CH673027A5 - - Google Patents

Description

DESCRIPTION

The present invention relates to new chemical compounds consisting of derivatives of chroman and thiochroman, as well as the preparation process for obtaining these new compounds. The present invention also relates to the use of these new compounds either in cosmetics, or in human and veterinary medicine, as pharmaceutical preparations, in particular in the treatment of dermatological conditions linked to a disorder of keratinization (differentiation, proliferation), in the treatment dermatological or other affections with an inflammatory and / or immunoallergic component, in the treatment of certain rheumatic affections such as rheumatoid psoriasis, in the treatment of cutaneous or respiratory atopy, degenerative diseases of the connective tissue and tumors, as well as in ophthalmology, in particular in the treatment of corneopathies.

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”, volume 34, pages 1105-1119 (1978)]; this action in the treatment of cutaneous proliferation, acne, psoriasis and similar affections will be designated hereafter by the generic expression “action of retinoid type”. It has been found that products having a structure similar to vitamin A also exhibit a retinoid-like action, but that the side effect of toxic hypervitaminosis 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, No. 1, pages 9-15); P. Loeliger et al. describes, in this last publication, a derivative of formula (a):

C02C2H5

It has been found, according to the invention, that it was possible to replace the benzene nucleus of the above-mentioned compound with a chroman or thiochroman nucleus and that other substitutions could be provided on the side chain of said compound, without losing for that the benefit of retinoid action.

The present invention therefore firstly relates to the new industrial product which constitutes a new chemical compound corresponding to the general formula (I):

(I)

formula in which:

- X represents - O— or —S—;

- Rj, R2, R3 and R4 independently represent a hydrogen atom or a linear or branched Q-Cö alkyl radical, and

- A represents:

a) or a radical of formula (II):

30

50

(at)

(II)

formula in which R7 represents:

- a radical of formula (III):

-CH2OR8

formula in which Rs represents:

- a hydrogen atom;

- a C2-C6 alkyl radical;

- a C 2 -C 6 mono- or polyhydroxyalkyl radical;

- a radical of formula (IV):

-C-R9

II

O

formula in which R9 represents:

- a hydrogen atom;

- a C1-Ca alkyl radical;

- a radical

(III)

(IV)

-NOT.

where R 'and R ", identical or different, represent a hydrogen atom, an alkyl radical Cj-Ce, an alkenyl radical C3-C6, R' and R" can form a heterocycle with the nitrogen atom to which they are connected, the radical

, R '

CH30

which may also be the residue of an amino acid or an amino sugar, or

- a radical - O — R10, where R10 represents a hydrogen atom, an alkyl radical CI-C20, a mono- or polyhy-droxyalkyl C2-C6 radical, the group - O — Ri0 can also be derived from a sugar ;

b) or a radical of formula (V):

673,027

5 R7

00

formula in which:

- R, has the meaning indicated above, and

- Rs and R6 represent, independently, a hydrogen atom or an alkyl radical, linear or branched, in CVQ;

and the geometric or optical isomers of the compounds of formula (I), as well as their salts.

Among the QQ alkyl radicals which can be particularly used in the meanings of the radicals Rj to R6, Rs and R9, R 'and R ", mention may be made of the methyl, ethyl, isopropyl, butyl and tert-butyl radicals and, preferably, for Rt at R6, the methyl radical.

Among the C1-C20 alkyl radicals which can be particularly used in the meanings of the radical R10, mention may preferably be made of methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.

When the radical R10 represents a mono- or polyhy-droxyalkyl in C2-C6, this one is, preferably, the radical hydroxy-2 ethyl, the radical dihydroxy-2,3 propyl or the rest of pentaerythri-tol.

Among the C3-C6 alkenyl radicals which can be used in the meanings of the radicals R 'and R ", mention will be made, in particular, of the propenyl, butenyl and isopentenyl radicals.

When the radicals R 'and R "form a heterocycle with the nitrogen atom to which they are attached, the latter is preferably a piperidino, morpholino, piperazino, pyrrolidino or (2-hydroxyethyl) -4 radical. piperazino.

When the group - O — R10 is derived from a sugar, the latter is, for example, glucose, mannitol or erythritol.

The compounds of formula (I) or their isomers can be in the form of their salts; they may be either zinc salts, an alkali or alkaline earth metal or an organic amine, when they contain at least one free acid function, or salts of a mineral or organic acid, in particular hydrochloride , bromhydrate or citrate, when they contain at least one amine function.

Among the particularly preferred compounds according to the invention, mention may be made of those corresponding to the following general formulas:

X

(the)

formulas in which:

- X represents - O— or —S—, and

- R9 represents a radical

-not;

/ \

r '

r "

CH

17

(Ib)

Or a radical —O — R10, R ′ and R ″ representing a hydrogen atom or a Ct-C6 alkyl radical and R10 representing a hydrogen atom, a CrC20 alkyl radical or a C2-C6 mono- or polyhydroxyalkyl radical .

Among the preferred compounds of formula (la), mention may be made of the following compounds:

- [(methoxycarbonyl-4'-phenyl) -4-methyl-3-butadiene-1 E, 3E] -yl-6-dimethyl 1-4,4-chroman;

- [(methoxycarbonyl-4'-phenyl) -4-methyl-3-butadiene-1E, 3E] -yl-6-dimethyl-4,4-thiochroman;

- [(carboxy-4'-phenyl) -4-methyl-3-butadiene-1 E, 3E] -yl-6-dimé-thyl-4,4-chromane;

- [(carboxy-4'-phenyl) -4-methyl-3-butadiene-1E, 3E] -yl-6-dimé-thyI-4,4-thiochroman, and

- [(ethylaminocarbonyl-4'-phenyl) -4-methyl-3-butadiene-3o 1 E, 3E] -yl-6-dimethyl-4,4-chroman.

Among the preferred compounds of formula (Ib), mention may be made of the following compounds:

- [(methoxycarbonyl-4'-phenyl) -4-methyl-3-butadiene-1Z, 3E] -yl-6-dimethyl-4,4-chromane;

35 - [(methoxycarbonyl-4'-phenyl) -4-methyl-3-butadiene-1Z, 3E] -yl-6-dimethyl-4,4-thiochroman;

- [(carboxy-4'-phenyl) -4-methyl-3-butadiene-1Z, 3E] -yl-6-dimé-thyl-4,4-chromane, and

- [(carbòxy-4'-phenyl) -4-methyl-3-butadiene-1 Z, 3E] -yl-6-dimé-40 thyl-4,4'-thiochromane.

Among the preferred compounds of formula (Ie), the following compounds may be mentioned:

- [(ethoxycarbonyI-6-dimethyl-l, 5-hexatriene-lE, 3E, 5E] -yl-6-dimethyl-4,4-chromane, and

45 - [carboxy-6-dimethyl-1,5-hexatriene, 1 E, 3E, 5E] -yl-6-dimethyl-4,4-chromane.

The present invention also relates to a process for the preparation of the new compounds of formula (I), including their geometric and optical isomers, and their salts. According to the invention, the synthesis of the compounds of formula (I) consists in reacting a compound of formula (VI):

R,

(VI)

on a compound of formula (VII):

(VII)

formulas in which R ,, R2, R3, R4 and A have the meanings

673,027

6

indicated above, provided that R7 cannot represent the group of formula (IV):

-C-Rp (IV)

II

O

when R9 is a hydrogen atom or an alkyl radical C, -C6, the groups B1 and B2, in the formulas respectively (VI) and (VII) above, representing, one, an oxo group, while the other is:

a) or a triarylphosphonium group of formula (VIII):

—P [Q] ® Y® (VIII)

formula in which:

- Q is an aryl group, and

- Y is a monovalent anion of an organic or inorganic acid;

b) or a dialkoxyphosphinyl group of formula (IX):

-P [Z] 2 (IX)

• L o formula in which Z represents an alkoxy residue Q-Cg.

In the case where Bt and B2 represent, one, an oxo group, and the other, a triarylphosphonium group of formula (VIII), the condensation of the compounds of formulas (VI) and (VII) is carried out in the presence of an alkali metal alcoholate such as sodium methylate, in the presence of an alkali metal hydride such as sodium hydride, or in the presence of butyllithium, in a solvent such as tetrahydrofuran or dimethylformamide, condensation can also be carried out in the presence of an alkaline carbonate such as potassium carbonate, in an alcohol such as isopropanol, or in the presence of an alkylene oxide optionally substituted by an alkyl group, optionally in a solvent such as dichloromethane, the reaction temperature being between -80 ° C and the boiling temperature of the reaction mixture.

When B, and B2 represent, one, an oxo group, and the other, a dialkoxyphosphinyl group of formula (IX), the condensation of the compounds of formulas (VI) and (VII) is carried out in the presence of a base and preferably in the presence of an inert organic solvent, for example by means of sodium hydride in benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane or also by means an alcoholate, for example by means of sodium methylate in methanol. This condensation can also be carried out using a mineral base such as potassium hydroxide or sodium hydroxide in an organic solvent such as tetrahydrofuran or also by means of an alkali carbonate, for example by means of potassium carbonate in water, or again by means of butyllithium in tetrahydrofuran. It is possible to add to the reaction mixture a crown ether capable of complexing the metal cation contained in the base and thus making it possible to increase the strength of the latter. The reaction temperature is between - 80 ° C and the boiling temperature of the reaction mixture.

The compounds of formulas (VI) and (VII) are known compounds or which can be prepared by known methods.

The compound of formula (I), obtained by the preparation process according to the invention, can undergo functional modifications of the substituent R7. Among the functional modifications of this substituent R7, mention will be made, for example, of the saponification of a carboxylic acid ester or the reduction of the carboxylic acid ester group to the hydroxymethyl group. The hydroxymethyl group can also be oxidized to formyl group, or else be esterified or etherified. On the other hand, a carboxyl group can be converted to a salt, an ester, an amide, an alcohol, an acetyl group or to the corresponding acid chloride. A carboxylic acid ester group can be converted to an acetyl group. The acetyl group can be converted to the secondary alcohol group by reduction, and the secondary alcohol group can itself be alkylated or acylated by known procedures. All these functional modifications can be carried out by procedures known in themselves.

The compounds of formula (I) are obtained in the cis / trans mixture which can be separated, if desired, in a manner known per se, into pure compounds of the eis or trans type.

The compounds of formula (I) according to the present invention, including their isomers and their salts, have an activity ranging from “good” to “excellent” in the test for inhibition of ornithine decarboxylase after induction, by “ tape Stripping ", in the naked rat [M. Bouclier et al., "Dermatologica", page 169, No. 4 (1984)]. This test is accepted as a measure of the action of retinoids on the phenomena of cell proliferation.

The compounds according to the invention also exhibit enhanced activity in the differentiation test of mouse embryonic teratocarcinoma cells (F9 cells: “Cancer Research”, 43, page 5268,1983).

These compounds are particularly suitable for treating dermatological conditions linked to a disorder of keratinization (differentiation, proliferation), as well as dermatological conditions, or others, with an inflammatory and / or immunoallergic component, in particular:

- vulgar, comedonian or polymorphic acnes, senile, solar acnes, and medicinal or professional acnes;

- widespread and / or severe forms of psoriasis, and other keratinization disorders, and in particular ichthyoses and ich-tyosiform states;

- Darier's disease;

- palmoplantar keratoderma;

• - leukoplakias and leukoplasiform states, lichen planus;

- any benign or malignant, severe or extensive dermatological proliferation.

They can also be recommended in epidermolysis bullosa dystrophic and in the molecular pathology of collagen. They also find application in carcinomas induced by ultraviolet rays (solar carcinogenesis), in wart-skin epidermodysplasia and related forms.

They are also active for certain rheumatic affections, in particular rheumatoid psoriasis, as well as in the treatment of atopy, whether cutaneous or respiratory. These compounds also find application in the ophthalmological field, in particular in the treatment of corneopathies.

The present invention therefore also relates to medicinal compositions containing at least one compound of formula (I) as defined above and / or one of its isomers and / or one of its salts.

The present invention thus 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) and / or one of its salts and / or one of its isomers.

The compounds according to the invention are generally administered at a daily dose of approximately 2 ng / kg to 2 mg / kg of body weight.

As support for the compositions, any conventional support can be used, the active compound being either in the dissolved state or in the dispersed state in the support.

The administration of the compositions according to the invention can be carried out by enteral, parenteral, topical or ocular route. For the enteral route, the drugs can be in the form of tablets, capsules, dragees, syrup, suspension, solution, powder, granules, emulsion. For the parenteral route, the compositions may be in the form of a solution or a suspension for infusion or for injection.

For the topical route, the pharmaceutical compositions based on compounds according to the invention are in the form of an ointment, tincture, cream, ointment, powder, patch, soaked tampon, solution, lotion, gel, spray or suspension or emulsion. These compositions preferably contain 5

10

15

20

25

30

35

40

45

50

55 '

60 i

65 i

7

673,027

rence, from 0.0005 to about 2% by weight of compound (s) of formula®.

The compositions which can be used topically can be presented either in anhydrous form or in aqueous form according to the clinical indication. , 5

For the ocular route, the compositions are mainly eye drops.

The compounds of formula (I) according to the invention also find an application in the cosmetic field, in particular in body and hair hygiene, and in particular in the treatment of acne prone skin, for hair regrowth or action against hair loss, to fight against the oily appearance of the skin or hair, as well as for the treatment of physiologically dry skin. Finally, they have a preventive and curative power against the harmful effects of the sun. 15

The present invention therefore also relates to a cosmetic composition containing, in a cosmetically acceptable carrier, at least one compound of formula (I) and / or one of its salts and / or one of its isomers, this composition being in particular in the form of a lotion , gel, cream, soap, shampoo or the like. 2o

The concentration of compound (s) of formula (I) in the cosmetic compositions according to the invention is between 0.0005 and 2% by weight and, preferably, between 0.01 and 1% by weight.

The medicinal and cosmetic 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 or anti-acne agents such as S-carboxymé-thylcystéine, S-benzylcystéamine and their derivatives, tioxolone or even benzoyl peroxide; antibiotics, such as erythromycin and its esters, neomycin, tetracyclines or polymethyl-4,5-isothiazolinones-3; agents promoting hair regrowth, such as Minoxidil (diamino-2,4 piperidino-6 pyrimidine-oxide-3) and its derivatives, anthralin and its derivatives, Diazoxide (chloro-7 methyl-3 benzothiadiazine-1, 2.4 dioxide-1,1) and Phenytoin (5,5-diphenyl imidazolidinedione-2,4); steroidal and nonsteroidal anti-inflammatory agents; carotenoids and, in particular, P-carotene; antipsoriatic agents such as anthralin and its derivatives and eicosatetraynoic-5,8,11,14 and -triynoï-que-5,8,11 acids, their esters and their amides. 40

The compositions according to the invention can also contain flavor-enhancing agents, preserving agents, stabilizing agents, humidity-regulating agents, pH-regulating agents, agents for modifying osmotic pressure, emulsifying agents, UV-A and UV-B filters, antioxidants such as α-tocopherol, butylhydroxyanisole or butylhy-droxytoluene.

To better understand the object of the invention, we will now describe several embodiments.

Example 1

Preparation of a compound of formula:

a) 4.85 g of trimethyl-4,4,6 chromane are dissolved in 150 cm 3 of anhydrous carbon tetrachloride. 5 g of N-bromosuc-cinimide and 0.05 g of azobisisobutyronitrile are added. The mixture is heated for 65 1 hour at reflux under UV irradiation. After cooling, the juice-cinimide formed is filtered and the solution is washed with 150 cm3 of a saturated solution of sodium bicarbonate. After drying the organic phase, the solvent is evaporated. 4.59 g of bro-momethyl-6,4-dimethyl-4,4 chromane are obtained.

b) 5.8 g of 6-bromomethyl-4,4-dimethyl chromane obtained above are dissolved in 150 cm 3 of toluene. 6.6 g of triphé-nylphosphine are added. The reaction mixture is heated at 100 ° C for 6 hours. After evaporation of the solvent, the solid residue is reduced to powder and washed several times with ether. 10.64 g of [(dimethyl-4,4-chromanyl-6) methyl] triphenylphosphonium bromide are obtained in the form of a white powder.

c) 15.4 g of the phosphonium bromide obtained above are suspended in 250 cm3 of anhydrous tetrahydrofuran. 1.1 equivalent of n-butyllithium in 1.6N solution in hexane are added at 0 ° C. After 15 minutes at 0 ° C., the excess butyllithium is destroyed by the addition of 20 cm 3 of anhydrous dichloromethane. The mixture is then cooled to -78 ° C. and 0.95 equivalent of (methoxycarbonyl-4-phenyl) -3-methyl-2-propene-2-al dissolved in 15 cm3 of anhydrous dichloromethane. Leave to react for 30 min at -78 ° C. and finally allow the temperature to rise to ambient in 2 hours. The reaction mixture is poured onto 200 cm3 of a saturated solution of ammonium chloride. After dilution with 50 cm3 of water, the aqueous solution is extracted with 2 times 100 cm3 of ether. The organic phase is dried over sodium sulphate and quickly filtered through silica gel. After evaporation of the solvent and recrystallization from hexane, 3.58 g of expected product is obtained having the following characteristics:

- melting point: 113 ° C

- the 1H nuclear magnetic resonance spectrum (200 MHz, CDCI3) corresponds to the expected structure

Elementary analysis for C24H2603:

Calculated: C 79.53 H 7.23%

Found: C 79.69 H 7.37%

Example 2

This compound is obtained from the mother liquors of recrystallization of the compound of Example le.

It has the following characteristics:

- melting point: 83 ° C

- the nuclear magnetic resonance spectrum 'H (200 MHz, CDCI3) corresponds to the expected structure

Elementary analysis for C24H2fi03:

Calculated: C 79.53 H 7.23%

Found: C 79.77 H 7.51%

Example 3

Preparation of a compound of formula:

673,027

8

2.17 g of the compound obtained in Example 1c are heated for 1 hour at 50 ° C. in a mixture containing 70 cm 3 of water, 50 cm 3 of ethanol and 20 g of sodium hydroxide. After cooling, the mixture is diluted by adding 300 cm 3 of water and the ethanol is distilled under reduced pressure. The residual aqueous solution is acidified to pH 2 with a 10% hydrochloric acid solution. The acid, which precipitates, is filtered and then washed with water. After recrystallization from acetone, the expected product is obtained in the form of a yellow solid having the following characteristics:

- melting point: 188 ° C (with decomposition)

- the 1H nuclear magnetic resonance spectrum (200 MHz, CDCI3) corresponds to the expected structure

Elementary analysis for C23H24.O3:

Calculated: C 79.28 H 6.94%

Found: C 79.20 H 7.02%

Example 4

Preparation of a compound of formula:

This compound is obtained according to the procedure described in Example 3 in which the compound of Example 1c is replaced by the compound of Example 2. After recrystallization from acetone, the expected product is obtained in the form of '' a yellow solid with the following characteristics:

- melting point: 150 ° C (with decomposition)

- the nuclear magnetic resonance spectrum 'H (200 MHz, CDCI3) corresponds to the expected structure

Elementary analysis for C23H24.03:

Calculated: C 79.28 H 6.94%

Found: C 79.24 H 7.07%

Example 5

Preparation of a compound of formula: Q

II

1.2 g of the compound obtained in Example 3 are dissolved in 80 cm 3 of tetrahydrofuran. Cooled to 0 ° C and introduced, under argon, about 1.5 equivalent of diimidazolesulfonyl in solution in tetrahydrofuran. The mixture is left at 0 ° C. for 5 min, then 10 cm 3 of ethylamine are added. The mixture is stirred for 30 min at room temperature. The reaction mixture is washed twice with 80 cm3 of water. The organic phase is dried over magnesium sulfate. After evaporation of the solvent and recrystallization from acetone, 670 mg of expected product is obtained having the following characteristics:

- melting point: 186-187 ° C

- the nuclear magnetic resonance spectrum 'H (200 MHz, CDCI3) corresponds to the expected structure

Elemental analysis for C25H29NO2: Calculated: C 79.96 H 7.78 N3.73% Found: C 79.79 H 7.92 N3.74% Example 6

Preparation of the compounds of formula:

C02CH3

These compounds are obtained according to the procedure described in Example 1e in which the bromide of [(dimethyl-4,4-chromanyl-6) -methyljtriphenylphosphonium is replaced by the bromide of [(di-methyl-4,4-thiochromanyl -6) -methyl] triphenylphosphonium. The products are obtained with a yield of 80% in the form of a mixture of Z, E (45%) and E, E (55%) isomers, the proportions of which were determined by 1H nuclear magnetic resonance.

The E, E isomer is isolated from the reaction mixture by crystallization and has the following characteristics:

- melting point: 110-112 ° C

- the 1H nuclear magnetic resonance spectrum (200 MHz, CDCI3) conforms to the expected structure

Elementary analysis for C24.H2602S:

Calculated: C 76.15 H 6.92%

Found: C 76.19 H 7.19%

The Z, E isomer is obtained from the mother liquors of crystallization by chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent; it has the following characteristics:

- melting point: 84-86 ° C

- the nuclear magnetic resonance spectrum 'H (200 MHz, CDCI3) conforms to the expected structure

Elementary analysis for C ^ H ^ OjS:

Calculated: C 76.15 H 6.92%

Found: C 76.20 H 7.13%

Example 7

Preparation of a compound of formula:

This compound is obtained according to the procedure described in Example 3 in which the compound of Example 1c is replaced by the compound of Example 6 in the form of the E, E isomer.

5

10

15

20

25

30

35

40

45

50

55

60

65

9

673,027

The product obtained has the following characteristics:

- melting point: 178 ° C (with decomposition)

- the nuclear magnetic resonance spectrum * H (200 MHz, CDC13) corresponds to the expected structure

Elementary analysis for C23H2402S:

Calculated: C 75.82 H 6.59 0 8.79 S 8.79%

Found: C 75.31 H 6.77 0 8.94 S 8.17%

Example 8

Preparation of a compound of formula:

This compound is obtained according to the procedure described in Example 3 in which the compound of Example 1c is replaced by the compound of Example 6 in the form of the Z, E isomer.

The product obtained has the following characteristics:

- melting point: 160-165 ° C (with decomposition)

- the nuclear magnetic resonance spectrum 'H (200 MHz, CDCI3) corresponds to the expected structure

Elementary analysis for C23H24O2S:

Calculated: C 75.72 H 6.58%

Found: C 75.65 H 6.55%

Example 9

Preparation of a compound of formula:

a) 10.2 g of aluminum chloride are added in small portions to a solution of 12 g of dimethyl-4,4-chromane and 6 g of acetyl chloride in 105 cm3 of nitromethane under argon. After 6 hours of reaction at room temperature, 100 cm 3 of 6N hydrochloric acid are slowly added. The mixture is stirred for 10 min, then 120 cm3 of ether are added. The organic phase is washed with water, then with a saturated aqueous solution of sodium bicarbonate and, again, with water. After drying the organic phase and distilling off the solvent under reduced pressure, 8.5 g of acetyl-6-dimé-thyl-4,4-chromane are obtained.

b) A solution of 8 g of acetyl-6-dimethyl-4,4-chroman in 50 cm3 of anhydrous ether is added slowly under argon to a suspension of 6 g of aluminum and lithium hydride in 150 cm3 anhydrous ether. The reaction mixture is left under stirring at room temperature for 20 hours. 3 cm3 of ethyl acetate are added, then 10 cm3 of 5% hydrochloric acid. After 5 min of stirring, the organic phase is decanted. The aqueous phase is washed twice with 150 cm3 of ether. The organic phases are combined, then washed with 200 cm3 of 5% potassium carbonate solution, then with 150 cm3 of saturated aqueous sodium chloride solution.

After drying over sodium sulfate, the solvent is distilled under reduced pressure. The residue is purified by crystallization from hexane. 6.3 g of dimethyl-4,4-hydroxyethyl-6-chro-mane are obtained.

C) 10 g of triphenylphosphine are dissolved in 100 cm 3 of ether. Passage of hydrobromic acid gas causes precipitation of triphenylphosphine hydrobromide, which is filtered and used without further purification.

A solution of 6 g of 4,4-dimethyl-6-hydroxyethyl chromane and 10 of 10.3 g of triphenylphosphine hydrobromide in 250 cm 3 of methanol is stirred for 24 hours under argon. The solvent is distilled under reduced pressure. The oily residue is washed with ether until crystallization. After filtration and drying, 13.15 g of the expected phosphonium bromide are obtained.

D) The phosphonium bromide obtained above is condensed on ethoxycarbonyl-5-methyl-4-pentadiene-2E, 4E-al-1 under the same conditions as those described in Example 1c. The crude product is separated from the triphenylphosphine oxide by treatment with hexane. After evaporation of the solvent, the expected product is obtained ([6-ethoxycarbonyl-1,5-dimethyl-1,5 hexatriene-1,3,5] -yl-6 dimé-thyl-4,4-chromane) in the form of a mixture of isomers 1Z, 3E, 5E (33%) and 1E, 3E, 5E (66%). The proportions of each of the two isomers were determined by 1H nuclear magnetic resonance. e) The hydrolysis of the mixture of isomeric esters obtained in 9d is carried out according to the same procedure as that described in Example 3. After recrystallization from acetone, the expected compound is obtained entirely of trans structure. It has the following characteristics:

- melting point: 175 ° C (with decomposition) 30 - the nuclear magnetic resonance spectrum * H (200 MHz, CDCI3) corresponds to the expected structure

Elementary analysis for C20H24O3:

Calculated: C 76.89 H 7.74%

35 Found: C 76.81 H 8.01%

Example A

Preparation of 0.5 g insoluble tablets having the following formulation:

40

- Compound of Example 3 0.050 g

- Lactose 0.082 g

- Stearic acid 0.003 g

- Purified talc 0.015 g 45 - Sweetener q.s.

- Colorant q.s.p.

- Rice starch q.s. 0.500 g

These tablets, at 0.05 g of active compound (compound of Example 3), are obtained by direct dry compression of the mixture of the 50 different constituents above. These tablets are administered 2 to 4 times daily for the treatment of psoriasis.

Example B

Preparation of a gel for topical application having the following formulation 55:

- Compound of example 5 0.05 g

- Ethanol 43.00 g

- a-tocopherol 0.05 g 60 - Crosslinked carboxyvinyl polymer

sold under the trade name "Carbopol 941" by the company

Goodrich Chemical Co. 0.50 g

- Triethanolamine in 20% aqueous solution 3.80 g 6d - Water 9.30 g

- Propylene glycol q.s.p. 100.00 g

This gel is applied to dermatosis skin or acne skin! 3 times a day.

673,027

10

Example C

Preparation of a gel for topical application having the following formulation:

- Compound of Example 6 0.025 g

- Erythromycin base 4,000 g

- Butylhydroxytoluene 0.050 g

- Hydroxypropylcellulose sold under the trade name "Klucel HF"

by Hercules 2,000 g

- Ethanol (95 ") q.s.p. 100,000 g

This gel is applied to acne skin 1 or 2 times a day. Example D

Preparation of a 0.3 g capsule having the following formulation:

- Compound of example 6 0.05 g

- Corn starch 0.06 g

- Lactose q.s.p. 0.3 g The capsules used consist of gelatin, titanium oxide and a preservative; they are administered at a rate of 2 to 4 per day in the treatment of psoriasis.

Example E

Preparation of a sunscreen cosmetic composition having the following formulation:

Composed of Example 1

Benzylidene camphor

Triglycerides of fatty acids (Cs to Ci8)

Glycerol monostearate

Stearic acid

Cetyl alcohol

Lanolin

Preservatives

Propanediol

Triethanolamine

Perfume.

Demineralized water q.s.p.

Example F

Preparation of an antiseborrheic cream having the following formulation:

- Polyoxyethylene stearate (40 moles of ethylene oxide) sold under the trade name "MYRJ 52" by the company Atlas

- Mixture of lauric ester of sorbitol and sorbitan, polyoxyethylenated with 20 moles of ethylene oxide, sold under the trade name "Tween 20" by the company Atlas

■ Mixture of glycerol mono- and distearate sold under the trade name "Géléol" by the company Gattefosse

• Propylene glycol

■ Butylhydroxyanisole Butylhydroxytoluene Cetostearyl alcohol Preservatives q.s.

Perhydrosqualene

Mixture of caprylic-capric triglyceride sold under the trade name "Miglyol 812" by the company Dynamit Nobel S-carboxymethylcysteine Triethanolamine 99%

Compound of example 4 Water q.s.p.

4g

1.8g

4.2 g 10 g 0.01g 0.02 g 6.2 g

20

25

Example G

Preparation of an anti-acne cream having the following formulation:

- Mixture of glycerol stearate and polyethylene glycol (75 moles) sold under the trade name "Gelot 64"

by the company Gattefosse 15g

- Polyoxyethylenated core oil with 6 moles of ethylene oxide sold under the trade name "Labrafil M 2130 CS"

by the company Gattefosse 8 g

- Perhydrosqualene 10 g

- Colorant q.s.

- Curator q.s.

- Perfume q.s.

- Tioxolone 0.4 g

- Polyethylene glycol 400 8 g

- Purified water 58.5 g

- Disodium salt of ethylene acid-

0.05 g diaminetetracetic

- Compound of Example 4 0.05 g

Example H

Preparation of a hair lotion for hair regrowth having the following formulation:

1.00 g 4.00 g 31.00 g 6.00 g 2.00 g 1.20 g 4.00 g 0.30 g 2.00 g 0.50 g 0.40 g 100.00 g

- Propylene glycol

- Ethanol

- Polyethylene glycol 400

- Water

- Butylhydroxyanisole

- Butylhydroxytoluene

- Composed of example 9

- Monoxidil.

Example I

20 g 34.92 g 40 g 4g

0.01g 0.02g 0.05g 1g

40

45

Preparation of an anti-acne cream having the following formulation:

- Polyoxyethylene stearate (40 moles of ethylene oxide) sold under the trade name "MYRJ 52" by the company Atlas

- Mixture of lauric ester of sorbitol and sorbitan, polyoxyethylenated with 20 moles of ethylene oxide, sold under the trade name "Tween 20" by the company Atlas

- Mixture of glycerol mono- and distearate

- Propylene glycol

- Butylhydroxyanisole

- Butylhydroxytoluene 50 - Cetostearyl alcohol

- Preservatives q.s.

- Poyltetrahydrofuran dimethyl ether

- Mixture of caprylic-capric triglycerides sold under the name

55 “Miglyol 812” commercial by Dynamit Nobel

- Composed of example 9

- Water q.s.p.

4g

1.8 g 4.2 g 10 g 0.01g 0.02 g 6.2 g

18g

4g 0.02 g 100 g

18g 60

Example J

It is an anti-acne kit comprising two parts:

a) A gel having the following formulation is prepared: - Ethyl alcohol 4 g - Propylene glycol 3 g 65 - Cross-linked carboxyvinyl polymer 2.5 g sold under the trade name

0.02 g "Carbopol 940" by the company 100 g Goodrich Chemical Co.

48.4 g 50 g lg

11

673,027

Diisopropanolamine 99%

Butylhydroxyanisole Butylhydroxytoluene a-tocopherol Compound of Example 9

A gel having the following formulation is prepared.

Propylene glycol ethyl alcohol

Disodium salt of ethylene acid-

0.3 g diaminetetracetic 0.05 g 0.05 g - Crosslinked carboxyvinyl polymer 0.05 g sold under the name "Carbopol 940"

0.1 g by Goodrich Chemical Co. 1 g

0.1 g 5 - Triethanolamine 99% 1 g

- Sodium lauryl sulfate 0.1 g

- Purified water 75.05 g

- Benzoyl peroxide 25% hydrated 12.8 g

5 g The two gels are mixed extemporaneously, weight i ° for weight.

Claims (24)

673027 i 1. Chemical compound corresponding to the general formula (I): (I) formula in which: - X represents - O— or - S—; ■ - Rj, R2, R3 and R4 represent, independently, a hydrogen atom or an alkyl radical, linear or branched, in Q-C * and - A represents: a) or a radical of formula (II): (II) formula in which R7 represents: - a radical of formula (III): —CH2ORa formula in which Rs represents: - a hydrogen atom; - a Q-Q alkyl radical; - a C 2 -C 6 mono- or polyhydroxyalkyl radical; - a radical of formula (IV): -C-R9 II O formula in which Rg represents: - a hydrogen atom; - a Cx-C6 alkyl radical; - a radical (III) 30 formula in which: R, has the meaning indicated above, and - Rs and Rs represent, independently, a hydrogen atom or an alkyl radical, linear or branched, in Q-Q; and the geometric or optical isomers of the compounds of formula (I), as well as their salts. 2. Compound according to Claim 1, characterized in that the C1-C6 alkyl radicals which are involved therein for the meanings of the radicals R! at R6, R8 and R9, R 'and R "are chosen from the group formed by the methyl, ethyl, isopropyl, butyl and tert-butyl radicals. 3. Compound according to Claim 1, characterized in that the C 1 -C 20 alkyl radical which intervenes therein for the meaning of R10, is chosen from the group consisting of the methyl, ethyl, propyl and 2-ethylhexyl radicals , octyl, dodecyl, hexadecyl and octa-decyl. 4. Compound according to Claim 1, characterized in that the C2 or C6 mono- or polyhydroxyalkyl radicals which are involved in the definition of R10 are chosen from the 2-hydroxy-ethyl, 2,3-dihydroxy-propyl radicals and the rest of pentaerythritol. 5. Compound according to one of claims 1 to 4, in the form of a salt, characterized in that, if the compound of formula (I) comprises at least one free acid function, said salt is chosen from the group formed by the salts of zinc, of an alkali or alkaline earth metal or of an organic amine, and that, if the compound of formula (I) comprises at least one amine function, said salt is chosen from the group formed by the salts of 'a mineral or organic acid and, in particular, the hydrochloride, hydrobromide and citrate. 6. Compound according to claim 1, characterized in that it corresponds to one of the following general formulas (la) to (le): -not: / * ' \ R " where R 'and R ", identical or different, represent a hydrogen atom, an alkyl radical in C ^ Cg, an alkenyl radical in C3-C6, R' and R" being able to form a heterocycle with the nitrogen atom to which they relate, the radical , / R ' -NOT \ r " which may also be the residue of an amino acid or an amino sugar, or A radical —O — R10, where Ri „represents a hydrogen atom, an alkyl radical in Q-Qo, a mono- or polyhydroxyalkyl in C2-C6, the group - O — R10 can also be derived from a sugar; b) or a radical of formula (V): (V) formulas in which: - X represents - O— or —S—, and - R9 represents a radical 65 R ' "V 3 673,027 or a radical —O — R10, R ′ and R ″ representing a hydrogen atom or a C1-Cf alkyl radical, and R10 representing a hydrogen atom, a C1-C20 alkyl radical or a mono- or polyhydroxyalkyl radical C2-C6. 7. Compound according to claim 6, characterized in that it is chosen from the following compounds: - [(methoxycarbonyl-4'-phenyl) -4-methyl-3-butadiene-1E, 3E] -yl-6-dimethyl-4, -4-chromane; - [(methoxycarbonyl-4'-phenyl) -4-methyl-3-butadiene-1E, 3E) -yl-6-dimethyl-4,4-thiochroman; - [(carboxy-4'-phenyl) -4-methyl-3-butadiene-1E, 3E] -yl-6-dimé-thyl-4,4-chromane; - [(carboxy-4'-phenyl) -4-methyl-3-butadiene-1E, 3E] -yl-6-dimé-thyl-4,4-thiochromane; - [(ethylaminocarbonyl-4'-phenyl) -4-methyl-3-butadiene-1E, 3E] -yl-6-dimethyl-4,4-chromane; - [(methoxycarbonyl-4'-phenyl) -4-methyl-3-butadiene-1Z, 3E] -yl-6-dimethyl-4,4-chromane; - [(methoxycarbonyl-4'-phenyl) -4-methyl-3-butadiene-1Z, 3E] -yl-6-dimethyl-4,4-thiochroman; - [(carboxy-4'-phenyl) -4-methyl-3-butadiene-1Z, 3E] -yl-6-dimé-thyl-4,4-chromane; - [(carboxy-4'-phenyl) -4-methyl-3-butadiene-1Z, 3E] -yl-6-dimé-thyl-4,4-thiochromane; - [ethoxycarbonyl-6-dimethyl-1,5-hexatriene-lE, 3E, 5E] -yl-6-dimethyl-4,4-chromane; - [carboxy-6-dimethyl-1,5-hexatriene-lE, 3E, 5E] -yl-6-dimethyl-4,4-chromane. 8. Process for the preparation of a compound as defined in one of claims 1 to 7, characterized in that a compound of formula (VI) is reacted: (VI) on a compound of formula (VII): (VII) formulas in which R1; R2, R3, R4 and A have the meanings indicated in claim 1, provided that R7 cannot represent the group of formula (IV): -C-R9 II O (IV) when R9 is a hydrogen atom or an alkyl radical Cj-Q, the groups Bi and B2, in the formulas respectively (VI) and (VII) above, representing, one, an oxo group, while l the other is: a) either a triarylphosphonium group of formula (VIII): -P [Q] 3® Y® (VIII) formula in which: - Q is an aryl group, and - Y is a monovalent anion of an organic or inorganic acid; b) or a dialkoxyphosphinyl group of formula (IX): -P [Z] 2 O formula in which Z represents a Q-Cg alkoxy residue. (IX) 9. The method of claim 8, wherein B! and B2 represent, one, an oxo group, and the other, a triarylphosphonium group of formula (VIII), characterized in that the condensation of the compounds of formulas (VI) and (VII) is carried out in the presence 5 of an alkali metal alcoholate, in the presence of an alkali metal hydride, or in the presence of butyllithium, in a solvent such as tetrahydrofuran or dimethylformamide, or else in the presence of an alkali carbonate, in an alcohol, or also in the presence of an alkylene oxide optionally substituted by an alkyl group, io optionally in a solvent such as dichloromethane, the reaction temperature being between -80 ° C. and the boiling temperature of the reaction mixture. 10. The method of claim 8, wherein B] and B2 represent, one, an oxo group, and the other, a dialkoxy group. 15 phosphinyl of formula (IX), characterized in that the condensation of the compounds of formulas (VI) and (VII) is carried out in the presence of a base and, preferably, in the presence of an inert organic solvent, the temperature of reaction being between -80 ° C and the boiling temperature of the reaction mixture. 11. Method according to one of claims 8 to 10, characterized in that the compound obtained by reaction of the compounds of formulas (VI) and (VII) subsequently undergoes functional modifications of the substituent R7. 12. Drug composition, characterized in that it 25 comprises, in a pharmaceutically acceptable carrier, at least one compound as defined in one of claims 1 to 7. 13. Composition according to claim 12, characterized in that it is intended for the treatment of dermatological conditions linked to a disorder of keratinization (differentiation, proliferation- 30)), dermatological or other affections, with an inflammatory and / or immunoallergic component, of any benign or malignant, severe or extensive dermatological proliferation, dystrophic epidermis bullosa and of the molecular pathology of collagen, carcinomas induced by ultraviolet (carcinogenesis 35 solar), epidermodysplasia verruciformis and related forms, rheumatic conditions such as rheumatoid psoriasis, ophthalmological treatments, as well as atopy treatment. 14. Composition according to one of claims 12 and 13 intended for administration by the enteral route, characterized in that it is 40 present in the form of tablets, capsules, dragees, syrup, suspension, solution, powder, granules or emulsion. 15. Composition according to one of claims 12 and 13 intended for parenteral administration, characterized in that it is in the form of solution or suspension for infusion or for injection. 16. Composition according to one of claims 12 and 13 intended for topical administration, characterized in that it is in the form of an ointment, tincture, cream, ointment, 50 of powder, patch, soaked tampon, solution, lotion, gel, spray, suspension or emulsion. 17. Composition according to Claim 16, characterized in that the concentration of compound (s) according to one of Claims 1 to 7 is between 0.0005 and 2% by weight. 55 18. Composition according to one of claims 12 and 13 intended for administration by the ocular route, characterized in that it is in the form of eye drops. 19. Composition according to one of claims 12 to 18, characterized in that it contains inert additives or pharmacody- 60 namically active. 20. Composition according to claim 19, characterized in that the additives are taken from the group formed by moisturizing agents, antiseborrheic and anti-acne agents, antibiotics, agents promoting hair regrowth, anti- 65 inflammatory drugs, carotenoids, antipsoriatic agents, flavor enhancers, preservatives, stabilizers, moisture regulators, pH regulators, osmotic pressure modifiers, 45 673,027 4 emulsifying agents, UV-A and UV-B filters and antioxidant agents. 21. Cosmetic composition, characterized in that it contains, in a cosmetically acceptable carrier, at least one compound according to one of claims 1 to 7. 22. Composition according to Claim 21, characterized in that it is in a form intended for the treatment of skin prone to acne, to regrowth of the hair, to an action against hair loss, to the fight against oily appearance of the skin or hair, to the treatment of physiologically dry skin and to the treatment and prevention of the harmful effects of the sun. 23. Composition according to one of claims 21 and 22, characterized in that the compound (s) according to one of 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. 24. Composition according to one of claims 21 to 23, characterized in that it is in the form of a lotion, gel, cream, soap or shampoo. 25. Composition according to one of claims 21 to 24, characterized in that it contains inert or cosmetically active additives. 26. Composition according to claim 25, characterized in that the inert or cosmetically active additives are taken from the group formed by hydrating agents, antiseborrhoeic agents, anti-acne agents, agents promoting hair regrowth, carotenoids , flavor enhancers, preservatives, stabilizers, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifiers, UV-A and UV- filters B and antioxidants.