Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/02—Linear peptides containing at least one abnormal peptide link
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • 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
  • A61P37/02—Immunomodulators
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
  • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/10—Tetrapeptides
  • C07K5/1002—Tetrapeptides with the first amino acid being neutral
  • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
  • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the subject of the invention is new molecules capable of being used as vector for active principles, active molecules comprising such a vector and their use in the field of pharmacy, in particular for the preparation of medicaments.
• the active ingredient must, as far as possible, be isolated from the physiological medium in order to avoid any harmful interaction either for the drug or for the organism.
• the support must not alter or better must improve the bioavailability of the drug.
• the therapeutic agent must be released within the molecule target (preferably at the intracytoplasmic level, in some cases intranuclear) and keep its full activity there.
• telomeres small amphiphilic polymers
• telomeres capable of modulating the hydrophilic-lipophilic balance of the active principle (and therefore its intrinsic physicochemical properties) but also of promoting its intracellular penetration and of it. ensure cell targeting by means of suitably chosen recognition agents.
• This vectorization method significantly increases the effectiveness of the anticancer agent since it inhibits the proliferation of metastases, slows tumor growth and prolongs the lifespan of treated mice by a factor greater than 3 compared to control mice.
• telomeres which have been described in the document WO 92/02560, one of the major problems with which such vectors are confronted and which could disturb their marketing and their use is their polydispersity, that is to say their absence of well defined mass and structure.
• the Applicant has set itself the objective of designing and preparing molecules capable of being vectors of active principle having a well-defined structure, the preparation of which is easy and which facilitate the transport of the active principle to its target.
• PA represents the active principle capable of acting on a biological target and which it is desired to promote the routing to its biological target;
• x represents an integer chosen from 0 and 1;
• X represents a peptide chain comprising from 1 to 5 amino acids; AA ls AA 2 , AA 3 , identical or different, each represents an amino acid; a 2 , a 3 , identical or different, each represents an integer chosen from
• R represents a group chosen from a targeting agent and a solubilizing agent.
• targeting agent is meant within the meaning of the present invention: a molecule promoting the routing of the whole molecule of formula (I) to its target or any molecule capable of being recognized by the target of the principle active PA.
• solubilizing agent is meant an agent allowing the modulation of the HLB balance of the molecule of formula (I), in particular a hydrophilic agent.
• targeting agents which can be used in the present invention, mention may be made of monosaccharides, amino sugar derivatives, polysaccharides, natural or synthetic hormones, peptides, antibodies, and in general, any molecule capable of being recognized. by the target of O 2004/043993
• solubilizing agents which can be used in the present invention, mention may be made in particular of polyols, polyethers, peptides, polysaccharides.
• Y represents a fluorinated C 4 -C 12 hydrocarbon chain comprising an O
• the dashes - between PA- (X) X and the chain [AA 3 ] a3 - [AA 2 ] a2 - [AA 1 ] indicate that the binding of PA- (X) X with the rest of the molecule is made with the side chain of one of the amino acids AAi, AA, AA 3 or optionally at the end of the peptide chain.
• the active principle is chosen from all organic molecules having a recognized biological activity and being capable of being linked to an amino acid by means of a bond which can be chosen from the functions -
• active principles there may be mentioned in particular those having an anticancer, anti-inflammatory, antiseptic, analgesic, neuroleptic, antifungal activity, molecules having an anti-free radical activity.
• the active principle may consist of a branched or cyclic linear molecule comprising from 1 to 30 carbon atoms, one or more unsaturations, in particular one or more aromatic rings, and one or more functions chosen from:
• the link with one of the two groups Y and - (X) x-PA is made on the side chain of one of the amino acids A Ai, AA, AA 3 .
• the amino acid linked to PA- (X) X - or to Y by its side chain is chosen from those comprising an acid, amide, amino, thiol or alcohol function on their side chain. Among these, mention may in particular be made of lysine, arginine, ornithine, aspartic acid, glutamic acid, asparagine, glutamine, serine, tyrosine, cysteine.
• the amino acid linked by its side chain to PA- (X) X - or to Y is chosen from: aspartic acid or lysine
• the spacer arm X when present, consists of a peptide chain engaged at one end in a bond, with the side chain or the end of one of the amino acids AAi, AA, AA and other end in a connection with the active ingredient P A.
• This spacer arm comprises 1 to 5 amino acids, preferably 1 to 3 amino acids.
• the spacer arm X and / or the peptide chain [AA 3 ] a 3 - [AA 2 ] a 2 - [AA ⁇ ] can be chosen for their affinity for the target of the active ingredient PA. They can also comprise or consist of tyrosine residues allowing the in vivo monitoring of the molecule of formula (I) after labeling with 125 I,
• R is chosen as a function of the cell target, it may be of a saccharide nature (targeting of specific membrane lectins which are found in particular tissues and which selectively recognize either galactose - cases of the liver, bones, certain cancerous tumors -, either mannose - case of macrophages, of the heart -, or sialic acid - case of erythrocytes - Among, of a hormonal nature (such as steroids), of a synthetic nature such as imatinib mesylate (ST571, Gleevek ®) to target kinases, specific antibodies, in particular peptides.
• R can be chosen from any substrate for which previous research has demonstrated the specificity of recognition. When R is a mono or a polysaccharide or a hydrophilic peptide, it may moreover provide the molecule with the water solubility necessary for its IV or IP administration.
• R when R is a peptide chain, R advantageously comprises from 3 to 15 amino acids, even more advantageously from 3 to 10 amino acids. It can also comprise one or more tyrosine residues allowing the in vivo monitoring of the molecule of formula (I) after labeling with 125 I, the amino acids constituting the spacer arm X, just like those constituting the chain [AA 3 ] a3 - [ AA] a - [AA 1 ] or the group R are chosen from natural amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine , histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or unnatural amino acids such as hydroxyprolme , norleucine, ornithine, citruline, cyclohe
• ⁇ -amino acids such as -3-aminopropionic acid and 4-amino-butyric acid.
• R peptide chain can be an antibody fragment or epitope having a pronounced affinity for the biological target of PA.
• RGD sequence known for its affinity for the ⁇ V ⁇ 3 integrins.
• R can also be chosen from polyols or polyethers, in particular polyethylene oxides so as to give the molecule of formula (I) a hydrophilic / lipophilic balance promoting its solubility in water and its penetration into the cell up to to the target of the active ingredient PA.
• R consists of a polyol
• the latter advantageously consists of an alkyl chain comprising from 4 to 16 carbon atoms and from 4 to 16 hydroxyl groups.
• R consists of a polyethylene oxide chain as a solubilization unit, this advantageously comprises from 5 to 30 ethylene oxide units.
• R can in particular be chosen from monosaccharides, amino sugar derivatives, polysaccharides.
• the mono-saccharides which can be used in the present invention mention may be made of: glucose, fructose, mannose, galactose, ribose.
• the amino sugar derivatives mention may in particular be made of glucosamine.
• the polysaccharides which can be used in the present invention mention may be made of lactose, cellobiose or maltose and lactobionamide, sucrose.
• the polysaccharide chains used in the invention are di-saccharides. The fixation of R on one end of the chain [AA 3 ] a3 - [AA] a2 -
• [AA]] is done by a suitable bond: ether, amide, carbamate, thioether, ester, urea, urethane, depending on the functionality which can be grafted on R.
• the fluorinated hydro carbon chain is preferably chosen from those corresponding to the formula A- Y 'in which A represents a group chosen O
• the invention also relates to any biologically active molecule comprising a fragment of formula (II)
• the invention provides a fragment of a molecule of formula (II) to which an active principle of any kind can be attached by an appropriate bond, as explained above, so as to promote the penetration of this active principle into the human or animal organism and so as to allow this active principle to reach its biological target.
• an active principle of any kind can be attached by an appropriate bond, as explained above, so as to promote the penetration of this active principle into the human or animal organism and so as to allow this active principle to reach its biological target.
• the amphiphilic nature of the molecule promotes transmembrane passages and the possible presence of a specific target recognition agent with which the active ingredient is associated promotes its progression to this target.
• the invention therefore also relates to the use of a molecule fragment of formula (II) as defined above to promote the bioavailability of an active ingredient.
• the preparation of the molecules of formula (I) is illustrated below by examples corresponding to several variants of the invention. More generally, use is made of the methods of protection, deprotection and coupling of peptide synthesis, methods well known to those skilled in the art and which are exposed in particular in the work "The peptides" Gross and Meienhofer, 3 vols , Academy Press, New York, 1979-1981.
• Su represents a variant of the group R, chosen from a monosaccharide, an amino derivative of monosaccharide, a polysaccharide, a polyol or optionally a polyether as defined above;
• AAj represents an amino acid carrying an acid, amino, alcohol, thiol function, on its side chain, via which it is linked either to (X) X -PA or to Y; AAi is connected to Su and either to (X) X -PA, or to Y, by its N- and C-terminal ends.
• X, x, PA and Y have the same definition as in formula (I) above.
• Y is attached to the amino or acid end of AAi or possibly to its side chain
• - Su represents a mono or a polysaccharide
• - X represents a spacer arm of peptide nature comprising at least one tyrosine residue; preferably X represents tyrosine;
• - AAi represents an amino acid chosen from arginine and lysine
• - Y represents a fluorinated C 6 -C 12 hydrocarbon chain comprising from 5 to 23 fluorine atoms, linked to the amino acid AAj by a -NH- function.
• Angiogenesis is a natural biological process of creating new blood microvessels from preexisting venules. It is a complex phenomenon that normally occurs in adults only under certain specific conditions such as wound healing, inflammation or the development of the corpus lutheum during the menstrual cycle. Under normal conditions, the angiogenesis process stops after an appropriate period of time indicating good regulation of the stimulating and inhibiting factors. Under certain pathological conditions such as the growth of solid tumors, rheumatoid arthritis, psoriasis and diabetic retinopathy, angiogenesis develops in a markedly less controlled manner ("Antiangiogenic agents and their promising potential in combined therapy". PA Burke, SJ DeNardo, Crit. Rew.
• the idea that prevailed in the work carried out was to graft the thalidomide on the vector previously provided with a radioactive motif such as tyrosine labeled with iodine 125.
• the aim sought in this example is to easily visualize the angiogenic sites in vivo, so solid tumors, and block their development.
• a central lysine motif has been provided with a fluorocarbon chain on the primary acid function, of a lactose type motif capable to provide the molecule with the water solubility necessary for its intravenous or intraperitoneal administration, tyrosine which is then marked with iodine 125 and onto which the thalidomide is grafted beforehand endowed with a reactive acid function in position 3.
• the active principle is chosen from molecules capable of blocking the angiogenesis process, in particular thalidomide.
• the active principle is chosen from molecules capable of blocking the angiogenesis process, in particular thalidomide.
• Mitochondrial cytopathies include a wide variety of diseases, the common denominator of which is a deficit in the mitochondrial respiratory chain. Due to the ubiquitous presence of mitochondria in the body, this dysfunction can affect any organ. The involvement can be isolated or, on the contrary, multi-organ then generally having a dominant neuromuscular. There is currently no treatment for these diseases which can be classified as "orphan diseases". It is nevertheless now clear that since mitochondria are the privileged place in the cell for the production of free radicals, deficits in the respiratory chain are very often associated with an overproduction of free radicals, resulting in accelerated cell death in the affected tissues. Recent work done at Necker Hospital in the team of Dr P.
• Rustin Increased apoptosis in vivo in cells lacking mitochondrial DNA gene expression
• Wang J, Silva JP, Gustafsson C, Rustin P, Larsson NG. Proc Natl Acad Sci USA (2001) (in press) have shown the importance of this production of free oxygen radicals on a series of human cells in culture.
• These cell cultures represent all types of deficits affecting the various complexes of the respiratory chain known in humans. They have been characterized both from the point of view of the deficit affecting the respiratory chain and from the point of view of the production of free radicals and its consequences on cell survival. This collection of cells represents an irreplaceable tool for studying the effectiveness of any molecule targeting radical reactions associated with deficits in the respiratory chain.
• Hum Mol Genêt (2001) (in press)
• the aim here was to refine and simplify the structure of these substrates while retaining their activity biological in order to develop a synthetic process easily adaptable to the industrial stage.
• the tests were carried out on several cell models: cell cultures with a deficit in the mitochondrial respiratory chain (fibroblasts in culture), neuron / muscle cell cocultures subjected to the action of free radicals and finally on cells extracted from skins with suffered a burn 3rd degree.
• the molecule E built on the previous model, was endowed in this particular case with a well-known and effective spin-trap which contains a derivative of PBN.
• the active principle is chosen from anti-radical agents, in particular derivatives of N-benzylidene tert-butyl amine oxide.
• Pep which is a variant of R, represents a peptide chain comprising from 2 to 10 , preferably from 4 to 6 amino acids.
• Pep or AAi comprise at least one tyrosine motif.
• Pep is chosen for its affinity for a given biological target, in particular this peptide chain can comprise an RGD (argine-glycine-aspartic acid) sequence which is known to be recognized by the ⁇ V ⁇ 3 integrins.
• RGD argine-glycine-aspartic acid
• Pep is a peptide recognized by the integrins ⁇ V ⁇ 3 and PA is an antimitotic agent;
• Pep or AAi contains at least one tyrosine residue
• - X represents a chain of 1 to 3 amino acids
• Example 3 Anti-cancer therapy.
• the ⁇ V ⁇ 3 integrins recognize a particular peptide sequence, the RGD (arginine-glycine-aspartic acid) sequence.
• the grafting of this motif onto the proposed vector must therefore provide it with a specific targeting capacity for angiogenesis sites and therefore ultimately for tumor sites.
• the addition of an antimitotic agent to this same vector should allow the selective destruction of cancer cells.
• molecule B was first prepared to verify the safety of the vector and determine its specificity. In order to give the targeting agent a greater degree of freedom, it has been grafted onto the central lysine via a hydrophobic amino acid, serine. The molecule is water-soluble and has an amphiphilic nature.
• vectors C, F and D The antimitotic agents chosen are only models here and simply illustrate the convenience of introducing and transporting a given antimitotic agent.
• This type of vector can and will also be used as a vectorizing agent for substrates such as adryamicin (in this precise case the molecule (it) comprises a peptide fragment, either in X or in Pep, of Gly-Phe-Leu- type. Gly), 5-Fu (5-Fluorouracil), Melphalan, tyrosine kinase inhibitors such as imatinib mesylate (STI571, Glivec®) for example or more generally of any anticancer agent capable of being grafted on these supports .
• the presence of the hydrophobic fluorocarbon chain promotes the passage transmembrane.
• the release of the active principle is ensured by hydrolysis of the peptide bonds via suitable cytoplasmic enzymes.
• a subject of the invention is also the use of the compounds corresponding to formula (I) as defined above for the preparation of a medicament.
• the products of the invention can be used for the prevention and / or treatment of all kinds of pathologies, in particular the various forms of cancer, pathologies linked to oxidative stress and to the formation of oxygenated radical species .
• the invention therefore relates to pharmaceutical compositions comprising a compound according to the invention in a pharmaceutically acceptable carrier.
• a compound of formula B for the preparation of a pharmaceutical composition intended for detecting the presence of cancer cells. It also relates to the use of a compound of formula E for the preparation of a pharmaceutical composition intended to prevent and / or treat pathologies linked to oxidative stress and to the formation of oxygenated radical species, in particular immune and inflammatory, ischemia-reperfusion syndrome, arteriosclerosis, Alzeimer disease, Parkinson's disease, lesions due to UV and ionizing radiation, certain cancers such as melanomas, cell aging.
• the products of the invention can be administered by any route known to a person skilled in the art, in particular by intravenous or intramuscular injection, by oral or cutaneous administration. They can be used alone or in combination with other active ingredients. Their dosage and the amount administered daily are adapted according to the activity measured for the molecule concerned and according to the weight of the patient. - in the cosmetic field, the compound of formula E can be used to prevent and / or treat the effects of aging.
• the invention therefore also relates to a cosmetic composition
• a cosmetic composition comprising a compound of formula E in a cosmetically acceptable carrier.
• Said composition can be intended for application to the skin or to the integuments (nails, hair).
• It can 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 anti-free radical activity is sought: a skin care cream, a sun protection product, a makeup remover, a mask for the skin or the hair, a shampoo, a product make-up such as lipstick, make-up, foundation, nail polish, etc.
• the compounds of the invention are easy to use and can be used under very diverse conditions.
• A- Preparation of the molecule A 2g (4mmol) of azide compound of 1H, 1H, 2H, 2H perfluorodecane dissolved in 30ml of anhydrous methanol, are subjected to hydrogenation in the presence of palladium on carbon. After 4 hours of reaction, the medium is filtered through Celite and the solvent evaporated under reduced pressure. The corresponding amine 2 is isolated without purification (quantitative yield). Compound 2 is reacted in 30 ml of dichloromethane in the presence of 2.2g (4mmol) of Boc-Lys- (Z) - OPhF 5 3. The pH of the solution is brought to 8 by adding a few drops of DIEA.
• reaction medium After 16 hours of stirring at room temperature, the reaction medium is concentrated under reduced pressure. The medium is purified by chromatography on a column of silica gel
• reaction medium is concentrated under reduced pressure. 40 ml of a 1: 1 acetic anhydride / pyridine mixture are added cold to the reaction crude. Stirring is maintained at room temperature for 18 hours then the reaction mixture is poured onto 150 ml of IN HCl. The aqueous phase is extracted 3 times with 50 ml of dichloromethane. The organic phase is respectively washed twice with 60 ml of IN HCl, then with 60 ml of brine and finally dried over Na 2 SO 4 .
• NMR 13 C (62.86 MHz, CDC1 3 ): ⁇ 171.3 (CO-NH), 170.5, 170.5, 170.1, 170.0, 170.0, 169.7, 169.2 (7s, CO-O), 167.9 (CO-NH), 156.7 (O -CO-NH), 136.7 (C IV arom.), 128.4, 128.0, 127.9, (CH arom.), 101.6 (CH-1 '), 77.9 (CH-4), 72.7 (CH-2), 71.1, 70.9 (CH-5 'and CH-3'), 70.0 (CH-5), 69.4 (CH-3), 69.0 (CH-2 '), 66.9 (CH-4'), 66.5 (CH 2 - O) , 61.6, 61.0 (CH 2 -6 and CH 2 -6 '), 52.6 (CH-CO), 40.4 (CH 2 -NH), 31.9 (CH 2 -NH), 31.2 (CH 2 -), 30.5 (CH 2 -Rf), 29.1 (CH 2
• the amine 10 obtained is reacted in dichloromethane in the presence of 0.107 g (0.23mmol) of active ester of thalidomide 11 and DIEA is added in order to bring the pH of the solution to 8.
• reaction medium After complete disappearance of amine 10 (TLC), the reaction medium is concentrated under reduced pressure and purified by chromatography on a silica gel column (eluent: ethyl acetate / cyclohexane 8/2 to 9/1).
• the deacetylation of the saccharide part of the molecule is carried out at room temperature in methanol containing a catalytic amount of sodium methylate.
• Such a substrate exhibits no unacceptable toxicity on cell cultures of fibroblasts and B16 melanomas.
• the molecule In vivo, the molecule is concentrated in the stroma of the tumor, which makes it possible to visualize it very clearly (see Table 1).
• Table 1 Radioactivity measured in different organs of mice carrying B16 melanomas after IP injection of the molecule A (10 ⁇ Ci / animal).
• Example 2 preparation of the molecule E. This synthetic example is illustrated by FIG. 1.
• N- (tert-butyl) hydroxylamine acetate is dissolved in a saturated aqueous solution of sodium carbonate.
• the hydroxylamine is extracted with ether.
• the organic phase is dried over Na SO 4 then the solvent is removed under reduced pressure to yield free N-tert-butylhydroxylamine in the form of powdery white crystals.
• reaction mixture is filtered through a celite layer, the solvent is removed under reduced pressure and the crude is purified by flash chromatography on silica gel (eluent: ethyl acetate / cyclohexane 6: 4). After recrystallization from a methanol / ether mixture, the nitrone X (0.590 g - 2.67 mmol - 40%) is obtained in the form of a white powder.
• the lactobionolactone and amine 4 are dissolved in an argon atmosphere in 40 ml of methanol.
• the pH of the solution is brought to 9 by addition of TEA then the medium is brought to reflux for 24 hours.
• 40 ml of a 1: 1 acetic anhydride / pyridine mixture are added cold to the crude. Stirring is continued for 18 hours then the reaction mixture is poured onto 150 ml of IN HCl.
• the aqueous phase is extracted with 3 times 50 mL of dichloromethane.
• the organic phase is respectively washed with twice 60 ml of IN HCl, then with 60 ml of brine and finally dried over Na 2 SO 4 .
• the amine 6 is dissolved in a stream of argon in 5 ml of anhydrous dichloromethane.
• 0.090 g of active ester X (0.28 mmol - 1 equiv.) are added to the medium and the pH is brought to 9 by addition of DIEA. Stirring is continued under an argon atmosphere for 24 hours.
• This synthesis is preceded by deprotection of the tripeptide according to the same protocol as for the synthesis of this tripeptide (compound 3). It is 500 mg (6.10 "4 mole) of 3 which are deprotected. Once deprotected, this peptide is dissolved in 10 ml of dichloromethane in a 100 ml flask. 278 mg (6.10 " 4 mole, leq) of compound 4 are added to the reaction medium. The reaction is carried out at room temperature under a stream of nitrogen, and is maintained at pH 8 using DIEA. After 16 hours, the reaction is complete (TLC).
• pentapeptide 5 is carried out under the same conditions as during the synthesis of compound 1. 400 mg (4.5 ⁇ 10 ⁇ 4 " mole) of the tetrapeptide are deprotected. Once deprotection is complete, this tetrapeptide is dissolved in 15 ml of dichloromethane in a 50 ml monocol flask. 219 mg (4.5.10 " mole, leq) of Boc Arg (Mtr) OH and 188 mg (5.85.10 " 4 mole, l, 3eq) of TBTU are added. takes place at room temperature under nitrogen flow, protected from light and is maintained at pH 8 with DIEA. After 16 hours, the reaction is complete (TLC).
• this molecule was tested on B16 melanoma cells, no toxicity could be measured up to concentrations greater than 100 ⁇ M.
• this molecule injected IV into a batch of mice carrying a melanoma accumulates in the stroma of the tumor and then diffuses slowly within the tumor (see Table 2)
• FIGS. 3A, 3B and 3C Method for preparing F identical to the previous ones, the synthesis is summarized in FIGS. 3A, 3B and 3C.

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