LU85700A1 - New alkenyl substd. benzo:norbornene derivs. and keto intermediates - with vitamin=A activity, useful in pharmaceutical and cosmetic formulation e.g. for treating disease of keratinisation (BE 5.3.86) - Google Patents

Abstract

Benzonorbornene derivs. of formula (I), their isomers and salts are new: R1, R3 and R4 = H, 1-8C alkyl, alkoxy or acyloxy, halo or OH; R' = H or 1-6C alkyl; R" is (II) or (III); A2 = CH2OR6 or COR7; R6 = H or 1-6C alkyl; R7 = H, 1-6C alkoxy, aryloxy, benzyloxy, sugar residue, opt. substd. amino, 1-6C alkyl or OH, and the corresp. carboxylic acid salts; A3 is as A2 or also H, 1-6C alkyl, SR5, SOR5 or SO2R5; R5 = 1-6C alkyl. Proviso: where R' = H or Me; R1 and R4 = H and R3 = H or Me, then R" cannot be 4-(COR7)-phenyl; R7 = OH, alkoxy, aryloxy or NR10R11; R10 = alkyl, opt. substd. by OH; R11 = H or as R10. Also new are intermediates (VII); (R gps. are as defined for (I) but R' is not H or Me if R1 and R4 = H and R3 = H or Me).

Description

NOVEL BENZONORBORNENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND DRUG AND COSMETIC COMPOSITIONS CONTAINING THEM.

The invention relates to new chemical compounds V 5 consisting of benzonorbornenes substituted on the benzene ring, as well as, on the one hand, the preparation process making it possible to obtain these new compounds and, on the other hand, the use of these new compounds in cosmetic compositions or in pharmaceutical preparations for the treatment of dermatological or other ailments, linked to a disorder of keratinization (differentiation-proliferation), for the treatment of dermatological affections with an inflammatory and / or immuno-allergic component , as well as for the treatment of cutaneous atopy or respiratory atopy.

The therapeutic action of vitamin A in its acid, aldehyde or alcohol form is well known in dermatology (see - in this regard the publication "EXPER1ENTIA, volume 34 pages 1105 - 1119 (1978)); this action in the treatment of proliferative -rj 20 skin conditions, acne, psoriasis and the like will be referred to hereinafter by the generic term "retinoic action". It has been found that products having a structure analogous to vitamin A also have an action retinoic, but that the side effect of toxic hypervitami-25 nose could, for certain compounds, be multiplied by a factor smaller than the multiplicative factor of the retinoic effect sought (see in this regard "EUR. J. MED.

CHEM.-CHIMICA THERAPEUTICA, January-February 1980, 15, n ° 1, pages 9 - 15); thus, French patent applications 2,422,620 and 2,529,458 describe new derivatives of stilbene and methylstyryl-naphthalene comprising, on the nucleus where an unsaturated substitutive chain is grafted, a number of methyl groups, because it It appeared from the studies carried out that the multiplication of methyl groups seemed to improve the therapeutic efficacy (see publication / y '2 "EUR. J. MED. CHEM, cited above).

Benzonorbornene and some of its derivatives were already known (see in this regard J. ORG. CHEM., 32, pages 893 - 901 (1967) and J. AM. CHEM. SOC., 87: 21, pages 4794 - 4804 5 (1965)), but it has never been demonstrated that these benzonorbornene derivatives can have retinoic action. It was then indicated that certain derivatives of norborenene had a retinoic activity (see in this regard the publication J. MED. CHEM. 1980, 23, pages 1013-1022 and 1981, 10 24, pages 1214-1223). However, in the search for improvement in therapeutic efficacy, those skilled in the art, knowing that it was necessary to increase the methyl substitutions on this nucleus, were led to deviate from the benzonorbornene derivatives. Now, it has been found, according to the invention, that, surprisingly, certain derivatives of benzonorbornene have a particularly interesting retinoic action.

The subject of the invention is therefore the new industrial product which constitutes a new chemical compound derived from benzonorborene corresponding to the general formula (I): ΰ 20

ï | h1 Y

25 | \ H2 «<I> | tah * '4 30 formula in which: - R1, R3 and R4 represent, independently of one another, a hydrogen atom, a C1-C8 alkyl radical, a radical C1-C6 alkoxy, a halogen atom, a C- | -Cg acyloxy radical or a hydroxyl radical; _ R 'represents a hydrogen atom or an alkyl radical 3 Cη “C5, with the proviso that R' cannot represent CH3 when the three substituents R η 7 R3, R4 represent a hydrogen atom; - R "represents an unsaturated group which is ç. 1) or else a polyene chain of formula (II): I FH3; 'lC X | (11)

10 a.m.

in which the group A2 represents a group in which R5 is a hydrogen atom or an alkyl radical

Ci-C5 or a COR7 group, in which R7 is a hydrogen atom, a Cj-Cg alkoxy radical, aryloxy, benzyloxy, a sugar residue, an amino radical, a Cj-Cg alkyl radical or else a hydroxyl radical; 2) or a benzene nucleus of formula (III) 20

i h

(III) 25 & in which A3 can take all the meanings previously given for A2 and, in addition, can represent a hydrogen atom, a C1-C5 alkyl radical, an alkylthio-SR5 group, alkylsulfinyl - S-R5 or alkylsulfonyl -SO2R5, where

AT

0 R5 represents an alkyl radical C-j - C5- * "r 4 The invention also relates to the salts and isomers of the compound of formula (I).

^ When the substituent A2 or A3 represents a CORy group and Rj is an alkoxy radical Cγ-C5, it is preferred • 5 that R7 is an ORq radical, R8 being chosen from the group formed by methyl, ethyl, propyl, butyl, hexyl and C1-C4 alkyl radicals substituted by one or more hydroxyl, such as 2-hydroxyethyl, 2-hydroxypropyl or di-hydroxypropyl isomers such as dihy -10 droxy-2,3 propyl and (dihydroxy-1,3) propyl-2.

When the substituent A2 or A3 represents a COR7 group and R7 is a hydroxyl, this carboxyl group can advantageously be salified with a strong base, such as sodium hydroxide or potassium hydroxide, or with an amine compatible with the skin, such as than triethanolamine.

When the substituent A2 or A3 is a COR7 group and R7 is an aryloxy, the aryl radical of R7 may advantageously correspond to the formula (IV): γ -> <-

If (IV) 25 r9 30 formula in which Rg and R13 represent, independently of one another, a hydrogen atom, a C1-C4 alkyl radical, a hydroxyl, a halogen atom, a carbon group xyl or a trifluoromethyl group.

s.

5

When the substituent A ^ or A ^ is a group COR ^ and that R ^ is a benzyloxy, the benzyl radical of R ^ may advantageously correspond to formula (V): 5 - * "9 ^ formula in which Rg and R ^ have the same meanings as in formula (IV).

When the substituent A2 or A ^ is a group COR ^ and that is a sugar residue, COR ^ comes, advantageously, from a glucose ester, a mannitol ester or a pentaerythritol ester.

When the substituent A0 or A-, is a group-

15, d J

CORy ment and that R ^ represents an amino of formula NR ^ qR ^, R 0 and R ^ can advantageously represent, independently of one another, a hydrogen atom, an alkyl radical C ^ -C ^, linear or branched, substituted or not By one or more hydroxyl, ---- or, taken together, form a heterocycle substituted or not, one of the two radicals R- | o or ^ 11 can also be, when the another is a hydrogen atom, an aryl radical of formula (IV) or a benzyl radical of formula (V), formulas in which Rg 25 and R η 3 have the meanings indicated above. NR-igR-pl can also correspond to the amine function of an amino acid or to the amine function of a glucosamine.

When R "is a polyene chain of formula (II), if 2 is numbered the carbon carrying the substituent A2, 3 the carbon carrying the methyl substituent and A the subsequent carbon adjacent to the latter on the chain, the structures at the level carbons 2 and A can be 2-E, AE or 2-Z, AZ or 2-E, AZ or even 2-Z, AE. In general, the compounds of formula (I) according to the invention can be of struc -35 ture trans (structure E) or of structure cis ----------------- 6 (structure Z); the invention relates to all of the isomers as well as to the isomers It should also be noted that when these products are exposed to light, there can be a transformation of one type of iso-5 mother into another type.

â ’The subject of the invention is also two methods for preparing the new compounds of formula (I). In all cases, these preparation processes use, as starting compounds, a substituted 2-acyl benzonorbornene of formula: 10 R1 R 'AJLJL (vii) 15 Ri * The invention also relates to the new industrial product which constitutes a compound corresponding to the formula (VII) above mentioned formula in which R ^, R ^, and R 'have the meanings previously indicated.

This compound of formula (VII) can be obtained in different ways depending on the nature of the substituents, as will be indicated below.

According to the first process of the invention, the compound of formula (VII) is reacted directly with a dialkyl phosphonate of formula; R12 ° \ jj P — CH2 — R "R12 ° (VIII) formula in which R ^ represents an alkyl radical 2 ° C -C, or with a triphenylphosphonium salt of formula (IX): 1 6 (Ο, ίΟ-ρΦ— CH0-R "XÔ (IX) o 5 3 2 R" having, in these two formulas, the meanings previously indicated, X ® designating a halide.

-ï 35 7

According to the second method of the invention, in a first step, the compound of formula (VII) y is obtained and, in a second step, it is reduced by sodium borohydride to a secondary alcohol of formula:, τΆλ - In a third step, the compound of formu-15 (X) is transformed by the action of phosphorus tribromide into a bromide of formula; R1 R '20 (<XI> in a fourth step, action is taken on the compound of 2 ^ formula (XI), triphenylphosphine to obtain the triphenylphosphonium bromide of formula *.

R-, R 'ΓΓΥίΤ "P® (C6H513 (Rr @ (XII) 30 \ R4 in a fifth step, the compound of formula-XII (XII) is reacted on an aldehyde R" -CH0 to obtain the compound of formula (I), R ', R ", R ^, R ^ and R ^ having in these formulas the meanings previously indicated.

It should be noted that the two access routes to the product of formula (I) which constitute the two preparation processes mentioned above, are not equivalent and must be chosen according to the nature of the substituents. .

• To obtain the compounds of formula (VII) which serve as starting material in the two preparation methods according to the invention, it is possible, in a first variant, to prepare, in a first stage, a substituted benzonorbornene of formula (VI):

(your

15 / (VI) K4 20 formula in which R ^ and R ^ have the meanings previously indicated; in a second stage, the compound of formula (VI) is acylated with an acyl chloride R'COCl, in the presence of aluminum chloride, to obtain the substituted 2-acyl benzonorbornene of formula (VII), R 'having the 25 meanings previously indicated.

According to another variant, in a first stage, acylation is carried out with a chloride or an anhydride of acid showing the group R '-CO- on the nucleus of benzonorbornene, then, in a second stage, it is fixed on the compound obtained the substituents R ^, R ^ and R ^, R ', R ^, R ^ and R ^ having the meanings previously indicated.

The choice between the two aforementioned variants for obtaining the compound of formula (VII) is made according to the nature of the substituents.

According to a third variant, which can also be used when the nature of the substituents allows, the compound of formula (VII) is obtained by carrying out, in a first stage, the cyclo-addition of a substituted benzyne of formula (XXV ): 5 (XXV) 10 with cyclopentadiene, R ^ having the meanings previously indicated; in a second stage, the substituted benzonorbornadiene of formula (XXIII): 15 riyv "3 \ (XXIII)

vV

thus obtained is reduced to substituted benzonorbornene of formula (XXIV): tfYY3 25 ((XXIV) "· in a third stage, the compound of formula 2Q (XXIV) is acylated with an acyl chloride R'COCl, in the presence of chloride aluminum, to obtain the compound of formula (VII), R 'having the meanings previously indicated.

By way of nonlimiting examples of the methods of obtaining defined above, the access routes corresponding to certain compounds of formula (VII) will be indicated below in a more precise manner.

'10

First example of access to the compounds of formula (VII):

Synthesis of the compounds of formula (VII) for which - R1 = - H? R3 = C- | -Cg alkyl; and R '= alkyl

The unsubstituted acyl-2 5 5 benzonorbornene of formula (XIV) is used as starting material: formula R ”'/ ry \\ / (XIV) 10 formula in which R"' is defined by the fact that 15 R3 = R ” '-CH ^; the compound of formula (XIV) in which R'1' = CH3 is described in Luxembourg patent application No. 85,531 filed on September 5, 1984. The compound of formula (XIV) is subjected to a Wolff-Kishner reduction to obtain the 2-alkylbenzonorbornene of formula (XV): 20 R '"((XV) MA / 25

The compound of formula (XV) is then acylated by Friedel and Craft reaction with an acyl chloride R'COCl, in the presence of aluminum chloride, to obtain 2-acyl-3-alkyl benzonorbornene of formula (XVI) : 30 ?'

r7YVX

/ (XVI) 35.> * 11

Second example of access to the compounds of formula (VII):

Synthesis of the compounds of formula (VII) for which R .J and / or R ^ = Br; r3 - Ο alkyl, -Cgou H; and R '= C | -Cg alkyl.

The compounds of formulas (XVI) or (XIV) previously used are used and are treated directly with one or two equivalents of bromine in the presence of aluminum bromide; "Thus obtaining 2-acyl benzonorbornene mono or dibromo, * optionally alkylated in 3, of formula (XVII): 10 R1 R’ rfVVS "((XVII)

"AT

Third example of access to the compounds of formula (VII):

Synthesis of the compounds of formula (VII) for which = R ^ = C ^ -Cg alkoxy and R ^ = H or C ^ -Cg alkyl.

Dihydroxy-1, A benzonorbornene of formula (XIX) is used as starting material:

OH

fîrS

25 / (XIX) 30 This commercial product is subjected, in basic medium, to an alkylation by an alkyl halide R '”X, where X is a halogen atom and R' '' is defined by the fact that R ^ = R ^ = OR "'. This gives a 1-dialcoxy, A benzonorbornene of formula (XX): 35 - Ή r 12 OR" "" 5 ((XX) OR "' • The compound of formula (XX) is then acylated with an acyl chloride R'COCl in the presence of aluminum chloride in order to obtain a 2-acyl-1,4-dialkoxy benzonorbornene of formula (XVIII) "ÎîyV ^ A (XVIII) R4 formula where R 'a the meanings indicated for formula (I), this compound being the compound of formula (VII) desired.

For further information, it may be mentioned that the compound of formula (XVIII) can be used to obtain compounds of formula (I) by condensing it directly with compounds of formula (VIII) or '(IX), c that is to say by implementing the first preparation process according to the invention.

30 Fourth example of access to the compounds of formula (VII):

Synthesis of the compounds of formula (VII) for which R ^ = R ^ = alkoxy C ^ -Cg and R ^ = alkyl C ^ -Cg.

The compound of formula (XVIII) is used as starting material. The acyl group of the compound of formula 35 (XVIII) is reduced to the corresponding alkyl group to obtain the compound of formula (XXVI): // L ·. / 13 ϊ ΐ ίΤΥτ ^ Η "{(XXVI) 5 s Trisubstituted benzonorbornene of formal (XXVI)" is acylated with an acyl chloride R'COCI, in the presence of aluminum chloride, to obtain a 2-acyl 3-alkyl-1,4-dialkoxy-benzonorbornene of formula (VII), R 'being defined by the fact that R3 = CH2R'.

According to the invention, it has been found that the compounds of formula (I) have a retinoic action and are particularly suitable for treating dermatological or other conditions, linked to a disorder of keratinization (differentiation-proliferation) as well as dermatological conditions. with inflammatory and / or immuno-allergic components, in particular for treating vulgar, comedonian or poly-morphic acne, solar senile acne, medicinal or professional acne, extensive and / or severe forms of psoriasis and the others keratinization disorders, in particular ichthyosis and ichyosiform states, Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplasiform states, lichen planus, as well as all benign or malignant dermatological proliferations, severe or extensive; they are also active for certain rheumatic affections, in particular psoriatic arthritis; they can also be used in the treatment of cutaneous and respiratory atopy. Accordingly, the invention also relates to drug compositions containing the compounds of formula (I).

The present invention therefore also relates to a new medicinal composition, intended in particular for the treatment of the abovementioned conditions, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one compound of formula (I).

14

Good activity of the compounds of formula (.1) is observed over a very wide dilution range; it is possible in particular to use concentrations of active compound (s) ranging from 0.0005% to 2% by weight. It is, of course, possible to use higher concentrations, when this is necessary for a particular therapeutic application; however, the preferred concentrations of active ingredient are between 0.01 and 1% by weight.

When the compounds according to the invention are used by topical administration, they are advantageously in the form of ointments, ointments, tinctures, creams, emulsions, solutions, lotions, sprays, gels, suspensions, powders, stamps 15 or soaked pads. The compounds according to the invention are mixed with inert non-toxic supports, generally liquid or pasty, suitable for topical treatment. It is advantageous to use solutions containing approximately 0.001% - 0.3% by weight of active substance (s), or creams containing approximately 0.002% -0.5% of active substance (s).

The compounds of formula (I) can be used enterally. By the oral route, the compounds of formula (I) are administered at a rate of approximately 2 / g up to 2 mg per day and per kg of body weight; an excessive dosage can manifest itself in the form of a hypervitaminosis A recognizable by its symptoms and which can give rise to fear of hepatic toxicity requiring a biological control of the hepatic function. The required dose can be administered in one or more doses. For oral administration, suitable forms are, for example, tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions; a preferred mode of administration is the use of capsules containing from 0.1 mg to about 1 mg of active substance (s).

15

The compounds of formula (I) can also be administered parenterally in the form of solutions or suspensions for intravenous or intramuscular infusions or injections. In this case, the compounds of formula (I) are advantageously admitted at the rate of approximately 2 ^ g up to 2 mg per day per kg of body weight; in general, parenteral administration is carried out at a rate of 0.01 mg to 1 mg of active substance (s) per ml.

10 ------------------------------------------------- ---------

The pharmaceutically acceptable carrier may, depending on the forms used, contain, for example, water, gelatin, lactose, starch, talc, petroleum jelly, gum arabic, polyalkylene glycols, magnesium stearate. Tablets, powders, granules, dragees or 6 capsules can contain binders, fillers, powdery supports; solutions or suspensions may contain thinners, solvents, thickeners.

In the treatment of keratinization disorders, the compounds of formula (I) used in the medicinal compositions according to the invention act by increasing the follicular epithelial production of nonadherent cells, thus dislodging and causing the content of the acne comedone to disappear. These compounds reduce the size of the sebaceous glands and partially inhibit the secretion of this sebum.

The compounds of formula (I) according to the invention also find application in the cosmetic field, in particular in body and hair hygiene and, in particular, for acne, for hair regrowth, for combating hair loss. hair, to fight against the oily appearance of the skin or hair ^ for 16: protection against the harmful effects of the sun or to treat physiologically dry skin.

The present invention therefore also relates to a cosmetic composition containing, in a cosmetically acceptable carrier, at least one compound of formula (I) or “one of its salts, this composition being in particular in the form of a lotion, gel, cream. , soap or shampoo.

The concentration of compound (s) of formula (I) in these cosmetic compositions is between 0.0005% 10 and 2% by weight and, preferably, between 0.01% and 1% by weight relative to the total weight of the composition.

The compositions according to the invention may contain inert additives or even pharmacodynamically or cosmetically active additives and in particular: hydrating agents such as thiamorpholinone and its derivatives or urea; antiseborrhoeic agents, such as S-carboxymethylcysteine, S-benzylcysteamine and their derivatives, tioxolone; antibiotics, such as erythromycin, neomycin or tetracyclines; agents promoting hair regrowth, such as "Minoxidil" (2,4-diamino-piperidino-6 pyrimidine oxide-3) and its derivatives, Diazoxide and Phenytoin; anti-inflammatory agents, steroid or non-steroid; carotenoids and, in particular, (^ -carotene; anti-psoriatic agents, such as anthralin and its derivatives, eicosatetraynoic acids 5,8,11,14 and -triynoic 5,8,11.

The compositions according to the invention may also contain flavor enhancers, preserving agents, stabilizing agents, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents , UV-A and UV-B filters, antioxidants such as 1 o (-tocopherol, butylhydroxy-35 anisole or butylhydroxy-toluene.

/ J

17

To better understand the object of the invention, we will now describe several examples of embodiment. Examples A and D to H illustrate the preparation of a number of compounds of formula (VII).

Examples B and C illustrate the preparation of the precursors of compounds of formula (VII).

EXAMPLE A Preparation of 2-isobutyryl benzonorbornene In a solution of 35 g of benzonorbornene in. 600 cm of methylene chloride, 48.6 cm of isobutyric anhydride are added. Then at a temperature of about 10 ° C., 77.8 g of aluminum chloride are introduced in solid form in small fractions.

The reaction is exothermic and the temperature of the mixture is maintained at around 10 ° C. The initially colorless solution becomes brown. When all the aluminum chloride is introduced, it is checked by thin layer chromatography (C.C.M.) that the benzonorbornene is completely transformed. The reaction mixture is then poured into one liter of ice water. The organic phase is decanted, washed with sodium bicarbonate and dried over magnesium sulfate.

- The solvent is rectified under reduced pressure.

53 g of isobutyryl-2 benzonorbornene are obtained, the nuclear magnetic resonance spectrum of which conforms to the expected structure.

EXAMPLE B Preparation of 2-isobutyl benzonorbornene

40 g of isobutyryl-2 3 benzonorbornene obtained in Example A, 80 cm of hydrazine 3 3q in 500 cm of butanol, are placed in a flask provided with a condenser with a water separator (Dean-Stark) .-------------------------------------

The mixture is brought to 150 ° C. The water-butanol azeotrope distills. When the theoretical amount of water is eliminated (43 cm), it is verified by thin layer chromatography that the isobutyryl-2 benzonorbornene is transformed into the corresponding hydra-zone. The butanol is then removed by vacuum distillation. The crude hydrazone is taken up by

O

500 cm of diethylene glycol, to which 20 g of potassium hydroxide are added. The solution obtained is then brought to 220 ° C for 15 hours.

5 The reaction mixture is then poured into 2 liters of ice water, to which 300 g of ammonium chloride are added.

This solution is then extracted three times with 350 cm of ethyl ether. The ethereal phases are collected, washed with water, dried over magnesium sulphate and the solvent eliminated by evaporation under vacuum. 36.5 g of 2-isobutyl benzonorbornene are obtained, which is purified by distillation under a pressure of 23 mBars. The boiling point at this pressure is 136 ° C. The nuclear magnetic resonance spectrum and thin layer chromatography indicate that the 30 g of product obtained is pure.

EXAMPLE C Preparation of 2-ethyl benzonorbornene

Bring to the boiling point of butanol, <· a solution of 20 g of 2-acetylbenzonorbornene (prepared as indicated in the Luxembourg patent application No. 85 531 ------ filed on September 5, 1984 ), 10 cm ^ 3 of hydrazine hydrated in 100 cm of butanol. The butanol-water azeotrope is distilled, then the butanol is evaporated under reduced pressure.

The crude hydrazone thus obtained is directly dissolved in 100 cm of ethylene glycol, to which 5 g of potassium hydroxide are added and the whole is brought to reflux of the ethylene glycol until the hydrazone is completely transformed.

At room temperature, the reaction mixture is poured into water and 2-ethyl benzonorbornene is extracted with methylene chloride. The methylene chloride phase is washed with sodium bicarbonate, dried over sodium sulfate and concentrated. After evaporation of the methylene chloride, 15 g of 2-ethyl benzonorborn are obtained.

• VS

At t 19 which is used crude for the acylation reactions below: - EXAMPLE D: Preparation of 2-acetyl-3-isobutyl benzonorborene (Formula VII in which R3 = isobutyl, 5 Ri = R4 = H, R '= CH3) To a solution of 30 g of 2-isobutyl benzonorbornene (prepared according to example B) in 500 ml of chloride

* f χ O

, anhydrous methylene and 12.8 cm of acetyl chloride, cooled to a temperature in the region of 10 ° C, 2A g of aluminum chloride are added while maintaining this temperature in small portions.

At the end of the addition, it is checked by thin layer chromatography that all the starting material is transformed. The reaction mixture is treated as in Example A above and 35 g of 2-acetyl-3-isobutyl benzonorbornene are obtained.

s EXAMPLE E: Preparation of 2-acetyl-3-ethyl benzonorbornene (Formula VII in which R1 = = H, 20 R3 = ethyl, R '= CH3) The 2-ethyl benzonorbornene prepared according to Example C is treated with acetyl chloride and aluminum chloride in methylene chloride under the same conditions as the 2-isobutyl benzonorbornene of Example D above.

25 ‘2-ethyl-benzonorbornene is quantitatively transformed into 2-acetyl-3-ethyl benzonorbornene.

EXAMPLE F Preparation of 2-acetyl-1,4-dibromo-benzonorbornene (Formula VII in which R1 = = Br, R3 = H, R '= CH3) To a solution of 10 g of 2-acetylbenzonorbornene in 130 cnr of anhydrous methylene chloride, cooled to 0 ° C., 1A, 3 g of aluminum chloride are introduced then, drop by drop, 5 cm of bromine diluted in A0 cm of methylene chloride. The solution is then stirred for 1 hour - 48 hours at room temperature. At this point, most of the starting material is processed.

3

300 cm of water are then introduced into the reaction mixture. The methylene chloride solution is decanted, washed with bicarbonate water, dried over sodium sulfate and concentrated. 18 g of a crude product are obtained which is purified by passage through a column of silica gel. The expected product is eluted with a 95/5 mixture of hexane / ethyl acetate ‘.

After concentrating the elution phases, 15 g of 2-acetyl-1,4-dibromo-benzonorbornene are obtained, the nuclear magnetic resonance spectrum of which conforms to the structure.

EXAMPLE G Preparation of 2-acetyl-1,4-dimethoxy-benzonorbornene In a solution stirred at room temperature and protected from humidity, 60 g of potassium tert-butylate in 200 cm of dimethyl sulfoxide Anhydrous, 45 g of 1,4-dihydroxy benzonorbornene are added.

After about one hour, 36 cm of methyl iodide are then introduced dropwise.

The reaction is exothermic and the temperature is maintained between 20 and 30 ° C using an ice bath.

It is then verified by thin layer chromatography that the reaction is complete.

The reaction mixture is then poured into 300

O

water crn and extracted twice with ether. The ethereal phase is washed with water, dried over sodium sulfate and concentrated. 44 g of 1,4-dimethoxy-benzonorbornene are obtained which is used directly for the following acylation reaction.

To a mixture of 30 g of 1,4-dimethoxy benzonor-

O

bornene and 13.8 g of acetyl chloride in 300 cm of methylene chloride, are added in small portions

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i a h / 21 23.5 g of aluminum chloride. At this stage, it is verified that all the starting material is transformed. The reaction mixture is poured into 300 cm 3 of water. The organic phase is washed with sodium bicarbonate, then with water and dried over 5 pounds of magnesium sulfate.

. After evaporation of the solvent under reduced pressure, 28 g of 2-acetyl-dimethoxy-1,4 benzonorbomene are obtained.

EXAMPLE H Preparation of triphenylphosphonium-1 'bromide of 2-ethyl-1,4-dimethoxybenzonorbomene The phosphonium salt is obtained according to the operating mode described in the Luxembourg patent application No. 85.531 filed on September 5, 1984 The 2-acetyl-1,4-dimethoxy-benzonorbomene of Example G is reduced to the corresponding alcohol by sodium borohydride. This alcohol is quantitatively transformed into the brominated derivative by reaction with PBr3 and the triphenylphosphonium salt is obtained by heating this brominated derivative in the presence of an equivalent of triphenylphosphine in toluene.

The salt obtained is a crystalline product which melts between: 20 16C and 165 ° C (slight decomposition from 130 ° C).

EXAMPLE I Preparation of 2-formyl benzonorbomene (formula (VII) in which R ^ rR ^ R ^ R '= H) from benzonorbomene according to a procedure described in "Organic syntheses" Collective VqI.V - p.49, 25 which relates to the formylation of 2,4,6-trimethyl benzaldehyde to a solution of 5.91 g (0.041 mole) of benzonorbor-. 2 nene in 50 cm of anhydrous dichloromethane, stirred at 0 ° C, 3, 9 cm of titanium tetrachloride (0.082 mol) are added, then

O

Dropwise, a solution containing 3.2 cm of dichloro-methyl methyl ether (0.04 mol) in 10 cm of anhydrous dichloromethane. The temperature is maintained at 0 ° C for the entire duration of the addition and, then, the reaction medium is allowed to return to ambient temperature. It is then poured 35 onto 60 g of melting ice and extracted with 60 cm of dichloro- / 1 22 methane. The organic phase is decanted, washed three times with 400 cm of water, dried over sodium sulphate and concentrated. The 2-formyl benzonorbornene is then purified by distillation at a pressure of 0.027 bar (20 mmHg). It's a . 5 colorless liquid (T ^ ci 144 ° C-147 ° C / 0.027 bar).

EXAMPLE J Preparation of triphenylphosphonium bromide of 2-methyl-benzonorbornene The phosphonium salt is obtained according to the same procedure as that described for Example H and included in the Luxembourg patent application No. 85.531 filed on September 5, 1984. Formyl-2 benzonorbornene leads after reduction, bromination and treatment with triphenylphosphine to a crystalline product which melts between 185 and 190 ° C.

15 "\ 2 ° \ 25 \ 30 \

•AT

you

35> .......... - 23 EXAMPLE 1: Preparation of lucid [cis (1,4-dibromo-methano- * '5.8 tetrahydro-5,6,7,8 naphthyl-2) -2 propenyl " ] -4 benzoic of formula:

Br

COOH

A solution stirred at room temperature of 0.5 g of sodium hydride (50% suspension in oil) in 50 cm of anhydrous tetrahydrofuran, protected from light and air humidity, is add four drops of crown ether (15 C 5), then at a temperature of 10 ° C, "* 5 a solution containing the mixture of 3 g of 2-acetyl-1,4-dibromo-1,4-benzonorbornene is added dropwise and 2.9 g of 4-ethoxycarbonyl-diethyl benzylphosphonate The progress of the reaction mixture is followed by thin layer chromatography. -------- After five hours at room temperature, 5 cm ^ of ethanol to destroy any remaining unreacted sodium hydride. The reaction mixture is then poured into 200 ml of 2N hydrochloric acid and extracted with ethyl ether. The ethereal phase is dried over magnesium sulfate, evaporated to dryness.

25 The cis £ (1,4-dibromo-5,8-tetrahydro-5,6,7,8 naphthyl-2) -2 propeny; ethyl T] -4 benzoate is obtained in the form of a brown oil which it is treated directly at 50 ° C. in a mixture consisting of 30 cm of ethanol and 30 cm of 6 N potassium hydroxide for three hours, protected from light. The ethanol 30 is then evaporated. The basic aqueous phase is diluted with 100 cm of water and extracted three times with ether, which allows some impurities to be extracted.

"/ 24

The aqueous phase is decanted, then acidified to pHaM, a light yellow precipitate is formed. It is wrung, washed with water and twice with 10 cm of ether. 1.7 g of [cis (1,4-dibromo-5,8-tetrahydro-5,6,7,7,8-naphthyl-2) -2 propenyll -4 benzoic acid whose structure * * is confirmed by an H 250 MHz spectrum. It is a light beige solid melting at 267 ° C.

Analysis of the product obtained gives the following results: 10

Analysis Calculated for C ^ H ^ Br ^ Found C% 54.57 54.32 15 H% 3.92 3.86

Br% 34.58 34.50 0% 6.92 6.72 EXAMPLE 2: Preparation of the Cis (1,4-dibromo-5,8-tetrahydro-5,6,7,8 naphthyl-2) -2 propenylJ -4 ethyl benzoate of formula: 25

Br C00C.H ,.

<5 Protected from light and under an inert atmosphere, 3q is carried under reflux a solution of 0.5 g of the above acid in 30 cm 3 of ethanol in the presence of one gram of para-toluene sulfonic acid . It takes five hours to transform all of the acid into the corresponding ethyl ester. The ethanol is removed by evaporation under vacuum. The crude ester 35 is dissolved in 50 cm of methylene chloride. The solution is washed with potassium bicarbonate, then with water; Â, 25 dried over magnesium sulfate and concentrated. The ethyl ester thus obtained is crystallized from methanol. 0.2 g of cream-colored crystals are obtained, melting at 79 ° C.

Λ

The H 5 250 MHz nuclear magnetic resonance spectrum confirms the cis structure of the product obtained.

EXAMPLE 3 Preparation of [cis (isobutyl-3 methano-5,8 tetra-hydro-5,6,7,8 naphthyl-2) -2 propenyj-4 ethyl benzoate of formula: ΦΟ ^ α I cooc2h5 15 A a solution stirred at room temperature of 1 g of sodium hydride (50% suspension in oil) in 50 cm of anhydrous tetrahydrofuran, protected from light and air humidity, four drops are added 20 crown ether (15 C 5). Then, at ordinary temperature, a 30 cm solution of tetrahydrofuran is then introduced, containing a mixture of 5 g of 4-ethoxycarbonyl-benzylphosphona-te and 4.03 g of 2-acetyl-3-isobutyl-benzonor-bornene .

After one hour at the boiling point of tetrahydro furan, an additional 0.5 g of phosphonate is introduced.

The mixture is further stirred for 4 hours at 70 ° C. At this point, the reaction is complete. By adding 30 cm of ethanol, the unreacted sodium hydride is destroyed.

The reaction mixture is then poured into 200 cm 3 of water and then extracted with ether. The ethereal phase is washed, dried and concentrated. The product obtained is purified by chromatography on silica gel and eluted with

Kr / ¥ 26 methylene.

2.5 g of viscous liquid are obtained, the nuclear magnetic resonance spectrum * of which corresponds mainly to [cis (3-isobutyl-5,8-tetrahydro-5,6,7,8 naphthyl-2) -2 ί 5 propenylj - 4 ethyl benzoate.

EXAMPLE 4 Preparation of {cis (isobutyl-3-methano-5.8 tetrahydro-5.6.7.8 naphthyl-2) -2 propenvj] -4 * benzoic acid of formula: 10

COOH

3 3

A mixture of 20 cm of ethanol, 20 cm of 6N potassium hydroxide and 2 g of the above ester is brought to 50 ° C. for two hours, protected from light. The alcohol is evaporated, the residual solution is diluted with 100 cm of water and extracted twice with 25 cm of ether.

The aqueous phase is acidified by adding 3N hydrochloric acid 3 and extracted three times with 30 cm of ether.

The ethereal phases are combined, dried over magnesium sulfate and concentrated. 1.2 g of acid are obtained, which contains the two cis and trans isomers. By crystallization in 10 cm of methanol, 0.6 g of acid [cis (3-isobutyl-5,8-tetrahydro-5,6,7,8 naphthyl-2) -2 propenylj -4 benzoic acid is isolated. These are cream-colored crystals with a melting point of 191 ° C.

I /// 27

Analysis Calculated for 28®2 Found C% 83.29 83.09 5H% 7.83 7.85 0% 8.88 8.89 EXAMPLE 5 - Preparation of the Cis (methano-5.8 tetrahydro-5.6, 7.8 10 2-naphthyl) -2-methyl-3-butenyl] -4 ethyl benzoate of formula: C00C2H5

Under experimental conditions identical to those described in Example 1, 3 g of 2-isobutyryl-benzonorbornene and 5 g of 4-ethoxycarbonyl-4-benzylphosphonate are treated in 50 cm of anhydrous tetrahydrofuran with 0, 87 g of sodium hydride (50% suspension in oil) in the presence of a few drops of crown ether.

The mixture is brought to reflux for five hours and then treated according to Example 1.

After evaporation of the ethereal extracts, 5 g of the expected product are obtained. It is purified by passage through a silica gel column and eluted with a 97/3 mixture of hexane / ethyl acetate.

30 g of [cis (5,8-methano-5,6,7,8-naphthyl-2) -2 ethyl-3-butenyil-4 benzoate is obtained, 3 g of which is the nuclear magnetic resonance 1 / H spectrum 250 MHz confirms the cis structure.

/ U

28

Analysis Calculated for C25H28 ° 2 Found C% 83.29 83.27 5H% 7.83 7.90 0% 8.88 8.86 s EXAMPLE 6 - Preparation of strans (methano-5.8 tetrahydro - ^^ 5, 6,7,8-naphthyl-2) -2 3-methyl-butenyl-4-ethyl benzoate of formula: C00CoH, _ 2 5

A solution of 3 g of the cis ester prepared according to Example 5 in 400 cm of methanol is exposed to natural light. The cis-trans isomerization is followed by H.P.L.C ..

After 24 hours of exposure, approximately 80% of the cis isomer is

O

transformed into trans. The solution is concentrated to approximately 50 cm and placed at -20 ° C. The expected trans isomer crystallizes. It is wrung, dried and analyzed. 2 g of (trans (5,8-methano-5,6,7,8-naphthyl-2) -2-methyl-3-butenyl] -4 ethyl benzoate are obtained. The trans structure is confirmed by the resonance spectrum nuclear magnetic 30 "'h 250 MHz. It is a white solid with a melting point of 65 ° C.

EXAMPLE 7 Preparation of trans acid (5,8-methano-5,6,7,8-naphthyl-2-naphthyl) -2-methyl-3-butenylJ-benzoic 29

C02H

cDCr00 9 10 To a suspension of 1 g of the previous ester prepared 3 according to Example 6 in 30 cm of absolute alcohol, 30 cm of a 6N aqueous potassium solution are added. The mixture is stirred for two hours at 60 ° C protected from light. At this stage, all of the ester is saponified. The mixture 15 is poured into 70 cm of water and extracted twice with ether.

The aqueous phase is then acidified to pH - 1.

The expected acid is extracted with ether. The ethereal phase is washed, dried over magnesium sulfate, filtered, then concentrated under reduced pressure. The solid obtained is recrystallized from 20 cm of inethanol at -20 ° C. The crystals are wrung, dried. 600 mg of [trans (5,8-tetrahydro-5,6,7.8 naphthyl-2) -2-methyl-3-butenyl-benzoic acid, whose melting point is 61 ° C., are obtained.

25 Analysis Calculated for C23 H2Z (O2 Found C% 83.10 82.98 H%. 7.27 7.30 0% 9.63 9, A5 30 _L_____ A.

f h "* EXAMPLE 8 - Preparation of ^ cis acid (1,4-dimethoxy-5,8-tetrahydro-5,6,7,8-2-naphthyl) -2 -2-propenyl-4

benzoic J

30 5 0CH3 îTYji ru

10 l ^ JI

C02H

and its trans isomer.

A mixture of 1.05 g of sodium hydride (50% in oil), a few drops of crown crown ether 15 crown 5 3 15 in 50 cm of anhydrous tetrahydrofuran is stirred under an inert atmosphere for half an hour at Room temperature. Then, at around 10 ° C., a solution of 4.5 g of 2-acetyl-1,4-dimethoxy-1,4-benzonorbornene (prepared according to Example G) and 6 g of 4-ethoxycarbonyl is added dropwise. diethyl benzylphosphonate in 50 cm of tetrahydrofuran. The mixture is then brought to reflux for five hours. At ordinary temperature, 5 cm of acetic acid are then added and the mixture is treated according to Example 1. After purification by passage through a column of silica gel, 4.1 g of £ cis (methano -5.8 tetrahydro-5,6,7,8 naphthyl-2) -2 propenyf] -4 ethyl benzoate in mixture with its trans isomer. This mixture, dissolved in 40 cm of ethanol, is directly treated with 40 cm of 6N aqueous potassium hydroxide, at a temperature of 50 ° C., until the total transformation into the corresponding acid. The alcohol is evaporated. The aqueous phase is extracted once with ether, then acidified to pHil and extracted again with ether, several times. The organic phase is dried, then concentrated. The product obtained is then crystallized from mini-mum of acetonitrile. A gram of white crystals melting at at f) i 31 212 ° C is thus isolated. The nuclear magnetic resonance spectrum corresponds to the structure of the acid £ cis (diraétbo-xy-1,4 méthano-5,8 tétrahydro-5,6,7,8 naphtyl-2) -2 propé-nyl ^ j - 4 benzoic.

5 To obtain the corresponding trans isomer, the mixture of Z and E isomer obtained after saponification, then * acidification, is directly taken up in inethanol. In this solvent, trans acid is the first to crystallize.

Trans acid (1,4-dimethoxy-5,8 methano-5,6,7,8,8 naphthyl-2) -2 propenyl]] - ^ benzoic is a white solid melting at 180 ° C.

EXAMPLE 9 Preparation of [trans (methano-5,8 tetrahydro-5,6,7,8 naphthyl-2) -2 ethenyH-4 ethyl benzoate 15 C ° 2C “3 20

A suspension of A, 5 g (8.9 mmol) of 4-carbethoxy-benzyl phosphonium bromide, 1.54 g (11.1 mmol) of anhydrous potassium carbonate and 1.5 g (8.7 mmol) of 2-formyl benzonorbornene in 50 cm of ethanol is brought to the boiling point of the solvent for one hour in the dark and under an inert atmosphere.

The reaction medium is then filtered through celite and the solution concentrated under reduced pressure. The product obtained, dissolved in methylene chloride, is filtered through silica gel. By evaporation of the filtrate and drying, 2.5 g of crystals are obtained which correspond to the mixture of cis-trans isomers. The trans isomer is obtained pure by 3 recrystallization of the 2.5 g obtained in 20 cm of isopro-panol. 0.9 g of trans £ is thus isolated (methano-5.8 tetra-35 hydro-5,6,7,8 naphthyl-2) -2 ethenylj-4 ethyl benzoate under /), *! /, / 32 form of white crystals with a melting point of 109-111 ° C.

EXAMPLE 10 Preparation of j ^ trans acid (methano-5,8 tetrahydro-5,6,7,8 naphthyl-2) -2 ethenyl -4 5 benzoic 9 co2h 10 15 A suspension of 0.7 g of l 'previous ester in a mixture of 10 cm of alcohol and 10 cm of 6N potassium hydroxide is heated with stirring and protected from light at 50 ° C for four hours. The solution obtained is diluted with 30 cm of water and the ethanol is evaporated under reduced pressure. The expected product is precipitated at 5 ° C by adding 100 cm of 1N hydrochloric acid. It is filtered, washed with water and dried. 0.5 g of [_trans (methano-5,8 tetrahydro-5,6,7,8 naphthyl-2) -2 ethenyl ^ -4 benzoic acid is thus isolated. These are white crystals, the melting point of which is 272-273 ° C.

Analysis Calculated for Found ‘__C20H18 ° 2__ 30 C% 82.73 82.52 H% 6.25 6.48 0% 11.02 10.99

O I

nor EXAMPLE 11 - Preparation of all-trans acid (5,8-methano-5,6,7,8-naphthyl-2,6-naphthyl) -3-methyl-2,4,6,6-heptatrienoic acid.

33 '. s 10

According to the procedure described in the Luxembourg patent application No. 85.531 filed on September 5, 1984, 5 g of phosphonium salt of Example J are suspended in tetrahydrofuran and treated with 6 cm 2 of butyl-15 lithium ( 2.5M). After 2 hours of stirring at room temperature of the intense red solution, 1 cm 3 of dichlo-romethane is added and then 1.85 g of 5-formyl-3-methyl-pentadieno-2,4-ate in solution in dichloromethane, protected from light. After 1 hour of reaction at room temperature-20 te, the reaction medium is hydrolyzed by addition of acetic acid. The solution is concentrated under reduced pressure, and the residue is purified by chromatography on silica gel.

3 g of a yellow oil are obtained, the NMR spectrum of which corresponds to a cis and trans mixture of (methano-5,8 tetrahydro-5,6, 25,8 naphthyl-2) -7 methyl-3 heptatrienoate-2, 4.6 ethyl.

This oil is heated to 50 ° C in a mixture of 50 cm3 of ethanol and 50 cm ^ of 6N potassium hydroxide. Heating is maintained (approximately 4 h) until complete disappearance of the starting material.

The reaction medium is concentrated under reduced pressure and acidified with 2N hydrochloric acid. The product obtained is filtered and crystallized from methanol. 500 mg of a yellow product are recovered whose H NMR spectrum 250 MHZ corresponds to the expected structure and whose melting point is 199 - 201 ° C.

EXAMPLE 12 Preparation of all-trans (1,4-dimethoxy-metha- // 34 no-5.8 tetrahydro-5,6,7-8 naphthyl-2) -7 methyl-3 octatrienoate-2,4,6 ethyl.

OCH3 OCH3 10 To a suspension in 100 cm3 of tetrahydrofuran of 5 g of the phosphonium salt of Example H, 5 cm3 of n-butyllithium (2.5 M) are added under an inert atmosphere. After 2 hours of stirring at room temperature, the total solubilization of the salt is observed. and an intense red coloration. 1.5 g of 5-formyl-3-methyl-2,4-pentadienoate, then dissolved in dichloromethane, are protected from light. After reaction of the starting aldehyde, the reaction medium is hydrolyzed with acetic acid. The solution is concentrated under reduced pressure, ------------- and the residue is purified by chromatography on silica gel. A pure fraction of a yellow oil is obtained, the H NMR spectrum of which corresponds to the expected all-trans structure. EXAMPLE 13 Preparation of all-trans acid (1,4-dimethoxy-5,8 methano-5,6,7,8 naphthyl-2) -7 methyl-3,4-octatrienoic 2,4,6.

25 OCH3. 0 ^ 0CH3

: îJ

35

A mixture is brought to 50 ° C. for approximately 2 hours.

O O

1 g of the ester of Example 12, 25 cm of ethanol and 25 cm of 6N aqueous potassium hydroxide. After evaporation of the alcohol under reduced pressure, the aqueous phase is acidified with 2N hydrochloric acid and the expected product is extracted with ethyl acetate. After recrystallization from ethanol, 350 mg of a yellow product is recovered, the structure of which in 1 H NMR 250 MH is in accordance with the all-trans atten-z structure due and the melting point of which is 193 ° - 195 ° C.

10 EXAMPLE 14

The following composition is prepared: - Compound of Example 7, .................... 0.1 g - Polyethylene glycol (average molecular weight = 400) ... ............................ 60.0 g 15 - Polyethylene glycol (average molecular weight = 4000) ........ ...................... 25.0 g - Vaseline oil ... qs ................ .... 100.0 g

A suspension is thus obtained constituting an ointment which can be removed with water. This preparation is used t \ / 36 on acne, dermatosis or psoriasis skin and applied one to three times a day; good results are obtained within 6 to 12 weeks depending on the severity of the case treated.

5 EXAMPLE 15

The following composition is prepared: - Compound of Example 8 (trans) ............ 0.15 g - Mixture of lanolin alcohols emulsifiers and refined waxes and oils based 10 of hydrocarbons sold by BDF MEDICAL under the name of "Eucerin anhydrous" .................................. 40.0 g - Preservatives. ..qs ........................

- Sterile demineralized water ... qs ........... 100.0 g 15 A nonionic suspension is thus obtained constituting a cream. This cream is used for the treatment of ichthyosis and applied one to three times a day; good results are obtained within 6 to 12 weeks depending on the severity of the case treated.

20 EXAMPLE 16

The following composition is prepared: - Compound of Example 10 ................... 1.0 g - Sodium dodecyl sulfate .......... ........ 0.78 g - Propanediol-1.2 ........................... 1.56 g 25 - Cetyl alcohol .......................... 19.50 g - Thick petrolatum oil · .......... ...... 19.50 g - Preservatives ... qs ........................

- Sterile demineralized water ... qs .......... 100.00 g

An anionic suspension constituting a cream is thus obtained. This cream is used for the treatment of dry acne and the demarcated spots of psoriasis.

Applied one to three times a day, good results are obtained within 6 and 12 weeks depending on the severity of the case treated.

'o tf

H

37 EXAMPLE 17

An anti-seborrheic lotion is prepared in the following manner: »3 To a solution consisting of 10 cm of ethanol 5 at 95 ° and 30 cm of polyethylene glycol (molecular weight: about 400) containing 20 mg of butylhydroxytoluene, * is added 0.1 g of the compound of Example 3.

After solubilization with stirring, the lotion is applied to the whole of the hair.

Preferably, a treatment is carried out twice a day. After 15 days of treatment, there is a satisfactory result.

λ Λ

U

Claims (37)

38 1. Compound derived from benzonorbornene corresponding to the general formula (I) P: 5 i î1 Γ I \ H2 I 4! I) Î i 3 and all its isomers and salts, formula in which: - R ^, and R ^ represent, independently of one another, a hydrogen atom, an alkyl radical C ^ -C g an alkoxy radical C ^ -C ^, a halogen atom, an acyloxy radical C -C or a hydroxyl radical; - 1 o 20. R ’represents a hydrogen atom or an alkyl radical C ^ -Cg, with the proviso that R 'cannot represent CH ^ when the three substituents R, R ^ and R ^ represent a hydrogen atom; - R "represents an unsaturated group which is: 1) or else a polyene chain of formula (II) f? H3 - ^ iC 1 (II) HH 35 in which the group A2 ---------- ----------------- ΐ fi f \ 39 --------- represents a group CH ^ OR ^ in which Rg is a hydrogen atom or a radical C 1 -C alkyl, or ID also a COR group in which R 7 is a hydrogen atom (15 gene, a C 1 -C 6 alkoxy radical, aryloxy, benzyloxy, a sugar residue, an amino radical, a Cj-C6 alkyl radical or a hydroxyl radical; 2.or a benzene nucleus of formula (III) 10 H 11 c ^ CH 15 i H in which A ^ can take all the meanings previously given for A ^ and, in addition, can represent a hydrogen atom, an alkyl radical Cj-Cg, an alkylthio-SR group , alkylsulfinyl -S-Rj. or alkyl- J ψ 0 0 sulfonyl -SO ^ R ^, where R ^ represents an alkyl radical CrC6. 2. Compound according to claim 1, in which the substituent A ^ or A ^ represents a group COR ^ and R ^ is a radical ORg, Rg being chosen from the group formed by the radicals methyl, ethyl, propyl, butyl, hexyl. and by C 1 -C 4 alkyl radicals substituted by one or more hydroxyls. 3. Compound according to Claim 1, in which the substituent A ^ or A ^ represents a group COR ^ and R ^ is a hydroxyl, characterized in that the carboxylic group COR ^ is salified by a strong base or by 1 a 40 an amine compatible with the skin. 4. Compound according to claim 1, in which the substituent A2 or A3 is a group COR ^ and is an aryloxy, ---------------------- characterized by the 5 means that the aryl radical of corresponds to the formula (IV) K'3 io (P (iv) w R9 15 formula in which R ^ and R. ^ represent, independently of one another, an atom of hydrogen, a C 1 -C 4 alkyl radical, a hydroxyl, a halogen atom, a carboxyl group or a trifluoromethyl group. 5. Compound according to claim 1, in which the substituent A ^ or A ^ is a group COR ^ and is a benzyloxy, --------------------- characterized by the fact that the benzyl radical of R ^ corresponds to the formula (V) 25 - q> (V) R9 formula in which R ^ and R ^ 3 represent, independently of one another, a hydrogen atom, a C 1 -C 4 alkyl radical, a hydroxyl, a halogen atom, a carboxyl group or a trifluoromethyl group. [if Al 6. Compound according to claim 1, in which the substituent A2 or A ^ is a group COR ^, and R ^ is a sugar residue, characterized in that COR ^ comes from a glucose ester, from a mannitol ester or a pentaerythritol ester. 7. A compound according to claim 1, in which the substituent A or A is a group COR and R ^ ^ It is an amino of formula NR ^ R ^, characterized in that R ^ Q and R independently represent l 'a die . the other, a hydrogen atom, a linear or branched C 1 -C 6 alkyl radical, whether or not substituted by one or more hydroxyls, or together form a substituted or unsubstituted heterocycle, one of the two radicals R10 or R -] - | may also be, when the other is a hydrogen atom, an aryl radical of formula (IV) 15 Rl3 (P (iv) R9 or a benzyl radical of formula (V) 25 ^^ / R13 i oP ^ (V) 30 * 9 formulas in which R and R represent, independently IJ ment one of the other, a hydrogen atom, a C 1 -C 4 alkyl radical, a hydroxyl, a halogen atom, a carboxyl group or a trifluoromethyl group "the amino NR ^ R ^ fj 42 also corresponding to the amine function of an amino acid or the amino function of a glucosamine. 8. Compound corresponding to formula (VII) 5 i1 f ((VII) 10 r4 formula in which R ^, R ^, R ^ and R 'have the meanings mentioned in claim 1. A3 9. Process for the preparation of the compounds of formula (I), characterized in that, in a first step, a 2-acyl substituted benzonorbornene of formula (VII) ”rrrV" "\, (VII) is prepared Ra 3 H ', R ^, R ^ and R ^ having the meanings mentioned in claim 1, and that, in a second step, the compound of formula (VII) is reacted directly with a dialkyl phosphonate of formula ( VIII) R12 ° \ fi 25 p_CH2 — R "P 0 ^^ (VIII) r12u ^^ 2 being a C ^ -C ^ alkyl and R" having the meanings indicated in claim 1, or 30 with a triphenylphosphonium salt of formula (IX) (Ο, Η.ΚΐΦ— CH5-R "X® (IX) 6 5 3 2 rJ 44 where R” has the meanings given in claim 1, and X ® is a halide. 10. Process for the preparation of the compounds of formula (I), characterized in that, in a first step, “S1 ç-? ^ ^ o prepared a substituted 2-benzonorbornene acyl of formula (VII) R1 R '10. d [(VII) * 4 3 15 where R', R ^, R ^ and R ^ have the meanings indicated in claim 1 ; that, in a second step, the compound of formula (VII) is reduced, by sodium borohydride, to a secondary alcohol of formula (X) irtV '· AAA \ \ R3. K *, where R ’, R ^, R ^ and R ^ have the above-mentioned meanings; that, in a third step, the compound of formula (X) is transformed by the action of phosphorus tribromide into a bromide of formula (XI) U kh R1 R '\ (Xi) Ù5 * 1 5 where R', R, R ^ and R ^ have the meanings indicated above; • that, in a fourth step, the compound 10 of formula (XI) is made to act triphenylphosphine to obtain the triphenylphosphonium bromide of formula (XII) R1 R ' 15. Br® UII) ’20 where R ', R ^, R ^ and R ^ have the meanings mentioned above; and that, in a fifth step, the compound of formula (XII) is reacted with an aldehyde R "CH0 (R" having the meanings indicated in claim 1) to obtain the compound of formula (I). 11. Method according to one of claims 9 or 10,: · characterized in that to obtain the compound of formula (VII): r * eJ. 46 R1 R · TY ^ t * 0: 5 \ Xtfkh r4 * we prepare, in a first stage, a substituted benzonorbornene of formula (VI) \ _ 'ni 47 - Γ 5 {(VI) 10 where R ^, R ^ and R ^ have the meanings mentioned in claim 1; and that, in a second step, the compound of formula (VI) is acylated with an acyl chloride R'COCl in the presence of aluminum chloride, R ’having the meanings indicated in claim 1. 12. Method according to one of claims 9 or 10, characterized in that, to obtain the compound of formula (VII): R1 R ’îo iTyy ^ · \ / 3 (VII) 25 Ra in a first stage, an acyl chloride R'COCl or an acid anhydride is produced, an acylation revealing the group R * -CO- in ----------- ----------------------------------------- position 2 on the nucleus of benzonorbornene and that , in a second step, the substitutions are made showing the groups R ^, R ^ and R ^ respectively in positions 1, 3 and 4 on the nucleus of benzonorbornene, R ', R ^ and R ^ having the meanings indicated to claim 1.: A / 48 13. Method according to one of claims 9 or 10, characterized in that, to obtain the compound of formula (VII) 5 R1 R "// 7Sss ^ 2 (VII) R4 is carried out, in a first stage, the cyclo-addition of a substituted benzyne of formula (XXV) 15 (XXV) ^ 20 where has the meanings indicated in claim 1 , with cyclopentadiene; that, in a second stage, the substituted benzonorbornadiene of formula (XXIII) Rs / (XXIII) 30 \ 35 thus reduced is reduced, where R ^ has the meanings indicated in: il 49 claim 1, in substituted benzonorbornene of formula ( XXIV); 5 ((XXIV) s 10 \ where has the meanings indicated above; and that, in a third stage, the compound of formula (XXIV) is acylated with an acyl chloride R'COCl, in the presence of chloride d 'aluminum, R' having the meanings given in claim 1. 14. Medicinal composition, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one compound according to one of claims 1 to 7. 25 \ 30 \ 35 \: / J 50 15. Composition according to claim IA, characterized in that it is intended for the treatment of dermatological or other affections linked to a disorder of w keratinization (differentiation-proliferation) and of 5 dermatological affections with inflammatory components and / or immunoallergic and, in particular, acne, ichthyosis and ichthyosiform states, Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplakia. forms, lichen and psoriasis, of all 10 proliferations benign or malignant dermatologic or to the treatment of certain rheumatic affections such as psoriatic arthritis, or to the treatment of atopia-cutaneous or respiratory. 16. Composition according to one of claims · 15 14 or 15, characterized in that the concentration of compound (s) according to one of claims 1 to 7 is between 0.0005 and 2% by weight. 17. Composition according to claim 15, characterized in that the weight concentration of compound (s) according to one of claims 1 to 7 'is between 0.01 and 1% by weight. 18. Composition according to one of claims 14 to 17 ', characterized in that it can be administered topically, in particular in the form of an ointment, gel, cream, ointment, powder, tincture, solution, suspension, emulsion, lotion, stamp spray and soaked pads. 19. Composition according to claim 18, presented in the form of a solution, characterized in that it contains from 0.001% to 0.3% by weight of compound (s) according to one of claims 1 to 7. 2Q - Composition according to claim 18, presented in the form of a cream, characterized in that it contains from 0.002% to 0.5% by weight of compound (s) 35 lbs according to one of claims 1 to 7. ilf 4, 51 21. Composition according to one of claims .14 to 17, characterized in that it can be used enterally. - 22 - Composition according to claim 21 »usable orally, characterized in that it is administered in an amount of about 2 f * g up to 2 mg of compound (s) according to one claims 1 to 7 ”per day. and per kg of body weight. 23. Composition according to one of claims 14 10 to 17, characterized in that it is in the form of a solution or suspension intended to be administered parenterally. 24. Composition according to claim 23, characterized in that it is administered at the rate of 15. J * g up to 2 mg of compound (s) according to one of claims 1 to 7, per day and per kg of body weight. 25. Composition according to one of claims 23 or 24, characterized in that it contains, 20 per ml of solution or suspension, from 0.01 to 1 mg of compound (s) according to one of the claims 1 to 7. 26. Composition according to claim 14, characterized in that the pharmaceutically acceptable carrier of the composition contains at least one product taken from the group formed by water, gelatin, lactose, starch, talc, petrolatum, gum arabic, polyalkylene glycols, magnesium stearate, diluents, solvents, thickeners, binders and fillers. : u 52 27. Cosmetic composition, characterized in that it contains, in a cosmetically acceptable carrier - * = table, at least one compound according to one of claims; 1 to 7. 28. Composition according to claim .27, charac- terized in that the compound (s) according to one of j claims 1 to 7 is (or are) present (s) at a concentration • between 0.0005 and 2% by weight and, preferably, between 0.01 and 1% by weight. 10 '29 - Composition according to one of claims 27 or 28, characterized in that it is in the form of a lotion, gel, cream, soap or shampoo. 30. Use of a composition according to one of claims 27 to 29, in body and hair hygiene, and in particular in the treatment of acne, seborrhea, hair loss, for hair regrowth, in protection against the harmful effects of the sun and for the treatment of physiologically dry skin. 20 31 - Composition according to one of claims 14 to 29, characterized in that it contains inert additives or bharmacodynamically or cosmetically active. 32. Composition according to claim 3.1, characterized in that the additives are taken from the group formed by hydrating agents, anti-seborrheic agents, antibiotics, agents promoting hair regrowth, anti-inflammatory agents, carotenoids, anti-psoriatic agents, flavoring agents, preserving agents, stabilizing agents, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents, UV-A and UV-B filters and antioxidants. Drawings; ........ ^ plates ..... pagtës ffput ..... ji ......... cover page ç description pages - f-'scvs this claim .. .... ^ ... ^ s'r.îcos descriptif Luxembou.ro, fa dk L ·. ,:> / * û