CA2218892C - Diaromatic propynyl or dienyl compounds - Google Patents

Abstract

Novel diaromatic propynyl or dienyl compounds having general formula (I), and the use thereof in pharmaceutical compositions useful in human or veterinary medicine (in particular for the treatment of dermatological, rheumatic, respiratory, cardiovascular and ophthalmological disorders), or in cosmetic compositions, are disclosed.

Description

BIAROMATIC PROPYNYL OR DIENYL COMPOUNDS
The invention relates, as new and useful industrial products, to propynyl or biaromatic dienyl compounds. It also concerns use of these novel compounds in pharmaceutical compositions 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 the differentiation and cell proliferation, and find more apps particularly in the topical and systemic treatment of affections dermatological disorders related to a disorder of keratinization, diseases dermatological (or other) inflammatory and / or immunoallergic, and dermal or epidermal proliferations that they be benign or malignant. These compounds can also be used in the treatment of connective tissue degenerative diseases, to fight against aging of the skin, be it photoinduced or chronological, and To treat cicatrization disorders. They also find a application in the ophthalmological field, particularly in the treatment of corneopathies.
The compounds according to the invention can also be used in compositions cosmetics for body and hair hygiene.
The compounds according to the invention can be represented by the formula General (!) next Ra Ri ~
Ar Rz ~ Xi so (I) in which:
- R1 represents (i) ie radical -CHg (ü) the radical -CH2-O-Rg (iii) the radical -O-Rg (iv) the radical -CO-R ~
Rg and R ~ having the meanings given below,

2 Ar represents a radical chosen from radicals of formulas (a) - (e) following:
R $ ' ta) O. ~ b) S ic) N ~ d) N Life) Rs R5 and Rg having the meanings given below, X represents a radical of formula:
or ~ or Rs Rs Rs Rs Rg and Rg having the meanings given below, - R2 and Rg, identical or different, represent (i) a hydrogen atom, (ü) a linear or branched alkyl radical having from 1 to 20 carbon atoms, (iii) a radical -ORg, (iv) a radical -SRg, Rg having the meaning given below, it being understood that R2 and R3 taken together can form with the cycle adjacent aromatic ring a 5- or 6-membered ring optionally substituted by of the WO 97! 33856 PCTIFR97 / 00390

3 methyl groups and / or optionally interrupted by an oxygen atom or sulfur, and with the understanding that R2 and Rg can not at the same time have the same meanings (i), (iii) and (iv) mentioned above.
o - R4 and Rb, identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical having from 1 to 20 atoms of carbon, a radical -ORg, it being understood that when Rc is a hydroxyl radical then R2 and Rg form with the adjacent aromatic ring a 5- or 6-membered ring possibly substituted by methyl groups and possibly interrupted by an oxygen or sulfur atom, R 6 represents a hydrogen atom, a lower alkyl radical or a radical -COR10 R10 having the meaning given below, R7 represents:
(a) a hydrogen atom {b) a lower alkyl radical (c) a radical of formula:
for R "
w NOT
R ' R 'and R "having the meaning given below, {d) a radical -OR11, (e) a radical -NHORg, R11 having the meaning given below, - Rg and Rg, taken separately, have simultaneously the same meaning 40 a hydrogen atom or a radical -OR10, either one represents an atom of hydrogen and the other a lower alkyl radical or, taken together, form a ring -Y- (CH2) nY-, with Y representing an oxygen or sulfur atom and with n equal to 2 or 3, - R1 p represents a lower alkyl radical, WO 97133856 PCT / F'R97 / 00390

4 R11 represents a hydrogen atom, a linear or branched alkyl radical, having 1 to 20 carbon atoms, an alkenyl radical, a mono radical or polyhydroxyalkyl, an optionally substituted aryl or aralkyl radical) or a residue of sugar or a residue of amino acid or peptide, R 'and R ", which are identical or different, represent a hydrogen atom, a lower alkyl radical, a mono or polyhydroxyalkyl radical, a radical aryl optionally substituted or a residue of amino acid or sugar or taken together form a heterocycle.
The invention also relates to the compounds, which are intermediates of synthesis of compounds of general formula (I), of general formula (II) R ~ a ~ R ~
Ar R'2 H (II) in which R1 and Ar have the same meanings as for the formula General (I) and R'2 and R'4, identical or different, represent an alkyl radical linear or branched having from 1 to 20 carbon atoms.
The invention also relates to the salts of the compounds of formulas (I) and (11) when R1 represents a carboxylic acid function and the geometric isomers and optical of said compounds of formulas (I) and (II).
When the compounds according to the invention are in the form of salts, is preferably salts of an alkali metal or alkaline earth metal, or alternatively zinc or an organic amine.
According to the present invention, the term "internal alkyl radical" means a radical having from 1 to 12, preferably from 1 to 9, carbon atoms, advantageously the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl, nonyl, decyl and dodecyl.
By linear alkyl radical having from 1 to 20 carbon atoms is meant in particular the radicals methyl, ethyl, propyl, pentyl, hexyl, octyl, decyl dodecyl, hexadecyl and octadecyl.
By branched alkyl radical having from 1 to 20 carbon atoms is meant in particular the 2-ethylhexyl, 2-methylbutyl and 2-methylpentyl radicals, 1 Methylhexyl, 3-methylheptyl.

Among the monohydroxyalkyl radicals, a radical having 2 or 3 is preferred.
carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl.
Among the polyhydroxyalkyl radicals, a radical having 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as 2,3-radicals dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl or rest pentaerythritoi.
Among the aryl radicals, a phenyl radical is preferably substituted by at least one halogen atom, a hydroxyl or a function in vitro.
Among the aralkyl radicals, the benzyl or phenethyl radical is preferred.
optionally substituted by at least one halogen atom, a hydroxyl a function vitro.
Among the akenyl radicals, a radical containing from 2 to 5 atoms is preferred.
of carbon and having one or more ethylenic unsaturations, as more particularly the allyl radical.
By sugar residue is meant a radical derived in particular from glucose, galactose or mannose, or else glucuronic acid.
By amino acid residue is meant in particular a residue derived from lysine, glycine or aspaitic acid, and by peptide residue is meant more particularly a residue of dipeptide or tripeptide resulting from the combination of amino acids.
Heterocycle finally is understood to mean preferably a piperidino radical, morpholino, pyrrolidino or piperazino, optionally substituted in the 4-position by a radical C1-C6 alkyl or mono or polyhydroxyalkyl as defined above.
When the radicals R4 and R5 represent a halogen atom, it is of preferably a fluorine, bromine or chlorine atom.
Among the compounds of formula (I) above falling within the scope of the present invention, there may be mentioned the following compounds:
4- [3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1-propynyl] benzoic acid.
- 2-hydroxy-4- [3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1-propynyl] acid benzoic.
4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] acid benzoic.
2-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-methyl propynyl] benzoate.

- 2-Hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid.
- 2-Hydroxy-4- [3- (3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid.
2-hydroxy-4- [3- {5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzenemethanol.
2-hydroxy-4- [3- {5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzoate diethanolamine.
2-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
lithium benzoate.
4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2-propynyl]
benzoic.
2-hydroxy-4- [3- {4,4-dimethylthiochroman-6-yl) -1-propynyl] benzoic acid.
- 2-hydroxy-4- [3- (8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl] acid benzoic.
- 2-Hydroxy-4- [3- (5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1 -acetate propynyl]
benzoic.
4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoate ethyl.
4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzamide.
N-ethyl-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzamide.
- Morpholide of 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid.
N- (4-hydroxyphenyl) -4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propynyl] benzamide.
4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzaldehyde.
4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] phenol.
- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzene methanol.
4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] toluene.

4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl) benzoate hexyl.
N-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzamide.
N-hydroxy-2-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propynyl] benzamide.
2-methyl-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-acid propynyi] benzoic acid.
3-methyl-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-acid propynyl] benzoic acid.
6- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) propa-1,2-acid dienylJnicotinique.
4- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) propa-1,2-acid Dieny (] benzoic acid.
- 2-Hydroxy-4- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) acid propa-1,2-dienyiJbenzoïque.
- 2-Hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-butynyi] benzoic acid.
5- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] -2-pyTidinecarboxy (ic.
4- [3- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl] acid benzoic.
2- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] -4-acid thiophenecarboxy (ic.
2- [3- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl) -acetic acid thiophenecarboxylic acid.
2-hydroxy-4- [3- (3-tert-butyl-4-methoxyphenyl) -1-propynyl] benzoic acid.
2-hydroxy-4- [3- (3-tert-butyl-4-hydroxyphenyl) -1-propynyl] benzoic acid.
Among the compounds of formula ((I) above falling within the scope of the present invention, there may be mentioned the following compounds:

4- [3- (3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene) -1-propynyl] benzoic acid.
2-Hydroxy-4- [3- (3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene) -propynyljbenzoïque.
According to the present invention the compounds of formula (i) or (II) more particularly preferred are those for which at least one of, and preferably all the following conditions are fulfilled R1 represents the radical -CO-R ~, Ar represents the radicals of formula (a) or (e).
More particularly, the preferred compounds of formula (I) are those for which Rg and Rg, taken separately, represent hydrogen atoms, either one represents a hydrogen atom and the other an alkyl radical inferior. Of even more preferably, Rg and Rg represent hydrogen atoms.
The subject of the present invention is also the processes for the preparation of compounds of formulas (I) and (II) above according to the reaction schemes given in Figures 1, 2 and 3.
Thus, the derivatives of formula (Ia) can be prepared (FIG.
Following reactions comprising the action of a benzoyl chloride of formula (1) with a acetylenic derivative of formula (2) in the presence of a Lewis acid (by example AIC13) in a chlorinated solvent, te! dichloromethane. Ketone (3) as well obtained is reduced to alcohol (4) by the action of an alkaline hydride, such as borohydride of sodium, in an alcoholic solvent (for example methanol). The reduction of the carbide alcohol function can be carried out in the presence of iodide triméthyisilane in a solvent such as hexane or by hydride transfer from a silane, such as triethylsilane in the presence of BFg, Et20 in a chlorinated solvent such as chloride of methylene.
The derivatives of formula (la) may also be prepared (FIG.
of reactions comprising the action of a benzoyl chloride of formula (1) with the lithium trimethylacetylenide in the presence of a Lewis acid (e.g.
AlCl3) in a chlorinated solvent, such as dichloromethane. Ketone (5) as well obtained is first reduced to alcohol (6) by the action of an alkaline hydride, such as borohydride of sodium, in an alcoholic solvent (for example methanol) and then carbide (7) for example by hydride transfer from a silane, such as triethylsilane presence of BF3, Et20 in a chlorinated solvent such as methylene chloride.
Then, the compound (7) is coupled with a halogenated derivative (8), preferably iodinated or brominated in the presence of a palladium catalyst [by Bis- (triphenylphosphine) palladium (II) chloride in a solvent, such triethylamine.

The compounds of formula (Ib) can be obtained (FIG. 1) from the derivative ketone (3) by reaction with a glycol (ethylene glycol, propylene glycol) or a dithiol (ethanedithiol, propanedithiol) in the presence of pyridinium tofuenesulfonate in an aromatic solvent te (toluene with azeotropic water formed.
The compounds of formula (Ia) can be further prepared (FIG.
after of reactions comprising the action of trimethylsilyl acetylenide of lithuim on the aldehyde compounds (9) and deprotection with fluoride tetrabutylammonium in THF and obtaining propargyl alcohol (6).
Then, coupling is carried out with a halogenated derivative (8), preferably iodinated or brominated in the presence of a palladium catalyst [e.g.

(triphenylphosphine) palladium (II) in a solvent, such as triethylamine, and reduction of the carbide alcohol function as previously.
The compounds of formula (1c) can be prepared (FIG.
derivatives propargyl alcohol (15) by reducing the carbide alcohol function as Previously. The propargyl derivatives {15) being prepared:
or by action of a boron acetylenide (12) (prepared in situ for phenyl acetylenide of lithuim (11) and boron trifluoride at -78 ° C
in the IT-IF) with a tertiary benzamide of formula (13) in an organic solvent, such as THF
or by action of lithium phenyl acetylenide (11) on the derivatives aldehydic (14).
The compounds of formula (1c) can be prepared (F1G 3) from compounds of formula (11) by the action of an alkaline hydride, such as borohydride of sodium, in an alcoholic solvent (for example methanol). The compounds of formula (II) being prepared by a sequence of reactions from the compounds hydroxybenzaldehydes {16) including the protection of the phenol function by action of 2- (trimethylsilyl) ethoxymethane (SEMCI) chloride (17), then the action trimethylsilyi acetylenide of lithuim (18) and the selective deprotection of trimethylsilyl group carried by acetylenic acid with fluoride tetrabutylammonium in THF and obtaining propargyl alcohol (19).
By coupling with a halogenated derivative (8), preferably iodinated or brominated in the presence Palladium catalyst [eg Bis chloride]
(triphenylphosphine) palladium (11) in a solvent such as triethylamine, gets the compound (20). The cleavage of the protective group (SEM) is carried out with trifluoroacetic acid in a chlorinated solvent, such as methylene.
The subject of the present invention is also, as a medicament, the compounds of formulas (I) and (II) as defined above.
These compounds exhibit activity in the differentiation test of cell (F9) mouse embryonic teratocarcinoma (Cancer Research 43, p.5288, 1983) and / or in the inhibition test of ornithine decarboxylase after induction by TPA in mice (Cancer Research 38, 793-801, 1978). These tests show the activities of the compounds respectively in the fields of differentiation and cell proliferation.
These compounds also have very advantageous kinetic parameters

For the pharmaceutical field compared with other synthetic compounds of the retinoid type (elimination half-life time and residence time of these compounds in the body are low) The compounds of formula (I) or (II) according to the invention are particularly 10 well in the following areas of treatment 1) to treat dermatological conditions related to a disorder of ia keratinization on differentiation and proliferation especially for treat acne vulgaris, comedones, polymorphs, rosaceae, acne nodulocystic, conglobata, senile acnes, secondary acnes such that solar acne, medicated or professional, 2) to treat other types of keratinization disorders, including ichthyosis, ichthyosiform states, Damer's disease, keratoderma 2o pafmoplantaires, leukoplasias and leucopiasiform states, lichen cutaneous or mucous (buccal), 3) to treat other dermatological conditions related to a disorder of the keratinization with an inflammatory and / or immunoallergic component and especially all forms of psoriasis, be it cutaneous, mucous or nail, and even psoriatic rheumatism, or even cutaneous atopy, such as eczema or respiratory atopy or gingival hypertrophy; the compounds may also be used in certain inflammatory conditions not presenting no keratinisation disorder, 4) to treat all dermal or epidermal proliferations they are benign or malignant, whether or not of viral origin such than common warts, flat warts and verruciform epidermodysplasia, Oral or florid papillomatosis and proliferations that can be induced by the ultraviolet, particularly in the case of baso and squamous epithelioma, 5) to treat other dermatological disorders such as dermatitis bullous and collagen diseases,

6) to treat certain ophthalmological disorders, including corneopathies,

7) to repair or fight against skin aging, whether or not Photo-induced or chronological or to reduce pigmentations and keratoses actinic, or any pathologies associated with chronological aging or actinic,

8) to prevent or cure the stigmata of epidermal and / or dermal induced by focal or systemic corticosteroids, or any other form of cutaneous atrophy,

9) to prevent or treat healing disorders or to prevent or to repair stretch marks,

10) to combat sebum function disorders such as hyperseborrhoea of acne or simple seborrhea,

11) in the treatment or prevention of cancerous conditions or precancerous,

12) in the treatment of inflammatory conditions such as arthritis,

13) in the treatment of any condition of viral origin at the cutaneous level, such as Kaposis syndrome, or general,

14) in the prevention or treatment of alopecia,

15) in the treatment of dermatological or general conditions at immunological component,

16) in the treatment of cardiovascular system conditions such as arteriosclerosis or hypertension and non-insulin dependent,.

17) in the treatment of cutaneous disorders due to exposure to UV radiation.
In the therapeutic areas mentioned above, the compounds according to the invention can be advantageously employed in combination with other compounds with retinoid-like activity, with the vitamins D or their derivatives, with corticosteroids, with anti-free radicals, hydroxy or a-keto acids or their derivatives, or else with channel blockers Ionic. By vitamin D or derivatives thereof, for example, derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3. By anti radical fibers, for example, α-tocopherol, superoxide Dismutate, Ubiquinol or certain metal chelants. By oc-hydroxy or a, -acetoacids or their derivatives are, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acid or their salts, amides or esters. Finally, ion channel blockers mean, for example, the Minoxidil (2,4-diamino-6-piperidino-pyrimidine-3-oxide) and its derivatives.
The present invention also relates to compositions medicaments containing at least one compound of formula (I) or (I) such that defined above, one of its optical or geometric isomers or one of its salts.

The present invention therefore thus relates to a new composition medicinal product intended in particular for the treatment of affections mentioned, and which is characterized by the fact that it includes, in a pharmaceutically acceptable and compatible with the mode chosen for the latter, at least one compound of formula (I) or (II), one of its optical or geometric isomers or a salt thereof.
The administration of the compounds according to the invention can be carried out by enteral, parenteral, topical or ocular.
Enterally, medications may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric vesicles for controlled release. By way parenteral, the compositions may be in the form of solutions or suspensions for infusion or injection.
The compounds according to the invention are generally administered at a dose daily intake of approximately 0.01 mg / kg to 100 mg / kg body weight, and this at reason from 1 to 3 shots.
Topically, pharmaceutical compositions based on compounds according to the invention are more particularly intended for the treatment of the skin and of the mucous membranes and can then be presented in the form of ointments, creams, milks, ointments, powders, soaked swabs, solutions, gels, sprays, lotions or suspensions. Elves can also introduce themselves under form of microspheres or nanospheres or lipid or polymeric vesicles or polymeric patches and hydrogels for controlled release.
These compositions topically can also be presented either under anhydrous form, or in an aqueous form, depending on the clinical indication.
Eyes are mainly eye drops.
These compositions for topical or ocular use contain at least one compound of formula (1) or (II) as defined above, or one of its isomers optical or geometric or one of its salts, at a concentration of preference between 0.001% and 5% by weight relative to the total weight of the composition.
The compounds of formula (I) or (II) according to the invention also find a application in the cosmetics field, in particular in hygiene corporeal and capillary and in particular for the treatment of acne-prone skin, for the regrowth of the hair, the anti-fall, to fight against the bold appearance of the skin or hair, in protection against the harmful aspects of the sun or in the treatment of physiologically dry skin, to prevent and / or for fight against photo-induced or chronological aging.

WO 97/33856 PCTIFR97 / 00390 _ In the cosmetic field, the compounds according to the invention can elsewhere advantageously used in combination with other retinoid-type activity, with the D vitamins or their derivatives, with corticosteroids, with anti-free radicals, a.-hydroxy or a-keto acids or their derivatives, or even with ion channel Mockers, all these different products being such as would break above.
The present invention therefore also aims at a cosmetic composition which is characterized by the fact that it comprises, in a cosmetically acceptable and suitable for topical application, at least one compound of formula (!) or (il) as defined above or one of its isomers optical or geometries or one of its salts, this cosmetic composition being especially in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipid or polymeric vesicles, soap or shampoo.
The concentration of compound of formula (I) or (II) in the compositions cosmetics according to the invention is advantageously between 0.001% and 3%
by weight relative to the entire composition.
The medicinal and cosmetic compositions according to the invention may in additionally contain inert additives or even pharmacodynamically or cosmetically active substances or combinations of these additives, and in particular:
wetting agents; depigmenting agents such as hydroquinone, acid azelaic acid, caffeic acid or koic acid; emollients; agents moisturizers such as glycerol, PEG 400, thiamorpholinone, and its derivatives or still urea; antiseborrhoeic or anti-acne agents, such as S
carboxymethylcysteine, S-benzylcysteamine, their salts or derivatives, or the benzoyl peroxide; antibiotics such as erythromycin and its esters, the 3o neomycin, clindamycin and its esters, tetracyclines; agents antifungal agents such as ketoconazole or 4,5-polymethylenes isothiazolidones-3; agents that promote 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 (5,4-diphenyl-imidazolidine 2,4-dione); nonsteroidal anti-inflammatory agents; of the carotenoids and, in particular, (3-carotene), asti-psoriatic agents such as than anthralin and its derivatives; and finally eicosa-5,8,11,14,14-tetraynoic acids and eicosa-5,8,11-trynoic acid, their esters and amides.
The compositions according to the invention may also contain agents flavor enhancers, preservatives such as parahydroxybenzoic acid, stabilizing agents, regulating agents humidity, pH-regulating agents, pressure-modifying agents osmotic agents, emulsifiers, UV-A and UV-B filters, antioxidants, such as α-tocopherol, butylhydroxyanisole or butylhydroxytoluene.

WO 97/33856 ~ PCT / FR97 / 00390 We will now give, as an illustration and without any character limited several examples of obtaining active compounds of formula (I) or (II) according to the invention, as well as various concrete formulations based on such compounds.
In what follows or the above, the percentages are given by weight, except otherwise stated.
hXEMPLE 1 4- (3 - [(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-7-ylidene, -7-pro ~ ynyllbenzoique.
(a) 3,5-di-tert-butyl-4- (2-trimethylsilylethoxymethoxy) benzaldehyde.
In a flask, 12.3 g (52 mmoles) of 3,5-di-wax-butyl-4- was introduced.
hydroxybenzaldehyde and 100 ml of THF. 10 ml (58 ml) are added successively mmol) of diisopropylethylamine and 10.3 ml (58 mmol) of trimethylsilylethoxymethane and refluxed for three hours. We pays the reaction medium in water, extracted with ethyl ether, decant the organic phase, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of ethyl acetate and hexane (3/97% by volume). After evaporation solvents, 15.6 g (82%) of the expected product are collected in the form of a oil colorless.
(b) α-Trimethylsilylethynyl-3,5-di-art-butyl-4- (2-) triméthylsilyléthoxyméthoxy) benzenemethanol.
In a knit, 6.6 ml (46.5 mmoles) of trimethylsilylacetylene are introduced and 50 ml of THF. At -78 ° C. under a stream of nitrogen, add dropwise a solution of 18.6 ml (46.5 mmol) of n-butyllithium (2.5 M in hexane) and we allow to return to room temperature.
This solution is introduced dropwise into a solution of 15.4 g (42.3 mmol) of 3,5-di-wax-butyl-4- (2-trimethylsilylethoxymethoxy) benzaldehyde in 50 ml THF at -8 ° C. The reaction medium is allowed to return to temperature ambient, poured into an aqueous solution of ammonium chloride, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate, and evaporated. 18.5 g (95%) of the alcohol is obtained expected in the form of a yellow oil.
(c) a.-ethynyl-3,5-di-art-butyl-4.
triméthylsilyléthoxyméthoxy) benzenemethanol.
78.5 g (40 mmol) of α, β-trimethylsilylethynyl-3,5-di tert-butyl-4- (2-trimethylsilylethoxymethoxy) benzenemethanol 50 ml THF and we 40 ml (44 mmol) of a solution of fluoride tetrabutylammonium (1.1 M in THF). The mixture is stirred at room temperature hour, the reaction medium is poured into water and extracted with ether.
ethyl acetate, the organic phase is decanted and dried over magnesium, evaporates. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and hexane (5-95 by volume). After After evaporation of the solvents, 13.5 g (88%) of α-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsuloxymethoxy) benzene methanol as an oil colorless.
(d) 4 - [[3-hydroxy-3- [3,5-di-tert-butyl-4- (2-triméthyisilyléthoxyméthoxy) phenyl] -1-Methyl propynyl] benzoate.
In a knit, 6 g (15.4 mmol) of a-ethynyl-3,5-di-tert-butyl-4-(2-trimethylsilylethoxymethoxy) benzenemethanol, 4.1 g (15.4 mmol) of 4-methyl iodobenzoate and 50 ml of triethylamine. We degas the medium Reaction with nitrogen for 30 minutes, then add successively 820 mg (1.2 mmol) of bis (triphenylphosphine) palladium (II) chloride and 360 mg (1.9 mmole) copper iodide. Stir at room temperature for four hours hours, the reaction medium is evaporated to dryness, the residue obtained is taken up by water and ethyl ether. The organic phase is decanted, dried over sulphate magnesium, then evaporate. The residue obtained is purified by chromatography on cotton wool eluted with a mixture of dichloromethane and heptane (80120% by volume), 6.7 g (84%) of 4 - [[3-hydroxy-3- [3,5-di-tert-butyl Methyl 4- (2-trimethylsilylethoxymethoxy) phenyl] -1-propynyl] benzoate mp 91-2 ° C.
(e) 4 - [[3-hydroxy-3- [3,5-di-tert-butyl-4- (2-trimethylsilylethoxymethoxy) -phenyl] -1-propynyl]] benzoic acid.
2.4 g (4.6 mmol) of the preceding ester are introduced into a flask 8.4 g {200 mmol) of lithium hydroxide and 100 ml of THF. It is refluxed during

18 hours and the reaction medium is evaporated to dryness. The residue is taken up water, acidified to pH 1, extracted with ethyl ether, decanted the sentence organic, dried over magnesium sulfate, and evaporated. We triturate residue in heptane, filters and collects 2.2 g (94%) of the expected acid from point of melting 155-6 ° C.
(f) 4- [3- (3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-1-ylidene) -1-propynyl]
benzoic.
In a knit, 2.2 g (4.7 mmol) of 4 - [[3-hydroxy-3- [3,5-diol]
di-tert butyl-4- (2-trimethylsifylethoxymethoxy) phenyl] -1-propynyl] benzoic and 75 ml of dichloromethane. 360 μl (4.7 mmol) of acid are added at -78 ° C.
trifluoroacetic and can go back to room temperature. The reaction medium is poured in water, extracted with ethyl ether, decanted phase organic, it is dried over magnesium sulphate and evaporated. The residue obtained is triturated in heptane, filtered, and then dried. 1.6 g (90%) of 4- [3- (3,5-di-tert-Butyl-4-oxo-2,5-cyclohexadiene-1-ylidene) -1-propynyl] benzoic Point of mp 216-8 ° C.

4- (3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1-, -ropynyl benzoic acid In a knit, 756 mg (2 mmol) of 4- [3- (3,5-di-tert-butyl) oxo-2,5-cyclohexadien-1-ylidene) -1-propynyl] benzoic acid and 50 ml. a mixture (50-50) THF and methanol. At 0 ° C., 152 mg (4 mmol) of sodium borohydride and allowed to warm to room temperature. We pour the reaction medium in water, extracted with ethyl ether, decant the organic phase, dried over magnesium sulfate, and evaporated. The residue obtained is triturated in heptane at reflux, filtered and dried. 510 is collected mg (64%) 4- [3- (3,5-di-tert-butyl-4-hydroxyphenyl) -1-propynyl] benzoic acid of melting point 198-9 ° C.

2- (3,5-di-tari-butyl) -4-oxo-2,5-cyclohexadiene-7-ylidene 2-hydroxy acid pro ~ r ~ ynyl benzoiçrue.

(a) 2-Hydroxy-4- [3-hydroxy-3- [3,5-di-tert-butyl-4- (2-) triméthylsilyléthoxyméthoxy) methyl phenyl-1-propynyl] benzoate.
In a similar manner to Example 1 (d) by reaction of 6.7 g (17.3 mmol) of ethynyl-3,5-di-tert-butyl-4- (2-triméthylsilyléthoxyméthoxy} benzenemethanol with 4.8 g (17.3 mmol) of methyl 2-hydroxy-4-iodobenzoate gives 8.5 g (91%) of the expected ester as a yellow hula.
(b) 2-hydroxy-4 - [[3-hydroxy-3- [3,5-di-butyl-4- (2-trimethylsilylethoxy methoxy) phenyl] -1-propynyl]] benzoic acid.
In a similar manner to Example 1 (e) from 8.4 g (15.5 mmol) of 2-hydroxy-4- [j3-hydroxy-3- [3,5-di-fart-butyl-4- (2-triméthyisilyléthoxyméthoxy) methyl phenyl] -1-propynyl]] benzoate gives 7.4 g (91%) of the acid.
mp 146-7 ° C.
(c) 2-hydroxy-4- [3- (3,5-di-tert-butyl-4-oxo-2,5-cyclohexadiene) ylidene) -1-propynyl] benzoic acid.
In a similar manner to Example 1 (f) from 2.6 g (5 mmol) of 2-4-hydroxy-4 - [[3-hydoxy-3- [3,5-d] -bartyl-4- (2-trimethylsilylethoxymethoxy) phenyl] -1-propynyl] benzoic acid, 1.7 g are obtained (89%) 2-Hydroxy-4- [3- (3,5-di-tert-butyl-4-oxo-2,5-cyclohexadiene) ylidene} -1-propynyl] benzoic melting point 203 ° C and decomposition.

2-hydroxyl acid, ~ 4- (3-i ~ 3 5-di-tert-but ~ h ~ drox ~, ohen ~ l) -7-prop ~~ IJ benzoic.
In a similar manner to Example 2 from 1 g (2.6 mmol of 2-Hydoxy-4- [3- (3,5-di-tert-butyl-4-oxo-2,5-cyclohexadiene-1-yl) ideene) -1-propynyl]
benzoic acid, 510 mg (51%) of 2-hydroxy-4- [3- (3,5-di-tert-butyl-4-hydroxyphenyl) 1-propynylbenzoic acid, m.p. 205-6 ° C.

4- (3- (5,6,7,8-tetrahydro-5,8,8-tereframethyl) -2-naphthalenol, orop-1-yl benzoi'gue.
(a) methyl 4-trimethylsilylethylbenzoate.
In a knit and under a stream of nitrogen, 21.5 g (0.1 mol) of methyl bromobenzoate, 300 ml of triethylamine and a mixture of 200 mg of palladium acetate and 400 mg of triphenylphosphine. Then add g (0.20 mol) of trimethylsilylacetylene, it is gradually heated to 90 ° C
during 1 hour and leave at this temperature for 5 hours. We cool the reaction medium, the salt is filtered and evaporated. We take the residue with 200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. We decant the phase ethereal, washed with water, dried over magnesium sulfate, and evaporated. The The residue obtained is purified by chromatography on a silica column, eluted with of dichloromethane. After evaporation of the solvents, 23 g (100%) of the expected derivative in the form of a colorless oil.
(b) 4- [3-oxo-3- (5,5,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
methyl benzoate.
In a flask, 8.4 g (36 mmol) of chloride of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl, 6.9 g (29.7 mmol) of 4-triméthylsilyléthynyl-methyl benzoate and 100 ml of dichloromethane. It is added at 0 ° C., small amounts, 16.8 g (125 mmol) of AlCl3 and stirred at room temperature for 8 hours. The reaction medium is poured into the ice, extracted with some dichloromethane, the organic phase is decanted, dried over sodium sulfate magnesium, and evaporate. The residue obtained is purified by chromatography on silica column eluted with a mixture of dichloromethane and hexane (50/50 in volume). 6.8 g (61%) of expected product, of melting point 113-4 ° C.
(c) 4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
methyl benzoate.
In a flask was charged with 4.7 g (125 mmol) of the product obtained previously.
and 100 ml of methanol. While cooling to 0 ° C, add successively 5.7 g (150 mmol) of CeC13.7H2O and 530 mg (125 mmol) of sodium borohydride were sodium and stirred at room temperature for 4 hours. We pour the medium reaction in a water-ethyl ether mixture, decanted the organic phase, washed with water, dried over magnesium sulfate, and evaporated. The residue obtained is triturated in 100 ml of hexane, filtered and dried. We collect 4 g (85%) expected product melting point 142-3 ° C.
(d) 4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid.
In a similar manner to Example 1 (e) from 1.7 g (4.5 mmol) of the ester methyl, 1.3 g (79%) of 4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid fusion 146-7 ° C.
(e) 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzoic.
In a knit fabric and under a stream of nitrogen, 2.1 ml (8.1 mmol) of Et 2 O (48%) and 50 ml of dichloromethane. At -20 ° C, 2.6 ml is added (16.2 mmol) of triethylsane and then a solution of 1 g (2.7 mmol) of 4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzoic acid in 30 ml of dichloromethane and stirred at room temperature during 30 minutes. The reaction medium is poured into water and extracted with of ethyl ether, the organic phase is decanted, dried over sodium sulfate magnesium, and evaporate. The residue obtained is purified on a silica column eluted with dichloromethane. After evaporation of the solvents, 780 mg are collected (82%) 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyny1]
benzoic acid melting point 167-8 ° C.

2-hydrox ~ - ~ 4 ~ 3 ~ 5 6 7 $ -tetrahydro-5 8 8-tetramethyl-2-na, ~ htKlL, oro ~, ~ Kl1 methyl benzoafe.
(a) a.-Trimethylsilylethynyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene) methanol.
In a knitted fabric, 17.13 ml (0.121 mol) of trimethylsilylacetylene were introduced.
and 100 ml of THF. At -78 ° C. under a stream of nitrogen, add dropwise a solution of 48.5 m ((0.121 mole) of n-butyl lithium (2.5 M in hexane) and allow to return to room temperature.
This solution is introduced dropwise into a solution of 23.8 g (0.11 mole} of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxaldehyde in 100 ml THF at -78 ° C. We leave the reaction medium back to room temperature, it is poured into an aqueous solution of chloride ammonium chloride, extracted with ethyl ether, decanted the phase organic,

19 it is dried over magnesium sulphate and evaporated. The resulting residue is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and hexane (50/50% by volume). After evaporation of solvents, 29.9 g (86%) of the expected alcohol is collected in the form of an oil.
yellow.
(b) α-ethynyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtha (en) methanol.
29.9 g (95.2 mmol) of α-trimethylsilyiethynyl are introduced into a flask.
(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene) methanol 100 ml THF and added dropwise 103.8 ml (114.2 mmol) of a solution of fluoride tetrabutylammonium (1.1 M in THF). The mixture is stirred at room temperature hour, the reaction medium is poured into water and extracted with ether.
ethyl acetate, the organic phase is decanted, dried over magnesium sulphate, and we evaporate. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and hexane (1/4 by volume).
After solvent evaporation, 18.1 g (79%) of α-ethynyl- (5,8,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene) methanol with a melting point 7 ° C.
(c) 2-hydroxy-4- [3-hydroxy-3- (5,6,7,8-tetrahydroc -5,5,8,8-tetramethyl-2-naphthyl) -1-methyl propynyl] benzoate.
In a similar manner to Example 1 (d) by reaction of 10.3 g (42.5 mmol) of ethynyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene) methanol with 11.8 (42.5 mmol) methyl 2-hydroxy-4-iodobenzoate gives 13.6 g.
{82%) of the expected methyl ester having a melting point of 92-3 ° C.

(d) 2-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyi]
methyl benzoate.
In a similar manner to Example 5 (e) from 1 g (2.6 mmol) of the ester methyl, 210 mg (22%) of 2-hydroxy-4- [3- (5,6,7,8-methyl tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoate melting point 75-7 ° C.

2-hydroxy-4- (3- (5,6,7,8-tetrahydro-5b) -8-tetramethyl-2-naphthalene, r ~ ht ~
-1-, ropwljbenzoique.
(a) 2-Hydroxy-4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-) naphthyl) -1-propynyl] benzoic acid.
In a manner similar to Example 1 (e) from 8.5 g (21.6 mmol) of 2-hydroxy-4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoate of methyl, 7.8 g (95%) of the expected acid of melting point are obtained.
203 °
with decomposition.

(b) 2-Hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid.
In a similar manner to Example 5 (e) from 1 g (2.6 mmol) of 2-hydoxy-4- [3-hydoxy-3- (5,6,7,8-tetrahydro) -5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid, 820 mg (86%) of 2-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl benzoic acid fusion 178-80 ° C.

2-hydroxy-4- (3- ~ (3-hydroxy-5.6-7.8-tetrahydroxy) -5,8-tetramethyl acid, I- ~ ~ phfyl - ~ -, nr, p ~, Kllbenzoi'nue.
(a) 3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromo-naphthalene.
In a knit fabric and under a stream of nitrogen, 720 mg (24 mmol) are introduced.
hydride of sodium (80% in oil and 50 ml of DMF).
solution of 5.7 g (20 mmol) of 3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol dissolved in 75 ml of DMF and stirred until the end of gassing. At 0 ° C., 6.8 ml (59.3 mmol) of chloride of methoxyethoxymethane and stirred for four hours. We pour the medium reaction in water, extracted with ethyl ether, decanted phase organic, dried over magnesium sulfate, and evaporated. We collect 16.6 g (91%) of the expected product as an oil.
(b) 3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl carboxaldehyde.
In a knit fabric and under a stream of nitrogen, 18.3 g (44 mmol) of methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene and 50 ml of THF. At -78 ° C, added dropwise 19.3 ml of n-butyllithium (2.5 M in hexane) and stir 30 minutes, then add 3.7 ml (48.4 mmol) of DMF and allowed to warm to room temperature. We pour the reaction medium in an aqueous solution of ammonium chloride, extracted with ethyl ether, the organic phase is decanted, dried over magnesium sulfate, and evaporated. 13.9 g (100%) of the aldehyde is collected expected in the form of an oil.
c) a.-Trimethylsilylethynyl- (3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene) methanol.
In a similar manner to Example 1 (b) by reaction of 13.5 g (42.1 mmol) of methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-WO 97/33856 PCTIFR97 / 00390 _ naphthylcarboxaldehyde with 7.1 ml (50.6 mmol) of trimethylsilyfacetylene, 17.5 g (100%) of the expected alcohol is obtained in the form of a yellow oil.
(d) a-ethynyl- (3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene) methanol.
In a similar manner to Example 1 (c) from 17 g (40.6 mmol) of Trimethylsilylethynyl- (3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalene) methanol, 12.4 g (88%) of α-ethynyl- (3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene) methanol as an oil.

20 (e) 2-hydroxy-4- [3-hydroxy-3- (3-methoxyethoxymethoxy-5,6,7,8-tetrahydro) Methyl 5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoate.
In a similar manner to Example 1 (d) by reaction of 7.1 g (20.5 mmol) of ethynyl- (3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene) methanol with 5.7 g (20.5 mmol) of 2-hydroxy-4-iodobenzoate methyl, 9.6 g (94%) of the methyl ester is obtained as an oil.
(f) 2-hydroxy-4- [3-hydroxy-3- (3-methoxyethoxymethoxy-5,6,7,8-tetrahydro) -acetate 5,5,8,8-tetramethyl-2-naphthyl} -1-propynyl] benzoic acid.
In a similar manner to Example 1 (e) from 9 g (21.6 mmol) of the ester above, give 7.8 g (89%) of the expected acid from the point of melting 106-8 ° C. ' (g) 2-Hydroxy-4- [3- (3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid.
In a similar manner to Example 5 (e) from 1.7 g (3.5 mmol) of 2-hydroxyoxy-4- [3-hydroxyoxy-3- (3-methoxyethoxymethoxy-5,6,7,8-tetrahydro-5,5,5-tetrahydro);
8, 8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid gives 670 mg (50%) of acid mp 216-7 ° C.

2-hydroxy-3- (5,7,7,8-tetrahydro-5.5.8.8-trimethyl, IY 2-naphthyl) Pro ~~ Lllbenzèneméthanol.
In a knit fabric and under a stream of nitrogen, 760 mg (2.2 mmol) of hydoxy-4- [3- (5,6,7,8-tetrahydro-5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
methyl benzoate and 20 ml of toluene. At -78 ° C. 4.4 ml is added.
hydride dusobutyialuminium (1 M in toluene) and allows to rise to temperature room. 9 ml of methanol are successively introduced, followed by 9 ml of acid hydrochloric acid (1 N), the reaction medium is poured into an acetate mixture of ethyl-water, the organic phase is decanted, dried over sodium sulfate magnesium, then evaporate. The residue is purified by chromatography on silica column eluted with a mixture of ethyl acetate and heptane (50/50%
in volume). After evaporation of the solvents, 200 mg (30%) of alcohol are collected.
mp 94-5 ° C.

2-hydroxy-4-chloro-5.5-tetrahydro-5.5. 8.8-tetramethol I- ~ 2-naphthyl propynyl ~ benzoate diethanolamine.
In a flask, 100 mg (2.76 mmol) of 2-hydroxy-4- [3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid 5 ml of methanol and added 29 mg (2.78 mmol) of diethanolamine. Shake during one hour, the reaction medium is evaporated to dryness and the residue obtained is triturated a mixture of heptane and ethyl ether (50-50). The solid is filtered and dried. We collects 100 mg (78%) diethanolamine salt with a melting point of 100-5 ° C.

2-Hydroxy-4- (3-6,7,8-tetrahydro-5,8,8,8-tetramethylti-2-na, ohtylL) , ~ p ~ nvllbenzoafe of lithium.
In a manner analogous to Example 10 by reaction of 200 mg (5.5 mmol) of 2-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid with 23 mg (5.5 mmol) of lithium hydroxide hydrate, obtains 150 mg (74%) of expected lithium salt of melting point 225-9 ° C.

4- (5-6,8,8-tetrahydro-5,88,8-tetrafamyl) -2α, oht3rl) -2-pro acid, ovnvll benzoi ~ Street.
In a similar manner to Example 5 (e) from 1.66 g (4.6 mmol) 4- [1-Hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2-propynyl] benzoic acid (prepared in Example 10 (b) of Patent EP 0 661 258), obtains 310 mg (19.5%) of 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -2-propynyl] benzoic acid, m.p. 159-60 ° C.

2-hydroxyl-4-yl-4-dimethylthiochroman-6-yl acid R ro ~ o ~~ ~ Services ~ Jbenzoi street In a similar manner to Example 5 (e) from 750 mg (2 mmol) of 2-hydroxy-4- [3-hydroxy-3- (4,4-dimethylthiochroman-6-yl) -1-propynyl] benzoic acid (prepared in the example of EP 0 661 258).
after chromatography on a column of silica eluted with a mixture of dichloromethane and methanol (80-20) 340 mg (28%) of 2-hydroxy-4- [3-(4,4-dimethylthiochroman-6-yl) -1-propynyl] benzoic acid, m.p.
6 ° C.

2-hydroxy acid = 4 -3- (8.8-dimethyl-5-7,6-tetrahydro-2-naphthalene) -9-R ~ ro ~ yn ~ l ~ l6enzoique.
(a) 2-hydroxy-4- [3-oxo-3- (8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl]
methyl benzoate.
In a flask, 12 g (54 mmol) of chloride of 5,6,7,8-dimethyl-tetrahydro-2-naphthoyl 14.7 g (59 mmol) of 2-hydroxy-4-methyl trimethylsilylethynylbenzoate (prepared in Example 5 (a) of the patent 661 258) and 200 ml of dichloromethane. It is added at 0 ° C in small quantities

21.6 g (162 mmol) of AlCl 3 and stirred at room temperature for 8 hours.
The reaction medium is poured into ice and extracted with dichloromethane.
decant the organic phase, dried over magnesium sulfate, evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50-50), 12.5 g (64%) of expected product, mp 114-6 ° C.
(b) 2-hydroxy-4- [3-hydroxy-3- (8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-methyl propynyl] benzoate.
In a flask, 7.95 g (22 mmol) of 2-hydroxy-4- [3-oxo-3-Methyl (8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl] benzoate 150 m (of THF and 20 ml of methanol) 660 mg (17.4 mmol) of sodium borohydride and stirred at room temperature two o'clock. The reaction medium is poured into ice water, neutralized with of hydrochloric acid, extracted with ethyl acetate, decants the phase organic, washed with water, dried over magnesium sulfate, evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (80-20). After evaporation of solvents 3.8 g (47.5%) of expected product are collected in the form of an oil.
(c) 2-hydroxy-4- [3- (8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-methyl propynyl] benzoate.
In a similar manner to Example 5 (e) from 4 g (11 mmol) of the ester methyl, 1.13 g (29.5%) of 2-hydroxy-4- [3- (8,8-dimethyl Methyl 5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl] benzoate as a orange oil.

(d) 2-Hydroxy-4- [3- (8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl]
benzoic.
In a similar manner to Example 1 (e) from 1 g (2.9 mmol) of the ester methyl, 370 mg (39%) of 2-hydroxy-4- [3- (8,8-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl] benzoic melting point 18567 ° C.

2-hydroxy-4-yl-5-dimethoxy-5,8,8-tetrahydro-2-naphthol) -9-~ Ro ~ l ~ QYN lbenzaique.
(a) 2-hydroxy-4- [3-oxo-3- (5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl]
methyl benzoate In a similar manner to Example 14 (a) by reaction of 4.7 g (21 mmol) of 5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthoyl chloride with 5.7 g (22.8 mmol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate (prepared in Example 5 (a) of EP 0 661 258), 5.14 g (68.5%) of the ester is obtained.
expected methyl melting point 89-90 ° C.
(b) 2-hydroxy-4-yl-hydroxy-3- (5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-methyl propynyl] benzoate.
In a similar manner to Example 14 (b) from 2.4 g (6.6 mmol) of 2-hydoxy-4- [3-oxo-3- (5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-methyl propynyl] benzoate gives 1.6 g (67%) of 2-hydroxy-4- [3-hydroxy-Methyl 3- (5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl] benzoate in the form of an orange oil.
(c) 2-Hydroxy-4- [3-hydroxy-3- (5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -propynyl] benzoic acid.
In a similar manner to Example 1 (e) from 1.61 g (4.4 mmof) of the above methyl ester, 1.2 g (77.4%) of the expected acid of point melting point 141-2 ° C.
(d) 2-Hydroxy-4- [3- (5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl]
benzoic.
Analogously to Example 5 (e) from 580 mg (1.65 mmol) of 2-hydroxy-4- [3-hydroxy-3- (5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl] benzoic acid, 470 mg (85%) of 2-hydroxy-4- [3- (5,5-5,6,7,8-tetrahydro-2-naphthyl) -1-propynyl] benzoic melting point 152-3 ° C.

4- (3- (5,6,7,8-tetrahydro-5,8,8-tetramethyl) -2-naphtha, KIL, propylbenzoate 5 of eth, (a) methoxyallene.
In a knit and under argon, 210 ml (2.5 moles) of prapargyl are introduced.
90 mg of methyl ether and 12 g (0.11 mole) of potassium tert-butoxide. We heat to reflux for three hours and distils the reaction medium under pressure atmospheric and collects the fraction at 51 ° C. 153.5 g (88%) of the expected product in the form of a colorless oil.
(B) 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyne.
In a reactor of four liters and under a stream of nitrogen, 20 g (0.82 moles) magnesium activated with 0.1 ml of dibromoethane. We add drop dropwise a solution of 200 g (0.75 mole) of 2-bromo-5,6,7,8-tetrahydro-5,5,8,8 Tetramethylnaphthalene so as to maintain the reflux of THF and stir at 50 ° C
during two hours. The reaction medium is then cooled to -5 ° C.
and adds 1.2 g (8.2 mmol) of CuBr and dropwise introduced a solution of 58 g (0.82 mole) of methoxyallene in 100 ml of THF. Stir one hour at -5 ° C
then allowed to rise to room temperature and stirred for two hours. We pay Reaction medium in a saturated solution of ammonium chloride, extract with ethyl acetate, decant the organic phase, dried over sodium sulphate magnesium, evaporates. The oil obtained is distilled under 0.02 mmHg and collected the fraction rising to 95-100 ° C. 79 g (47%) of the expected product are obtained under form of a colorless oil.
(c) 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoate ethyl.
In a knit fabric and under a stream of nitrogen, 7.4 g (32.7 mmol) of 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyne 8.2 g (29.7 mmol) of ethyl 4-iodobenzoate and 50 ml of triethylamine. We degas the reaction medium by bubbling nitrogen, and introduced 360 mg (0.5 mmol) of Bis (triphenylphosphine) palladium (li) chloride, 130 mg of copper iodide and agitated at room temperature for eight hours. The medium is evaporated to dryness 4o reaction, taken up with ethyl acetate and hydrochloric acid (1 N), decant the organic phase, dried over magnesium sulfate, evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of heptane and of ethyl acetate (70-30). After evaporation of the solvents, one collects a welded triturate in heptane, filter, dry. 9.3 g (84%) of !'ester Ethyl expected mp 59-60 ° C.

WO 97/33856 ~ PCT / FR97 / 00390 4-I3 ~ 5 8.7.8-tetrahydro-5.5.8.8-tetramethyl-2-na, nht-1) -1-, ~ Ero ynvllbenzamide. -(a) 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzoic.
In a similar manner to Example 16 (c) by reaction of 8 g (35.3 mmol) 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyn with 8 g (32.1 mmol) of 4-iodobenzoic acid, 10.4 g (94%) of the expected acid of m.p. 167-8 ° C.
(b) 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynylj benzoyl.
In a flask and under a stream of nitrogen, 2.9 g (8.3 mmol) are introduced.
4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] acid benzoic acid 100 ml of dichloromethane and added dropwise 2.4 ml (12.1 mmol) of dicyclohexylamine. Stir at room temperature for a hour, add dropwise 1.2 ml (11.7 mmol) of thionyl chloride and shake an hour. The reaction medium is evaporated to dryness and the residue is taken up in ether.
ethyl, filter dicyclohexylamine salt, evaporates. We collect 3 g (100%) of crude acid chloride which will be used as it is for the rest of the synthesis.
(c) 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzamide.
3 g (8.3 mmol) of the above acid chloride are introduced into a flask dissolved in 100 ml of THF and added 1 ml (9.1 mmol) of ammonia (32%) and stirred at room temperature for one hour. The reaction medium is poured into water, extracted with dichloromethane, decanted the organic phase, washed with the water, dried over magnesium sulfate, evaporated. The soda obtained is triturated in heptane, filtered, dried. 2.5 g (87%) of 4- [3- (5,6,7,8-tetrahydro) 5,5,8,8-tetramethyl-2-naphthyl) -1-propynylbenzamide melting point 207-8 ° C.

N-eth, ~ j3- ~ 5 6 7 8 -tetrahydro-5.5.8.8-tetramethyl-2-naphthol) -9-prop ~ yrl benzamide.
In a similar manner to Example 17 (b) by reaction of 3 g (8.3 mmol) of 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) chloride) -1-propyny1]
benzoyl with 650 μl (10 mmol) of ethylamine (70%), 1.84 g (59.4%) are obtained.
of ethyl amide expected mp 128-9 ° C.

mor ~ holide of the acid 4-f3- (5 6 7 8 -tetrahydro-5,88-tetramethyl-2-naphth-1) -1-, r ~ ro, o ~ yl benzoiçrue Analogously to Example 17 (b) by reaction of 1.25 g (3.4 mmoles) 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynylj benzoyl with 320NL (3.8 mmol) of morphofine, 430 mg (31%) of the morpholide of 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -propynylbenzoic acid melting point 98-9 ° C.

N-f4-hydrox ~, Ahenyl) -4- ~ 3- (5,6,7,8-tetrahydro-5,8,8-tetramethyl-2-n-htvl) 1-, aro, o, rLnvllbenzamide In a similar manner to Example 17 (b) by reaction of 3 g (8.3 mmol) of 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynylj benzoyl with 1 g (9.2 mmol) of 4-aminophenol, 1.94 g (54%) of N- (4-Hydroxyphenyl) -4- [3- (5,6,7,8-tetrahydro) -5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzamide melting point 159-60 ° C.

4-f3-X5.6.7.8-tetrahydro-5,88-tetramethyl-2-naphthalenyl-l-rop-myl benzenemethanol.
Analogous to Example 16 (c) by reaction of 3.87 g (16.2 mmol) of 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyn with 3.45 g (14.8 mmol) of 4-iodobenzenemethanol gives 4.9 g (100%) of 4-(3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzenemethanol as a viscous orange oil.
1 H NMR (CDCl3, 250 Mf-fz) 1.27 (fiH, s), 1.29 (6H, s), 1.68 (4H, s), 3.77 (2H, s), 4.67 (2H, d), 7.17 (1H Ar, dd), 7.27 (2H Ar, d), 7.30 (2H Ar, d), 7.42;
(2H
Bow).

4-t3- (5,6,7,8-tetrahydro-5,8,8-tetramethyl-2-naphthyl) -9-pro-nynyl, 1 benzaidehvde.
In a flask, 1.3 g (4 mmol) of 4- [3- (5,6,7,8-tetrahydro) 5,5,8,8-tetramethyl-2-naphthyl) -1-propynylbenzenemethanol 20 ml of dichloromethane and added 3.4 g (39.2 mmol) of manganese oxide. We shake at room temperature for eight hours. The reaction medium is added to magnesium sulfate, filter and evaporate the filtrate. The residue obtained is purified by WO 97/33856 PCTlFR97 / 00390 chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10-90). After evaporation of the solvents, 930 mg (29.5%) are collected 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl]
benzaidehyde as a yellow oil.
1 H NMR (CDCl 3, 250 MHz) 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 3.81 (2H, s), 7.20 (1H Ar, dd), 7.31 (2H Ar, c) 7.59 (2H Ar, d), 7.80 (2H Ar, d), 9.99 {1 H, s).

4 f3 ~ (5 6 7 8 fetahydro-5 5 8 8 -fetrameth ~ l-2-na, ~ ht ~ lL, nrop ~~ lyphenol.
In a similar manner to Example 16 (c) by reaction of 1.13 g (5 mmol) 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyne with 1 g (4.5 mmol) of 4-iodophenol, 1.28 g (88%) of 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] phenol as an oil viscous red-orange.
1 H NMR (CDCl 3, 250 MHz) 1.27 (6H, s), 1.29 (6H, s), 1.68 (4H, s), 3.75 (2H, s), 5.05 (1H, s), 6.76 (2H, d), 7.20 (1H Ar, dd), 7.25 (1H, d), 7.31 (b.p. 3H
Bow).

4 ~ 3 f5 6 7 8 Tetra ~ dro 5 5 8 8-tetramét ~ l-2-na ~ nht ~ I ~ prop ~~ IJtoluene.
In a similar manner to Example 16 (c) by reaction of 1.62 g (7.15 mmol) of 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyne with 1.42 g (6.5 mmol) of 4-iodotoluene gives 1.29 g (63%) of 4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] toluene in the form of a yellowish oil.
1 H NMR (CDCl 3, 250 MHz) 1.27 (6H, s), 1.29 (6H, s), 1.69 (4H, s), 2.33 (3H, s).
3.81 (2H, s), 7.20 (1H Ar, dd), 7.31 (2H Ar, c) 7.59 (2H Ar, d), 7.80 (2H Ar, d).

4 j3 ~ 5 6 7 8 tetrahydro 5 5 8 8-tetramethyl-2-naphtha ~ l ~ -9-prop ~ n ~ ~ I ~ ibenzoafe hex, the ~.
In a flask, 2 g (5.8 mmol) of 4- [3- (5,6,7,8 tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid 30 ml of DM1 = 2 drops of 15-crown-5 and 2 g (23.8 mmol) of sodium bicarbonate. We add 3.1 ml (20.8 mmol) of 1-iodohexane and stirred at room temperature for 24 hours. The reaction medium is poured into the water, extracted with acetate of ethyl, decanted the organic phase, washed with water, dried over sodium sulfate magnesium, evaporates. 2 g (80%) of the expected hexyl ester are collected under form of a slightly red oil.
1 H NMR (CDCl 3, 250 MHz) 0.9 (3H, t), 1.27 (6H, s), 1.29 (6H, s), 1.34 (6H, c), 1.66 (4H, s), 1.72 (2H, m), 3.81 (2H, s), 4.30 (2H, t), 7.20 (1H Ar, dd), 7.31; (2H
Bow) 7.50 (2H Ar d) 7.95 (2H Ar, d).

IV-hydroxy 2-h, p-hydroxy-4-yl 5.6.7.8-tetrahydro-5.5.8.8-tetramethyl-2-naphthyl) 1-, aropyn ~ llbenzamide.
(a) N-hydroxy-2-hydroxy-4-iodobenzamide.
23.3 g (84 mmol) of 2-methyl hydroxy-4-iodobenzoate and 360 ml of a solution of sodium (1 N). 8 g (113 mmol) of hydroxylamine hydrochloride are added and stirred at room temperature for two hours. The reaction medium is adjusted to pH
7-8 with concentrated hydrochloric acid, filter the solid. Dissolve solid in ethyl acetate, washed with water, decanted the organic phase, dried over magnesium sulfate, evaporates. The residue is triturated in heptane, filtered, dried.
17.6 g (71.5%) of the expected product with a melting point of 195.degree.
6 ° C.
(b) N-Hydroxy-2-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzamide.
In a similar manner to Example 16 (c) by reaction of 4 g (17.7 mmol) 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyne with 4.1 g (14.7 mmol) N-hydroxy-2-hydroxy-4-iodobenzamide gives 550 mg (10%) N-hydroxy-2-hydroxy-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzamide mp 119-20 ° C.

2-Methyl-2-Methyl-tetrahydrophenyl-2-methoxy-5-tetraethyl-2-naphthalate pro ~ ~ vn llbenzoique.
In a similar manner to Example 16 (c) by reaction of 10 g (44.2 mmol) 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyne with 6.5 g (29.5 mmol) 4-bromo-2-methylbenzoic acid, 1.18 g (11%) is obtained 2-methyl-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl benzoic acid melting point 149-50 ° C.

3-methyl-4-β- (5,7,7-tetrahydro-5.5.8.8-tetramethyl-2-naphthalenol) pro ~ r ~ n ~ l ~ benzoi ~ street.
In a similar manner to Example 16 (c) by reaction of 10 g (44.2 ormoies) 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propyn with 6.5 g (29.5 mmol) 4-bromo-3-methylbenzoic acid, 1.1 g (11%) is obtained.
of 3-methyl-4- [3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl] benzoic acid of melting point 196-7 ° C.

6-6- (5,58,8-tetramethyl-5,6,8,8-tetrahydro-2-na; bht-1Zpropa-1.2-Dieny nicotin ~ ~ ue.
(a) 6- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) propa-1,2-dienyl] methyl nicotinate.
In a similar manner to Example 16 (c) by reaction of 920 mg (4.1 mmol) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-propynyl with 1.1 g (4.2 mmol) of methyl 4-iodonicotinate gives 260 mg (18%) of 6- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro - 2-naphthyl) propa-1,2-dienyl] nicotinate of methyl in the form of an orange oil.
1 H NMR (CDCl 3, 250 MHz) 1.34 (12H, s), 1.75 (4H, s), 3.87 (3H, s), 6.56.
(1H, d), 6.92 (1H, d), 7.19 (1H, d), 7.29 (1H, dd), 7.42 (2H, t), 7.50 (1H, d), 1H, d), 9.10 (1 H, s).
(b) 6- [3- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) propa-1,2-dienyl]
3-nicotinic In a flask, 370 mg (1 mmol) of the methyl ester are introduced previous 10 ml of THF and 5 ml of a methanolic sodium hydroxide solution (2N). We heated at 40 ° C for one hour, evaporated to dryness, taken up by water, adjusts to pH
5 with hydrochloric acid, extracted with ethyl acetate, decanted the organic phase, dried over magnesium sulfate, evaporated. The residue is triturated in heptane, filtered, dried. 240 mg (66%) of the acid expected from point mp 224-5 ° C.

4- (3,5,8,8-tetramethyl-5.6,7,8-fetrahydro-2-naphthyl) -acrylic acid, aa-9.2-dien ~ l) benzoiçrue.
In a flask, 6.02 g (16 mmol) of 4- [3- (5,6,7,8-tetrahydro) Ethyl 5,5,8,8-tetramethyl-2-naphthyl) -1-propynylbenzoate 5 ml of methanol ml of THF and 50 ml of heptane. 850 mg of sodium hydroxide and reflux for one hour. The reaction medium is poured into the water, adjusts to pH 1 with hydrochloric acid extracted with acetate ethyl, decant the organic phase, dried over magnesium sulfate, evaporated. The residue obtained is triturated in ethyl alcohol, filtered, dried. We collect 1.37 g (24.5%) 4- [3- (5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) propa-1,2-dienyl] benzoic acid melting point 227-8 ° C.

2-Hydroxy-4- (3-n) 6 7 8 -tetrahydro-5 ~ 8 8 tetramethyl 2 NaHyIL acid but ~ n ~ l ~ benzotçrue. ' Analogous to Example 5 (e) starting from 1 g (2.55 mmol) of 2-hydroxy-4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -1-butynylbenzoic acid (prepared in Example 30 of Patent EP 0 867 258), 450 mg (47%) of 2-hydroxy-4- [3- {5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) -1-butynylbenzoic acid melting point 191-2 ° C.

In this example, we have illustrated various concrete formulations based on compounds according to the invention.
A- ORAL WAY
(a) 0.2 g tablet Composite of Example 2 0.001 g - 0.114 g starch - Dicalcium phosphate 0.020 g - Silica 0.020 g - Lactose 0.030 g - Talc 0.010 g - magnesium starate 0,005 g (b) Oral suspension in ampoules of 5 ml - Compound of Example 6 0.001 g - Glycerine 0.500 g - 70% sorbitol 0,500 g Sodium saccharin O, plO g - Methyl parahydroxybenzoate 0.040 g - Arome qs - Purified water qs 5 ml (c) 0.8 g tablet - Composite of Example 5 0.500 g - Preglatinis starch 0,100 g - 0.15 g microcrystalline cellulose - Lactose 0.075 g - 0.010 g magnesium starate (d) Oral suspension in 10 ml ampoules - Composite of Example 2 0.05 g - Glycrine 1, OOOg - Sorbitol 70% 1, OOOg - Sodium saccharinate 0.010 g - Methyl parahydroxybenzoate 0.080 g - Arome qs - Purified water qs 10 ml B- ROUTE TOP! (~ EU
(a) Ointment - Compound of Example 9 0.020 g - Isopropyl myristate 81,700 g - Vaseline oil * fluid 9,1008 - Silica ("Aerosil '~'200" sold by DEGUSSA) 9,180 g (b) Ointment - Compound of Example 7 0.300 g - White Vaseline codex 100 g (c) Water-in Cream = Nonionic Oil - Compound of Example 25 0.100 g - Mix of emulsified lanolin alcohols, waxes and oils ("Eucerine * anilydre" sold by BDF) 39,900 g - Methyl parahydroxybenzoate 0.075 g - propyl parahydroxybenzoate 0.075 g - Sterile demineralized water qs 100 g * (trademarks) (d) Lotion - Compound of Example 8 0.100 g - Polyethylene glycol (PEG 400) 89.900 g - 95% ethanol 30,000 g (e) Hydrophobic ointment - Compound of Example 20 0.300 g - Isopropyl Mirystate 36.400 g - Silicone oil ("Rhodorsil * 47 V 300" sold by RHONE-POULENC) 36,400 g - Beeswax 13,, 600 g - Silicone oil ("Abi1 ~ 300.000 cst" sold by GOLDSCHM (DT) 1008 (~ Nonionic Oil-in-Water Cream Composite of Example 30 0.500 g - 4ctylic acid alcohol - Monostarate of glycerol 2,500 g - PEG starate 50 2,500 g - 9,200 g shea butter - Propylene glycol 2,000 g - Methyl parahydroxybenzoate 0.075 g - Propylene parathyhydroxybenzoate 0.075 g - Water of mineralization * (trademarks)

Claims (29)

1. Biaromatic compound, characterized by the fact that it corresponds to the following general formula (I):
in which:
- R1 represents (i) the radical -CH3 (ii) the radical -CH2-O-R6 (iii) the radical -O-R6 (iv) the radical -CO-R7 R6 and R7 having the meanings given below, - Ar represents a radical chosen from the radicals of formulas (a)-(e) following:
R5 and R6 having the meanings given below, - X represents a radical of formula:
R8 and R9 having the meanings given below, R2 and R3, identical or different, represent (i) a hydrogen atom, (ii) a linear or branched alkyl radical having from 1 to 20 carbon atoms, (iii) a radical -OR6, (iv) a radical -SR6, R6 having the meaning given below, it being understood that R2 and R3 taken together can form with the ring aromatic adjacent a 5- or 6-membered ring optionally substituted by from methyl groups and/or optionally interrupted by an oxygen or sulfur, and it being understood that R2 and R3 cannot have at the same time the meanings (i), (iii) and (iv) mentioned above.
- R4 and R5, identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical having from 1 to 20 atoms of carbon, a radical -OR6, it being understood that when R4 is a hydroxyl radical then R2 and R3 form with the adjacent aromatic ring a 5- or 6-membered ring optionally substituted with methyl groups and/or optionally interrupted by an oxygen or sulfur atom, - R6 represents a hydrogen atom, a lower alkyl radical or a radical -COR10 R10 having the meaning given below, - R7 represents:

(a) a hydrogen atom (b) a lower alkyl radical (c) a radical of the formula:
R' and R" having the meaning given below, (d) a radical -ORS11 (e) a radical -NHOR6, R11 having the meaning given below, - R8 and R9, taken separately, either have simul-the same meaning: a hydrogen atom, or one represents a hydrogen atom and the other a radical alkyl having 1 to 12 carbon atoms or, taken together, form a ring -Y-(CH2)nY-, with Y representing an atom of oxygen or sulfur and with n equal to 2 or 3, - R10 represents an alkyl radical having from 1 to 12 carbon atoms, - R11 represents a hydrogen atom, a radical linear or branched alkyl, having from 1 to 20 carbon atoms carbon, an alkenyl radical containing 2 to 5 carbon atoms carbon, a mono or polyhydroxyalkyl radical containing respectively from 2 to 3 or from 3 to 6 carbon atoms, a aryl or aralkyl radical, optionally substituted by a halogen, a hydroxyl or a nitro function, or a residue of sugar derived from glucose, mannose or glucuronic acid or a residue of an amino acid or of peptide derived from lysine, glycine, acid aspartic acid, dipeptide residue or tripeptide residue, - R' and R", identical or different, repre-feel a hydrogen atom, an alkyl radical having from 1 to 12 carbon atoms, a mono or polyhydroxyalkyl radical containing respectively from 2 to 3 or from 3 to 6 atoms of carbon, an aryl radical optionally substituted by a halogen, a hydroxide or a nitro function, or a residue amino acid derived from lysine, glycine, aspartic acid, dipeptide or tripeptide residue, or sugar derived from glucose, mannose and glucuronic acid, or taken together form a heterocycle, as well as their salts and their optical isomers and geometric. 2. Compound characterized by the fact that it meets the following general formula (II):
in which R1 and Ar have the same meanings as for the general formula (I) defined in claim 1 and R'2 and R'4, identical or different, represent a linear or branched alkyl radical having from 1 to 20 atoms of carbon. 3. Compound according to claim 1 or 2, characterized by the fact that it is in the form of salts of a metal alkali or alkaline-earth, zinc or an amine organic. 4. Compound according to claim 1, characterized by the fact that it is taken, alone or mixed, in the group consisting of:
- 4-[3-(3',5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid - 2-Hydroxy-4-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-propynyl] acid benzoic - 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl] acid benzoic - 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-methyl propynyl]benzoate.
- 2-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-acid propynyl]benzoic acid.
-2-Hydroxy-4-[3-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-acid) naphthyl)-1-propynyl]benzoic acid - 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl] benzenemethanol - 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl] diethanolamine benzoate - 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl] lithium benzoate - 4-(3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl acid]
benzoic - 2-Hydroxy-4-[3-(4,4-dimethylthiochroman-6-yl)-1-acid propynyl]benzoic acid -2-Hydroxy-4-[3-(8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-acid propynyl] benzoic acid -2-Hydroxy-4-(3-(5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-acid propynyl] benzoic acid - 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate of ethyl - 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]
benzamide - N-ethyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]
benzamide - 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-acid morpholide) naphthyl)-1-propynyl]benzoic acid - N-(4-hydroxyphenyl)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide - 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]
benzaldehyde - 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]phenol - [3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzene methanol - 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]toluene - 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate of hexyl - N-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl] benzamide - N-hydroxy-2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzamide - 2-Methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-acid propynyl]benzoic acid - 3-Methyl-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-acid propynyl]benzoic acid -6-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro--2-naphthyl)propa-1,2-acid dienyl]nicotinic - 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro--2-naphthyl)propa-1,2-acid dienyl]benzoic acid - 2-hydroxy-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro--2-naphthyl) acid propa-1,2-dienyl]benzoic acid -2-Hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-acid butynyl}benzoic acid - 5-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl}-2-acid pyridinecarboxylic - 4-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-propynyl} acid benzoic - 2-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl}-4-acid thiophenecarboxylic - 2-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1-acid propynyl]-4-thiophenecarboxylic - 2-Hydroxy-4-[3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl]benzoic acid and -2-Hydroxy-4-[3-(3-tert-butyl-4-hydroxyphenyl)-1-propynyl]benzoic acid. 5. Compound according to claim 2, characterized by the the fact that it is taken from the group consisting of:
- 4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadiene-1-ylidene)-1-acid propynyl]benzoic and - 2-Hydroxy-4-[3-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadiene-1-acid) ylidene)-1-propynyl]benzoic acid. 6. Compound according to claim 1 or 2, characterized by the fact that it has at least one of the characteristics following:
- R1 represents the radical -CO-R7, - Ar represents the radicals of formula (a) or (e). 7. Compound according to claim 1 or 2, characterized by the fact that it presents all the characteristics following:
- R1 represents the radical -CO-R7, - Ar represents the radicals of formula (a) or (e). 8. Compound according to one of claims 1, 3 or 6, characterized in that it has a formula (I) as defined in claim 1 wherein R8 and R9, taken separately, either represent atoms of hydrogen, or one represents a hydrogen atom and the other a lower alkyl radical. 9. Compound of formula (I) or (II) according to any of claims 1 to 8, for use as medication. 10. Compound according to claim 9, for use as a drug for the treatment of ailments dermatological related to a disorder of keratinization on differentiation and proliferation. 11. Compound according to claim 9, for treating acne vulgaris, comedonian, polymorphic, rosacea, nodulocystic acne, conglobata, senile acne, secondary acne. 12. A compound according to claim 9, for treating other types of keratinization disorders, selected in the group consisting of ichthyosis, the states ichthyosiformes, Darier's disease, keratoderma palmoplantar, leukoplakia and leuco-plasiform, cutaneous or mucosal (oral) lichen. 13. A compound according to claim 9, for treating other dermatological conditions related to a disorder of keratinization with an inflammatory component and/or immuno-allergic and all forms of psoriasis that it either cutaneous, mucous or nail; psoriatic arthritis;
cutaneous atopy; respiratory atopy or hypertrophy gingival. 14. A compound according to claim 9, for treating all the dermal or epidermal proliferations that they be benign or malignant, whether or not they are of viral origin, oral or florid papillomatosis and the proliferations that can be induced by ultra-purple. 15. A compound according to claim 9, for treating bullous dermatoses and collagen diseases. 16. A compound according to claim 9, for treating certain ophthalmological disorders. 17. Compound according to claim 9, for repairing or fight against skin aging, whether photoinduced or chronological or to reduce pigmentations and actinic keratoses, or all pathologies associated with chronological aging or actinic. 18. Compound according to claim 9, for preventing or cure the stigmata of epidermal atrophy and/or dermal induced by local corticosteroids or systemic, or any other form of skin atrophy. 19. Compound according to claim 9, for preventing or treat wound healing disorders or to prevent or repair stretch marks. 20. A compound according to claim 9, for promoting the healing, to fight against disorders of the sebaceous function. 21. A compound according to claim 9, for the treatment or the prevention of cancerous or precancerous conditions. 22. A compound according to claim 9, for the treatment inflammatory conditions for the treatment of any affection of viral origin at the cutaneous or general levels. 23. A compound according to claim 9, for the treatment immune-component dermatological conditions;
for the treatment of disorders of the cardio-vascular. 24. A compound according to claim 9, for the treatment skin disorders due to radiation exposure UV. 25. Pharmaceutical composition, characterized by the fact that it comprises, in a pharmaceutically carrier acceptable, at least one of the compounds as defined in any of claims 1 to 8. 26. Composition according to claim 25, characterized in what the concentration of compound(s) according to one any one of claims 1 to 8 is between 0.0001% and 5% by weight relative to the whole composition. 27. Cosmetic composition, characterized by the fact that it comprises, in a cosmetically acceptable, at least one of the compounds as defined in any of claims 1 to 7. 28. Composition according to claim 27, characterized in what the concentration of compound(s) according to one any one of claims 1 to 8 is between 0.001% and 3% by weight relative to the whole composition. 29. Use of a cosmetic composition such as defined in any one of claims 27 or 28 for body or hair hygiene.