MXPA96005940A

MXPA96005940A - Bio-aromatic compounds carrying an adamantyl group in ortho, pharmaceutical and cosmetic compositions containing them and utilization

Info

Publication number: MXPA96005940A
Application number: MXPA/A/1996/005940A
Authority: MX
Inventors: Bernardon Jeanmichel
Original assignee: Centre International De Recherches Dermatologiques Galderma
Priority date: 1995-12-01
Filing date: 1996-11-28
Publication date: 1998-04-01

Abstract

The invention refers to new bio-aromatic compounds presenting as general fórmula (I):(See Formula), as well as to these last utilization in pharmaceutical compositions to be used in human or veterinary medicine (mainly dermatológical, rheumatic, respiratory, cardiovascular and ophthalmologic diseases), or else even in cosmetic compositions.

Description

ADAMANTINO IN ORTO. PHARMACEUTICAL AND COSMETIC COMPOSITIONS THAT I-OS CONTAINS AND UTILIZATIONS DESCRIPTION PE IA INVENTION The invention relates, as new and useful industrial products, to biaromatic compounds. It also relates to the use of these novel compounds in pharmaceutical compositions intended for use in human or veterinary medicine, or even in cosmetic compositions. The compounds according to the invention have a marked activity in the fields of cell differentiation and proliferation, and find applications more particularly in the topical and systemic treatment of the dermatological conditions associated with a keratinization disorder, dermatological conditions (or other ) of inflammatory and / or immunoallergic components, and of dermal or epidermal proliferations, whether benign or malignant. These compounds can also be used in the treatment of diseases of connective tissue degeneration, to combat skin aging, whether photo-induced or chronological, and to treat healing disorders. On the other hand, REF: 23642 find an application in the treatment of corneopathies. The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene. The compounds according to the invention can be represented by the following general formula (I): wherein: Rx represents (i) the radical -CH3 (ii) the radical - (CH2) n-0-R4 (iii) the radical -0- (CH2)? n- (CO) n -R5 (iv) the radical -C0 -R6 (v) the radical -C0-0-R7 having the values m and n, as well as the different radicals R, the meaning given above, R2 represents a hydrogen, halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, a radical -0R4, a radical -0-CH2-0-CH2-CH2-0-CH3, R3 represents (i) a radical -Y- (CH2) pY- (CH2) q-R8 (ii) a radical - (CH2) pY- (CH2) qR8 (iii) a radical -Y- (CH2) q -R8 (iv) a radical -CH = CH- (CH2) r-R8 (v) ) radical uri - (CH2) q-R8 having the values p, q, r and the radicals Y and R8 the meaning given above, X represents the links of the following formulas (a) - (k) which can be joined in the two senses: (e) (f) Ar represents a radical selected from among the following formulas (a) - (f): understanding that in all that precedes: m is an integer equal to, 2 or 3 n is an integer equal to 0 or 1 p is an integer between 1 and 12, inclusive q is an integer between 0 and 12, inclusive r is an integer between 0 and 10, inclusive - t is an integer equal to 0, 1 or 2 Y represents the oxygen atom or the radical S (0) t W represents the oxygen atom, the radical s (0) to the radical NR10-R4 represents a hydrogen atom, a lower alkyl radical or a -C0-Rxl radical, R5 represents a lower alkyl or a heterocycle, R6 represents a hydrogen atom, a lower alkyl radical or a radical • N- 'R' wherein R 'and R "represent a hydrogen atom, a lower alkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or peptide or sugar residue or even, taken together, they form a heterocycle, R7 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical or a radical of sugar or an amino acid or peptide residue, R8 represents a hydrogen atom, a branched alkyl radical having from 1 to 20 carbon atoms, a cycloaliphatic radical of 3 to 6 carbon atoms, a monohydroxyalkyl radical or a polyhydroxyalkyl radical , whose hydroxy are eventually protected in the form of methoxy or acetoxy or acetonide, an aryl radical, an alkenyl radical, an alkynyl radical, a -C0-R6 radical, a -C0-0-R7 radical, an aminoalkyl radical, whose amine function is optionally substituted by one or two lower alkyl groups, a heterocycle, wherein R7 has As given above, R9 represents a hydrogen atom, a halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, a radical -0R4, a radical -0-CH2-0-CH2-CH2-0- CH3, R10, identical or different, represents a hydrogen atom, a lower alkyl radical - R1X represents a lower alkyl radical, since when: X represents the bond of formulas (a), (b), (c), ( d), (h), (j) or (k) then R3 is different from the radical of formulas (iii), (iv) or (v) in which R8 is a hydrogen atom. X represents the bond of formula (a), then R3 is different from radical (iii), X represents the bond of formula (b) and R3 represents the radical of formula (iii) in which Y represents an atom of sulfur, then R8 is different from the aryl radical, X represents the bond of formulas (g), (h), (j) or (k) and R3 represents the radical of formula (v), then R8 is different from a radical monohydroxyalkyl or polyhydroxyalkyl. The invention also relates to the salts of the compounds of the formula (I) when R, or R8 represents a carboxylic acid function and / or when R8 represents an amine function, the chiral analogues and the geometric isomers of said compounds the formula (I). When the compounds according to the invention are present in the form of salts, by addition of an acid, they are pharmaceutically or cosmetically acceptable salts obtained by addition of a mineral or organic acid, in particular hydrochloric, sulfuric, acetic, citric, fumaric acid, hemisuccinic, maleic and mandélico. When the compounds according to the invention are present in the form of salts by the addition of a base, they are alkali metal or alkaline earth metal salts or even zinc or an organic amine. According to the present invention, the term "lower alkyl radical" means a radical having from 1 to 12, preferably from 1 to 9, carbon atoms, advantageously methyl, ethyl, isopropyl, butyl, tertiary butyl, hexyl, nonyl and dodecyl radicals. The term "linear alkyl radical" having from 1 to 20 carbon atoms is understood to mean, in particular, methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals. By branched alkyl radical having from 1 to 20 carbon atoms, the radicals are understood to be 2-methylbutyl, 2-methylpentyl, 1-methylhexyl, 3-methylheptyl. Among the monohydroxyalkyl radicals, a radical having 2 or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical, is preferred. Among the polyhydroxyalkyl radicals, a radical having 3 to 6 carbon atoms and 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2, 3, 4 -trihydroxybutyl, 2,3,4-radicals, is preferred. 5-tetrahydroxypentyl or the pentaerythritol residue. Among the aryl radicals, a phenyl radical optionally substituted by at least one halogen atom, a hydroxyl or a nitro function is preferred. Among the aralkyl radicals, a benzyl or phenethyl radical optionally substituted by at least one halogen atom, a hydroxyl or a nitro function is preferred. Among the alkenyl radicals, a radical containing 1 to 5 carbon atoms and having one or more ethylenic unsaturation, such as more particularly the allyl radical, is preferred. A sugar residue is a residue that is derived mainly from glucose, from galactose or from mannose, or even from glucuronic acid.

By "amino acid residue" is meant primarily a moiety derived from lysine, glycine or aspartic acid, and peptide moiety is more particularly understood as a dipeptide or tripeptide moiety resulting from the combination of amino acids. Finally, heterocycle is preferably understood to mean a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in the 4-position by an alkyl radical of 1 to 6 carbon atoms or mono or polyhydroxyalkyl radicals as defined above. By "aminoalkyl radical" is meant a radical preferably containing from 1 to 6 carbon atoms, in particular the radicals aminomethyl, 3-aminopropyl, 6-aminohexyl. Among the alkynyl radicals, a radical having from 2 to 6 carbon atoms mainly a propargyl radical is preferred. Among the cycloaliphatic radicals of 3 to 6 carbon atoms, the cyclopropyl and cyclohexyl radical can be more particularly mentioned. When the radicals R2 and R9 represent a halogen atom, this is preferably a fluorine, bromine or chlorine atom.

Among the compounds of formula (I) above which are within the scope of the present invention, mention may be made, in particular, of the following: 4- [3- (1-adamantyl) -4-methoxyphenylthiomethyl] -benzoic acid; 4- [3- (1-adamantyl) -4-methoxyphenylsulfinyl-methyl] benzoic acid; 4- [3- (1-adamantyl) -4-methoxyphenylmethyl-sulfonyl] benzoic acid; 4- [3- (1-adamantyl) -4-methoxyphenylmethyl-sulfinyl] benzoic acid; 4- [3- (1-adamantyl) -4-methoxyphenylsulfonyl-methyl] benzoic acid; 4- [3- (1-adamantyl) -4-methoxyphenylthiocarboxamido] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyphenyl-methylthio] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyphenylmethylamino] -benzoic acid; 4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxyphenyl] -1-propynyl]] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-benzamido] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-benzoyloxy] benzoic acid; (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl] -1-propenyl]] benzoic acid; 4- [[3-hydroxy-3- [3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl] -1-propynyl]] benzoic acid; 4- [3- (l-adamantyl) -4- (2,2-dimethyl-1,3'-dioxolan-4-methyloxy) phenylcarboxamido] benzoic acid; . 4 - [3 - (1-adamantyl) -4- (2,3-dihydroxy-propyloxy) phenylcarboxamido] benzoic acid; 4- [3- (l-adamantyl) -4-methoxycarbonylmethyl-oxyphenylcarboxamido] benzoic acid; 2- [3- (l-adamantyl) -4-methoxyphenoxymethyl] -4-thiophenecarboxylic acid; 2- [3- (l-adamantyl) -4-methoxyphenylamino-methyl] -4-thiophenecarboxylic acid; 2- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] -4-thiophenecarboxylic acid; 4- [3- (l-adamantyl) -4- (2,2-dimethyl-l, 3-dioxolan-4-methyloxy) benzoyloxy] benzoic acid; 4- [3-hydroxy-3- [5- (l-adamantyl) -2,4-di-methoxyethoxymethoxyphenyl] -1-propynyl] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-benzoylthio] benzoic acid; N-methyl-4- [3- (l-adamantyl) -4-methoxyethoxy-methoxyphenylcarboxamido] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl-thiocarboxamido] benzoic acid; (E) -4 - [[3-oxo -3- [3- (l-adamantyl) -4-methoxymethoxyphenyl] -1-propenyl]] benzoic acid; (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-hydroxyphenyl] -1-propenyl]] benzoic acid; (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxy-phenyl] -1-propenyl]] benzoic acid; (E) -4- [[3-OXO-3 [3- (l-adamantyl) -4- (3-hydroxypropyloxy) phenyl] -1-propenyl]] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxybenzoyloxy] -benzaldehyde; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxybenzoyloxy] -benzenemethanol; (E) -N-ethyl-4- [[3-oxo-3 [-3- (l-adamantyl) -4-methoxy-ethoxymethoxyphenyl] -1-propenyl]] enZoamide; (E) -N- (4-Hydroxyphenyl) -4- [[3 -oxo-3- [3 - (1-adamantyl) -4-methoxyethoxymethoxyphenyl] -1-propenyl]] benzamide; (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxyethoxy-methoxyphenyl] -1-propenyl]] phenol; According to the present invention, the compounds of the formula (I) which are more particularly preferred are those in which at least one and preferably all of the following conditions are fulfilled: R, is the radical -C00-R7 or -C0-R6 -R3 is the radical -Y - (CH2) pY- (CH2) q -R8 - (CH2) p- (CH2) q -R8 -Y- (CH2) q -R8 X represents a bond of formulas (a), (e), (f ), (j), or (k). Ar represents the radical of formula (a) or (b). The subject of the present invention is also methods of preparing the compounds of the formula (I), in particular according to the reaction schemes given in FIGS. 1, 2, 3. Thus, the compounds of the formula I (a) can be obtained (FIG. Figure 1) by reacting in an anhydrous medium, in an organic solvent preferably THF and in the presence of a tertiary amine (for example triethylamine or pyridine) an activated form of a benzoic acid (2) for example an acid chloride (3) on a Phenolic compound of the formula (7). Thus the compounds of the formula I (b) can be obtained (figure 1) by reacting in an anhydrous medium, in an organic solvent preferably THF and in the presence of a tertiary amine (for example triethylamine or pyridine) an activated form of a benzoic acid ( 2) for example an acid chloride (3) on an amino compound of the formula (8).

Thus the compounds of the formula I (c) can be obtained (Figure 1) by reacting in an anhydrous medium, in an organic solvent preferably THF and in the presence of a tertiary amine (for example triethylamine or pyridine) an activated form of an aromatic carboxylic acid (2) for example an acid chloride (3) on an amino compound of formula (9). Thus the compounds of the formula I (d) can be obtained (Figure 1) from the compounds of the formula I (c) by reaction with Lawesson's reagent. Thus the compounds of the formula I (e) can be prepared (Figure 1) from benzylic alcohols (5) by transformation into brominated derivatives (6) with phosphorus tribromide, then by reaction in the presence of potassium carbonate or a hydride alkaline (sodium hydride) or by phase transfer using for example tetrabutylamino bromide as a quaternary salt with a compound (10) carrying a hydroxy or thiol or amino function. Thus, the compounds of the formula I (f) can be obtained (FIG. 2) from the acetophenone derivative (11) by transformation into brominated derivative (12) with the aid of bromine, then reaction in the presence of potassium carbonate or an alkali hydride (sodium hydride) or by phase transfer using for example tetrabutylammonium bromide as a quaternary salt with a compound (10) carrying a hydroxy or thiol or amino function. The compounds of the formula I (g) can be obtained from the derivative I (f) by reaction with sodium borohydride in an alcoholic solvent. Thus the compounds of the formula I (h) can be obtained (FIG. 2) from the acetophenone derivatives (11) by reaction with aromatic aldehyde derivatives (13) in the presence of sodium methylate or soda in an alcoholic solvent such as methanol. From these compounds by reaction with sodium borohydride in the presence of cerium trichloride, the compounds of the formula I (i) are obtained. Thus the compounds of the formula I (j) can be prepared (Figure 2) from aromatic aldehyde derivatives (4) by reaction with lithium trimethylsilylacetylene, then by deprotection with tetrabutylammonium fluoride to obtain the α-hydroxyacetylene derivatives (14) . Then coupling with halogenated derivatives (15) preferably iodinated in the presence of a palladium catalyst (for example, bis (triphenylphosphine) palladium (II) chloride in a solvent such as triethylamine.The oxidation of these compounds with pyridinium dichromate or magnesium oxide or the Swern reagent leads to the derivatives of the formula I (k).

When R3 represents the radicals - (CH2) p- (CH2) q-Rβ or -CH = CH- (CH2) r-R8, the compounds can be obtained (Figure 3 in which s is equal to p-2) from of phenolic derivatives (16) which are transformed into triflate derivatives (17), then nucleophilic substitution in the presence of a palladium catalyst according to the general conditions described by: S. Cacchi et al. Tetrahedron Letter, 1986, 27, 3931-3934. -. J. Scott et al. J. Org. Chem. 1985, 50, 2302-2308. J. K. Stille et al. J. Am. Chem. Soc; 1987, 109, 5478-5486. When R. represents the radical -COOH, the compounds are prepared by protecting RL with a protecting group of the alkyl, allyl, benzyl or tert-butyl type. The transition to the free form can be carried out: in the case of an alkyl protecting group, by means of sodium hydroxide or lithium hydroxide in an alcoholic solvent such as methanol or in THF, in the case of an allyl protecting group, by means of a catalyst such as certain transition metal complexes in the presence of a secondary amine such as morpholine, in the case of a benzyl protecting group by debenzylation in the presence of hydrogen by means of a catalyst such as palladium on carbon, in the case of a protective group of terbutyl type by means of trimethylsilane iodide. The subject of the present invention is also, as a medicament, the compounds of the formula (I) as defined above. These compounds exhibit an activity in the mouse embryonic teratocarcinoma cell (F9) differentiation assay (Cancer Research 43. pages 5268, 1983) and / or in the inhibition assay of ornithine decarboxylase after induction by TPA in the mouse (Cancer Research 23., pages 793-801, 1978). These assays show the activities of these compounds, respectively, in the fields of cell differentiation and proliferation. In the cell differentiation assay (F9), it is possible to evaluate an agonist activity, such as an antagonistic activity to the retinoic acid receptors. Indeed, an antagonist is inactive when it is alone in this assay, but partially or totally inhibits the effect produced by a retinoid agonist on the morphology and on the secretion of the plasminogen activator.

Some of these compounds therefore also have an activity in an assay that consists of identifying antagonist molecules of the RARs, as described in the French patent application No. 95-07302 filed on June 19, 1995 by the applicant. This assay comprises the following steps: (i) a sufficient quantity of an RAR agonist molecule is applied topically on a part of the skin of a mammal, (ii) it is administered systemically or topically on this same mammal or on this same mammal same part of the skin of the mammal before, during or after step (i), a molecule capable of presenting an antagonistic activity of the RARs and (iii) the response is evaluated on the part of the skin thus treated of the mammal. In this way, the response to a topical application on the ear of a mammal of an agonist molecule of the RARs corresponding to an increase in the thickness of this ear can be inhibited by the systemic or topical administration of an antagonist molecule of the RARs. . The compounds according to the invention are particularly suitable in the following fields of treatment: 1) for treating the dermatological conditions associated with a keratinization disorder that is based on differentiation and proliferation mainly for treating vulgar, comedonic, polymorphic acnes, rosacea, nodulocystic acnes, conglobations, senile acnes, secondary acnes such as solar acne, medication or professional, 2) to treat other types of keratinization disorders, mainly ichthyosis, ichthyosiform states, Darrier's disease, palmoplantar keratoderma, leukoplakias and leukoplasiform states, cutaneous lichen or mucosal (buccal), 3) to treat other dermatological conditions associated with a keratinization disorder with an inflammatory and / or immuno-allergic component and mainly all forms of psoriasis and are cutaneous, mucosal or ungular, and even the psoriatic umatism, or even cutaneous atopy, such as eczema or respiratory atopy or even gingival hypertrophy; the compounds can also be used in certain inflammatory conditions that do not present disorders of keratinization, 4) to treat all dermal or epidermal proliferations, whether benign or malignant, either of viral origin such as vulgar warts, flat warts and the like. warty epidermodysplasia, oral or florid papillomatosis and proliferations that may be induced by ultra-violets, mainly in the case of basal and spinocellular epitheliomas, 5) to treat other dermatological disorders such as vesicular dermatoses and collagen diseases, 6) to treat certain ophthalmological disorders, mainly corneopathies, 7) to repair or fight against aging of the skin, either photo-induced or chronological or to reduce pigmentations and actinic keratosis, or all the pathologies associated with chronological or actinic aging , 8) to prevent or cure stigmas of epidermal and / or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy, 9) to prevent or treat disorders of healing or to prevent or repair stretch marks, 10) to fight against disorders of sebaceous function such as acne hyperseborrhea or simple seborrhea, 11) in the treatment or prevention of cancerous or precancerous conditions, 12) in the treatment of inflammatory conditions such as arthritis, 13) in the treatment of any condition of viral origin at the cutaneous or general level, 14) in the prevention or treatment of alopecia, 15) in the treatment of dermatological or general conditions of immunological component, 16) in the treatment of conditions of the cardiovascular system such as Arteriosclerosis In the therapeutic fields mentioned above, the compounds according to the invention can be advantageously used in combination with other compounds of retinoid-like activity, with vitamins D or their derivatives, with corticosteroids, with free radicals, α-hydroxy or α-keto acids or their derivatives, or well even with ion channel blockers. Vitamins D or their derivatives are understood, for example, as derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3. By free radicals, it is understood, for example, α-tocopherol, Super Oxide Dismutate, Ubiquinol or certain metal chelators. By "a-hydroxy" or "a-keto acids" or their derivatives, are meant, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or their salts, amides or esters. Finally, by ion channel blockers, it is understood, for example, Minoxidil (2,4-diamino-6-piperidino-pyrimidin-3-oxide) and its derivatives.

The present invention also relates to pharmaceutical compositions containing at least one compound of the formula (I) as defined above, one of its optical or geometric isomers or one of its salts. Therefore, the subject of the present invention is also a new medicament composition intended primarily for the treatment of the aforementioned conditions, and which is characterized in that it comprises, in a pharmaceutically acceptable carrier and compatible with the mode of administration maintained by the latter, the minus a compound of the formula (I), one of its optical or geometric isomers or one of its salts. The administration of the compounds according to the invention can be carried out enterally, parenterally, topically or ocularly. Enterally, drugs can be presented in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles that allow a controlled release. Parenterally, the compositions may be in the form of solutions or suspensions for perfusion or injection.

The compounds according to the invention are also administered in a daily dose of about 0.01 mg / kg to 100 mg / kg of body weight, and this at a rate of 1 to 3 doses. Topically, the pharmaceutical compositions based on compounds according to the invention are intended more particularly for the treatment of the skin and mucous membranes and can then be presented in the form of ointments, creams, milks, ointments, powders, impregnated tampons, solutions, gels , sprays, lotions or suspensions. It can also be present in the form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels that allow a controlled release. These topical compositions can be presented, on the other hand, either in anhydrous form, or in aqueous form, according to the clinical indication. By ocular route, they are mainly eye drops. These compositions for topical or ocular use contain at least one compound of the formula (I) as defined above, or one of its optical or geometric isomers or even one of its salts, in a concentration preferably comprised between 0.001% and 5% in weight with respect to the total weight of the composition. The compounds of formula (I) according to the invention also find an application in the cosmetic field, in particular in body and hair hygiene and mainly for the treatment of acne-prone skin, for hair growth, anti-hair loss, to fight against the oily appearance of the skin or the hair, in the protection against the harmful aspects of the sun or in the treatment of physiologically dry skin, to prevent and / or to fight against photo-induced or chronological aging. In the cosmetic field, the compounds according to the invention can also be used advantageously in combination with other compounds of retinoid-like activity, with vitamins D or their derivatives, with corticosteroids, with anti-free radicals, α-hydroxy or α-keto acids or their derivatives, or even with ion channel blockers, all of these different products being defined above. Therefore, the present invention also relates to a cosmetic composition characterized in that it comprises, on a cosmetically acceptable support suitable for a topical application, at least one compound of the formula (I) as defined above or one of its optical or geometric isomers or one of its salts, this cosmetic composition can be present mainly in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipid or polymeric vesicles, a soap or a shampoo. The concentration of the compound of the formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001% and 3% by weight with respect to the composition as a whole. The medicinal and cosmetic compositions according to the invention may also contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives, and in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents such as glycerol, PEG 400, thiamorpholinone, and their derivatives or even urea; antiseborrhoeic or anti-acne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, its salts or derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamycin and their esters, tetracyclines; antifungal agents such as ketoconazole or the 4,5-polymethylene-3-isothiazolidones; agents that promote the growth of hair, such as Minoxidil (2, 4-diamino-6-piperidino-3-pyrimidinoxide) and its derivatives, Diazoxide (7-chloro 3-methyl 1, 2, 4 - benzot iadiaz ina 1,1-dioxide) and Phenytoin (5,4-diphenyl-2,4-imidazolidinone); non-steroidal anti-inflammatory agents; carotenoids and mainly β-carotene; anti-psoriatic agents such as anthralin and its derivatives; and finally the 5, 8, 11, 14-eicosatetranoic and 5, 8, 11-eicosatrinoic acids, their esters and amides. The compositions according to the invention may also contain flavor improving agents, preservatives such as parahydroxybenzoic acid esters, stabilizing agents, moisture regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifying agents, UV-filters. A and UV-B, antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene. In the following, various examples of the preparation of active compounds of the formula (I) according to the invention, as well as various specific formulations based on such compounds, will be given by way of use and without any limiting character.

EXAMPLE 1 4-Í3- (l-adamantyl) -4-methoxy-enylthiomethyl benzoic acid (a) 0-3- (l-adamantyl) -4-methoxyphenyldimethylthio-carbamate.

In a flask and under a stream of nitrogen, 600 mg (20 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced. It is cooled to 0 ° C and a solution of 5.5 g (20 mmol) of 3- (l-adamantyl) -4-methoxyphenol in 100 ml of DMF is added dropwise and stirred until the gaseous release ends, then a solution of 3.3 g (26 mmol) of dimethylthiocarbamoyl chloride in 50 ml of DMF is added and stirred for eight hours at room temperature. The reaction medium is poured into water, extracted with ethyl acetate, the organic phase is separated out, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (70-30). After evaporation of the solvents, 3.1 g (46%) of the expected melt product of 162-164 ° C are collected. (b) S-3- (l-adamantyl) -4-methoxyphenyldimethylthio-carbamate.

Into a flask and under a stream of nitrogen, 3 g (8.7 mmol) of the preceding product are introduced and heated at 300 ° C for thirty minutes. The reaction medium is extracted with dichloromethane, washed with water, the organic phase is separated out, dried over magnesium sulphate and evaporated. 2.4 g (80%) of the expected product of melting point 154-155 ° C are collected. (c) 3- (l-adamantyl) -4-methoxyphenylthiol.

Into a flask, 2.3 g (6.6 mmol) of the preceding product and 50 ml of a methanolic sodium hydroxide solution (2N) are introduced and heated at reflux for three hours. The reaction medium is evaporated, recovered by water, acidified with concentrated hydrochloric acid, filtered. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (10-90). After evaporation of the solvents, 1.2 g (66%) of the expected thiol derivative of melting point of 149-151 ° C are collected. (d) 4- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] benzoic acid.

Into a three-necked flask under a stream of nitrogen, 1.1 g (36.6 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced. A solution of 4.2 g (15.2 mmol) of 3-l-adamantyl) -4-methoxyphenylthiol in 20 ml of DMF is added dropwise and stirred until the gas liberation is complete. Then a solution of 3.3 g (15.2 mmol) of 4-bromomethylbenzoic acid in 20 ml of DMF is added and stirred at room temperature for eight hours. The reaction medium is poured into water, acidified to pH 1 with hydrochloric acid, extracted with ethyl ether, the organic phase is separated out, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and ethyl ether (95-5). After evaporation of the solvents, 4.2 g (68%) of expected product of melting point of 204-205 ° C are collected.

EXAMPLE 2 4- .3- (l-adamantyl) -4-methoxy-enylsulfinyl-methyl-benzoic acid. (a) Methyl 4- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] -benzoate.

Into a flask, 5 g (12.3 mmoles) of 4- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] benzoic acid are introduced, 50 ml of methanol and 330 μl of concentrated sulfuric acid are added. Heat to reflux for eight hours, then evaporate the reaction medium dry. It is recovered by water, neutralized with sodium bicarbonate, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (40-60). After evaporation of the solvents, 4.1 g (79%) of methyl 4- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] -benzoate are collected. (b) Methyl 4- [3- (l-adamantyl) -4-methoxyphenylsulfinylmethyl] -benzoate.

Into a flask are introduced 844 mg (2 mmol) of methyl 4- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] benzoate, 20 ml of dichloromethane and 386 mg (1.9 mmol) of meta-chloroperbenzoic acid are added. The mixture is stirred at room temperature for two hours, the reaction mixture is poured into water, extracted with dichloromethane, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and ethyl ether (90-10). After evaporation of the solvents, 270 mg (30%) of the expected ester of melting point 121-122 ° C are collected. (c) 4- [3- (l-adamantyl) -4-methoxyphenylsulfinyl-methyl] benzoic acid. 1.1 g (2.7 mmol) of the preceding methyl ester, 40 ml of THF and 40 ml of a methanolic sodium hydroxide solution (2N) are introduced into a flask and stirred at room temperature for eight hours. The reaction medium is evaporated to dryness, recovered by water, acidified to pH 1, extracted with ethyl ether, the organic phase is separated out after settling, dried over magnesium sulphate and evaporated. The residue obtained is triturated in hexane, filtered and dried. 900 mg (78%) of the expected acid having a melting point of 164-165 ° C is collected.

EXAMPLE 3 Ácid 4- .3- (l-adamantyl) -4-methoxyphenylmethylsulfonyl-benzoic acid (a) Methyl 4- [3- (l-adamantyl) -4-methoxyphenylmethylsulfonyl] -benzoate.

In a manner similar to Example 2 (b), by reaction of 4.22 g (10 mmol) of methyl 4- [3- (l-adamantyl) -4-methoxyphenyl-methylthio] benzoate with 10.35 g (30 mmol) of acid meta-chloroperbenzoic there are obtained 1.66 g (37%) of the expected methyl ester having a melting point of 168-170 ° C. (b) 4- [3- (l-adamantyl) -4-methoxyphenylmethyl-sulfonyl] benzoic acid.

In a manner similar to Example 2 (c), from 3.98 (8.7 mmol) of the preceding methyl ester, 3.13 g (81%) of the expected acid of melting point of 231-232 ° C are obtained.

EXAMPLE 4 Acid 4-. 3 - (l-adamantyl) -4-methoxyphenylmethylsulfini 11 -benzoic acid. (a) Methyl 4- [3- (l-adamantyl) -4-methoxyphenylmethylsulfinyl] -benzoate.

In a manner similar to Example 2 (b), by reaction of 2.96 g (7 mmol) of methyl 4- (3- (l-adamantyl) -4-methoxyphenyl-methylthio] benzoate with 1.42 g (7 mmol) of meta acid -chloroperbenzoic, 2.33 g (76%) of the expected methyl ester of melting point of 151-152 ° C are obtained. (b) 4- [3- (l-adamantyl) -4-methoxyphenylmethyl-sulfinyl] benzoic acid.

In a manner similar to Example 2 (c), from 2.7 g (6.2 mmol) of the preceding methyl ester, 2.36 g (90%) of the expected acid of melting point 192-193 ° C are obtained.

EXAMPLE 5 4-T3- (l-adamantyl) -4-methoxyphenylsulonyl-11-benzoic acid. (a) Methyl 4- [3- (l-adamantyl) -4-methoxyphenylsulfonylmethyl] -benzoate. 1.8 g (4.2 mmol) of methyl 4- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] benzoate, 20 ml of dichloromethane are introduced into a flask and 3.4 g (16.9 mmoles) of meta-chloroperbenzoic acid are added. The mixture is stirred at room temperature for two hours, the reaction mixture is poured into water, extracted with dichloromethane, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (90-10). After evaporation of the solvents, 1.8 g (93%) of expected ester of melting point 166-168 ° C are collected. (b) 4- [3- (l-adamantyl) -4-methoxyphenylsulfonyl-methyl] benzoic acid.

In a manner similar to Example 2 (a), from 2.1 g (4 mmol) of the preceding methyl ester, 1.3 g (68%) of the expected acid of melting point of 238-239 ° C are obtained.

EXAMPLE 6 4- .3- (l-adamantyl) -4-methoxyphenyl-io-arboxamidol benzoic acid. (a) Methyl 4- [3- (l-adamantyl) -4-methoxyphenylthiocarboxamido] -benzoate. 6.7 g (16.6 mmoles) of methyl 4- [3- (l-adamantyl) -4-methoxyphenylcarboxamido] benzoate, 60 ml of toluene are introduced into a flask and 4.1 g (9.9 mmoles) of Lawesson's reagent are added. . Heat to reflux for three hours, evaporate the reaction medium dry. The residue obtained is recovered by water and dichloromethane, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. After evaporation of the solvents, 6 g (83%) of the expected ester of melting point of 198-200 ° C are collected. (b) 4- [3 - (L-adamantyl) -4-methoxyphenylthiocarboxamido] benzoic acid.

In a manner similar to Example 2 (a), from 6 g (14.3 mmol) of the preceding methyl ester, 5.6 g (92%) of the expected acid of melting point 255-256 ° C are obtained.

EXAMPLE 7 4 -? 3 - (l -adamantyl) -4-methoxy-enyltriol-benzoic acid (a) 3- (l-adamantyl) -4-methoxybenzenemethanol.

Into a three-neck flask and under a stream of nitrogen, 8 g (0.2 moles) of double hydroxide of lithium and aluminum and 50 ml of anhydrous THF are introduced. A solution of 28.6 g (0.1 mol) of 3- (l-adamantyl) -4-methoxybenzoic acid in 260 ml of anhydrous THF is added dropwise and heated to reflux for 16 hours. The reaction medium is cooled and hydrolyzed with 14.4 ml of a solution of double tartrate of sodium and potassium. The salt is filtered, the filtrate is evaporated, the solid obtained is triturated in hexane, filtered, dried. 26.2 g (96%) of the expected benzyl alcohol of melting point 134-135 ° C are collected. (b) 3- (l-adamantyl) -4-methoxybenzyl bromide.

In a three-necked flask, 2.72 g (10 mmol) of the preceding benzyl alcohol, 30 ml of toluene and 800 μl (10 mmol) of pyridine are introduced. At 0 ° C, a solution of 940 μl (10 mmol) of phosphorus tribromide in 9 ml of toluene is added dropwise and stirred at room temperature for 4 hours. The reaction medium is evaporated to dryness, the residue is recovered by water and ethyl ether, the organic phase is decanted, dried over magnesium sulphate and evaporated. The residue obtained is triturated in hexane, filtered and dried. 2.35 g (70%) of the expected benzyl bromide of melting point 95-99 ° C are collected. (c) Methyl 4- [3- (l-adamantyl) -4-methoxyphenylmethylthio] benzoate.

Into a three-necked flask under a stream of nitrogen, 1.44 g (48 mmol) of sodium hydride (80% in oil) and 25 ml of DMF are introduced. A solution of 6.73 g (40 mmol) of methyl 4-mercaptobenzoate in 60 ml of DMF is added dropwise and stirred until the gas liberation is complete. Then a solution of 16.1 g (48 mmol) of 3- (l-adamantyl) -4-methoxybenzyl bromide in 90 ml of DMF is added and stirred at room temperature for eight hours. The reaction medium is poured into water, acidified to pH 1 with hydrochloric acid extracted with ethyl ether, the organic phase is separated out, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (40-60). After evaporation of the solvents, 16.75 g (99%) of the expected methyl ester of melting point 143-145 ° C are collected. (d) 4- [3- (l-adamantyl) -4-methoxyphenylmethylthio] -benzoic acid.

In a manner similar to Example 2 (a), 3.15 g (77%) of the expected acid of melting point 225-227 ° C is obtained from 4.22 g (10 mmol) of the preceding methyl ester.

EXAMPLE 8 4- .3- (l-adamantyl) -4-methoxyphenylmethylamino1 - (a) Benzyl N-terbutyloxycarbonyl-3- (l-adamantyl) -4-methoxy-phenylmethylamino] benzoate.

In a manner similar to that of Example 7 (c), by reaction of 10.6 g (34.6 mmol) of 3- [l-adamantyl) -4-methoxybenzyl bromide with 8.6 g (26.3 mmol) of benzyl 4-tert-butyloxycarboxamidobenzoate, 14 g. g (91%) of expected benzyl ester in the form of a yellow oil. (b) benzyl 3- (l-adamantyl) -4-methoxyphenylmethylamino] benzoate.

In a three-necked flask under a stream of nitrogen, 13.96 g (24 mmol) of the preceding benzyl ester and 100 ml of carbon tetrachloride are introduced. 5 ml (48 mmol) of trimethylsilane iodide are added dropwise and the mixture is stirred at room temperature for 12 hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (55-45). After evaporation of the solvents, 6.64 g (57%) of the expected benzyl ester are collected. (c) 4- [3- (l-adamantyl) -4-methoxyphenylmethylamino] -benzoic acid.

Similar to example 2 (a), starting from 1. 44 g (3 mmol) of the preceding benzyl ester give 877 mg (75%) of the expected acid of melting point of 259-260 ° C.

EXAMPLE 9 ------- Í ------- 2 4- r 3 -oxo-3-. 3 - (l-adamantyl) - methoxy-phenyl-1-propynyl-1-benzoic acid. (a) Methyl 4-trimethylsilylethynylbenzoate.

In a three-necked flask under a stream of nitrogen, 21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml of triethylamine and a mixture of 200 mg of palladium acetate and 400 mg of triphenylphosphine are introduced. 20 g (0.204 mol) of trimethylsilylacetylene are then added, they are progressively heated at 90 ° C for 1 hour and left at this temperature for 5 hours. The reaction medium is cooled, the salt is filtered and evaporated. The residue is recovered with 200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. The ethereal phase is decanted, washed with water, dried over magnesium sulfate, evaporated. The residue obtained is purified by chromatography on a column of silica, eluted with dichloromethane. After evaporation of the solvents, 23 g (100%) of the obtained derivative is recovered in the form of a colorless oil. (b) methyl 4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxyphenyl] -1-propynyl]] benzoate.

In a flask, 3 g (10 mmol) of 3- (l-adamantyl) -4-methoxybenzoyl chloride, 2.3 g, are introduced. (10 mmoles) of the preceding derivative and 100 ml of dichloromethane. Small amounts 4.7 g are added at 0 ° C (35 mmoles) of A1C1-, and stirred at room temperature for 8 hours. The reaction medium is poured onto ice, extracted with dichloromethane, the organic phase is separated out by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (80-20). 970 mg (23%) of the expected product of melting point 156-158 ° C are collected. (c) 4- [[3-OXO-3 - [3- (l-adamantyl) -4-methoxy-phenyl] -1-propynyl]] benzoic acid.

Into a flask, 962 mg (2.2 mmol) of the preceding methyl ester, 10 ml of THF are introduced and 283 mg (6.7 mmol) of lithium hydroxide are added. The mixture is refluxed for 5 hours, the reaction mixture is poured into water, acidified to pH 1 with concentrated hydrochloric acid, the organic phase is separated out, dried over magnesium sulphate and evaporated. The solid obtained is triturated in hexane, filtered, dried. 600 mg (85%) of the expected acid of melting point 232-234 ° C are collected.

EXAMPLE ÍQ AC-Ü-Q 4- Í3- (l-adamantyl) -4-methoxyethoxymethoxy-benzamidol benzoic acid. (a) 3- (l-adamantyl) -1-bromo-4-methoxyethoxymethoxy-benzene.

In a three-necked flask and under a stream of nitrogen, 3.8 g (0.13 mol) of sodium hydride (80% in oil) are introduced into 50 ml of DMF., a solution of 40 g (0.13 mol) of 2- (l-adamantyl) -4-bromophenol in 100 ml of DMF is added dropwise and stirred until the gas liberation is complete. A solution of 18 ml (0.15 mol) of 2-methoxyethoxymethylene chloride in 20 ml of DMF is then added dropwise and stirred for four hours at room temperature. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is separated out, washed with water, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (50-50). After evaporation of the solvents, 40.1 g (78%) of the expected product of melting point 69-70 ° C are collected. (b) 3- (l-adamantyl) -4-methoxyethoxymethoxybenzoic acid.

The preceding compound (28.5 g, 72 mmol) is dissolved in 200 ml of THF. The solution obtained is added dropwise over magnesium (2.4 g, 100 mmol) and a crystal of iodine. After the introduction, it is heated to reflux for two hours, cooled to -78 ° C and a stream of C02 is passed for one hour. The mixture is allowed to rise to room temperature, the reaction medium is poured into an aqueous solution saturated with ammonium chloride, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is triturated in hexane, filtered and dried. 15.5 g (60%) of the expected acid are collected from mp 115-116 ° C. (c) 3- (l-adamantyl) -4-methoxyethoxymethoxy-benzoyl chloride.

Into a flask, a solution of 3 g (8.3 mmoles) of 3- (l-adamantyl) -4-methoxyethoxymethoxy-benzoic acid in 50 ml of anhydrous dichloromethane is added, 1.7 ml are added (8.3 mmoles) of dicyclohexylamine and stir for one hour. Then 600 μl (8.3 mmoles) of thionyl chloride are added and stirred for one hour. Dry evaporate, recover with anhydrous ethyl ether, filter the dicyclohexylamine salt and evaporate the filtrate. 3.3 g (100%) of crude acid chloride is collected and will be used as such for the continuation of the synthesis. (d) Allyl 4- [3- (l-adamantyl) -4-methoxyethoxymethoxybenzamido] -benzoate.

Into a flask, 700 mg (3.95 mmol) of allyl 4-aminobenzoate, 1 ml (4.3 mmol) of triethylamine and 50 ml of THF are introduced. A solution of 1.5 g (3.96 mmoles) of 3- (l-adamantyl) -4-methoxyethoxymethoxybenzoyl chloride is added dropwise and stirred at room temperature for 4 hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. 1.7 g (83%) of the expected allyl ester are collected in the form of an oil. (e) 4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-benzamido] benzoic acid.

In a three-neck flask and under a stream of nitrogen, 1.7 g (3.2 mmol) of the preceding allyl ester, 50 ml of THF and 200 mg of tetrakis (triphenylphosphine) Pd (0) are introduced. A solution of diethyl malonate sodium salt, prepared from 105 mg (3.5 mmol) of sodium hydride (80% in oil) and 500 μl (3.2 mmol) of diethyl malonate, is added dropwise and Stir at room temperature for 2 hours. The reaction medium is evaporated to dryness, the residue is taken up in water, acidified to pH 4, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with ethyl ether. 1.1 g (70%) of the expected acid are recovered from melting point 150-152 ° C.

EXAMPLE 11 4-T3- (l-adamantyl) -4-methoxyethoxymethoxybenzoyl and 1-benzoic acid. (a) Allyl 4- [3- (l-adamantyl) -4-methoxyethoxymethoxyethoxy] benzoyloxy] benzoate.

In a similar manner to example 10 (d), by reaction of 1.5 g (3.9 mmol) of 3- (l-adamantyl) -4-methoxyethoxymethoxybenzoyl chloride with 705 mg (3.9 mmol) of Allyl 4-hydroxybenzoate gives 1.45 g (70%) of the expected allyl ester in the form of a yellow oil. (b) 4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-benzoyloxy] benzoic acid.

In a manner similar to Example 10 (e), from 1.45 g (2.8 mmol) of the preceding allyl ester, 870 mg (65%) of the expected acid of melting point 211-213 ° C are obtained.

EXAMPLE 12 £ i Ú £ (R) -4- f .3-QXQ-3- Í3- (l-adamantyl) -4-methoxy or i-methoxy-enyl-1-benzyl-1-methoxy, (a) 3- (l-adamantyl) -4-methoxyethoxymethoxyacetophenone.

In a three-necked flask and under a stream of nitrogen, 15.5 g (43 mmol) of acid are introduced. 3- (l-adamantyl) -4-methoxyethoxymethoxybenzoic acid and 300 ml of anhydrous ethyl ether. At -20 ° C, 80 ml are added dropwise (0.13 moles) of methyl lithium (1.6 M in ether), then stirred for three hours at room temperature. The reaction medium is poured into an aqueous solution saturated with ammonium chloride, the organic phase is separated out, dried over magnesium sulphate and evaporated. 15.4 g (100%) of the expected acetophenone are collected in the form of a slightly yellow oil. (b) (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxyethoxy-methoxyphenyl] -1-propenyl]] methyl benzoate.

Into a flask, 1.8 g (5 mmoles) of 3- (l-adamantyl) -4-methoxyethoxymethoxyacetophenone, 820 mg (5 mmol) of methyl 4-formylbenzoate and 20 ml of methanol are introduced. 10 mg of 18-crown-6 and 200 mg of soda are added to the tablet and stirred at room temperature for 4 hours. The mixture is evaporated to dryness and the residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. 1.4 g (55%) of the expected methyl ester are collected. (c) (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxy-ethoxymethoxyphenyl] -1-propenyl]] benzoic acid.

Similar to example 2 (a), starting from 700 mg (1.4 mmol) of methyl (E) -4- [[3-oxo-3 - [3- (1-adamantyl) -4-methoxyethoxymethoxyphenyl] -1-propenyl]] benzoate yields 590 mg (87 %) of the expected acid of melting point 154-156 ° C.

EXAMPLE 13 -4-r .3-Hydroxy-3- .3- (l-adamantyl) -4-me orxri-β-methoxymethoxyphenyl-1-propynyl-1-benzoic acid. (a) 3- (l-adamantyl) -4-ethoxyethoxyethoxy f -ylcarboxaldehyde.

In a three-necked flask under a stream of nitrogen, 34 g (89 mmol) of 3- (l-adamantyl) -l-bromo-4-methoxyethoxymethoxybenzene and 250 ml of THF At -78 ° C, 43 ml (106 mmol) of a solution of n-butyllithium (2.5 M in hexane) are added dropwise and stirred for 30 '. 8.3 ml (106 mmol) of DMF are then added dropwise and allowed to rise to room temperature.

The reaction medium is poured into an aqueous solution of ammonium chloride, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. After evaporation of the solvents, 17.6 g are collected (58%) of expected aldehyde of melting point 63-64 ° C. (b) α-Trimethylsilylethynyl-3- (1-adamantyl) -4-methoxy-ethoxymethoxyphenylmethanol.

In a three-necked flask, 1.7 ml are introduced (11.9 mmol) of trimethylsilylacetylene and 25 ml of THF. TO -78 ° C and under nitrogen stream, a solution of 5 ml (11.9 mmoles) of n-butyllithium (2.5 M in hexane) is added dropwise and allowed to return to room temperature. This solution is introduced dropwise into a solution of 3.7 g (10.7 mmol) of 3- (l-adamantyl) -4-methoxyethoxymethoxyphenylcarboxaldehyde in 50 ml of THF at -78 ° C. The reaction medium is allowed to return to room temperature, poured into an aqueous solution of ammonium chloride, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. 4.7 g (97%) of the expected alcohol are obtained in the form of a yellow oil. (c) α-ethynyl-3- (1-adamantyl) -4-methoxyethoxymethoxyphenyl-methanol.

Into a flask, 4.7 g (10.5 mmol) of a-trimethylsilylethynyl-3- (l-adamantyl) -4-methoxyethoxy-methoxyphenylmethanol, 50 ml of THF are introduced and 11.4 ml (12.6 mmol) of a solution are added dropwise. of tetrabutylammonium fluoride (1.1 M in THF). The mixture is stirred at room temperature for one hour, the reaction mixture is poured into water, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and heptane (30-70). After evaporation of the solvents, 2.5 g (64%) of a-ethynyl-3- (l-adamantyl) -4-methoxyethoxymethoxyphenylmethanol are collected. (d) Methyl 4- [[3-hydroxy-3- [3- (l-adamantyl) -4-methoxyethoxy-methoxyphenyl] -1-propynyl]] benzoate.

In a three-neck flask, 2.5 g are introduced (6.7 mmol) of a-ethynyl-3- (l-adamantyl) -4-methoxyethoxy-methoxyphenylmethanol, 1.2 g (6.7 mmol) of methyl 4-iodobenzoate and 50 ml of triethylamine. The reaction medium is degassed with nitrogen for 30 ', then 380 mg (0.5 mmol) of Bis (triphenylphosphine) palladium (II) chloride and 190 mg (0.8 mmol) of copper iodide are successively added. The mixture is stirred at room temperature for four hours, the reaction medium is evaporated to dryness, the residue obtained is recovered with water and ethyl ether. The organic phase is decanted, dried over magnesium sulfate, evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and heptane (20-80). 2.7 g (79%) of methyl 4- [[3-hydroxy-3- [3- (l-adamantyl) -4-methoxyethoxy-methoxyphenyl] -1-propynyl]] benzoate of melting point 95-96 are collected. ° C. (d) 4- [[3-Hydroxy-3- [3- (l-adamantyl) -4-methoxy-ethoxymethoxyphenyl] -1-propynyl]] benzoic acid.

In a manner similar to Example 9 (c), from 2.66 g (5.3 mmol) of the preceding methyl ester, 1.52 g (88%) of the expected acid of melting point 148-149 ° C are obtained.

EXAMPLE 14 4-, 3- (l-adamantyl) -4- (2,2-dimethyl-1,3-d-ioxolan-4-methyloxy) phenylcarboxamidol benzoic acid. (a) Methyl 3- (l-adamantyl) -4- (2,2-dimethyl-l, 3-dioxolan-4-methyloxy) benzoate.

To a solution of 10 g (0.0349 moles) of 3- (l-adamantyl) -4-hydroxybenzoate in 100 ml of DMF containing 5.31 g (0.0384 mol) of potassium carbonate, a solution of 12 g (0.0419 mol) of 3-tosyloxy- is added dropwise. 1, 2-propanediolacetonide. The reaction medium is heated at 100 ° C for twelve hours, then poured into ice water and extracted with ethyl ether. The organic phase is decanted, dried over sodium sulphate, evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of hexane and ethyl acetate (80-20). After evaporation of the solvents, 8.8 g (63%) of the expected product of melting point 158-159 ° C are collected. (b) 3- (L-adamantyl) -4- (2,2-dimethyl) -1,3-dioxolan-4-methyloxy) benzoic acid.

Into a flask, 8.8 g (0.022 mol) of the preceding methyl ester and 200 ml of a methanolic solution (2N) are introduced. Heat to reflux for three hours, and evaporate dry. The residue is recovered with a mixture of ethyl ether-water, acidified to pH 3, the organic phase is separated out, dried over magnesium sulphate and evaporated. The solid obtained is triturated in hexane, filtered, dried. 8.3 g (98%) of the expected acid of melting point 224-225 ° C are collected. (c) 3- (l-adamantyl) -4- (2, 2-dimethyl-l, 3-dioxolan-4-methyloxy) benzoyl chloride.

In a flask, 8.3 g (0.0215 mol) of 3- (1-adamant il) -4- (2, 2-dimetyl 1- 1, 3-dioxolan-4-methyloxy) benzoic acid, 80 ml of dichloromethane are introduced. and 4.3 ml (0.0216 moles) of dicyclohexylamine. They are stirred for one hour at room temperature, then 1.7 ml (0.0236 moles) of thionyl chloride are introduced. The mixture is stirred for four hours, evaporated to dryness, recovered with ethyl ether, the dicyclohexylamine salt is filtered, evaporated and 8.5 g (100%) of acid chloride are collected and used for the continuation of the synthesis. (d) methyl 4- [3- (l-adamantyl) -4- (2,2-dimethyl-l, 3-dioxolan-4-methyloxy) phenylcarboxamido] benzoate.

Into a flask, 1.62 g (10.7 mmol) of methyl 4-aminobenzoate, 30 ml of THF and 1.65 ml (11.8 mmol) of triethylamine are introduced; A solution of 4.3 g (10.7 mmol) of 3- (l-adamantyl) -4- (2,2-dimethyl-1,3-dioxolan-4-methyl-oxy) -benzoyl chloride in 30 ml of a solution is added dropwise. THF and stirred at room temperature for sixteen hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is separated out, dried over a magnesium surface and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and ethyl ether (98-2). 3.1 g (56%) of the expected methyl ester of melting point 174-175 ° C are collected. (e) 4- [3- (l-adamantyl) -4- (2,2-dimethyl-l, 3-dioxolan-4-methyloxy) phenylcarboxamido] benzoic acid.

Similar to example 14 (b), starting from 1 g (1.92 mmol) of the preceding methyl ester, 900 mg (93%) of 4- ['3 - (1-adamantyl) -4- (2, 2-dimethyl-1,3-dioxolan-4-) are collected. methyloxy) phenylcarboxamido] benzoic melting point 245-246 ° C.

EXAMPLE 15 As- O 4- .3- (l-adamantyl) -4- (2,3-dihydroxy-propyloxy) phenylcarboxamidol benzoic acid. (a) Methyl 4- [3- (l-adamanyl) -4- (2,3-dihydroxypropyloxy) -phenylcarboxamido] benzoate.

In a flask, 1.96 g (3.78 mmol) of methyl 4- [3- (l-adamantyl) -4- (2,2-dimethyl-1,3-dioxolan-4-methyloxy) phenylcarboxamido] benzoate are introduced. ml of dichloromethane, 8 ml of THF and 7.24 g (38 mmol) of para-toluenesulfonic acid are added. The mixture is stirred at room temperature for four hours, the reaction mixture is poured into water, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and chloromethane (90-10). 1.46 g (81%) of the expected product of melting point 111-112 ° C are collected. (b) 4- [3- (l-adamantyl) -4- (2,3-dihydroxy-propyloxy) phenylcarboxamido] benzoic acid.

In a similar manner to example 14 (b), from 1.42 g (2.96 mmol) of the preceding methyl ester, 650 mg (47%) of 4 - [3 - (l-adamantyl) -4- (2, 3-dihydroxypropyloxy) phenylcarboxamido] benzoic melting point 236-237 ° C.

EXAMPLE 16 O ± UO 4- .3- (l-adamantyl) -4-methoxycarbonyl-methyloxyphenylcarboxamidol benzoic acid. (a) benzyl 3- (l-adamantyl) -4-methoxycarbonylmethyloxybenzoate.

In a three-necked flask, 2.1 g are introduced (5.79 mmoles) of benzyl 3- (l-adamantyl) -4-hydroxybenzoate and 20 ml of DMF and added in small amounts 191 mg (6.34 mmol) of sodium hydride (80% in oil). The mixture is stirred until the gas liberation is complete, then 565 μl (5.79 mmol) of methyl bromoacetate are added 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 separated out, dried over magnesium sulphate and evaporated. The solid is triturated in hexane, filtered, dried. 2.36 g (94%) of expected product of mp 134-135 ° C are collected. (b) 3- (L-adamantyl) -4-methoxycarbonylmethyloxy-benzoic acid.

In a reactor, 2.34 g (5.38 mmol) of benzyl 3- (l-adamantyl) -4-methoxycarbonylmethyloxybenzoate, 40 ml of dioxane, 500 μl of acetic acid and 234 mg of palladium (10%) are introduced. They are hydrogenated at 40 ° C and at a pressure of 7 bars for three hours. The catalyst is filtered, evaporated dry. The solid obtained is triturated in hexane, filtered, dried. 1.74 g (94%) of the expected acid of melting point 230-231 ° C are collected. (c) 3- (l-adamantyl) -4-methoxycarbonyl-methyloxybenzoyl chloride.

Into a flask, 1.78 g (5 mmol) of 3- (l-adamantyl) -4-methoxycarbonylmethyloxybenzoic acid, 15 ml of thionyl chloride are introduced and heated at reflux for one hour. Dry evaporate and collect the crude acid chloride which will be used as such for the continuation of the synthesis. (d) benzyl 4- [3- (l-adamantyl) -4-methoxycarbonylmethyloxy-phenylcarboxamido] benzoate.

In a manner similar to Example 14 (d) by reaction of 1.13 g (5 mmol) of benzyl 4-aminobenzoate with 1.8 g (5 mmol) of 3- (l-adamantyl) -4-methoxy-carbonylmethyloxybenzoyl chloride, obtain 1.7 g (61%) of the expected benzyl ester of melting point 95-96 ° C. (e) 4- [3- (l-adamantyl) -4-methoxycarbonylmethyloxy-phenylcarboxamido] benzoic acid.

In a manner similar to Example 16 (b), from 1.69 g (3 mmol) of benzyl 4- [3- (l-adamantyl) -4-methoxycarbonyl-methyloxyphenylcarboxamido] benzoate, 1.13 g (80%) of expected acid of melting point 291-292 ° C.

EXAMPLE 17 2-. 3- (l-adamantyl) -4-methoxyphenoxymethyl-4-thiofencarboxylic acid. (a) Methyl 2- [3- (l-adamantyl) -4-methoxyphenoxymethyl] -4-thio-phencarboxylate.

In a three-necked flask under a stream of nitrogen, 210 mg (7 mmol) of sodium hydride (80% in oil) and 10 ml of DMF are introduced. A solution of 1.8 g (7 mmol) of 3- (l-adamantyl) -4-methoxyphenol in 20 ml of DMF is added dropwise and stirred until the gaseous release ends. A solution of 1.7 g (7.2 mmoles) of methyl 2-bromomethyl-4-thiophenecarboxylate in 15 ml of DMF is then added and stirred at room temperature for two hours. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The solid obtained is triturated in hexane, filtered, dried. 2.6 g (90%) of the expected methyl ether of melting point 97-98 ° C are recovered. (b) 2- [3- (l-adamantyl) -4-methoxyphenoxymethyl] -4-thiophenecarboxylic acid.

In a manner similar to Example 14 (b), from 2 g (5.6 mmol) of the preceding methyl ester, 1.7 g (88%) of 2- [3- (l-adamantyl) -4-methoxyphenoxymethyl] -4 are obtained -tephencarboxylic melting point 198-200 ° C.

EXAMPLE 18 2- f3- (l-adamantyl) -4-methoxy-n-amino-ethyl-4-thiophenecarboxylic acid. (a) Methyl 2- [3- (l-adamantyl) -4-methoxyphenylaminomethyl] -4-thiophenecarboxylate.

In a similar manner to example 17 (a), by reaction of 2.4 g (6.8 mmol) of 3- (l-adamantyl) -4-methoxytrifluoroacetanilide with 1.6 g (6.8 mmol) of methyl 2-bromomethyl-4-thiophenecarboxylate , 2.6 g (75%) of the expected methyl ester are obtained in the form of a yellow oil. (b) 2- [3- (l-adamantyl) -4-methoxyphenylamino-methyl] -4-thiophenecarboxylic acid.

In a manner similar to Example 14 (b), from 2.6 g (5.1 mmol) of the preceding methyl ester, 1.5 g (74%) of 2- [3- (l-adamantyl) -4-methoxy-phenylaminomethyl are obtained. ] -4-thiophenecarboxylic melting point 212-214 ° C.

EXAMPLE 19 2- .3- (l-adamantyl) -4-methoxy-nylthiomethyl-11 acid. -4-thiophenecarboxylic acid. (a) Methyl 2- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] -4-thio-phencarboxylate.

In a manner similar to Example 17 (a), by reacting 800 mg (2.9 mmol) of 3- (l-adamantyl) -4-methoxythiophenol with 690 mg (2.9 mmol) of methyl 2-bromoethyl-4-thiophenecarboxylate, obtain 700 mg (56%) of the expected methyl ester in the form of a colorless oil. (b) 2- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] -4-thiophenecarboxylic acid.

Similar to example 14 (b), starting from 700 mg (1.6 mmol) of the preceding methyl ester gives 460 mg (68%) of 2- [3- (l-adamantyl) -4-methoxy-phenylthiomethyl] -4-thiophene carboxylic acid of melting point 154-156 ° C.

EXAMPLE 2Q O ± UO 4- .3- (l-adamantyl) -4- (2,2-dimethyl-1,3-dioxolan. 4 -methyloxy) benzoyloxyl benzoic acid. (a) Allyl 4- [3- (l-adamantyl) -4- (2,2-dimethyl-l, 3-dioxolan-4-methyloxy) benzoyloxy] benzoate.

In a similar manner to example 14 (d), by reaction of 4.3 g (10.7 mmol) of 3- (l-adamantyl) -4- (2,2-dimethyl-1,3-dioxolan-4-methyloxy) benzoyl chloride with 1.9 g (10.7 mmoles) of allyl 4-hydroxybenzoate, 4.24 g (72%) of the expected aulic ester of mp 106-107 ° C are obtained. (b) 4- [3- (l-adamantyl) -4- (2,2-dimethyl-l, 3-dioxolan-4-methyloxy) benzoyloxy] benzoic acid.

In a three-necked flask under a stream of nitrogen, 1 g (1.83 mmol) of the preceding allyl ester, 10 ml of THF and 104 mg of tetrakis (triphenylphosphine) palladium (0) are introduced. 1.6 ml (18.3 mmoles) of morpholine are added dropwise and stirred at room temperature for three hours. The reaction medium is poured into ice water, acidified to pH 3, extracted with ethyl ether, the organic phase is separated out after settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and ethyl acetate (50-50). After evaporation of the solvents, 435 mg (47%) of 4- [3- (l-adamantyl) -4- (2,2-dimethyl-1,3-dioxolan-4-methyloxy) benzoyloxy] are collected. Benzoic melting point 238-240 ° C.

EXAMPLE 21 ? - L ------ 2 4-. 3 -hydroxy -3-. 5 - (l-adamantyl) -2,4-dimethoxyethoxymethoxyphenyl-1-propynyl benzoic acid. (a) 5- (l-adamantyl) -2,4-dihydroxybenzaldehyde.

Into a flask, 40 g (0.29 mole) of 2,4-dihydroxybenzaldehyde, 600 ml of dichloromethane, 46.4 g (0.34 mole) of 1-adamantanol are introduced and 24 ml of concentrated sulfuric acid are added. The mixture is stirred at room temperature for twelve hours, the reaction mixture is poured into water, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. 50.8 g (64%) of the expected aldehyde of melting point 259-261 ° C are collected. (b) 5 - (1 -admant il) -2,4-di-methoxyethoxymethoxybenzaldehyde.

In a similar manner to example 17 (a), by reaction of 25 g (91.9 mmol) of 5- (l-adamantyl) -2,4-dihydroxy-benzaldehyde with 26.2 ml (0.23 mol) of 2-methoxyethoxymethyl, 31 g (75%) of expected product are obtained in the form of a yellow oil. (c) α-Trimethylsilylethynyl-5- (1-adamant i 1) -2,4-dimethoxyethoxymethoxybenzenemethanol.

In a three-neck flask, 450 μl is introduced (3.2 mmol) of trimethylsilylacetylene and 50 ml of THF. TO -78 ° and under a stream of nitrogen, a solution of 1.3 ml (3.2 mmol) of n-butyllithium (2.5 M in hexane) is added dropwise and allowed to return to room temperature. This solution is introduced dropwise into a solution of 1.3 g (2.9 mmol) of 5- (l-adamantyl) -2,4-dimethoxyethoxy-methoxybenzaldehyde in 50 ml of THF at -78 ° C. Allow the reaction medium to return to room temperature, pour into an aqueous solution of ammonium chloride, extract with ethyl ether, decant the organic phase, dry over magnesium sulfate, evaporate. 1.6 g (100%) of the expected alcohol are obtained in the form of a yellow oil. (d) α-ethynyl-5- (1-adamantyl) -2,4-di-methoxyethoxymethoxy-benzenemethanol.

Into a flask, 1.6 g (2.9 mmol) of a-trimethylsilylethynyl-5- (l-adamantyl) -2,4-di-methoxyethoxy-benzenemethanol, 50 ml of THF are introduced and 3.2 ml are added dropwise. (3.5 mmoles) of a solution of tetrabutylammonium fluoride (1.1 M in THF). The mixture is stirred at room temperature for one hour, the reaction mixture is poured into water, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and ethyl ether (95-5). After evaporation of the solvents, 760 mg (55%) of expected product are collected in the form of a yellow oil. (e) Methyl 4- [3-hydroxy-3- [5- (l-adamantyl) -2,4-di-methoxy-ethoxymethoxyphenyl] -1-propynyl] benzoate.

In a three-necked flask, 760 mg are introduced (1.6 mmol) of α-ethynyl-5- (1-adamantyl) -2,4-dimethoxyethoxy-methoxybenzenemethanol, 420 mg (1.6 mmol) of methyl 4-iodobenzoate and 20 ml of triethylamine. The reaction medium is degassed with nitrogen for 30 ', then 90 mg of Bis (triphenylphosphine) palladium (II) chloride and 37 mg of copper iodide are successively added. The mixture is stirred at room temperature for four hours, the reaction medium is evaporated to dryness, the residue obtained is recovered by means of water and 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 dichloromethane, 800 mg (82%) of the expected methyl ester are collected in the form of a brown oil. (f) 4- [3-Hydroxy-3- [5- (l-adamantyl) -2,4-di-methoxyethoxymethoxyphenyl] -1-propynyl] benzoic acid.

Into a flask, 800 mg (1.3 mmol) of the preceding methyl ester, 340 mg (7.8 mmol) of lithium hydroxide and 50 ml of THF are introduced and heated at reflux for twelve hours. Dry evaporate, recover with water, acidify to pH 1, extract with ethyl ether, decant the organic phase, dry over magnesium sulphate, evaporate. The residue obtained is purified by chromatography on a column of silica eluted with ethyl ether. 420 mg (54%) of 4- [3-hydroxy-3- [3- (l-adamantyl) -2,5-dimethoxyethoxymethoxyphenyl] -1-propynyl] -benzoic acid of melting point 79-81 ° C are collected. .

EXAMPLE 22 -IDO 4 -. 3 - (l -adamantyl) -4-methoxyethoxymethoxy-benzoylthiol benzoic acid.

In a flask, 1.54 g (10 mmol) of 4-mercaptobenzoic acid and 40 ml of pyridine are introduced. A solution of 3.75 g (10 mmol) of 3- (l-adamantyl) -4-methoxyethoxymethoxybenzoyl chloride prepared in Example 10 (c) is added dropwise and stirred at room temperature for six hours. Dry evaporate, recover with water and ethyl ether, decant the organic phase, wash with water, dry over magnesium sulfate, evaporate. The solid obtained is recrystallized from a mixture of diisopropyl ether-methanol, filtered, dried. 2.94 g (59%) of 4- [3- (l-adamantyl) -4-methoxyethoxy-methoxybenzoylthio] benzoic acid of melting point 187-188 ° C are collected.

EXAMPLE 23 c.rio-N-methyl-4-. 3 - (l-adamantyl) -4-methoxyethoxy-methoxyphenylcarboxamidol benzoic acid. (a) Allyl N-methyl-4- [3- (l-adamantyl) -4-methoxyethoxymethoxy] benzoate.

In a similar manner to example 16 (a), by reaction of 1.35 g (2.6 mmol) of allyl 4- [3- 1-adamantyl) -4-methoxyethoxy-methoxybenzamido] benzoate prepared in the example (d) with 190 μl (3.1 mmol) of iodomethane, are obtained 1. 38 g (100%) of the expected allyl ester. (b) N-Methyl-4- [3- (l-adamantyl) -4-methoxyethoxy-methoxyphenylcarboxamido] benzoic acid.

Similar to example 20 (b), starting from 1. 32 g (2.5 mmol) of the preceding allyl ester give 740 mg (60%) of N-methyl-4- [3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl carboxamido] benzoic acid of melting point 159-160 °. C.

EXAMPLE 24 4-f3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl-thiocarboxamidol benzoic acid. (a) Allyl 4- [3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl-thiocarboxamido] benzoate.

In a manner similar to Example 6 (a), by reacting 2 g (3.9 mmol) of allyl 4- [3- (l-adamantyl) -4-methoxyethoxy-methoxybenzamido] benzoate with 940 mg (2.3 mmol) of Lawesson, 1.93 g (92%) of the expected allyl ester are obtained. (b) -4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-phenylthiocarboxamido] benzoic acid.

In a manner similar to Example 20 (b), from 1.9 g (3.5 mmol) of the preceding allyl ester, 50 mg (29%) of -4- [3 - (1-adamantyl) -4-methoxyethoxy- methoxyphenylthiocarboxamido] benzoic melting point 98-99 ° C.

EXAMPLE 25 & EMI (E) -4- r f3-oxo-3- .3- (l-adamantyl) -4-methoxymethoxy-phenyl-1-propenyl-1-benzoic acid. (a) Methyl 3- (l-adamantyl) -4-methoxymethoxybenzoate, In a three-necked flask and under a stream of nitrogen, 9 g (0.3 mole) of sodium hydride (80% in oil) and 50 ml of DMF are introduced. A solution of 71.6 g (0.25 mol) of methyl 3- (l-adamantyl) -4-hydroxybenzoate in 500 ml of DMF is added dropwise and stirred until the gas liberation is complete. 22.8 ml (0.3 moles) of methoxymethyl chloride are then added and stirred at room temperature for one hour. The reaction medium is poured into water, extracted with ethyl ether, the organic phase is separated out, dried over magnesium sulphate and evaporated. 67.7 g (82%) of the expected product are collected in the form of an oil. (b) 3- (l-adamantyl) -4-methoxymethoxybenzoic acid.

Analogously to example 14 (b), from 57.7 g (0.2 mol) of the preceding methyl ester, 59 g (91%) of 3- (l-adamantyl) -4-methoxy-methoxybenzoic acid are obtained. (c) 3- (l-adamantyl) -4-methoxymethoxyacetophenone.

In a three-necked flask and under a stream of nitrogen, 58 g (0.183 mol) of 3- (l-adamantyl) -4-methoxymethoxybenzoic acid and 500 ml of anhydrous ethyl ether are introduced. At -20 ° C, 252 ml (0.4 moles) of methyl lithium (1.6 M in ether) are added dropwise, then stirred for three hours at room temperature. The reaction medium is poured into an aqueous solution saturated with ammonium chloride, the organic phase is separated out, dried over magnesium sulphate and evaporated. 59.6 g (100%) of the expected acetophenone are collected in the form of a slightly yellow oil. (d) (E) -4 [[3-OXO-3- [3- (l-adamantyl) -4-methoxymethoxy-phenyl] -1-propenyl]] methyl benzoate.

Into a flask, 40.9 g (0.13 mol) of 3- (l-adamantyl) -4-methoxymethoxyacetophenone, 23.47 g are introduced. (0.143 mol) of methyl 4-formylbenzoate and 600 ml of methanol. Add 24.8 ml (0.13 mol) of a sodium methylate solution (5.25 M) and stir at room temperature for 18 hours. Dry evaporate, recover with a water-ethyl acetate mixture, decant the organic phase, dry over magnesium sulfate, evaporate. The residue obtained is purified by trituration in a mixture of hexane and ethyl acetate, filtered, dried. 46.1 g (77%) of methyl (E) -4- [[3-oxo-3- [3- (1-adamantyl) -4-methoxymethoxyphenyl] -1-propenyl]] benzoate melting point 170 are collected. -171 ° C. (e) (E) -4- [[3-OXO-3 - [3- (l-adamantyl) -4-methoxymethoxyphenyl] -1-propenyl]] benzoic acid.

Similar to example 2 (a), from 5 g (10.8 mmol) of (E) -4- [[3-oxo-3- [3- (l-adamantyl) -4-methoxy-methoxyphenyl] - Methyl 1-propenyl] benzoate gives 3 g (62%) of the expected acid of melting point 205-206 ° C.

EXAMPLE 26 Acid (E) -4- F r3-oxo-3-. 3-fl-adaman i 1.1 -4-hi-droxy-phenyl-1-propenyl-1-benzoic acid. (a) (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-hydroxyphenyl] -1-propenyl]] methyl benzoate.

In a flask, 40.2 g (87.4 mmol) of (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxymetho-xyphenyl] -1-propenyl]] benzoate are introduced. methyl, one liter of methanol and 300 ml of THF. 50 ml of concentrated sulfuric acid are added and heated at reflux for four hours.

The reaction medium is evaporated, it is recovered with a mixture of ethyl acetate-water, the organic phase is decanted, dried over magnesium sulphate and evaporated. The solid obtained is triturated in a mixture of ethyl acetate-hexane (30-70), filtered, dried. 32.1 g (88%) of the expected methyl ester of melting point 256-257 ° C are collected. (b) (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-hydroxyphenyl] -1-propenyl]] benzoic acid.

In a manner similar to Example 2 (a), from 5 g (12 mmol) of the preceding methyl ester, 4.8 g (100%) of (E) -4- [[3-oxo-3- [3 - (l-adamantyl) -4-hydroxyphenyl] -l-propenyl]] benzoic melting point > 300 ° C with decomposition.

EXAMPLE 27 In this example, various specific formulations based on compounds according to the invention are illustrated.

A- ORAL ROUTE (a) 0.2 g tablet - Compound of example 1 0.001 g - Starch 0.114 g - Dicalcium phosphate 0.020 g - Silicon 0.020 g - Lactose 0.030 g - Talc 0.010 g - Magnesium stearate 0.005 g (b) Drinkable suspension in 5 ml ampoules - Compound of example 2 0.001 g - Glycerin 0.500 g - Sorbitol at 70% 0.500 g - Sodium saccharinate 0.010 g - Methyl parahydroxybenzoate 0.040 g - Aroma cs - Purified water 5 ml (c) 0.8 g tablet - Compound of example 6 0.500 g - Pregelatinous starch 0.100 g - Microcrystalline cellulose 0.115 g - Lactose 0.075 g - Magnesium stearate 0.010 g (d) Drinkable suspension in 10 ml ampoules - Compound of example 4 0.05 g - Glycerin 1,000 g - Sorbitol at 70% • 1,000 g - Sodium saccharinate 0.010 g - Methyl parahydroxybenzoate 0.080 g - Aroma cs - Purified water esp 10 ml B- TOPICAL ROUTE (a) Ointment - Compound of example 1 0.020 g - Isopropyl myristate 81,700 g - Liquid vaseline oil 9.100 g - Silicon ("Aerosil 200" sold by DEGUSSA) 9.180 g (b) Ointment - Compound of Example 6 0.300 g - White Vaseline codex 100 g (c) Non-ionic Water-in-Oil Cream - Compound of Example 1 0.100 g - Mixture of emulsifying lanolin alcohols, waxes and oils ("Eucerin anhydrous" sold by BDF) 39,900 g - Methyl parahydroxybenzoate 0.075 g - Propyl parahydroxybenzoate 0.075 g - Sterile demineralised water, 100 g (d) Lotion - Compound of Example 1 0.100 g - Polyethylene glycol (PEG 400) 69,900 g - Ethanol at 95 30,000 g (e) Hydrophobic ointment - Compound of example 2 0.300 g - Isopropyl myristate 36,400 g - Silicone oil ("Rhodorsil 47 V 300" sold by RHONE-POULENC) 36,400 g - Beeswax 13,600 g - Silicone oil ("Abil 300,000 cts" sold by GOLDSCHMIDT) 100 g (f) Non-ionic Oil-in-Water Cream - Compound of example 4 0.500 g - Cetyl alcohol 4,000 g - Glycerol monostearate 2,500 g - PEG 50 stearate 2,500 g - Carite butter 9,200 g - Propylene glycol 2,000 g - Methyl parahydroxybenzoate 0.075 g - Propyl parahydroxybenzoate 0.075 g - Demineralised water sterile 100 g It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the objects to which it refers. Having described the invention as above, property is claimed as contained in the following:

Claims

IONS

1. Aromatic heterocyclic compounds, characterized in that they correspond to the following general formula (I): wherein: R1 represents (i) the radical -CH3 (ii) the radical - (CH2) n-0-R4 (iii) the radical -0- (CH2) m- (CO) n -R5 (iv) the radical -C0-R6 (v) the radical -C0-0-R7 having the values m and n, as well as the different radicals R4 to R7 the meaning given above, R2 represents a hydrogen, halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, a radical -OR4, a radical -0-CH2-0-CH2-CH2-0-CH3, R3 represents (i) a radical -Y- (CH2 2) > -Y- (CH • -2,) l "qR (ii) a radical - (CH2 2) '_p-Y- (CH ••, 2)' q ZR * (iii) a radical -Y- (CE 2 'q -R' (iv) a radical -CH = CH- (CH2) R-R8 (v) a radical - (CH2) q -R8 having the values p, q, r and the radicals Y and R8 the meaning given above , X represents the links of the following formulas (a) - (k) that can be linked in both directions: O '(a) R10 W (g) (h) (i) Ar represents a radical selected from the radicals of the following formulas (a) - (f): understanding that in all that precedes: m is an integer equal to l, 2 or 3; n is an integer equal to 0 or 1; p is an integer between 1 and 12, inclusive; q is an integer between 0 and 12, inclusive; r is an integer between 0 and 10, inclusive; - t is an integer equal to 0, 1 or 2; Y represents the oxygen atom or the radical S (0) t; W represents the oxygen atom, the radical S (0) t or the radical N-R10; - R4 represents a hydrogen atom, a lower alkyl radical or a radical -CO-R ^; R5 represents a lower alkyl or a heterocycle; R6 represents a hydrogen atom, a lower alkyl radical or a radical; 'N' R1 wherein R 'and R "represent a hydrogen atom, a lower alkyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid or peptide or sugar residue or, taken together, form a heterocycle R7 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, a mono or polyhydroxyalkyl radical, an optionally substituted aryl or aralkyl radical or a sugar moiety or a moiety amino acid or peptide; Re represents a hydrogen atom, a branched alkyl radical having from 1 to 20 carbon atoms, a cycloaliphatic radical of 3 to 6 carbon atoms, a monohydroxyalkyl radical or a polyhydroxyalkyl radical, the hydroxy of which is optionally protected in the form of methoxy or acetoxy or acetonide, an aryl radical, an alkenyl radical, an alkynyl radical, a -C0-R6 radical, a -C0-0-R7 radical, a adical aminoalkyl, whose amine function is optionally substituted by one or two lower alkyl groups, a heterocycle, R7 having the meaning given above; R9 represents a hydrogen atom, a halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, a radical -0R4, a radical • -0-CH2-0-CH2-CH2-0-CH3; R10, identical or different, represents a hydrogen atom, a lower alkyl radical; RX1 represents a lower alkyl radical, since when: - X represents the bond of the formulas (a), (b), (c), (d), (h), (j) or (k) then R3 is different from the radical of formulas (iii), (iv) or (v) in which R8 is an atom of hydrogen; X represents the bond of formula (a), then R3 is different from radical (iii); X represents the bond of formula (b) and R3 represents the radical of formula (iii) in which Y represents a sulfur atom, then R8 is different from the aryl radical; - X represents the link of the formulas (g), (h), (j) or (k) and R3 represents the radical of formula (v), then R8 is different from a monohydroxyalkyl or polyhydroxyalkyl radical; as well as its salts and its optical and geometric isomers.

2. The compositions according to claim 1, characterized in that they occur in the form of salts of an alkali metal or alkaline earth metal, or even of zinc or of an organic amine.

3. The compounds according to one of claims 1 or 2, characterized in that the lower alkyl radicals are selected from the group consisting of the methyl, ethyl, isopropyl, butyl, tertiary butyl, hexyl, nonyl or dodecyl radicals.

4. The compounds according to one of the preceding claims, characterized in that the linear or branched alkyl radicals, having from 1 to 20 carbon atoms, are selected from the group consisting of the methyl, ethyl, propyl, 2-ethylhexyl, octyl radicals , dodecyl, hexadecyl and octadecyl.

5. The compounds according to one of the preceding claims, characterized in that the monohydroxyalkyl radicals are selected from the group consisting of the 2-hydroxyethyl radicals, 2 - . 2-hydroxypropyl or 3-hydroxypropyl.

6. The compounds according to one of the preceding claims, characterized in that the polyhydroxyalkyl radicals are selected from the group consisting of 2, 3-dihydroxypropyl, 2, 3, 4-trihydroxybutyl, 2, 3, 4, 5-tetrahydroxypentyl radicals or rest of pentaerythritol.

7. The compounds according to one of the preceding claims, characterized in that the aryl radical is a phenyl radical optionally substituted by at least one halogen atom, a hydroxyl or a nitro function.

8. The compounds according to one of the preceding claims, characterized in that the aralkyl radicals are selected from the group consisting of benzyl or phenethyl radicals, optionally substituted by at least one halogen atom, a hydroxyl or a nitro function.

9. The compounds according to one of the preceding claims, characterized in that the alkenyl radicals are selected from the group consisting of radicals containing from 1 to 5 carbon atoms and having one or more ethylenic unsaturations, and in particular the allyl radical.

10. The compounds according to one of the preceding claims, characterized in that the sugar moieties are selected from the group consisting of the glucose, galactose, mannose and glucuronic acid moieties.

11. The compounds according to any one of the preceding claims, characterized in that the amino acid residues are selected from the group consisting of the residues that are derived from lysine, glycine or aspartic acid.

12. The compounds according to any one of the preceding claims, characterized in that the peptide residues are selected from the group consisting of the dipeptide or tripeptide residues.

13. The compounds according to any one of the preceding claims, characterized in that the heterocyclic radicals are selected from the group consisting of the piperidino, morpholino, pyrrolidino or piperazino radicals, optionally substituted in the 4-position by an alkyl radical of 1 to 6 carbon atoms or of mono or polyhydroxyalkyl.

14. The compounds according to any one of the preceding claims, characterized in that the halogen atoms are selected from the group consisting of fluorine, chlorine and bromine.

15. The compounds according to any one of the preceding claims, characterized in that the branched alkyl radical, having from 1 to 20 carbon atoms, is selected from the radicals 2-methylbutyl, 2-methylpentyl, 1-methylhexyl, 3-methylheptyl.

16. The compounds according to any one of the preceding claims, characterized in that the aminoalkyl radical is selected from the aminomethyl, 3-aminopropyl, 6-aminohexyl radicals.

17. The compounds according to any one of the preceding claims, characterized in that the alkynyl radical has from 2 to 6 carbon atoms.

18. The compounds according to any one of the preceding claims, characterized in that the cycloaliphatic radicals of 3 to 6 carbon atoms are selected from the cyclopropyl radical and the cyclohexyl radical.

19. The compounds according to claim 1, characterized in that they are included, alone or in combination, in the group consisting of: 4- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] -benzoic acid; 4- [3- (l-adamantyl) -4-methoxyphenylsulfinyl-methyl] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyphenylmethyl-sulfonyl] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyphenylmethyl-sulfinyl] benzoic acid; 4-13- (l-adamantyl) -4-methoxyphenylsulfonyl-methyl] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyphenylthiocarboxamido] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyphenyl-methylthio] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyphenylmethylamino] -benzoic acid; 4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxyphenyl] -1-propynyl]] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-benzamido] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-benzoyloxy] benzoic acid; (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl] -1-propenyl]] benzoic acid; 4 - [[3-Hydroxy-3 - [3- (1-adamantyl) -4-methoxyethoxymethoxyphenyl] -1-propynyl]] benzoic acid; 4- [3- (l-adamantyl) -4- (2,2-dimethyl-l, 3-dioxolan-4-methyl-oxy) phenylcarboxamido] benzoic acid; 4- [3- (l-adamantyl) -4- (2,3-dihydroxy-propyloxy) phenylcarboxamido] benzoic acid; 4- [3- (l-adamantyl) -4-methoxycarbonylmethyl-oxyphenylcarboxamido] benzoic acid; 2- [3- (l-adamantyl) -4-methoxyphenoxymethyl] -4-thiophenecarboxylic acid; 2- [3- (l-adamantyl) -4-methoxyphenylaminoethyl] -4-thiophenecarboxylic acid; 2- [3- (l-adamantyl) -4-methoxyphenylthiomethyl] -4-thiophenecarboxylic acid; 4- [3- (l-adamantyl) -4- (2,2-dimethyl-l, 3-dioxolan-4-methyloxy) benzoyloxy] benzoic acid; 4- [3-hydroxy-3- [5- (l-adamantyl) -2,4-di-methoxyethoxymethoxyphenyl] -1-propynyl] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxy-benzoylthio] benzoic acid; N-methyl-4- [3- (l-adamantyl) -4-methoxyethoxy-methoxyphenylcarboxamido] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl-thiocarboxamido] benzoic acid; (E) -4- [[3-oxo-3 - [3- (l-adamantyl) -4-methoxymethoxyphenyl] -1-propenyl]] benzoic acid; (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-hydroxyphenyl] -1-propenyl]] benzoic acid; (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxy-phenyl] -1-propenyl]] benzoic acid; (E) -4- [[3-OXO-3 [3- (l-adamantyl) -4- (3-hydroxypropyloxy) phenyl] -1-propenyl]] benzoic acid; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxybenzoyloxy] -benzaldehyde; 4- [3- (l-adamantyl) -4-methoxyethoxymethoxybenzoyloxy] -benzenemethanol; (E) -N-ethyl-4- [[3-OXO-3 [-3- (l-adamantyl) -4-methoxy-ethoxymethoxyphenyl] -1-propenyl]] benzamide; (E) -N- (4-hydroxyphenyl) -4- [[3 -oxo -3- [3- (1-adamantyl) -4-methoxyethoxymethoxyphenyl] -1-propenyl]] benzamide; (E) -4- [[3-OXO-3- [3- (l-adamantyl) -4-methoxyethoxymethoxyphenyl] -1-propenyl]] phenol.

20. The compounds according to claim 1, characterized in that they have at least one of the following characteristics: R. is the radical -COO-R7 or -CO-R6 -R3 is the radical -Y- (CH2) pY- (CH2) q-R8 - (CH2) p- (Y) n- (CH2) q -R8 -Y- (CH3) -RR X represents a bond of formulas (a), (e), (f), (j) , okay) . Ar represents the radical of formula (a) or (b).

21. The compounds according to any of the preceding claims for use as a medicament.

22. The compounds according to claim 21 for use as a medicament for the treatment of dermatological, rheumatic, respiratory, cardiovascular and ophthalmological conditions.

23. Use of at least one of the compounds defined in claims 1 to 20 for the manufacture of a medicament for the treatment of dermatological, rheumatic, respiratory, cardiovascular and ophthalmological conditions.

24. Pharmaceutical composition, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one of the compounds defined in any one of claims 1 to 20.

25. Composition according to claim 24, characterized in that the concentration of compound (s) according to one of claims 1 to 16 is between 0. 001% and 5% by weight with respect to the composition as a whole.

26. Cosmetic composition, characterized in that it comprises, in a cosmetically acceptable support, at least one of the compounds defined in any one of claims 1 to 20.

27. Composition according to claim 26, characterized in that the concentration of compound (s) according to one of claims 1 to 20 is comprised between 0.001% and 3% by weight with respect to the composition as a whole.

28. Use of a cosmetic composition as defined in one of claims 26 or 27 for body or hair hygiene. PF-gpMTüpi OF THE INVENTION The invention relates to novel biaromatic compounds which have as general formula (I): as well as the use of the latter in pharmaceutical compositions intended for use in human or veterinary medicine (mainly dermatological, rheumatic, respiratory, cardiovascular and ophthalmological conditions), or even in cosmetic compositions.