Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • 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
  • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
  • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
  • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds

Definitions

• the invention relates, as new and useful industrial products, to new derivatives of 1-oxa-spiro [2,5] octan-6-ol. It also relates to their preparation process and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or in cosmetic compositions.
• Angiogenesis is known to be the formation of new blood microvessels from already existing vessels. Angiogenesis plays an important role in the development of embryonic tissues but practically never occurs in healthy adult tissues.
• Angiogenesis is also associated with the pathological process of various inflammatory diseases. As such, inhibition of angiogenesis may have an implication in the treatment and prevention of these diseases.
• An abnormal angiogenesis is thus involved in various inflammatory diseases such as rheumatic arthritis or others such as atherosclerosis, retinopathy of diabetic origin.
• Many groups of researchers have tried to discover new molecules capable of inhibiting angiogenesis, such as for example Taylor by application of Protamine (Taylor, S. et al., Nature, 1982, 297, 307) or else the use of heparin in the presence of cortisone by Folkman (Folkman, J. et al., Science, 1983, 221, 719).
• angiogenesis In dermatology, it is widely accepted that a dysregulation of the control of angiogenesis is associated with multiple disorders: tumors, psoriasis, hemangiomas (exaggerated angiogenesis) (Creamer, D. et al., Br. J. Dermatol, 1997 , 136 (6), 859-865; Jackson, JR et al. FASEB.J, 1997, 11 (6), 457-465), ulcers (angiogenesis deficient).
• steroids have been used for the treatment of hemangiomas, the efficacy of which is probably due to their antiangiogenic activity. It is also clear that increased attention is being paid to angiogenesis as a target for therapeutic intervention in other dermatological conditions.
• TNP-470 AGM 1470
• EP 357,061 and its successor, FR-118,847 described in patent.
• EP 386 667 are active in numerous models of angiogenesis and have a recognized antitumor activity (Logothetis,
• fumagillin derivatives such as 6-epifumagillols described in patent EP 387,650 also have applications in the inhibition of angiogenesis, suppression of cell proliferation and immunosuppression. In this case also, their synthesis is done by a hemisynthetic process.
• the Applicant has thus invented new derivatives thanks to the development of a new process for total synthesis.
• This total synthesis gives access to very difficult or even impossible analogues to prepare by hemisynthesis.
• it allows the functionalization of positions 7 and 8 of the 1-oxaspiro [2,5] octane cycle and the introduction of very varied side chains, it also allows the synthesis of optically active products.
• This total synthesis process also offers the advantage of allowing better control and a more economical implementation compared to previous hemisynthesis processes.
• the Applicant has moreover discovered that a key zone during the formation of the active molecule-biological target complex was at the level of the substituents in positions 7 and 8 of the 1-oxaspiro [2,5] octane ring, and that it could be advantageous to be able to benefit from new fumagillin derivatives having a substitution in position 7 and 8 of the 1-oxaspiro [2,5] octane ring and / or a modified side chain and not comprising an epoxy function, in order to be able to identify best anti-angiogenic candidates for topical and systemic treatment of conditions which may have a proliferative, inflammatory, and / or immunosuppressive component, in particular in the dermatological field.
• Rx represents H, a linear or branched alkyl radical of 1 to 5 carbon atoms or a linear or branched 1-hydroxyalkyl radical of 1 to 5 carbon atoms;
• - Ri represents a linear or branched alkyl radical of 1 to 5 carbon atoms, or an alkenyl radical having the structure (a) or the corresponding epoxide represented by the
• R 5 and R 6 having the meanings given below, - R 2 is H or a linear alkyl radical of 1 to 5 carbon atoms, 25 - R 3 is H or a radical represented by the formulas (c) or (d )
• R is H, a linear or branched alkyl radical of 1 to 5 carbon atoms, or an XRn radical, R is preferably a methyl or ethyl radical,
• R 6 is H or a linear or branched alkyl radical of 1 to 5 carbon atoms, the radicals R 5 and R 6 , taken together, can form a carbocycle of 3 to 10 carbon atoms, unsaturated or not, such as, for example , a cyclohexene,
• R 7 is a polyunsaturated chain comprising from 5 to 7 carbon atoms and a terminal carboxyl function or an aromatic ring corresponding to the general formula (e),
• R 8 , R 9 , R 10 are independently H or OCH 3
• - Ru is H, an alkyl radical of 1 to 5 carbon atoms or an aromatic ring
• Y represents a halogen atom chosen from chlorine, bromine, iodine and fluorine, since,
• Ri represents an alkyl of 1 to 5 carbon atoms or an alkenyl having the structure (a) and
• the invention also relates to the optical and geometric isomers, the salts and the mixtures of said compounds of formula (I).
• the compounds of the present invention may in fact be in the form of pharmaceutically or cosmetically acceptable salts, in particular in the form of salts of a base obtained by addition of a base, in particular, sodium salts, potassium salts, ammonium, or salts derived from lysine or ethanolamine.
• a base in particular, sodium salts, potassium salts, ammonium, or salts derived from lysine or ethanolamine.
• alkyl radical of 1 to 5 carbon atoms means a linear or branched radical having. 1 to 5 carbon atoms, and preferably the methyl, ethyl, isopropyl, tert-butyl and isopentyl radicals.
• aromatic nucleus preferably means the thiophene, pyrrole, naphthalene, benzene or furan radical.
• carbocycles radicals is meant, for example, an unsaturated or unsaturated ring having from 3 to 10 carbon atoms, such as more particularly the cyclohexene radical.
• the compounds of formula (I) more particularly preferred are those for which at least one, and preferably all the conditions below are met:
• - Ri represents the radicals of formula (a) or (b), - R 2 represents the methyl radical,
• R 7 represents an aromatic ring of formula (e).
• the present invention also relates to the processes for preparing the compounds of formula (I), in particular according to the reaction schemes given in FIG. 1.
• This figure shows a synthesis first of all involving an asymmetric aldolization reaction between a derivative suitably chosen chiral carboxylic acid carrying a "chiral copula" (1) and an aldehyde (2).
• the aldol (3) thus obtained can then be, by conventional methods, converted into diene derivative (4) which is subjected to a cyclizing metathesis reaction.
• the cyclic compound obtained (5) can be converted into a cyclohexanone derivative (6).
• the epoxidation of the ketone (6) into (7), then, optionally of the side chain R T followed by the cleavage of the protective group P and the esterification of the alcohol thus obtained allows access to the products of formula general (8).
• the groups RrR 4 and Rx have the values defined above, insofar as they are compatible with the reaction conditions employed. Otherwise, a precursor of the desired group may be used which will be converted to the latter at the end of the synthesis. For example, if it is desired that Ri contains an epoxide, the synthesis steps will be carried out using the corresponding olefin which can be converted at the end of the synthesis to epoxide by conventional methods of oxidation of the olefinic double bonds.
• the group R 1 is the group 1, 2-epoxy-1, 5-dimethylhexyl
• the precursor R 1 1,5-dimethyl-hex-1-enyl will be used in the synthesis, this the latter being epoxy at the end of synthesis.
• the present invention relates to a method for the total synthesis of fumagillin derivatives comprising the following steps:
• X n represents a chiral auxiliary
• auxiliaries mention may be made of Evans chiral oxazolidinones or Oppolzer's chiral sultones.
• starting compounds (1) there may be mentioned:
• Pi represents a protective group compatible with the reaction conditions and which can be removed without affecting the other functions present in the intermediate compounds in order to allow the introduction of the groups R 3 and R.
• Many protective groups correspond to this definition, for example the methoxyethyl-, 2,4-dimethoxybenzyl-, trimethylsilylethyl-, te / t-butyldimethylsilyl groups.
• the p-methoxybenzyl (PMB) group can advantageously be used for Pi.
• G represents an olefinic double bond or a precursor which can be easily converted into this double bond.
• aldehydes (2) having these characteristics are given below: 2- (?) - 4-phenylselenyl-2-p-methoxybenzyloxybutanal;
• 2- (f?) - 4-phenylselenyl-2- p-methoxybenzyloxybutanal is used as the starting aldehyde (2).
• This method can also include variants making it possible to introduce substituents in position 7 or 8 from the cyclic compound (5).
• this method may include an additional step of conjugate addition of a substituent R 4 on the ketone system, ⁇ of the cyclic compound (5) after step (d).
• organometallics such as, for example, organolithians, organomagnesiums, organocuprates, trialkylaluminiums, optionally in the presence of copper salts and Lewis acids.
• the synthesis method may include an additional step after step (c) of introduction of a 1-hydroxyalkyl group, precursors of alkyl groups, in position 8 (Rx) of the 1-oxaspiro [2,5] octane ring by a Baylis-Hillman reaction (see Figure 1, compound (5 ")).
• the synthesis method can also comprise an additional step after step (c) of epoxidation of the conjugated double bond located between positions 7 and 8 of the ring 1 -oxaspiro [2,5] octane and then of its regioselective opening, allowing the introduction of a hydroxyl group in position 7 (see Figure 1, compound (5 "')). More generally, the well-known reactivity of the unsaturated ⁇ - ⁇ ketone systems allows the introduction of a wide variety of substituents in positions 7 and 8 of the ring 1 - oxaspiro [2,5] octane.
• the compounds according to the invention have an activity in the fields of angiogenesis, cell proliferation and inflammation and more particularly find applications in the topical and systemic treatment of conditions linked to a disorder of angiogenesis, of keratinization. , conditions with an inflammatory and / or immunoallergic component and hyperproliferation of tissues of ectodermal origin (skin and epithelium in particular), whether benign or malignant and also find application outside of dermatology.
• These compounds can also be used to fight against aging of the skin, whether photoinduced or chronological and to treat scarring disorders.
• the compounds of general formula (I) have biological, anti-angiogenic, antiproliferative and anti-inflammatory properties. This activity can be demonstrated "in vitro" by a method using a biological target, a methionine aminopeptidase (MetAP-2) identified by Griffith et al. (Griffith, E.C. et al. Chem Biol, 1997, 4 (6), 461 - 471). The inhibitory activity of different fumagillin derivatives vis-à-vis this enzyme has a good correlation with the antiangiogenic effect.
• MethodAP-2 methionine aminopeptidase
• the biological activity of the compounds is evaluated by measuring their inhibitory activity of the methionine aminopeptidase MetAP-2 (Li, X., Chang, YH. Biochem. Bichem. Res. Comm. 1996, 227, 152 ).
• the biological activity is characterized in this system, by determining the concentration of compound necessary in inhibitor to inhibit 50% of the enzymatic activity (IC 50 ).
• the test protocol used is described in Example 13 of the present application.
• the antiangiogenic activity of the compounds according to the invention can also be measured by their capacity to inhibit the proliferation of endothelial cells. This activity is described in Example 13 of the present application.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least one compound of formula (I) as defined above in a pharmaceutically acceptable carrier.
• the present invention therefore also relates to such a pharmaceutical composition as a medicament intended in particular for the treatment of the aforementioned conditions.
• compositions according to the invention can be carried out by oral, parenteral, topical or ocular route.
• the pharmaceutical compositions can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, suspensions of microspheres or nanospheres or lipid vesicles or polymers allowing controlled release.
• compositions may be in the form of solutions or suspensions for infusion or for injection.
• the compounds according to the invention are generally administered at a daily dose of approximately 0.001 mg / kg to 500 mg / kg and preferably of approximately 0.01 mg / kg to 50 mg / kg in body weight in 1 to 3 doses. .
• the invention are intended for the treatment of the skin and mucous membranes and are in the form of ointments, creams, milks, ointments, powders, soaked pads, solutions, gels, sprays, lotions or suspensions. They can also be in the form of suspensions of microspheres or nanospheres or lipid or polymeric vesicles or of polymeric patches and of hydrogels allowing controlled release.
• topical compositions can be presented either in anhydrous form or in aqueous form according to the clinical indication.
• compositions of the present invention in particular for the topical or ocular route, contain at least one compound of formula (I) as defined above at a concentration preferably between 0.0001 and 20% and preferably between 0.001 at 5% relative to the total weight of the composition.
• the present invention also relates as a medicament to the pharmaceutical compositions as defined above.
• compositions of the present invention are particularly suitable for the treatment of conditions linked to a disorder of angiogenesis, to cell proliferation, of an inflammatory nature or not such as hemangiomas, malignant or benign tumors, cancers, melanomas , basal cell carcinomas, pyogenic granuloma, angiofibromas, scleroderma, eye tumors, chorioretinal ischemia e, retinal neovascularization, neovascular glaucoma, trachomatous scars, rheumatoid arthritis, rheumatic arthritis, psoriasis , Kaposi's sarcoma, angiosarcoma, lupus, rosacea, proliferative retinopathy of diabetic origin, transplant rejection, scarring disorders such as keloids and hypertrophic scars.
• an inflammatory nature or not such as hemangiomas, malignant or benign tumors, cancers, melanomas , basal cell carcinomas
• the compounds of formula (I) according to the invention also find an application in the cosmetic field, in particular in the care of the skin or the scalp and in particular for the treatment of skin prone to acne, for hair regrowth, Panti -fall, to fight against the oily appearance of the skin or hair, in protection against the harmful effects of the sun or in the treatment of physiologically dry skin, to prevent and / or fight against photo-induced or chronological aging.
• the present invention therefore also relates to a cosmetic composition containing, in a cosmetically acceptable carrier, at least one compound of formula (I) as defined above.
• This cosmetic composition can be in particular in the form of a cream, a milk, a lotion, a gel, suspensions of microspheres or nanospheres or lipid or polymeric vesicles, a soap or a shampoo .
• concentration of compound of formula (I) in the cosmetic compositions can be between 0.0001 and 3% by weight relative to the total weight of the composition.
• the compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
• the compounds according to the invention can be advantageously used in combination with retinoids, with corticosteroids or estrogens, in combination with anti-free radicals, with ⁇ -hydroxy or ⁇ -keto acids or their derivatives, with salicylic acid derivatives, or with ion channel blockers such as potassium channels or, more particularly for pharmaceutical compositions, in combination with drugs known to interfere with the immune system (for example the ciclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors ).
• drugs known to interfere with the immune system for example the ciclosporin, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors .
• retinoids ligands of the RAR or RXR receptors, natural or synthetic.
• antioxidants is meant, for example, ⁇ -tocopherol, Super Oxide Dismutase, Ubiquinol or certain metal chelating agents.
• ⁇ -hydroxy or ⁇ -keto acids or their derivatives is meant for example lactic, malic, citric, glycolic, mandelic, tartaric, glyceric, ascorbic acids, as well as their salts, amides or esters.
• potassium channel blockers is meant, for example, Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives.
• compositions according to the invention can, in addition, contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and, in particular:
• - depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid
• - emollients such as glycerol, PEG 400, thiamorpholinone and its derivatives or urea;
• antiseborrhoeic or anti-acne agents such as S-carboxymethylcysteine, S-benzyl-cysteamine, their salts and their derivatives, or benzoyl peroxide
• antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines
• antifungal agents such as ketoconazole or polymethylene-4,5-isothiazolinones-3;
• agents promoting hair regrowth such as Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro 3-methyl 1, 2,4-benzothiadiazine 1 , 1-dioxide) and Phenytoin (5,4-diphenyl-imidazolidine 2,4-dione);
• anti-psoriatic agents such as anthralin and its derivatives
• eicosa-5,8,11, 14-tetraynoic and eicosa-5,8,11-trynoic acids their esters and amides.
• compositions according to the invention can also contain flavor-enhancing agents, preserving agents such as esters of parahydroxybenzoic acid, stabilizing agents, humidity-regulating agents, pH-regulating agents. , osmotic pressure modifying agents, emulsifying agents, UV-A and UV-B filters, antioxidants, such as ⁇ -tocopherol, butylhydroxyanisole or butylhydroxytoluene.
• a solution of 29 g (93 mmol, 1.0 eq) of diphenyl diselenide in 150 ml of DMF is added slowly to a solution of 7.04 g (186 mmol, 2.0 eq) of sodium borohydride in 100 ml of DMF.
• the reaction medium is stirred at 20 ° C. until discoloration then the temperature is brought to 80 ° C.
• a solution of 9.50 g (93 mmol, 1.0 eq) of (R) - (+) - ⁇ -hydroxybutyrolactone in 25 mL of DMF is added slowly at 80 ° C using a cannula.
• the reaction mixture is stirred for 2 hours at 80 ° C and then 1 hour at 20 ° C.
• reaction mixture is stirred for 1 hour 30 minutes.
• the reaction is stopped by adding 0.5 ml of a saturated solution of sodium hydrogencarbonate, then extracted with ethyl acetate.
• the organic phases are combined, dried over sodium sulfate and then concentrated to give a colorless oil which is then filtered through a bed of silica gel: (eluent Cy / AcOEt 1/1).
• the dry ice bath is removed, allowing the temperature of the reaction medium to reach 0 ° C., this is transferred using a cannula to a saturated solution of potassium carbonate.
• the reaction medium is extracted with 4 x 250 mL of a 2/1 cyclohexane-ether mixture.
• the organic phases are combined, washed with a saturated solution of sodium chloride and then dried over anhydrous sodium sulfate.
• the solvents are evaporated and then the residue is dissolved in 100 mL of THF.
• This oil is dissolved in 50 ml of THF, then 16 ml (16 mmol, 1.1 eq) of a 1M solution in THF of te abutyl ammonium fluoride are added. The reaction is stirred for 2 hours at room temperature. The reaction is stopped by adding 100 ml of a saturated solution of ammonium chloride, then extracted with 250 ml of diethyl ether. The organic phases are combined, dried over anhydrous sodium sulfate and then the residue is filtered through silica gel: eluent (Cy / AcOEt 98/2 - ⁇ 75/25).
• RMN 13 C (62.9 MHz. CDCI.): 171.6, 153.3, 135.3, 130.2, 129.4, 128.9, 127.6, 127.3, 66.1, 55.2, 45.4, 38.6, 37.8, 27.6, 25.9, 22.5, 16.6.
• RMN 13 C (62.9 MHz. CDCI a ): 159.0, 135.5, 131.8, 130.5, 129.6, 129.3, 119.7, 113.7, 81.2, 72.9, 69.7, 61.0, 55.2, 51.3, 38.6, 32.0, 27.7, 26.0, 22.5, 22.4 , 15.2.
• OPMB 10 mL (10 mmol, 5.0 eq) of a 1 M vinylmagnesium bromide solution in THF are added at 0 ° C to a solution of 877 mg (2.02 mmol, 1.0 eq) of methoxy-methyl amide of l 2 (S) -2 - [(1S, 2fî) -2-methoxy-3-p-methoxybenzyloxy-but-3-enyl] -3,7-dimethyloct-3-enoic acid in 5 mL of THF.
• RMN 13 C (62.9 MHz. CDCI a ): 166.9, 161.3, 144.5, 131.0, 130.8, 129.7, 127.2, 115.9, 114.3, 79.2, 66.7, 60.6, 57.0, 55.3, 51.4, 49.4, 38.8, 28.8, 27.7, 25.8 , 25.7, 22.6, 22.4, 14.1.
• EXAMPLE 3 (3ft 4S. 5S. QR, 7f ⁇ -6-hvdroxy-5-methoxy-7-methyl-4-r (a-1.5- dimethylhexyn-1-oxaspiror2.51octane
• reaction medium is extracted with diethyl ether.
• organic phases are combined and then dried over anhydrous sodium sulfate.
• RMN 13 C (62.9 MHz. CDCI a : 208.3, 131.3, 128.8, 82.3, 66.4, 61.0, 57.7, 41.2, 38.7, 38.6, 27.6, 25.9, 25.0, 22.6, 22.5, 14.2, 11.6.
• RMN 13 C (62.9 MHz. CDC I: 166.0, 132.9, 131.2, 130.8, 130.5, 129.7, 128.3, 80.1, 68.8, 60.2, 57.2, 51.2, 49.2, 38.8, 38.3, 35.4, 27.7, 25.7, 24.8, 22.6, 22.4, 14.0, 11.6.
• EXAMPLE 7 4-methoxy-cinnamate (3R 4S. 5S. 6R 7fl ⁇ -7-ethyl-5-rnethoxy-4- 1 (1 R 2ffl-1, 2-épo ⁇ y-1.5-diméthylhexyn-1-oxaspiror2.51oct- 6-yl
• reaction mixture is then stirred for 1.5 h at -78 ° C. then the reaction is stopped by the addition of 5 ml of a saturated ammonium chloride solution.
• the flask is then reheated to 20 ° C and then extracted with diethyl ether.
• the organic phases. are combined and then dried over anhydrous sodium sulfate.
• the residue is redissolved in 10 mL of chloroform and then 1.2 g (2.8 mmol) of tetrabutylammonium periodate are added and the reaction mixture is stirred for 2 h at 60 ° C.
• the product is purified by preparative chromatography on a silica plate (eluent: ether / pentane 1: 1) to give 9 mg (42%) of 4-methoxy-cinnamate from (3R4S, 5S, 6f?) - 4- (cyclohex- 1-enyl) -5-methoxy-1 -oxaspiro [2,5] oct-6-yle. (containing 90% trans isomer and 10% cis isomer).
• Glacial acetic acid (6 ⁇ l, 0.5 eq.) Is then added, followed by the epoxide (1 H, _3S, 4S, 5fî, 6S) -3- (1, 5-Dimethyl-hex-1-enyl) -4-methoxy-5- (4-methoxy-benzyloxy) -7-oxa-bicyclo [4.1.0] heptan-2-one dissolved in 3 ml of ethanol. After 15 min. at 0 ° C, the reaction is stopped by adding AcOEt, then washed with a saturated aqueous NaCl solution. This aqueous phase is then extracted three times using AcOEt.
• reaction is stopped by adding 0.5 ml of a saturated sodium hydrogen carbonate solution, then extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate and then concentrated under reduced pressure. The residue is then chromatographed on preparative silica plates (eluent CH 2 CI 2 ).
• the composition is injected into an adult individual at a frequency of 1 to 7 times a week for 1 to 12 months.
• the composition is injected into an adult individual at a frequency of 1 to 7 times a week for 1 to 12 months.
• the composition is injected into an adult individual at a frequency of 1 to 7 times a week for 1 to 12 months.
• the composition is injected into an adult individual at a frequency of 1 to 7 times a week for 1 to 12 months.
• the enzymatic activity is measured as follows: to an appropriate quantity of enzyme, the substrate solution is added so that the final concentration is 1 mM, and the mixture is incubated at 37 ° C for 10 - 30 minutes. The reaction is stopped by adding a 100 mM EDTA solution. or by heating in a boiling water bath for 2 minutes. b.
• the N-terminal methionine released is quantified by measuring the absorbance at 450 nm (A 50 ) by incubating for 30 to 60 minutes at 37 ° C. with the following colored reagent: buffer B (Hepes buffer, 10 mM, pH 7, 4) (Ben-Bassat A .; Bauer K .; Chang SY et al., J. Bacteriol. 1987, 169, 751-757), containing 70 ⁇ g / ml of amino acid oxidase, 10 ⁇ g / ml of horseradish peroxidase and 1 mM o-dianisidine.
• the activities are expressed in mmol of methionine produced, using the conversion factor of 1mmol of methionine / ml ⁇
• the IC 50s are determined by incubating the enzyme and its substrate (using the experimental conditions described above) with increasing concentrations of inhibitor.
• the control is 4-methoxycinnamate of 5-Methoxy-4- [2-methyl-3- (3-methyl-but-2-enyl) - oxiranyl] -1 -oxa-spiro [2.5] octan-6-yle described in the publication of Han et al., Bioorganic & Medicinal Chemistry Letters, 2000, 10, 39-43.
• the cells prepared in the laboratory are sown in enriched SFM medium (Gibco).
• the growth is stopped by 2 washes in a serum-free medium and they are returned to culture without serum for 24 hours. They are trypsinized and reseeded in a 48-well plate: 50,000 cells per well in 500 ⁇ l.
• the value of the IC50 is determined graphically by representation of the radioactivity curve measured as a function of the increasing doses of inhibitor.

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