Bi-aromatic esters, process for their preparation and their use in human or animal medicine and in cosmetics.

The present invention relates to new bi-aromatic esters, their preparation process and their use in human and veterinary medicine and in cosmetics.

These new bi-aromatic esters 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, and have anti-tumor activity. In addition, these derivatives can be used in the treatment of atopy, whether cutaneous or respiratory, and rheumatoid psoriasis.

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

The bi-aromatic esters according to the invention can be represented by the following general formula:<chemistry id="chem0001" num="0001"><img file="EP0409728A2_D0001.tif" /></chemistry> in which: R₁ represents a hydrogen atom, the OH group, the radical -CH₃, -CH₂OH, -CH (OH) CH₃, -COOR₉,<chemistry id="chem0002" num="0002"><img file="EP0409728A2_D0002.tif" /></chemistry> or SO₂R₁₀, R₉ represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms or a mono or polyhydroxyalkyl radical, R₁₀ representing the OH group, an alkyl radical having from 1 to 6 carbon atoms or the radical<chemistry id="chem0003" num="0003"><img file="EP0409728A2_D0003.tif" /></chemistry> r ′ and r˝ representing a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, aryl, aralkyl, mono or polyhydroxyalkyl, or r ′ and r˝ taken together form a heterocycle, R₂ represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, the OR₉ radical, a fluorine atom or the -CF₃ radical, R₃, R₄ and R₅ represent a hydrogen atom, a fluorine atom, the OH group, the radical -CH₃, -OCH₃, -CF₃, -COOH or -CH₂OH, R₆ and R₈ represent a hydrogen atom, an α-substituted alkyl radical having from 3 to 15 carbon atoms, an α-α′-disubstituted alkyl radical having from 4 to 12 carbon atoms, a cycloalkyl radical having from 3 to 12 carbon atoms, a mono or polycyclic cycloalkyl radical having 5 to 12 carbon atoms in which the bonding carbon is trisubstituted, the radical -SR₁₁, -SOR₁₁ or -SO₂R₁₁, R₁₁ representing an alkyl radical having from 1 to 6 carbon atoms or a cycloalkyl radical, R₆ and R₈ cannot simultaneously represent a hydrogen atom, R₇ represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, an alkenyl radical, an alkenyloxy radical, the radical OR₁₂, SR₁₃, SO R₁₄ or SO₂R₁₄, R₁₂ representing a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, an alkenyl radical, a mono or polyhydroxyalkyl radical or the radical - (CH₂)_not-COR₁₅ n being 0, 1 or 2 and R₁₅ representing a hydrogen atom, the OH group, an alkyl radical having from 1 to 6 carbon atoms or an alkoxy radical having from 1 to 6 carbon atoms, R₁₃ representing a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms or an aralkyl radical, R₁₄ representing the OH group, an alkyl radical having from 1 to 6 carbon atoms or an aralkyl radical, provided that when R₁ represents -CH₂OH, -CH (OH) CH₃, -COOR₉ or<chemistry id="chem0004" num="0004"><img file="EP0409728A2_D0004.tif" /></chemistry> and R₂ represents a hydrogen atom then:<ul id="ul0001" list-style="none"><li>(i) either R₃ and R₄ are different from a hydrogen atom or from the radical -CH₃,</li><li>(ii) either R₇ is different from the radical OR₁₂ and R₆ or R₈ is a cycloalkyl radical having more than 7 carbon atoms,</li><li>(iii) either R₇ represents the radical OR₁₂, but R₆ and R₈ are then different from a hydrogen atom,</li><li>(iv) either R₇ represents the radical OR₁₂, but then R₅ is different from a hydrogen atom.</li></ul>

The compounds according to the invention can also be in the form of salts, when they contain an acid function; these are salts of an alkali or alkaline earth metal or also of zinc or an organic amine.

By alkyl radical having from 1 to 6 carbon atoms, one must understand the methyl, ethyl, isopropyl, butyl and tert-butyl radicals.

By α-substituted alkyl radical having 3 to 15 carbon atoms should be understood an isopropyl, 1-methyl propyl, 1-ethyl propyl, 1-methyl hexyl, 1-methyl decyl or 1-ethyl dodecyl radical.

The term α, α′-disubstituted alkyl radical having from 4 to 12 carbon atoms should be understood in particular to mean a tert-butyl, 1,1-dimethylpropyl, 1-methyl 1-ethyl propyl, 1-methyl 1-ethyl hexyl or 1 radical. , 1-dimethyl decyl.

The 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.

The 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.

By alkenyl radical is meant a radical having from 2 to 6 carbon atoms, such as the vinyl, allyl or 2-butenyl radicals.

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

By aralkyl radical should be understood the benzyl or phenethyl radical optionally substituted by at least one halogen atom, a hydroxyl or a nitro function.

By cycloalkyl radical is meant a cyclopentyl or cyclohexyl radical.

By mono or polycyclic cycloalkyl radical having from 5 to 12 carbon atoms whose bonding carbon is trisubstituted should be understood the radical 1-methyl cyclohexyl or 1-adamantyl.

When the radicals r ′ and r˝ taken together form a heterocycle, the latter is preferably a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in position 4 by a C₁-C₆ alkyl radical or mono or polyhydroxyalkyl as defined above.

Among the compounds of formula (I) above, the following may be mentioned in particular: 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-fluorobenzoic acid, 4- [3- (1-adamantyl) -4-methoxybenzoyloxyl] -2-fluorobenzoic acid, 4- [3- (1-adamantyl) -4-methoxybenzoyloxyl] -2-methylbenzoic acid, 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoic acid, 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-methoxybenzoic acid, 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-methoxybenzoic acid, 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-trifluoromethylbenzoic acid, Methyl 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoate, 4- [5- (1-adamantyl) -2-fluoro-4-methoxybenzoyloxy] benzoic acid, 4- [5- (1-adamantyl) -2,4-dimethoxybenzoyloxy] benzoic acid, 4 - [(3- (1-adamantyl) benzoyloxy] benzoic acid, Benzoic 4- [3,5-di-tert-butyl-4-hydroxybenzoyloxy] acid, Benzoic 4- [3- (1-adamantyl-4-vinylbenzoyloxy] acid, 4- [3- (1-adamantyl) -4-ethylbenzoyloxy] benzoic acid, 4- [3- (1-adamantyl) -4-butylbenzoyloxy] benzoic acid, 4- [3- (1-adamantyl) -4-allyloxybenzoyloxy] benzoic acid, 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] isophthalic acid, 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] benzenesulfonamide acid, 3- (1-adamantyl) -4-4-hydroxyphenyl methoxybenzoate, 3- (1-adamantyl) -4-phenyl methoxybenzoate, 3- (1-adamantyl) -4-methoxybenzoate from 4-methyl phenyl, 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-hydroxymethyl benzoic acid, 4- [3- (1-adamantyl) -4-methylthiobenzoyloxy] benzoic acid, 4- [3- (1-adamantyl) -4-acetoxybenzoyloxy] benzoic acid, 4- [3- (1-adamantyl) -4-methylsulfone benzoyloxy] benzoic acid, 4- [3- (1-adamantyl) -4- (carboxymethyleneoxy) benzoyloxy] benzoic acid, 4- [3- (1-adamantyl) -4- (2,3-dihydroxypropyloxy) benzoyloxy] benzoic acid, 4- [3- (1-adamantyl) -4-methoxycarbonylmethyloxy] benzoic acid.

The particularly preferred compounds according to the invention can be represented by the general formula (II)<chemistry id="chem0005" num="0005"><img file="EP0409728A2_D0005.tif" /></chemistry> in which:<ul id="ul0002" list-style="none"><li>(i) either R₃ to R₉ are as defined above for formula (I), and R₂ represents an alkyl radical having from 1 to 6 carbon atoms, the radical OR₉, a fluorine atom or the radical -CF₃,</li><li>(ii) either R₂ to R₄ and R₆ to R₉ are as defined above for formula (I) and R₅ represents a fluorine atom</li></ul>

The present invention also relates to the process for the preparation of the compounds of formula (I). (a) When R₁ represents a hydrogen atom or the radical -CH₃. the compounds according to the invention can be prepared according to the following reaction scheme:<chemistry id="chem0006" num="0006"><img file="EP0409728A2_D0006.tif" /></chemistry>

The main stage of this preparation consists in reacting in an anhydrous medium, in an organic solvent such as tetrahydrofuran or methylene chloride containing a tertiary amine (pyridine or triethylamine), or an alkali hydride (sodium hydride), a form activated with a substituted benzoic acid, for example an acid chloride (<u style="single">1</u>), or a mixed anhydride, on a benzene compound carrying a hydroxy function in para of the radical R₁ (<u style="single">2</u>), the reaction being carried out at ambient temperature and with stirring. (b) For the other meanings of R₁, the compounds are prepared by protecting R₁ by a protective group of the allylic or benzyl type.

The transition to the free form can be carried out, in the case of an allylic protective group, by means of a catalyst such as certain transition metal complexes in the presence of a secondary amine, and in the case of a group benzyl protector, by debenzylation in the presence of hydrogen, by means of a catalyst such as palladium on carbon. For R₁ = OH the protective group is preferably benzyl, for R₁ = -CH₂OH or CH (OH) CH₃, it is preferably allylic, for R₁ = COOR₉, it can be either allylic or benzyl. For R₁ = COOH, the compounds of formula Ia can be prepared according to the following reaction scheme:<chemistry id="chem0007" num="0007"><img file="EP0409728A2_D0007.tif" /></chemistry>

The action of acid chloride (<u style="single">1</u>) with an allyl p-hydroxybenzoate (<u style="single">3</u>), optionally mono or poly substituted, in the presence of a tertiary amine such as pyridine or triethylamine, leads to the allyl esters (Ib). The transition to free acid can be carried out using a catalyst such as certain transition metal complexes, for example tris (triphenylphosphine) rhodium (1) chloride or tetrakis (triphenylphosphine) palladium (o) in the presence of a secondary amine.

The acids (Ic) thus obtained can be converted in a known manner into the corresponding acid chloride which, treated with an alcohol (R₉OH) or an amine<chemistry id="chem0008" num="0008"><img file="EP0409728A2_D0008.tif" /></chemistry> gives the corresponding ester or amide.

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

The compounds according to the invention exhibit good stability to light and to oxygen.

These compounds exhibit good activity in the differentiation test of mouse embryonic teratocarcinoma cells (F9 cells) (Cancer Research 43, p5268, 1983) and / or in the inhibition test of ornithine decarboxylase after induction by " tape stripping "in the naked rat (Lab. Animals 21, p233-240, 1987) and / or in the test for ear edema induced by topical application of arachidonic acid in mice (J. Invest. Dermatol 82, p367-371, 1984). These tests show the activities of the compounds respectively in the fields of differentiation, proliferation and inflammation.

Finally, the new compounds are characterized by the introduction into the chemical structure of an ester bond highly sensitive to the action of various esterases in vivo, which leads to the rapid inactivation of the molecules by conversion into biologically inactive fragments.

The compounds according to the invention are particularly suitable in the following fields of treatment:<ul id="ul0003" list-style="none"><li>1) to treat dermatological conditions linked to a keratinization disorder relating to differentiation and proliferation, in particular to treat vulgar, comedonian, polymorphic acnes, nodulocystic acne, conglobata, senile acne, secondary acne such as acne solar, medicated, professional acne;</li><li>2) to treat other types of keratinization disorder, in particular ichthyosis, ichthyosiform states, Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplasiform states, lichen;</li><li>3) to treat other dermatological conditions linked to a keratinization disorder with an inflammatory and / or immuno-allergic component and, in particular, all forms of psoriasis, whether cutaneous, mucous or nail, and even psoriatic arthritis , or cutaneous atopy, such as eczema, or respiratory atopy; the compounds can also be used in certain inflammatory conditions which do not have a keratinization disorder.</li><li>4) to treat all dermal or epidermal proliferations, whether benign or malignant, whether they are of viral origin such as common warts, flat warts and epidermodysplasia verruciformis, the proliferations can also be induced by ultra -violets especially in the case of basal and spino cell epithelioma;</li><li>5) to treat other dermatological disorders such as bullous dermatoses and collagen diseases;</li><li>6) to treat certain ophthalmological disorders, in particular corneopathies;</li><li>7) to combat aging of the skin, whether photoinduced or not;</li><li>8) to prevent or cure the stigma of epidermal and / or dermal atrophy induced by local or systemic corticosteroids, or any other form of skin atrophy.</li></ul>

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

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

The compounds according to the invention are generally administered at a daily dose of approximately 0.01 mg / kg to 100 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 vehicle.

Administration 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 or nanoparticles. By the parenteral route, the compositions may be in the form of solutions, suspensions or nanoparticles for infusion or for injection.

By topical route, the pharmaceutical compositions based on the compounds according to the invention are intended for the treatment of the skin and mucous membranes, being in the form of ointments, creams, milks, ointments, powders, soaked tampons, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or lipid or polymeric vesicles or of polymeric patches or of hydrogels allowing a controlled release.

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

By eye, these are mainly eye drops.

These 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.

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 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.

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

The 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 0.01% by weight.

The 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 anti-acne agents, such as S-carboxymethylcysteine, S-benzyl-cysteamine, their salts and their 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 nonsteroidal anti-inflammatory agents; carotenoids and, in particular β-carotene; anti-psoriatic agents such as anthralin and its derivatives and eicosatetraynoic-5,8,11,14 and triynoic-5,8,11 acids, their esters and their amides.

The 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 butylhydroxytoluene.

We 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

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-fluorobenzoic acid

(a) allyl 3-fluoro-4-hydroxybenzoate.

5.35 g (35 mmol) of 3-fluoro-4-hydroxybenzoic acid and 50 ml of allyl alcohol are introduced into a flask. 1.5 ml of concentrated sulfuric acid are added and the mixture is heated at 100 ° C. for twelve hours. Evaporate to dryness, add 200 ml of water, neutralize with sodium bicarbonate, extract with dichloromethane. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (80-20). 3.7 g (55%) of expected ester of melting point are collected: 42-43 ° C.

(b) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-allyl fluorobenzoate.

3- (1-adamantyl) -4-methoxybenzoyl chloride prepared from 2.8 g (10 mmoles) of 3- (1-adamantyl) -4-methoxybenzoic acid, described in Example 1 (b) of the European patent application No. 0.232.199 is dissolved in 50ml of tetrahydrofuran (THF). The solution is added dropwise to a mixture of 1.96 g (10 mmoles) of allyl 3-fluoro-4-hydroxybenzoate and 1.5 ml (10 mmoles) of triethylamine in 50 ml of THF. The mixture is stirred for twelve hours at room temperature, the reaction mixture is poured into water, and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (50-50). After evaporation of the solvents, 3.3 g (72%) of the expected ester with a melting point of 123-125 ° C. are obtained.

(c) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-fluorobenzoic acid.

108 mg (3.6 mmol) of sodium hydride (80% in oil) and 20 ml of THF are introduced into a flask and under a stream of nitrogen. 546 μl (3.6 mmoles) of ethyl malonate are added dropwise and the mixture is stirred at room temperature until the evolution of gas is stopped.

This solution is added dropwise to a mixture of 1.65 g (3.6 mmoles) of the ester obtained in Example 1 (b) above, 208 mg of tetrakis (triphenylphosphine) palladium (O) and 30 ml of THF. Stirred for one hour at room temperature, the reaction medium is evaporated, the residue obtained is triturated in 100 ml of ethyl ether and the sodium salt is filtered. The solid is introduced into 100 ml of water, acidified to pH 1 with concentrated hydrochloric acid, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. 1.1 g (72%) of 4 - [(3- (1-adamantyl) -4-methoxybenzoyloxy] -3-fluorobenzoic acid with a melting point of 258-260 ° C. are obtained.

EXAMPLE 2

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-fluorobenzoic acid

(a) allyl 2-fluoro-4-hydroxybenzoate.

Analogously to Example 1 (a), starting from 8.3 g (53 mmol) of 2-fluoro-4-hydroxybenzoic acid treated for two hours at 100 ° C. with 60 ml of allyl alcohol and 1.5 ml of concentrated sulfuric acid, 7.2 g (69%) of the expected ester with a melting point of 80-81 ° C. are obtained.

(b) Allyl 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-fluorobenzoate.

To a mixture of 1.96 g (10 mmoles) of allyl 2-fluoro-4-hydroxybenzoate, 1.53 ml (11 mmoles) of triethylamine and 25 ml of THF, a solution of 3 g (10 mmoles) of chloride chloride is added dropwise. 3- (1-adamantyl) -4-methoxybenzoyl in 50ml of THF. The mixture is stirred at ambient temperature for twelve hours, the reaction mixture is poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (50-50). After evaporation of the solvents, 3.63 g (78%) of the expected ester are obtained with a melting point of 102-104 ° C.

(c) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-fluorobenzoic acid.

2.32 g (5 mmoles) of ester obtained in 2 (b), 145 mg of tetrakis (triphenylphosphine) palladium (O) and 25 ml of anhydrous THF are introduced into a three-necked flask and under a stream of nitrogen. 4.35 ml (50 mmol) of morpholine are added dropwise and the mixture is stirred at room temperature for one hour. The reaction medium is evaporated to dryness, the residue is triturated in ethyl ether and the morpholine salt formed is filtered. The salt is introduced into 100 ml of water, acidified to pH 1 with concentrated hydrochloric acid, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulphate and evaporated. The solid is triturated in 20 ml of ethyl ether, filtered and dried. 1.86 g (88%) of the expected acid with a melting point of 254-256 ° C. are obtained.

EXAMPLE 3

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-methylbenzoic acid

(a) allyl 4-hydroxy-2-methylbenzoate.

Analogously to Example 1 (a), 5.34 g (32 mmol) of 4-hydroxy-2-methyl benzoic acid treated at 100 ° C. for twelve hours with 50 ml of allyl alcohol and 1.5 ml of acid concentrated sulfuric acid, give 4g (76%) of the ester expected to have a melting point of 76-77 ° C.

(b) 4- 3- (1-adamantyl) -4-methoxybenzoyloxy-2-methylbenzoate allyl.

In a three-necked flask and under a stream of nitrogen, 330 mg (11 mmol) of sodium hydride (80% in oil) and 20 ml of THF are introduced. A solution of 1.92 g (10 mmol) of ester prepared in Example 3 (a) is added dropwise and the mixture is stirred at ambient temperature until the evolution of gas is stopped. Then a dropwise solution of 3g (10mmol) of 3- (1-adamantyl) -4-methoxybenzoyl chloride in 30ml of THF is introduced dropwise and the mixture is stirred at room temperature for six hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (40-60). After evaporation of the solvents, 2.9 g (63%) of the expected ester with a melting point of 136-137 ° C. are collected.

(c) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-methylbenzoic acid.

Analogously to Example 2 (c), starting from 1.38 g (3 mmoles) of 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-methylbenzoate, 780 mg is obtained (62 %) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-methylbenzoic acid, melting point: 236-237 ° C.

EXAMPLE 4

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoic acid

(a) Benzyl 2,4-dihydroxybenzoate.

To a solution of 3 g (0.1 mol) of sodium hydride (80% in oil) and 50 ml of dimethylformamide (DMF), 15.4 g (0.1 mol) of 2.4 acid are added dropwise. -dihydroxybenzoic acid dissolved in 50ml of DMF and stirred at room temperature until gas evolution ceases. Then added 13.1 ml (0.1 mol) of benzyl bromide and stirred at room temperature until the reaction medium is dissolved. The reaction mixture is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate, evaporated. The residue is purified by chromatography on a silica column, eluting with dichloromethane. 19.7 g (81%) of the expected ester of melting point are collected: 94-95 ° C.

(b) Benzyl 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoate.

Analogously to Example 2 (b), starting from 9.8 g (40 mmoles) of benzyl 2,4-dihydroxybenzoate, 16.5 g (81%) of 4- [3- (1-adamantyl) are obtained -4-methoxybenzoyloxy] -2-benzyl hydroxybenzoate with melting point: 171-172 ° C.

(c) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoic acid.

5.1g (10 mmoles) of ester obtained in 4 (b), 1 g of palladium on carbon (5%) and 250 ml of dioxane are introduced into a reactor. Hydrogenation is carried out at ambient temperature and under a pressure of 4 bars, for one hour. The catalyst is filtered, the filtrate is evaporated and the solid obtained is triturated in 100 ml of ethyl ether. After filtration and drying, 3.6 g (86%) of 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoic acid with a melting point of 243 ° -244 ° C. are obtained.

EXAMPLE 5

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-methoxybenzoic acid

(a) Benzyl 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-methoxybenzoate.

To a solution of 5.12 g (10 mmoles) of 4- [3- (1-adamantyl-4-methoxybenzoyloxy] -2-benzyl hydroxybenzoate and 200 ml of DMF, 360 mg (12 mmoles) of sodium hydride are added in small amounts (80% in oil) and stirred at room temperature until gas evolution ceased, then added 750 μl (12 mmol) of methyl iodide and stirred for four hours at room temperature. The reaction medium is poured into the water extracted with 300 ml of ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulphate, evaporated. The residue obtained is purified by chromatography on a silica column, eluted with dichloromethane. After evaporation of the solvents, 4.9 g (94%) of the expected ester with a melting point of 102-103 ° C. are collected.

(b) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-methoxybenzoic acid.

4.5 g (8.5 mmol) of the benzyl ester obtained in 5 (a), 450 mg of palladium on carbon (5%) and 120 ml of dioxane are introduced into a reactor. Hydrogenation is carried out at ambient temperature and under a pressure of 4 bar for two hours, the catalyst is filtered and the filtrate is evaporated. The solid obtained is triturated in 50 ml of ethyl ether, filtered and dried. 3 g (82%) of 4- [3- (1-adamantyl) -4-methoxybenzoyloxy-3-2-methoxybenzoic acid with a melting point of 199-200 ° C. are collected.

EXAMPLE 6

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-methoxybenzoic acid

(a) allyl 4-hydroxy-3-methoxybenzoate.

Analogously to Example 1 (a), 5 g (30 mmoles) of 4-hydroxy-3-methoxybenzoic acid treated at 100 ° C. for four hours with 50 ml of allyl alcohol and 820 μl of concentrated sulfuric acid, give 4 , 65g (75%) of the expected ester, in the form of a slightly yellow oil.

(b) allyl 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-methoxybenzoate.

Analogously to Example 2 (b), starting from 2.35 g (12 mmoles) of allyl 4-hydroxy-3-methoxybenzoate, 4.12 g (77%) of the expected ester of melting point are obtained : 146-148 ° C.

(c) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-methoxybenzoic acid.

Analogously to Example 1 (c), starting from 2 g (4.2 mmol) of the ester prepared in 6 (b), 1.35 g (74%) of 4- [3- (3-) acid are obtained. 1-adamantyl) -4-methoxybenzoyloxy] -3-methoxybenzoic acid melting point: 282-284 ° C.

EXAMPLE 7

4- 3- (1-adamantyl) -4-methoxybenzoyloxy 2-trifluoromethylbenzoic acid

(a) allyl 4-hydroxy-2-trifluoromethylbenzoate.

Analogously to Example 1 (a), starting from 2 g (9.7 mmol) of 4-hydroxy-2-trifluoromethylbenzoic acid treated at 100 ° C. for twelve hours with 20 ml of allyl alcohol and 260 μl of acid concentrated sulfuric, 1.4 g (59%) of the expected ester are obtained with a melting point of 82-83 ° C.

(b) 4- [3- (1-adamantyl) 4-methoxybenzoyloxy] -2-allyl trifluoromethylbenzoate, 1.78 g (66%) of the expected ester are obtained with a melting point of 100-102 ° C.

(c) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2- trifluoromethylbenzoic acid.

Analogously to Example 1 (c), starting from 1.78 g (3.46 mmol) of the allylic ester prepared in 7 (b), 700 mg (39%) of the expected acid with the point of melting: 228-230 ° C.

EXAMPLE 8

Methyl 4 - [(3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoate

1.68 g (10 mmoles) of methyl 2,4-dihydroxybenzoate, 1.55 ml (11 mmoles) of triethylamine and 50 ml of THF are introduced into a flask. A solution of 3g (10mmol) of 3- (1-adamantyl) -4-methoxybenzoyl chloride in 50ml of THF is added dropwise and the mixture is stirred at room temperature for twelve hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (50-50). After evaporation of the solvents, 2.55 g (59%) of methyl 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoate are collected, mp: 125-127 ° C.

EXAMPLE 9

Benzoic 4- [5- (1-adamantyl) -2-fluoro-4-methoxybenzoyloxy] acid

(a) allyl 5- (1-adamantyl) -2-fluoro-4-hydroxybenzoate.

To a solution of 3 g (20 mmol) of 1-adamantanol in 10 ml of n-heptane, 63 μl of concentrated sulfuric acid and 2.16 ml (23 mmol) of acetic anhydride are successively added and the mixture is stirred at room temperature for three hours. 540 μl (10 mmoles) of concentrated sulfuric acid are then added dropwise, followed by a solution of 3.92 g (20 mmoles) of allyl 2-fluoro-4-hydroxybenzoate in 50 ml of dichloromethane and the mixture is stirred for 24 hours at room temperature. The reaction medium is evaporated to dryness, the residue is introduced into water, neutralized with sodium bicarbonate, the solid is filtered and dried. The solid is purified by chromatography on a silica column, eluting with dichloromethane. After evaporation of the solvents, 3.86 g (58%) of the expected ester having a melting point of: 219-222 ° C. is collected.

(b) allyl 5- (1-adamantyl) -2-fluoro-4-methoxybenzoate.

350 mg (11.6 mmol) of sodium hydride (80% in oil) and 10 ml of DMF are introduced into a three-necked flask and under a stream of nitrogen. A solution of 3.84 g (11.6 mmol) of the ester prepared in Example 9 (a) in 30 ml of DMF is added dropwise and the mixture is stirred at room temperature until gas evolution ceases. 730 μl (11.7 mmol) of methyl iodide are added dropwise and the mixture is stirred at room temperature for six hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (50-50). After evaporation of the solvents, 2.9 g (72%) of 5- (1-adamantyl) -2-fluoro-4-methoxybenzoate of allyl with a melting point of 101-102 ° C. are collected.

(c) 5- (1-adamantyl) -2-fluoro-4-methoxybenzoic acid.

A suspension of 2.87 g (8.3 mmol) of ester obtained in 9 (b) in 100 ml of 2N methanolic sodium hydroxide is heated at reflux for six hours. Evaporated to dryness, taken up in water, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate, evaporated. 2.5 g (100%) of the expected acid are obtained, which melts at 282-284 ° C.

(d) 5- (1-adamantyl) -2-fluoro-4-methoxybenzoyl chloride.

2.13 g (7 mmol) of 5- (1-adamantyl) -2-fluoro-4-methoxybenzoic acid and 20 ml of thionyl chloride are heated to reflux until the evolution of gas is stopped. Evaporated to dryness and 2.26 g (100%) of the crude acid chloride are obtained, which is used as it is for the rest of the synthesis.

(e) allyl benzoate 4- [5- (1-adamantyl) -2-fluoro-4-methoxybenzoyloxy] benzoate.

1.25 g (7 mmoles) of allyl 4-hydroxybenzoate, 1.1 ml (7 mmoles) of triethylamine and 20 ml of THF are introduced into a flask. A solution of 2.26 g (7 mmol) of the acid chloride prepared in 9 (d) in 60 ml of THF is added dropwise and the mixture is stirred at room temperature for twenty hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (70-30). After evaporation of the solvents, 2.4 g (74%) of the expected ester with a melting point of 130-131 ° C. are collected.

(f) 4- [5- (1-adamantyl) -2-fluoro-4-methoxybenzoyloxy] benzoic acid.

Analogously to Example 1 (c), starting from 2.33 g (5 mmoles) of 4- [5- (1-adamantyl) -2-fluoro-4-methoxybenzoyloxy] allyl benzoate, 1 is obtained, 69g (79%) 4- [5- (1-adamantyl) -2-fluoro-4-methoxybenzoyloxy] benzoic acid, melting point: 268-270 ° C.

EXAMPLE 10

4- [5- (1-adamantyl) -2,4-dimethoxybenzoyloxy] benzoic acid

(a) Methyl 5- (1-adamantyl) -2,4-dihydroxybenzoate.

Analogously to Example 9 (a), starting from 24.5 g (0.146 mol) of methyl 2,4-dihydroxybenzoate, 32.5 g (74%) of 5- (1-adamantyl) -2 are obtained , Methyl 4-dihydroxybenzoate, melting point: 167-169 ° C.

(b) Methyl 5- (1-adamantyl) -2,4-dimethoxybenzoate.

To a suspension of 1.32 g (44 mmol) of sodium hydride (80% in oil) in 30 ml of DMF, a solution of 6 g (20 mmol) of the ester prepared in 10 (a) is added dropwise in 100ml of DMF and stirred at room temperature until gas evolution ceases. 2.75 ml (44 mmol) of methyl iodide are then added and the mixture is stirred at room temperature for twenty-four hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (90-10). After evaporation of the solvents, 3.4 g (51%) of the expected ester with a melting point of 148-151 ° C. are collected.

(c) 5- (1-adamantyl) -2,4-dimethoxybenzoic acid.

Analogously to Example 9 (c), starting from 3.3 g (10 mmoles) of the methyl ester prepared in 10 (b), 3 g (94%) of 5- (1-adamantyl acid) are obtained ) -2,4-dimethoxybenzoic acid melting point: 213-214 ° C.

(d) 5- (1-adamantyl) -2,4-dimethoxybenzoyl chloride.

Analogously to Example 9 (d), starting from 2.94 g (9.3 mmol) of 5- (1-adamantyl) -2,4-dimethoxybenzoic acid, 3.12 g (100%) of crude acid chloride, which is used as it is for the rest of the synthesis.

(e) allyl 4- [5- (1-adamantyl) -2,4-dimethoxybenzoyloxy] benzoate.

Analogously to Example 9 (e), by reacting 3.12 g (9.3 mmol) of the acid chloride prepared in 10 (d) with 1.66 g (9.3 mmol) of allyl 4-hydroxybenzoate , 1.8 g (41%) of the expected ester with a melting point of 120-121 ° C. are obtained.

(f) 4- [5- (1-adamantyl) -2,4-dimethoxy benzoyloxy] benzoic acid.

Analogously to Example 1 (c), starting from 1.77 g (3.71 mmol) of the ester prepared in 10 (e), 1.16 g (72%) of 4- [5 acid] are obtained. - (1-adamantyl) -2,4-dimethoxybenzoyloxy] benzoic melting point: 236-238 ° C.

EXAMPLE 11

4- [3- (1-adamantyl) benzoyloxy] benzoic acid

(a) Methyl 3- (1-adamantyl) -4-hydroxybenzoate.

Analogously to Example 9 (a), from 22.8 g (0.15 mol) of methyl 4-hydroxybenzoate, 36 g (84%) of methyl 3- (1-adamantyl) -4-hydroxybenzoate are obtained. melting point: 183-184 ° C.

(b) Methyl 3- (1-adamantyl) -4- (trifluoromethyl) sulfonyloxybenzoate.

A solution of 14.4 g (50.4 mmol) of methyl 3- (1-adamantyl) -4-hydroxybenzoate, 13.6 ml (168 mmol) of pyridine, 61 mg (0.5 mmol) of 4 is cooled to -78 ° C. -dimethylaminopyridine and 100ml of anhydrous dichloromethane and added dropwise 10ml (59.5mmol) of trifluoromethanesulfonic anhydride. The temperature is allowed to rise to 20 ° C and stirred for six hours. The reaction medium is poured into water, acidified to pH 1 with concentrated hydrochloric acid and extracted with dichloromethane. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with hexane. After evaporation of the solvents, 17.5 g (83%) of the expected product with a melting point of 90-91 ° C. are obtained.

(c) methyl 3- (1-adamantyl) benzoate.

3 g (7.2 mmol) of 3- (1-adamantyl) -4- (trifluoromethyl) methyl sulfonyloxybenzoate, 415 mg (0.36 mmol) of tetrakis (triphenylphosphine) palladium (O), 3 ml (21, 3) are introduced into a flask 5mmoles) of triethylamine and 15ml of DMF. 547 μl (14.4 mmol) of formic acid are added dropwise and the mixture is heated at 80 ° C. for one hour. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with hexane. 1.78 g (90%) of methyl 3- (1-adamantyl) benzoate are collected, melting point: 147-149 ° C.

(d) 3- (1-adamantyl) benzoic acid.

Analogously to Example 9 (c), starting from 3.45 g (12.7 mmol) of the ester prepared in 11 (c), 2.81 g (86%) of 3- (1) acid are obtained. -adamantyl) benzoic melting point: 247-249 ° C.

(e) 3- (1-adamantyl) benzoyl chloride.

Analogously to Example 9 (d), from 1.4 g (5.5 mmol) of 3- (1-adamantyl) benzoic acid, 1.5 g (100%) of the crude acid chloride are obtained , used as is for the rest of the synthesis.

(f) Allyl 4- [3- (1-adamantyl) benzoyloxy] benzoate.

Analogously to Example 9 (e), by reacting 1.5 g (5.5 mmoles) of 3- (1-adamantyl) benzoyl chloride with 980 mg (5.5 mmoles) of allyl 4-hydroxybenzoate, 1.5g (68%) of the expected ester is obtained in the form of a colorless oil.

(g) 4- [3- (1-adamantyl) benzoyloxy) benzoic acid.

Analogously to Example 1 (c), from 1.45 g (3.6 mmoles) of allyl 4- [3- (1-adamantyl) benzoyloxy] benzoate, 600 mg (40%) of 4- [3- (1-adamantyl) benzoyloxy] benzoic acid, melting point: 237-239 ° C.

EXAMPLE 12

Benzoic 4- [3,5-di-tert-butyl-4-hydroxybenzoyloxy] acid

(a) 3,5-Di-tert-butyl-4-hydroxybenzoyl chloride.

1.88 g (7.5 mmol) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 15 ml of thionyl chloride are heated at reflux until the gas evolution ceases. Evaporated to dryness and 2.1g (100%) of the crude acid chloride is obtained, which is used as it is for the rest of the synthesis.

(b) Allyl 4- [3,5-di-tert-butyl-4-hydroxybenzoyloxy] benzoate.

Analogously to Example 9 (e), by reacting 2.1 g (7.5 mmol) of the acid chloride prepared in 12 (a) with 1 g (7.5 mmol) of allyl 4-hydroxybenzoate, obtains 1.48 g (49%) of the expected ester of melting point: 114-116 ° C.

(c) 4- [3,5-di-tert-butyl-4-hydroxybenzoyloxy] benzoic acid.

Analogously to Example 2 (c), from 1.47 g (3.6 mmoles) of the ester prepared in 12 (b), 750 mg (57%) of 4- [3.5 acid are obtained. -di-tert-butyl-4-hydroxybenzoyloxy] benzoic, which melts at 223-224 ° C.

EXAMPLE 13

4- [3- (1-adamantyl) -4-vinylbenzoyloxy] benzoic acid

(a) Methyl 3- (1-adamantyl) -4-vinylbenzoate.

4.1g (10mmol) of methyl 3- (1-adamantyl) -4- (trifluoromethyl) sulfonyloxybenzoate in 50ml of DMF are introduced into a flask and under argon and successively add 3.1ml of vinyltributyltin (10.3mmol), 1.3g (30mmol) of lithium chloride and 141mg (0.2mmol) of bis- (triphenyl phosphine) -palladium (II) chloride. The mixture is heated to 80 ° C. for sixteen hours, the reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (20-80). 2.7 g (93%) of expected product of melting point: 86-87 ° C. are collected.

(b) 3- (1-adamantyl) -4-vinylbenzoic acid.

1.48 g (5 mmoles) of the above ester, 100 ml of 2N methanolic soda and 250 ml of THF are introduced into a flask. Stirred at room temperature for three hours, evaporated to dryness, taken up in water, acidified to pH 1 with concentrated hydrochloric acid, filtered the solid obtained and dried under vacuum in the presence of phosphorus pentoxide. 1.4 g (100%) of expected acid are collected, melting point: 315-317 ° C.

(c) 3- (1-adamantyl) -4-vinylbenzoyl chloride.

1.4 g (5 mmoles) of 3- (1-adamantyl) -4-vinyl benzoic acid are introduced into a flask in 100 ml of dichloromethane and dropwise added 940 μl (5 mmoles) of dicyclohexylamine. After obtaining a homogeneous reaction medium, 360 μl (5 mmol) of thionyl chloride are added dropwise and the mixture is stirred at room temperature for one hour. Evaporated to dryness, taken up in 200 ml of ethyl ether, filtered the dicyclohexylamine salt and evaporated. 1.5 g (100%) of crude acid chloride are obtained, which is used as it is for the rest of the synthesis.

(d) Allyl 4- [3- (1-adamantyl) -4-vinylbenzoyloxy] benzoate.

Analogously to Example 9 (e), by reaction of 1.35 g (4.5 mmoles) of 3- (1-adamantyl) -4-vinylbenzoyl chloride with 800 mg (4.5 mmoles) of 4-hydroxybenzoate allyl, 1.4 g (70%) of the expected ester are obtained, in the form of a colorless oil.

(e) 4- (3- (1-adamantyl) -4-vinylbenzoyloxy] benzoic acid.

Analogously to Example 2 (c), from 1.2 g (2.7 mmoles) of allyl 4- [3- (1-adamantyl) -4-vinylbenzoyloxy] benzoate, 750 mg is obtained (75% ) 4- [3- (1-adamantyl) -4-vinylbenzoyloxy] benzoic acid with a melting point of 235-236 ° C.

EXAMPLE 14

4- [3- (1-adamantyl) -4-ethylbenzoyloxy] benzoic acid.

(a) Methyl 3- (1-adamantyl) -4-ethylbenzoate.

3 g (10 mmol) of methyl 3- (1-adamantyl) -4-vinylbenzoate, 270 mg of palladium on carbon (5%) and 50 ml of dioxane are introduced into a reactor. Hydrogenation is carried out at ambient temperature and under a pressure of 4 bars for four hours, the catalyst is filtered and the filtrate is evaporated. 3 g (100%) of the expected product are collected, in the form of a colorless oil.

(b) 3- (1-adamantyl) -4-ethylbenzoic acid.

Analogously to Example 13 (b), starting from 2.54 g (8.5 mmol) of the preceding ester, 2.4 g (100%) of 3- (1-adamantyl) -4 acid are obtained -ethylbenzoic acid.

(c) 3- (1-adamantyl) -4-ethylbenzoyl chloride.

Analogously to Example 9 (d), starting from 2.3 g (8.1 mmoles) of the preceding acid, 2.35 g (100%) of the crude acid chloride are obtained, used as it is for the continuation of the synthesis.

(d) Allyl 4- [3- (1-adamantyl) -4-ethylbenzoyloxy] benzoate.

Analogously to Example 9 (e), by reaction of 2.35 g (8.1 mmoles) of 3- (1-adamantyl) -4-ethylbenzoyl chloride with 1.44 g (8.1 mmoles) of 4-hydroxybenzoate allyl, 2.54 g (71%) of the expected ester are obtained with a melting point of 111-113 ° C.

(e) 4- [3- (1-adamantyl) -4-ethylbenzoyloxy] benzoic acid.

Analogously to Example 2 (c), starting from 2.5 g (5.6 mmol) of the ester prepared in 14 (d), 1.65 g (73%) of the acid 4- 3 are obtained. - (1-adamantyl) -4-ethylbenzoyloxy benzoic melting point: 239-241 ° C.

EXAMPLE 15

4- [3- (1-adamantyl) -4-butylbenzoyloxy] benzoic acid

(a) Methyl 3- (1-adamantyl) -4-butylbenzoate.

4.1g (10mmol) of methyl 3- (1-adamantyl) -4- (trifluoromethyl) sulfonyloxybenzoate in 50ml of DMF are introduced into a flask and under argon and successively added 3.6ml (11mmol) of tetrabutyltin, 1, 3g (30mmol) of lithium chloride and 141mg (0.2mmol) of bis- (triphenylphosphine) palladium (II) chloride. The mixture is heated to 80 ° C. for twenty-four hours, the reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate, evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a dichloromethane-hexane mixture (30-70). After evaporation of the solvents, 2.6 g (80%) of the expected product are obtained, in the form of a slightly yellow oil.

(b) 3- (1-adamantyl) -4-butylbenzoic acid.

Analogously to Example 13 (b), starting from 2.3 g (7 mmoles) of the preceding ester, 2.1 g (100%) of 3- (1-adamantyl) -4-butylbenzoic acid are obtained melting point: 209-210 ° C.

(c) 3- (1-adamantyl) -4-butylbenzoyl chloride.

Analogously to Example 9 (d), starting from 2 g (6.4 mmol) of the preceding acid, 2.1 g (100%) of the crude acid chloride are obtained, used as it is for the continuation of synthesis.

(d) Benzyl 4- [3- (1-adamantyl) -4-butylbenzoyloxy] benzoate.

The above acid chloride, dissolved in 50 ml of THF, is added dropwise to a mixture of 1.46 g (6.4 mmol) of benzyl 4-hydroxybenzoate and 1 ml (7.1 mmol) of triethylamine in 50 ml of THF . The mixture is stirred at ambient temperature for eight hours, the reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (50-50). After evaporation of the solvents, 2.2 g (75%) of the expected ester are collected, in the form of a colorless oil.

(e) 4- [3- (1-adamantyl) -4-butylbenzoyloxy] benzoic acid.

2g (3.8 mmol) of the ester prepared in Example 15 (d), 340 mg of palladium on carbon (5%) and 100 ml of dioxane are introduced into a reactor. Hydrogenation is carried out at ambient temperature and under a pressure of 4 bar for four hours, the catalyst is filtered, the filtrate is evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and ethyl ether (70-30). After evaporation of the solvents, 1.1 g (68%) of 4- [3- (1-adamantyl) -4-butylbenzoyloxy] benzoic acid with a melting point of 205-206 ° C. are collected.

EXAMPLE 16

4- [3- (1-adamantyl) -4-allyloxybenzoyloxy] benzoic acid

To a solution of 1.17 g (3 mmol) of 4- [3- (1-adamantyl) -4-hydroxybenzoyloxy] benzoic acid in 100 ml of a mixture of THF and DMF (50-50), small amounts are added 180 mg (6mmol) of sodium hydride (80% in oil) and stirred at room temperature until gas evolution ceases. 260 μl (3 mmol) of allyl bromide are then added and the mixture is stirred at room temperature for three hours. The reaction medium is poured into water, acidified to pH 4 with 1N hydrochloric acid, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on silica, eluted with ethyl ether. After evaporation of the solvents, 880 mg (68%) of 4- [3- (1-adamantyl) -4-allyloxybenzoyloxy] benzoic acid with a melting point of 260-261 ° C. are collected.

EXAMPLE 17

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] isophthalic acid

(a) Benzyl 4-hydroxyisophthalate.

To a solution of 5.5 g (30 mmoles) of 4-hydroxyisophthalic acid in 200 ml of DMF, 1.8 g (60 mmoles) of sodium hydride (80% in oil) are added in small amounts and stirred until cessation of gas evolution. Then 7.2 ml (60 mmol) of benzyl bromide is added and the mixture is stirred for four hours at room temperature. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (30-70). After evaporation of the solvents, 6.5 g (60%) of the expected ester with a melting point of 68-70 ° C. are collected.

(b) Benzyl 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] isophthalate.

Analogously to Example 1 (b), by reaction of 5.4 g (18 mmoles) of 3- (1-adamantyl) -4-methoxybenzoyl chloride with 6.5 g (18 mmoles) of benzyl 4-hydroxyisophthalate, obtains 7.5 g (67%) of 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] benzyl isophthalate with melting point: 102-104 ° C.

(c) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] isophthalic acid.

Analogously to Example 15 (e), starting from 3.1 g (5 mmoles) of the preceding ester, 1.2 g (55%) of 4- [3- (1-adamantyl) - acid are obtained. 4-methoxybenzoyloxy] isophthalic, melting point: 172-173 ° C.

EXAMPLE 18

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] benzenesulfonamide acid

2.86 g (10 mmoles) of 3- (1-adamantyl) -4-methoxybenzoic acid, 1.73 g (10 mmoles) of 4-hydroxybenzenesulfonamide and 50 ml of THF are introduced into a flask. 2.1 g (10 mmol) of 1,3-dicyclohexylcarbodiimide and then 1.22 g (10 mmol) of 4-dimethylaminopyridine are successively added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The solid obtained is purified by chromatography on a silica column, eluted with a mixture of ethyl ether and hexane (60-40). After evaporation of the solvents, 2 g (46%) of 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] benzenesulfonamide with a melting point of 223-224 ° C. are collected.

EXAMPLE 19

3- (1-adamantyl) -4-4-hydroxyphenyl methoxybenzoate

(a) 4-Benzyloxyphenyl 3- (1-adamantyl) -4-methoxybenzoate.

In a three-necked flask, under a stream of nitrogen, containing 663 mg (22 mmoles) of sodium hydride (80% in oil), 4 g (20 mmoles) of 4-benzyloxyphenol in 30 ml of anhydrous and stirred THF are added dropwise until the gas evolution ceases. 6.4 g (20 mmol) of 3- (1-adamantyl) -4-methoxybenzoyl chloride are then introduced dropwise in 60 ml of THF and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, extracted with dichloromethane, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is triturated in hexane to yield 9 g (96%) of the expected ester with a melting point: 183-185 ° C.

(b) 4-hydroxyphenyl 3- (1-adamantyl) -4-methoxybenzoate.

4g (8.5 mmol) of the benzyl ether obtained in Example 19 (a), 400 mg of palladium on carbon (10%), 70 ml of dioxane, 70 ml of acetic acid and 0.2 ml are introduced into a reactor. hydrochloric acid (12N). The mixture is stirred at 50 ° C. under a pressure of 4 bars. After filtration and evaporation, the solid is taken up with 400ml of dichloromethane, and the organic phase is washed with water. After drying over magnesium sulfate, filtration and evaporation, 2.85 g (88%) of the expected compound with a melting point of 236-237 ° C. are isolated.

EXAMPLE 20

Phenyl 3- (1-adamantyl) -4-methoxybenzoate

Analogously to Example 3 (b), 0.95 g (10 mmoles) of phenol in 10 ml of THF are treated with 332 mg (11 mmoles) of sodium hydride (80% in oil). Then introduced dropwise, a solution of 3.2g (10mmol) of 3- (1-adamantyl) -4-methoxybenzoyl chloride in 30ml of THF and allowed to stir at room temperature for 4 hours. The reaction medium is poured into water, extracted with ethyl ether, washed with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica, with a mixture of hexane and dichloromethane (60-40). After evaporation and precipitation in hexane, 3 g (83%) of the expected ester with a melting point of 165-166 ° C. are isolated.

EXAMPLE 21

4-methylphenyl 3- (1-adamantyl) -4-methoxybenzoate

Analogously to Example 3 (b), 1.08 g (10 mmoles) of paracresol in 10 ml of THF are treated with 332 mg (11 mmoles) of sodium hydride (80% in oil). A solution of 3.2 g (10 mmoles) of 3- (1-adamantyl) -4-methoxybenzoyl chloride in 30 ml of THF is then introduced dropwise, and the mixture is left to stir at room temperature overnight. The reaction medium is poured into water and extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated. the residue obtained is recrystallized from ethyl acetate to yield 2.91 g (77%) of 3- (1-adamantyl) -4-4-methylphenyl methoxybenzoate with a melting point of 206 ° C.

EXAMPLE 22

4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-hydroxymethylbenzoic acid

(a) Benzyl 4-hydroxy-3-hydroxymethylbenzoate.

A solution of 27.4 g (0.12 mol) of benzyl 4-hydroxybenzoate, 14.7 g (0.12 mol) of benzeneboronic acid, 6 g (0.135 mol) of paraformaldehyde and 0.9 ml (12 mmol) of propionic acid in 600 ml of anhydrous benzene are heated at reflux for twelve hours using a Dean-Stark to separate the water formed. The reaction medium is poured into bicarbonate water, extracted with ethyl ether, the organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with dichloromethane. After evaporation of the solvent, 8.9 g (30%) of the expected product are obtained, with a melting point of 109-110 ° C.

(b) Benzyl 3-tert-butyldimethylsilyloxymethyl-4-hydroxybenzoate.

To a solution of 2.7 g (10.5 mmol) of 4-hydroxy-3-hydroxy benzyl methylbenzoate in 50 ml of DMF, 1.47 ml (10.5 mmol) of triethylamine and 51 mg (0.4 mmol) of 4 are successively added -N, N-dimethylamino pyridine. The reaction medium is cooled to 0 ° C. and a solution of 1.6 g (10.5 mmol) of tert-butyldimethylsilyl chloride in 20 ml of DMF is added dropwise. Stirred at room temperature for eight hours, pour the reaction medium into water, extract with ethyl ether, decant the organic phase, dry over magnesium sulfate and evaporate. The residue obtained, which contains two products, is purified by chromatography on a silica column, eluting with a mixture of hexane and ethyl ether (90-10). 850 mg (23%) of benzyl 3-tert-butyldimethyl silyloxymethyl-4-hydroxybenzoate are thus obtained in the form of a colorless oil and 930 mg (27%) of benzyl 4-tert-butyldimethylsilyloxy-3-hydroxymethylbenzoate in the form of a slightly yellow oil.

(c) Benz 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-tert-butyldimethyl silyloxymethylbenzoate.

Analogously to Example 1 (b), by reaction of 2.2 g (7.25 mmol) of 3- (1-adamantyl) -4-methoxybenzoyl chloride with 2.7 g (7.25 mmol) of 3-tert benzyl butyldimethylsilyloxymethyl-4-hydroxybenzoate, 3.1 g (71%) of the expected product are obtained, in the form of a colorless oil.

(d) Benz 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-hydroxymethyl benzoate.

To a solution of 2.7 g (4.5 mmol) of the ester obtained in Example 22 (c) in 50 ml of THF, 5 ml of a molar solution of tetrabutylammonium fluoride in THF is added dropwise and stirred thirty minutes at room temperature. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with dichloromethane. After evaporation of the solvent, 700 mg (30%) of the expected ester are obtained in the form of an opaque oil.

(e) 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-hydroxymethylbenzoic acid.

Analogously to Example 15 (e), starting from 700 mg (1.3 mmol) of the preceding ester, 300 mg (55%) of 4- [3- (1-adamantyl) -4- acid are obtained. methoxybenzoyloxy] -3-hydroxymethylbenzoic acid melting point: 214-216 ° C.

EXAMPLE 23

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

(a) Methyl 3- (1-adamantyl) -4- (dimethylaminothiocarbonyloxy) benzoate.

2.4 g (0.08 mole) of sodium hydride (80% in oil) and 250 ml of DMF are introduced into a flask. Under a stream of nitrogen, 22.9 g (0.08 mole) of methyl 3- (1-adamantyl) -4-hydroxybenzoate are added dropwise and the mixture is stirred until the evolution of gas is stopped. 12.9 g (0.104 mole) of dimethylthiocarbamoyl chloride are then added all at once and the mixture is stirred for 16 hours at room temperature. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate, evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (70-30). After evaporation of the solvents, 1.8 g (63%) of the expected product are collected, with a melting point of 174 ° to 175 ° C.

(b) Methyl 3- (1-adamantyl) -4- (dimethylaminocarbonylthio) benzoate.

17.9 g (0.048 mole) of the preceding ester are heated under a stream of nitrogen at 300 ° C for 15 minutes. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (90-10). After evaporation of the solvents, 14.2 g (80%) of ester with a melting point of 150 ° -151 ° C are collected.

(c) 3- (1-adamantyl) -4-mercapto benzoic acid.

14.2 g (38 mmol) of the above ester, 200 ml of 2N methanolic sodium hydroxide are introduced into a flask and the mixture is heated at reflux for 4 hours. The reaction medium is evaporated to dryness, taken up in water, acidified to pH = 1 with concentrated hydrochloric acid, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulphate and evaporated. 10.9 g of crude acid are collected which will be used as such for the rest of the synthesis.

(d) Methyl 3- (1-adamantyl) -4 methylthio benzoate.

2.2 g (73 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a flask. A solution of 10.5 g (36.5 mmol) of 3- (1-adamantyl) -4-mercapto benzoic acid in 100 ml of DMF is added dropwise and the mixture is stirred until gas evolution ceases. Then 5.7 ml (92 mmol) of iodomethane is added and the mixture is stirred for 8 hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and hexane (40-60). After evaporation of the solvents, 10 g (87%) of the expected ester with a melting point of 112 ° -113 ° C. are obtained.

(e) 3- (1-adamantyl) -4-methylthiobenzoic acid.

Analogously to Example 1 (c), starting from 2 g (6.3 mmol) of the preceding ester, 1.76 g (91%) of the expected acid with a melting point are obtained: 264-265 ° C.

(f) 3- (1-adamantyl) -4-methylthiobenzoyl chloride.

1.7 g (5.6 mmol) of 3- (1-adamantyl) -4-methylthiobenzoic acid and 20 ml of thionyl chloride are heated to reflux until gas evolution ceases. Evaporated to dryness and 1.8 g (100%) of crude acid chloride are obtained, which is used as it is for the rest of the synthesis.

(g) Tert-butyl 4- [3- (1-adamantyl) -4 methylthiobenzoyloxy] benzoate.

1 g (5.6 mmol) of tert-butyl 4-hydroxybenzoate, 780 μl (5.6 mmol) of triethylamine and 50 ml of THF are introduced into a flask. 1.8 g (5.6 mmol) of the acid chloride prepared in 1 (f) in 50 ml of THF are added dropwise and the mixture is stirred at ambient temperature for 8 hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column, eluted with a mixture of dichloromethane and hexane (60-40). After evaporation of the solvents; 2.1 g (76%) of expected ester are obtained with a melting point of 133-134 ° C.

(h) 4- [3- (1-adamantyl) -4-methylthiobenzoyloxy] benzoic acid.

1.9 g (3.8 mmol) of the above ester and 40 ml of carbon tetrachloride are introduced into a flask.

Under nitrogen, 550 μl (3.8 mmol) of iodotrimethylsilane are added dropwise and the mixture is stirred at room temperature for three hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The solid obtained is recrystallized from ethyl acetate. After filtration and drying, 920 mg (57%) of 4- [3- (1-adamantyl) -4-methylthiobenzoyloxy] benzoic acid, of melting point: 276-277 ° C., are obtained.

EXAMPLE 24

4- [3- (1-adamantyl) -4-acetoxybenzoyloxy] benzoic acid

(a) 4- 3 (1-adamantyl) -4-benzyl acetoxybenzoyloxy benzoate.

In a flask, 66 mg (2.2 mmol) of sodium hydride (80% in oil) and 50 ml of THF are introduced, a solution of 964 mg (2 mmol) of 4- is added dropwise [3- (1-adamantyl) -4-hydroxybenzoyloxy benzoate] benzyl in 20 ml of THF and stirred until cessation of gas evolution. 150 μl (2.2 mmol) of acetyl chloride are then introduced and the mixture is stirred at ambient temperature for 8 hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The residue obtained is purified by simple filtration on silica, eluting with dichloromethane. After evaporation of the solvents, 870 mg (83%) of the expected product are collected, with a melting point of 131-132 ° C.

(b) 4- [3- (1-adamantyl) -4-acetoxybenzoyloxy] benzoic acid.

750 mg (1.4 mmol) of the above ester, 100 mg of palladium on carbon (10%) and 20 ml of dioxane are introduced into a reactor. Hydrogenation is carried out at ambient temperature and under a pressure of 6 bars for two hours, the catalyst is filtered, and the filtrate is evaporated. The residue obtained is triturated in the minimum amount of ethyl ether, filtered and dried. 500 mg (81%) of 4- [3- (1-adamantyl) -4-acetoxybenzoyloxy] benzoic acid with a melting point of 264-265 ° C. are obtained.

EXAMPLE 25

4- [3- (1-adamantyl) -4-methylsulfone benzoyloxy] benzoic acid

(a) Tert-butyl 4- [3- (1-adamantyl) -4-methylsulfone benzoyloxy] benzoate.

940 mg (1.9 mmol) of tert-butyl 4- [3- (1-adamantyl) -4-methylthiobenzoyloxy] benzoate and 40 ml of dichloromethane are introduced into a flask. 700 mg (4 mmol) of 3-chloroperoxybenzoic acid are added at 0 ° C. and the mixture is stirred at room temperature for 6 hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a silica column, eluted with ethyl ether. After evaporation of the solvents, 670 mg (67%) of sulfone are collected in the form of a slightly yellow oil.

(b) 4- [3- (1-adamantyl) -4-methylsulfone benzoyloxy] benzoic acid.

Analogously to Example 23 (h) from 630 mg (1.2 mmol) of the preceding ester, 190 mg (35%) of 4- [3- (1-adamantyl) - acid are obtained. 4-methylsulfone benzoyloxy] benzoic melting point: 248-250 ° C.

EXAMPLE 26

4- [3- (1-adamantyl) -4- (carboxymethyleneoxy) benzoyloxy] benzoic acid.

(a) Benzyl 4- [3- (1-adamantyl) -4- (benzyloxycarbonylmethyleneene) benzoyloxy] benzoate.

Analogously to Example 24 (a) by reaction of 964 mg (2 mmol) of benzyl 4- [3- (1-adamantyl) -4-hydroxybenzoyloxy] benzoate with 350 μl (2.2 mmol) of 2-bromo benzyl acetate, 800 mg (63%) of the expected product are obtained with a melting point of 129-130 ° C.

(b) 4- [3- (1-adamantyl) -4- (carboxymethylene oxy) benzoyloxy] benzoic acid.

Analogously to Example 21 (b) from 750 mg (1.2 mmol) of the preceding ester, 400 mg (75%) of the expected acid are obtained, with a melting point of 287-288 °. vs.

EXAMPLE 27

4- [3- (1-adamantyl) -4- (2,3-dihydroxypropyloxy) benzoyloxy] benzoic acid.

(a) methyl 3- (1-adamantyl) -4- (2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoate:

In a three-necked flask containing 10.0 g (34.9 mmol) of 3- (1-adamantyl) -4-hydroxybenzoic acid and 5.31 g (38.4 mmol) of potassium carbonate in 100 ml of dimethylformamide, add 12.0 g (41.9 mmol) of 2,2-dimethyl-1,3-dioxolane-4-methyltosylate in 75 ml of dimethylformamide dropwise and stir at 100 ° C for 12 hours. The reaction medium is poured into ice water and extracted with 900 ml of ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica in the eluent hexane / ethyl acetate (80:20) to yield, after evaporation, 8.82 g (63%) of 3- (1-adamantyl) -4- (2,2- dimethyl-1,3-dioxolane-4-methyloxy) methyl benzoate melting point: 159 ° C.

(b) 3- (1-adamantyl) -4- (2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoic acid.

To a solution of 8.80 g (22 mmol) of 3- (1-adamantyl-4- (2,2-dimethyl-1,3-dioxolane-4-methyloxy) methyl benzoate in 200 ml of methanol, the following is added 16 g (0.4 moles) of sodium hydroxide and heated to reflux for 3 hours 30 minutes The reaction medium is evaporated and taken up in 250 ml of water, then acidified to pH 3. The precipitate is extracted with 1.4 liters of ethyl ether The organic phase is washed with water, dried over magnesium sulphate and evaporated. After trituration in hexane, 8.32 g (98%) of 3- (1-adamantyl) -4- (2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoic acid are isolated mp: 224-225 ° C.

(c) Allyl 4- [3- (1-adamantyl) -4- (2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoyloxy] benzoate.

To a solution of 4.15 g (10.75 mmol) of 3- (1-adamantyl) -4- (2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoic acid in 40 ml of dichloromethane is added 2.15 ml of dicyclohexylamine (10.8 mmol), left to stir for one hour at room temperature and 0.85 ml (11.8 mmol) of thionyl chloride is added dropwise. After stirring at room temperature for 4 hours, it is evaporated to dryness, taken up in ethyl ether, the insoluble material is filtered off and the filtrate is evaporated. The chloride of 3- (1-adamantyl) -4- (2,2-dimethyl-1,3 dioxolane-4-methyloxy) benzoic acid thus obtained is placed in 30 ml of THF and added dropwise to a solution. with stirring containing 1.91 g (10.7 mmol) of allyl 4-hydroxybenzoate, 1.65 ml (11.8 mmol) of triethylamine and 13 mg of dimethylaminopyridine in 30 ml of tetrahydrofuran. The reaction medium is stirred at room temperature under nitrogen for 20 hours then is poured into ice water. This suspension is extracted with 600 ml of ethyl ether, then the organic phase is dried and evaporated. The residue is chromatographed on silica eluting with dichloromethane to yield 4.24 g (72%) of 4- [3- (1-adamantyl) -4- (2,2-dimethyl-1,3-dioxolane-4 - methyloxy) benzoyloxy] allyl benzoate, melting point: 106-107 ° C.

(d) Allyl 4- [3- (1-adamantyl) -4- (2,3-dihydroxypropyloxy) benzoyloxy] benzoate.

1.09 g (2 mmol) of 4- [3- (1-adamantyl) -4- (2,2-dimethyl-1,3-dioxolane-4-methyloxy) benzoyloxy] allyl benzoate are placed in 50 ml of dichloromethane and added 3.80 g (20 mmol) of paratoluene sulfonic acid. The reaction is left under stirring for 48 hours at room temperature then evaporated to dryness and the residue is taken up in 50 ml of dichloromethane. The organic phase is neutralized by washing with saturated NaHCO₃, then rinsed with water, dried and evaporated. The residue is chromatographed on silica in a dichloromethane / ethyl ether mixture (90:10) to yield 900 mg (89%) of 4- [3- (1-adamantyl) -4- (2,3-dihydroxypropyloxy) benzoyloxy] allyl benzoate.

(e) 4- [3- (1-adamantyl) -4- (2,3-dihydroxypropyloxy) benzoyloxy] benzoic acid.

To a solution of 891 mg (1.76 mmol) of 4- [3- (1-adamantyl) -4- (2,3-dihydroxypropyloxy) benzoyloxy] allyl benzoate in 15 ml of tetrahydrofuran, 102 mg ( 0.088 mmol) of tetrakis (triphenylphosphine) palladium (0) then introduced dropwise a suspension consisting of 58 mg (1.93 mmol) of 80% sodium hydride in oil and 294 μl (1.93 mmol) ethyl malonate in 6 ml of tetrahydrofuran. Stirred under nitrogen at room temperature for 1 hour, then evaporate to dryness, wash the solid with 50 ml of ether, place it in 50 ml of water, acidify to pH 1 and extract with 100 ml of ether. The organic phase is rinsed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from ethyl acetate to yield 634 mg (77%) of 4- [3- (1-adamantyl) -4- (2,3-dihydroxypropyloxy) benzoyloxy] benzoic acid, of point mp 238-239 ° C.

EXAMPLE 28

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

(a) Benzyl 4- [3- (1-adamantyl) -4-tert-butyldimethylsilyloxybenzoyloxy] benzoate.

38.66 g (0.1 mole) 3- (1-adamantyl) -4-tertbutyldimethylsilyloxy benzoic acid are converted to acid chloride according to the method described above, are dissolved in 140 ml of tetrahydrofuran and are added dropwise to a suspension containing 1.66 g (0.055 mmol) of 80% NaH in oil and 1.41 g (0.05 mol) of benzyl 4-hydroxybenzoate in 5 ml of tetrahydrofuran. The mixture is left stirring at room temperature for 24 hours and then the reaction mixture is poured into ice water and extracted with ethyl ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica in a dichloromethane / hexane mixture (40:60) to yield 28 g (47%) of benzyl benzyl benzoate 4- [3- (1-adamantyl) -4- tert-butyl dimethylsilyloxy] benzoate : 151-152 ° C.

(b) Benzyl 4- [3- (1-adamantyl) -4-hydroxybenzoyloxy] benzoate.

A solution of 5.7 g (9.55 mmol) of 4- [3- (1-adamantyl) -4-tertbutyldimethylsilyloxybenzoyloxy] benzyl benzoate in 35 ml of tetrahydrofuran is treated with 10.5 ml of tetrabutylammonium fluoride in tetrahydrofuran (1 M). The reaction medium is stirred at room temperature for one hour then is poured into ice water and extracted with 700 ml of ethyl ether. The organic phase is washed with 1N HCl, rinsed with water, dried over magnesium sulphate and evaporated. Is isolated 4.60 g (100%) of 4- [3- (1-adamantyl) -4-hydroxybenzoyloxy] benzyl benzoate, melting point: 164-165 ° C.

(c) Benzyl 4- [3- (1-adamantyl) -4-methoxycarbonylmethyloxy] benzoate.

1.0 ml (10.2 mmol) of methyl bromoacetate is added dropwise to a solution of 4.49 g (9.3 mmol) of 4- [3- (1-adamantyl) -4-hydroxybenzoyloxy] benzoate benzyl in 40 ml of dimethylformamide containing 309 mg (10.2 mmol) of 80% NaH in oil. The reaction medium is left stirring at room temperature overnight then is poured into ice water and extracted with 550 ml of ethyl ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated. Is isolated after chromatography on silica in the dichloromethane / hexane mixture (90: 10) 3.50 g (68%) of 4- [3- (1-adamantyl) -4-methoxycarbonylmethyloxy] benzyl benzoate with melting point: 123 -124 ° C.

(d) 4- [3- (1-adamantyl) -4-methoxycarbonyl methyloxy] benzoic acid.

3.46 g (6.24 mmol) of 4- [3- (1-adamantyl) -4-methoxycarbonylmethyloxy] benzyl benzoate in 50 ml of dioxane are hydrogenated at 7 bar pressure in the presence of 346 mg of Pd-C (10%) for 2 hours at 40 ° C. The reaction medium is filtered through celite and evaporated to yield, after recrystallization from ethyl acetate, 2.55 g (88%) of 4- [3- (1-adamantyl) -4-methoxycarbonylmethyloxy] benzoic acid of point mp: 252-253 ° C.

FORMULATION EXAMPLES

A. ORAL ROUTE

<tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(a) 0.2g tablet</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-fluoro benzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.001g</entry></row><row><entry namest="col1" nameend="col1" align="left">Starch .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.114g</entry></row><row><entry namest="col1" nameend="col1" align="left">Bicalcium phosphate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.020g</entry></row><row><entry namest="col1" nameend="col1" align="left">Silica .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.020g</entry></row><row><entry namest="col1" nameend="col1" align="left">Lactose .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.030g</entry></row><row><entry namest="col1" nameend="col1" align="left">Talc .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.010g</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Magnesium stearate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.005g</entry></row></tbody></tgroup></table></tables><tables id="tabl0002" num="0002"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(b) oral suspension in 5ml ampoules</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-fluoro benzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.001g</entry></row><row><entry namest="col1" nameend="col1" align="left">Glycerine.....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.500g</entry></row><row><entry namest="col1" nameend="col1" align="left">Sorbitol at 70% .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.500g</entry></row><row><entry namest="col1" nameend="col1" align="left">Sodium saccharinate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.010g</entry></row><row><entry namest="col1" nameend="col1" align="left">Methyl parahydroxybenzoate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.040g</entry></row><row><entry namest="col1" nameend="col1" align="left">Aroma qs</entry><entry namest="col2" nameend="col2" /></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Purified water qs .....</entry><entry namest="col2" nameend="col2" align="char" char=",">5ml</entry></row></tbody></tgroup></table></tables><tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(c) 0.8g tablet</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.500g</entry></row><row><entry namest="col1" nameend="col1" align="left">Pregelatinized starch .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.100g</entry></row><row><entry namest="col1" nameend="col1" align="left">Microcrystalline cellulose .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.115g</entry></row><row><entry namest="col1" nameend="col1" align="left">Lactose.....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.075g</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Magnesium stearate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.010g</entry></row></tbody></tgroup></table></tables>

In this example (c), 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoic acid can be replaced by 4- [5- (1-adamantyl) -2- fluoro-4-methoxybenzoyloxy] benzoic. <tables id="tabl0004" num="0004"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(d) oral suspension in 10ml ampoules</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Benzoic acid 4- (3,5-di-tert-butyl-4-hydroxybenzoyloxy) .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.200g</entry></row><row><entry namest="col1" nameend="col1" align="left">Glycerine.....</entry><entry namest="col2" nameend="col2" align="char" char=",">1,000g</entry></row><row><entry namest="col1" nameend="col1" align="left">Sorbitol at 70% .....</entry><entry namest="col2" nameend="col2" align="char" char=",">1,000g</entry></row><row><entry namest="col1" nameend="col1" align="left">Sodium saccharinate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.010g</entry></row><row><entry namest="col1" nameend="col1" align="left">Methyl hydroxybenzoate ...</entry><entry namest="col2" nameend="col2" align="char" char=",">0.080g</entry></row><row><entry namest="col1" nameend="col1" align="left">Aroma qs</entry><entry namest="col2" nameend="col2" /></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Purified water qs .....</entry><entry namest="col2" nameend="col2" align="char" char=",">10ml</entry></row></tbody></tgroup></table></tables>

B. TOPICAL ROUTE

<tables id="tabl0005" num="0005"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(a) ointment</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-fluoro benzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.020g</entry></row><row><entry namest="col1" nameend="col1" align="left">Isopropyl myristate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">81,700g</entry></row><row><entry namest="col1" nameend="col1" align="left">Fluid petroleum jelly oil .....</entry><entry namest="col2" nameend="col2" align="char" char=",">9.100g</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Silica sold by DEGUSSA under the name "Aérosil 200" .....</entry><entry namest="col2" nameend="col2" align="char" char=",">9.180g</entry></row></tbody></tgroup></table></tables><tables id="tabl0006" num="0006"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(b) ointment</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-fluoro benzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.300g</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">White Vaseline codex qsp .....</entry><entry namest="col2" nameend="col2" align="char" char=",">100g</entry></row></tbody></tgroup></table></tables><tables id="tabl0007" num="0007"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(c) non-ionic W / O cream</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Benzoic acid 4- (3,5-di-tert-butyl-4-hydroxybenzoyloxy) .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.100g</entry></row><row><entry namest="col1" nameend="col1" align="left">Eucerin anhydrous .....</entry><entry namest="col2" nameend="col2" align="char" char=",">39,900g</entry></row><row><entry namest="col1" nameend="col1" align="left">Methyl parahydroxybenzoate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.075g</entry></row><row><entry namest="col1" nameend="col1" align="left">Propyl parahydroxybenzoate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.075g</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Sterile demineralized water qs .....</entry><entry namest="col2" nameend="col2" align="char" char=",">100g</entry></row></tbody></tgroup></table></tables><tables id="tabl0008" num="0008"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(d) lotion</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.100g</entry></row><row><entry namest="col1" nameend="col1" align="left">PEG 400 .....</entry><entry namest="col2" nameend="col2" align="char" char=",">69,900g</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Ethanol 95% .....</entry><entry namest="col2" nameend="col2" align="char" char=",">30,000g</entry></row></tbody></tgroup></table></tables><tables id="tabl0009" num="0009"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(e) hydrophobic ointment</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">4- [5- (1-adamantyl) -2-fluoro-4-methoxybenzoyloxy] benzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.300g</entry></row><row><entry namest="col1" nameend="col1" align="left">Isopropyl myristate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">36,400g</entry></row><row><entry namest="col1" nameend="col1" /></row><row><entry namest="col1" nameend="col1" align="left">Silicone oil sold by the Rhône Poulenc Company under the name "Rhodorsil 47 V 300" .....</entry><entry namest="col2" nameend="col2" align="char" char=",">36,400g</entry></row><row><entry namest="col1" nameend="col1" align="left">Beeswax.....</entry><entry namest="col2" nameend="col2" align="char" char=",">13,600g</entry></row><row><entry namest="col1" nameend="col1" /></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Silicone oil sold by the Goldschmidt Company under the name "Abil 300,000 cst" qs .....</entry><entry namest="col2" nameend="col2" align="char" char=",">100g</entry></row></tbody></tgroup></table></tables><tables id="tabl0010" num="0010"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">(f) nonionic O / W cream</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -3-fluoro benzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">1,000g</entry></row><row><entry namest="col1" nameend="col1" align="left">Cetyl alcohol .....</entry><entry namest="col2" nameend="col2" align="char" char=",">4,000g</entry></row><row><entry namest="col1" nameend="col1" align="left">Glycerol monostearate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">2,500g</entry></row><row><entry namest="col1" nameend="col1" align="left">PEG 50 stearate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">2,500g</entry></row><row><entry namest="col1" nameend="col1" align="left">Shea Butter.....</entry><entry namest="col2" nameend="col2" align="char" char=",">9.200g</entry></row><row><entry namest="col1" nameend="col1" align="left">Propylene glycol.....</entry><entry namest="col2" nameend="col2" align="char" char=",">2,000g</entry></row><row><entry namest="col1" nameend="col1" align="left">Methyl parahydroxybenzoate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.075g</entry></row><row><entry namest="col1" nameend="col1" align="left">Propyl parahydroxybenzoate .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.075g</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Sterile demineralized water qs .....</entry><entry namest="col2" nameend="col2" align="char" char=",">100g</entry></row></tbody></tgroup></table></tables>

C. INJECTION ADMINISTRATION

<tables id="tabl0011" num="0011"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row><entry namest="col1" nameend="col2" align="left">3ml injectable ampoule</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Micronized 4- [3- (1-adamantyl) -4-methoxybenzoyloxy] -2-hydroxybenzoic acid .....</entry><entry namest="col2" nameend="col2" align="char" char=",">0.003g</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Water for injectable preparation qs .....</entry><entry namest="col2" nameend="col2" align="char" char=",">3 ml</entry></row></tbody></tgroup></table></tables>