Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
  • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems

Definitions

• the present invention relates to new derivatives of 3,4 dihydro-2,5,7,8 tetramethyl-benzopyran-6-ol, their manufacturing process, the pharmaceutical compositions containing them and their use as medicaments.
• the generation of highly reactive oxygen metabolites is an essential feature of many components of normal metabolism (generation of energy metabolism by the mitochondrial respiration chain, detoxification of xenobiotics by cytochromes, destruction of microorganisms by phagocytosis, and even ovulation and fertilization).
• examples include probucol, vitamin C, ⁇ -carotene, flavonoids such as quercetin or ebselen, (H. Sies, "Oxidative stress", Académie Press, 1991; A. Ong, L. Packer, "Lipid-soluble antioxidants: biochemistry and clinical applications”, Birkhauser, 1992; B. Halliwell, Drugs, 42, 569, 1991; M. Santrucek, J. Krepelka, Drugs of the future, 13, 974, 1988), as well as 2H-1-benzopyrans derivatives such as vitamin E or tocopherols, trolox, tocotrienols, derivatives MDL 72720, 74366 and 74405 (Free Radical Biol.
• the subject of the present invention is new derivatives of 3,4-dihydro-2,5,7,8-tetramethyl-benzopyran-6-ol corresponding to the general formula (I)
• R represents CH2OR1, CONR1R2, CH2NR1R2 or A in which Ri, R2, identical or different, each represent a hydrogen, a linear or branched alkyl radical comprising from 1 to 20 carbon atoms which can itself contain one or more unsaturations such as double or triple bonds and can be substituted by an aromatic residue (such as a phenyl, a pyridine or a benzopyran variously substituted) by a halogen (chlorine, bromine or fluorine), by an alkoxy, (OR4) by a thiother (SR4), by a silane (SÎR4R5R6) or by an amine (NR4R5) in which R4, R5 and R ⁇ represent an alkyl or aryl radical.
• R represents CH2OR1, CONR1R2, CH2NR1R2 or A in which Ri, R2, identical or different, each represent a hydrogen, a linear or branched alkyl radical comprising from 1 to 20 carbon atoms which can itself contain one or
• R and R2 when attached to the same nitrogen atom, can also form a variously functionalized ring such as a 3.8 diazo-l-oxa-2-oxaspiro [4,5] decane.
• Ar represents an aromatic radical such as a phenyl which can be variously substituted in various positions by a halogen (chlorine, bromine, fluorine or iodine), an amine (NR1R2), an alkoxy (OR), a thiother (SRi), a radical linear or branched alkyl comprising from 1 to 10 carbon atoms in a straight or branched chain which can itself be substituted by an alkoxy (ORi), an amine (NR1R2), or a thioether (SRi) and moreover, Ri and R2 can also form a cycle with the nitrogen to which they are attached.
• the compounds of formula (I) containing one or more asymmetric centers have isomeric forms. The racemates and then the enantiomers of these compounds are also part of this invention.
• the invention also includes the salts, solvates (for example hydrates) and bioprecursors of these compounds acceptable for therapeutic use.
• bioprecursors as used in the present invention applies to compounds which, when administered to an animal or to a human being, are converted in the organism into a compound of formula (I). It is thus and by way of nonlimiting example that derivatives of formula la
• P for example an acyl, a phosphoryl or a glycosyl
• P represents a bio-labile group (defined so that this compound la can be transformed into corresponding compound I within a living organism) must also be considered as part of the present invention.
• the compounds of the present invention are generally prepared by condensation of an intermediate of formula (II)
• P represents a protecting group for a phenol such as a methoxymethyl ether, a benzyloxymethyl ether, a methoxyethoxymethyl ether, a tetrahydropyranyl ether or alternatively a 2- (trimethyl-silyl) ethoxy methyl ether, with an appropriate electrophile which will depend on the nature of n and R:
• a particularly appreciated synthesis method consists in condensing an intermediate of formula (II) with an electrophile of formula (III)
• Y represents a leaving group such as a halogen (bromine, chlorine or iodine) a mesylate, a tosylate or a triflate in the presence of an organic or inorganic base such as NaH, KH, ⁇ uOK, in an anhydrous polar solvent such as THF, DMF, DMSO or BuOH at a temperature between 0 and 60 ° C, followed by deprotection of the thus formed intermediate using appropriate methods depending of the nature of P and which are described in "Protective Groups in Organic Synthesis", TW Greene, P. W Wutz, J. Wiley & Sons, NY, 1991.
• a leaving group such as a halogen (bromine, chlorine or iodine) a mesylate, a tosylate or a triflate in the presence of an organic or inorganic base such as NaH, KH, ⁇ uOK, in an anhydrous polar solvent such as THF, DMF, DMSO or BuOH
• a particularly preferred method consists in using sulfuric acid diluted in a methanol-THF mixture to carry out this transformation.
• an alternative synthesis method more particularly illustratedted consists in first condensing the alcohol of formula (II) with a dibromo derivative of formula (TV)
• a base such as NaH
• a solvent such as THF, DMF or DMSO
• CH2NR1R2 are prepared by condensation of an amine (R R2NH) with an intermediate of formula (V) in the presence of a base such as K2CO3, Na2CO3,
• CS2CO3, DBU, DIPEA in the possible presence of Kl or BU4NI in a polar anhydrous solvent such as methyl ethyl atone, DMF, THF or DME at a temperature between 0 ° C and 60 ° C, followed by deprotection of the phenol as previously indicated.
• a polar anhydrous solvent such as methyl ethyl atone, DMF, THF or DME
• n, Y and R4 are described as above, in the presence of a base such as NaH, KH or 1 BuOH in an anhydrous polar solvent such as DMSO, DMF or uOK.
• a base such as NaH, KH or 1 BuOH
• an anhydrous polar solvent such as DMSO, DMF or uOK.
• the compounds of the present invention all have at least one asymmetric center located in position 2 on the pyrannic cycle.
• the preparation of the derivatives of formula (I) in the form of the pure isomers (R or S) at this asymmetric center is carried out by substituting the racemic product (XIII) by its R enantiomer or by its S enantiomer for the preparation of the compounds of formula (I) by following the procedures described above and this, for each isomer.
• the pure enantiomers (R and S) of the esters of formula (XIII) are prepared by esterification of the corresponding optically pure acids (for example, the ethyl esters R and S of formula XIII which are particularly preferred for the preparation of the compounds of the present invention are obtained by reaction of the acids optically then R and S corresponding with ethanol in the presence of sulfuric acid) which are themselves accessible according to the methods described (for example J. Scott et al., J. Am. Oil Chem. Soc. 51, 200, 1974 and N. Cohen et al. J. Org. Chem. 4-6, 2445, 1981) .
• the derivatives of formula (I) in which R represents CH2-NR1R2 can be prepared from a derivative of formula (I) in which R represents CONR1R2, by reduction to using agents derived from aluminum or boron such as lithium aluminum hydride in ether or THF.
• a compound of the present invention comprising basic nitrogen in the form of a salt, for example a salt by addition with an acid
• this can be achieved by treating the free base of formula (I) with an appropriate acid of preferably in equivalent quantity.
• these isomers can be separated by conventional methods such as preparative chromatography. It will be understood that in certain reactions or sequences of chemical reactions which lead to the preparation of compounds of general formula (I) it is necessary or desirable to protect sensitive groups or functions in the synthesis intermediates in order to avoid undesirable side reactions.
• ester obtained above (10 g; 36 mmol) in dichloromethane (70 ml) and maintained at 0 ° C. is added successively diisopropylethylamine (24.6 ml; 144 mmol; 4 eq.) Of N, N'- dimethylaminopyridine (220 mg; 1.8 mmol; 5%) and chloro-methyl-ethoxy-trimethylsilane (9.5 ml; 54 mmol; 1.5 eq.). The medium is then heated at reflux for 5 hours then cooled to room temperature, diluted in CH2Cl2 and washed with water until neutral pH.
• the oil obtained previously (14 g; 34.3 mmol) is diluted in THF (300 ml) and brought to -30 ° C.
• the lithium aluminum hydride (1 M in THF; 34.3 mmol; 34.3 ml; 1 eq.) Is then added dropwise, then the temperature of the medium is brought back to 0 ° C.
• the solution is hydrolyzed at 0 ° C with wet Na2SO4 then the resulting precipitate is filtered through celite and the solvent evaporated.
• the oil obtained is purified by "flash chromatography" on a silica column (95 / 4.5 / 0.5 Dichloromethane / MeOH / NH4 ⁇ H) to provide in the majority fraction the compound N, N'-diethyl-3 - [(3,4- dihydro-6 - [(2-trimethylsilyl-ethoxy) -methoxy] -
• the deprotection of the trimethylsilyl-ethoxy-methyl group to lead to 3 (67%) is carried out according to a procedure identical to that used in the last stage of the synthesis of 1.
• the compound obtained in the form of the free base is hydrochloride with using a saturated solution of hydrochloric acid in ether. Melting point: 113 ° C IR (KBr, cm-): 3250, 2644, 2588, 1480, 1187, 796 NMR (CDCI3, 200 MHz, ppm): 12.27 (br m, 1H); 7.70-7.35 (m, 4H); 4.70-4.50
• the oil obtained is purified by "flash chromatography” on a silica column (90/10 Petroleum Ether / Ethyl Ether then 75/25 Petroleum Ether / Ethyl Ether) to provide the expected ester (3.26 g; 62%).
• the amine is reacted with a solution of the preformed mesylate in DMF in the presence of K1 (1 eq.) And potassium carbonate (4 eq.) Then the resulting medium is heated to 100 ° C for 8 h.
• the oil obtained is purified by "flash chromatography” on a silica column
• NMR H corresponds to the structure of product 17.
• Compound 20 (226 mg; 0.58 mmol) is prepared by reduction of 19 with lithium aluminum hydride (1 M in THF; 1.2 ml; 1.2 mmol; 2 eq) for 2 h at room temperature. After hydrolysis with wet Na2SO4 and evaporation, the oil collected and purified on a silica column (95 / 4.5 / 0.5
• This compound is prepared from the acid Xla according to the same sequence of steps as for the preparation of compound 20 by first reacting Xla with l-oxa-2-oxo-3,8-diazaspiro [4,5] -decane then by reducing the intermediate formed by LiAlH4.
• the antioxidant activity of the derivatives of the present invention has been more particularly demonstrated on microsomes of rat livers, following a chemical peroxidation induced by ferric ions and on human LDL.
• the inhibitory action of the compounds of the present invention with respect to the oxidation of human LDL has been demonstrated whether it is following a chemical oxidation by copper sulphate or following a biological oxidation by human endothelial cells from umbilical veins.
• Example 4 0.06 2. Inhibition of oxidation of human LDL by copper sulphate The studies were carried out with human LDL incubated with copper sulphate (10 ⁇ M) for 6 hours at 37 ° C. with or without test compound. Lipid peroxidation is evaluated by the TBARS technique as described by C. Breugnot et al., Biochem. Pharmacol. 4fl, 1975-1980 (1990). The antioxidant activity of the compounds of the present invention has been studied in comparison with vitamin E. The few illustrative examples given in the table below show that the derivatives of the present invention have a favorable antioxidant profile vis- with regard to vitamin E:
• the endothelial cells, line ECV304 (ATCC CRL-1998) are cultivated in wells of 35 mm in diameter in a DMEM-HEther of Petroleum ES- Glutamax I medium supplemented with a fetal calf serum 10%, penicillin- streptomycin 100 IU / ml - 100 ⁇ g / ml, and fungizone 2.5 ⁇ g / ml up to a sub-state meet.
• the cells are then incubated for 24 hours in DMEM-HEther of PetroleumES-Glutamax I medium containing ultroser G 2%; then, the oxidation of LDL is triggered by their contact with the cells for 24 hours in the nutrient medium HAM F-10 (Breugnot C, Maziere C, Salmon S., Auclair M., Santus R., Morliere P. , Lenaers A. and Mazière JC: Phenothiazines inhibit copper and endothelial cell-induced peroxidation of lo density lipoprotein. A comparative study with probucol, butylated hydroxy toluene and vitamin E. Biochemical Pharmacology, 1990, 40: 1975-1980).
• the samples are heated for 30 minutes at 95 ° C., the TBARs are extracted with butanol-1 and quantified by fluorimetry (excitation wavelengths 515 nm, emission wavelength 548 nm, Perkin Elmer LS-50B spectrofluorimeter). The results are expressed in nmol malondialdehyde equivalent / mg LDL proteins.
• the antioxidant activity of ⁇ compounds of the present invention in this model was studied in comparison with vitamin E. As shown by some illustrative examples in the table below, the compounds of the present invention were very much superior to vitamin E in this test.
• Example 14 0.1 These results clearly indicate the greater potency of certain derivatives forming part of the present invention compared to vitamin E as lipid protectors such as microsomes or human LDL against oxidative modifications and in particular during biological oxidation mediated by human endothelial cells.
• the antioxidant properties, in particular at the LDL level, of the derivatives of the present invention allow their use as medicaments in the treatment and / or prevention of atherosclerosis including its various peripheral vascular localizations, coronary or cerebral, diseases due vascular complications linked to lipoproteins, but also pathologies in which a membrane lipid peroxidation plays an initiating and / or aggravating role such as ischemical heart disease, organ reperfusion, including transplant, ischemical traumatic pathologies of the central nervous system or peripheral, autoimmune diseases and metabolic diseases such as diabetes.
• the derivatives of the present invention have been shown to be particularly effective in neutralizing hydroxyl radicals (OH): this is how, in a test making it possible to determine the ability of compounds to trap the hydroxyl radical (method using the assay of the radical 2-hydroxy-5,5 dimethyl-1-pyrroline-N-oxide by RPE according to Miyagawa et al., J. Clin. Biochem. Nutr. 5, 1-7, 1988), certain products of the present invention are are shown to be more active than vitamin E or BHT; by way of example, the table below gives the comparative activities of these two reference products and of example 8 of the present invention.
• Example 8 6.4 Hydroxyl radicals constitute a source of extremely aggressive radicals at the cellular and molecular levels and, therefore, the compounds of the present invention which have the advantage of being both inhibitors of lipid peroxidation and free radical scavengers are also found. their usefulness in dermatology and dermo-cosmetology and in the treatment of various pathologies such as certain forms of cancer (in particular of tumors linked to ionizing radiation such as certain skin cancers), the aging of tissues (in particular the aging of the skin), and certain forms of degeneration such as Parkinson's or Alzheimer's disease. As such, various antioxidants such as vitamin E have shown a protective effect in a model of MPTP-induced neurotoxicity (cf. TL Perry et al, Neurosc.
• the present invention also relates to pharmaceutical compositions containing as active ingredient a compound of general formula I or one of its acceptable salts for pharmaceutical use, mixed or associated with a suitable excipient.
• These compositions can take, for example, the form of solid, liquid compositions, emulsions, lotions or creams.
• solid compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
• the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon.
• These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
• liquid compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin.
• These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
• the sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
• compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
• the compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
• the doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 0.001 g and 1 g (preferably between 0.005 g and 0.25 g) per day, preferably orally for an adult with unit doses ranging from 0J mg to 500 mg of active substance, preferably from 1 mg to 50 mg.
• active component denotes one or more
• the active component is passed through a sieve with a mesh opening of 250 ⁇ m side, it is mixed with the excipients and it is compressed using 6.0 mm punches. Tablets with other mechanical strengths can be prepared by varying the compression weight with the use of appropriate punches.
• Compression weight 100.0 The active component is passed through a sieve with a mesh opening of 250 ⁇ m and mixed with lactose, starch and pregelatinized starch.
• the mixed powders are moistened with purified water, they are granulated, dried, sieved and mixed with magnesium stearate.
• the lubricated granules are put into tablets as for the formulas by direct compression.
• a coating film can be applied to the tablets using suitable film-forming materials, for example methylcellulose or hydroxypropyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated.
• the active component is passed through a sieve with a mesh opening of 250 ⁇ m and mixed with the other substances.
• the mixture is introduced into hard gelatin capsules No. 2 on an appropriate filling machine.
• Other dosage units can be prepared by changing the filling weight and, if necessary, changing the size of the capsule.
• the active component, the buffer, the flavor, the color and the preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 80 ° C. and the sucrose is dissolved therein and then cooled. The two solutions are combined, the volume is adjusted and mixed. The syrup obtained is clarified by filtration.
• a suspension of the active component in Witepsol H 15 is prepared and introduced into a suitable machine with 1 g suppository molds.
• Sodium chloride can be added to adjust the tone of the solution and adjust the pH to maximum stability and / or to facilitate the dissolution of the active component by means of a dilute acid or alkali or by adding buffer salts. appropriate.
• the solution is prepared, clarified and introduced into ampoules of appropriate size which are sealed by melting the glass.
• the liquid for injection can also be sterilized by heating in an autoclave according to one of the acceptable cycles.
• the solution can also be sterilized by filtration and introduced into a sterile ampoule under aseptic conditions.
• the solution can be introduced into the ampoules in a gaseous atmosphere.
• Cartridges for inhalation g / cartridge active component micronized 1, 0 lactose Codex 39.0 The active component is micronized in a fluid energy mill and brought to the state of fine particles before mixing with lactose for tablets in a high blender energy.
• the powder mixture is introduced into hard gelatin capsules No. 3 on an appropriate encapsulating machine.
• the contents of the cartridges are administered using a powder inhaler.
• dichlorodifluoromethane for pharmaceutical use 60.90 14.62g
• the active component is micronized in a fluid energy mill and placed in the form of fine particles.
• the oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C. and the micronized drug is introduced into the solution using a mixer with a high shearing effect.
• the suspension is introduced in measured quantity into aluminum aerosol cans on which are fixed appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the boxes by injection through the valves.

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• 1994
  • 1994-11-25 FR FR9414142A patent/FR2727414A1/fr active Granted
• 1995
  • 1995-11-23 AU AU42640/96A patent/AU4264096A/en not_active Abandoned
  • 1995-11-23 WO PCT/FR1995/001547 patent/WO1996016957A1/fr active Application Filing

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