EP1999138A1 - Neue amphiphile derivate von alpha-c-phenyl-n-tert.-butylnitron - Google Patents
Neue amphiphile derivate von alpha-c-phenyl-n-tert.-butylnitronInfo
- 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- Withdrawn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
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 230000036542 oxidative stress Effects 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 10
- 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
- -1 polyoxyethylene chain Polymers 0.000 claims description 22
- 150000003254 radicals Chemical class 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 9
- 150000001299 aldehydes Chemical class 0.000 claims description 9
- 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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- 239000001301 oxygen Substances 0.000 claims description 5
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- 229920001282 polysaccharide Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- 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
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical group C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
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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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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([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
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 2
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
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- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 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
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 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
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229930182830 galactose Natural products 0.000 claims description 2
- 229960002442 glucosamine Drugs 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 230000003902 lesion Effects 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 238000007348 radical reaction Methods 0.000 claims description 2
- 239000002516 radical scavenger Substances 0.000 claims description 2
- 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
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 12
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- 239000003480 eluent Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
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- 238000004519 manufacturing process Methods 0.000 description 5
- MVGJRISPEUZYAQ-UHFFFAOYSA-N 2-methyl-2-nitropropan-1-ol Chemical compound OCC(C)(C)[N+]([O-])=O MVGJRISPEUZYAQ-UHFFFAOYSA-N 0.000 description 4
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- 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
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/52—Stabilizers
- A61K2800/522—Antioxidants; Radical scavengers
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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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0602355A FR2898602B1 (fr) | 2006-03-17 | 2006-03-17 | Nouveaux derives amphiphiles de l'alpha-c-phenyl-n-tert butyl nitrone |
| PCT/FR2007/000446 WO2007118947A1 (fr) | 2006-03-17 | 2007-03-15 | Nouveaux derives amphiphiles de l'alpha-c-phenyl-n-tert-butyl nitrone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1999138A1 true EP1999138A1 (de) | 2008-12-10 |
Family
ID=37400864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP07731140A Withdrawn EP1999138A1 (de) | 2006-03-17 | 2007-03-15 | Neue amphiphile derivate von alpha-c-phenyl-n-tert.-butylnitron |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US8173843B2 (de) |
| EP (1) | EP1999138A1 (de) |
| JP (1) | JP2009530252A (de) |
| CN (1) | CN101421288A (de) |
| FR (1) | FR2898602B1 (de) |
| RU (1) | RU2008141144A (de) |
| WO (1) | WO2007118947A1 (de) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2009214727B2 (en) | 2008-02-12 | 2014-12-11 | 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 (zh) * | 2017-06-13 | 2019-08-23 | 贵州医科大学 | 酚氧类氮氧化物作为去乙酰化酶抑制剂的抗肿瘤应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MA26553A1 (fr) * | 1997-10-17 | 2004-12-20 | Centaur Pharmaceuticals Inc | Alpha-aryl-n-alkylnitrones et compositions pharmaceutiques contenant ceux-la |
| FR2846968B1 (fr) * | 2002-11-08 | 2005-02-04 | Salles Jean Pierre | Nouveaux derives amphiphiles de l'alpha-c-phenyl-n-tert- butyl nitrone |
-
2006
- 2006-03-17 FR FR0602355A patent/FR2898602B1/fr not_active Expired - Fee Related
-
2007
- 2007-03-15 JP JP2008558852A patent/JP2009530252A/ja active Pending
- 2007-03-15 EP EP07731140A patent/EP1999138A1/de not_active Withdrawn
- 2007-03-15 CN CNA2007800131063A patent/CN101421288A/zh active Pending
- 2007-03-15 RU RU2008141144/04A patent/RU2008141144A/ru not_active Application Discontinuation
- 2007-03-15 US US12/282,755 patent/US8173843B2/en not_active Expired - Fee Related
- 2007-03-15 WO PCT/FR2007/000446 patent/WO2007118947A1/fr active Application Filing
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2007118947A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2898602A1 (fr) | 2007-09-21 |
| US20090306001A1 (en) | 2009-12-10 |
| JP2009530252A (ja) | 2009-08-27 |
| US8173843B2 (en) | 2012-05-08 |
| RU2008141144A (ru) | 2010-04-27 |
| FR2898602B1 (fr) | 2012-06-22 |
| CN101421288A (zh) | 2009-04-29 |
| WO2007118947A1 (fr) | 2007-10-25 |
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