CA2013661A1 - Benzyl-cyclanone derivatives, process for their preparation and cosmetic and pharmaceutical compositions containing the same - Google Patents

Abstract

The invention relates to cosmetic and pharmaceutical compositions containing a benzyl-cyclanone derivative of formula: (I) in which R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, a linear or branched alkyl residue in C1-C8 or a linear or branched C1-C8 alkoxy residue; R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, it being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical; R5, R6, R7 and R8, identical or different, represent a hydrogen atom, a linear or branched C1-C18 alkyl radical, an aralkyl radical unsubstituted or substituted by a C1-C4 alkyl radical or C1-alkoxy C4, an aryl residue which is unsubstituted or substituted by a C1-C4 alkyl residue, the substituents R5 and R6 and / or the substituents R7 and R8 possibly forming, with the carbon atom of the ring to which they are attached, a saturated ring containing from 5 to 12 carbon atoms unsubstituted or substituted by one or more linear or branched C1-C8 alkyl radicals; X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a methyl residue; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing 7 or 8 carbon atoms; moreover, when X represents a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the ring to which they are attached to a bicyclic system containing 7 carbon atoms, R7 can also represent a residue -CH2-SO3H, optionally in the form of an alkali metal, alkaline earth metal or amine salt. The compounds of formula (I) are useful as antioxidants and drugs for the treatment of skin inflammation and allergies.

Description

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The present invention relates to new derivatives.
ves of benzyl-cyclanones, their process of preparation and their use in cosmetic compositions for use daily or sunscreen and in pharmaceutical compositions for the treatment of inflammations and go-cutaneous gies.
During its research, the Applicant comes to discover that the benzyl-cyclanone derivatives having the.
`following formula:. ...
R6 Rl R ~ (I) in which:
. Rl and R3, identical or different, represent ; a hydrogen atom, a hydroxyl radical, an al-linear or branched kyle in Cl-C8 or an alkoxy line residue area or branch into Cl-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a . hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched into Cl-C18, an aralkyl residue such as benzyl not substituted or substituted by a C1-C4 alkyl residue or C1-C4 alkoxy, an aryl residue such as phenyl non-subs-: -titrated or substituted by a C1-C4 alkyl residue, the subs ..:
tltuants R5 and R6 and / or the substituents R7 and R8 which may form, with the carbon atom of the cycle to which they are ~:

..... . . .
-. .

rattaches, a saturated cycle containing 5 to 12 atoms of carbon not substituted or substituted by one or more linear or branched C1-C8 alkyl radicals;
X represents either an oxygen atom or a radical - (CRgRlo) n in which n is equal to 1 or 2 and Rg and Rlo represent a hydrogen atom or a me-thyle; in the case where X represents a radical - (CRgRlo) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X repre-feels a radical - (CRgRlo) n- in which n is equal to 1, R9 and Rlo representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt -alkali, alkaline earth or amine metal;
unexpectedly exhibit excellent properties your antioxidants against lipid peroxidation polyunsaturated and also towards substances likely to undergo thermo- or photoinduced (such as proteins, sugars, pigments, vitamins, polymers ...).
However, we know that lipid peroxidation plicates the formation of intermediate free radicals which damage the consisting cell membranes, between others, phospholipids and are responsible in particular of aging skin phenomena (AL TAPPEL
in "Federation Proceedings" Vol. 32, ~ oa, ~ out 1973). ~:

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By their antioxidant properties, the compounds of the invention can therefore make it possible to better fight against premature aging of the skin due to peroxidation of skin lipids.
They can also help ensure better storage of cosmetic or pharmaceutical compositions ceutiques with an oily phase avoiding ran-curing of the unsaturated lipids contained therein and which may be of animal origin such as lanolin, ce-tine (whale white), beeswax, perhydro-squalene, turtle oil, or vegetable origin like olive oil, castor oil, corn oil, oil sweet almond, avocado oil, shea oil, sunflower oil, soybean oil, peanut oil, coconut or palm kernel oils, fatty acids are such as vitamin F and certain essential oils present in perfumes such as lemon oil or lavender.
They can also help prevent de-oxidative gradation of active compounds contained in pharmaceutical compositions (vitamin A, carotenoi-...).
The Applicant has also discovered in a manner extremely surprising that the compounds of formula (I) above could be used for the treatment of ~ -skin inflammations and allergies.
In addition to their good antioxidant properties, compounds according to the invention have a very good thermal bility.

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These compounds also have the advantage of not be toxic or irritating and to have a perfect harmless to the skin.
Some of the compounds of formula (I) above are new. These are benzyl-cyclanone derivatives of formula (I ') below:

R6 Rl ~ R3 (I ') in which:
Rl and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an alkyl residue linear or branched in Cl-C8 or an alkoxy line residue-area or branch into Cl-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radi.cal, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched into Cl-C18, an aralkyl residue such as benzyl not substituted or substituted by a C1-C4 alkyl residue or C1-C4 alkoxy, an aryl residue such as non-sub-phenyl substituted or substituted by a C1-C4 alkyl residue, the substituents R5 and R6 and / or the substituents R7 and R8 can form, with the carbon atom of the cycle at which they are attached, a saturated cycle containing from 5 to 12 carbon atoms unsubstituted or substituted by one or several linear or branched C1-C8 alkyl radicals;

.

.
-. . . : -~ 3 ~

X represents either an oxygen atom or a radical - (CRgRlo) n in which n is equal to 1 or 2 and Rg and Rlo represent a hydrogen atom or a me-thyle; in the case where X represents a radical - (CR9Rlo) nr the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X repre-feels a radical - (CRgRlo) n ~ in which n is equal to 1, ~ Rg and Rlo representing a methyl residue, R5 representing : 10 a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine, under reserve ve that when R5 ~ R6, R7 and R8 designate a radical radical-thyle, X an oxygen atom, R2 a hydrogen atom and R4 a hydroxyl radical, at least one of the radicals R1 and R3 denotes a hydroxyl, alkyl or alkoxy radical.
Among the preferred compounds of general formula `20 (I '), we can quote:
- 3 ', 4', 5'-trihydroxy-4-benzyl-tetrahydro-2,2,5,5-té
tramethyl-furan-3-one, - 3 ', 5'-ditert.butyl-4'-hydroxy-4-benzyl-tetrahydro-2, 2,5,5-tetramethyl-furan-3-one, - 3 ', 5'-diisopropyl-4'-hydroxy-4-benzyl-tetrahydro-2, 2,5,5-tetramethyl-furan-3-one, - 3 ', 5'-ditert.butyl-4'-hydroxy-3-benzyl-camphor, - 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor, - 3 ', 5'-dimethyl-4'-hydroxy-3-benzyl-camphor, - 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor, - 3 ', 4', 5'-trihydroxy-3-benzyl-camphor, .

... .
,, 2 ~ 3 ~ 6 ~

- 3 ', 5'-di-isopropyl-4'-hydroxy-3-benzyl-camphor, - 3'-methyl-4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor.
The compounds of formula (I ') can be obtained according to several processes:
~ - I. First procedure _ This process involves reducing a benzylidene cyclanone of formula (II) according to the reaction scheme below:
R6 R'l R6 R

R8 ~ ~ R3 R ~ 4 O 4 (II) (I ') In the compound of formula (II), the substituents R5, R6, R7, R8 and X have the meanings indicated above above for the compound of formula (I '), R'l, R'2, R'3 and;
R'4 can respectively represent Rl, R2, R3 or R4 or well an arylalkoxy residue.
The reduction can be achieved either by hydroge-~ 20 catalytic nation, either by hydrogenation in the presence - a hydrogen transfer agent under the conditions described by G. Brieger and RJ Nestrick in CHEMICAL
REVIEWS Vol. 74 (No. 5) pages 567-580, for example, at `means of cyclohexene or formic acid in the presence of a catalyst such as palladium on carbon, optionally ment in the presence of an inert solvent. The reaction is ~ -performed at a temperature between -78C and -boiling point of the reaction mixture.
When in formula (I '), cyclanone repre-~ 30 feels a camphor residue, we get a mixture of isomers ; ~ (endo and exo). We can direct the formation of the isomer . ~ - '. :
~ ~ - 6 - --` 2 ~ 3 ~

most stable, treating the mixture in alcohol, basic medium preferably with potash or sodium methylate and optionally heating The compounds of formula (II) are obtained by condensation of an aromatic aldehyde of formula (III) ~ -J ~ (III) R'4 on a cyclanone of formula:

X ~ R5:
R8 ~ ~ 1 (IV) O
The aldehydes of formula (III) and the cyclanones of formula (IV) in which the substituents R'1 to R'4, R5 to R8 and X have the meanings mentioned above for the compound of formula (II), are known compounds.
The condensation of the aldehyde of formula (III) on the cyclanone of formula (IV) can be carried out according to one of the following two methods:
a) First method:
Condensation is carried out in the presence of a alkali metal alcoholate such as sodium methylate or potassium tert-butoxide, in a solvent such as toluene, 1,2-dimethoxyethane or 1,2-diethoxy-~ d ethane, at a temperature between -78C and the point solvent boiling. Condensation can also be carried out in the presence of a mineral base such as hydroxide, an amide an an alkali metal hydride, in . , ' 2 ~: ~ 3 ~

a solvent such as 1,2-dimethoxyethane or toluene, to a temperature between 0C and the boiling point tion of the reaction mixture.
b) Second method:

. _ The condensation of the aldehyde of formula (III) on the cyclanone of formula (IV) is carried out in the presence a borane of the following formula (V):

Rll ~ B - O - e R12 (v, Rll in which R11 and R12 represent an alkyl residue in Cl-C6. This compound is obtained according to the operating mode described by LH TOPORCER and al., J. Am. Chem. Soc. 87, 1236 (1965). Its isolation and purification are not necessary to carry out the condensation of the aldehyde of:
formula (III) on the cyclanone of formula (IV).
The condensation reaction is carried out at a temperature of about 150C, without solvent.
II. Second process This process consists in condensing a base of Mannich of formula (VI): Rl R113 ~ R2 (VI) R ~ N ~ ~ 3 on a cyclanone of formula (IV) above. The basics of Mannich of formula (VI) in which the substituents Rl to R4 have the meanings mentioned above for - ~.
the compounds of formula (I ') and R13 and R14 represent a ~

:: - 8 - -. ~::

: -. . --. ,. :: ~. .
. . .

remains C1-C4 alkyl or R13 and R14 form, with the nitrogen atom to which they are attached, a hetero-ring containing 5 or 6 atoms, are known compounds.
Condensation is carried out in the presence of a alkali metal alcoholate such as sodium methylate or potassium tert.-butoxide, in a solvent such as ethylene glycol, 1,2-dimethoxyethane or 1,2-diethoxyethane, at a temperature between -78C and the boiling point of the solvent.
The compounds of formula (I ') can be isolated as pure optical isomers or as racemic mixture.
The subject of the present invention is therefore the new calves composed of formula (I ') as well as their method of preparation.
The invention also relates to a composition cosmetic item comprising, in a cosmetic holder acceptable, an effective amount of at least one derivative of benzyl-cyclanone of formula (I) above.
The cosmetic composition of the invention can be used as a protective composition for the epidermis human or hair.
The present invention also relates to a method for protecting the skin or natural or sensitive hair bilises, consisting in applying to them a quantity effective of at least one cosmetic composition such as defined above.
By "sensitized hair" is meant hair having undergone a treatment of perm, coloring or discoloration.

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The invention also relates to a composition colored or non-colored cosmetic item, stabilized at oxidation, comprising an effective amount of at least a benzyl-cyclanone derivative of formula (I) above.
When used as a composition intended born to protect the human epidermis, the cosmetic composition that according to the invention can be in the forms the most diverse usually used for this type of composition. It can in particular be in the form lotions, emulsions such as cream or milk, oleoalcoholic or hydroalcoholic gels, sticks solids, or be aerosolized to form a spray or foam.
It may contain cosmetic adjuvants usually used in this type of composition such as thickeners, softeners, humectants, surfactants, preservatives, defoamers, perfumes, oils, waxes, lanolin, propellants, dyes and / or pigments having for function tion of coloring the composition itself or the skin or any other ingredient usually used in cosmetics than.
The compound of formula (I) is present in proportions preferably between 0.1 and 8 ~ in weight, and more particularly between 0.1 and 5 ~ by weight, relative to the total weight of the cosmetic composition ~ -protective of the human epidermis. - ~
One embodiment of the invention is a emulsion in the form of protective cream or milk com ~ -taking in addition to the compound of formula (I), alcohols fatty acids, esters of fatty acids and in particular triglycerides ~.

~ - - -. . . ,,. ..,:.
-. .
.

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wrinkles of fatty acids, fatty acids, lanolin, natural or synthetic oils or waxes and emulsi-in the presence of water.
The cosmetic composition of the invention can also be a hydroalcoholic or oleoalcoholic gel comprising one or more lower alcohols or polyols such as ethanol, propylene glycol or glycerin and a thickener. Oleoalcoholic gels contain in addition to a natural or synthetic oil or wax.
The solid sticks are made of waxes and natural or synthetic oils, fatty alcohols, esters of fatty acids, lanolin and other fatty substances.
The present invention also relates to the compounds anti-sun cosmetics containing at least one composed of formula (I) and UV-B and UV-A filters.
In this case, the amount of compound of formula (I) ., is preferably between 0.1 and 8% by weight, the total quantity of filters present in the composition sunscreen being between 0.5 and 15% by weight, by relative to the total weight of the sunscreen composition.
When the cosmetic composition according to the invention is intended to protect natural or sensitive hair sibilized, this composition can be in the form shampoo, lotion, gel or emulsion to rinse off, apply before or after shampooing, before or after ; coloring or discoloration, before or after permanent, of styling or treating lotion or gel, lotion or gel for brushing or styling, hairspray want, permanent composition, coloring or deco-~ hair coloring. Preferably, it contains 0.25 to 8% by weight of compound of formula (I).

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The present invention also relates to the compounds : cosmetic compositions containing at least one compound of formula ~ I) as an antioxidant, consisting of hair compositions such as hairsprays want, possibly treatment styling lotions your or detangling, shampoos, shampoos colo-rants, the dye compositions for hair, by makeup products such as nail polish, . creams and oils for treatment of the epidermis, funds - 10 of complexion, the lipstick sticks, the compositions:
for skin care such as oils or creams for the bath, as well as any other cosmetic composition may present because of its constituents, problems oxidation stability during storage. Of such compositions preferably contain between 0.1 and 8% by weight of compound of formula (I).
The invention also relates to a method of protecting tion of cosmetic compositions against oxidation, consisting in incorporating into these compositions a quantity effective of at least one compound of formula (I).
Another object of the invention is the use as antioxidants of the compounds of formula -.

The antioxidant effect of these compounds can be highlighted by chemiluminescence of cellular homogenates ~; laires. This technique is based on the spon-tan of light that results from radiative deactivation breakdown products of peroxide lipids.
The kinetic study is carried out on crushed brains of rats, diluted in phosphate buffer and is carried out in parallel with a control solution not containing .

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antioxidant and solutions containing the antioxidant to different concentrations, varying from 10 to 10 5 mo-laire.
By reference to the witness, one can determine the Cx antioxidant concentrations allowing inhibition of x% of the peroxidation.
The invention also relates to the application as cosmetic products, compounds of formula (I).
As indicated above, the Applicant has further discovered during his research, that the compounds of formula (I) exhibited pharmaceutical activity ecological interesting in the field of treatment of skin inflammations and allergies.
The subject of the invention is therefore the compound of mule (I) for use as a medicament.
The invention also relates to a composition pharmaceutical tion containing an effective amount of at least minus a compound of formula (I) as an active ingredient tif, in a non-toxic carrier or excipient.
The pharmaceutical composition in accordance with the invention tion can be administered orally or topical.
For the oral route, the pharmaceutical composition may be in the form of tablets, capsules, dragees, syrups, solution suspensions, emulsifier sions, etc. For the topical route, the pharmaceutical composition according to the invention is in the form of on-guent, cream, ointment, solution, lotion, gel, spray, suspension, etc.

. . .

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This drug composition may contain inert or pharmacodynamically active additives and including: moisturizers, antibiotics, steroidal or nonsteroidal anti-inflammatory agents, carotenoids, anti-psoriatic agents.
This composition can also contain flavor enhancers, preservatives stabilizers, regulating agents humidity, pH regulating agents, modifying agents ; 10 osmotic pressure boosters, emulsion agents nants, local anesthetics, tampons, etc.
It can also be packaged in forms delay or progressive release known in themselves.
The compound of formula (I) according to the invention is present in pharmaceutical compositions in proportions preferably between 0.01 and 80 ~ in weight, relative to the total weight of the composition, and more particularly between 0.1 and 20% by weight.
In the therapeutic application, the treatment is determined by the doctor and may vary according to age, the patient's weight and response as well as the severity of symptoms.
When the compounds of formula (I) are administered very orally, the dosage is generally understood between 0.1 and 50 mg / kg / day and preferably between 0.2 and 20 mg / kg / day. The duration of treatment is variable depending on `~ before the severity of the symptoms and can range between 1 and 25 weeks, continuously or discontinuously.

Topical compositions contain; 30 preference from 0.25 ~ to 8% by weight of compound of formula (I).

::
. . . . .

~ d As carrier or excipient of the composition pharmaceutical of the invention, one can use all sup-conventional non-toxic ports or excipients.
The following examples are intended to illustrate the invention without however presenting a limited character.
tative.
PREPARATION EXAMPLES
. . _ _ _.

. . . _ Pre aration of the compound of formula (I) in which R = R =
P ~ 2-R3 = OH, R4 H ~ Rs R6 R7 R8 C 3 CH ~ I ~ OH

3 ~ ~ OH

1) Preparation of 3 ', 4', 5'-tribenzyloxy-4-benzylidene-tetrahydro-2,2,5,5-tétramethylfurane-3-one:
To a solution of 14.2 g (0.1 mole) of tetra-hydro-2,2,5,5-tetramethyl-furane-3-one in 20 cm3 of 1,2-dimethoxyethane is added, between 5 and 10C, 5.4 g (0.1 mole) of sodium methylate, then 39.8 g (0.094 mole) of 3,4,5-tribenzyloxy-4-benzaldehyde in 100 cm3 of 1,2-dimethoxyethane. The reaction mixture is stirred for 30 minutes at a temperature close to 0C then pour the reaction mixture in a dilute acid solution hydrochloric. The precipitate is filtered, washed thoroughly with water then hot heptane and dry under pressure reduced ~ 35.8 g of expected product is obtained having the following characteristics: -'.

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- Melting point: 73-75C
- Elementary analysis: C36H36O5 C% H% O%
Calculate 78.81 6.61 14.58 Found 78.78 6.61 14.64 - UV spectrum (CH2C12) ~: 340 nm max . ~: 11400 max 2) Preparatlon of the 3 ', 4', 5'-trihydroxy-4-benzyl-tetrahy-dro-2,2,5,5-tetramethylfurane-3-one It is refluxed for one hour 5 g (0.009 mole) of 3 ', 4', 5'-tribenzyloxy-4-benzylidene-tetrahydro-2,2,5,5-tetramethylfurane-3-one obtained above in cm3 of a 50/50 mixture of ethanol and tetrahydro-furan containing 5 g of ammonium formate and 0.5 g palladium hydroxide. Let cool then filters the reaction mixture on Celite. The cake Celite is washed with a 50/50 mixture of ethanol and tetrahydrofuran. The solvent is distilled under pressure reduced and the residue is recrystallized from ethanol to 50%.
The product obtained has the characteristics following:
- Melting point: 186C
- Elementary analysis: C15H20O
C ~ H% O%
Calculated 64.27 7.19 28.54 Found 64.54 6.60 28.76 $ ~

Preparation of the compound of formula (I) in which . ~
R = R = tert.-butyl, R = OH, R = H, R = R = R = R = CH and X = 0:

CH3 tert.-butyl 3 / --I-- fi '' ~ OH

~ ~ tert.-butyl 1) Preparation of the 3 ', 5'-ditert -butyl-4'-hydroxy-4-ben-zylidene-tetrahydro-2,2,5,5-tetramethylfurane-3-one 10A 100 cm of 1M solution of triethylborane in hexane, 8.2 g (0.08 mole) of pivotal acid are added at 0 ° C.
lique. After 15 minutes of stirring, it is allowed to return to room temperature, then 5.4 g (0.038 mole) of tetrahydro-2,2,5,5-tetramethyl-furan-3-one and 8,9 g (0.038 mole) of 3,5-ditert.-butyl-4-hydroxy-benzaldehyde.
The hexane is distilled and heated to 150C for 3 ~ -hours. Volatile products are distilled under pressure reduced (2 K.Pa then 13 Pa). After recrystallization of the residue in an ethanol-water mixture, 5.5 g of product expected as pale yellow crystals possessed with the following characteristics:
- Melting point: 146C
- Elementary analysis: C23H34O3 C% H ~ O%
Calculated 77.05 9.56 13.39 Find 76.65 9.56 13.78 - UV spectrum (CH2C12) ~: 335 nm max . ~ max: 18170 ':

3 ~

2) Preparation of the 3 ', 5'-ditert.butyl 4'-hydroxy-4-benzyl-tetra-hydro-2,2,5,5-tetramethylfurane-3-one:
Suspendlon, under argon, 3 g (0.0083 mole) of 3 ', 5'-ditert.-butyl-4'-hydroxy-4-benzylidene-tetrahydro-2,2,5,5-tetramethyl-furane-3-one obtained below above in 50 cm3 of formic acid. We add 4 g of palladium on carbon containing 50 ~ of water (5% by weight of palladium compared to coal). Shake for 1 hour at room temperature then filter on Celite after dilution with 50 cm3 of water. Celite's cake is washed several times with dichloromethane. The organizational phase that is decanted and then dried over sodium sulfate. The solvent is distilled under reduced pressure. After recris-tallization of the residue in diisopropyl ether, 0.8 g of expected product is obtained in the form of crystals -white wines with the following characteristics:
- Melting point: 104C
- Elementary analysis: C23H36O3 C% H% O%
Calculate 76.62 10.06 13.31 Find 76.69 10.18 13.50 Preparation of the compound of formula (I) in which R = R = tert.-butyl, R = OH, R = H, R = H, R -R = -CH -CH -, R7-cH3 and X = -C (CH3) 2-tert.-butyl tert.-butyl ~,.
:

2 ~

1) Preparation of 3 '~ 5'-ditert.-butyl-4'-hydroxy-3-ben lidene-camphor:
This compound is prepared according to the operating mode described in the first part of Example 2. The tetra-hydro-2,2,5,5-tetramethylfurane-3-one is replaced by d, l-camphor.
The expected product is obtained in the form of cris-white levels after recrystallization from diisopropyl ether pylic. It has the following characteristics:
10- Melting point: 158C
- Elementary analysis: C25H36O2 C% H% O%
Calculate 81.47 9.84 8.60 Found 81.37 9.84 8.78 - UV spectrum (CHC13) max 323 nm ~ maX: 24200 2) Preparation of 3 ', 5'-ditert.-butyl-4l-hydroxy-3-benzyl-camphor 2a) Preparation of a mixture of isomers mainly ~ _. .
e We put in suspension, under argon, 3 g t0.008 mole) of 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzylidene-camphor obtained above in 50 cm3 of formic acid. We add 4 g of palladium on carbon containing 50% water (5 ~ by weight of palladium relative to coal). We stirred for 1 hour at room temperature then filtered be on Celite after dilution with 50 cm3 of water. The cake of Celite is washed several times with dichloromethane. the organic phase is decanted and then dried over sulphate sodium. The solvent is distilled under reduced pressure.

.

2 ~

After recrystallization of the residue in diisopropyl ether lique, 1.9 g of expected product are obtained in the form of white crystals, consisting of a mixture of compressed isomers mainly in the exo form, having the characteristics following ques:

- Melting point: 166C
- Elementary analysis C25H382 C% H% O ~
- Calculates 81.03 10,348.64 Find 80.81 10.14 9.17.
2b) Preparation of a mixture of isomers mainly endo The mixture of isomers above (1.9 g) is put dissolved in 14 cm3 of ethanol in the presence of 0.5 g of sodium methylate. The mixture is heated, under argon, at reflux for 2 hours. After which, the environment reac-tional is acidified with 2N hydrochloric acid; the expected product precipitated; we filter it. After recrystal-reading of the precipitate in an ethanol / water medium 90/10) obtains white crystals made up of a mixture of iso-mothers mainly containing the endo form, possessing the following features:
- Melting point: 166C
- Elementary analysis: C25H38O2 C ~ H% O%
Calculates 81.03 10,348.64 Found 81.13 10.38 8.68 Both endo and exo forms have the same characteristics physico-chemical.

2 ~ 'L

Preparation of a compound of formula tI) in which . . _ _. . .
R = CH, R = OH, R = tert.-butyl, R = R = H, R -R = -CH CH -, _7 CH3 and X ~ -C (CH3) 2-~ tert.-butyl 10 1) Preparation of 3'-tert.-bu-tyl-4'-hydroxy-5'-methyl-3-benzylidene-camphor 10.5 g are refluxed for 30 minutes (0.068 mole) of d, l-camphor and 15.2 g (0.136 mole) of potassium tert.-butoxide in 100 ml of toluene. We add to 80C 13 g (0.068 mole) of 3-tert.-butyl-4-hydroxy-5-methyl-benzaldehyde puls is distilled 80 cm3 of solvent. After 1 hour of heating, the reaction mixture-nel is cooled to room temperature then poured into an aqueous solution of hydrochloric acid. We extract at dichloromethane. The organic phase is washed with water, dried over sodium sulfate, then evaporated to dryness.
The product is dispersed in heptane.
4.1 g of expected product are obtained in the form of very slightly beige crystals with the characteristics following ques:
- Fuslon point: 152C
- Elementary analysis: C22H30O2 C% H ~
Calculated 80.94 9.26 Found 80.97 9.26 - UV spectrum (CH2Cl2) maX = 3lg nm . ~ = 23280 max 2) Preparation of 3'-tert.-butyl-4'-hydroxy-5'-methyl-3-benzyl-camphor:
This compound is prepared according to the operating mode described in the second part of Example 3.
The expected product is obtained in the form of cris-white levels after recrystallization in heptane. he lO has the following characteristics:
- Melting point: 147C
- Elementary analysis: C25H36O2 C% H% O%
Calculated 80.44 9.82 9,174 Found 80.00 9.88 9.98 Preparation of the compound of formula (I) in which:
Rl = R3 = tert.-bUtYle ~ R2 = H ~ R4 = H ~ R5 H ~ R6 R3 CH-2 - 2 ' R7 = H and ~ = ~ CH2_ ~ ert.-butyle tert.-butyl O

l) Preparation of 3 ', 5'-ditert.-butxl-4'-hydroxy-3- benzy- ~ -lidene-nor-camphor:

~ This compound is prepared according to the operating mode :! described in the first part of Example 2. The tetra-i hydro-2,2,5,5-tetramethyl-furane-3-one, is replaced by 1 nor-camphor.

, ~:
,.
':. .

- 2 ~ 1 3 ~

The expected product is obtained in the form of cris-white levels after recrystallization from heptane; he has the following characteristics:
- Melting point: 134C
- Elementary analysis: C25H36O2 C% H% O%
Calculates 80.94 9.26 9.80 Found 81.07 9.34 10.06 - UV spectrum (CH2C12) 10maX: 323 nm maX: 24350 2) Preparation of 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl nor-camphor This compound is prepared according to the operating mode described in the second part 2a) of example 3.
~ e expected product is obtained in the form of cris-white levels, after recrystallization from diiso- ether propyl. It has the following characteristics:
- Melting point: 112-114C
- Elementary analysis: C22H32O2 C% H% O ~:.
Calculated 80,449.82 9.74 Found 79.869.86 10.22 .
Preparation of a compound of formula (I) in which . . . _.
R = R3 = OCH, R = OH, R4 = R = H, R -R = -CH -CH -, R = CH and X =

-C (CH) -3 ~ OC33 O ~

.
-: ... .:.,. ::, 2 ~ 3 ~

1) Preparation of 3 ', 5'-dimethoxy-4'-hydroxy-3-benzy-lidene-camphor:
This compound is obtained according to the operating mode described in the first part of example 4 above in which 3-tert.-butyl-4-hydroxy-5-methyl-benzal-dehyde is replaced by 3,5-dimethoxy-4-hydroxybenzal-dehyde.
The expected product is obtained in the form of cris-white levels, after recrystallization from ether diiso-propyl. It has the following characteristics:
- Melting point: 158C
- Elementary analysis: ClgH24O4 C% H% O%
Calculate 72.13 7.65 20.23 Found 72.17 7.64 20.30 - UV spectrum (dichloromethane) . ~: 327 nm max . ~: 21300 max 2) Pre ~ aration of 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-cam-.
phre This compound is prepared according to the procedure.
described in the second part 2a) of example 3.
The expected product is obtained in the form of cris-white levels after recrystallization from diisopropyl ether pylic. It has the following characteristics:
- Melting point: 87C
- Elementary analysis ClgH26O4 C ~ H ~ O%

Calculated 71,678.2320.10 Found 71.578.2320.18 .

. ,.

2 ~ to 3 ~

1) Preparation of a compound of formula (I) in which Rl = R3 = isopropyl, R2 = OH, R4 = Rs = H ~ R6 R8 CH2 _ 2 -R = CH and X = -C (CH) -.
-7 3 3-2- lsopropyle lsopropyle 1) Preparation of 3 ', 5'-diisopropyl-4'-hydroxy-3-benzyli-dene-camphor This compound is obtained according to the operating mode described in the first part of example 4 above in which 3-tert.-butyl-4-hydroxy-5-methyl-benzal-dehyde is replaced by 3,5-diisopropyl-4-hydroxy-benzaldehyde.
The expected product is obtained in the form of cris-white levels after recrystallization from diisopropyl ether pylic. It has the following characteristics:
- Melting point: 159-160C
- Elementary analysis: C23N32O2 C% H% O ~
Calculate 81.13 9.47 9.40 Found 81.08 9.41 9.66 - UV spectrum (CH2C12) max 318 nm . ~ max: 25300 2) Pre aration of 3 ', 5'-diisopropyl-4'-hydroxy-3-benzyl-P
camphor This compound is prepared according to the operating mode ~ -30 described in the second part 2a) of example 3. ~ -.

2 ~

The expected product is obtained in the form of cris-white levels after recrystallization from diisopropyl ether pylic. It has the following characteristics:
- Melting point: 122C
- Elementary analysis: C23H34O2 C ~ H ~ O%
Calculates 80.65 10.01 9.34 Found 80.64 10.02 9.46 Preparation of a compound of formula (I) in which R = R = CH R2 = H ~ R4 = R5 = H ~ R6 R8 CH2- 2 7 _ 3 X = -C (CH) -:
~ 3-2- CH3 ;; 1) Preparation of 3 ', 5'-dimethyl-4'-hydroxy-3-benzylidene-camphor : This compound is obtained according to the operating mode described in the first part of example 4 above in which 3-tert.-butyl-4-hydroxy-5-methyl-benzalde-hyde is replaced by 3,5-dimethyl-4-hydroxy-benzal-dehyde.
The expected product is obtained in the form of cris-j white levels after recrystallization from ether diiso-:.
propyl. It has the following characteristics:

- Fuslon point: 170C

: - Elementary analysis: ClgH24O2 C ~ H% ~ O ~
::
~ ~ Calculated 80.24 8.51 11.25 Found 80.21 8.50 11.28 ~::. ::
.::. . -, 2 ~ 3; ~ 6 ~
~.

- UV spectrum (CH2C12) max 318 nm . ~ max: 24100 : 2) Preparation of 3 ', 5'-dimethyl-4'-hydroxy-3-benzyl-cam-. . ~
phre This compound is prepared according to the operating mode described in the second part 2a) of Example 3.
The expected product is obtained in the form of cris-white levels, after recrystallization from heptane. It ~ -:
has the following characteristics:
- Melting point: 150C
- Elementary analysis: ClgH26O2 C% H ~ O ~
; Calculate 79.68 9.15 11.17 -:
Found 79.61 9.09 11.34 ~ -Preparation of a compound of formula ~ I) in which Rl = R = R = OH, R = R = H, R -R = -CH -CH -, R = CH and x = -C (CH3) 2_ OH

O:
a) Preparation of 3 ', 4', 5'-tribenzyloxy-3-benzylidene cam-E ~
This compound is prepared according to the operating mode described in the first part of example 1. The tetra-hydro-2,2,5,5-tetramethylfurane-3-one is replaced by the : d, l-camphor.

.

2 ~ 3 ~

The expected product is obtained in the form of cris- -white levels, after recrystallization from 95% ethanol.
It has the following characteristics:
- Melting point: 88C
- Elementary analysis: C38H38O4 C% H% O%
Calculate 81.69 6.86 11.45: ~:
Find 81.60 6.87 11.51 b) Preparation of 3 ', 4', 5'-trihydroxy-3-benzyl-camphor This compound is prepared according to the procedure described in the second part 2a) of example 3.
The expected product is obtained in the form of cris-white levels after recrystallization from diisopropyl ether pylic. It has the following characteristics:
- Melting point: 153C
- Elementary analysis: C17H22O4 C ~ H% O%
Calculates 70.32 7.64 22.04 Found 70.26 7.66 22.09 Preparation of the compound of formula (I) in which R = OCH, R = H, R = tert.-butyl, R = OH, R = H, R -R = -CH2-CH -, R = CH -SO H and X = -C (CH) 2 - 2- --7 - 2 ~ 3 3-bO3S ~ ert.-butyl H

$ ~

1) Preparation of 3'-tert.-butyl-2'-hydroxy-5'- acid methoxy-3-benzylidene-campho-10-sulfonic , Heat at reflux for 1 hour 8.8 g (0.038 mole) of d, l-campho-10-sulfonic acid, 6.1 g (0.114 mole) sodium methylate and 7.9 g (0.038 mole) of 3-tert.
butyl-2-hydroxy-5-methoxy-benzaldehyde in 13Q cm3 of 1,2-dimethoxyethane. After cooling, add, with stirring, 2 equivalents of 2N hydrochloric acid.
The aqueous phase is saturated with sodium chloride.
Extraction is carried out with dichloromethane, then the solvent is evaporated.
pore. The yellow solid thus obtained is hot dispersed in diisopropyl ether. Filter then dry under empty. The sodium salt thus obtained is redissolved in the water and the solution is filtered through a resin column DOWEX * 50 ion exchanger. We obtain, after evaporation water under reduced pressure, at room temperature, the expected compound in the form of an orange solid having the following features:
- Elementary analysis: C22H30O6S
C% H% O% S% -Calculate 62.54 7.16 22.72 7.59 Found 62.57 7.49 22.97 6.93 - UV spectrum (in the form of sodium salt, in the water) maxl 295 nm maxl: 11150 max2,355 nm max2 7500 *Trademark.

... . ..... ... . . .. - ... . :. -. :,:. .:. -. : - - ....

2 ~

2) Preparation of 3'-tert.-butyl-2'-hydroxy-5'- acid methoxy-3-benzyl-campho-10-sulfonic .
This compound is prepared according to the procedure.
described in the second part 2a) of example 3.
The expected product is obtained in the form of cris-white levels after recrystallization from diisopropyl ether pylic. It has the following characteristics:
- Melting point c 250C
- Elementary analysis: C22H32O6S, 1 / 2H2O
C% H ~ O% S%
Calculate 60.96 7.62 24.01 7.39 Found 61.23 7.97 24.18 6.60 Preparation of the com ose of formula (I) in which P
R = R3 = isoprOPYle, R2 = OH ~ R4 = H ~ R5 R6 R7 R8 - 3 CH3 ~ sopropyl CH3 / ~ OH

1 CH ~ isopropyl 1) Preparation of 3 ', 5'-d ~ pro_yl-4'-hydroxy-4- ben-zylidene tetrahydro-2,2, _5,5-tetramethylfurane-3- one:
This compound is obtained according to the operating mode described in the first part of example 1 above in which 3,4,5-tribenzyloxy-4-benzaldehyde is replaced placed by 3,5-diisopropyl-4-hydroxy-benzaldehyde.
l The expected product is obtained in the form of a l solid white. It has the following characteristics:
- Melting point: 142C
- Elementary analysis: C21H30O3 i ~ ~ - 30 -. "........ ~ ~.. .....

2 ~ 3 ~
,. ~

C ~ H% o ~
Calculates 76.33 9.15 14.52 Found 76.57 9.23 14.68 - UV spectrum (CH2C12) 335 nm max -~: 22400 2) Pre ~ aration of the 3 ', 5'-diisopropyl-4'-hydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethylfurane-3-one:
... . _.
This compound is prepared according to the operating mode 10 described in the second part of Example 3.:
The expected product is obtained in the form of cris- -white levels after recrystallization from heptane. He -: -has the following characteristics:
- Melting point: 90C
- ~ elementary analysis: C21H32O3 C ~ H% O%
Calculated 75.86 9.70 14.44 Found 75.81 9.77 14.44 Preparation of the compound of formula _ (I) _ in which R = R = tert.-butyl, R = OH, R = H, R = H, R -R = -CH -CH -, R = CH and X = -C (CH) tert.-butyl ert.-butyl 2 ~

1) Preparation of 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzy-. . _ lidene-camphor:
This compound is prepared according to the operating mode described in the first part of Example 2. The tetra-hydro-2,2,5,5-tetramethylfurane-3-one is replaced by d-camphor.
The expected product is obtained in the form of cris-white levels after recrystallization from dilsopro- ether pylic. It has the following characteristics:
10- Melting point: 186C
- Elementary analysis: C25H36O2 C% H ~ O ~
Calculated 81.47 9.84 8.60 ; Found 81.40 9.87 8.79 - UV spectrum (CH2C13) max 325 nm . ~ max: 23000 2) Preparation of 3 ', 5'-ditert.-butyl-4'-hydroxy-3-be ~ zyl-cam ~ hre (D) This compound is prepared according to the procedure.
described in the second part of Example 3.
The expected product is obtained in the form of cris-white levels after recrystallization from a mixture ethanol / water 95/5.
It has the following characteristics:
- Melting point: 166C:
- Elementary analysis: C25H38O2 C ~ H ~ O ~
Calculated 81.03 10.34 8.63 Found 81.22 10.29 8.79 2 ~ $ ~

Highlighting the antioxidant properties of these compounds by chemiluminescence of cellular homogenates - The chemiluminescence test is performed according to the publication of EA LISSI, T. CACERES and LA VIDELA
"Visible Chemilumuninescence from rat brain homogenates undergoing autoxidation. I. Effect of additives and products accumulation "in" Journal of Free Radicals in ~ -Biology and Medicine ", Vol. 2, pp. 63-69 (1986). This test has been simplified in the sense that we only measured the chemiluminescence without measuring acid accumulation thiobarbiturate after 1 hour of irradiation. However, according to the publication, there is a good correlation between chemiluninescence and the measurement of the accumulation of thlobarbituric acid.
Rat brains are immediately exposed ment after cervical dislocation. They are washed with buffer solution containing 140 mM NaCl and 40 mM
potassium phosphate, cleared of blood vessels exposed and the outer membrane, then ground with

4 times their volume of buffer solution. This ground material is diluted 3 times with the buffer solution (total dilution 12 times compared to the departure bodies).
10 ml of diluted homogenate is introduced into counting flasks containing 200 μl of solution of the antioxidant product to be tested, dissolved in different concentrations tions in methanol or dimethylsulfoxide.
Immediately after shaking, the vials are entered into a scintillation counter (BECKMAN) and counted periodically.
At the same time, a study is being carried out on a solution control containing no antioxidant.
.

3 ~

We thus establish, for each concentration a chemiluminescence intensity curve as a function of time.
By comparing the slopes of the curves obtained with solutions at different concentrations and the control solution, C50 is determined, i.e. the concentration tration in antioxidant allowing the inhibition of 50% of peroxidation.
Compound of example 2 = C50 = 1.10.10 M
'3 = C50 = 2.00.10 6M
"4 = C50 = 1.40.10 6M
~ '"5 = C50 = 1.50.10 6M
"" 6 = C50 = 1.25.10 6M
"7 = C50 = 0.80.10 6M
~ "9 = C50 = 0.80.10 6M
By comparison, the C50 of BHT (ditert.-butyl-hydroxy toluene), which is a classic antioxidant, is 3.20.10 M.
Pharmaceutical compositions used topically:
Example A - Soothing Ointment (To apply on irritated skin to calm) - Compound of Example 3 2.0 g - Fluid vaseline oil 9.1 g - Silica sold by DEGUSSA under the brand name AEROSIL 200 9.2 g - Isopropyl myristate qs 100 g Example B - Anti-inflammatory (oil-in-water) cream - Compound of Example 6 2.5 g - Sodium dodecyl sulfate 0.8 g 30 - Glycerol 2.0 g - Stearyl alcohol 20.0 g 2 ~ 13 ~

- Triglycerides of capric acid / capryli-that sold by DYNAMIT NOBEL
under the trademark MIGLYOL 812 20.0 g - Preservative qs - Demineralized water qs 100 g Example C - Soothing gel - Compounds of Example 7 1.5 g - Hydroxypropyl cellulose sold by the HERCULES under the brand name KLUCEL HF merce 2.0 g - Ethanol 70.0 g - Water qs 100 g Cosmetic composition EXAMPLE D Protective Gel for the Skin - Compound of Example 1 0.2 g - Glycerin 12.0 g , j.
'- Polyacrylic acid crosslinked by an agent ; polyfunctional sold under the brand of I CARBOPOL 934 trade by the Company GOODRICH 0.8 g.
.
i - Ethanol 15.0 g - Preservative, scent qs.
- Triethanolamine qs pH: 5.3 - Demineralized water qs 100 g . ~:. .
.:
, ~.
., :::

::::

~ ~, - -,, .
: -:

Claims (42)

1. Use as an antioxidant agent for minus a compound of formula:

(I) in which:
R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an al-linear or branched C1-C8 kyle or a linear alkoxy residue-area or branched in C1-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched in C1-C18, an unsubstituted aralkyl residue or substituted by a C1-C4 alkyl or C1-C4 alkoxy residue, an aryl residue unsubstituted or substituted by a residue C1-C4 alkyl, the substituents R5 and R6 and / or the sub-stituants R7 and R8 which can form, with the carbon atom of the cycle to which they are attached, a saturated cycle contains from 5 to 12 unsubstituted or substituted carbon atoms killed by one or more linear or branched alkyl residues trusted in C1-C8;

X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a metallic residue thyle; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine. 2. Use as an antioxidant agent for minus a compound of formula (I) as defined in claim 1, selected from the group consisting of 3 ', 4', 5'-trihydroxy-4-benzyl-tetrahydro-2,2,5,5-tetra-methyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-4-benzyl-tetrahydro-2, 2,5,5-tetramethyl-furan-3-one, the 3 ', 5'-diisopropyl-4'-hydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hy-droxy-3-benzyl-camphor, 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor, 3 ', 4', 5'-trihydroxy-3-benzyl-camphor, 3 ', -5'-diisopropyl-4'-hydroxy-3-benzyl-camphor, 3'-methyl- 4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor.

3. Use as cosmetic product of minus a compound of formula:

(I) in which:
R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an al-linear or branched C1-C8 kyle or a linear alkoxy residue-area or branched in C1-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched in C1-C18, an unsubstituted aralkyl residue or substituted by a C1-C4 alkyl or C1-C4 alkoxy residue, an aryl residue unsubstituted or substituted by a residue C1-C4 alkyl, the substituents R5 and R6 and / or the subs-titers R7 and R8 which can form, with the carbon atom of the cycle to which they are attached, a saturated cycle contains from 5 to 12 unsubstituted or substituted carbon atoms killed by one or more linear or branched alkyl residues trusted in C1-C8;
X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a metallic residue thyle; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine.

4. Use as cosmetic product of minus one compound of formula (I) as defined in claim 1, selected from the group consisting of 3 ', 4', 5'-trihydroxy-4-benzyl-tetrahydro-2,2,5,5-tetra-methyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-4-benzyl-tetrahydro-2, 2,5,5-tetramethyl-furan-3-one, the 3 ', 5'-diisopropyl-4'-hydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hy-droxy-3-benzyl-camphor, 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor, 3 ', 4', 5'-trihydroxy-3-benzyl-camphor, 3 ', - 5'-diisopropyl-4'-hydroxy-3-benzyl-camphor, 3'-methyl-4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor.

5. Use as a medicament of at least one composed of formula:

(I) in which:
R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an al-linear or branched C1-C8 kyle or a linear alkoxy residue-area or branched in C1-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched in C1-C18, an unsubstituted aralkyl residue or substituted by a C1-C4 alkyl or C1-C4 alkoxy residue, an aryl residue unsubstituted or substituted by a residue C1-C4 alkyl, the substituents R5 and R6 and / or the subs-titers R7 and R8 which can form, with the carbon atom of the cycle to which they are attached, a saturated cycle contains from 5 to 12 unsubstituted or substituted carbon atoms killed by one or more linear or branched alkyl residues trusted in C1-C8;
X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a metallic residue thyle; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine. 6. Use as medicine of at least one compound of formula (I) as defined in the claim cation 3, chosen from the group consisting of 3 ', 4', -5'-trihydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-4-benzyl-tetrahydro-2, 2,5,5-tetramethyl-furan-3-one, la 3 ', 5'-diisopropyl-4'-hydroxy-4-benzyl-tetrahydro-2,2,5,5-tétra-methyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor, the 3 ', 4', 5'-trihydroxy-3-benzyl-camphor, 3 ', 5'-diisopro-pyl-4'-hydroxy-3-benzyl-camphor, 3'-methyl-4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor. 7. Use as a medicament of at least one compound of formula (I) as defined in the claim cation 5, or 6, in the treatment of inflammation and skin allergies. 8. Use of at least one compound of formula:

(I) in which:
R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an al-linear or branched C1-C8 kyle or a linear alkoxy residue-area or branched in C1-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched into C1-C18, an unsubstituted aralkyl residue or substituted by a C1-C4 alkyl or C1-C4 alkoxy residue, an aryl residue unsubstituted or substituted by a residue C1-C4 alkyl, the substituents R5 and R6 and / or the subs-titers R7 and R8 which can form, with the carbon atom of the cycle to which they are attached, a saturated cycle contains from 5 to 12 unsubstituted or substituted carbon atoms killed by one or more linear or branched alkyl residues trusted in C1-C8;
X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a metallic residue thyle; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine;
for the preparation of a drug intended for treatment skin inflammation and allergies. 9. Use according to claim 8, character-sed by the fact that the compound of formula (I) is chosen in the group consisting of 3 ', 4', 5'-trihydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, the 3 ', 5'-ditert.butyl-4'-hydroxy-4-benzyl-tetrahydro-2,2, -5,5-tetramethyl-furan-3-one, 3 ', 5'-diisopropyl-4'-hydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor, 3', 5'-dimethyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor, 3 ', 4', 5'-trihy-droxy-3-benzyl-camphor, 3 ', 5'-diisopropyl-4'-hydroxy-3-benzyl-camphor, 3'-methyl-4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor. 10. Cosmetic composition, characterized by the fact that it includes, in a cosmetically acceptable carrier ble, an effective amount of at least one compound of mule:
(I) in which:
R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an al-linear or branched C1-C8 kyle or a linear alkoxy residue-area or branched in C1-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched in C1-C18, an unsubstituted aralkyl residue or substituted by a C1-C4 alkyl or C1-C4 alkoxy residue, an aryl residue unsubstituted or substituted by a residue C1-C4 alkyl, the substituents R5 and R6 and / or the subs-titers R7 and R8 which can form, with the carbon atom of the cycle to which they are attached, a saturated cycle contains from 5 to 12 unsubstituted or substituted carbon atoms killed by one or more linear or branched alkyl residues trusted in C1-C8;
X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a metallic residue thyle; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine. 11. Cosmetic composition according to claim 10, characterized in that the compound (I) is chosen in the group consisting of 3 ', 4', 5'-trihydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, the 3 ', 5'-ditert.butyl-4'-hydroxy-4-benzyl- tetrahydro-2,2, -5,5-tetramethyl-furan-3-one, 3 ', 5'-diisopropyl-4'-hydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor, 3', 5 _ dimethyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor, 3 ', 4', 5'-trihy-droxy-3-benzyl-camphor, 3 ', 5'-diisopropyl-4'-hydroxy-3-benzyl-camphor, 3'-methyl-4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor. 12. Cosmetic composition according to claim 10, characterized by the fact that it is in the form of lotion, emulsion, oleoalcoholic or hydroalcoholic gel, solid stick or aerosol. 13. Cosmetic composition according to claim 12, characterized by the fact that it also contains minus a cosmetically acceptable adjuvant selected from the group consisting of thickeners, softeners, humectants, surfactants, preservatives, anti-foam, perfumes, oils, waxes, lano-line, lower monoalcohols and polyols, propellants dyes, dyes and pigments. 14. Cosmetic composition according to claim 10, 11, 12, or 13, characterized in that it constitutes a protective composition for the human epidermis and that the compound of formula (I) is present in a proportion of 0.1 to 8% by weight, relative to the total weight of the compound sition. 15. Cosmetic composition according to claim 10, 11, 12 or 13, characterized in that it constitutes a protective composition for the human epidermis and that the compound of formula (I) is present in a proportion of 0.1 to 5% by weight, based on the total weight of the position. 16. Cosmetic composition according to claim 10, 11, 12 or 13, characterized in that it occurs in the form of an anti-sun composition further containing UV-A and UV-B filters and that the compound of formula (I) is present in a proportion of 0.1 to 8% by weight, by relative to the total weight of the composition, the quantity total of filters present being between 0.5 and 15%
in weight. 17. Cosmetic composition according to claim 10 or 11, in the form of a cosmetic composition whether colored or not, stabilized on oxidation, characterized by the fact that it is made up of a composition hair, a makeup product or a composition for skin care or treatment, the compound of formula (I) being present in a proportion of 0.1 to 8%
by weight, relative to the total weight of the composition. 18. Cosmetic composition according to claim 10 or 11, intended to protect the hair, characterized by the fact that it comes in the form of shampoo, lotion, gel or emulsion to rinse, lotion or gel coif-fants, or treating agents, lotion or gel for brushing or styling, hairspray, composition of permanent, coloring or discoloration, the compound of formula (I) being present in a proportion of 0.25 to 8% by weight, relative to the total weight of the composition. 19. Method for protecting the skin or the hair, characterized by the fact that it consists in applying to these an effective amount of at least one composition cosmetic as defined in claim 10, 11, 12 or 13. 20. Method for protecting a cosmetic composition that against oxidation, characterized in that it consists in incorporating into this composition a quantity effective of at least one compound of formula:

(I) in which:
R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an al-linear or branched C1-C8 kyle or a linear alkoxy residue-area or branched in C1-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched in C1-C18, an unsubstituted aralkyl residue or substituted by a C1-C4 alkyl or C1-C4 alkoxy residue, an aryl residue not substituted or substituted by a residue C1-C4 alkyl, the substituents R5 and R6 and / or the sub-stituants R7 and R8 which can form, with the carbon atom of the cycle to which they are attached, a saturated cycle contains from 5 to 12 unsubstituted or substituted carbon atoms killed by one or more linear or branched alkyl residues trusted in C1-C8;
X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a metallic residue thyle; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine. 21. Method according to claim 20, characterized by the fact that the compound of formula (I) is chosen from the group consisting of 3 ', 4', 5'-trihydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, la 3 ', 5'-ditert.butyl-4'-hydroxy-4-benzyl-tetrahydro-2, 2,5,5-tetramethyl-furan-3-one, 1a 3 ', 5'-diisopropyl-4'-hy-droxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor, 3', 5'-dimethyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor, 3 ', 4', 5'-trihy-droxy-3-benzyl-camphor, 3 ', 5'-diisopropyl-4'-hydroxy-3-benzyl-camphor, 3'-methyl-4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor. 22. Pharmaceutical composition, characterized by fact that it includes, in a carrier or excipient phar-maceutically acceptable, an effective amount of at least minus a compound of formula:

(I) in which:
R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an al-linear or branched C1-C8 kyle or a linear alkoxy residue-area or branched in C1-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched in C1-C18, an unsubstituted aralkyl residue or substituted by a C1-C4 alkyl or C1-C4 alkoxy residue, an aryl residue unsubstituted or substituted by a residue C1-C4 alkyl, the substituents R5 and R6 and / or the sub-stituants R7 and R8 which can form, with the carbon atom of the cycle to which they are attached, a saturated cycle contains from 5 to 12 unsubstituted or substituted carbon atoms killed by one or more linear or branched alkyl residues trusted in C1-C8;
X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a metallic residue thyle; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine. 23. Pharmaceutical composition according to claim 22, characterized in that the compound of formula (I) is chosen from the group consisting of 3 ', 4', 5'-trihy-droxy-4-benzyl-tetrahydro-2,2,5,5-tetramethyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-4-benzyl-tetra-hydro-2, 2,5,5-tetramethyl-furan-3-one, la 3 ', 5'-diiso-propyl-4'-hydroxy-4-benzyl-tetrahydro-2,2,5,5-tetramé
thyl-furan-3-one, 3 ', 5'-ditert.butyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-dimethyl-4'-hydroxy-3-benzyl-camphor, 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor, the 3 ', 4', 5'-trihydroxy-3-benzyl-camphor, 3 ', 5'-diisopro-pyI-4'-hydroxy-3-benzyl-camphor, 3'-methyl-4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor. 24. Pharmaceutical composition according to claim 22 or 23, characterized in that the compound of-mule (I) is present in a proportion between 0.1 and 20% by weight, relative to the total weight of the composition. 25. Pharmaceutical composition according to claim 22 or 23, characterized in that the compound of-mule (I) is present in a proportion between 0.1 and 20% by weight, relative to the total weight of the composition. 26. Pharmaceutical composition according to claim 22 or 23, characterized in that it contains in addition to at least one inert or pharmacodynamically additive active ingredient chosen from the group consisting of hy-dratants, antibiotics, anti-inflammatory agents steroidal or non-steroidal tails, carotenoids, anti-psoriatic agents, agents for improving flavor, preservatives, stabilizers humidity regulating agents, regulating agents pH readers, pressure modifiers osmotic, emulsifying agents, anesthetics premises and buffers. 27. Pharmaceutical composition according to claim 22 or 23, intended to be administered topically, characterized by the fact that it is in the form of cream, ointment, ointment, solution, gel, lotion, spray or suspension. 28. Pharmaceutical composition according to claim 22 or 23, intended to be administered topically, characterized in that the compound of formula (I) is present in a proportion between 0.25 and 8% in weight, relative to the total weight of the composition. 29. Pharmaceutical composition according to claim 22 or 23, intended for oral administration, characterized by the fact that it is in the form of tablets, capsules, dragees, syrups, suspensions, solutions or emulsions. 30. Benzyl-cyclanone derivatives corresponding to the formula:

(I ') in which:
R1 and R3, identical or different, represent a hydrogen atom, a hydroxyl radical, an al-linear or branched C1-C8 kyle or a linear alkoxy residue-area or branched in C1-C8;
R2 and R4, identical or different, represent a hydrogen atom or a hydroxyl radical, being understood that at least one of the radicals R2 and R4 represents a hydroxyl radical;
R5, R6, R7 and R8, identical or different, re-have a hydrogen atom, a linear alkyl residue or branched in C1-C18, an unsubstituted aralkyl residue or substituted by a C1-C4 alkyl or C1-C4 alkoxy residue, an aryl residue unsubstituted or substituted by a residue C1-C4 alkyl, the substituents R5 and R6 and / or the sub-stituants R7 and R8 which can form, with the carbon atom of the cycle to which they are attached, a saturated cycle contains from 5 to 12 unsubstituted or substituted carbon atoms killed by one or more linear or branched alkyl residues trusted in C1-C8;
X represents either an oxygen atom or a radical - (CR9R10) n in which n is equal to 1 or 2 and R9 and R10 represent a hydrogen atom or a me-thyle; in the case where X represents a radical - (CR9R10) n, the substituents R6 and R8 form with the atoms of the ring to which they are attached a bicyclic system containing having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a remainder -CH2-SO3H, provided that when R5, R6, R7 and R8 denotes a radi-cal methyl, X an oxygen atom, R2 a hydrogen atom and R4 a hydroxyl radical, at least one of the radicals R1 and R3 denotes a hydroxyl, alkyl or alkoxy radical, optionally in the form of an alkali metal salt, an alkali metal no-earthy or amine. 31. The 3 ', 4', 5'-trihydroxy-4-benzyl-tetrahydro-2,2, -5,5-tetramethylfuran-3-one. 32. The 3 ', 5'-ditert.-butyl-4'-hydroxy-4-benzyl-tétra-hydro-2,2,5,5-tétramethylfurane-3-one. 33. The 3 ', 5'-diisopropyl-4'-hydroxy-4-benzyl-tetra-hydro-2,2,5,5-tetramethylfuran-3-one. 34. The 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-camphor. 35. 3 ', 5'-dimethoxy-4'-hydroxy-3-benzyl-camphor. 36. 3 ', 5'-dimethyl-4'-hydroxy-3-benzyl-camphor. 37. The 3 ', 5'-ditert.-butyl-4'-hydroxy-3-benzyl-nor-camphor. 38. 3 ', 4', 5'-trihydroxy-3-benzyl-camphor. 39. 3 ', 5'-diisopropyl-4'-hydroxy-3-benzyl-camphor. 40. 3'-methyl-4'-hydroxy-5'-tert.-butyl-3-benzyl-camphor. 41. Process for the preparation of the compound of formula (I ') as defined in claim 30, characterized by the fact that it consists in a first step to condensing an aromatic aldehyde of formula:

(III) in which R'1 and R'3 are identical or different, represent a hydrogen atom, a hydroxyl radical, a linear or branched C1-C8 alkyl residue, a residue linear or branched C1-C8 alkoxy, or a residue arylalkoxy, R'2 and R'4, identical or different, represent a hydrogen atom, a hydroxyl radical, or an arylalkoxy residue, it being understood that at least one radicals R'2 and R'4 represents a hydroxyl radical, on a cyclanone of formula:

(IV) in which R5 to R8 and X have the meanings indi-as in claim 30, in the presence of an alcoholate of alkali metal, in a solvent, at a temperature between -78 ° C and the boiling point of the solvent, or in the presence of a mineral base, in a solvent, at a temperature between 0 ° C and the boiling point of reaction mixture, or in the presence of a borane of formula:

(V) in which R11 and R12 represent an alkyl radical in C1-C6, at a temperature of approximately 150 ° C, without solvent, to obtain a benzylidene cyclanone of formula (II):

(II) in which R'1 to R'4, R5 to R8 and X have the significant mentioned above, which is subjected in a second step to a reduction by catalytic hydrogenation or by hydrogenation tion in the presence of a hydrogen transfer agent and of a catalyst, in the presence or absence of an inert solvent, to a temperature between -78 ° C and the boiling point tion of the reaction mixture. 42. Process for the preparation of the compound of formula (I ') as defined in claim 30, characterized by fact that it consists in condensing a Mannich base of formula (VI):

(VI) formula in which R1 to R4 have the meanings indi-quées in claim 30 and R13 and R14 denote a remains C1-C4 alkyl or R13 and R14 form, with the nitrogen atom to which they are attached, a heterocy-key containing 5 or 6 atoms, on a cyclanone of formula:

(IV) in which R5 to R8 and X have the meanings indi-as in claim 30, in the presence of an alcoholate of alkali metal, in a solvent, at a temperature between -78 ° C and the boiling point of the solvent.

having 7 or 8 carbon atoms; moreover, when X represents feels a radical - (CR9R10) n- in which n is equal to 1, R9 and R10 representing a methyl residue, R5 representing a hydrogen atom and R6 and R8 forming with the atoms of the cycle to which they are attached a bicyclic system containing 7 carbon atoms, R7 can also represent ter a residue -CH2-SO3H, possibly in the form of salt of alkali, alkaline earth metal or amine. The ingredients its of formula (I) are useful as antioxidants and drugs for the treatment of inflammation and go-cutaneous gies.