
Elle possède une grande spécificité d'action cérébrale probablement en raison de son hydrophobie importante qui lui permet de franchir la barrière hématoméningée, comme cela a été montré par Cheng H. Y., Liu T., Feuerstein G., Barone F.C. Free Radie. Biol. Med. (1993) 14, 243-250.It has a high specificity of brain action probably because of its significant hydrophobia that allows it to cross the blood-brain barrier, as has been shown by Cheng H. Y., Liu T., Feuerstein G., Barone F.C. Free Radie. Biol. Med. (1993) 14, 243-250.
Parmi les nitrones, les plus connus et les plus efficaces sont les α-C- phényl-iV-tert-butylnitrone (PBN), les 5,5-diméthylpyrrolidine-iV-oxide (DMPO) et des molécules découvertes plus récemment : la iV-benzylidène-1-diéthoxyphosphoryl-I-
méthyléthylamine iV-oxyde (PBNP) et la 5-diéthyl-phosphono 5-méthyl pyrroline-iV-oxyde (DEPMPO).Among the nitrones, the most known and most effective are the α-C-phenyl-N-tert-butyl nitrone (PBN), the 5,5-dimethylpyrrolidine-IV-oxide (DMPO) and molecules discovered more recently: the IV benzylidene-1-diethoxyphosphoryl-I- methylethylamine N-oxide (PBNP) and 5-diethylphosphono-5-methylpyrroline-N-oxide (DEPMPO).
On peut également citer un dérivé disulfonate de la PBN, le NXY-059 (disodium 4-[(tert-butylimino)-méthylbenzene-l,3-disulfonate N-oxyde) possédant une activité neuroprotectrice supérieure à la PBN et qui est en cours d'étude pharmacologique et de développement clinique :There may also be mentioned a disulfonate derivative of PBN, NXY-059 (disodium 4 - [(tert-butylimino) -methylbenzene-1,3-disulphonate N-oxide) having a neuroprotective activity greater than PBN and which is in progress pharmacological study and clinical development:
Kuroda S., Tsuchidate R., Smith MX., Maples K.R., Siesjo B.K. J Cereb. Blood Flow Metab. (1999) 19, 778-787 ;Kuroda S., Tsuchidate R., Smith MX., Maples K.R., Siesjo B.K. J Cereb. Blood Flow Metab. (1999) 19, 778-787;
Lees K.R., Sharma A.K., Barer D., Ford G.A., Kostulas V., Cheng Y.F., Odergren T. Stroke (2001) 32, 675-680.Lees K.R., Sharma A.K., Barer D., Ford G.A., Kostulas V., Cheng Y.F., Odergren T. Stroke (2001) 32, 675-680.
Toutefois, aucune des molécules citées ci-dessus ne possède une efficacité in vivo ou ex vivo satisfaisante à faible dose, même si leur concentration cytotoxique est très élevée : Almli L.M., Hamrick S.E.G., Koshy A.A ., Tâuber M.G., Ferriero D.M. Dev. Brain Res. (2001) 132, 121-129 ; Nakao N., Grasbon-Frodl E.M., Widner H., Brundin P. Neuroscience (1996) 73, 185-200. Ce manque d'efficacité est probablement lié à une mauvaise biodisponibilité de la drogue et à un problème de pénétration cellulaire.However, none of the above-mentioned molecules has satisfactory in vivo or ex vivo efficacy at low dose, even if their cytotoxic concentration is very high: Almli L.M., Hamrick S.E.G., Koshy A.A., Tâuber M.G., Ferriero D.M. Dev. Brain Res. (2001) 132, 121-129; Nakao N., Grasbon-Frodl E.M., Widner H., Brundin P. Neuroscience (1996) 73, 185-200. This lack of efficacy is probably related to a poor bioavailability of the drug and a problem of cellular penetration.
Il subsiste donc le besoin d'une molécule de type piège à spin, capable de piéger des radicaux libres, et qui soit également susceptible d'être acheminée par l'organisme humain ou animal jusqu'à sa cible au niveau intracellulaire.There is therefore still a need for a spin trap type molecule, capable of trapping free radicals, and which is also likely to be conveyed by the human or animal body to its target at the intracellular level.
En particulier, une molécule capable de traverser la membrane cellulaire et, challenge encore plus important et difficile, la membrane mitochondriale afin d'entrer dans le compartiment où est produit le radical superoxyde.In particular, a molecule able to cross the cell membrane and, even more important and difficult challenge, the mitochondrial membrane to enter the compartment where the superoxide radical is produced.
Dans ce but, Ouari O., Polidori A., Pucci B., Tordo P., Chalier F. J. Org. Chem. (1999) 64, 3554-3556 et Geromel V., Kadhom N., Cebalos-Picot L, Ouari O., Polidori A., Munnich A., Rôtig A., Rustin P. Hum. Mol. Genêt. (2001) 10, 1221-1228, ont proposé un dérivé amphiphile perfluorocarboné de Ia PBN : la TAlPBN.For this purpose, Ouari O., Polidori A., Pucci B., Tordo P., Chalier F. J. Org. Chem. (1999) 64, 3554-3556 and Geromel V., Kadhom N., Cebalos-Picot L, Ouari O., Polidori A., Munnich A., Rtig A., Rustin P. Hum. Mol. Broom. (2001) 10, 1221-1228, have proposed a perfluorocarbon amphiphilic derivative of PBN: TAlPBN.
Cette molécule a été testée sur des lignées cellulaires de fibroblastes souffrant d'un sévère déficit d'activité du complexe V de la chaîne respiratoire (ATPase) et elle a donné des résultats encourageants.
Cependant, la synthèse de la TAlPBN présente des difficultés qui rendent sa production à l'échelle industrielle difficilement envisageable.This molecule has been tested on fibroblast cell lines suffering from a severe deficiency of respiratory chain V (ATPase) activity and has given encouraging results. However, the synthesis of TAlPBN presents difficulties which make its production on an industrial scale difficult to envisage.
La demande internationale WO 2004/04982 décrit des dérivés de l'α-C- phényl-TV-te/t-butyl nitrone. Ces molécules de type piège à spin, sont faciles à synthétiser, capables de piéger des radicaux libres et ils sont dotés d'une bonne biodisponibilité. L'un de ces composés, le N-[4-(octa-O-acétyllactobionamidométhylène)benzylidène]-N[l,l- diméthyl-2-(N-octanoyl)amido]-éthylamine N-oxide, ou LPBNAH, a montré une activité biologique supérieure à celle du PBN dans des tests de vieillissement oxydatif (B.Poeggeler et al., Journal of Neurochemistry, 2005, 95, 962-973). Toutefois, il subsiste le besoin de composés ayant une activité encore plus importante, dotés d'une biodisponibilité encore accrue.International application WO 2004/04982 describes derivatives of α-C-phenyl-γ-tert-butyl-nitrone. These spin trap molecules are easy to synthesize, able to trap free radicals and have good bioavailability. One of these compounds, N- [4- (octa-O-acetyl-lactobionamidomethylene) benzylidene] -N [1,1-dimethyl-2- (N-octanoyl) amido] -ethylamine N-oxide, or LPBNAH, has showed biological activity superior to that of PBN in oxidative aging tests (B.Poeggeler et al., Journal of Neurochemistry, 2005, 95, 962-973). However, there is still a need for compounds with even greater activity, with even greater bioavailability.
La Demanderesse s'est fixée pour objectif la conception et la fabrication de nouvelles molécules, ayant une activité de piège à spin, présentant une biodisponibilité accrue par rapport aux molécules de l'art antérieur et dont la préparation soit simple et permette d'envisager une production à l'échelle industrielle.The Applicant has set itself the objective of designing and manufacturing new molecules, having a spin trap activity, having an increased bioavailability compared to the molecules of the prior art and whose preparation is simple and allows to envisage a production on an industrial scale.
L'invention a pour objet de nouvelles molécules, caractérisées en ce qu'elles répondent à la formule (I) ci-dessous :The subject of the invention is new molecules, characterized in that they correspond to formula (I) below:
(I) dans laquelle :(I) in which:
X représente un groupement hydrophile choisi parmi un mono ou un polysaccharide, ainsi que les dérivés aminés de mono et de polysaccharides, une chaîne polyoxyde d'éthylène, une chaîne peptidique, un groupement polaire ionique choisi parmi un ammonium quaternaire, un oxyde d'aminé, un groupement carnitine, un groupementX represents a hydrophilic group chosen from a mono or a polysaccharide, as well as the amine derivatives of mono- and polysaccharides, an ethylene oxide chain, a peptide chain, an ionic polar group chosen from a quaternary ammonium, an amine oxide, , a carnitine group, a group
Θ O rrsΘ O rrs
/> phosphate, un groupement choline, un groupement ° un groupement/> phosphate, a choline group, a group ° a group
m représente un entier égal à 1 , 2 ou 3 ; m represents an integer of 1, 2 or 3;
Y représente un bras espaceur ou une liaison destiné à relier les substituants hydrophiles X au reste de la molécule ;
Y est choisi parmi les fonctions ester, amide, urée, uréthane, éther, thio- éther, aminé, les chaînes hydrocarbonées en C1-C6, éventuellement interrompues par une ou plusieurs fonctions ester, amide, urée, uréthane et par un ou plusieurs ponts éther, aminéY represents a spacer arm or a bond for connecting the hydrophilic X substituents to the rest of the molecule; Y is chosen from ester, amide, urea, urethane, ether, thioether, amine or C 1 -C 6 hydrocarbon chains optionally interrupted by one or more ester, amide, urea, urethane and one or more several ether bridges, aminated
- O-C-NH-9 un pOnt éther -O-, un pont thio-éther -S- ; un ou plusieurs aminoacides, le sérinol. n est un entier égal à 0, 1 ou 2 ; m1 représente un entier égal à 1 ou 2 ; - OC 9-NH- p is t ether -O-, a thio-ether bridge -S-; one or more amino acids, serinol. n is an integer of 0, 1 or 2; m 1 represents an integer of 1 or 2;
X' représente un atome d'hydrogène ou une chaîne alkyle en C4-C14 éventuellement substituée par un ou plusieurs atomes de fluor.X 'represents a hydrogen atom or a C 4 -C 14 alkyl chain optionally substituted by one or more fluorine atoms.
Le substituant (X')m'-Y-(CH2)n-, placé sur le noyau aromatique, peut être en position ortho, meta ou para.The substituent (X ') m ' -Y- (CH 2) n -, placed on the aromatic ring, may be in the ortho, meta or para position.
Parmi les mono-saccharides utilisables dans la présente invention, on peut citer : le glucose, le lactose, le fructose, le mannose, le galactose, le ribose, le maltose, le saccharose. On peut également citer les monosaccharides à chaîne ouverte. Parmi les dérivés aminés de sucres, on peut citer notamment la glucosamine, la galactosamine. Parmi les polysaccharides utilisables dans la présente invention, on peut citer les chaînes constituées de plusieurs unités monosaccharide comme par exemple : le saccharose, le maltose et l'acide lactobionique.Among the monosaccharides that can be used in the present invention, mention may be made of: glucose, lactose, fructose, mannose, galactose, ribose, maltose, sucrose. One can also mention open-chain monosaccharides. Amino derivatives of sugars include glucosamine and galactosamine. Among the polysaccharides that may be used in the present invention, there may be mentioned chains consisting of several monosaccharide units, for example: sucrose, maltose and lactobionic acid.
Lorsque la partie hydrophile X de la molécule de formule (I) est une chaîne polyoxyde d'éthylène, celle-ci comprend avantageusement de 30 à 100 unités oxyde d'éthylène, de préférence de 50 à 60 unités.When the hydrophilic part X of the molecule of formula (I) is a polyethylene oxide chain, it advantageously comprises from 30 to 100 ethylene oxide units, preferably from 50 to 60 units.
De préférence la chaîne peptidique est constituée d'acides aminés naturels comme l'alanine, l'arginine, rasparagine, l'acide aspartique, la cystéine, la glutamine, l'acide glutamique, la glycine, l'histidine, l'isoleucine, la leucine, la lysine, la méthionine, la phénylalanine, la proline, la serine, la thréonine, le tryptophane, la tyrosine, la valine.Preferably the peptide chain consists of natural amino acids such as alanine, arginine, rasparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine.
Des exemples de groupements hydrophiles ioniques ou non ioniques utilisables dans la présente invention sont donnés dans le schéma 1 ci-dessous.
Examples of ionic or nonionic hydrophilic groups that can be used in the present invention are given in Scheme 1 below.
Têtes polaires non ioniquesNonionic polar heads
Schéma 1 : structure générale des têtes polairesFigure 1: General structure of the polar heads
En fonction de la mono ou de la plurifonctionnalité du bras espaceur Y, celui-ci est substitué une ou deux fois par le groupement X.Depending on the mono or the multifunctionality of the spacer arm Y, it is substituted once or twice by the group X.
Le groupement X1 peut par exemple être choisi parmi les radicaux suivants :The group X 1 may for example be chosen from the following radicals:
- radical octyl- octyl radical
- radicaux hydrocarbonés : le n-butyle, le ter-butyle, l'isobutyle, le n- pentyle, l'isopentyle, le n-hexyle, le n-heptyle, le n-octyle, le n-nonyle, le n-décyle, le n- undécyle, le n-dodécyle, le n-tridécyle, le n-tétradécyle...
- radicaux hydrocarbonés fluorés : on peut citer ceux répondant à la formule -(CH2)r(CF2)rF, dans laquelle r et t représentent deux entiers avec : 14 > r+t > 4, tels que par exemple :hydrocarbon radicals: n-butyl, tert-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-butyl; decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl ... fluorinated hydrocarbon radicals: mention may be made of those corresponding to the formula - (CH 2 ) r (CF 2 ) r F, in which r and t represent two integers with: 14> r + t> 4, such as, for example:
-(CF2)4F ; -(CF2)5F ; -(CF2)6F ; -(CF2)7F ; -(CF2)8F ; -(CF2)9F ; - (CF2)10F ; -(CF2)IiF ; -(CF2) , 2F ; -(CF2) , 3F ; -(CF2)I4F ; -CH2-(CF2)3F ; -CH2-(CF2)4F ; - CH2-(CF2)5F ; -CH2-(CF2)6F ; -CH2-(CF2)7F ; -CH2-(CF2)8F ; -CH2-(CF2)9F ; -CH2- (CF2)10F ; -CH2-(CF2)πF ; -CH2-(CF2)12F ; -CH2-(CF2)J 3F ; -(CH2)2-(CF2)2F ; -(CHb)2- (CF2)3F ; -(CH2)2-(CF2)4F ; -(CH2)2-(CF2)5F ; -(CH2)2-(CF2)6F ; -(CH2)2-(CF2)7F ; -(CH2),- (CF2)8F ; -(CH2)2-(CF2)9F ; -(CH2)2-(CF2))0F ; -(CH2)HCF2)! jF ; -(CH2)HCF2) 12F ; - (CH2)3-(CF2)]F ; -(CH2)13-(CF2)F .- (CF 2 ) 4 F; - (CF 2 ) 5 F; - (CF 2 ) 6 F; - (CF 2 ) 7 F; - (CF 2 ) 8 F; - (CF 2 ) 9 F; - (CF 2 ) 10 F; - (CF 2 ) I iF; - (CF 2 ), 2 F; - (CF 2 ), 3 F; - (CF 2 ) I4 F; -CH 2 - (CF 2 ) 3 F; -CH 2 - (CF 2 ) 4 F; - CH 2 - (CF 2 ) 5 F; -CH 2 - (CF 2 ) 6 F; -CH 2 - (CF 2 ) 7 F; -CH 2 - (CF 2 ) 8 F; -CH 2 - (CF 2 ) 9 F; -CH 2 - (CF 2 ) 10 F; -CH 2 - (CF 2 ) π F; -CH 2 - (CF 2 ) 12 F; -CH 2 - (CF 2 ) J 3 F; - (CH 2 ) 2 - (CF 2 ) 2 F; - (CHb) 2 - (CF 2 ) 3 F; - (CH 2 ) 2 - (CF 2 ) 4 F; - (CH 2 ) 2 - (CF 2 ) 5 F; - (CH 2 ) 2 - (CF 2 ) 6 F; - (CH 2 ) 2 - (CF 2 ) 7 F; - (CH 2 ), - (CF 2 ) 8 F; - (CH 2 ) 2 - (CF 2 ) 9 F; - (CH 2 ) 2 - (CF 2 ) ) 0 F; - (CH 2 ) HCF 2 )! jF; - (CH 2 ) HCF 2 ) 12 F; - (CH 2 ) 3 - (CF 2 ) ] F; - (CH 2 ) 13 - (CF 2 ) F.
De façon préférentielle, l'une au moins des conditions ci-dessous est satisfaite :Preferably, at least one of the conditions below is satisfied:
X représente un groupement lactobionamide, carnitine ou une chaîne polyoxyéthylène ; m représente 1 ; m' représente 1 ou 2 n représente 1 ;X represents a lactobionamide, carnitine or a polyoxyethylene chain; m is 1; m 'is 1 or 2 n is 1;
X' est choisi parmi les radicaux octyl, heptyl, octyl, décyl, dodécyl, CF3(CF2)rCH2CH2-, avec 8>r>6X 'is selected from octyl, heptyl, octyl, decyl, dodecyl, CF 3 (CF 2 ) r CH 2 CH 2 -, with 8>r> 6
L'invention a également pour objet un procédé de préparation des composés répondant à la formule (I), ce procédé étant caractérisé en ce que l'on fait réagir un aldéhyde répondant à la formule (II) avec une hydroxylamine répondant à la formule (III) suivant le schéma 2 ci-dessous :The invention also relates to a process for the preparation of the compounds corresponding to formula (I), this process being characterized in that an aldehyde corresponding to formula (II) is reacted with a hydroxylamine corresponding to the formula ( III) according to diagram 2 below:
(H) (III) (I)(H) (III) (I)
Schéma 2Figure 2
dans lequel X, m, Y, X', m', n et Y' ont la même définition que ci- dessus.wherein X, m, Y, X ', m', n and Y 'have the same definition as above.
Les composés de formule (III) sont préparés suivant un procédé décrit dans le schéma 3 ci-dessous :
.The compounds of formula (III) are prepared according to a process described in scheme 3 below: .
O9N + HY(X)m YO 9 N + HY (X) m Y
O2N (X)mO 2 N (X) m
(VI) (V) (IV)(VI) (V) (IV)
Z = OH, NH2 ou TosylZ = OH, NH 2 or Tosyl
(III)(III)
Schéma 3Figure 3
En fonction de la nature mono ou bicaténaire du groupement lipophile, le schéma 2 est mis en œuvre dans des conditions qui seront exposées ci-dessous. A titre d'exemple une tête polaire commune lactobionamide a été choisie. a- Synthèse de Ia partie hydrophile lactobionamideDepending on the mono or double-strand nature of the lipophilic group, scheme 2 is carried out under conditions which will be explained below. For example, a common polar head lactobionamide was chosen. a Synthesis of the Hydrophilic Lactobionamide Part
La figure 1 illustre la préparation du composé de formule (III) avec : m = 1 ;Figure 1 illustrates the preparation of the compound of formula (III) with: m = 1;
X = lactobionamide OX = lactobionamide O
II γ = HN-CII γ = HN-C
La partie hydrophile est synthétisée à partir du 2-méthyl 2-nitro propanol.The hydrophilic portion is synthesized from 2-methyl-2-nitro propanol.
La fonction alcool est convertie en aminé par tosylation suivie d'une substitution par l'azoture de sodium. Par réaction de Staudinger, l'azoture d'alkyle est transformé en aminé en présence de triphényl phosphine et de soude.The alcohol function is converted to amine by tosylation followed by substitution with sodium azide. By reaction of Staudinger, the alkyl azide is converted into amine in the presence of triphenyl phosphine and sodium hydroxide.
Cette aminé peut réagir avec la lactobionolactone, cette réaction permet de greffer la tête polaire par une liaison amide.This amine can react with lactobionolactone, this reaction makes it possible to graft the polar head by an amide bond.
La fonction nitro est ensuite réduite en hydroxylamine par l'intermédiaire de 4 équivalents de zinc dans un mélange THF-eau en présence de chlorure d'ammonium.The nitro function is then reduced to hydroxylamine by means of 4 equivalents of zinc in a THF-water mixture in the presence of ammonium chloride.
La réaction de réduction permet d'accéder au composé 1 avec un rendement de 80 %. b- Synthèse de la partie hydrophobe monocaténaire hydro ou perfluorocarbonée (Figure 2) :The reduction reaction gives access to compound 1 with a yield of 80%. b- Synthesis of the hydro-carbon or perfluorocarbon single-stranded hydrophobic part (FIG. 2):
La figure 2 illustre la préparation des composés de formule (II) constitués d'une chaîne aliphatique avec : n = O, 1 ou 2 ;Figure 2 illustrates the preparation of compounds of formula (II) consisting of an aliphatic chain with: n = O, 1 or 2;
X' = (CH2)2-R avec R = C6Fj3, C8F17, CH3(CH2)n X '= (CH 2 ) 2 -R with R = C 6 F 13 , C 8 F 17 , CH 3 (CH 2 ) n
4<n<14; -
O4 <n <14; - O
IIII
Y' = -CH2-CH2-S- (composé 2), -CH2-NH — C — (composé 3), O O OY '= -CH 2 -CH 2 -S- (Compound 2), -CH 2 -NH-C- (Compound 3), OOO
II II IIII II II
-CH3-NH-C-NH (compOSé 4), -HN- C— O (composé 5), — C-O — (composé 6),-CH 3 -NH-C-NH (com p OS E 4) -HN- CO (compound 5), - CO - (compound 6),
O II — C NH — (composé 7),II - C NH - (compound 7),
Le dérivé 2 est obtenu à partir du 3-vinylbenzaldéhyde par condensation directe en milieu basique du thiol aliphatique. Le composé 3 est synthétisé à partir du A- cyanobenzaldéhyde. La fonction aldéhyde est protégée par acétalisation et la fonction nitrile réduite en aminé. Sur celle-ci est condensée la fonction acide de la chaîne aliphatique. Le produit 4 est obtenu par condensation de l'isocyanate de la chaîne aliphatique sur cette aminé dans le toluène. La fonction aldéhyde de ces deux composés est déprotégée par transacétalisation dans l'acétaldéhyde. Les dérivés 5, 6 et 7 sont synthétisés à partir du 4-carboxybenzaldehyde dont la fonction aldéhyde est préalablement protégée par acétalisation. Le composé 5 est obtenu après avoir obtenu l'azoture d'acyle par traitement au diphénylphosphorylazide. L'azoture est transposé en isocyanate par chauffage dans le toluène. L'alcool aliphatique est condensé en présence de DABCO pour obtenir après transacétalisation le composé 5. Le composé 6 est obtenu à partir de l'acide par couplage en présence d'un agent de couplage peptidique, la dicyclohexylcarbodiimide de l'aminé aliphatique et déprotection de l'aldéhyde par chauffage en milieu acide dans l'acétaldéhyde. c- Synthèse de Ia partie hydrophobe bicaténaire hydro ou perfluorocarbonée (Figure 3) :Derivative 2 is obtained from 3-vinylbenzaldehyde by direct condensation in basic medium of the aliphatic thiol. Compound 3 is synthesized from A-cyanobenzaldehyde. The aldehyde function is protected by acetalization and the nitrile function reduced to amine. On this one is condensed the acid function of the aliphatic chain. Product 4 is obtained by condensation of the isocyanate of the aliphatic chain on this amine in toluene. The aldehyde function of these two compounds is deprotected by transacetalization in acetaldehyde. Derivatives 5, 6 and 7 are synthesized from 4-carboxybenzaldehyde whose aldehyde function is previously protected by acetalization. Compound 5 is obtained after having obtained the acyl azide by treatment with diphenylphosphorylazide. The azide is converted to isocyanate by heating in toluene. The aliphatic alcohol is condensed in the presence of DABCO to obtain, after transacetalization, the compound 5. The compound 6 is obtained from the acid by coupling in the presence of a peptide coupling agent, the dicyclohexylcarbodiimide of the aliphatic amine and deprotection. of the aldehyde by heating in an acidic medium in acetaldehyde. c) Synthesis of the hydro-carbon or perfluorocarbon double-stranded hydrophobic part (FIG. 3)
La figure 3 illustre la synthèse de la partie hydrophobe bicaténaire à partir du sérinol.Figure 3 illustrates the synthesis of the double-stranded hydrophobic portion from serinol.
Le composé 7 est obtenu à partir du 4-carboxybenzaldéhyde". La fonction aldéhyde est protégée par acétalisation. Le sérinol est condensé sur la fonction acide après que celle-ci ait été activé par couplage du N-hydroxysuccinimide en présence de dicyclohexylcarbodiimide. Sur les fonctions alcools sont condensées les chaînes aliphatiques par condensation d'isocyanates d'alkyle dans le toluène. Le composé 8 est obtenu après transacétalisation dans l'acétaldéhyde. d- Obtention des nitrones amphiphiles mono et bicaténaires dérivées de la lactobionolactone (Figure 4) :Compound 7 is obtained from 4-carboxybenzaldehyde. " The aldehyde function is protected by acetalization Serinol is condensed on the acid function after it has been activated by coupling of N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide. Aliphatic chains are condensed by condensation of alkyl isocyanates in toluene The compound 8 is obtained after transacetalization in acetaldehyde d-Obtaining mono and double-chain amphiphilic nitrones derived from lactobionolactone (FIG.
Les différentes nitrones amphiphiles sont obtenues par couplage de la fonction aldéhyde des différents synthons hydrophobes sur le groupement hydroxylamine de la partie hydrophile lactobionamide. La réaction de couplage est effectuée sous argon dans un mélange THF/acide acétique pendant 24h00.
Toutes les nitrones ont été purifiées par CLHP en phase inverse (colonne Cl 8/éluant méthanol-eau).The various amphiphilic nitrones are obtained by coupling the aldehyde function of the various hydrophobic synthons on the hydroxylamine group of the hydrophilic lactobionamide part. The coupling reaction is carried out under argon in a THF / acetic acid mixture for 24 hours. All nitrones were purified by reverse phase HPLC (Cl 8 column / methanol-water eluent).
L'invention a en outre pour objet l'utilisation des composés répondant à la formule (I) telle que définie ci-dessus comme agent anti-radicaux libres.The invention further relates to the use of compounds of formula (I) as defined above as an anti-free radical agent.
En effet, il a été démontré que les composés selon la présente invention étaient dotés d'une capacité à piéger les radicaux libres équivalente à celle des composés de l'art antérieur.Indeed, it has been demonstrated that the compounds according to the present invention have a capacity to trap free radicals equivalent to that of the compounds of the prior art.
Cette propriété permet d'envisager l'utilisation des molécules de l'invention dans des domaines variés :This property makes it possible to envisage the use of the molecules of the invention in various fields:
- dans le domaine thérapeutique, les produits de l'invention peuvent être employés pour la prévention et/ou le traitement des pathologies liées au stress oxydatif et à la formation des espèces radicalaires oxygénées.in the therapeutic field, the products of the invention can be used for the prevention and / or treatment of pathologies related to oxidative stress and to the formation of oxygen radical species.
L'invention a par conséquent pour objet les compositions pharmaceutiques comprenant un composé selon l'invention dans un support pharmaceutiquement acceptable. Elle a pour objet l'utilisation d'un composé selon l'invention pour la préparation d'un médicament destiné à prévenir et/ou traiter les effets des radicaux libres.The invention therefore relates to pharmaceutical compositions comprising a compound according to the invention in a pharmaceutically acceptable carrier. It relates to the use of a compound according to the invention for the preparation of a medicament for preventing and / or treating the effects of free radicals.
Elle a également pour objet l'utilisation d'un composé de l'invention pour la préparation d'une composition pharmaceutique destinée à prévenir et/ou traiter les pathologies liées au stress oxydatif et à la formation des espèces radicalaires oxygénées, notamment les maladies immunitaires et inflammatoires, le syndrome d'ischémie- reperfusion, l'athérosclérose, la maladie d'Alzeimer, la maladie de Parkinson, la maladie de Huntington, les lésions dues aux radiations UV et ionisantes, les cancers, le vieillissement cellulaire.It also relates to the use of a compound of the invention for the preparation of a pharmaceutical composition for preventing and / or treating pathologies related to oxidative stress and the formation of oxygen radical species, including immune diseases and inflammatory, ischemia-reperfusion syndrome, atherosclerosis, Alzeimer's disease, Parkinson's disease, Huntington's disease, UV radiation and ionizing radiation, cancers, cellular aging.
Les produits de l'invention peuvent être administrés par toute voie connue de l'homme du métier, notamment par injection intraveineuse ou intramusculaire, par administration orale ou cutanée. Ils peuvent être utilisés seuls ou en association avec d'autres actifs. Leur dosage et la quantité administrée quotidiennement sont adaptés en fonction de l'activité mesurée pour la molécule concernée et en fonction du poids du patient.The products of the invention may be administered by any route known to those skilled in the art, in particular by intravenous or intramuscular injection, by oral or dermal administration. They can be used alone or in combination with other assets. Their dosage and the quantity administered daily are adapted according to the activity measured for the molecule concerned and according to the weight of the patient.
- dans le domaine cosmétique, les composés de l'invention peuvent être utilisés pour prévenir et/ou traiter les effets du vieillissement ainsi que les effets des radiations solaires.in the cosmetic field, the compounds of the invention may be used for preventing and / or treating the effects of aging as well as the effects of solar radiation.
L'invention a donc également pour objet une composition cosmétique comprenant un composé de l'invention dans un support cosmétiquement acceptable.The invention therefore also relates to a cosmetic composition comprising a compound of the invention in a cosmetically acceptable carrier.
Ladite composition peut être destinée à une application sur la peau ou sur les phanères (ongles, cheveux).
Elle peut se présenter sous forme d'une solution aqueuse ou huileuse, d'une émulsion eau-dans-1'huile ou huile-dans-1'eau, d'une émulsion triple, d'un onguent.Said composition may be intended for application on the skin or on the integuments (nails, hair). It may be in the form of an aqueous or oily solution, a water-in-oil or oil-in-water emulsion, a triple emulsion, an ointment.
Les composés de l'invention peuvent être introduits dans toute composition cosmétique pour laquelle une activité antiradicalaire est recherchée : une crème de soin cutanée, un produit de protection solaire, un démaquillant, un masque pour la peau ou les cheveux, un shampoing, un produit de maquillage tel qu'un rouge à lèvres, un fard, un fond de teint, un vernis à ongles, etc..The compounds of the invention can be introduced into any cosmetic composition for which an antiradical activity is sought: a skin care cream, a sunscreen product, a makeup remover, a mask for the skin or hair, a shampoo, a product make-up such as a lipstick, a make-up, a foundation, a nail polish, etc.
- dans le domaine de la synthèse organique, les composés de l'invention peuvent être utilisés comme capteurs de radicaux libres dans des réactions radicalaires.in the field of organic synthesis, the compounds of the invention can be used as free radical scavengers in radical reactions.
Du fait de leur solubilité dans des milieux variés, les composés de l'invention sont faciles à mettre en œuvre et peuvent être employés dans des conditions très diverses.Because of their solubility in various media, the compounds of the invention are easy to implement and can be used under a wide variety of conditions.
PARTIE EXPERIMENTALEEXPERIMENTAL PART
I- Evaluation biologique :I- Biological evaluation:
Les essais biologiques ont été faits en suivant les modes opératoires décrits dans Journal of Neurochemistry, 2005, 95, 962-973. Afin d'évaluer les potentialités de ces nouveaux dérivés nous avons mesuré l'aptitude du composé 10 à réduire et prévenir les phénomènes de mort cellulaire par apoptose. Le peroxyde d'hydrogène est très largement utilisé comme inducteur d'apoptose dans de nombreux modèles cellulaires. Ainsi la viabilité de cultures cellulaires de cortex d'embryon de rat Sprague-Dawley est grandement altérée après traitement par du peroxyde d'hydrogène à des concentrations de 50 à 200 μM. L'ajout de PBN (10 μM) permet de restaurer de manière très incomplète la viabilité de ces cultures. L'ajout du composé 10 à cette même concentration (10 μM) permet par contre de restaurer de manière complète la viabilité de telles cultures démontant ainsi une efficacité à réduire les phénomènes d'apoptose oxydo-induits 5 à 10 supérieures à celle de la PBN. Ces mêmes cultures ont également été soumises à un inducteur de stress oxydant sélectif de la mitochondrie, la Doxorubicine (Kotamraju, S.; Konorev, E. A.; Joseph, J.; Kalyanaraman, B. J. Biol. Chem. 2000, 275, 33 585-33 592.). Les observations sont les mêmes que pour l'induction par le peroxyde d'hydrogène. Alors que la PBN ne conduit qu'à une protection partielle de la mort cellulaire le composé 10 permet un maintien parfait de la viabilité cellulaire. Ces résultats préliminaires soulignent la forte aptitude du composé 10 à prévenir les phénomènes d'apoptose induits à des niveaux cellulaires variables. Il peut réduire les dommages intracellulaires causés par un traitement au peroxyde d'hydrogène mais son efficacité vis-à-vis de la doxorubicine suggère également une incorporation accrue de ce dérivé dans le compartiment mitochondrial. Un dysfonctionnement de la mitochondrie, organite central dans le contrôle de l'apoptose, est impliqué dans une très large variété de troubles pathologiques. Les propriétés anti-
apoptotiques du dérivé 10 conjugué à son incorporation dans la mitochondrie permettent d'envisager son utilisation dans les domaines cités précédemment.The bioassays were made following the procedures described in Journal of Neurochemistry, 2005, 95, 962-973. In order to evaluate the potentialities of these novel derivatives we have measured the ability of the compound to reduce and prevent cell death phenomena by apoptosis. Hydrogen peroxide is very widely used as an inducer of apoptosis in many cell models. Thus, the viability of Sprague-Dawley rat embryo cortex cell cultures is greatly altered after treatment with hydrogen peroxide at concentrations of 50 to 200 μM. The addition of PBN (10 μM) makes it possible to very incompletely restore the viability of these cultures. The addition of compound 10 at this same concentration (10 μM) makes it possible, on the other hand, to completely restore the viability of such cultures, thus dismantling an efficacy in reducing the phenomena of oxidative-induced apoptosis 5 to 10 greater than that of PBN. . These same cultures were also subjected to a selective mitochondrial oxidative stress inducer, Doxorubicin (Kotamraju, S. Konorev, EA, Joseph, J. Kalyanaraman, BJ Biol Chem., 2000, 275, 33585-33. 592.). The observations are the same as for induction with hydrogen peroxide. While PBN only leads to partial protection of cell death, compound 10 allows perfect maintenance of cell viability. These preliminary results underline the strong ability of compound 10 to prevent apoptosis phenomena induced at varying cellular levels. It may reduce the intracellular damage caused by hydrogen peroxide treatment, but its efficacy against doxorubicin also suggests increased incorporation of this derivative into the mitochondrial compartment. Mitochondria dysfunction, a central organelle in the control of apoptosis, is involved in a very wide variety of pathological disorders. The anti-aging properties The apoptotic derivative 10 conjugate to its incorporation into the mitochondria can consider its use in the fields mentioned above.
II- Exemple : Synthèse de la nitrone monocaténaire lactobionamide 10 (R = CsH11)II-Example: Synthesis of lactobionamide single-stranded nitrone (R = CsH 11 )
1- Synthèse du composé 11- Synthesis of compound 1
Le composé 1 précurseur de la tête polaire peut être facilement préparé à partir du 2-méthyl-2-nitropropanol suivant une méthode déjà décrite dans WO 2004/043982 : Le 2-méthyl-2-nitropropanol est converti en 2-méthyl-2-nitro- propylamine par une suite de 3 étapes consistant : 1- à activer la fonction alcool en formant un ester sulfonique du chlorure de tosyle, 2- à substituer cet ester de sulfonyl par un groupement azido, 3- à réduire sélectivement le groupement azido en aminé par la réaction de Staudinger. La 2-méthyl-2-nitropropylamine est condensée sur la lactobionolactone dans le méthoxyéthanol en milieu basique à 60°C. Cette réaction est suivie d'une réaction de peracétylation des groupements hydroxyles dans un mélange Anhydride acétique/Pyridine. Enfin, le groupement nitro est réduit sélectivement en hydroxylamine en suivant une procédure largement décrite dans la littérature. (Janzen, E. G. ; Dudley, R.L.; Shetty, R.V. J. Am. Chem. Soc. 1979, 101, 243-245) La réaction est conduite dans un mélange THFZH2O) à température ambiante en présence de Zinc en poudre et de chlorure d'ammonium. Le composé 1 est ensuite aisément purifié par chromatographie sur gel de silice (Eluant : AcOEt/cyclohexane, 8 :2, v/v) pour conduire à une poudre blanche avec 25 % de rendement depuis le 2-méthyl-2-nitropropanol.The precursor compound 1 of the polar head can be easily prepared from 2-methyl-2-nitropropanol according to a method already described in WO 2004/043982: 2-methyl-2-nitropropanol is converted into 2-methyl-2- nitro-propylamine by a sequence of 3 steps consisting of: 1- activating the alcohol function to form a sulphonic ester of tosyl chloride, 2-substituting this sulphonyl ester with an azido group, 3- selectively reducing the azido group to aminated by the reaction of Staudinger. 2-methyl-2-nitropropylamine is condensed on lactobionolactone in methoxyethanol in basic medium at 60 ° C. This reaction is followed by a peracetylation reaction of the hydroxyl groups in an acetic anhydride / pyridine mixture. Finally, the nitro group is selectively reduced to hydroxylamine following a procedure widely described in the literature. (Janzen, EG, Dudley, RL, Shetty, RVJ Am., Chem Soc., 1979, 101, 243-245) The reaction is carried out in a THFZH 2 O) mixture at room temperature in the presence of powdered zinc and sodium chloride. 'ammonium. Compound 1 is then easily purified by chromatography on silica gel (eluent: AcOEt / cyclohexane, 8: 2, v / v) to give a white powder with 25% yield from 2-methyl-2-nitropropanol.
Rf= 0,52 (Eluant :AcOEt/MeOH, 9 :1, v/v)Rf = 0.52 (eluent: AcOEt / MeOH, 9: 1, v / v)
RMN 1H (CDCl3) δ(ppm) : 6,62 (IH); 5,58-5,63 (2H); 5,39 (IH); 5,03- 5,25 (3H); 4,68 (IH); 4,55 (2H); 4,35 (IH); 3,95-4,21 (3H); 3,27 (2H); 1,99-2,18 (24H); 1,06 (6H). 1 H NMR (CDCl 3 ) δ (ppm): 6.62 (1H); 5.58-5.63 (2H); 5.39 (1H); 5.03-5.25 (3H); 4.68 (1H); 4.55 (2H); 4.35 (1H); 3.95-4.21 (3H); 3.27 (2H); 1.99-2.18 (24H); 1.06 (6H).
RMN 13C (DMSO) δ(ppm) : 166,7-170,7 (CO); 101,1 (CH); 78,4; 72,1; 70,8; 70,2; 70,0, 69,5; 69,3; 69.3; 69.3; 67,6 (CH); 61,7, 61,4; 57,4 (CH2); 45,4 (C); 22,8; 20,9 (CH3). 13 C NMR (DMSO) δ (ppm): 166.7-170.7 (CO); 101.1 (CH); 78.4; 72.1; 70.8; 70.2; 70.0, 69.5; 69.3; 69.3; 69.3; 67.6 (CH); 61.7, 61.4; 57.4 (CH 2 ); 45.4 (C); 22.8; 20.9 (CH 3 ).
2- Synthèse du composé 3
2- Synthesis of compound 3
Le composé 3 porteur de la chaîne hydrocarbonée peut être facilement préparé à partir du 4-cyanobenzaldéhyde suivant une méthode déjà décrite dans WO 2004/043982 : Le 4-cyanobenzaldéhyde est converti en 4-(l,3-dioxacyclopent-2- yl)benzylamine par une suite de 2 étapes consistant : 1- à protéger la fonction aldéhydique sous forme de dioxolane, 2- réduire le groupement cyano en aminé.Compound 3 carrying the hydrocarbon chain can be easily prepared from 4-cyanobenzaldehyde according to a method already described in WO 2004/043982: 4-cyanobenzaldehyde is converted into 4- (1,3-dioxacyclopent-2-yl) benzylamine by a sequence of 2 steps consisting of: 1- protecting the aldehyde function in the form of dioxolane, 2- reducing the cyano group to amine.
La 4-(l,3-dioxacyclopent-2-yl)benzylamine est condensée sur l'acide octanoïque dans le dichlorométhane en présence d'un système de couplage peptidique constitué de DCC et d'HOBt suivant une méthode déjà décrite (Ouari, O.; Polidori, A.; Pucci, B.; Tordo, P.; Chalier, F. J. Org. Chem. 1999, 64, 3554-3556) puis le groupement protecteur dioxolane est éliminé par un traitement dans un mélange acide acétique/eau 1 :1 v/v. Le composé 3 est ensuite purifié par chromatographie sur gel de silice (Eluant : Cyclohexane/AcOEt, 6 :4 v/v) pour conduire à une poudre blanche avec 40 % de rendement depuis le 4-cyanobenzaldéhyde.The 4- (1,3-dioxacyclopent-2-yl) benzylamine is condensed on octanoic acid in dichloromethane in the presence of a peptide coupling system consisting of DCC and HOBt according to a method already described (Ouari, O Polidori, A., Pucci, B., Tordo, P., Chalier, FJ Org Chem 1999, 64, 3554-3556) then the dioxolane protecting group is removed by treatment in a mixture of acetic acid / water 1 : 1 v / v. Compound 3 is then purified by chromatography on silica gel (eluent: Cyclohexane / AcOEt, 6: 4 v / v) to give a white powder with 40% yield from 4-cyanobenzaldehyde.
Rf= 0,47 (Eluant : AcOEt/Cyclohexane, 6/4 v/v)R f = 0.47 (Eluent: AcOEt / cyclohexane, 6/4 v / v)
RMN 1H (CDCl3) δ(ppm) : 9,98 (IH); 7,84 (2H); 7,42 (2H); 6,18 (IH); 4,50 (2H); 2,26 (2H); 1,63 (2H); 1,29 (8H); 0,88 (3H). 1 H NMR (CDCl 3 ) δ (ppm): 9.98 (1H); 7.84 (2H); 7.42 (2H); 6.18 (1H); 4.50 (2H); 2.26 (2H); 1.63 (2H); 1.29 (8H); 0.88 (3H).
RMN 13C (CDCl3) δ(ppm) : 191,9; 173,0 (CO); 137,0, 139,7 (C); 127,9, 126,8 (CH); 65,3; 43,3; 36,8; 31,7; 29,3; 29,0; 25,8; 22,6 (CH2); 14,1 (QH3). 13 C NMR (CDCl 3 ) δ (ppm): 191.9; 173.0 (CO); 137.0, 139.7 (C); 127.9, 126.8 (CH); 65.3; 43.3; 36.8; 31.7; 29.3; 29.0; 25.8; 22.6 (CH 2 ); 14.1 (QH 3 ).
3- Synthèse du composé 103- Synthesis of compound 10
Le composé 10 est obtenu par condensation du composé 1 avec le composé 3 suivant une méthode déjà décrite dans WO 2004/043982 : L'hydroxylamine 1 et le dérivé benzaldéhydique 3 sont mis en solution en quantité stoechiométrique dans le THF anhydre sous atmosphère d'argon et en présence de tamis moléculaire 4A. Le milieu réactioπnel est porté à 60 °C à l'abri de la lumière. L'hydroxylamine est additionnée de manière séquentielle toute les 24 heures par fraction de 0.20 équivalent jusqu'à consommation du dérivé benzaldéhydique. L'utilisation d'acide acétique comme co- solvant permet d'augmenter considérablement la cinétique de reaction, comme cela a déjà
été démontré. (Poeggeler, B.; Durand, G.; Polidori, A.; Pappola, M. A.; Vega-Naredo I.; Conto-Montes, A.; Bôker, J.; Hardeland, R.; Pucci, B. J. Neurochem. 2005, 95, 962-973.). La nitrone formée est purifiée par chromatographie sur gel de silice (Eluant : AcOEt/Cyclohexane, 7:3 v/v) puis par chromatographie d'exclusion de taille sur résine Sephadex LH-20 (Eluant : Dichlorométhane/Méthanol, 1:1 v/v). Enfin les groupements acétyls de la tête polaire sont éliminés suivant la méthode de Zemplén par transestérification dans le méthanol en présence d'une quantité catalytique de méthanolate de sodium. Le composé 10 est purifié par chromatographie d'exclusion de taille sur résine Sephadex LH-20 (Eluant : Méthanol) pour conduire à une poudre blanche avec 70 % de rendement.The compound 10 is obtained by condensation of the compound 1 with the compound 3 according to a method already described in WO 2004/043982: the hydroxylamine 1 and the benzaldehyde derivative 3 are dissolved in a stoichiometric amount in anhydrous THF under an argon atmosphere and in the presence of molecular sieve 4A. The reaction medium is brought to 60 ° C away from light. The hydroxylamine is added sequentially every 24 hours per fraction of 0.20 equivalent until the benzaldehyde derivative is consumed. The use of acetic acid as a co-solvent considerably increases the kinetics of reaction, as already been demonstrated. (Poeggeler, B., Durand, G., Polidori, A, Pappola, MA, Vega-Naredo I., Conto-Montes, A., Boker, J, Hardeland, R. Pucci, BJ Neurochem, 2005, 95, 962-973.). The nitrone formed is purified by chromatography on silica gel (Eluent: AcOEt / Cyclohexane, 7: 3 v / v) and then by size exclusion chromatography on Sephadex LH-20 resin (eluent: Dichloromethane / Methanol, 1: 1). / v). Finally, the acetyl groups of the polar head are removed by the Zemplen method by transesterification in methanol in the presence of a catalytic amount of sodium methanolate. Compound 10 is purified by size exclusion chromatography on Sephadex LH-20 resin (eluent: methanol) to yield a white powder with 70% yield.
Rf= 0,38 (Eluant: AcOEt/MeOH/H2O, 7:2:1, v/v) RMN 1H (MeOD) δ(ppm) : 8,35 (2H); 7,89 (IH); 7,41 (2H); 4,30-4,71 (3H) ; 4,19 (IH) ; 3,32-3,90 (13H) ; 2,28 (2H) ; 1,61 (8H) ; 1,33 (8H) ; 0,93 (3H).Rf = 0.38 (Eluent: AcOEt / MeOH / H 2 O, 7: 2: 1, v / v) 1 H NMR (MeOD) δ (ppm): 8.35 (2H); 7.89 (1H); 7.41 (2H); 4.30-4.71 (3H); 4.19 (1H); 3.32-3.90 (13H); 2.28 (2H); 1.61 (8H); 1.33 (8H); 0.93 (3H).
RMN 13C (MeOD) δ(ppm) : 174,2 (CONH); 142,4, 135,1 (C); 129,2; 129,9, 127,1; 104,3; 81,7; 75,8; 73,8; 73,3 (CH); 72,5 (C); 71,7; 71,3; 71,1; 68,9 (CH); 62,3, 61,3; 45,7; 42,4; 35,7; 31,5; 28,9, 28,7; 25,7 (CH2); 23,5, 23,4 (CH3); 22,3 (CH2); 13,0 (CH3).
13 C NMR (MeOD) δ (ppm): 174.2 (CONH); 142.4, 135.1 (C); 129.2; 129.9, 127.1; 104.3; 81.7; 75.8; 73.8; 73.3 (CH); 72.5 (C); 71.7; 71.3; 71.1; 68.9 (CH); 62.3, 61.3; 45.7; 42.4; 35.7; 31.5; 28.9, 28.7; 25.7 (CH 2 ); 23.5, 23.4 (CH 3 ); 22.3 (CH 2 ); 13.0 (CH 3 ).
Claims
1. Composé, caractérisé en qu'il répond à la formule (I) :A compound, characterized in that it corresponds to formula (I):
(I) dans laquelle :(I) in which:
X représente un groupement hydrophile choisi parmi un mono ou un polysaccharide, ainsi que les dérivés aminés de mono et de polysaccharides, une chaîne polyoxyde d'éthylène, une chaîne peptidique, un groupement polaire ionique choisi parmi un ammonium quaternaire, un oxyde d'aminé, un groupement carnitine, un groupementX represents a hydrophilic group chosen from a mono or a polysaccharide, as well as the amine derivatives of mono- and polysaccharides, an ethylene oxide chain, a peptide chain, an ionic polar group chosen from a quaternary ammonium, an amine oxide, , a carnitine group, a group
phosphate, un groupement choline, un groupement O un groupementphosphate, a choline group, a group O a group
m représente un entier égal à 1 , 2 ou 3 ; m represents an integer of 1, 2 or 3;
Y représente un bras espaceur ou une liaison, destiné à relier le noyau aromatique et les substituants hydrophiles X ;Y represents a spacer arm or a bond, intended to connect the aromatic ring and the hydrophilic substituents X;
Y est choisi parmi les fonctions ester, amide, urée, uréthane, éther, thio- éther, aminé, les chaînes hydrocarbonées en Cj-C6, éventuellement interrompues par une ou plusieurs fonctions ester, amide, urée, uréthane et par un ou plusieurs ponts éther aminé ou thio-éther ;Y is chosen from ester, amide, urea, urethane, ether, thioether, amine, C 1 -C 6 hydrocarbon chains optionally interrupted by one or more ester, amide, urea, urethane and one or more functions. amino ether bridges or thioether;
Y' représente un groupement choisi parmi une fonction ester, une fonction amide, une fonction urée, une fonction uréthane, un pont éther un pont thio-éther, un ou plusieurs aminoacides, le sérinol ; m' représente un nombre entier égal à 1 ou 2 ; n est égal à 0, 1 ou 2 ;Y 'represents a group chosen from an ester function, an amide function, a urea function, a urethane function, an ether bridge, a thioether bridge, one or more amino acids, and serinol; m 'represents an integer equal to 1 or 2; n is 0, 1 or 2;
X' représente un atome d'hydrogène ou une chaîne alkyle en C4-C14 éventuellement substituée par un ou plusieurs atomes de fluor.X 'represents a hydrogen atom or a C 4 -C 14 alkyl chain optionally substituted by one or more fluorine atoms.
2. Composé selon la revendication 1, caractérisé en ce que X représente un groupement choisi parmi : le glucose, le lactose, le fructose, le mannose, le galactose, le ribose, le maltose, la glucosamine, le saccharose et le lactobionamide. 2. Compound according to claim 1, characterized in that X represents a group chosen from: glucose, lactose, fructose, mannose, galactose, ribose, maltose, glucosamine, sucrose and lactobionamide.
3. Composé selon la revendication 1, caractérisé en ce que X représente un groupement choisi parmi les chaînes polyoxyde d'éthylène comprenant de 30 à 100 unités oxyde d'éthylène, de préférence de 50 à 60 unités.3. Compound according to claim 1, characterized in that X represents a group chosen from polyethylene oxide chains comprising from 30 to 100 ethylene oxide units, preferably from 50 to 60 units.
4. Composé selon la revendication 1, caractérisé en ce que X représente un groupement choisi parmi4. Compound according to claim 1, characterized in that X represents a group chosen from
5. Composé selon la revendication 1, caractérisé en ce que l'une au moins des conditions ci-dessous est satisfaite :5. Compound according to claim 1, characterized in that at least one of the conditions below is satisfied:
X représente un groupement choisi parmi : la lactobionamide, la carnitine ou une chaîne polyoxyéthylène ; m représente 1 ; m' représente 1 ou 2 ; n est égal à 1X represents a group chosen from: lactobionamide, carnitine or a polyoxyethylene chain; m is 1; m 'is 1 or 2; n is 1
X' est choisi parmi choisi parmi octyl, décyl, dodécyl, CF3(CF2)rCH2CH2-X 'is selected from among octyl, decyl, dodecyl, CF 3 (CF 2 ) r CH 2 CH 2 -
8>r>6.8> r> 6.
6. Procédé de préparation d'un composé répondant à la formule (I) selon l'une quelconque des revendications 1 à 5, ce procédé étant caractérisé en ce que l'on fait réagir un aldéhyde répondant à la formule (II) avec une hydroxylamine répondant à la formule (III) suivant le schéma 2 ci-dessous :6. Process for the preparation of a compound corresponding to formula (I) according to any one of Claims 1 to 5, this process being characterized in that an aldehyde corresponding to formula (II) is reacted with a hydroxylamine corresponding to formula (III) according to scheme 2 below:
(H) (HO (I)(H) (HO (I)
Schéma 2Figure 2
7. Procédé selon la revendication 6, caractérisé en ce que le composé de formule (III) est préparé suivant un procédé décrit dans le schéma 3 : 7. Process according to claim 6, characterized in that the compound of formula (III) is prepared according to a process described in scheme 3:
(VI) (V) (IV)(VI) (V) (IV)
Z = OH, NH2 ou TosylZ = OH, NH 2 or Tosyl
(HI) Schéma 3(HI) Figure 3
8. Composition pharmaceutique comprenant au moins un composé répondant à la formule (I) selon l'une quelconque des revendications 1 à 5 dans un support pharmaceutiquement acceptable.8. Pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 5 in a pharmaceutically acceptable carrier.
9. Utilisation d'un composé répondant à la formule (I) selon l'une quelconque des revendications 1 à 5 pour la préparation d'un médicament destiné à prévenir et/ou traiter les effets des radicaux libres.9. Use of a compound of formula (I) according to any one of claims 1 to 5 for the preparation of a medicament for preventing and / or treating the effects of free radicals.
10. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 pour la préparation d'un médicament destiné à la prévention ou au traitement des pathologies liées au stress oxydatif et à la formation des espèces radicalaires oxygénées.10. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the prevention or treatment of pathologies related to oxidative stress and the formation of oxygen radical species.
11. Utilisation selon la revendication 10, pour la prévention ou le traitement d'une pathologie choisie parmi les maladies immunitaires et inflammatoires, le syndrome d'ischémie-reperfusion, l'athérosclérose, la maladie d'Alzeimer, la maladie de Parkinson, les lésions dues aux radiations UV et ionisantes, la maladie de Huntington, les cancers, le vieillissement cellulaire.11. The use as claimed in claim 10, for the prevention or the treatment of a pathology chosen from immune and inflammatory diseases, ischemia-reperfusion syndrome, atherosclerosis, Alzeimer's disease, Parkinson's disease, lesions due to UV and ionizing radiation, Huntington's disease, cancers, cellular aging.
12. Composition cosmétique, caractérisée en ce qu'elle comprend au moins un composé répondant à la formule (I) selon l'une quelconque des revendications 1 à 5 dans un support cosmétiquement acceptable.12. Cosmetic composition, characterized in that it comprises at least one compound of formula (I) according to any one of claims 1 to 5 in a cosmetically acceptable carrier.
13. Procédé de traitement cosmétique pour prévenir et/ou traiter les effets du vieillissement, caractérisé en ce que l'on applique sur la peau ou sur les phanères une composition selon la revendication 12.13. Cosmetic treatment process for preventing and / or treating the effects of aging, characterized in that a composition according to Claim 12 is applied to the skin or to the integuments.
14. Utilisation d'un composé répondant à la formule (I) selon l'une quelconque des revendications 1 à 5, en synthèse organique comme capteur de radicaux libres dans des réactions radicalaires. 14. Use of a compound of formula (I) according to any one of claims 1 to 5, in organic synthesis as a free radical scavenger in radical reactions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0602355A FR2898602B1 (en) | 2006-03-17 | 2006-03-17 | NEW AMPHIPHILIC DERIVATIVES OF ALPHA-C-PHENYL-N-TERT BUTYL NITRONE |
| PCT/FR2007/000446 WO2007118947A1 (en) | 2006-03-17 | 2007-03-15 | Novel amphiphilic derivatives of alpha-c-phenyl-n-tert-butylnitrone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1999138A1 true EP1999138A1 (en) | 2008-12-10 |
Family
ID=37400864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP07731140A Withdrawn EP1999138A1 (en) | 2006-03-17 | 2007-03-15 | Novel amphiphilic derivatives of alpha-c-phenyl-n-tert-butylnitrone |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US8173843B2 (en) |
| EP (1) | EP1999138A1 (en) |
| JP (1) | JP2009530252A (en) |
| CN (1) | CN101421288A (en) |
| FR (1) | FR2898602B1 (en) |
| RU (1) | RU2008141144A (en) |
| WO (1) | WO2007118947A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009102808A2 (en) | 2008-02-12 | 2009-08-20 | Tosk, Incorporated | Doxorubicin adjuvants to reduce toxicity and methods for using the same |
| US10660851B2 (en) | 2015-01-02 | 2020-05-26 | Rxos Medical | Polyfunctional radical scavenger hydrogel formulation |
| CN107118132B (en) * | 2017-06-13 | 2019-08-23 | 贵州医科大学 | Antitumor application thereof of the phenol oxygen class nitrogen oxides as deacetylase inhibitor |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6046232A (en) * | 1997-10-17 | 2000-04-04 | Centaur Pharmaceuticals, Inc. | α-aryl-N-alkylnitrones and pharmaceutical compositions containing the same |
| FR2846968B1 (en) * | 2002-11-08 | 2005-02-04 | Salles Jean Pierre | NOVEL AMPHIPHILIC DERIVATIVES OF ALPHA-C-PHENYL-N-TERT-BUTYL NITRONE |
-
2006
- 2006-03-17 FR FR0602355A patent/FR2898602B1/en not_active Expired - Fee Related
-
2007
- 2007-03-15 WO PCT/FR2007/000446 patent/WO2007118947A1/en active Application Filing
- 2007-03-15 RU RU2008141144/04A patent/RU2008141144A/en not_active Application Discontinuation
- 2007-03-15 CN CNA2007800131063A patent/CN101421288A/en active Pending
- 2007-03-15 US US12/282,755 patent/US8173843B2/en not_active Expired - Fee Related
- 2007-03-15 JP JP2008558852A patent/JP2009530252A/en active Pending
- 2007-03-15 EP EP07731140A patent/EP1999138A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2007118947A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2898602B1 (en) | 2012-06-22 |
| US20090306001A1 (en) | 2009-12-10 |
| FR2898602A1 (en) | 2007-09-21 |
| JP2009530252A (en) | 2009-08-27 |
| US8173843B2 (en) | 2012-05-08 |
| CN101421288A (en) | 2009-04-29 |
| RU2008141144A (en) | 2010-04-27 |
| WO2007118947A1 (en) | 2007-10-25 |
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