Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
• • 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
  • 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
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/92—Naphthofurans; Hydrogenated naphthofurans

Definitions

• the present invention relates to particular lactone compounds which can be used as antioxidant agents for the manufacture of antioxidant compositions, in particular pharmaceutical, cosmetic or food compositions.
• the present invention also relates to a process for the preparation of such compounds.
• the general field of the invention is therefore that of antioxidants.
• Antioxidants have the particularity of capturing free radicals, which are very reactive molecules involved in many pathologies, in particular pathologies resulting from oxidative stress, such as, for example, inflammatory diseases, cardiovascular diseases, diabetes.
• antioxidants can be used for their anti-inflammatory activity, in particular the antioxidants making it possible to inhibit the production of pro-inflammatory cytokines such as factor TNF- ⁇ , in macrophages and monocytes.
• Antioxidants can also intervene in the protection of cells, by limiting the triggering of the genetic program of cell death or apoptosis, which can be caused by an accumulation of free radicals.
• the object of the present invention is to provide particular lactone compounds, some of which are new, usable, in a particularly effective manner as antioxidant agents for the manufacture of antioxidant compositions, such as pharmaceutical, cosmetic, and food compositions.
• the aim of the present invention is also to propose a process for the preparation of lactone compounds in accordance with the invention.
• the present invention relates, according to a first object, to compounds corresponding to the following formula (I):
• R 2 represents H, -OH or -0R 9 ,.
• R 3 represents H, R 9 , -C0 2 R 9 or -CO-NHR ⁇ 0 ; or R 2 and R 3 together form -O-CO-;
• - R 4 and R 5 identical or different, represent H or R 9 ;
• R 9 represents a linear or branched alkyl group, comprising from 1 to 20 carbon atoms; - Rio represents R 9 or a group - (CH 2 ) a -NH-
• OCH 3 , R 4 and R 5 represent -CH 3 and R 6 and R 8 represent H;
• the invention also includes the optional salts corresponding to the compounds as defined above.
• salts are meant, in the above and what follows, the ionic compounds resulting from the action of a mineral base on the labile proton (s) of a compound of formula (I).
• the symbol A can represent for the two salt forms mentioned above an alkali metal, such as Na + , K + , an ammonium cation NH 4 + .
• the potassium disels are in particular those represented by the formula (XII) below.
• linear or branched alkyl group containing from 1 to 20 carbon atoms means an unsaturated hydrocarbon group such as a methyl, ethyl or propyl group, isopropyl, butyl, isobutyl, tert-butyl.
• R x , R 4 , R 5 , R 6 , R 7 and R 8 meeting the same definition as that given above.
• R 2 and R 3 can also independently form identical or different radicals, such as hydrogen atoms.
• radicals such as hydrogen atoms.
• group R 9 representing a linear or branched alkyl group containing from 1 to 20 carbon atoms
• the present invention also relates to a process for the preparation of compounds of formula (I) below:
• R 2 represents H, -OH or -OR 9 ;
• R 3 represents H, R 9 , -C0 2 R 9 or -CO-NHRio; or R 2 and R 3 together form -O-CO-;
• R 4 and R 5 identical or different, represent H or R 9 ;
• R 9 represents a linear or branched alkyl group, comprising from 1 to 20 carbon atoms
• -the Ru, R12 are independently -B (0R ⁇ 3) (0R i4) or -Sn (R ⁇ 5) 3;
• R i3 and R i4 identical or different, represent H or an alkyl group of 1 to 7 carbon atoms or R ⁇ 3 and R 14 together form a linear or branched alkylene group;
• R 4 , R 5 , R 6 , R 7 and R 8 correspond to the same definition as that given previously;
• - X represents a leaving group, said reaction being carried out in the presence of a base and of a catalyst based on platinum or palladium; and optionally a treatment step intended to obtain a salt corresponding to the compound of formula (I).
• R ⁇ 3 and R i4 together form a linear or branched alkylene group
• this group includes, for example, from 2 to 3 carbon atoms, such as -CH 2 - CH 2 -, -CH 2 -CH 2 -CH 2 -, -C (CH 3 ) 2 -C (CH 3 ) 2 -, -CH (Ph) -CH 2 - CH (Ph) -, Ph representing a phenyl group.
• the leaving group X is chosen from halogens such as F, Cl, Br, I, the triflate -0-S0 2 CF 3 , the group of formula -0-S0 2 - (CF 2 ) n - CF 3 with n being an integer ranging from l to 8.
• the catalyst based on platinum or palladium is chosen so as to obtain a coupling reaction between the compound of formula (IV) and the compound of formula (V).
• this catalyst is a platinum or palladium complex, such as dichlorobis (triphenylphosphine) alladium PdCl 2 (PPh 3 ) 2 , tetrakis (triphenylphosphine) palladium Pd (PPh 3 ) 4 .
• the base used in the context of this process is a base chosen, for example, from NaOH, Ba (0H) 2 , Na 2 C0 3 , K 2 C0 3 , CsC0 3 , K 3 P0 4 , CH 3 C00Na, CH 3 C0OK, CH 3 0Na, CH 3 CH 2 0Na, amines such as triethylamine.
• the possible step intended to obtain the corresponding salts consists, once the compound of formula (I) obtained, in treating this product, for example by reacting on it a mineral base.
• process according to the invention may possibly include steps for protecting the functions sensitive to the reaction conditions, these functions then being deprotected at the end of the said process. These protection and deprotection steps are steps within the reach of the skilled person.
• a base is introduced, for example, sodium bicarbonate.
• reaction mixture is then brought to reflux with vigorous stirring for an adequate time (that is to say the time necessary to obtain the compound of formula (I), the progress of the reaction being able to be followed by techniques. such as thin layer chromatography).
• reaction mixture is then treated by adding water.
• aqueous phase is extracted with an organic solvent, for example dichloromethane.
• organic phases are combined, dried and then concentrated.
• the product obtained is finally purified by conventional techniques such as column chromatography.
• the process for the preparation of the compounds according to the invention involves compounds of formula (IV) and (V), which may be commercially available or prepared before the implementation of the process of the invention.
• the compound of formula (IV), with Ru and R12 representing -B (OR ⁇ 3 ) (0R i4 ), can be obtained by reacting a compound derived from naphthalene of formula (VI):
• the Y identical or different, represent leaving groups chosen, for example, from halogens such as fluorine, chlorine, bromine, iodine, triflate -0-S0 2 -CF 3 , with a boron compound corresponding to the one of the following formulas:
• R13 and R i4 having the same meaning as that given above, said reaction being carried out in the presence of a base and of a catalyst based on platinum or palladium such as 1, 1 '-bis (diphenylphosphino) ferrocene dichloropalladium or PdCl 2 (dppf), dppf meaning the
• R 5 / R 6 , R 7 and R 8 having the same definition as that given above, in basic medium, with an alkyl ⁇ -alkoxyacetate of formula R 4 0-CH 2 -C0-0Alk, R 4 corresponding to the same definition as that given above, the group Alk being a linear or branched alkyl group comprising from 1 to 20 atoms of carbon, at the end of which a compound of formula (VIII) is obtained below:
• this leaving group X can be chosen from halogens, triflate -O- S0 2 -CF 3 or the group of formula -0-S0 2 - (CF 2 ) n -CF 3 with n being a integer ranging from 1 to 8.
• step a) the reaction is carried out in a basic medium, this medium being intended to deprotonate the group -CH 2 - located in position ⁇ of the group -CO 2 R5 of the compound (VII).
• This basic medium can for example be a solution of lithium diisopropylamide (or LDA).
• LDA lithium diisopropylamide
• Steps b) and c), which consist in synthesizing a compound 1, 3-bis (trialkylsiloxy) -1, 3-butadiene (IX), followed by cyclization are adapted from Langer's works, such as those explained in the publication "Domino Reaction of 1, 3-bis (trimethylsilyloxy) -1, 3- dienes ith Oxalyl Chloride: General and Stereoselective Synthesis of ⁇ -Alkylidenebutenolides" P.Langer et al., Chem.Eur.J.2000, 6, N ° 7, 3204-3214 [6].
• step d) can be envisaged according to any type of reaction within the reach of those skilled in the art, said reactions making it possible to convert the group -OH into a reactive group such as a triflate or a fluoroalkylsulfonate -S0 2 - (CF 2 ) n -CF 3 with n being an integer ranging from 1 to 8.
• a reactive group such as a triflate or a fluoroalkylsulfonate -S0 2 - (CF 2 ) n -CF 3 with n being an integer ranging from 1 to 8.
• the compound referenced 5a forming part of the compounds of formula (V) can be synthesized according to the following specific reaction scheme:
• the triflate (5a) is prepared from the corresponding alcohol (X) by treatment with triflic anhydride (Tf 2 0), in the presence of a base such as pyridine.
• the alcohol (X) comes from the reaction of a 1,3-bis (trimethylsiloxy) -1,3-butadiene (9a) suitably substituted with oxalyl chloride, catalyzed by methyl triflate.
• This reaction of cyclization, as well as the preparation of 1,3-bis (trimethylsiloxy) -1, 3-butadiene (9a) are adapted from Langer's works, such as those mentioned above.
• the ⁇ -ketoester (VIII) precursor of 1,3- bis (trimethylsiloxy) -1, 3-butadiene (9a) is obtained by reaction of the lithiated enolate formed from the corresponding phenylacetate (VII) with a ⁇ -alkoxyacetate methyl.
• the inventors have discovered, surprisingly, that the compounds (I) as defined in the first subject, including the excluded compounds, can be used, effectively, as antioxidant agents for the manufacture of antioxidant compositions.
• R 2 represents H, -OH or -OR 9 ;
• R 3 represents H, R 9 , -C0 2 R 9 or -CO-NHRio; or R 2 and R 3 together form -O-CO-;
• R 4 and R 5 identical or different, represent H or R 9 ;
• R 9 represents a linear or branched alkyl group, comprising from 1 to 20 carbon atoms; - Ro represents R 9 or a group - (CH 2 ) a -NH-
• the antioxidant has a chemical structure identical to that of the compound of formula (II) defined above.
• Norbadione is a natural product, which has been extracted to date from two species of fungi. It constitutes one of the pigments of the hat of the bay bolete (Xerocomus badius), which is a highly appreciated edible species, as described in the article "Pigments from the cap cuticle of the Bay Boletus", Angew.Chem. Int.Ed.Engl.23 (1984), n ° 6 [4].
• Norbadione is extracted from these mushrooms in the form of potassium disel (formula XII) and can be converted into the corresponding diacid.
• the inventors have, surprisingly, demonstrated the antioxidant activity of norbadione.
• the antioxidant agents of formula (I) can be used in the manufacture of antioxidant compositions, in particular pharmaceutical compositions, cosmetic compositions or food compositions.
• the invention relates to pharmaceutical compositions, comprising at least one antioxidant agent according to the invention as defined previously and a pharmaceutically acceptable vehicle.
• pharmaceutically acceptable vehicle is intended to mean a vehicle which can be administered to an individual at the same time as the antioxidant agent and which does not have an undesirable biological effect.
• compositions can be used for the treatment of diseases arising from oxidative stress.
• compositions comprising the agents according to the invention can be used for the treatment of inflammatory diseases, in particular the diseases resulting, in reaction to an allergen, by the production of cytokines.
• compositions comprising norbadione in the form of diacid (formula XI) or disel (formula XII) contribute, in a dose-dependent manner to decrease the production of cytokines TNF- ⁇ and IL-10 of an infected host by an allergen such as a liposaccharide, which shows that the antioxidant agents according to the present invention exhibit anti-inflammatory activity.
• compositions can also be used to ensure a protective effect of cells against apoptosis following an accumulation of free radicals within said cells.
• these compositions can be used to treat, preventively or curatively, cells or a living organism exposed to ionizing radiation inducing the production of free radicals.
• these compositions are capable of countering the effects of ionizing radiation (for example, that emanating from an area contaminated by radioactive substances) or of ultraviolet radiation towards cells subjected to said radiation, due to the fact that the antioxidant agents according to the present invention incorporated in these compositions capture the radicals formed by the action of said radiation on these cells or living organisms.
• These compositions can also be used to inhibit the side effects of a drug inducing the production of free radicals. Therefore, these compositions can reduce the cytotoxicity of drugs, causing by their side effects, oxidative stress, as is the case with cisplatin.
• the invention relates to the use of an antioxidant agent as defined above for the manufacture of a pharmaceutical composition intended for the treatment of inflammatory diseases.
• the invention relates to the use of an antioxidant agent as defined above for the manufacture of a pharmaceutical composition intended for the treatment of a living organism exposed to ionizing radiation.
• the invention finally relates to the use of an antioxidant agent as defined above for the manufacture of a medicament intended to inhibit the side effects of a medicament inducing the production of free radicals.
• treatment treatment can be preventive but also curative.
• the present invention also relates to cosmetic compositions incorporating at least one antioxidant agent according to the invention.
• compositions can be in different forms, such as creams, oils, intended for topical skin use, the role of the antioxidant agents being to trap the free radicals at the level of the skin surface on which the cosmetic composition is applied.
• the compositions according to the invention thus contribute to slowing down the skin aging process, generated in particular by the accumulation of free radicals.
• the present invention relates to food compositions, comprising at least one antioxidant agent according to the invention.
• the agents antioxidants according to the present invention can be used, in particular, as additives in food compositions which can produce, during their aging, free radicals, such as oils, butter.
• antioxidant agents which can be used in pharmaceutical, cosmetic or food compositions correspond to the agents of formula (XI) or (XII), as defined above.
• Figures 1, 2 and 3 are graphs illustrating the antioxidant activity of norbadione in the form of potassium disel compared to conventional antioxidants, said antioxidant activity being demonstrated by monitoring the degradation of thymidine subjected to oxidative stress radiative in nature ( ⁇ rays emitted by 137 Cs in Figure 1 or UV rays in Figure 2) or chemical in nature (Figure 3);
• Figures 4 and 5 are graphs illustrating the anti-inflammatory effect of norbadione in the form of a diacid ( Figures 4) or potassium disel
• FIG. 5 by measuring the production of certain cytokines by cells subjected to an allergen
• FIG. 6 is a graph illustrating the protective activity of norbadione in the form of a diacid or potassium disel with respect to cells subjected to ionizing radiation
• FIG. 7 is a graph illustrating the protective activity of norbadione in the form of a diacid or of potassium disel with respect to cells subjected to the action of cisplatin
• FIG. 5 by measuring the production of certain cytokines by cells subjected to an allergen
• FIG. 6 is a graph illustrating the protective activity of norbadione in the form of a diacid or potassium disel with respect to cells subjected to ionizing radiation
• FIG. 7 is a graph illustrating the protective activity of norbadione in the form of a diacid or of potassium disel with respect to cells subjected to the action of cisplatin
• FIG. 8 is a graph which represents the vascular contraction of rat aorta rings C (g) (g meaning gram) as a function of the concentration of pyrrogallol [Pyr] ( ⁇ M), in the absence of norbadione and in presence of norbadione 100 ⁇ M;
• FIG. 9 is a graph representing the rate of vascular relaxation of rat aorta rings R (%) as a function of the concentration of Sin-1 [Sin-1] ( ⁇ M) in the absence of norbadione and in the presence 100 ⁇ M norbadione.
• Examples 1 to 5 illustrate the antioxidant properties of norbadione in the form of a diacid or a disel.
• Example 6 illustrates an example of total synthesis of a compound of formula (III) also exhibiting antioxidant activity.
• the antioxidant activity of the norbadione potassium disel was evaluated by an in vitro screening test.
• This test is based on monitoring the degradation of thymidine subjected to different oxidative stresses in the presence of different antioxidant agents, which are norbadione in the form of potassium disel.
• antioxidant agents quercetin (1), fisetin (2), myricetin (3), catechin
• thymidine In the presence of an antioxidant, thymidine is more or less effectively protected depending on the nature of said antioxidant.
• the effectiveness of the antioxidant is quantified by measuring the remaining thymidine (quantified in% on the ordinate of the graph) using an enzyme-linked immunosorbent assay, of the ELISA type called "by competition".
• This ELISA assay consists in performing a competition for binding to a thymidine-specific monoclonal antibody fixed on a solid phase, between the thymidine remaining at the end of the test and the thymidine labeled with an enzyme (acetylcholine esterase).
• cytokines produced by monocyte-type cells during treatment with an allergenic liposaccharide.
• This liposaccharide is an endotoxin located on the outer membrane of Gram-negative bacteria. In particular, it stimulates the production of proinflammatory cytokines by mononuclear cells (monocytes, macrophages) of the infected host.
• PBMC peripheral blood mononuclear cells
• norbadione in diacid or potassium disel form at increasing concentrations (from 10 "8 M to 10 " 5 M) with or simultaneous activation with the lipopolysaccharide of Salmonella abortus egui at a concentration of 5 ⁇ g.mL "1 , in culture plates 24 wells, for 24 hours at 37 ° C, in a humidified atmosphere of 5% C0 2 and 95% air. After incubation, the supernatant is removed and stored at -20 ° C until the test is carried out.
• the detection of cytokines present in the samples is measured using a cytometric ELISA assay of the “sandwich” type.
• Polystyrene microparticles (beads) (of 6 different types, each marked with a different quantity of fluorescent dye whose emission wavelength FL-3 is approximately 650 nm) are coupled to an antibody specific for l 'one of the 2 cytokines TNF ⁇ , IL-2, IL-10.
• Antibodies of the Ac-PS type are thus obtained.
• the cytokines present in the sample bind to Ac-PS antibodies.
• the captured cytokines are detected using a direct immunoassay, which uses 2 antibodies specific for each cytokine coupled to phycoerythrin which emits at an FL-2 wavelength of about 585 nm (Ac-PE ). After washing the excess Ac-PE, the presence of the cytokines is measured by flow cytometry.
• a direct immunoassay which uses 2 antibodies specific for each cytokine coupled to phycoerythrin which emits at an FL-2 wavelength of about 585 nm (Ac-PE ). After washing the excess Ac-PE, the presence of the cytokines is measured by flow cytometry.
• the fluorescence is measured according to the 6 fluorescence intensities FL-3 and according to the wavelength FL-2.
• the intensity of the FL-3 fluorescence makes it possible to determine the quantity of each cytokine present in the sample (by comparison with standard curves). More information about this technique is available in Cook's article et al, Journal of Immunological Methods, 2001, 254, pages 109-118 [7]
• FIGS. 4 to 5 represent the percentage of response noted% (that is to say the quantity of cytokine observed compared to the quantity observed during a control where the product does not has not been added) as a function of the concentration (in nM) of norbadione in the form of diacid or potassium disel, noted [Nor-A] or [Nor-B] in said figures.
• EXAMPLE 3 Evaluation of the norbadione protection activity of cells subjected to ionizing radiation.
• This test consists of measuring, in the presence or absence of norbadione in the form of a diacid or potassium disel, the survival rate of cells treated with ionizing radiation, using selective indicators of certain cellular organelles such than the mitochondria.
• Samples of norbadione in the diacid or potassium disel form are added to cultures of RDM4 cells (AKR mouse lymphomas) at increasing concentrations (0.12 to 20 ⁇ g / ml), two hours before irradiation. This is carried out by exposure of microtest plates containing the cells to X-rays of 15 MV, at 8 Gy, the culture medium being unchanged.
• the number of living cells is determined on the sixth day using the Uptiblue test (which measures the mitochondrial activity of the cells).
• the Uptiblue reagent (reazurine, still marketed under the brand name ALAMAR BLUE) is a colored indicator of redox. Reazurin (blue and non-fluorescent) is reduced to resorufin (pink and fluorescent) by living cells.
• Uptiblue (diluted 1/4 in the culture medium) is added to the cells at a rate of 20 ⁇ L per well of 200 ⁇ L. After a 4 hour incubation at 37 ° C., the fluorescence is measured at a wavelength of 590 nm, after excitation at a wavelength of 530 nm using a fluorescent microplate reader
• Fluorolite 1000 (Fluorolite 1000, Dynex). The intensity of fluorescence is proportional to the number of living cells.
• nordadione in its form of disel or diacid, protects the cells against ionizing radiation, in a significant and dose-dependent manner.
• norbadione has no effect on the growth and viability of RDM4 cells, even at 20 ⁇ g / ml.
• This test consists of measuring, in the presence of norbadione in the form of a diacid or potassium disel, the survival rate of cells treated with cisplatin.
• Ki cells of human thyroid carcinomas are cultured in 96 microtest plates flat well in the presence of a single concentration (20 ⁇ g / mL) of norbadione in the form of diacid or potassium disel.
• a genotoxic agent, cisplatin is added to the culture medium at increasing concentrations (from 12 to 100 ⁇ M). Two days later, the number of cells is determined using the sulforhodamine B test (called SRB), which measures the amount of cellular protein.
• SRB sulforhodamine B test
• SRB Sulforhodamine B
• FIG. 7 represents the fluorescence observed after addition of SRB (expressed in arbitrary units of fluorescence) as a function of the concentration of cisplatin (in ⁇ M).
• the purpose of this example is to show the antioxidant activity of norbadione in the form of potassium disel on rat aorta rings.
• the rat aorta rings are first subjected to pyrogallol, a generator of superoxide radicals, these radicals inducing a contraction of the rat aorta rings and we measure, in the absence of norbadione the rate of contraction of these rings.
• FIG. 8 represents the rate of vascular contraction of the C rings (g) as a function of the concentration of pyrrogallol [Pyr] ( ⁇ M), in the absence of norbadione (curve a) and in the presence norbadione at a concentration of 100 ⁇ M (curve b). It can be seen that curve (a) is located above curve (b), which means that the contraction of the aorta rings caused by pyrogallol is suppressed in the presence of norbadione, because the norbadione picks up reactive oxygen radical species generated by pyrogallol.
• the rat aorta rings are subjected to SYN-1 (3-morpholino-sydnonimime), generator of NO radicals, inducing relaxation of the rat aorta rings and the relaxation rate of these rings.
• SYN-1 3-morpholino-sydnonimime
• the relaxation rate of the rings is measured, under the same conditions as those mentioned above.
• FIG. 9 represents the rate of vascular relaxation of the R rings (%) as a function of the concentration of Sin-1 [Sin-1] ( ⁇ M) in the absence of norbadione (curve a) and in the presence of norbadione 100 ⁇ M) (curve b).
• curve (a) is located below curve (b), which means that the relaxation of the aorta rings caused by SYN-1 is lessened in the presence of norbadione, because the norbadione partially captures the NO radicals.
• This compound conforms to the general definition of the compounds of formula (I) with the R x , R 2 / R 3 / R 6 and R 8 represent H, the R 4 and R 5 represent - CH 3 , the R 7 represent - OCH 3 .
• methyl 4- ti ⁇ êthoxyphenylacetate (7a) (4.7 ml; 29.6 mmol; 2 eq) is dissolved in THF (15 ml) and the mixture is cooled to -70 ° C.
• a solution of 2M lithium diisopropylamide in heptane (15 mL; 30 mmol; 2 eq) is added dropwise to the syringe and the mixture is maintained for 1 hour at around -70 ° C.
• Methyl methoxyacetate (1.5 mL; 15 mmol; 1 eq) is added to the syringe and the mixture is left to react for 5 hours, slowly returning to room temperature.
• the condensation product (8a) prepared above (5.65 g; 22.4 mmol; 1 eq) is dissolved in THF (47 mL) in a 100 mL flask.
• Triethylamine (3.7 mL; 26.6 mmol; 1.2 eq.)
• trimethylsilyl chloride (3.7 mL; 29 mmol; 1.3 eq.)
• the residue is taken up in pentane.
• the precipitate formed is filtered through a frit and then through a 5 ⁇ m millipore and rinsed with pentane. After evaporation, 7.28 g of an orange oil are obtained.
• the monosilylated derivative obtained (7.27 g; 22.4 mmol; leq.) Is placed in a 100 ml flask and dissolved in THF (33 ml). The mixture is cooled to -70 ° C. A solution of LDA (lithium diisopropylamide) 2M in heptane (11.2 mL; 22.4 mmol; 1 eq.) Is added dropwise to the syringe and the mixture is maintained for 1 hour at -70 ° C. Trimethylsilyl chloride (3.4 mL; 26.7 mmol; 1.2 eq.) Is added to the syringe and the mixture is brought back to room temperature in 3 hours.
• LDA lithium diisopropylamide

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