LU85531A1 - 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, THEIR PREPARATION PROCESS AND MEDICINAL AND COSMETIC COMPOSITIONS

CONTAINING.

~ The invention relates to new chemical compounds 5 consisting of benzonorbornenes substituted on e *> one of the carbon atoms of the benzene ring, as well as, on the one hand, the preparation process allowing * "to obtain- A , to define these new compounds and, on the other hand, the use of these new compounds in cosmetic compositions or as pharmaceutical preparations in the treatment of dermatological conditions linked to a disorder of keratinization (differentiation-proliferation) as well as in the treatment of dermatological conditions with an inflammatory and / or immuno-go-go component.

The therapeutic action of vitamin A in its acid, aldehyde or alcohol form is well known in dermatology (see in this regard the publication "EXPERIENTIA, vol. 34 pages 1105-1119 (1978)); this action in the treatment of skin overgrowth, acne, psoriasis and the like will hereinafter be referred to generically as "retinoic action." Products having a structure similar to vitamin A have also been found to exhibit retinoic action, but that the side effect of toxic hypervitaminosis could, for certain compounds, be multiplied by a factor smaller than the multiplying factor of the retinoic effect sought (see in this regard "EUR. J. MED.

CHEM.-CHIMICA THERAPEUTICA, January-February 1980, 15, nc 1, pages 9-15); thus, the French patent applications 2 422 620 and 2 529 455 describe ----------------------- / 30 new derivatives of stilbene and methylstyryl-naphta - „-lene comprising, on the nucleus where is grafted an unsaturated substitute chain *, a certain number of methyl groups, because it emerged from the studies carried out that the multiplication of methyl groups seemed to improve J-

V

2% 1 "therapeutic efficacy (see the publication" EUR. J.

MED. CHEM, supra).

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

A subject of the invention is therefore the new industrial product which constitutes a new chemical compound derived from benzonorbornene corresponding to the general formula (I) f I C, H3 ‘25 h2ç ^ S ^ pn / Cn / Ri <*>

ί "2 i | C \ H

30 I I

H H

formula in which ie ernim. "Group R is in the cis (2) or trans (E) position relative to the group" ethyl, R, being an unsaturated group which can have one of the following two meanings:% * 3 1) a polyene chain of formula ( II) ** H CH * 5 I 1 T c \ "10 in which the substituents of each of the two double bonds can be in cis or in trans, the group being taken from the group formed by a group CH ^ OR ', in which R 'represents hydrogen or a C 1 -C 4 alkyl radical, and a group CO 2, in which R 2 represents a hydrogen atom, a radical? C 1 -C 4 alkoxy, aryloxy, benzyloxy, amino, C 1 -C 4 alkyl, a hydroxy radical and the corresponding carboxylic acid salts or else a sugar residue such as glucose, mannitol and pentaerythritol ; - 2) a benzene nucleus of formula (III)

H

i a wÇ 3 um f

H

the group of formula (111) being taken from the group formed by the meanings given above for the group A, a hydrogen atom, an alkyl radical

Cn-C ,, an alkylthio group SR ", alkylsulfinyl SR", 1 H φ o alkylsulfonyl SO ^ R ", in which R" represents an alkyl group *

AT

When A, or A_ represents a radical C0Ro and that R0 represents an alkoxy in C ^ Cg, it is preferred that R2 is a radical OR ,, R, being chosen from the group formed by the radicals methyl, ethyl, propyl, butyl, hexyl, or a C 1 -C 4 alkyl substituted by one or more hydroxyls and, in particular 2-hydroxyethyl, 2-hydroxypropyl or dihydroxyproçyl isomers * such as 2-dihydroxy, 3 propyl and (1,3-dihydroxy) propyl ^

When A2 or A ^ represents C0R2, R2 being a hydroxyl, this carboxylic group can advantageously be salified Ί0 with a strong base such as sodium hydroxide or potassium hydroxide or with an amine compatible with the skin such as trietha-nolamine.

When A2 or is a radical CO2 and that R2 is an aryloxy of formula 0-aryl, the aryl radical of R2 may advantageously correspond to the formula (IV) .CH * I —H * 5 (IV)

HC CH

20 wherein R ^ and R ^ represent, independently of one another, a hydrogen atom, a C ^ C ^ alkyl radical, a hydroxyl, a halogen atom, a carboxyl group or a trifluoromethyl.

-_ 5

When A0 or A_ is a radical C0Ro and R0 £ é J C. C.

is a benzyloxy of formula 0-benzyl, the benzyl radical of '' Rg may advantageously correspond to the formula (V) 5 / V ^ 114

- CH, —C - ^ CH

2 I —Ms CH CH (v)

^ CH

10 f formula in which and have the same meanings as in formula (V).

When Ag or A ^ is a CORg radical and Rg represents an amino of formula NR ^ R ^, R ^ and R ^ can advantageously represent, independently of one another, a hydrogen atom, a Ci_C4 alkyl> linear or branched, substituted or not by one or more hydroxyls, one of the two radicals R ^ or R ^ can also be, when the other is a hydrogen atom, an aryl radical of formula (IV) , a benzyl radical of formula (V) / formulas in les-gj. which and R, - have the meanings indicated above "a residue of amino acid or a residue of glucosamine.

When r, is a polyene chain of formula v * 30 (II), if we number 2 the carbon carrying the group  ^, ^ 3 the carbon carrying CH ^ and A the next adjacent carbon of the chain, the structures at the carbons 2 and A can be 2-E, AE, or 2-Z, AZ, or 2-E, AZ, or even 2-Z, AE.

ψ 6, The invention also relates to a process for the preparation of the new compounds of formula (I). According to the invention, the synthesis of the compounds of formula (I) uses as raw material 2-acetylbenzonorbornene 5 which is described in the publication J. AM. CHEM. SOC., 87, pages 4794-4804 cited above. In a first step, '2-acetyl benzonorbornene is reduced with sodium borohydride to obtain the corresponding secondary alcohol; in ----- a second step, the phosphorus tribromide 10 is made to act on the abovementioned secondary alcohol to obtain the corresponding bromide; ___ in a third step, the triphenylphosphine nour is made to act on the product obtained to obtain the corresponding triphenylphosphonium bromide ", in a fourth step, after purification of the compound obtained, it is reacted with ------- reaction of -Wittig, ^ on an aldehyde HCOR ^ where R ^ has the meanings indicated above, --------------- to obtain the product of a- formula (I).

The preparation process according to the invention therefore therefore uses, in its last step, triphenylphosphonium bromide of formula (VI) ch3. (Vi) a which is reacted with an aldehyde of formula {VII; r 30 H \ ^ -fy (VII) 35 7 *

Among the aldehydes that can be used, "Mention may be made of methyl formyl-4 benzoate, which can be found commercially.

^ There was also used, as example 5 of aldehyde, 5-formyl-3-methyl-pentadiene-2,4 ethyl oate, which is synthesized in two stages, as * indicated in the abovementioned publication EXPERIENTIA 1978,

* 34, pages 1105-1Π9 (see also CHEMICAL ABSTRACTS

57, 2056 b and 58, 10066 e); in this process, reaction is carried out in the presence of sodium hydride, in tetrahydrofuran, pyruvic aldehyde-dimethylacetal and triethylphosphonoacetate, which are both commercial products. An unsaturated ester is thus obtained on which the ethyl vinyl ether is condensed in the presence of boron trifluoroetherate; the condensation product is then hydrolyzed by phosphoric acid and the aldehyde obtained is purified by recrystallization.

i. According to a preferred embodiment of the process according to the invention, 2-acetyl benzonorbornene is obtained according to the following operating process: a) to obtain the benzonorbornadiene of formula (VIII); C0 30 k reacting the freshly distilled cyclopentadiene on the benzyne of formula (IX) 8 · * ^ CHv.

CH C

5 CH J (W

• î.

The benzyne of formula (IX) is prepared either from 2-amino benzoic acid of formula (X) ^> ^^^ C02h (X) i ^ 55> / ^ SsNH2 which is treated with isoamyl nitrite, ie from the organomagnesium of 2-bromo fluorobenzene of formula 20 (XI)

VS

(XI)

/ V

b) the benzonorbornadiene of formula (VIII) is purified by distillation then reduced by hydrogenation in the presence of palladium on carbon, the reduction making it possible to obtain the benzonorbornene of formula (XII) · * 9 CO ”: * 10 c) the benzonorbornene of formula (XII) is acetylated by Friedel and Craft reaction -------------------- with acetate chloride in the presence of chloride d aluminum; this acetylation is selective in form and the 2-acetyl benzonorbornene of formula (XIII) CH3 ^ -c = o. · ((XIII) which is used as raw material for the preparation process according to the invention is obtained.

The compounds of formula (I) according to the invention can be of trans structure (structure E) or of cis structure (structure Z); the invention relates to all of the isomers as well as to the optical isomers. It should moreover be specified that when these products are exposed to light, there may be transformations from one type of isomer to another type.

; 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 conditions linked to a keratinization disorder (differentiation-proliferation) as well as dermatological conditions with an inflammatory component. and / or 10 immunoallergic, in particular for treating vulgar, comedonian or polymorphic acnes, solar senile acne and drug or professional acne, extensive and / or severe forms of J psoriasis, and other keratinization disorders , and in particular 5 ichthyoses and ichthyosiform states, Darier's disease, palmoplantar keratoderma, leukoplakias and leukoplasiform states,

U

lichen planus, any benign or malignant, severe or extensive dermatological proliferation; they are also active for certain rheumatic affections, in particular psoriatic arthritis. The invention therefore also relates to medicinal 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 aforementioned conditions, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one compound of formula (I).

- A good activity of the compounds of formula (I) is observed over a very large 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 made 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, 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), creams containing approximately 0.002% - 0.5% of active substance (s).

¥ 11

The compounds of formula (I) can be used enterally. By the oral route, the compounds of formula (I) are administered in an amount of approximately up to Λ 2 mg per day per kg of body weight; an excessive dosage can manifest itself in the form of a hypervaminosis A recognizable by its symptoms and which can cause fear of hepatic toxicity necessitating a biological control of the hepatic function. The required dose can be administered; in one or more takes. For oral administration, suitable forms are, for example, tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions; a preferred mode of administration consists in using capsules containing from 0.1 mg to approximately 1 mg of active substance.

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 administered at the rate of about 20 zh g up to 2 mg per day and per kg of body weight; in general, parenteral administration is carried out at a rate of 0.01 mg to 1 mg of active compound (s) per ml.

The pharmaceutically acceptable carrier ---------------- 25 ceptable may contain, for example, water, gelatin, lactose, starch, talc, petrolatum, gum arabic, polyalkylene glycols, stearate, magnesium. Tablets, powders, granules, dragees or capsules can contain binders, fillers, powdery supports; the solutions or suspensions can contain diluents, solvents, thickeners.

*. 12

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 non-adherent cells, thus dislodging and causing the comedo to leave acne. These compounds reduce the size of the sebaceous glands and partially inhibit the secretion of 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, anti-hair loss, for fight against the oily appearance of the skin or hair or for protection against the harmful effects of the sun.

The present invention therefore also relates to a cosmetic composition containing, in a cosmetically acceptable medium, at least one compound of formula (I), 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 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-carboxymethyl-cys-teine, S-benzyl-cysteamine and their derivatives, tioxo-lone; antibiotics, such as erythromycin, neomyvein or tetracyclines; agents promoting hair regrowth, such as ^ Minoxidil "(2,4-diamino-piper-6-dino pyrimidine oxide-3) and its derivatives, Diazoxide and Phenytoin, anthralin and its derivatives, anti-agents -inflammatory, steroidal and non-steroidal; carotenoids and, in particular i-carotene; antipsoriatic agents, such as anthralin and its derivatives, eicosate-traynoic acids 5,8,11,14 and -triynoic 5,8,11.

The compositions according to the invention may also contain agents for improving the taste, preserving agents, stabilizing agents, humidity regulating agents, pH regulating agents, agents for modifying osmotic pressure, emulsifiers, UV-A and UV-B filters, antioxidants, such as (-tocopherol, butylhydroxy-anisole or butylhydroxy-toluene).

To better understand the object of the invention, we will now describe several examples of embodiments. Examples A, B, C describe preparation steps prior to the steps which are an integral part of the preparation process according to the invention.

"14

EXAMPLE A

, Preparation of 2-acetyl benzonorbornene (formula (XIII) v First step: preparation of benzonorbornadiene (formula (VIII) 5 In a flask fitted with a condenser, a thermometer, a nitrogen inlet, of a dropping funnel, and protected from the humidity of the air by a calcium chloride tube, 10 g of magnesium turnings are placed, which are covered with approximately 75 cm of anhydrous tetrahydrofuran. 10 then adds 25 cm of a solution, previously prepared, of 65 g of orthofluorobromobenzene and 26 g of cyclopentadiene in 200 cmJ of anhydrous tetrahydrofuran. By local heating with a hairdryer of the reaction mixture, the formation of 1 organo-magnesium begins and the boiling of the solvent is then maintained by dropwise addition of the remainder of the solution. The total introduction is carried out in about 1 hour. The mixture is then filtered at room temperature and the solution is concentrated under reduced pressure and the solution is taken up in ether. t the ethereal phase 20 is washed with ammonium chloride, decanted, dried over magnesium sulfate; the solvent is then removed by evaporation under vacuum. The residue is then distilled and benzonorbornadiene is obtained with a yield of 40%, the boiling point of which is 82-83 ° C under a pressure of 16 millibars.

15

Second step ; preparation of benzonorbornene (formula XII) To a solution of AO g of benzonorbornadiene 'in A00 cm of methanol degassed with nitrogen, there is added "5 A g of a catalyst which contains 10% of palladium on charcoal. nitrogen is bubbled through again and the heterogeneous solution is stirred for three hours at a relative hydrogen pressure of 2 bar .------- The mixture is then filtered, concentrated under reduced pressure and the benzonorbornene is purified by distillation, its boiling point at 22.5 millibars is 86 ° C. 33 g of product are obtained, the nuclear magnetic resonance spectrum of which corresponds to the expected structure.

15 Third step: preparation of 2-acetyl benzonorbornene (formula XIII) To a solution of 30 g of benzonorbornene in 3 3 5 AOO cm of carbon sulfide, 30 cm of acetyl chloride are added and then, gradually, by small amounts, 20.5 g of anhydrous aluminum chloride are introduced over approximately two hours. At this stage, the total transformation of the starting product is verified by thin layer chromatography. The reaction mixture is then poured into two liters of ice water and then neutralized with sodium bicarbonate. After three extractions with ether, the ethereal phase is dried over sodium sulfate and then concentrated. 38 g of orange oil are obtained, which corresponds to the expected product.

EXAMPLE B

30 Synthesis of (methano-5,8 tetrahydro-5,6,7,8 ^ naphthyl -2) -1 ethyl triphenylphosphonium bromide (formula VI)

15 g of 2-acetylbenzonorbornene (3) are dissolved in 75 cm of methanol cooled to 0 ° C. 3 g of sodium borohydride are introduced in small portions and the stirring is continued for one hour. When the starting product 16 is transformed (which is verified by thin layer chromatography), the reaction medium is concentrated by half and poured onto approximately 250 cm of 1N hydrochloric acid. The product is extracted twice with ether 5 times. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure.

The nuclear magnetic resonance spectrum 1 is H

conforms to the expected structure. The 14 g of alcohol as well

e O

obtained are dissolved in 75 cm of dichloromethane.

O

6 cm of phosphorus tribromide are added dropwise at 0 ° C. Stirring and the temperature are maintained at 0 ° C for about two hours; then pour the reaction medium onto 300 cm of ice water and extract with dichloromethane. The organic phase is washed with sodium bicarbonate solution, dried and concentrated under reduced pressure. 15 g of brominated derivative are recovered. s. The 1 ^ nuclear magnetic resonance spectrum conforms to the expected structure. The product thus obtained is dissolved in 1 * 50 cm of anhydrous toluene. 16 g of triphenylphosphine are added and the reaction medium is brought to reflux of toluene for 24 hours. After cooling, the expected product settles in the form of an oil and crystallizes from ether.

27 g of triphenylphosphonium salt are recovered, ie an overall yield of 65%.

Molecular Kasse Found: 513.

Melting point: 156-158 ° C.

EXAMPLE C

: Synthesis of 5-ethylformyl-3-methyl-2,4-pentadienoate 30 lbs First step: synthesis of ethyl dimethylacetaI-3 L isocrotonate

24 g of sodium hydride at 50% by weight, previously washed with hexane, suspended in 500 cm of tetrahydro-17 are introduced into a two-liter reactor fitted with mechanical stirring, under an inert atmosphere. anhydrous furan. The suspension is cooled to 0 ° C. and * 3 r is added approximately 1 cm of crown ether (IS-Crown-Ç1) · i "

Is added dropwise, keeping the temperature below 20 ° C, a solution of 112 g of triethylphosphonoacetate and 59 g of pyruvic aldehyde-diethyl acetal in 200 cm of anhydrous tetrahydrofuran. Gas evolution and thickening of the reaction medium are observed. After addition (about two hours), stirring is continued for one hour at room temperature. The solution is poured into about 1 liter of ice water and extracted with ether. The organic phase is washed with a sodium chloride solution, dried and concentrated under reduced pressure. The expected product is purified by distillation under reduced pressure: it boils at 50-53 ° C under a pressure of 0.13 millibar. We recover = 77 g of a mixture (20/80) of cis-trans isomers (determination by nuclear magnetic resonance 1 ^), which corresponds to a yield of 82%.

20 Second step: synthesis of 5-formyl-3-methyl

pentadienate-2, A

In a 1 liter flask, 75 g of the product obtained in the first step are dissolved in 500 cm 3 of anhydrous hexane and the solution is brought to 0 ° C. 1.8 cm of boron trifluoride diethyl etherate are added and we

X 3 F

add, under an inert atmosphere, 30 cm of ethyl vinyl ether while keeping the temperature below 50 ° C. After addition, stirring is continued for one hour at 40 ° -50 ° C. 10 g of sodium bicarbonate are added, filtered and concentrated under reduced pressure. The residue

O

thus obtained is taken up with 350 cmJ of ethyl acetate. This solution is introduced into a flask containing 60 g of orthophosphoric acid and 250 cm of distilled water. The reaction medium is brought to reflux of ethyl acetate (70-75 ° C. for five hours with vigorous stirring, then concentrated under reduced pressure and extracted with 3 × 3 with 500 cm of toluene. The organic phase is washed with a sodium bicarbonate solution and then dried and concentrated under reduced pressure, kl g of crude crystallized product is obtained 5. After recrystallization from hexane, 28 g of pure product are recovered, corresponding to the trans-trans structure.

The molecular weight found is 169- The melting point is 49-50 ° C.

10 EXAMPLE 1

Synthesis of all-trans (methano-5. 8 tetrahvdro-S; f> r 7. fi naphthyl-2) -7 methyl-3 octatrienoate-2, ethyl k.6, (compound of formula (I) in which is a polyene chain and A has the meaning COOC ^ E ^) To a suspension of 10.25 g (0.02 M) of the bromide prepared in Example B in 100 cmJ of anhydrous ether, it is added dropwise to drop, under inert atmosphere, 20 cnr of n-butyllithium (1.6M). After two hours of stirring at room temperature of the intense red solution, 3 cm of dichloromethane are added to destroy the excess butyllithium and 3.3 g of the ethyl ester are introduced, protected from light. prepared in Example C in solution in 20 cm3 of dichloromethane. Stirring is continued for two hours at room temperature. The reaction mixture is poured onto 150 cm3 of an ammonium chloride solution and extracted with 3 times 100 cm3 of ether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. A yellow oil is obtained, which is purified by passage over a column of silica gel h (eluent hexane / ethyl acetate 95/5). 3.9 g $ 30 of a yellow oil is obtained which, by crystallization from a hexane / methanol mixture, provides 2.1 g (31%) of the expected all-trans ester. The 1,250 MHz spectrum in nuclear magnetic resonance

H

conforms to the expected structure.

Molecular mass found: 322.

35 Melting point: 78-80 ° C.

19 EXAMPLE 2

Synthesis of all-trans acid (methano-5,8 tetrahydro-V 5,6,7,8 naphthyl-2) -7 methyl-3 octatrienoic-2,4,6 (compound of formula (I) in which is a polyene chain and in which A has the meaning COOH) 1.5 g of the ethyl ester of Example 1 are dissolved, protected from light, in 20 cm-3 of etfianol

"λ O

at 50 ° C. 20 cm of a 6N aqueous potassium hydroxide solution are added and the mixture is stirred for three hours while maintaining the temperature at 50 ° C. The methanol is evaporated under reduced pressure and the aqueous phase is acidified with 2N hydrochloric acid. A precipitate is formed which is extracted with ether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The expected product 15 crystallizes from hexane. 1.1 g of pure product are obtained (yield: 80%).

Molecular mass found: 294

Melting point: 178-179 ° C.

~ The analysis of the product obtained gives the following results:

Analysis C H 0

Theoretical 81.59 7.53 10.87

Found 81.46 7.56 10.66 25 _____ EXAMPLE 3

Synthesis of N-ethyl all-trans (methano-5,8 tetrahydro-5,6,7,8 naphthyl-2) -7 methyl-3 octatriensagide-2,4,6 30 (compound of formula (Iî in which R ^ is a polyene chain and A has the meaning CONIK ^ Hj.}

200 mg of the product of Example 2 3 are dissolved in approximately 5 cm of anhydrous toluene at 50 ° C. 65 mg of phosphorus trichloride is added and the temperature is maintained at 45-50 ° C for 15 minutes. The yellow solution 20 thus obtained is added dropwise, protected from light, to a solution of 5 ml of ethylamine in 20 cm of anhydrous toluene. During the addition, the temperature of the reaction mixture is kept below 10 ° C. After overnight at room temperature, the solution is poured into 100 cm of water and extracted with ether. The organic phase is washed and dried and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel (eluent = hexane / 10 ethyl acetate 50/50). After recrystallization from hexane, 150 mg of the expected product are recovered in the form of a white powder.

Molecular mass found: 321.

Melting point: 105-107 ° C.

15 EXAMPLE A

Synthesis of Çtrans (methano-5,8 tetrahydro-5,6,7,8 naphthyl-2) -2 propenylj -A methyl benzoate (compound of formula (I) in which represents a benzene ring and A has the meaning C00CH3) To a suspension of 5.2 g of the bromide of Example 3 B in 50 cm of anhydrous ether, 3 4 cm of butyllithium (2.5M) is added dropwise under an inert atmosphere.

After two hours of stirring at room temperature, 25 of the intense red solution, 1 cm of dichlo-romethane is added and then 1.65 g of methyl formyl-A benzoate in solution in dichloromethane, protected from the light. Stirring is continued for two hours at room temperature. The reaction medium 2 is poured over 100 cm of an ammonium chloride solution and extracted with ether. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. A yellow oil is obtained, which is purified by chromatography on silica gel (eluent = 35 hexane / ethyl acetate 95/5). 1.7 g of a ♦ 21 yellow oil are obtained. The 1H spectrum in nuclear magnetic resonance corresponds to the expected structure.

EXAMPLE 5 = Synthesis of trans acid (5,8-methano-tetrahydro-S ^,? ^ 5 naphthyl-2) -2 propenyl] -4 benzoic acid (compound of formula (I) in which R. is a benzene ring and A to I 4.

COOH meaning) 1.5 g of the methyl ester of Example A are dissolved, protected from light, in 20 cm 3 of ethanol at 50 ° C. 3 × 10 20 cm of a aqueous 6N potassium solution and stirred for four hours while maintaining the temperature at 50 ° C. The methanol is evaporated under reduced pressure and the aqueous phase is acidified with 2N hydrochloric acid. The expected product is extracted with 15 l ether The organic phase is dried over magnesium sulphate and concentrated under reduced pressure After recrystallization from ethyl acetate, 850 mg of a pure white product are recovered.

Molecular mass found: 30420 Melting point: 205-206 ° C.

22 EXAMPLE 6

Synthesis of trans-methano-5,8 tetrahydro-5,6,7,6 (^ -methyl styryl) -2 naphthalene (compound of formula (I) in which R ^ represents a benzene ring and A has the significance-5 tion H) To a suspension of 7.5 g of the bromide of Example 3 3 * · B, in 75 cm of isopropanol, 1.55 cm of benzaldehyde and 4.2 g of potassium carbonate are added. The reaction mixture is brought to reflux for 10 hours, then filtered through a sintered glass and concentrated under reduced pressure. 4.2 g of a colorless oil are obtained, which is purified by chromatography on silica gel (eluent = hexane / ethyl acetate 95/5).

2 g of an oil are obtained which crystallizes from iso-15 propanol in the freezer.

Molecular mass found: 260 e Melting point: 33 ° C

The analysis of the product obtained gives the following results: 20 ___

C H analysis

Theoretical 92.26 7.74

Found 92.24 7.79 25 s EXAMPLE 7

Synthesis of trans-methano-5,8 tetrahydro-5,6,7,8 (methyl-41 ft-methyl-styryl) -2 naphthalene (compound of formula (I) ^ in which represents a benzene ring and A has the ^ Meaning CH 3) To a suspension of 7.5 g of the bromide of Example 3 B, in 70 cm of isopropanol, 1.70 cm of toluylaldehyde and 4.2 g of potassium carbonate are added. The reaction mixture is brought to reflux of isopropanol 35 for 4 hours, then filtered through sintered glass and concentrated under reduced pressure. 2.3 g of a colorless oil are obtained after chromatography on silica gel (eluent = hexane). The product crystallizes in isopropanol, in the freezer. The nuclear magnetic resonance H spectrum 5 corresponds to the expected trans structure.

Molecular mass found: 274 t

Melting point: 59 ° C.

EXAMPLE 8

Synthesis of trans-methano-5,8 tetrahydro-5,6,7,8 (methvl 10 sulfonyl-4 'y $ —methylstyryl) -2 naphthalene (compound of formula (I) in which represents a benzene ring and A has the meaning SO ^ CH ^) To a suspension of 4.2 g of bromide of Example B, in 60 cm of isopropanol, 1.8 g of methyl-15-sulfonyl-4-benzaldehyde and 2.90 g of carbonate are added potassium. The reaction mixture is brought to reflux of the iso-? propanol peridant 4 hours, then filtered through sintered glass.

1.65 g of product are recovered, which crystallizes in the filtrate. The product is purified by chromatography on silica gel (eluent = dichloromethane). 1.2 g of white crystals are obtained. The H spectrum in nuclear magnetic resonance corresponds to the expected trans structure.

Molecular mass found: 338 25 Melting point: 152 ° C.

24 EXAMPLE 9

The following composition is prepared: ". - Compound of Example 2 ......................... 0.1 g - Polyethylene glycol (average molecular weight b 5 = 400) ... ................................ 60.0 g - Polyethylene glycol (average molecular weight = 4000) ..... ............................. 25.0 g - Vaseline oil ... qs ......... ............... 100.0 g

A suspension is thus obtained constituting a water-removable ointment. This preparation is used 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.

Ί 5 EXAMPLE 10

The following composition is prepared: - Compound of Example 1 ......................... 0.15 g - Mixture of lanolin alcohols emulsifiers and ^ waxes and refined oils based on hydrocarbons - 20 sold by BDF MEDICAL under the name of "Eucerin anhydrous" ....................... 40.0 g - Preservatives ... qs ...

- Sterile demineralized water ... qs ................ 100.0 g

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.

EXAMPLE 11 The following composition is prepared: - Compound of Example 3 ......................... 1.0 g - Sodium dodecyl sulfate. ...................... 0.78 g ~ - Propanediol-1,2 ................. ............... 1.56 g - Cetyl alcohol ............................ ... 19 »50 g 35 - Thick vaseline oil ...................... 19.50 g 25 - 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 demarcated spots of psoriasis and is applied one to three times a day; good results are obtained within a period of between 6 and 12 weeks according to the gravity of the case treated.

EXAMPLE 12 The following composition is prepared: - Compound of Example 5 ....................... 0.050 g - Wheat starch ..... ....................... 0.265 g - Dicalcium phosphate ...................... ... 0.040 g - Lactose (variety "fine crystals") ............ 0.040 g 15 - Talc ................... ...................... 0.010 g - Magnesium stearate ...................... .. 0.005 g

0.4 g tablets are thus obtained. These r. Tablets are to be taken twice a day for the treatment of psoriatic arthritis and there is a significant improvement after about 30 days.

EXAMPLE 13

The following composition is prepared: - Compound of Example 4 ....................... 0.05 g - Glycerin ........ ............................ 2.40 g 25 - Sorbitol 70% ............ .................. 2.00 g - Sucrose ... 0.10 g - Sodium farahydroxybenzoate ............... 0.08 g - Aroma..qs ....................................

- Purified water ... qs ........................... 10.00 ml 30 An oral suspension is thus obtained which - packaged in 10 ml ampoules. This oral suspension is used for the treatment of particularly severe cases of acne and psoriatic arthritis in one to three ingestion per day; a significant improvement is obtained after approximately 30 days.

26

EXAMPLE U

The following composition is prepared: i, - Compound of Example 5 ........................ 0.001. g - Sodium chloride ............................ 0.8 g; 5 Citric acid / soda buffer ... qs ............. pH 6 - Water for injection ... qs ......... 10Ç ml

This gives an injectable solution intravenously. This solution is used for the treatment of epithelial tumors.

10 EXAMPLE 15

An anti-seborrheic lotion is prepared as follows: / 3 To a solution consisting of 10 cm 3 of ethanol 3 at 95 ° and 30 cm of polyethylene glycol (molecular weight: about 400) containing 20 mg of butylhydroxy-toluene, 0.1 g of the compound of Example 6 is added.

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.

It is understood that the embodiments described above are in no way limiting and may give rise to any desirable modifications, without departing from the scope of the invention.

13

Claims (21)

27 1. Chemical compound corresponding to the formula, general (I); 5HH CH3 hÀA / V '™ Icxh2 I II XH 10 IIHH formula in which the group is in the cis or trans position relative to the methyl group, R ^ being an unsaturated group which may have one of the following two meanings: 1. a polyene chain of formula (II) "and" 20 "H ÇHj 1 Ni HH 25 in which the substituents of each of the two double bonds can be in cis or in trans, the group A being taken from the group formed by a group CH ^ OR ', in which R' represents hydrogen or an alkyl radical C ^ -C ^, and a group COR ^, in which - R ^ represents a hydrogen atom, an alkoxy radical C ^ -C ^., Aryloxy, benzyloxy, amino, alkyl C ^ -C ^, a hydroxyl radical and the corresponding carboxylic acid salts, or else a sugar residue; 2. a benzene nucleus of formula (III) 28 "H; HC ^ S / A3 (III) I II / C% C / CH A 10 the group A ^ of formula (III) being taken from the group formed by meanings given above for the group A ^, a hydrogen atom, an alkyl radical C1-C ,, an alkylthio group SR ", alkylsulfinyl SR", I η Φ o alkylsulfonyl SO ^ R "» in which R "represents an alkyl group and the corresponding isomers. "2 - A compound according to claim 1, in which ~ T 'A2 or A ^ represents a radical COR ^ and in which R ^ represents an alkoxy. C ^ -C ^, characterized in that R ^ is a radical OR ^, R3 being chosen from the group formed by the radicals methyl, ethyl, propyl, butyl, hexyl, or an alkyl C ^ -C ^ substituted by one or more hydroxyls and, in particular, hydroxy-2 ethyl, hydroxy-2 propyl, dihydroxy-2,3 propyl or (dihydroxy-1,3) propyl-2. 3 - Compound according to claim 1, in which A2 or A3 represents a radical CO2 and in which R2 represents a hydroxyl, characterized in that the said carboxylic group is salified by a strong base, such as sodium hydroxide or potassium hydroxide, or with a skin compatible amine such as triethanolamine. A - Compound according to claim 1, in which A ^ or A ^ is a radical COR ^ and R ^ is an aryloxy of formula // 29 O-aryl, characterized in that the aryl radical of R0 corresponds to the formula ( IV) Λ · (L '> * ^ r4 5 - (T ^ CH Il -1-R5 (iv) HO CH CH 10 formula in which R ^ and R ^ represent, independently of one another, an atom hydrogen, a C 1 -C 4 alkyl radical, a hydroxyl, a halogen atom, a carboxyl group or a trifluoromethyl. 5 - A compound according to claim 1, in which - ^ which A2 or A '^ represents a radical C0R2 and R2 is a benzyloxy of formula 0-benzyl, characterized in that the radical * "benzyl de * R2 corresponds to the formula (V) 20 - CH, —C ^ CH (V) 2. ii - I— * 5 25 CH JW formula in which R ^ and R ^ represent, independently of one another, a hydrogen atom, a C 1 -C 4 alkyl, a hydroxyLe, a halogen atom, a carboxyl or trifluoromethyl. 6. Compound according to claim 1, in which A ^ or A ^ is a radical COR ^ and R ^ represents an amino of formula NR ^, characterized in that Rg and R ^ 3 represent, independently one of the other, a hydrogen atom, a linear or branched C 1 -C 4 alkyl, whether or not substituted by one or more hydroxyls, one of the two * radicals R ^ or R ^ may also be , when the other 5 is a hydrogen atom, an amino acid residue, a glucosamine residue, an aryl radical of formula (IV) or a benzyl radical of formula (V), formulas (IV) and ( V * ·) in which R, and Rc represent, independently of each other, a hydrogen atom, a C 1 -C 4 alkyl, a hydro-10 xyl, a halogen atom, a carboxyl or trifluoromethyl. 7. Compound "according to claim 1, in which R ^ is a polyene chain of formula (II) in which 2 is numbered the carbon carrying the group A ^} 3 the carbon bearing CH ^ and A the next adjacent carbon of the chain, characterized in that the structures at the level of carbons 2 and A are 2- E, AE, * or 2-Z, AZ ,. or 2-E, A-Z, where again 2-Z, A-E. * ^ 8 -, Process for the preparation of a compound according to one - of claims 1 to 7, --------------------------- ------- 20 ---- characterized in that, in a first step, the 2-acetyl benzonorbornene is reduced with sodium borohydride to obtain the corresponding secondary alcohol; that, in a second step, the phosphorus tribromide is made to act on the abovementioned secondary alcohol to obtain the corresponding bromide; in a third step, the triphenylphosphine is made to act on the product to obtain the corresponding triphenylphosphonium bromide; and that ', in a fourth step, after purification of the compound obtained, it is reacted, by a Wittig reaction, - 30 on an aldehyde HCOR ^ where R has the meanings indicated in claim 1, to obtain the product of formula (I). 9. Drug composition t characterized by the fact that it comprises, in a pharmaceutically acceptable carrier, at least one compound according to one of claims 1 to 7. 10. Composition according to Claim 9, characterized in that it is intended for the treatment of 5 dermatological conditions linked to a disorder of kera- = 5 tinization (differentiation-proliferation) and dermatological conditions with an inflammatory component and / or immunoallergic and, in particular, acne, ichthyosis and ichthyotic states, Darier's disease, palmoplantar keratoderma, leukoplakias and leukoplasiform states, all benign or malignant dermatological proliferations, lichen and psoriasis, or to treat rheumatic conditions such as psoriatic arthritis. 11. Composition according to one of claims 15. or 10, characterized in that the concentration of compound (s) according to one of claims 1 to 7 is v between 0.0005 and 2% by weight. 12. Composition according to claim 11, charac-terized in that the weight concentration of 20 compound (s) according to one of claims 1 to 7 is between 0.01 and 1% by weight. 13. Composition according to one of claims 9 to 12, characterized in that it can be used enterally. 25 14 - Composition according to claim 13, usable orally, characterized in that it is' administered in an amount of about 2 ^ g up to 2 mg of compound (s) according to one of claims 1 at 7, per day per kg of body weight. 15 15 - Composition according to one of claims 9, to 12, characterized in that it is in the form of solution or suspension intended to be administered parenterally. 'R t / f 32 \% 16. Composition according to claim 15, charac-terized in that it is administered in an amount of '2 ^ g up to 2 mg of compound (s) according to one of claims 1 to 7, per day and per kg of weight cor-5 porel. j 17- Composition according to one of claims L 15 or 16, characterized in that it contains, per ml of solution or suspension, from 0.01 to 1 mg of compounds) according to one of claims 1 to 7. 18 18- Composition according to one of claims 9 to 12, 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 so.us form of solution, characterized in that it contains from 0.001% to 0.3% by weight of compound (s). According to one of the claims 1 to 7. 20 20 - 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) according to one of Claims 1 to 7- 21. Composition according to Claim 9, characterized in that the carrier is pharmaceutically. acceptable composition contains at least one product taken from the group formed by water, gelatin, lactose, starch, talc, petroleum jelly, gum arabic, polyalkylene glycols, stearate 30 magnesium, thinners, solvents, thickeners. I'm 33s 22. Cosmetic composition, characterized in that it contains, in a cosmetically acceptable carrier L, at least one compound according to one of claims 1 to 7. 23. Composition according to claim 22, characterized in that it finds an application in personal and hair hygiene, and in particular in the treatment of acne, seborrhea, hair loss, for hair regrowth and in protection 10 against the harmful effects of the sun. 24. Composition according to one of claims 22 or 23, characterized in that the compound (s) according to one of claims 1 to 3 is present at a concentration of between 0.0005 and 2% by weight And preferably between 0.01 and 1%. 25. Composition according to claims 22 to 24 characterized in that it is in the form of a lotion, gel, cream, soap or shampoo. 26. Composition according to one of claims 9 20 to 25, characterized in that it contains inert or pharmacodynamically or cosmetically active additives. 27. Composition according to claim 26, characterized in that the additives are taken from the group formed by hydrating agents, anti-seborrheic agents, antibiotics, agents promoting the regrowth of hair, anti agents -inflammatory, carotenoids, anti-psoriatic agents, flavoring agents, preserving agents, stabilizing agents, moisture regulating agents, pH regulating agents, pressure modifying agents osmotic, emulsifying agents, UV-A and UV-B filters and antioxidants. Drawings: .......... plates —i.fr-pages of which ........ has ...... cover page ....... Description pages .. ............... pesos of claim ·,,, ......... short description Luxembourg on -, S £ f, y The representative:, /