FR2725205A1 - New di:benzofuran derivs. useful in medicines and cosmetics - Google Patents

Abstract

Dibenzofuran derivs. of formula (I), their optical and geometric isomers and, when R1 or R9 are an acid gp. or R9 is an amine, their salts are new: R = H, halo, lower alkyl, lower acyl or OR'; A = a gp. of formula (a) - (c); R1 = H, methyl, -CH2-O-R5, -OR5, -COR6 or -S(O)tR6; R2 = H or OR5; either R3, R4 = H, lower alkyl or -(X)n-(CH2)m-R7; or R3 + R4 = oxo, thioketone, oxime, oxime, =N-O-R6, epoxy, cycloalkyl opt. substd. by halo or lower alkyl, or -O-(CH2)q-O-; q = 2 - 3; R3', R4' = H, lower alkyl or lower acyl; t = 0 - 2; R5 = H, lower alkyl or lower acyl; R6 = H, -NR"R"' or -OR8; R7 = H or -(CO)p-R9; p = 0 or 1; R8, R' = H, 1-20C alkyl, mono- or poly-hydroxyalkyl, aryl (opt. substd.), aralkyl (opt. substd.), a sugar residue or an amino acid residue; R9 = H, alkyl, alkenyl, alkynyl, aryl or -NR"R"'; or R9 is also -OR7 provided that m is not 0; R", R"' = H, lower alkyl, mono- or polyhydroxyalkyl, aryl (opt. substd.), aralkyl (opt. substd.), an amino acid, peptide, or sugar residue; or NR''R''' = a heterocyclyl; X = O or S; n = 0-1; m = 0-10.

Description

NOVEL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND
COSMETICS CONTAINING THEM
The invention relates, as new and useful industrial products, to polycyclic aromatic compounds. It also relates to the use of these novel compounds in pharmaceutical compositions intended for use in human or veterinary medicine, or even in cosmetic compositions.

The compounds according to the invention have a marked activity in the fields of cell differentiation and proliferation, and find applications more particularly in the topical and systemic treatment of dermatological disorders related to a disorder of keratinization, dermatological disorders (or others) has an inflammatory, viral and / or immunoallergic component, and dermal or epidermal proliferations, whether benign or malignant.

These compounds can also be used in the treatment of connective tissue degenerative diseases, to fight against aging of the skin, whether photoinduced or chronological, and to treat cicatrization disorders. They also find an application in the ophthalmological field, particularly in the treatment of cometopathies.

The compounds according to the invention can also be used in cosmetic compositions, especially for body and hair hygiene.

dans laquelle: * R représente un atome d'hydrogène, un atome d'halogène, un radical alkyle inféneur, un radical acyle inféneur, un radical OR', R' ayant la signification donnée ci-après, * A représente un radical choisi parmi les radicaux de formules (lla-ilc) suivantes

formules dans lesquelles: - R, représente : (i) un atome d'hydrogène,
(ii) le radical -C H3,
(iii) le radical -CH2-O-Rs
(iv) un radical -ORs (v) un radical

The compounds according to the invention, derived from dibenzofuran, are characterized by the fact that they have the following general formula (I)

in which: R represents a hydrogen atom, a halogen atom, an alkyl lower radical, a lower acyl radical, a radical OR ', R' having the meaning given below, A represents a radical chosen from the radicals of formulas (lla-ilc) following

formulas in which: - R, represents: (i) a hydrogen atom,
(ii) the radical -C H3,
(iii) the radical -CH2-O-Rs
(iv) a radical -ORs (v) a radical

(vi) a radical -S (O) t R6
t, R5 and R6 having the meanings given below, - R2 represents a hydrogen atom or the radical -ORs
R5 having the meaning given below, - or R3 and R4 independently represent a hydrogen atom, a lower alkyl radical or the radical - (X) n - (CH2) m - R7
X and R, having the meanings given below,
either R3 and R4, taken together, form an oxo (= O), thiocetone (= S), oxime or a derivative of the oxime (R6-ON =), epoxy, cycloalkyl optionally substituted by a halogen atom or a lower alkyl radical, or a dioxolane group [-O-
CH2) qO-] with q equal to 2 or 3. R6 having the meaning given below, - R3, and R4, independently represent a hydrogen atom, a lower alkyl radical, a lower acyl radical, it being understood that in all the above t is equal to 1 or 2,
R5 representing a hydrogen atom, a lower alkyl radical, or a lower acyl radical R6 represents: a hydrogen atom,
a radical -N (R ", R"'), R "and R"' having the meanings
given below,
a radical -OR8, Ra having the meaning given below,
R7 represents a hydrogen atom, a radical - (CO) p-R9 in which p may have the value 0 or 1, Rg having the meaning given below,
R8 and R 'independently represent a hydrogen atom, an alkyl radical having 1 to 20 carbon atoms, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical, optionally substituted aralkyl, a sugar residue or an amino residue. -acid, .Rg represents: a hydrogen atom,
an alkyl radical,
an alkenyl radical,
an alkynyl radical,
an aryl radical,
a radical -OR7 - in this case, m can not take the value O, R7
having the meaning indicated above.

a radical -N (R ", R"'), R "and R"' having the meanings given herein
after,
R "and R"', identical or different, represent a hydrogen atom. a lower alkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical, an optionally substituted aralkyl radical, an amino acid or peptide or sugar residue or R "and R"'taken together form a heterocycle, . X is an oxygen or sulfur atom,
n is 0 to 1 and m is 0 to 10, and the optical and geometric isomers of said compounds of formula (I), as well as their salts in the case where R1 or Rg represents an acid function, or when R9 represents a function amine.

When the compounds according to the invention are in the form of salts by adding a base, they are preferably salts of an alkali metal or alkaline earth metal or else zinc or an organic amine.

When the compounds are in the form of salts, by addition of an acid, they are pharmaceutically or cosmetically acceptable salts obtained by the addition of an inorganic or organic acid, in particular hydrochloric acid, sulfuric acid, acetic acid, citric acid. , fumaric, hemisuccinic, maleic and mandelic.

By lower alkyl radical is meant a radical having 1 to 6 carbon atoms and preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.

By alkenyl radical is meant a radical having from 1 to 20 carbon atoms. linear or branched with a double bond.

By alkynyl radical is meant a radical having 1 to 20 carbon atoms, linear or branched having a triple bond.

The term "lower acyl radical" means a radical having from 1 to 10 carbon atoms and preferably the acetyl, propionyl and pivaloyl radicals.

Alkyl radicals having 1 to 20 carbon atoms are linear or branched, optionally substituted with 1 or more fluorine atoms.

By monohydroxyalkyl radical is meant a radical having from 1 to 6 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.

By polyhydroxyalkyl radical is meant a radical containing 2 to 6 carbon atoms and 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5 tetrahydroxypentyl or the remainder of the pentaerythenol.

Among the aryl radicals, a phenyl radical is more preferably chosen, optionally substituted by one or more halogen atoms, a hydroxyl or nitro function or a methoxy group.

By optionally substituted aralkyl radical is meant the benzyl or phenethyl radical, optionally substituted by one or more halogen atoms, a hydroxyl or nitro function, or a methoxy group.

By amino acid residue is meant a residue derived for example from one of the 20 amino acids of L or D configuration constituting mammalian proteins.

By peptide residue is meant a linear peptide of 2 to 10 amino acids.

By sugar residue is meant a residue derived for example glucose, galactose, mannose or glucuronic acid.

The preferred heterocycles correspond to the piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in the 4-position by a C1-C6 alkyl or mono- or polyhydroxyalkyl radical as defined above.

Among the compounds of general formula (I), mention may notably be made of the following
Methyl [(1, 2,3,4-Tetrahydro-1,4a, 9b-methyl-1,4-methanodibenzofuran-8-yl) carbonyl] -6-naphthalene-2-carboxylate
[(1,2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methano-dibenzofuran-8-yl) carbonyl] -6-naphthalene-2-carboxylic acid
[(1,2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methano-dibenzofuran-8-yl) methyl] -6-naphthalene-2-carboxylic acid
Methyl [(1, 2,3,4-Tetrahydro-1,4a, 9b-methylmethyl-1,4-methanodibenzofuran-8-yl) hydroxymethyl] -6-naphthalene-2-carboxylate
[(1,2,4,4-Tetrahydro-1,4a, 9b-methyl-1,4-methano-dibenzofuran-8-yl) hydroxymethyl] -6-naphthalene-2-carboxylic acid
Methyl 4 - [(1,2,3,4-tetrahydro-1,4a, 9b-methyl-1,4-methanodibenzofuran-8-yl) carbonyl] benzoate
4 - [(1,2,3,4-Tetrahydro-1,4a, 9b-methyl-1,4-methano-dibenzofuran-8-yl) carbonyl] benzoic acid 4 - [(1, 2, 3,4- Tetrahydro-1,4a, 9b-methylmethyl-1,4-methanodibenzofuran-8-yl) hydroxymethyl] phenylcarbinol
4 - [(1,2,4,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) carbonyl] phenylcarboxaldehyde
2- (1,2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) -2- (4-methoxycarbonylphenyl) -1,3-dioxolan
2- (1,2,4,4-Tetrahydro-1,4a, 9b-methyl-1,4-methanodibenzofuran-8-yl) -2- (4-carboxyphenyl) -1,3-dioxolan
Among the compounds according to the invention, the compounds corresponding to the general formula (I) in which A represents the radical of formula (lob) are preferred.

The compounds that are more particularly preferred are those for which A represents the radical of formula (lob) in which R 1 represents the radical

The compounds of general formula (I) can be prepared in the following manner - either by Friedel-Crafts reaction between 1,2,3,4-Tetrahydro-1,4a, 9b-methyl-1,4-methanodibenzofuran or a derivative of this substituted ring of general formula (II) and an acid chloride of general formula (III) or (IV)

The formulas Ta and Ib correspond to the formula (I) in which A respectively represents the radicals of formulas IIa and IIb, in which R3 and R4 taken together form an oxo group.

or by reaction of an organometallic denucleate at the 8-position of the ring (formula III), such
an organozinc or organostannan (formula VII) on a compound of formulas
IV or V, catalyzed by a palladium derivative according to the scheme below,

<tb><SEP> v
<tb><SEP> w
<tb><SEP>? I
<tb> vi <SEP> R <SEP> s <SEP> lb
<tb><SEP> VI <SEP> VII
<tb> W -ZnCl ;; - Sn (nBu) 3 - either under carbonylation conditions

<tb><SEP> R2
<tb><SEP> VIII <SEP> Ia
<tb><SEP> Ia
<tb> VII
<tb><SEP> Baee
<tb><SEP> Base <SEP><
<tb><SEP> Y
<tb><SEP> Ib
<tb><SEP> R <SEP> lb
<tb><SEP> IX
<Tb>
In formulas (VIII) and (IX), Z represents Br, I or O-SO2-CF3
During these reactions leading to the compounds of general formula (I), the functions R 1 and R 2 will optionally be in a form protected to be compatible with the operating conditions. The protective groups employed are those described in the book "Protecting Groups in Organic Synthesis" by TW Greene,
Ed. By John Wiley and Sons (1981).

The derivatives (1a and 1b) then serve as a starting material for the manufacture of other compounds according to conventional methods of organic chemistry such as those described in J. March, John Wiley and sons' "Advanced Organic Chemistry". , 1985. In particular, the modification of the carbonyl function will lead to the different meanings of R3 and R4.

These compounds exhibit partial agonist or antagonist activity with respect to the expression of one or more biological markers in the embryonic teratocarcinoma cell (F9) differentiation test (Skin Pharmacol 3, p.256267 , 1990) and / or the differentiation of human keratinocytes in vitro (Skin
Pharmacol. P.70-85, 1990) in response to treatment with retinoids. These above-mentioned tests show the activities of the compounds in the fields of differentiation and proliferation. Their activities can also be measured in cell transactivation assays using recombinant RARs or
RXRs previously transfected. (BA Bernard et al., Biochemical and Biophysical
Research Communication 1992, vol. 186, 977-983; MF Boehm et al. Journal of
Medicinal Chemistry, 1994, 37, 408-414).

The subject of the present invention is also, as a medicament, the compounds of formula (I) as described above.

The compounds according to the invention are particularly suitable in the following treatment areas 1) To treat dermatological disorders related to a disorder of keratinization relating to differentiation and proliferation, in particular to treat vulgar, comedonal, polymorphic, rosacea acne, nodulocystic acnes, conglobata, senile acnes, secondary acnes such as solar acne, medicated or professional.

2) To treat other types of keratinization disorders, including ichthyosis, ichthyosiform states, Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplasiform states, cutaneous or mucosal lichen (buccal).

3) To treat other dermatological conditions related to a disorder of keratinization with an inflammatory and / or immunoallergic component and, in particular, all forms of psonasis whether cutaneous, mucous or ungueal, and even psonic rheumatism , or cutaneous atony, such as eczema or respiratory atopy or gingival hypertrophy; the compounds can also be used in certain inflammatory conditions that do not have a keratinization disorder.

4) To treat all dermal or epidermal proliferations, whether they are benign or malignant, whether or not they are viral ongine such as common warts, plane feces and epidermodysplasia veniform, oral or florid papillomatosis and proliferations which can be induced by ultraviolet light especially in the case of baso and squamous epithelioma.

5) To treat other dermatological disorders such as bullous dermatoses and collagen diseases.

6) To treat certain ophthalmological disorders, in particular corneopathies.

7) To repair or fight against skin aging, be it photoinduced or chronological or to reduce pigmentations and actinic keratoses, or any pathologies associated with chronological or actinic aging.

8) To prevent or cure the stigmata of epidermal and / or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy.

9) To prevent or treat healing disorders or to prevent or repair stretch marks.

10) To fight against sebaceous function disorders such as acne hyperseborrhea or simple seborrhea.

11) In the treatment or prevention of cancerous or precancerous conditions.

12) In the treatment of inflammatory conditions such as arthritis.

13) In the treatment of any condition of viral ongine at the cutaneous or general level.

14) In the prevention or treatment of alopecia.

15) In the treatment of dermatological or general affections with immunological component.

16) In the treatment of disorders of the cardiovascular system such as arteriosclerosis.

In the therapeutic areas mentioned above, the compounds according to the invention may be advantageously employed in combination with other retinoids, with RXR receptor ligands, with vitamin D derivatives, with corticosteroids or estrogens, combination with antioxidants, with α-hydroxy or α-keto acids or their derivatives, or with potassium channel blockers.

Among the RXR receptor ligands, mention may be made of 9-cis retinoic acid.

Among the vitamin D or their derivatives, mention may be made of the derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3.

Among the free antiradicals, there may be mentioned a-tocopherol, superoxide
Dismutase, ubiquinol or certain metal chelators.

Among the α-hydroxy or α-keto acids or their derivatives, there may be mentioned lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartic acid, glyceric acid, ascorbic acid or salicylic acid derivatives or their salts, amides or esters.

Among the potassium channel blockers, there may be mentioned Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives.

The subject of the present invention is therefore also a novel medicinal composition intended in particular for the treatment of the abovementioned affections, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one compound of formula (I), one of its isomers. optical or geometric or one of its salts.

The administration of the compounds according to the invention may be carried out enterally, parenterally, topically or ocularly.

Enterally, the drugs can be in the form of compounds, capsules, dragees, syrups, suspensions, solutions, powders. granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles for controlled release. Parenterally, the compositions may be in the form of solutions or suspensions for infusion or injection.

The compounds of the invention are generally administered at a daily dose of about 0.01 mg / kg to 100 mg / kg body weight in 1 to 3 times.

Topically, the pharmaceutical compositions based on compounds according to the invention are intended for the treatment of the skin and the mucous membranes and are in the form of ointments, creams, milks, ointments, powders, soaked swabs, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels allowing controlled release. These compositions topically can be presented in anhydrous form or in aqueous form according to the clinical indication.

Eyes are mainly eye drops.

These compositions for the topical or ocular route contain at least one compound of formula (I) as defined above, one of its optical or geometric isomers or one of its salts, at a concentration of preferably between 0.001 and 5. % relative to the total weight of the composition.

The compounds of formula (I), according to the invention, also find an application in the cosmetic field, in particular in body and hair hygiene and in particular for the treatment of acne-prone skin, for the regrowth of hair, anti-fall, to fight against the greasiness of the skin or the hair, in the protection against the harmful effects of the sun or in the treatment of the physiologically dry skins, to prevent and / or fight against the photo-induced aging or chronological .

In the cosmetic field, the compounds according to the invention can be advantageously used in combination with other retinoids, with the vitamins D or their derivatives, with corticosteroids, in combination with free antiradicals, with α-hydroxy or α-hydroxy derivatives. keto acids or their denvés, or with ion channel blockers. These different products used with the compounds of the present invention being as defined above.

The present invention therefore also relates to a cosmetic composition comprising, in a cosmetically acceptable carrier, at least one compound of formula (I), one of its optical or geometric isomers or one of its salts. This composition may be in particular in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipid or polymeric vesicles, a soap or a shampoo.

The concentration of compound of formula (I) in the cosmetic compositions is between 0.001 and 3% by weight.

The medicinal and cosmetic compositions according to the invention may, in addition, contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and especially wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or urea; antiseborheic or anti-acne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and derivatives, or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, tetracyclines; antifungal agents such as ketoconazole or polymethylen-4,5-isothiazolinones-3; agents that promote hair regrowth, such as Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) ) and phenytoin (5,4-diphenylimidazolidine 2,4-dione) 2,4-dione), non-steroidal anti-inflammatory agents; carotenoids and especially bcarotene; anti-psoriatic agents such as anthralin and its derivatives and finally, eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-trynoic acids, their esters and amides.

The compositions according to the invention may also contain flavor enhancers, preservatives such as parahydroxybenzoic acid esters, stabilizing agents, moisture regulating agents, pH regulating agents, preservatives and the like. osmotic pressure modifiers, emulsifiers, UV-A and UV-B filters, anti-oxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene.

Several examples of the preparation of the active compounds of formula (I) according to the invention, as well as examples of compositions containing them, will now be given by way of illustration and without any limiting nature.

A. EXAMPLES OF COMPOUNDS
All the products whose syntheses are presented below have been characterized by
Proton NMR (250 MHz), mass spectrometry and elemental analysis.

Example 1: 1, 2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran; 50 g (0.267 mmol) of bromoanisole in solution in 120 ml of ethyl ether are treated at 0 ° C. with 200 ml of n-butylithium (1.6 M in hexane), then the medium is left stirring at room temperature during the night. 41.57 g (273 mmol) of (+) Fenchone (Fluka) are then added dropwise in 100 ml of ethyl ether and the mixture is stirred for 6 hours at room temperature. The reaction medium is poured into 200 ml of a saturated solution of ammonium chloride.

After extraction with 600 ml of ethyl ether, rinsing with water, drying over magnesium sulphate, filtration and evaporation, the residue is chromatographed on silica to yield 61.26 g (88%) of the expected intermediate, melting at room temperature. 62-64 "C.

Method A
To a suspension of 55.24 g (0.21 mmol) of this intermediate and 4 g of calcium carbonate in 800 ml of chloroform was added at -10 C, 57.5 g (0.276 mmol) of phosphorus pentachloride.

The reaction mixture is stirred at room temperature for two hours, then potassium carbonate (30 g) is added and filtered. The solid residue was chloroformed and chromatographed on silica in hexane / CH 2 Cl 2 (9: 1) to afford 31.5 g (65%) of the expected derivative melting at 68 ° C.

The same synthesis from (-) fenchone results in the dextrorotatory isomer of 1,2,3,4-tetrahydro-1,4a, 9b-trimethyl-1,4-methano dibenzo furan, mp 68 ° C. .

Method B
To a solution of 55.24 g (0.21 mmol) of this intermediate in 800 ml of dichloromethane is added at 0 C, 28.6 g of zinc chloride.

The reaction mixture is stirred at room temperature overnight and then poured into 500 ml of ice water, and this medium is extracted with 500 ml of ether. After rinsing with water, drying over magnesium sulfate and evaporation, chromatography is isolated. The solid residue is rinsed with chloroform and then chromatographed on silica in hexane / CH 2 Cl 2 (9: 1) to yield 19.8 g (41%) of the expected derivative.

Example 2: 8-Bromo- (1,2,3,4-tert-1,4a, 9b-trimethyl-1,4-methanodibenzofuran) 11.42 g (50 mmol) of (-) (1, 2,3,4 Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran) obtained in Example 1 are dissolved in 110 ml of tetrahydrofuran and are treated dropwise with a solution containing 8.9 g of N
Bromosuccinimide (NBS) in 50 ml of dimethylformamide (DMF). Stirring is allowed to stir at room temperature for 2 h 30 then poured the reaction medium into ice water and extracted with 500 ml of ethyl ether. After rinsing with water, drying over magnesium sulphate, filtration and evaporation, 13.8 g (90%) of the expected derivative melting at 119.8 ° C. are isolated after chromatography on silica in hexane.

Example 3 Methyl [(1,2,3,4-tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) carbonyl] -6-naphthalene-2-carboxelate
To a suspension of 5.22 g (39.1 mmol) of aluminum chloride in 100 ml of anhydrous dichloromethane was added dropwise a solution of 5.96 g (26.1 mmol) of the derivative obtained from Example 2 and 6.49 g (26.1 mmol) of 6-methoxycarbonyl-2-naphthalenecarboxylic acid chloride in 100 ml of dichloromethane. The mixture is stirred for 4 hours at room temperature and then poured into ice water. After decantation, the aqueous phase is extracted with 500 ml of CH 2 Cl 2. The organic phases are rinsed with water, dried over magnesium sulphate and evaporated.

After chromatography on silica in CH 2 Cl 2 / hexane (9: 1), 7.53 g (65%) of the expected derivative melting at 146 ° C. was isolated.

Example 4
AcideF (1,2,4,4-tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) carbonyl-6-naphthalene-2-carboxylic acid.

7.52 g (17 mmol) of the methyl ester obtained in Example 3 in solution in 100 ml of methanol are treated with 8 g of sodium hydroxide and heated at reflux for 3 h. After evaporation, the residue is taken up in the aqueous solution. water and acidified to pH1 with concentrated hydrochloric acid. The precipitate is filtered, rinsed with water and then methanol recreated to yield 5.16 g (82%) of the expected denume melting at 269.7 ° C.

Example 5
[(1,2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) methyl-6-naphthalene-2-carboxylic acid, 0.5 g (1.17 mmol) of The acid obtained in Example 4 are placed in 50 ml of palladium (10%) on charcoal under a pressure of 7 bar of hydrogen for 24 hours. The reaction medium is filtered on celite and then evaporated. The residue is chromatographed on silica in CH2Cl2 / ethyl ether (9: 1) to give 110 mg (23%) of the expected derivative melting at 214-216 ° C.

Example 6 Methyl [(1,2,3,4-tetrahydro-1,4-a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) methanol] -6-naphthalene-2-carboxylate 944 mg (2.14 mmol) of the ester obtained in Example 3 dissolved in 30 ml of a methanol / tetrahydrofuran (1: 1) mixture are treated with 81 mg of sodium borohydride. The reaction medium is stirred for 5 hours at room temperature. It is evaporated to dryness, taken up in ether and this phase is washed to neutral pH. After drying and evaporation, 905 mg (96%) of the expected derivative melting at 140 ° -141 ° C. is isolated.

Example 7
[(1,2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) methanol] 6-naphthalene-2-carboxylic acid.

898 mg (2.03 mmol) of the ester obtained in Example 6 in 25 ml of methanol are treated with 2 g of sodium hydroxide. The reaction medium is stirred for 48 hours. The reaction medium is poured into ice water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated to yield 951 mg (92%) of the expected derivative, m.p. 146-148 ° C.

Example 8 Methyl 4-1 (1,2,4,4-tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) carbonyl benzoate
To a solution consisting of 6.76 g (29.6 mmol) of (+) THTMDBF and 5.72 g (28.8 mmol) of methyl monoterephthalate acid chloride in 130 ml of CH 2 Cl 2 was added dropwise. drop 5.92 g (44 mmol) of aluminum chloride and stir at room temperature overnight.

After the same treatment as in Example 13a, followed by chromatography on silica in the CH 2 Cl 2 / hexane (60:40) eluent mixture, 4.47 g (40%) of the expected denume melting at 150 ° C. are isolated. "C.

Example 9
4-1 (1,2,4,4-tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) carbonylbenzoic acid 2.52 g (6.44 mmol) of the ester obtained at 1 Example 8 in solution in 30 ml of methanol are treated with 2.5 g of sodium hydroxide and refluxed for 3 hours. After the same treatment as in Example 7, followed by recrystallization from hexane, 2.35 g (97%) of the expected product, m.p. 262-264 ° C, are isolated.

Example 10: 4-1 (1,3S4-tetrahedro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) hydroxymethyl] phenylarbinol
To a suspension of 1.14 g of lithium aluminum hydride in 10 ml of tetrahydrofuran, a solution of 3.76 g (10 mmol) of the acid obtained in Example 9 and stirring is added dropwise. hours at room temperature. The reaction medium is neutralized at 0 ° C. by the addition of a saturated solution of ammonium chloride dropwise. The precipitate is filtered, washed with hexane and dried to yield 3.13 g (86%) of the expected derivative, mp 113 ° -115 ° C.

Example 11: 4-1 (1,2,3,4-tetrahedro-1,4a, Sb-methylmethyl-1,4-methanodibenzofuran-8-yl) carbonyl phenylcarboxaldehyde 3.1 g (8.5 mmol) of the diol obtained from Example 10 in solution in 60 ml of CH2Cl2 are treated with 5.5 g of pyridinium chlorochromate. The reaction is stirred at room temperature for 3 hours. The reaction medium is then filtered on celite. The organic phase is washed with a saturated solution of ammonium chloride, rinsed with water, dried and evaporated to yield, after chromatography on silica, in the eluent mixture CH 2 Cl 2 / hexane (9: 1) at 2 g (66% ) of the expected derivative melting at 138-142 ° C.

Example 12: 2- (1, 2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8vl), 2- (4-methoxycarbonylphenyl) -1,3-dioxolan 2g (5.12mmol) ) of the ketone obtained in Example 8 in 20 ml of benzene are treated with 0.5 ml of ethylene glycol and 10 mg of TSOH. The reaction medium is refluxed for 24 hours and then neutralized with a saturated solution of sodium bicarbonate. After extraction with ethyl ether, the organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated to yield, after chromatography on silica in Hexane / AcoEt (90:10), and slurry in hexane, 910 mg (41%) of the expected derivative melting at 136-137 ° C.

Example 13: 2- (1,2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl), 2- (4-carboxyphenyl) -1,3-dioxolan 0.87 g (2 mmol) of the methyl ester obtained in Example 12 are saponified under the conditions described in Example 4. After the same treatment and recrystallization in the diisopropyl ester, 0.62 g (74%) of the expected follow-up melting at 234 236 ° C.

B. EXAMPLES OF FORMULATION 1) ORAL PATH
Example 14
The following composition is prepared in the form of a 0.8 g tablet
Composed of Example 4 ... 0.005g
Pregelatinized starch ... 0.265 g
Microcrystalline cellulose. . 0.300 g
Lactose ... 0.200 g
Magnesium stearate. . 0.030 g
For the treatment of acne, an adult individual is administered 1 to 3 tablets per day for 3 to 6 months depending on the severity of the case treated.

Example 15
An oral suspension is prepared to be packaged in ampoules of 5 ml
Compound of Example 4. 0.050 g
Glycerin ... 0.500 g Sorbitol 70%. - 500 g
Saccharin sodium . 0.010 g
Methyl parahydroxybenzoate ... 0.040 g
Aroma qs

Purified water qs. 5 ml
For the treatment of acne, an adult is administered 1 ampoule per day for 3 months depending on the severity of the case treated.

Example 16
The following formulation is prepared to be packaged in capsules
Composed of example 4.. 0.025 g
Corn starch. . 0.060 g
Lactose qs. .0,300 g
The capsules used consist of gelatin, titanium oxide and a preservative.

In the treatment of psoriasis, 1 adult capsule is administered daily for 30 days.

2) TOPICAL ROAD
Example 17
The water-in the following non-ionic oil cream is prepared
Composed of Example 4. .0,100 g
Mix of emulsified lanolin alcohols, waxes and oils
refined, sold by BDF under the name
"Eucerine anhydrous". .39.900 g
Methyl parahydroxybenzoate .0.075 g
Propyl parahydroxybenzoate ... .0,075 g
Sterile demineralized water qsp. .100,000 g
This cream is applied to a psoriatic skin 1 to 2 times a day for 30 days.

Example 18
A gel is prepared by carrying out the following formulation:
Composed of example 4. .0050 g
Erythromycin base .. .4,000 g
Butylhydroxytoluene. . .0,050 g
Hydroxypropylcellulose sold by the
Hercules company under the name "KLUCEL HF". .2,000 g
Ethanol (at 95) qs 100,000 g
This gel is applied to skin with dermatosis or acne skin 1 to 3 times a day for 6 to 12 weeks depending on the severity of the case treated.

Example 19
An antiseborrhoeic lotion is prepared by mixing the following ingredients
Composed of Example 4. .0,030 g
Propylene glycol. .5,000 g
Butylated hydroxytoluene .0,100 g
Ethanol (at 95) qs. 100,000 g
This lotion is applied twice a day to a scalp and there is a significant improvement in a period of between 2 and 6 weeks.

EXAMPLE 20
A cosmetic composition is prepared against the harmful effects of the sun by mixing the following ingredients
Compound of Example 5 .. .1,000 g
Benzylidene camphor .. .4,000 g
Triglycerides of fatty acids. .31,000 g
Glycerol monostearate. .6,000 g
Stearic acid. .2,000 g
Ethyl alcohol. .1,200 g
Lanolin .. .4,000 g
Preservatives .0,300 g
Propylene glycol .. .2,000 g
Triethanolamine .. .0,500 g
Perfume .. .0.400 g
Demineralized water qs 100.000 g
This composition is applied daily, it helps fight against photoinduced aging.

Example 21
The cream oil in the following nonionic water is prepared
Composed of Example 5. .0,500 g
Vitamin D3 .. .0,020 g
Cetyl alcohol. .4,000 g
Glycerol monostearate. .2,500 g
PEG 50 Stearate .2,500 g
Shea Butter. .9,200 g
Propylene glycol. .2,000 g
Methyl parahydroxybenzoate. .0,075 g
Propyl parahydroxybenzoate ... .0,075 g
Sterile demineralized water qs 100,000
This cream is applied to psoriatic skin 1 to 2 times daily for 30 days.
Days.

EXAMPLE 22
A topical gel is prepared by mixing the following ingredients:
Compound of Example 13 .. .0,050 g
Ethanol .. .43,000 g
a-tocopherol .0,050 g
Carboxyvinyl polymer sold under the name
"Carbopol 941" by the company "Goodrich" .0,500 g
Triethanolamine in aqueous solution at 20% by weight .. 3,800 g
Water 9,300 g
Propylene glycol qsp. 100,000 g
This gel is applied in the treatment of acne 1 to 3 times a day for 6 to 12 weeks depending on the severity of the case treated.

Example 23
An anti-hair loss hair lotion is prepared for hair regrowth by mixing the following ingredients
Compound of Example 13. .0.05 g
Compound sold under the name "Minoxidil" .1 g
Propylene glycol. . 20.009
Ethanol. 34.92 g
Polyethylene glycol (molecular weight = 400) ..40.00 g
Butylhydroxyanisole. 0.01 g
Butylhydroxytoluene. .0.02 g
Water qs. 100.00 g
This lotion is applied twice a day for 3 months on a scalp that has suffered a significant hair loss.

Example 24:
An anti-acne cream is prepared by mixing the following ingredients
Compound of Example 6 .. 0.050 g
Retinoic acid .. 0.010 g
Mixture of glycerol stearates and polyethylene glycol
(75 moles) sold under the name "Gelot 64" by the company
"Gattefosse". 15,000 g
Polyoxyethylenated core oil with 6 moles of oxide. ethylene
sold under the name "Labrafil M2130 CS" by the company
"Gattefosse". 8,000 g
Perhydrosqualene 10,000 g
Conservatives .. qs
Polyethylene glycol (molecular weight = 400) .. 8.000 g
Disodium salt of ethylene-diamine tetracetic acid. 0.050 g
Punished water qs. 100.009
This cream is applied to skin with dermatosis or acne skin 1 to 3 times a day for 6 to 12 weeks.

Example 25
An oil cream is prepared in water by carrying out the following formulation
Compound of Example 7 .. 0.020 g
Betamethasone 17-valerate 0.050 g
S-carboxymethyl cysteine. 3.000 g
Polyoxyethylene stearate (40 moles of ethylene oxide)
sold under the name "Myrj 52" by the company "ATLAS" 4.000 9
Sorbitan monolaurate, polyoxyethylene 20 moles oxide
ethylene sold under the name "Tween 20" by the company
"ATLAS" 1,800 g
Mixture of mono- and distearate of glycerol sold under the
denomination of "Géléol" by the company "GATTEFOSSE" 4,200 g
Propylene glycol .. 10,000 g
Butylhydroxyanisole. 0.010 g
Butylhydroxytoluene .. 0.020 g
Cetostearyl alcohol. 6.200 g
Conservatives .. qs

Perhydrosqualene 18,000 g
Mixture of caprylic-capric triglycerides sold under
denomination of "Miglyol 812" by the company "DYNAMIT NOBEL" 4,000 g
Triethanolamine (99% by weight) .. 2,500 g
Water qs. 100.009
This cream is applied twice a day on skin with dermatosis for 30 days.

Example 26:
The oil cream is prepared in the following water:
Lactic acid .. 5,000 g
Compound of Example 12. 0.020 g
Polyoxyethylene stearate (40 moles of ethylene oxide)
sold under the name "Myri 52" by the company "ATLAS" 4,000 g
Sorbitan monolaurate, polyoxyethylene 20 moles oxide
ethylene sold under the name Tween 20 "by the company
"ATLAS" 1,800 g
Mixture of mono- and distearate of glycerol sold under the
denomination of "Geleol" by the company "GATTEFOSSE" 4,200 g
Propylene glycol. 10,000 g
Butylhydroxyanisole. 0.010 g
Butylhydroxytoluene. 0.020 g
Cetostearyl alcohol. 6.200 g
Conservatives qs

Perhydrosqualene 18,0009
Caprylic triglyceride mixture - capnque sold under
the denomination of "Miglyol 812". by the company "DYNAMIT
NOBEL "4.000 g
Water qs. 100.009
This cream is applied once a day, it helps fight against aging whether photoinduced or chronological.

Claims (18)

1-Compounds, characterized in that they have the following formula (I)

 in which: R represents a hydrogen atom, an atom of halogen, a lower radical, a lower acyl radical, a radical OR '. R 'having the meaning given below, * A represents a radical chosen from the radicals of formulas (lla-llc) below

 formulas in which - R, represents: (i) a hydrogen atom,  (ii) the radical -CH3,  (iii) the radical -CH 2 -O-R 5,  (iv) a radical -ORs (v) a radical

 (vi) a radical -S (O) t R6  t, R5 and R6 having the meanings given below, - R2 represents a hydrogen atom or the radical -OR5  R5 having the meaning given below, - or R3 and R4 independently represent a hydrogen atom, a lower alkyl radical or the radical - (X) n - (CH2) m - R7,  X and R7 having the meanings given below,  or R3 and R4, together they form a group oxo (= O), thiocetone (= S), oxime or a derivative of the oxime (R6-ON =), epoxy, cycloalkyl optionally substituted by a halogen atom or a lower alkyl radical. or else a dioxolane group [-O CH2) qO-] with q equal to 2 or 3, R6 having the meaning given below, - R3, and R4 'independently represent a hydrogen atom, a lower alkyl radical, a lower acyl radical, it being understood that in all of the above: t is equal to 0.1 or 2,  R5 representing a hydrogen atom, a lower alkyl radical, or a lower acyl radical  R6 represents: a hydrogen atom,  a radical -N (R ", R" '), R "and R"' having the meanings  given below,  a radical -O R8, R8 having the meaning given below.  R7 represents a hydrogen atom, a radical (CO) p.Rg in which p may have the value 0 or 1, Rg having the meaning given below,  R8 and R 'independently represent a hydrogen atom, an alkyl radical having 1 to 20 carbon atoms, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical, optionally substituted aralkyl. a sugar residue or an amino acid residue,  Rg represents: a hydrogen atom,  an alkyl radical,  an alkenyl radical,  an alceynyl radical,  an aryl radical,  a radical -OR7 - in this case, m can not take the value O, R7  having the meaning indicated above.  a radical -N (R ", R" '), R "and R"' having the meanings given herein  after,  R "and R" ', which may be identical or different, represent a hydrogen atom, a lower alkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical, an optionally substituted aralkyl radical, an amino acid or peptide or sugar or R "and R" 'taken together form a heterocycle,  X is an oxygen or sulfur atom,  n ranges from 0 to 1 and m from 0 to 10, and the optical and geometric isomers of said compounds of formula (I), as well as their salts in the case where R1 or Rg represents an acid function, or when R9 represents a function amine. 2- Compounds according to claim 1, characterized in that they are in the form of salts by addition of a base or an acid. 3- compounds according to one of the preceding claims, characterized in that the lower alkyl radical is selected from the group consisting of methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl. 4. Compounds according to one of the preceding claims, characterized in that the lower acyl radical is chosen from the group consisting of acetyl, propionyl and pivaloyl radicals. 5. Compounds according to one of the preceding claims, characterized in that the monohydroxyalkyl radical is chosen from the group consisting of 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radicals. 6. Compounds according to one of the preceding claims. characterized in that the polyhydroxyalkyl radical is selected from the group consisting of 2,3dihydroxypropyl, 2,3,4-trihydroxybutyl radicals. 2,3,4,5-tetrahydroxypentyl or the remainder of pentaerythritol. 7- Compounds according to one of the preceding claims, characterized in that the aryl radical is a phenyl radical optionally substituted by one or more halogen atoms, a hydroxyl function, nitro or a methoxy group. 8- Compounds according to one of the preceding claims, characterized in that aralkyl radical is benzyl or phenethyl, optionally substituted with one or more halogen atoms, a hydroxyl or nitro function, or a methoxy group. 9- Compounds according to one of the preceding claims, characterized in that the sugar residue is a residue derived from glucose, galactose, mannose or glucuronic acid. 10- Compounds according to one of the preceding claims, characterized in that 'heterocycle is a piperidino radical, morpholino, pyrrolidino or piperazino, optionally substituted in the 4-position by a C1-C6 alkyl radical or mono- or polyhydroxyalkyl as defined herein. -above. 11- Compounds according to any one of the preceding claims, characterized in that they are chosen from the group consisting of: [(1, 2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran Methyl 8-yl) carbonyl] -naphthalene-2-carboxylate [(1, 2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) carbonyl] 6-naphthalene-2-carboxylic acid [(1,2,3,4-Tetrahydro-1,4a, 9b-trimethyl-4-methanodibenzofuran-8-yl) methyl] -6-naphthalene-2-carboxylic acid [1,2,3,4-Tetrahydro] Methyl 1,4a, 9b-methyl-1,4-methanodibenzofuran-8-yl) hydroxymethyl] -6-naphthalene-2-carboxylate [(1,2,3,4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) hydroxymethyl] -6-naphthalene-2-carboxylic acid 4 - [(1,2,3) Methyl 4-Tetrahydro-1,4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) carbonyl] benzoate 4 - [(1,2,4,4-Tetrahydro-1, 4a, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) carbonyl] benzoic acid 4 - [(1,2,3,4-Tetrahydro) 1,4-, 9b-trimethyl-1,4-methanodibenzofuran-8-yl) hydroxymethyl] phenylcarbinol 4 - [(1,2,4,4-tetrahydro-1,4a), 9b-trimethyl-1,4-methanodibenzofuran); 2- (1,2,3,4-Tetrahydro-1,4a, 9b-methylmethyl-1,4-methanodibenzofuran-8-yl) -2- (4-methoxycarbonylphenyl) -1- (4-yl) carbonyl] phenylcarboxaldehyde, 3-dioxolane 2- (1,2,3,4-Tetrahydro-1,4a, 9b-methyl-1,4-methanodibenzofuran-8-yl) -2- (4-carboxyphenyl) -1,3-dioxolane 12- Compounds according to Claim 1, characterized in that they correspond to the general formula (I), in which A represents the radical of formula (lob). 13- Compounds according to the preceding claim, characterized in that Rt represents the radical

 14- Medicinal product, characterized in that it consists of one of the compounds defined according to any one of the preceding claims. 15- Pharmaceutical composition, characterized in that it contains in a suitable vehicle, for enteral, parenteral, topical or ocular administration, at least one compound of formula (I) according to any one of claims 1 to 13 . 16. Composition according to claim 15, characterized in that it contains from 0.001 to about 5% by weight of a compound of formula (I). 17- Use of a compound according to any one of claims 1 to 13 for the preparation of a pharmaceutical composition for the treatment of dermatological, rheumatic, respiratory and ophthalmological conditions. 18- Cosmetic composition for body and hair hygiene, characterized in that it contains, in an appropriate cosmetic vehicle. at least one compound of formula (I) according to any one of claims 1 to 13. 19- Cosmetic composition according to claim 18, characterized in that it contains the compound of formula (I) at a concentration of between 0.001 and 3% by weight.