Aromatic benzamido compounds, process for their preparation and their use in human or veterinary medicine as well as in cosmetics.

0001The present invention relates to new aromatic benzamido derivatives, their preparation process and their use in human and veterinary medicine and in cosmetics.

0002These new benzamido-aromatic derivatives find application in the topical and systemic treatment of dermatological affections linked to a disorder of keratinization (differentiation-proliferation) and of dermatological or other affections, with inflammatory and / or immunoallergic components and in diseases. degeneration of connective tissue, as well as anti-tumor activity. In addition, these derivatives can be used in the treatment of atopy, that e_'It is either cutaneous or respiratory and rheumatoid psoriasis.

0003They also find an application in the ophthalmological field, in particular for the treatment of corneopathies.

0004The aromatic benzamido derivatives according to the invention can be represented by the following general formula:<chemistry id="chem0001" num="0001"><img file="EP0232199A2_D0001.tif" /></chemistry>in which :<ul id="ul0001" list-style="none"><li>R₁ represents - CH₂OH, -CHOHCH₃ or -COR₅, R representing a hydrogen atom. a lower alkyl radical, the radical -O^R₆ or<chemistry id="chem0002" num="0002"><img file="EP0232199A2_D0002.tif" /></chemistry>R₆ representing a hydrogen atom, a lower alkyl radical or a mono or polyhydroxyalkyl radical, r ′ and r "representing a hydrogen atom, a lower alkyl radical, a mono or polyhydroxyalkyl radical, an aryl or benzyl radical optionally substituted (s ), a residue of amino acid or amino sugar or taken together form a heterocycle,</li><li>R₂ represents a disubstituted alkyl radical α, α ′ having from 4 to 12 carbon atoms or a cycloalkyl, mono or polycyclic radical having from 5 to 12 carbon atoms whose bonding carbon is quaternary,</li><li>R₃ represents a hydrogen atom or an alkyl radical having from 1 to 10 carbon atoms, and</li><li>R₄ represents a hydrogen atom, a lower alkyl radical or a hydroxyl radical, and the salts of said aromatic benzamido derivatives of formula (I) when R₆ represents a hydrogen atom.</li></ul>

0005When the compounds according to the invention are in the form of salts, they may be salts of an alkali or alkaline-earth metal or alternatively of zinc or an organic amine.

0006The term “lower alkyl radical” should be understood to mean a radical having from 1 to 6 carbon atoms, in particular the methyl, ethyl, isopropyl, butyl and tert-butyl radicals.

0007The term “monohydroxyalkyl radical” should be understood to mean a radical having 2 or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.

0008The term “polyhydroxyalkyl radical” should be understood to mean a radical containing from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5- radicals. tetrahydroxypentyle or the rest of pentaerythritol.

0009The term “aryl radical” should be understood to mean a phenyl radical optionally substituted by a halogen atom, a hydroxyl or a nitro function.

0010By radical α, α'-disubstituted having from 4 to 12 carbon atoms, one must in particular understand a radical tert-butyl, 1,1-dimethylpropyl, 1-methyl 1-ethyl propyl, I-methyl 1-ethyl hexyl or 1 , 1-dimethyl decyl.

0011By mono or polycyclic cycloalkyl radical having 5 to 12 carbon atoms, the bonding carbon of which is quaternary, is meant a 1-methyl cyclohexyl or 1-adamantyl radical.

0012The term “amino acid residue” should be understood to mean a residue deriving for example from lysine or from glycine.

0013By residue of an amino sugar is meant a residue derived for example from glucosamine, galactosamine or mannosamine.

0014When the radicals r 'and r "taken together form a heterocycle, this is preferably a piperidino, piperazino, morpholino, pyrrolidino or (2 hydroxyethyl) -4-piperazino radical.

0015Among the aromatic benzamido derivatives of formula (I) which are preferred above, the following may in particular be cited:<ul id="ul0002" list-style="none"><li>- 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid.</li><li>- methyl 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoate,</li><li>- N-ethyl 4- [3- (1-adamantyl) -4-methoxybenzamido] benzamide,</li><li>- 4- [3- (1-adamantyl) -4-hydroxybenzamido] benzoic acid,</li><li>- methyl 4- [3- (1-adamantyl) -4-hydroxybenzamido] benzoate,</li><li>- 4- [3- (1-methylcyclohexyl) -4-methoxybenzamido] benzoic acid,</li><li>- ethyl 4- [3- (1-methylcyclohexyl) -4-methoxybenzamido] benzoate,</li><li>- 4- [3- (1-adamantyl) -4-decyloxybenzamido] benzoic acid,</li><li>- methyl 4- [3- (1-adamantyl) -4-decyloxybenzamido] benzoate, BSB / JD / LP - BR.14469</li><li>- 4- [3- (1-adamantyl) -4-hexyloxybenzamido] benzolque acid</li><li>- methyl 4- [3- (1-adamantyl) -4-hexyloxybenzamido] benzoate,</li><li>- 4- [3- (1,1-dimethyldecyl) -4-methoxybenzamido] benzoic acid,</li><li>- methyl 4- [3- (1,1-dimethyldecyl) -4-methoxybenzamido] benzoate</li><li>- 4- (3-tert-butyl-4 methoxybenzamido) benzoic acid,</li><li>- methyl 4- (3-tert-butyl-4-methoxybenzamido) benzoate,</li><li>- N- [4- [3- (1-adamantyl) -4-methoxybenzamido] -benzoyl] pyrrolidine,</li><li>- N- [4- [3- (1-adamantyl) -4-methoxybenzamido] -benzoyl] piperidine,</li><li>- the morpholide of 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid,</li><li>- tert [butyl amide of 4- [3- (l-adamantyl) -4-methoxybenzamido] benzoic acid,</li><li>- ethyl amide of 4- [3- (1-adamantyl) -4-methoxybenzamidolbenzoic acid,</li><li>- 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid anilide,</li><li>- benzyl amide of 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid,</li><li>- 2- [3- (1-adamantyl) -4-methoxybenzamido] 2-hydroxyethyl benzoate,</li><li>- N- (4-acetylphenyl) -3- (1-adamantyl) -4-methoxy benzamide,</li><li>- N- [4- (1-hydroxyethyl) phenyl] -3- (1-adamantyl) -4-methoxy benzamide,</li><li>2-hydroxyethyl amide of 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid,</li><li>- methyl 2-hydroxy-4- [3- (1-adamantyl) -4-methoxybenzamido] benzoate.</li></ul>

0016The present invention also relates to the process for the preparation of the compounds of formula (I) according to the following reaction scheme:<chemistry id="chem0003" num="0003"><img file="EP0232199A2_D0003.tif" /></chemistry>

0017The main stage of this preparation consists in reacting in an anhydrous medium, in an organic solvent preferably tetrahydrofuran and in the presence of a tertiary amine, an activated form of a substituted benzoic acid, for example an acid chloride ( 1) on an amino compound of formula (2), the reaction being carried out at ambient temperature and with stirring.

0018From the ester (Ia), the corresponding acid (Ib) is accessed by saponification, which can then be activated, for example using N, N'-carbonyldiimidazole (GDI) or by conversion to chloride. acid, and transformed into amide of formula (Ic), by the action of an amine of formula<chemistry id="chem0004" num="0004"><img file="EP0232199A2_D0004.tif" /></chemistry>(r 'and r "having the same meanings as given above).

0019When R₆ represents a monohydroxy or polyhydroxyalkyl radical it is preferable to prepare the acid (Ib) from the methyl ester (la) (R₆ = -CH₃) and then to esterify the acid BSB / JD / LT - BR.14469 thus obtained in ester of mono or polyhydric alcohol chosen according to known methods.

0020The compounds in which R₁= -CH₂OH and -CHOH-CH₃ are obtained in a conventional manner by reduction respectively of the corresponding esters and ketones.

0021A subject of the present invention is also, as a medicament, the compounds of formula (I) as defined above.

0022These compounds exhibit excellent activity in the test for inhibition of ornithine decarboxylase after induction, by "tape stripping", in the naked rat (M. Bouclier et al, DERMATOLOGICA 169 No. 4 I984). This test is accepted as a measure of the inhibitory action of certain compounds on the phenomena of cell proliferation.

0023These 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:<ul id="ul0003" list-style="none"><li>- vulgar, comedonian or polymorphic acnes, senile, solar acne and medicinal or professional acnes,</li><li>- widespread and / or severe forms of psoriasis, and other keratinization disorders, and in particular ichthyosis and ichthyosiform states,</li><li>- Darier's disease</li><li>- palmoplantar keratoderma</li><li>- leukoplakias and leukoplasiform states, lichen planus</li><li>- any benign or malignant, severe or extensive dermatological proliferation.</li></ul>

0024They are also active in the treatment of tumors, rheumatoid psoriasis, cutaneous or respiratory atopy and in the treatment of certain ophthalmological problems relating to corneopathies.

0025The present invention therefore also relates to medicinal compositions containing at least one compound of formula (I) as defined above, or one of its salts.

0026The 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 an acceptable pharmaceutical carrier, at least one compound of formula (I) and / or one of its salts.

0027The compounds according to the invention exhibit good stability to light and to oxygen. BSB / JD / LP - BR.14469

0028The compounds according to the invention are generally administered at a daily dose of approximately 0.01 mg / kg to 5 mg / kg of body weight.

0029As 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 vehicle.

0030Administration can be by enteral, parenteral, topical or ocular route. Enterally, the drugs can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions. Parenterally, the compositions may be in the form of solutions or suspensions for infusion or for injection.

0031Topically, the pharmaceutical compositions based on the compounds according to the invention are in the form of ointments, tinctures, creams, ointments, powders, patches, soaked pads, solutions, lotions, gels , sprays or suspensions.

0032These topical compositions can be presented either in anhydrous form or in aqueous form according to the clinical indication.

0033By eye, these are mainly eye drops.

0034These compositions contain at least one compound of formula (I) as defined above or one of its salts, at a concentration preferably of between 0.0001 and 5% relative to the total weight of the composition.

0035The 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 the treatment of acne prone skin, for hair regrowth, anti-fall, to fight against the oily appearance of the skin or hair, in the protection against the harmful effects of the sun or in the treatment of physiologically dry skin.

0036The 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, soap or shampoo.

0037The concentration of compound of formula (I) in the cosmetic compositions is between 0.0001 and 0.1% by weight and preferably between 0.001 and 0.01X by weight.

0038The medicinal and cosmetic compositions according to the invention can contain inert additives or even pharmacodynamically or cosmetically active and in particular: hydrating agents such as thiamorpholinone and its derivatives or urea; antiseborrhoeic or BSB / JD / LP - BR.14469 anti-acne agents, such as S-carboxymethylcysteine, S-benzyl-cysteamine, their salts and derivatives, tioxolone or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, tetracyclines or polymethylene-4,5-isothiazolinones-3; agents promoting hair regrowth, such as "Minoxidil" (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives, Diazoxide (7-chloro 3-methyl 1,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,5-diphenylimidazolidine 2,4-dione); steroidal and non-steroidal anti-inflammatory agents; carotenoids and, in particular β-carotene; anti-psoriatic agents such as anthralin and its derivatives and the eicosatetraynolic-5,8,11,14 and triynoic-5,8,11 acids, their esters and their amides.

0039The compositions according to the invention can also contain flavor-improving 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 butylhydroxy toluene.

0040We will now give, by way of illustration and without any limiting character, several examples of preparation of the active compounds of formula (I) according to the invention as well as examples of compositions containing them.

EXAMPLE 1

Methyl 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoate

(a) 3- (1-adamantyl) -4-methoxybenzolque acid.

00415.4 g (225 mmol) of Mg and 30 ml of tetrahydrofuran are introduced into a flask. A solution of 48.3 g (150 mmol) of 2-adamantyl-4 bromo anisole, 6 ml (70 mmol) of dibromoethane in 300 ml of tetrahydrofuran is added dropwise. The mixture is heated to reflux for 2 hours, cooled to -70 ° C. and the introduction of C0₂ gaseous for one hour. The temperature is allowed to rise to 20 ° C., thrown into water, acidified to pH = 1 with concentrated hydrochloric acid and extracted with ethyl ether. The organic phase is decanted, dried over magnesium sulfate and evaporated. After recrystallization from ethyl acetate, 37g of expected product is obtained (yield 86%), melting point: 238-239 ° C.

(b) 3- (1-adamantyl) -4-methoxybenzoyl chloride.

0042200 ml of thionyl chloride are introduced into a flask and 35g (122 mmol) of the acid obtained above are added in small quantities. The mixture is heated to reflux until the evolution of gas is stopped. Evaporated to dryness, taken up in 100 ml of anhydrous benzene and evaporated to dryness again. 37 g of expected product (yield 100%) of melting point are obtained: 153-154 ° C.

(c) Methyl 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoate.

00432.5 g (17 mmol) of methyl p-amino benzoate, 50 ml of tetrahydrofuran and 2.6 ml (18.5 mmol) of triethylamine are introduced into a flask. 5.64 g (18.5 mmol) of 3-adamantyl-4-methoxy benzoic acid chloride in 50 ml of tetrahydrofuran are added dropwise and the mixture is stirred at room temperature for two hours. Thrown into water, extracted with methylene chloride, decanted the organic phase, dried over magnesium sulfate and evaporated. After recrystallization from an isopropyl ether-ethyl acetate mixture (50-50), 7.1 g of expected product is obtained (Yield 92%), melting point: 179-180 ° C.

EXAMPLE 2

Benzoic 4 [3- (1-adamantyl) -4-methoxybenzamido] acid

00446 g (14 mmol) of the ester obtained in Example 1 and 200 ml of 2M methanolic sodium hydroxide are introduced into a flask. The mixture is heated at reflux for four hours. Evaporated to dryness, taken up in water, acidified with hydrochloric acid at pH = 1, extracted with ether. The organic phase is decanted, dried over magnesium sulfate and evaporated. After recrystallization from ethyl acetate, 4g of the expected acid is obtained (yield 69%), melting point: 286-287 ° C.

EXAMPLE 3

Methyl 4- [3- (1-adamantyl) -4-hydroxybenzamido] benzoate

(a) 3- (1-adamantyl) -4-tert-butyldimethylsilyloxybenzoic acid.

00451.18 g (48.8 mmol) of magnesium and 20 ml of THF are introduced into a flask. 13.7 g (32.5 mmol) of 2- (1-adamantyl) -4-bromophenol tert-butyl dimethylsilic ether (described in European Application No. 86 / 400785.1) are added dropwise and the mixture is heated under reflux for 2 hours. Cool to -70 ° C and pass a stream of CO₂ for 1 hour. The temperature is allowed to rise to 20 ° C., the reaction medium is thrown into water, acidified to pH = I (with concentrated HCl), and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and the solvents are evaporated. The residue is triturated in 200 ml of isopropyl ether at reflux. After cooling, the precipitate is filtered. 8.20 g (65%) are thus obtained 3- (1-adamantyl) -4-tert-butyldimethylsilyloxybenzoic acid which melts at 245-246 ° C. BSB / JD / LP - BR.14469

(b) 3- (I-adamantyl) -4-tert-butyldimethyl silyloxybenzoic acid chloride.

00466.45 g (16.7 mmol) of the acid obtained in 3 (a) are suspended in 100 ml of CH₂Cl₂. 3.3 ml (16.7 mmol) of dicyclohexylamine are added and the mixture is stirred for 1 hour at 20 ° C. Then added 1.35 ml (18.4 mmol) of thionyl chloride. The mixture is stirred for 2 hours at room temperature, evaporated to dryness, taken up in 300 ml of ether, the salt formed is filtered and the ethereal phase is evaporated. 6.9 g (100%) of 3- (1- adamantyl) -4-tert-butyldimethylsilyloxybenzolque acid chloride are thus obtained in the form of a solid which is used as it is for the following synthesis.

(c) Methyl 4- [3- (1-adamantyl) -4-tert-butyl-dimethylsilyloxybenzamido] benzoate.

00472.10 g (13.9 mmol) of methyl p-aminobenzoate, 2.10 ml (15.3 mmol) of triethylamine and 50 ml of THF are introduced into a flask. 6.20 g (15.3 mmol) of 3- (1-adamantyl) -4-methoxybenzoyl chloride are added dropwise and the mixture is stirred at room temperature for 4 hours.

0048The reaction medium is thrown into water and extracted with methylene chloride. We dry (MgS0₄) and evaporates the solvents. The solid obtained is recrystallized from a mixture of diisopropyl ether and ethyl acetate (10-1) to give 6.5 g (91%) of the expected ester, which melts at 183-184 ° C.

(d) Methyl 4- [3- (1-adamantyl) -4-hydroxybenzamido] benzoate.

00496.40 g (12.3 mmol) of ester obtained in 3 (c) and 75 ml of THF are introduced into a flask. 13.5 ml (13.5 mmol) of tetrabutylammonium fluoride (1M in THF) are added dropwise. Stirred at room temperature for 2 hours, then throw the reaction medium into water, extract with methylene chloride, decant the organic phase, dry over magnesium sulfate, and evaporate the solvents.

0050The solid obtained is triturated in 200 ml of ethyl acetate at reflux, cooled and filtered. 4.20 g (84%) of 4- [3- (1-adamantyl) -4-hydroxybenzamido] benzoic acid methyl ester are thus obtained, which melts at 305-306 ° C.

EXAMPLE 4

4- [3- (1-adamantyl) -4-hydroxybenzamido-benzoic acid

0051A suspension of 3.3 g (8.1 mmol) of ester obtained in 3 (d) in 100 ml of 2N methanolic sodium hydroxide is stirred for 12 hours at room temperature. Evaporated to dryness, taken up in water and acidified to pH: 0 with concentrated hydrochloric acid. The solid is filtered, washed with water and dried under vacuum in the presence of phosphorus pentoxide (P₂O₅). The solid BSB / JD / LP - BR.14469 is then triturated in 200 ml of ethyl acetate at reflux. The mixture is cooled to room temperature then the precipitate is filtered. This gives 2.8 g (88%) of 4- [3- (1-adamantyl) -4-hydroxybenzamido] benzoic acid which melts at 348-350 ° C.

EXAMPLE 5

Ethyl 4- [3- (1-methylcyclohexyl) -4-methoxybenzamido] benzoate

(a) 4-bromo-2- (1-methylcyclohexyl) phenol.

0052A mixture of methylene cyclohexane (0.96 g, 10 mmoles) of p-bromophenol (1.73 g, 10 mmoles) and acid resin (Dowex 50 × 12) (150 mg) is heated at 80 ° C. for 16 hours. The residue is purified by chromatography on a silica column (eluent: CH₂Cl₂/ hexane 50/50). By evaporation of the solvents, 0.50 g (19%) of 4-bromo-2- (1-methylcyclohexyl) phenol is obtained in the form of a yellowish oil.

(b) 4-bromo-2- (1-methylcyclohexyl) anisole.

0053The 4-bromo-2- (1-methylcyclohexyl) phenol (9.26 g, 34.4 mmol) is dissolved in 50 ml of THF. Cool to 0 ° C and add in small portions of sodium hydride (80% in oil, 1.14 g, 37.8 mmol). The mixture is stirred for 30 minutes at room temperature and 5.37 g (37.8 mmol) of methyl iodide are added dropwise. Stirring is continued for 16 hours, adding water (300ml) and extract with ether (3x300ml). The organic phase is washed with a saturated solution of sodium bicarbonate, then a saturated solution of sodium chloride. We dry (MgSO₄), filters and evaporates the solvents. The residue is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (20/80). 9g (92%) of 4-bromo-2- (1-methylcyclohexyl) anisole are thus obtained in the form of a colorless oil.

(c) 3- (1-Methylcyclohexyl) -4-methoxybenzolque acid.

0054The compound obtained in 5 (b) (9.0 g, 31.8 mmol) is dissolved in 50 ml of dry THF. The solution obtained is added dropwise to magnesium (850 mg, 35 mmol) and an iodine crystal. The mixture is heated to reflux after addition of the first 5 milliliters of solution. The reflux is maintained for 15 minutes after the addition is complete. It is then cooled to -40 ° C. and a current of CO is passed through.₂ for one hour, then throw the mixture into 6N hydrochloric acid, extracted with ether (3x300ml). The organic phase is washed with water until neutral, dried (MgSO₄), and evaporated. The residue obtained is triturated in hexane, filtered and dried. 6.50 g (82%) are thus obtained 3- (1-methylcyclohexyl) -4-methoxybenzoic acid, which melts at 199 ° C.

(d) 3- (1-methylcyclohexyl) -4-methoxybenzoyl chloride.

00554.96 g (20 mmol) of 3- (1-methyl cyclohexyl) -4-methoxybenzolque acid, 75 ml of dichloromethane are introduced into a flask, and 4 ml (20 mmol) of dicyclohexylamine are added. Stir for 1 hour. To the solution thus obtained, 1.45 ml (20 mmol) of thionyl chloride (SOCl) are added₂) and stirred for 2 hours at room temperature. Evaporated to dryness, taken up in 200 ml of ether, filtered dicyclohexylammonium chloride and then the solvent evaporated. 5.30 g (100%) of crude 3- (1-methylcyclohexyl) -4-methoxybenzoyl chloride are thus obtained. Which is used as it is for the following synthesis.

(e) Ethyl 4- [3- (1-methylcyclohexyl) -4-methoxybenzamido] benzoate.

00563.3 g (20 mmoles) of ethyl p-aminobenzoate, 3.1 ml (20 mmoles) of triethylamine and 75 ml of THF are introduced into a flask. 5.3 g (20 mmol) of the acid chloride obtained in 5 (d) dissolved in 50 ml of THF are added dropwise and the mixture is stirred at room temperature for 2 hours. The reaction medium is thrown into water, extracted with methylene chloride, the organic phase is decanted, dry (MgSO₄) and evaporates the solvents. 6.30 g (80%) of ethyl 4- [3-1-methylcyclohexyl) -4-methoxybenzamido] benzoate are thus obtained in the form of an oil.

EXAMPLE 6

4- [3- (1-methylcyclohexyl) -4-methoxybenzamido] benzoic acid

00575.20 g (13.1 mmol) of the ester obtained in 5 (e) and 150 ml of 2N methanolic sodium hydroxide are introduced into a flask. Stirred at room temperature 24 hours, evaporated to dryness, taken up in water, acidified to pH 0 with concentrated hydrochloric acid, extracted with ether, dried (MgSO₄) and evaporates. The residue is recrystallized from a mixture of isopropyl ether and ethyl acetate (8/2). 3.9 g (82%) of 4- [3- (1-methylcyclohexyl) -4-methoxybenzamido] enzoic acid are thus obtained, which melts at 230-231 ° C.

EXAMPLE 7

Methyl 4- [3- (1-adamantyl) -4-decyloxybenzamido] benzoate

00582.00g (5mmoles) of ester obtained in 3 (d) are dissolved in 70ml of dimethylformamide (DMF) and added dropwise to a suspension of sodium hydride (80% in oil, 150mg, 5mmoles ) in 20ml of DMF. The mixture is stirred at ambient temperature until the evolution of gas is complete, then 1.1 ml (5 mmol) of 1-iododecane is added, and agitation is carried out for 4 hours at ambient temperature. The reaction medium is thrown into water, extracted with ether, the organic phase is decanted, washed with water, dried (MgS0₄) and evaporates the solvents. The residue is purified by chromatography on a silica column (eluent: CH₂Cl₂). 2.5 g (92%) of methyl 4- [3- (1-adamantyl) -4-decyloxybenzamido] benzoate are thus obtained, which melts at 106-107 ° C.

EXAMPLE 8

Benzoic 4- [3- (1-adamantyl) -4-decyloxybenzamido] acid

0059Analogously to Example 4, 2.00 g (3.67 mmol) of ester obtained in 7, treated for 48 hours with 100 ml of 2N methanolic sodium hydroxide give 1.8 g (95%) of acid 4- [3 - (1-adamantyl) -4-decyloxybenzamido] benzoic which melts at 247-248 ° C.

EXAMPLE 9

Methyl 4- [3- (1-adamantyl) -4-hexyloxybenzamido] benzoate

0060Analogously to Example 7, starting from 2.50 g (6.2 mmol) of ester obtained in 3 (d) treated with 187 mg (6.2 mmol) of sodium hydride (80% in the oil) and 0.9 ml (6.2 mmol of 1-iodohexane), 2.9 g (96%) of methyl 4- [3- (1-adamantyl) -4-hexyloxybenzamido] benzoate are obtained, which melts at 154- 155 ° C.

EXAMPLE 10

Benzoic 4- [3- (1-adamantyl) -4-hexyloxybenzamido] acid

0061Analogously to Example 8, from 2.27 g (4.6 mmol) of ester obtained in 9, 2.10 g (96%) of 4- [3- (1-adamantyl) acid are obtained. -4-hexyloxybenzamido] benzoic, which melts at 256-257 ° C.

EXAMPLE 11

Methyl 4- [3- (1,1-dimethyldecyl) -4-methoxybenzamido] benzoate

(a) 4-bromo-2- (1,1-dimethyldecyl) phenol.

0062A mixture of p-bromophenol (25.85 g, 149 mmol) and 2-methyl-undec-1-ene (25.15 g, 149 mmol) is stirred at 110 ° C. for 48 hours in the presence of acid resin (Dowex 50x12, 3g). The mixture obtained is purified by chromatography on a silica column (eluent: dichloromethane, hexane 50/50). 25.04 g (49%) of 4-bromo-2 - (1,1-dimethyldecyl) phenol are thus obtained in the form of a light yellow oil.

(b) 4-bromo-2- (1,1-dimethyldecyl) anisole.

0063To a solution of phenol obtained in 11 (a) (24.88 g, 72.9 mmol) in THF (200 ml), 2.19 g (72.9 mmol) of sodium hydride (80%) are added in small fractions. in oil). Once the addition is complete, the mixture is stirred for 1 hour at ambient temperature, then methyl iodide (10.35 g, 72.9 mmol) is added dropwise. The reaction medium is stirred for 2 hours at room temperature, the solvent is evaporated and then water (300ml) is added and extracted with ether (3x200ml). The organic phase is washed with saturated sodium chloride solution, dried (MgSO₄) and evaporated solvents. 22.2 g (86%) of 4-bromo-2- (1,1-dimethyldecyl) anisole are thus obtained in the form of a yellow oil.

(c) 3- (1,1-Dimethyldecyl) -4-methoxybenzolque acid.

0064The 4-bromo-2- (I, I-dimethyldecyl) anisole (15.72 g, 44.2 mmol) is dissolved in THF (50 ml). This solution is added dropwise over magnesium (1.18 g, 48.7 mmol) and an iodine crystal, while maintaining at reflux by heating. Once the addition is complete, the mixture is maintained at reflux for 30 minutes and then cooled to -40 ° C. 300 ml of THF are then added and a current of CO is passed through.₂ during 2 hours. The reaction mixture is then poured into a hydrochloric acid solution (4N, 300ml), and the product is extracted with ether (3x300ml). The organic phase is washed with water until neutral, dried (MgS0₄), then the solvents are evaporated. The residue is triturated in isooctane to give 7.25 g (51%) of 3- (1,1-dimethyldecyl) -4-methoxybenzolque acid, which melts at 112 ° C.

(d) 3- (1,1-Dimethyldecyl) -4-methoxybenzoyl chloride.

0065The acid obtained in 11 (c) (7.18 g, 22.4 mmol) is suspended in 200 ml of dichloromethane. Dicyclohexylamine (4.06 g, 22.4 mmol) is added dropwise then the mixture is cooled to 0 ° C. Thionyl chloride (2.66 g, 22.4 mmol) is then added and the mixture is stirred for 16 hours at room temperature. The precipitate formed is filtered, the solvent evaporated. Crude 3- (1,1-dimethyldecyl) -4-methoxybenzoyl chloride is thus obtained quantitatively in the form of a white solid which is used as it is for the following synthesis.

(e) Methyl 4- [3- (1,1-dimethyldecyl) -4-methoxybenzamido] benzoate.

0066All of the acid chloride obtained in 11 (d) is dissolved in 50 ml of THF. The solution thus obtained is added to a solution of methyl p-aminobenzoate (3.39 g, 22.4 mmol) and triethylamine (2.27 g, 22.4 mmol) in THF (100 ml). Stirred for 1 hour at room temperature, then the precipitate is filtered, the solvent evaporated and the product purified by column chromatography (eluent: dichloromethane). The solvents are evaporated and the solid obtained is triturated in hexane, filtered and dried. 7.72 g (76%) of methyl 4- [3- (1,1-dimethyldecyl) -4-methoxybenzamido] benzoate are thus obtained, which melts at 120 ° C.

EXAMPLE 12

4- 3- (1,1-Dimethyldecyl) -4-methoxybenzamido benzoic acid

0067The ester obtained in 11 (e) (2.5 g, 5.51 mmol) is mixed with 110 ml of methanol. 11 ml of 5N sodium hydroxide are added and the reaction medium is stirred for three days. The methanol is evaporated, 4N hydrochloric acid (200ml) is added and the product is extracted with dichloromethane (3x300ml). The organic phase is washed with a saturated solution of sodium bicarbonate, then sodium chloride. We dry (MgS0₄) then evaporates the solvent. The solid obtained is triturated in hexane, filtered and then dried. 1.57 g (65%) are thus obtained of 4- [3- (1,1-dimethyldecyl) -4-methoxybenzamido] benzoic acid, which melts at 177 ° C.

EXAMPLE 13

4- (3-tert-butyl-4-methoxybenzamido) methyl benzoate

0068Chloride of crude 3- (tert-butyl) -4-methoxy benzoic acid prepared from 10.41 g (50 mmol) of 3- (tert-butyl) -4-methoxybenzoic acid described in the patent application French n ° 85.13747 (2.570.377), is dissolved in THF (60ml). The solution is added dropwise to a mixture of methyl 4-aminobenzoate (7.14 g; 47.2 mmol) and triethylamine (4.78 g, 47.2 mmol), in solution in THF (50 ml). The mixture is stirred for 3 hours at room temperature, the precipitate formed is filtered, then the solvents are evaporated. Water (300ml) is added and the product is extracted with ether (3x200ml).

0069The organic phase is washed with a saturated solution of sodium bicarbonate, then sodium chloride. We dry (MgSO₄), filters and evaporates the solvents. The solid obtained is recrystallized from hexane containing about 5% methanol. 14.02 g (87%) of methyl 4- (3-tert-butyl-4-methoxybenzamido) benzoate are thus obtained.

EXAMPLE 14

Benzoic 4- (3-tert-butyl-4-methoxybenzamido) acid

0070Analogously to Example 4, from 5 g (14.65 mmol) of ester obtained in Example 13, 4.27 g (89%) of 4- (3-tert-butyl-) acid are obtained. 4-methoxybenzamido) benzoic which melts at 250 ° C.

EXAMPLE 15

N- [4- [3- (1-adamantyl) -4-methoxybenzamido] -benzoyl] pyrrolidine

00711.7 g (9 mmoles) of N-p-aminobenzoyl pyrrolidine, and 1 g (10 mmoles) of triethylamine are dissolved in 30 ml of dichloromethane. With stirring, 2.8 g (9 mmol) of 3- (1-adamantyl) -4-methoxybenzoyl chloride dissolved in 60 ml of dichloromethane are added. Stir for 16 hours, add water and extract with dichloromethane. Wash with water, extract with methylene chloride, dry (MgSO₄) then evaporates the solvents. The residue (yellow foam) is crystallized from ethyl acetate to give 3.0 g (73%) of N- [4- [3- (3- (1-adamantyl) -4-methoxybenzamido] -benzoyl] pyrrolidine which melts at 239-242 ° C.

EXAMPLE 16

N- [4- [3 (1-adamantyl) -4-methoxybenzamido] -benzoyl] piperidine

0072Analogously to Example 15, from 0.7 g (3.6 mmol) of N- [4-aminobenzoyl] piperidine, 1.0 g (63%) of N- [4- [3- (1-adamantyl) -4-methoxybenzamido] -benzoyl] piperidine, which melts at 219-222 ° C.

EXAMPLE 17

Morpholide of 4- [3- (1-adamantyl) -4-methoxybenzamido] acid

benzoic

0073Analogously to Example 15, from 3.0 g (15 mmol) of N- [4-aminobenzoyl] morpholine, 5.6 g (81%) of 4- [3- (1-acid) morpholide are obtained. -adamantyl) -4-methoxybenzamido] benzoic, which melts at 238-241 ° C.

EXAMPLE 18

4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid tert-butyl amide

0074From 1.0 g (5 mmoles) of N-tert-butyl-4-aminobenzamide, 1.5 g (63%) of tert-butyl amide of 4- [3- (1-adamantyl) - are obtained. 4-methoxybenzamido] benzoic, which melts at 270-273 ° C.

EXAMPLE 19

4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid ethyl amide

a) 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid chloride

00752.0g (5mmoles) of 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid are dissolved in 60ml of THF. 1.1 g (6 mmol) of dicyclohexylamine are added dropwise. A white precipitate forms immediately. It is then cooled to 0 ° C. and 0.7 g (6 mmol) of thionyl chloride is added dropwise. The mixture is stirred for 3 hours at room temperature, the solid formed is filtered and the filtrate is evaporated. The residue obtained is used as it is for the rest of the synthesis.

b) Ethyl amide of 4- [3- (1-adamantyl) -4-methoyx- benzamido] benzoic acid

0076The crude acid chloride obtained is dissolved in 80 ml of THF then added dropwise to a solution of ethylamine (0.5 g, 11 mmol) in dry THF (20 ml). The mixture is stirred for 16 hours at room temperature, filtered and the filtrate is evaporated. The reddish residue thus obtained is recrystallized from ethanol to give 0.5g (24%) of ethyl amide of 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid which melts at 274-277 ° C.

EXAMPLE 20

4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid anilide

0077This compound is obtained according to the same procedure as that described in Example 19. 0.7g (30%) of the expected compound is obtained, which melts at 265-268 ° C.

EXAMPLE 21

Benzyl amide of 4- [3- (1-adamantyl) -4-methoxy- benzamidolbenzoic acid

0078This compound is obtained according to the same procedure as that described in Example 19. 0.2g (9%) of the expected product is obtained, which melts at 279-280 ° C.

EXAMPLE 22

4- [3- (1-adamantyl) -4-methyoxybenzamido] 2-hydroxyethyl benzoate

0079The crude acid chloride obtained in Example 19 (a) from 2 g of 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid is dissolved in a solution of ethylene glycol (1, 4g, 22mmol) and pyridine (0.8g, 10mmol) in dry THF (20ml). The mixture is stirred for 16 hours at room temperature. The reaction mixture is filtered, the filtrate evaporated to dryness to give a yellowish residue which is purified by column chromatography using as eluent a mixture of dichloromethane and ethyl acetate (1/1). The solvents are evaporated and thus 1.2g (55%) of the expected ester are obtained, which melts at 201-203 ° C.

EXAMPLE 23

N- (4-acetylphenyl) -3- (1-adamantyl) -4-methoxybenzamide A solution of 5.7 g of 3- {1-adamantyl chloride)

0080-4-methoxybenzoyl obtained in Example 1 (b) in dichloromethane (60ml) is added dropwise to a mixture of 4-aminoacetophenone (2.6g, 19mmol) and triethylamine (2.1g, 21mmol) in dichloromethane (30ml). The mixture is stirred for 16 hours then thrown into water and extracted with dichloromethane. The organic phase is collected, washed with water, dried over magnesium sulfate and then evaporated. The residue thus obtained is recrystallized from ethyl acetate and 3.0g (39%) of N- (4-acetylphenyl) -3- (1-adamantyl) -4-methoxybenzamide is thus obtained in the form of white crystals. melting point 200-20I ° C.

EXAMPLE 24

N- [4- (1-hydroxyethyl) phenyl] -3- (1-adamantyl) -4-methoxybenzamide

0081The amide obtained in Example 23 (0.9g, 2mmol) is dissolved in methanol (25ml) and treated with 0.12g (3mmol) of sodium borohydride. The mixture is stirred at room temperature for 2 days, thrown into water and extracted with ether. The extracts are dried over magnesium sulfate, then the solvent evaporated. The residue thus obtained is recrystallized from ethyl acetate to give the point N- [4- (1-hydroxyethyl) phenyl] -3- (1- adamantyl) -4-methoxybenzamide (0.5 g, 66%) mp: 207-209 ° C.

EXAMPLE 25

4- [3- (1-adamantyl) -4 - methoxybenzamido] benzoic acid 2-hydroxyethyl amide

0082Analogously to Example 19, 2-hydroxyethyl amide of 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid is obtained: (I, lg, 50%) which melts at 265 -268 ° C (crystallized from an ethanol-ether mixture).

EXAMPLE 26

Methyl 2-hydroxy-4 [3- (1-adamantyl) -4-methoxybenzamido] benzoate

a) methyl 4-amino-2-tert-butyldimethylsilyloxy benzoate.

00832.0 g (12mmol) of methyl 4-amino-2-hydroxybenzoate are dissolved in 30ml of dimethylformamide (DMF) containing 2.8g (28mmol of triethylamine, and 70mg (0.6mmol) of 4-N, N- dimethylaminopyridine, a solution of tert-butyldimethylsilyl chloride (4.2 g, 28 mmol) in 40 ml of DMF is added dropwise, the mixture is stirred for 2 days at room temperature and then heated to 100 ° C. for 8 hours. evaporated in vacuo, water is added and extracted with ether. The organic phase is collected, dried and then the solvent evaporated. Crude methyl 4-amino-2-tert-butyldimethylsilyloxybenzoate is thus obtained, which is used as it is for the rest of the synthesis.

b) Methyl 2-tert-butyldimethylsilyloxy-4- [3- (1-adamantyl) -4-methoxybenzamido] benzoate.

0084The crude methyl 4-amino-2-tert-butyldimethylsilyloxy benzoate (3.0 g, 10 mmoles) is dissolved in 20 ml of dry THF containing 1.1 g (10 mmoles) of triethylamine. A solution of 4-methoxy-3- (l-adamantyl) benzoyl chloride in 80 ml of dry THF is added dropwise and the reaction medium is stirred for 16 hours at 20 ° C. Evaporated to dryness, taken up in 100 ml of dichloromethane, washed with water, dried (Mg SO₄) and evaporates to dryness. The residue thus obtained is recrystallized from an ethanol / ethyl ether mixture. 2.7 g (48%) of methyl 2-tert-butyldimethylsilyloxy-4- [3- (1-adamantyl) -4-methoxybenzamido] methyl benzoate are thus obtained, which melts at 225-227 ° C.

c) methyl 2-hydroxy-4- [3- (1-adamantyl) -4-methoxybenzamido] benzoate.

00852.7 g (5 mmoles) of ester obtained (b) above, are dissolved in 80 ml of THF. A 1M solution of tetrabutylammonium fluoride in THF (6 ml) is added. The mixture is stirred for 16 hours at 20 ° C. (the formation of a white precipitate is observed). Evaporate to dryness, add water and extract with ether (3x100ml). We dry (Mg S0₄) and evaporated to dryness (2.0 g, 95%); the residue is crystallized by adding a small amount of ether. This gives methyl 2-hydroxy-4- [3- (1-adamantyl) -4-methoxybenzamido] benzoate (1.6 g, 76%) which melts at 207-209 ° C.

FORMULATION EXAMPLES

A. ORAL ROUTE

0086<tables id="tabl0001" num="0001"><img file="EP0232199A2_D0005.tif" /></tables>

B. TOPICAL ROUTE

0087<tables id="tabl0002" num="0002"><img file="EP0232199A2_D0006.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0232199A2_D0007.tif" /></tables>

0088This ointment is obtained by mixing petroleum jelly and "Miglyol 812" at 70 ° C. The active compound is then introduced by dispersing it very carefully with an ultrasonic bath while heating to 40 ° C / 50 ° C. Then cooled with stirring.

0089In this example, the active compound (0.10 g) can be replaced by 0.5 g of 4- [3- (1-adamantyl) -4-hexyloxybenzamido] benzoic acid.<tables id="tabl0004" num="0004"><img file="EP0232199A2_D0008.tif" /></tables>

0090This lotion is obtained by mixing polyethylene glycol (400) and ethanol, then the active compound is introduced and it is solubilized in an ultrasonic bath.<tables id="tabl0005" num="0005"><img file="EP0232199A2_D0009.tif" /></tables>

0091This emulsion is obtained by preparing the following mixtures A and B:<ul id="ul0004" list-style="none"><li>MIXTURE A - Sodium Lauryl Sulfate</li></ul><ul id="ul0005" list-style="none"><li>- 1.2 propanediol</li><li>- Methyl parahydroxybenzoate</li><li>- Sterile water</li></ul>

0092After dissolving the methyl parahydroxybenzoate with ultrasonic stirring, the mixture is brought to 75 ° C.<ul id="ul0006" list-style="none"><li>MELANGE B - White Vaseline</li></ul><ul id="ul0007" list-style="none"><li>- Cetyl alcohol</li><li>- Propyl parahydroxybenzoate</li></ul>

0093After having dissolved the propyl parahydroxybenzoate with ultrasonic stirring, the mixture is also brought to 75 ° C.

0094The emulsion is then formed by pouring mixture A into mixture B. After cooling to room temperature. the active compound is incorporated and stirred carefully to homogenize well. Before conditioning the emulsion, it is passed through a three-cylinder.

C - COSMETIC COMPOSITIONS

0095<tables id="tabl0006" num="0006"><img file="EP0232199A2_D0010.tif" /></tables>

0096This cream is obtained by bringing to 70 ° C a mixture of Palmito ethylene glycol stearate and polyoxyethylene glycol, saturated glycerides C₁₀-VS₁₈ glycolized polyoxyethylenes and petrolatum oil. The active compound is then introduced and carefully dispersed. Then poured into the fatty phase with stirring water and preservatives also brought to 70 ° C. Stirring is continued until it returns to room temperature and an emulsion is obtained.

0097In this example, the active compound may be replaced by the same amount of the 4- [3- (1-adamantyl) -4 methoxybenzamido] benzoic acid morpholide.<tables id="tabl0007" num="0007"><img file="EP0232199A2_D0011.tif" /></tables>

0098This cream is obtained according to the same procedure as that described above.

0099In this example, the active compound can be replaced by the same amount of 4- [3- (1-adamantyl) -4-methoxybenzamido] benzoic acid ethyl amide.<tables id="tabl0008" num="0008"><img file="EP0232199A2_D0012.tif" /></tables>

0100At the time of use, 10 g of the treating phase are mixed with 90 g of the washing phase.