NZ331458A - Use of 7-Adamantyl-naphth-2-yl(hetero)aryl carboxylic acids, derivatives thereof (retinoid analogues) in preparing medicaments; compounds having a polyether radical bound to a moiety of at least two carbon atoms in position-beta - Google Patents

Abstract

A retinoid analogue or a salt thereof or its chiral analogues has the formula (I) wherein: R1 is methyl, CH2OH, -OR3 or -CO-R4; Ar is a radical of formula (a) to (d); R2 is a polyether radical having carbon in the position a to the carbon which is in the 6th position of the naphthyl radical; R3 is H, alkyl or -(CH2)m(CO)n-R8; R4 is H, alkyl, -N(R')(R"), or -OR9; R5 is H or halogen, alkyl, hydroxy, -OR9 or -OCOOR10; R8 is alkyl or a saturated heterocycle; R9 is H, alkyl, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl or a sugar residue, amino acid or peptide residue; R10 is alkyl; R' and R" are independently H, alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl, or a sugar residue, amino acid or peptide residue or together can form a saturated heterocycle and m is 1 to 3. The compound is useful in treating disorders and/or aliments related to an over-regulation of RAR receptors and/or a hypervitaminosis A.

Description

NEW ZEALAND PATENTS ACT, 1953 No: Divided out of NZ 286444 Date: Filed on 24 April 1996 COMPLETE SPECIFICATION USE OF RETINOIDS IN A COSMETIC COMPOSITION We, CENTRE INTERNATIONAL DE RECHERCHES DERMATOLOGIQUES GALDERMA, a French company, 635, route des Lucioles, Sophia-Antipolis 06560 Valbonne, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: 1 (followed by page la) INTELLECTUAL property office i of n.z. | 19 AUG 1998 la This is a divisional application of nIm Zealand^ ^ Patent Specification No. 286444.

The present invention relates to compounds of retinoid type useful as active agents in compositions for the treatment of disorders and/or ailments related to an overregulation of RAR receptors and/or to a hypervitaminosis A.

The invention of NZ 286444 relates to the use of such compounds for the manufacture of pharmaceutical compositions.

It is known that retinoic acid and some of its analogues (also known as retinoids) are capable of inducing differentiation of embryonic teratocarcinoma cells (F9) in mice. Secretion of the plasminogen activator which accompanies this differentiation is an index of the biological response of F9 cells to retinoids. It is also known that the ability of these retinoids to induce the plasminogen activator directly correlates with the affinity which they have for RAR (retinoic acid receptors) receptors endogenous to F9 cells (Skin Pharmacol., 1990, 3, pp. 256-267).

It is also known that dermatological, rheumatic, respiratory, cardiovascular, osseous or alternatively ophthalmological disorders or ailments axe in particular' related to an overregulation (overexpression or overactivity) of RAR receptors and/or to a hypervitaminosis A (presence in the body of an abnormal amount of vitamin A or of its metabolites) . Thus, the advantage of finding compounds which will inhibit the biological effects of an overregulation of RAR receptors and/or of a hypervitaminosis A is understood.

In an entirely surprising and unexpected way, the Applicant Company has found that certain compounds of retinoid type do not induce differentiation of these F9 cells but, however, become bound to RARs, this binding being of the antagonist type.

The invention of NZ 286444 therefore relates to a use of an effective amount of at least one compound of retinoid type of formula (I) as active agent in a cosmetic composition, the said compositions being intended for the treatment of disorders or ailments related to an overregulation of RAR receptors and/or to a hypervitaminosis A.

These compounds have a general formula (I): 2 in which: Rx represents (i) the -CH3 radical (ii) the -CH2OH radical (iii) the -0-R3 radical (iv) the -CO-R4 radical R3 and R4 having the meanings given below, - Ar is a radical of formula: R, / N II (a) (b) (c> R5 having the meaning given below, (d) - R2 represents: (a) an - (X) n- (CH2) p-Rs radical (b) an - (X) n-(CH2) q-R7 radical (c) a -CH=CH- (CH2) s-R6 radical (d) a -CH=CH-(CH2) t-R7 radical R6, R7, X, n, p, q, s and t having the 30 meanings given below, it being understood that: - R3 represents a hydrogen atom, a lower alkyl 35 radical or a - (CH2) m-(CO) n-R8 radical, R8, m and n having the meanings given below, 3 - R4 represents: (a) a hydrogen atom, (b) a lower alkyl radical, (c) a radical of formula: ^R' I R" (d) an -0R9 radical, R', R" and R9 having the meanings given below, - R5 represents a hydrogen or halogen atom, a linear or branched alkyl radical having from 1 to 20 15 carbon atoms, a hydroxy1 radical or an -OR10 or -OCOR10 radical, R10 having the meaning given below, - R6 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, an alkenyl radical or an alkynyl radical, - R7 represents an aryl radical, a mono- or polyhydroxyalkyl radical in which the hydroxyls are optionally protected in the methoxy or acetoxy or acetonide form, an aminoalkyl radical in which the amine" functional group is optionally substituted by one or two lower alkyl groups, a polyether radical, a -COR4 radical, a saturated or unsaturated heterocycle radical or alternatively an aminoaryl radical, - Rs represents a lower alkyl radical or a saturated heterocycle, - Rg 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 40 radical or a sugar residue or an amino acid or peptide residue, - R10 represents a lower alkyl radical, 4 - X represents an oxygen atom or an -S(0)r radical, - R' and R", which are identical or different, 5 represent a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally substituted aryl radical or an amino acid, peptide or sugar residue or alternatively, taken together, form a saturated heterocycle, - m is an integer between 1 and 3 inclusive, - n is an integer between 0 and 1 inclusive, 15 - p is an integer between 5 and 12 inclusive, - q is an integer between 0 and 12 inclusive, - r is an integer between 0 and 2 inclusive, - s is an integer between 3 and 10 inclusive, - t is an integer between 0 and 10 inclusive, 2 5 as well as their salts and their chiral analogues.

These compounds of formula (I) can therefore also be salts, when Rx or R7 represents a carboxylic acid functional group and when R7 represents an amine 30 functional group, and the chiral analogues and the geometrical isomers of the said compounds of formula (I). When the compounds according to the invention are provided in the form of salts, they are preferably salts of an alkali metal or alkaline-earth metal or 35 alternatively of zinc or of an organic amine.

According to the present invention, lower alkyl radical is understood to mean a radical having from 1 to 6 carbon atoms and preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals. 40 Mention may in particular be made, among linear or branched alkyl radicals having from 1 to 20 carbon atoms, of the methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.

Preference is given, among monohydroxyalkyl radicals, to a radical having from 1 to 6 carbon atoms, in particular a hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.

Preference is given, among polyhydroxyalkyl radicals, to a radical containing from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals or the 10 pentaerythritol residue.

Preference is given, among aryl radicals, to a phenyl radical optionally substituted by at least one halogen atom, one hydroxyl or one nitro functional-group. Thus, preference is given, among aminoaryl 15 radicals, to an aminophenyl radical optionally substituted by at least one halogen atom, one hydroxyl or one nitro functional group.

Preference is given, among aralkyl radicals, to the benzyl or phenethyl radical optionally 20 substituted by at least one halogen atom, one hydroxyl or one nitro functional group.

Alkenyl radical is understood to mean a radical preferably containing from 2 to 5 carbon atoms and having one or a number of ethylenic unsaturations, 25 such as more particularly the allyl radical.

Sugar residue is understood to mean a residue deriving in particular from glucose, from galactose or from mannose or alternatively from glucuronic acid.

Amino acid residue is understood to mean in 30 particular a residue deriving from lysine, from glycine or from aspartic acid and peptide residue is understood to mean more particularly a dipeptide or tripeptide residue resulting from the combination of amino acids.

Saturated heterocycle is preferably 35 understood to mean a piperidino, morpholino, pyrrolidino or piperazino radical, optionally substituted in the 4 position by a C^-Cg alkyl or mono-or polyhydroxyalkyl radical as defined above.

Unsaturated heterocycle is preferably 40 understood to mean a pyridine, furan or thiophene radical.

Preference is given, among halogen atoms, to a fluorine, chlorine or bromine atom.

Aminoalkyl radical is understood to mean a 45 radical preferably containing from 1 to 6 carbon atoms, 6 in particular the aminomethyl, 3-aminopropyl and 6-aminohexyl radicals.

Polyether radical is understood to mean a radical preferably containing from 1 to 6 carbon atoms, 5 in particular the methoxymethoxy, methoxyethoxy, methoxyethoxymethoxy, methoxymethoxyethyl, methoxymethoxypropyl and methoxyhexyloxy radicals.

Alkynyl radical is understood to mean a radical preferably having 2 to 6 carbon atoms, in 10 particular a propargyl radical.

When the Rs radical represents a halogen atom, the latter is preferably a fluorine, bromine or chlorine atom.

Mention may in particular be made, among the 15 compounds of formula (I) above, of the following: 2-Hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoic acid. 2-Hydroxy-4-[7-(1-adamantyl)-6-hexyloxy-20 2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid. -[7-(1-Adamantyl)-6-benzyloxy-2-naphthyl]-2-thiophenecarboxylic acid. 4-[7-(1-Adamantyl)-6-benzyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-benzyloxycarbonyl-2-naphthyl]benzoic acid. 2-Hydroxy-4-[7-(1-adamantyl)-6-(4-fluorobenzyl)oxy-2-naphthyl]benzoic acid. 6- [7-"(1-Adamantyl) -6-methoxyethoxymethoxy-2-naphthyl]nicotinic acid. 4-[7-(1-Adamantyl)-6-heptyloxy-2-naphthyl]benzoic acid. 2-Hydroxy-4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid. 35 2-Chloro-4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-hydroxyhexyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-hydroxypropyl-2-naphthyl]benzoic 40 acid. 4-[7-(1-Adamantyl)-6-hydroxyoctyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-hydroxyethyl-2-naphthyl]benzoic acid. 7 4-[7-(1-Adamantyl)-6-hydroxyheptyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-hydroxypentyloxy-2-naphthyl]benzoic acid. 5 4-[7-(1-Adamantyl)-6-(4-morpholino)ethyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-(1-piperidino)ethyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-carbamoylpentyloxy-10 2-naphthyl]benzoic acid. 4 - [7 - (1-Adamantyl) -6-ethoxycarbonylpentyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-ethoxycarbonylbu tyloxy-2-naphthyl]benzoic acid. 15 4-[7-(1-Adamantyl)-6-carboxypentyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-carboxybutyloxy-2-naphthyl]benzoic acid. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-20 2-naphthyl]benzenemethanol. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthy1]benzaldehyde. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid morpholide. 25 N-Ethyl-4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthylJbenzamide. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzamide.

N-(4-Hydroxyphenyl)-4-[7-(1-adamantyl)-30 6-methoxyethoxymethoxy-2-naphthyl]benzamide. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoylpiperazine.

Propyl 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoate. 35 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]phenyl acetate. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]phenol. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-40 2-naphthyl]phenoxyethylmorpholine hydrochloride. 4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]phenoxyethylpiperidine hydrochloride.

Hexyl 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoate. y -* •J3 i s N- [ [4- [7- (1-Adamantyl) -6-methoxyethoxymethoxy-2-naphthyl]benzoyl]]glutamic acid. 4- [7- (1-Adamantyl) -6-methoacyhe2cylo3cy-2-naphthyl]benzoic acid. 4 - [7 - (1-Adamantyl) -6-methoxymethoxvpropyl-2-naphthyl]benzoic acid. 4- [7- (1-Adamantyl) -6-methoxymethoxyethyl-2-naphthyl]benzoic acid. 1 q According to the invention of NZ 286444, the more particularly used compounds of formula (I) are those in which: - Rx is the —CO—R4 radical, - R2 is the - (X) n-(CH2) p-Rs or -(X)n-(CH2)q-R7 radical Ar represents the radical of formula (a) or (b) .

T^-e present invention relates to a preferred subset of the compounds used in the invention of NZ 286444, that is to the compounds of formula (I) in which R2 is a polyether radical having a carbon in the position a to the carbon which is in the 6 position of the naphthyl radical. These compounds 25 prove to be very advantageous because they do not seem to be able to be metabolically modified, when they are administered, to compounds of retinoid type which induce differentiation of these F9 cells and which I INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 APR 2001 RECEIVED become bound to RARs, this binding being of the agonist type.

Preferred polyether radicals include methoxymethoxyethyl and methoxymethoxypropyl radicals. compounds, to 4- [7- (1-adamantyl)-6-methoxymethoxy-propyl-2-naphthyl]benzoic acid and to 4-[7-(1-adamantyl)-6-methoxymethoxyethyl-2-naphthyl]benzoic acid.

The compounds of formula (I) including those of the present invention can in particular be obtained: halogenated derivative (1) and a halogenated derivative Preference is given, among these new - Either by a coupling reaction between a (2) : > Ad Ar INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 6 MAR 2001 K IE GLOVED X and Y representing a chlorine, bromine or iodine atom. In a first step, the halide (1) is converted to a lithium or magnesium derivative and then to a zinc derivative and is coupled to the derivative (2) in the presence of a nickel or palladium catalyst, according to the biaryl coupling conditions described by E. Negishi et al., J. Org. Chem. (1977), 42, 1821.

- Or by a coupling reaction between a boronic acid (3) and a halogenated derivative (2): The coupling reaction is carried out in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)palladium, according to the conditions described by N. Miyaura et al., Synthetic Communications (1981), 11(7), 513-519.

The boronic acid derivative (3) can be obtained, for example, from the halogenated derivative (1) by 11 conversion to a lithium derivative, then reaction with trimethyl borate and hydrolysis.

In these formulae, Rx, R2 and Rs have the same meanings as those given above for the general formula (I) or are derivatives thereof which are suitably protected in order to be compatible with the coupling conditions.

In particular, when Rx represents the -COOH radical, the compounds are prepared by protecting Rx with a protective group of alkyl, allyl, benzyl or tert-butyl type.

Conversion to the free form can be carried out: - in the case of an alkyl protective group, by means of sodium hydroxide or of lithium hydroxide in an alcoholic solvent, such as methanol, or in THF, - in the case of an allyl protective 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 protective group, by debenzylation in the presence of hydrogen by means of a catalyst such as palladium-on-charcoal, - in the case of a protective group of tert-5 butyl type, by means of trimethylsilyl iodide.

When R2 represents the -(CH2)p-R6, -(CH2)q-R7, -CH=CH- (CH2) s-R6 or -CH=CH- (CH2) t-R7 radicals, the compounds can be obtained from the corresponding phenol derivatives (with R2 representing the -OH radical), 10 which are converted to triflate derivatives and then by nucleophilic substitution in the presence of a palladium catalyst according to the general conditions described by: S. Cacchi et al., Tetrahedron Letters, 15 1986, 27, 3931-3934.

W. J. Scott et al., J. Org. Chem., 1985, 50, 2302-2308.

J. K. Stille et al., J. Am. Chem. Soc. , 1987, 109, 5478-5486.

The cosmetic and pharmaceutical compositions containing at least one compound of formula (I) are therefore intended for the treatment of disorders or iii\i lL'.ZCTUaL PROPER OFFICE OF N.Z. 1 6 MAR 2001 13 ailments related to an overregulation of RAR receptors and/or to a hypervitaminosis A.

Overregulation of RAR receptors is understood to mean according to the invention an overexpression of RAR receptors and/or a biological overactivity of RAR receptors.

The biological overactivity of RAR receptors can be due to a chemical modification of the RAR receptors but it can also be due to a factor other than the receptor itself. Thus, the biological overactivity can be due to the overexpression of an endogenous gene or to the expression of an exogenous gene comprising the RARE (retinoic acid response element) response element to which a heterodimer comprising the RAR receptor comes to be bound, the latter carrying an agonist ligand. Mention may be made, as an example of the overexpression of an endogenous gene comprising the RARE response element, of the CRABP II (cellular retinoic acid binding protein II) gene, the overexpression of which has been demonstrated in psoriasis ("Overexpression of CRABP II and down-regulation of CRABP I in psoriatic skin", G. 14 Siegenthaler et al., Dermatology 1992, 185, 251-256). Mention may be made, as examples of the expression of an exogenous gene comprising the RARE response element, of the HIV-1 (human immunodeficiency virus) genome (Proc. Natl. Acad. Sci. USA, Lee et al., Vol. 91, pp. 5632-5636, June 1994) or of the genome of the hepatitis B virus ("Retinoid X receptor RXR alpha binds to and trans-activates the hepatitis B virus enhancer", B. Huan et al., Proc. Natl. Acad. Sci. USA, 1992, 89 (19), p 9059-63).

These disorders and/or ailments related to an overregulation of RAR receptors and/or to a hypervitaminosis A are most often reflected by an inflammatory, allergic and/or immunological component. They are more particularly present in the following pathologies or disorders: 1) acne vulgaris, comedonic or polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acnes such as solar, medicinal or occupational acne, 2) other types of disorders of keratinization, in particular ichthyoses, ichthyosiform conditions, Darrier's disease, palmoplantar keratoderma, leucoplakia and leucoplakiform conditions or cutaneous or mucosal (oral) lichen, 3) other dermatological conditions linked to a disorder of keratinization with an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, either cutaneous, mucosal or ungual, and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema, or respiratory atopy or alternatively gingival hypertrophy, 4) certain inflammatory conditions which do not show disorder of keratinization, such as arthritis, ) dermal or epidermal proliferations, whether they are benign or malignant or whether they are or are not of viral origin, such as common warts, flat warts and epidermodysplasia verruciformis, florid or oral papillomatoses and the proliferations which can be induced by ultraviolet radiation, in particular in the case of basal cell and prickle cell epithelioma, 6) other dermatological disorders, such as bullous dermatoses and collagen diseases, 16 7) certain ophthalmological disorders, in particular corneopathies, 8) ageing of the skin, whether photoinduced or chronologic, or actinic keratoses and pigmentations or any pathology associated with chronologic or actinic ageing, 9) the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy, ) disorders of healing or stretch marks, 11) disorders of the sebaceous function such as hyperseborrhoea of acne or simple seborrhoea, 12) cancerous or precancerous conditions, 13) condition of viral origin at the cutaneous or general level (human immunodeficiency virus, HIV-1, or hepatitis B virus), 14) alopecia, ) ailments of the cardiovascular system such as arteriosclerosis, In the context of the invention, the compounds of formula (I) can advantageously be employed in combination with other compounds possessing a retinoid-type activity, with vitamins D or their derivatives, with corticosteroids, with compounds which control free radicals, a-hydroxy or a-keto acids or their derivatives, or alternatively with ionic channel 5 blockers. Vitamins D or their derivatives is understood to mean, for example, derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3. Compounds which control free radicals is understood to mean, for example, cc-tocopherol, Super Oxide Dismutate, ubiquinol 10 or certain metal chelating agents. ct-Hydroxy or a-keto acids or their derivatives is understood to mean, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or their salts, amides or esters. Finally, ionic channel blockers is 15 understood to mean, for example, minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives.

The cosmetic and pharmaceutical composition, comprising an effective amount of at least one compound 2 0 of formula (I), one of its chiral analogues or alternatively one of its salts comprises a cosmetically INTELLECTUAL PROPERTY OFFICE Or N.Z. 1 6 MAR 2001 iEOEHWEi and pharmaceutically acceptable vehicle which is compatible with the method of administration used.

The effective amount, which of course depends on the treatment desired and on the nature of the 5 compound chosen, is thus determined by the person skilled in the art.

The administration of the compounds according to the invention can be carried out enterally, parenterally, topically or ocularly. 10 For enteral administration, the composition, more particularly the pharmaceutical composition, can be provided in the form of tablets, hard gelatin capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions or polymeric or lipid 15 microspheres or nanospheres or vesicles which make possible controlled release. For parenteral administration, the composition, can be provided in the form of solutions or suspensions for perfusion or for 20 injection.

The compounds according to the invention are generally administered at a daily dose of approximately lisVi:L'.EC"! 'JaL prop:.; OFFICE OF N.Z. 1 6 MAR 2001 19 0.01 mg/kg to 100 mg/kg by body weight, at the rate of 1 to 3 intakes.

For topical administration, the composition is more particularly intended for treating the skin and the mucosal membranes and can then be provided in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions; suspensions or shampoos. It can also be provided in the form of polymeric or lipid vesicles or nanospheres or microspheres or of polymeric patches and of hydrogels which make possible controlled release. This composition for topical administration can moreover be provided either in anhydrous form or in an aqueous form.

For ocular administration, they are mainly eye washes.

This composition for topical or ocular use contains at least one compound of formula (I) as defined above, or one of its chiral analogues or alternatively one of its salts, at a concentration preferably of between 0.001 % and 5 % by weight with respect to the total weight of the composition.

The composition according to the invention can additionally contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and especially: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; hydrating agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or alternatively urea; anti-seborrhoeic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts or their derivatives, or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, clindamycin and its esters, or tetracyclins; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; agents promoting hair regrowth, such as minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) and its derivatives, diazoxide (7-chloro-3-methyl-l,2,4-benzothiadiazine 1,1-dioxide) and phenytoin (5,4-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and especially p-carotene; anti-psoriatic agents such as anthralin and its derivatives; and finally eicosa-5,8,11,14-tetraenoic and eicosa-5,8,11-trienoic acids, their esters and amides.

The composition can also contain flavour-improving agents, preserving agents such as the esters 5 of para-hydroxybenzoic acid, stabilizing agents, moisture-regulating agents, pH-regulating agents, osmotic-pressure-modifying agents, emulsifying agents, UV-A and UV-B screening agents and anti-oxidizing agents such as a-tocopherol, butylated hydroxyanisole 10 or butylated hydroxytoluene.

A number of examples of the preparation of active compounds of formula (I) (including those of the present invention), as well as various concrete formulations based on such compounds, will now be given by way of illustration and without any implied 15 limitation.

EXAMPLE 1 2-Hydroxy-4- [7- (l-adamanty!) -6-benzyloxy-2-naphthyl]benzoic acid. (a) 7-(1-adamantyl)-6-benzyloxy-2-bromonaphthalene. 20 1.26 g (42 mmol) of sodium hydride (80 % in oil) and 50 ml of DMF are introduced into a 3-necked flask, a solution of 12.5 g (35 mmol) of 1 INTELLECTUAL PROr>:.VfY OFFiCE Of N.Z. 1 6 MAR 2001 n? (p ID 22 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene in 100 ml of DMF is added dropwise and stirring is carried out until gas evolution has ceased. 5 ml (42 mmol) of benzyl bromide are then added and stirring is carried out at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is taken up in ethanol, heated to reflux, cooled, filtered and dried. 12.5 g (80 %) of the expected product are collected, which product has the melting point 150-1°C. (b) 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid. 3 g (6.7 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-bromonaphthalene and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 3.2 ml (8 mmol) of n-butyllithium (2.5M in hexane) are added dropwise at -78°C and stirring is carried out for 15', at the same temperature 2.1 g (20 mmol) of trimethyl borate are added and stirring is 23 carried out for 2 hours. 23 ml of hydrochloric acid (IN) are added at -50°C and the temperature is allowed to rise to room temperature. The reaction mixture is extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is triturated in heptane, filtered and dried. 2.8 g (100 %) of the expected boronic acid are collected, which acid is used as is in the continuation of the synthesis. (c) methyl 2-hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate. 300 mg (8.8 mmol) of tetrakis(triphenyl-phosphine)palladium(0), 50 ml of toluene and 2.46 g (8.8 mmol) of methyl 2-hydroxy-4-iodobenzoate are introduced into a three-necked flask under a stream of nitrogen and stirring is carried out at room temperature for 20'. 5.52 g (13.4 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid and 8.8 ml of an aqueous potassium carbonate solution (2N) are then added and the reaction mixture is heated at reflux for 8 hours. The reaction mixture is evaporated 24 to dryness, the residue is taken up in water and ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). 1.65 g (36 %) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate are obtained. (d) 2-hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoic acid. 930 mg (1.8 mmol) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate and 100 ml of a 2N methanolic sodium hydroxide solution are introduced into a round-bottomed flask and the reaction mixture is heated at reflux for one hour. The reaction mixture is evaporated to dryness, the residue is taken up in water and acidified to pH 1 with concentrated hydrochloric acid and the solid is filtered. The solid obtained is triturated in ethyl acetate, filtered and dried. 710 mg (79 %) of the expected acid are collected, which acid has the melting point 263-4°C.

EXAMPLE 2 2-Hydroxy-4 - [7- (1-ad^rn^ntyl) -6-hexyloxy-2-naphthyl]benzoic acid. (a) methyl 2-hydroxy-4-[7-(1-adamantyl)-6-hexyloxy-2-naphthyl]benzoate.

Analogously to Example 1(a), by reaction-of 430 mg (1 mmol) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 180 jj.1 (1.2 mmol) of 10 6-iodohexane, 280 mg (55 %) of methyl 2-hydroxy- 4-[7-(1-adamantyl)-6-hexyloxy-2-naphthyl]benzoate are obtained. (b) 2-hydroxy-4-[7-(1-adamantyl)-6-hexyloxy-15 2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 100 mg (0.2 mmol) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-hexyloxy-2-naphthyl]benzoate, 90 mg (92 %) of the expected acid are obtained, which acid has the melting 20 point 281-3°C. 26 EXAMPLE 3 4- [7- (1-Adamantyl) - 6-methoxye thoxyme thoxy— 2-naphthyl]benzoic acid. (a) methyl 4-[7- (1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate.

Analogously to Example 1(c), by reaction of 2.8 g (6.7 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 950 mg (4.4 mmol) of methyl 4-bromobenzoate, 1.6 g (72 %) of the expected product are obtained. (b) methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate. 1.38 g (2.75 mmol) of methyl 4-[7-(l-adamantyl-6-benzyloxy-2-naphthyl]benzoate, 450 mg of palladium-on-charcoal (10 %) and 50 ml of dioxane are introduced into a reactor. 5 drops of acetic acid are added and hydrogenation is carried out at 50°C and under a pressure of 6.5 bars of hydrogen for 4 hours. The catalyst is filtered off and washed with two times 20 ml of dioxane and the filtrates are evaporated. The residue obtained is purified by 27 chromatography on a silica column eluted with a mixture of dichloromethane and hexane (50/50). 980 mg (86 %) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate are collected in the form of an oil. (c) methyl 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoate.

Analogously to Example 1(a), by reaction of 980 mg (2.4 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 330 (il (28.6 mmol) of methoxyethoxymethyl chloride, 650 mg (55 %) of the expected product are obtained in the form of an oil. (d) 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 650 mg (1.3 mmol) of methyl 4-[7-(1-adamantyl)- 6-methoxyethoxymethoxy-2-naphthyl]benzoate, 580 mg (92 %) of the expected acid are obtained, which acid has the melting point 234-6°C. 28 EXAMPLE 4 - [7- (l-Arj^-m^ntyl) -6-benzyloxy-2-naphthyl] -2-thiophenecarboxylic acid. (a) methyl 5-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]-2-thiophenecarboxylate.

Analogously to Example 1(c), by reaction of 1.5 g (3.6 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 400 mg (1.8 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 600 mg (65 %) of the expected product are obtained, which product has the melting point 170-1°C. (b) 5-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]-2-thiophenecarboxylic acid.

Analogously to Example 1(d), from 600 mg (1.2 mmol) of methyl 5-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]-2-thiophenecarboxylate, 460 mg (79 %) of the expected acid are obtained, which acid has the melting point 271-3°C. 29 EXAMPLE 5 4-[7- (l-Ai-la-manty!) -6-benzyloxy-2-na.phth.yl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate.

Analogously to Example 1(c), by reaction of 1.5 g (3.6 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 500 mg (1.9 mmol) of methyl 4-iodobenzoate, 320 mg (33 %) of the expected product are obtained, which product has the melting point 170-3°C. (b) 4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 320 mg (0.6 mmol) of methyl 4-[7-(1-adamantyl)-6-benzyloxy-2-naphthyl]benzoate, 195 mg (63 %) of the expected acid are obtained, which acid has the melting point 305-10°C.

EXAMPLE 6 4- [7- (1 -Aria-ma.nt.yl) -6-benzyloxycarbonyl-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-trifluoromethyl-sulphonyloxy-2-naphthyl]benzoate. 2.7 ml (16 mmol) of trifluoromethanesulphonic anhydride are added dropwise to a solution, cooled -to -78°C, of 5.5 g (13.3 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate, 3.2 ml (40 mmol) of pyridine and 162 mg of 4-dimethylamino-pyridine in 100 ml of dichloromethane and the reaction mixture is stirred at room temperature for 12 hours. The reaction mixture is poured into ice-cold water and extracted with ethyl ether and the organic phase is separated by settling, washed with a saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (10/90). 1.94 g (27 %) of methyl 4-[7-(1-adamantyl)- 6-trifluoromethylsulphonyloxy-2-naphthyl]benzoate are collected, which product has the melting point 226-7°C. 31 (b) methyl 4-[7-(1-adamantyl)-6-benzyloxycarbonyl-2-naphthyl]benzoate.

A solution of 1.91 g (3.5 mmol) of methyl 4-[7-(1-adamantyl)-6-trifluoromethylsulphonyloxy-2-naphthyl]benzoate in 50 ml of DMF, 980 (J.1 (7 mmol) of triethylamine, 39 mg of palladium acetate, 195 mg (0.35 mmol) of 1,1'-bis(diphenylphosphino)ferrocene and 3.65 ml (35.1 mmol) of benzyl alcohol are introduced successively into a reactor. The reaction mixture is heated at 80°C under a pressure of 2.5 bars of carbon monoxide for 12 hours. The reaction mixture is poured into a saturated sodium chloride solution and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of ethyl acetate and heptane (15/85). After evaporation of the solvents, 720 mg (40 %) of the expected product are collected, which product has the melting point 143-4°C. 32 (c) 4- [7- (1-adamantyl) -6-benzyloxycarbonyl-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 260 mg (0.5 mmol) of methyl 4-[7-(1-adamantyl)-6-benzyloxycarbonyl-2-naphthyl]benzoate, 200 mg (79 %) of the expected acid are obtained, which acid has the melting point 224-6°C.

EXAMPLE 7 2-Hydroxy-4 - [7 -(1-adamantyl)-6-(4-fluoro-benzyl)oxy-2-naphthyl]benzolc acid. (a) 7-(1-adamantyl)-6-(4-fluorobenzyl)oxy-2-bromonaphthalene.

Analogously to Example 1(a), by reaction of 1.1 g (3 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene with 420 p.1 (3.3 mmol) of 4-fluorobenzyl bromide, 1.2 g (86 %) of the expected product are obtained in the form of a colourless oil. (b) 7-(1-adamantyl)-6-(4-fluorobenzyl)oxy-2-naphthylboronic acid.

Analogously to Example 1(b), from 1.14 g (2.45 mmol) of 7-(1-adamantyl)-6-(4-fluorobenzyl)oxy- 33 2-bromonaphthalene, 560 mg (57 %) of the expected boronic acid are obtained. (c) methyl 2-hydroxy-4-[7-(1-adamantyl)- 6-(4-fluorobenzyl)oxy-2-naphthyl]benzoate.

Analogously to Example 1(c), by reaction of 560 mg (1.41 mmol) of 7-(1-adamantyl)-6-(4-fluorobenzyl)oxy-2-naphthyIboronic acid with 330 mg (1.17 mmol) of methyl 2-hydroxy-4-iodobenzoate, 10 490 mg (78 %) of the expected ester are obtained, which ester has the melting point 189-91°C. (d) 2-hydroxy-4-[7-(1-adamantyl)- 6-(4-fluorobenzyl)oxy-2-naphthyl]benzoic acid. Analogously to Example 1(d), from 490 mg 15 (0.91 mmol) of methyl 2-hydroxy-4-[7-(1-adamantyl)- 6-(4-fluorobenzyl)oxy-2-naphthyl]benzoate, 440 mg (92 %) of the expected acid are obtained, which acid has the melting point 240-l°C. 34 EXAMPLE 8 6- [7- (l-A<-la-mantyl) - 6 -me thoxye thoxyme thoxy-2-naphthyl]nicotinic acid. (a) 3-(1-adamantyl)-6-bromo-2-naphthol. 56 g (0.25 mol) of 6-bromo-2-naphthol, 38.2 g (0.25 mol) of 1-adamantanol and 500 ml of a mixture of dichloromethane and heptane (40/60) are introduced-into a round-bottomed flask. 15 ml of concentrated sulphuric acid are added and the reaction mixture is stirred at room temperature for 48 hours. The solid is filtered off, washed with heptane (3 x 100 ml) and dissolved in ethyl ether and the organic phase is washed with water, separated by settling, dried over magnesium sulphate and evaporated. 60.1 g (67 %) of the expected product are collected, which product has the melting point 215-6°C . (b) 7-(1-adamantyl)-6-methoxyethoxymethoxy-2-bromonaphthalene. 17.85 g (0.05 mol) of 3-(1-adamantyl)-6-bromo-2-naphthol and 200 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. 1.8 g (0.06 mol) of sodium hydride (80 % in oil) are added portionwise and the reaction mixture is stirred until gas evolution has ceased. 6.9 ml (0.06 mol) of methoxyethoxymethyl chloride are then added and the 5 reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into ice-cold water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is 10 purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (40/60). 19.5 g (87 %) of the expected product are collected, which product has the melting point 99-100°C. (c) 7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyIboronic acid.

Analogously to Example 1(b), from 61.9 g (0.139 mol) of 7-(1-adamantyl)-6-methoxyethoxymethoxy-2-bromonaphthalene, 54 g (95 %) of 7-(1-adamantyl)-2 0 6-methoxyethoxymethoxy-2-naphthyIboronic acid are obtained, which product has the melting point 172-4°C. 36 (d) methyl 6- [7- (1-adamantyl) -6-methoxyethoxymethoxy-2-naphthyl]nicotinate.

Analogously to Example 1(c), by reaction of 1.3 g (3.1 mmol) of 7-(1-adamantyl)-6-methoxyethoxyme thoxy-2 -naph thy Iboronic acid with 790 mg (3 mmol) of methyl 6-iodonicotinate, 860 mg (57 %) of the expected ester are obtained, which ester has the melting point 166-7°C. (e) 6-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]nicotinic acid.

Analogously to Example 1(d), from 853 mg (1.7 mmol) of the above methyl ester, 790 mg (95 %) of the expected acid are obtained, which acid has the melting point 247-8°C.

EXAMPLE 9 4 - [7- (1-ArtaTnantyl) -6-heptyloxy-2-naphthyl]benzoic acid. (a) 7-(1-adamantyl)-6-heptyloxy-2-bromonaphthalene.

Analogously to Example 8(b), by reaction of 3.4 g (9.5 mmol) of 3-(1-adamantyl)-6-bromo-2-naphthol 37 with 2.05 g (11.4 mmol) of 1-bromoheptane, 3.4 g (79 %) of 7-(1-adamantyl)-6-heptyloxy-2-bromonaphthalene are obtained. (b) 7-(1-adamantyl)-6-heptyloxy-2-naphthyIboronic acid.

Analogously to Example 1(b), from 3.5 g (17.7 mmol) of 7-(1-adamantyl)-6-heptyloxy-2-bromonaphthalene, 1.67 g (51 %) of 7-(1-adamantyl)-6-heptyloxy-2-naphthyIboronic acid are obtained. (c) methyl 4-[7-(1-adamantyl)-6-heptyloxy-2-naphthyl]benzoate.

Analogously to Example 1(c), by reaction of 1.6 g (3.8 mmol) of 7-(1-adamantyl)-6-heptyloxy-2-naphthyIboronic acid with 830 mg (3.17 mmol) of methyl 4-iodobenzoate, 460 mg (29 %) of the expected methyl ester are obtained. (d) 4-[7-(1-adamantyl)-6-heptyloxy-2-naphthyl]benzoic acid. 38 Analogously to Example 1(d), from 330 mg (0.65 mmol) of methyl 4-[7-(1-adamantyl)-6-heptyloxy-2-naphthyl]benzoate, 260 mg (81 %) of the expected acid are obtained, which acid has the melting point 266-7°C.

EXAMPLE 10 2-Hydroxy-4-[7-(1-adamantyl)- 6-me thoxye thoxymethoxy-2-naphthyl]benzoic acid (a) methyl 2-hydroxy-4-[7-(1-adamantyl)- 6-methoxyethoxymethoxy-2-naphthyl]benzoate Analogously to Example 1(c), by reaction of 2.25 g (5.5 mmol) of 7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyIboronic acid with 1.39 g (5 mmol) of methyl 2-hydroxy-4-iodobenzoate, 2.1 g (81 %) of the expected ester are obtained, which ester has the melting point 101-2°C. (b) 2-hydroxy-4-[7-(1-adamantyl)-6-methoxyethoxyme thoxy-2 -naph thyl] benzoic acid.

Analogously to Example 1(d), from 2.08 g (4 mmol) of the above methyl ester, 1.72 g (86 %) of 39 the expected acid are obtained, which acid has the melting point 225-6°C.

EXAMPLE 11 2-Chloxo-4- [7- (1-adamantyl) - 6-me thoxye thoxy me thoxy-2-naphthyl]benzoic acid. (a) methyl 2-chloro-4-[7-(1-adamantyl)- 6-methoxyethoxymethoxy-2-naphthyl]benzoate.

Analogously to Example 1(c), by reaction of 10 2.25 g (5.5 mmol) of 7-(1-adamantyl)-6-methoxy-ethoxymethoxy-2-naphthyIboronic acid with 1.48 g (5 mmol) of methyl 2-chloro-4-iodobenzoate, 2.32 g (87 %) of the expected ester are obtained, which ester has the melting point 112-3°C. (b) 2-chloro-4-[7-(1-adamantyl)-6-methoxyethoxyme thoxy-2 -naphthyl]benzoic acid.

Analogously to Example 1(d), from 2.31 g (4.3 mmol) of the above methyl ester, 1.97 g (88 %) of 2 0 the expected acid are obtained, which acid has the melting point 190-2°C. 40 EXAMPLE 12 4-[7-(1-Adamantyl)- 6-hydroxyhexyloxy-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-hydroxyhexyloxy-5 2-naphthyl]benzoate. 1.62 g (40 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]lbenzoate,-830 mg of potassium carbonate and 60 ml of methyl ethyl ketone are introduced into a round-bottomed flask under 10 a stream of nitrogen. 1.09 g (60 mmol) of 6-bromo- 1-hexanol are added and the reaction mixture is heated at reflux for 12 hours. The reaction mixture is poured into IN hydrochloric acid and extracted with ethyl ether and the organic phase is separated by settling, 15 dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with dichloromethane. After evaporation of the solvents, 1.58 g (77 %) of the expected methyl ester are collected, which ester has 20 the melting point 153-5°C. 41 (b) 4-[7-(1-adamantyl)-6-hydroxyhexyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 700 mg (1.36 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-5 hexyloxy-2-naphthyl]benzoate, 417 mg (61 %) of the expected acid are obtained, which acid has the melting point 254-6°C.

EXAMPLE 13 4 - [7- (1-Adamantyl) -6-hydroxypxopyl- 2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-allyl-2-naphthyl]benzoate. 4 g (7.34 mmol) of methyl 4-[7-(1-adamantyl)-15 6-trifluoromethylsulphonyloxy-2-naphthyl]benzoate, 2.30 ml (7.9 mmol) of allyltributyltin, 630 mg of lithium chloride and 40 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. The reaction mixture is stirred at room temperature for 20 30 minutes, 104 mg (0.146 mmol) of bis(triphenyl-phosphine) palladium (II) chloride are added and the reaction mixture is heated at 100°C for three hours. The 42 reaction mixture is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and dichloromethane (50/50). 1.7 g (53 %) of the expected product are collected, which product has the melting point 171-3°C. (b) methyl 4-[7-(1-adamantyl)-6-hydroxypropyl-2-naphthyl]benzoate. 1.7 g (3.9 mmol) of methyl 4-[7-(1-adamantyl)-6-allyl-2-naphthyl]benzoate and 40 ml of THF are introduced into a round-bottomed flask under a stream of nitrogen. A solution of 23.5 ml (11.7 mmol) of 9-borabicyclo[3.3.1]nonane (0.5M in THF) is added dropwise at 0°C and the reaction mixture is stirred for one hour at room temperature. 12 ml (12 mmol) of a sodium hydroxide solution (1M) and 10 ml of a 30 % hydrogen peroxide solution are then added successively and at 0°C and the reaction mixture is stirred at room temperature for one hour. The reaction 43 mixture is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The white powder obtained is purified by chromatography on a silica column eluted with dichloromethane. 1.67 g (94 %) of the expected product are collected, which product has the melting point 184-6°C. (c) 4-[7-(1-adamantyl)-6-hydroxypropyl-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 500 mg (1.1 mmol) of the above ester, 417 mg (86 %) of 4-[7-(1-adamantyl)-6-hydroxypropyl-2-naphthyl]benzoic acid are collected, which acid has the melting point 268-9°C.

EXAMPLE 14 4-[7-(1-Adamantyl)- 6-hydroxyoctyloxy-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-hydroxyoctyloxy-2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 1.5 g (3.6 mmol) of methyl 4-[7-(1-adamantyl)- 44 6-hydroxy-2-naphthyl]benzoate with 930 (J.1 (5.45 mmol) of l-bromo-8-octanol, 800 mg (41 %) of the expected product are obtained, which product has the melting point 120-1°C. (b) 4-[7-(1-adamantyl)-6-hydxoxyoctyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 630 mg" (1.17 mmol) of the above ester, 487 mg (79 %) of 4-[7-(1-adamantyl)-6-hydroxyoctyloxy-2-naphthyl]benzoic acid are obtained, which acid has the melting point 242-3°C.

EXAMPLE 15 4- [7- (1-Adamantyl) -6-hydroxyethyl-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-vinyl-2-naphthyl]benzoate.

Analogously to Example 13(a), by reaction of 4.82 g (8.86 mmol) of methyl 4-[7-(1-adamantyl)-6-tri-fluoromethylsulphonyloxy-2-naphthyl]benzoate with 3.90 ml (13.3 mmol) of vinyltributyltin, 805 mg (21.5 %) of methyl 4-[7-(1-adamantyl)-6-vinyl- 45 2-naphthyl]benzoate are obtained, which product has the melting point 221-2°C. (b) methyl 4-[7-(1-adamantyl)-6-hydroxyethyl-5 2-naphthyl]benzoate.

Analogously to Example 13(b), from 794 mg (1.88 mmol) of methyl 4-[7-(1-adamantyl)-6-vinyl-2-naphthyl]benzoate, 430 mg (54 %) of the expected alcohol are obtained, which alcohol has the melting 10 point 168-70°C. (c) 4-[7-(1-adamantyl)-6-hydroxyethyl-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 108 mg (0.25 mmol) of the above ester, 60 mg (38 %) of 15 4-[7-(1-adamantyl)-6-hydroxyethyl-2-naphthyl]benzoic acid are collected, which acid has the melting point 2 76-8°C. 46 EXAMPLE 16 4 - [7- (1-Adamantyl) -6-hydroxyheptyloxy-2-naphthyl]benzoic acid. (a) methyl 4-[7- (1-adamantyl)-6-hydroxyheptyloxy-2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 1.5 g (3.6 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 840 p.1 (5.45 mmol) of l-bromo-7-heptanol, 1 g (52 %) of the expected product is obtained, which product has the melting point 150-1°C. (b) 4-[7-(1-adamantyl)-6-hydroxyhepty1oxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 1 g (1.9 mmol) of the above methyl ester, 830 mg (86 %) of 4-[7-(1-adamantyl)-6-hydroxyheptyloxy-2-naphthyl]benzoic acid are obtained, which acid has the melting point 227-8°C. 47 EXAMPLE 17 4 - [7- (1-Adamantyl) - 6-hydroxypentyloxy-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-acetoxypentyloxy-5 2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 1 g (2.4 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 760 mg (3.6 mmol) of 5-bromo-pentyl acetate, 1.3 g (100 %) of the expected methyl 10 ester are obtained, which ester has the melting point 132-3°C. (b) 4-[7-(1-adamantyl)-6-hydroxypentyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 1.3 g (2.4 mmol) of the above ester, 1 g (79 %) of the expected acid is obtained, which acid has the melting point 271-2°C. 48 EXAMPLE 18 4- [7-(1-Adamantyl)-6-(4-morpholino)ethyloxy-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-(4-morpholino)-ethyloxy-2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 1.5 g (3.6 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 5.45 g (5.45 mmol) of 4-(2-chloroethyl)morpholine hydrochloride, 1.52 g (88 %) of the expected methyl ester are obtained, which / ester has the melting point 198-9°C. (b) 4-[7-(1-adamantyl)-6-(4-morpholino)ethyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 1.45 g (2.76 mmol) of the above ester, 956 mg (68 %) of the expected acid are obtained, which acid has the melting point 280°C with decomposition.

EXAMPLE 19 4- [7- (1-Aria-mantyl) -6- (1-piperidino) ethyloxy-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)- 6-(1-piperidino)ethyloxy-2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 1.5 g (3.6 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 1 g (5.45 mmol) of 1-(2-chloroethyl)piperidine hydrochloride, 1.46 g (77 %) of the expected methyl ester are obtained, which ester has the melting point 240-l°C. (b) 4-[7-(1-adamantyl)-6-(1-piperidino)ethyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 1.25 g (2.3 mmol) of the above ester, 640 mg (53 %) of the expected acid are obtained, which acid has the melting point 250°C with decomposition. 50 EXAMPLE 20 4-[7- (1-Aria-mantyl) -6-carbamoylpentyloxy-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-carbamoylpentyloxy-5 2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 640 mg (1.55 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 450 mg (2.32 mmol) of 6-bromohexanamide, 520 mg (65 %) of the expected 10 product are obtained, which product has the melting point 209-10°C. (b) 4-[7-(1-adamantyl)-6-carbamoylpentyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 400 mg (0.76 mmol) of the above ester, 350 mg (90 %) of the expected acid are obtained, which acid has the melting point 270-l°C. 51 EXAMPLE 21 4-[7- (1-Adamantyl) -6-ethoxycarbonylpentyloxy-2-naphthyl]benzoic acid. (a) Allyl 4-[7-(1-adamantyl)-6-ethoxycarbonyl-pentyloxy-2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 3 g (6.8 mmol) of allyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 2.3 g (10.2 mmol) of ethyl 6-bromohexanoate, 2.15 g (55 %) of the expected product are obtained, which product has the melting point 116-7°C. (b) 4-[7-(1-adamantyl)-6-ethoxycarbonylpentyloxy-2-naphthyl]benzoic acid. 1.5 g (2.58 mmol) of allyl 4-[7-(1-adamantyl)-6-ethoxycarbonylpentyloxy-2-naphthyl]benzoate, 50 ml of THF and 90 mg (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0) are introduced into a three-necked flask under a stream of nitrogen. 1.13 ml (13 mmol) of morpholine are added dropwise and the reaction mixture is stirred at room temperature for two hours. The reaction mixture is 52 evaporated to dryness, the residue is taken up in water, acidified to pH 1 with hydrochloric acid and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The solid is triturated in heptane, filtered and dried. 1 g (72 %) of the expected acid is collected, which acid has the melting point 270-l°C\ EXAMPLE 22 4- [7- (1-Adamantyl) -6-ethoxycarbonyUbutyloxy-2-naphthyl]benzoic acid. (a) allyl 4-[7-(1-adamantyl)-6-ethoxycarbonylbutyloxy-2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 2 g (4.5 mmol) of allyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 1.4 g (6.7 mmol) of ethyl 5-bromovalerate, 1.55 g (59 %) of the expected product are obtained, which product has the melting point 117-8°C. (b) 4-[7-(1-adamantyl)-6-ethoxycarbonylbutyloxy-2-naphthyl]benzoic acid. 53 Analogously to Example 21(b), from 1.48 g (2.6 mmol) of the above ester, 1.19 g (87 %) of 4-[7-(1-adamantyl)-6-ethoxycarbonylbutyloxy-2-naphthyl]benzoic acid are obtained, which acid has the melting point 200°C with decomposition.

EXAMPLE 23 4 - [7- (1-Adamantyl) -6-carboxypentyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 690 mg (1.28 mmol) of 4-[7-(1-adamantyl)-6-ethoxycarbonyl-pentyloxy-2-naphthyl]benzoic acid, 250 mg (39 %) of the expected acid are obtained, which acid has the melting point 305-6°C.

EXAMPLE 24 4-[7- (1-Adamantyl) -6-carboxybutyloxy-2-naphthyl] benzoic acid.

Analogously to Example 1(d), from 730 mg (1.4 mmol) of 4-[7-(1-adamantyl)-6-ethoxycarbonyl-butyloxy-2-naphthyl]benzoic acid, 510 mg (90 %) of the 54 expected acid are obtained, which acid has the melting point 317-8°C.

EXAMPLE 25 4-[7- (1-Adamantyl) - 6-me thoxye thoxyme thoxy-2-naphthyl]benzenemethanol. 3 g (6.1 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 40 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 20 ml of a solution of borane (1M in THF) are added dropwise and the reaction mixture is heated at 40°C for one hour. The reaction mixture is poured into a IN hydrochloric acid solution and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (60/40). 2.44 g (84 %) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]-benzenemethanol are collected, which product has the melting point 131-2°C. 55 EXAMPLE 26 4- [7- (1 -Arl^-m^n tyl) - 6-me thoxye thoxyme thoxy-2 -naph thyl ] benzal dehyde. 2.63 g (5.9 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzenemethanol and 40 ml of dichloromethane are introduced into a round-bottomed flask and 4.2 g of pyridinium dichromate are added. The reaction mixture is stirred at room temperature for twelve hours, is filtered through silica and the filtrate is evaporated. The solid obtained is recrystallized from heptane and 490 mg (19 %) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzaldehyde are collected, which product has the melting point 83-4°C.

EXAMPLE 27 4-[7-(1-Adamantyl)- 6-methoxyethoxymethoxy-2-naphthyl]benzoic acid mozpholide. (a) 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid chloride. g (20.6 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 56 100 ml of dichloromethane are introduced into a round-bottomed flask and 4.3 ml (21.6 mmol) of dicyclohexyl-amine are added dropwise. The reaction mixture is stirred at room temperature for one hour and 2.2 ml (21.6 mmol) of thionyl chloride are added dropwise. The reaction mixture is stirred for one hour and is evaporated to dryness, the residue is taken up in e'thyl ether, the dicyclohexylamine salt is filtered off and the filtrate is evaporated. 10.4 g (100 %) of the crude acid chloride are collected, which acid chloride will be used as is in the continuation of the synthesis. (b) 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid morpholide. 1.8 ml (20.6 mmol) of morpholine and 40 ml of THF are introduced into a round-bottomed flask. A solution of 3.5 g (6.9 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid chloride in THF is added dropwise and the reaction mixture is stirred at room temperature for two hours. The reaction mixture is poured into water and extracted with ethyl acetate and the organic phase is separated by settling, 57 dried over magnesium sulphate and evaporated. The solid obtained is triturated in hexane, filtered and dried. 2.8 g (74 %) of the expected amide are collected, which amide has the melting point 86-7°C.

EXAMPLE 28 N-Ethyl-4- [7- (1-adama.ntyl) - 6-me thoxye thoxyme thoxy -2-naphthyl]benzamide.

Analogously to Example 27(b), by reaction of 10 3.5 g (6.9 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxy-methoxy-2-naphthyl]benzoic acid chloride with 1.7 ml (20.6 mmol) of ethylamine (70 %), 2.6 g (75 %) of the expected ethyl amide are obtained, which ethyl amide has the melting point 154-5°C.

EXAMPLE 2 9 4- [7- (1 -Aria-man tyl) - 6-me thoxye thoxyme thoxy 2-naphthyl]benzami de.

Analogously to Example 27(b), by reaction of 20 3.5 g (6.9 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxyme thoxy-2 -naph thyl] benzoic acid chloride with 1.5 ml (26.2 mmol) of aqueous ammonia (32 %), 2.9 g (89 %) of 58 the expected amide are obtained, which amide has the melting point 198-9°C.

EXAMPLE 30 N- (4-Hydroxyphenyl)-4-[7-(1-adamantyl)- 6-me thoxy -ethoxymethoxy-2-naphthyl]benzamide. (a) N-(4-acetoxyphenyl)-4-[7-(1-adamantyl)-6-methoxy-ethoxymethoxy-2-naphthyl]benzamide. 970 mg (6.4 mmol) of 4-acetoxyaniline, 50 ml of THF and 990 jil (7 mmol) of triethylamine are introduced into a round-bottomed flask. A solution of 3.2 g (6.4 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxyme thoxy-2-naphthyl]benzoic acid chloride in THF is added dropwise and the reaction mixture is stirred at room temperature for two hours. The reaction mixture is poured into water and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is triturated in heptane, filtered and dried. 3.15 g (81 %) of the expected product are collected, which product has the melting point 206-7°C. 59 (b) N-(4-hydroxyphenyl)-4-[7-(1-adamantyl)-6-methoxy-ethoxymethoxy-2-naphthyl]benzamide.

Analogously to Example 1(d), from 3.15 g (5.2 mmol) of N-(4-acetoxyphenyl)-4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzamide, 2.3 g (77 %) of N-(4-hydroxyphenyl)-4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzamide are obtained, which product has the melting point 231-3°C.

EXAMPLE 31 4-[7- (1-Adamantyl) - 6-methoxyethoxymethoxy-2-naphthyl]benzoylpiperazine. (a) N-benzyl-4-[7-(1-adamantyl)-6-methoxyethoxyme thoxy-2 -naph thyl] benzoylpiperazine .

Analogously to Example 27(b), by reaction of 7.3 g (14.4 mmol) of 4-[7-(1-adamantyl)-6-methoxy-ethoxymethoxy-2-naphthyl]benzoic acid chloride with 2.5 ml (14.4 mmol) of 4-benzylpiperazine, 3 g (33 %) of the expected product are obtained, which product has the melting point 176-7°C. 60 (b) 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoylpiperazine. 500 mg (0.8 mmol) of the above amide and 20 ml of methanol are introduced into a three-necked flask. 900 mg of Pd/C (10 %) and then 900 p.1 of formic acid are added and the reaction mixture is stirred at room temperature for three hours. The catalyst is filtered off, the filtrate is poured into an aqueous bicarbonate solution and extracted with ethyl acetate and the organic phase is separated 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 methanol (80/20). 310 mg (72 %) of the expected product are collected, which product has the melting point 177-8°C.

EXAMPLE 32 Propyl 4-[7-(1-adamantyl)- 6-methoxye thoxyme thoxy-2-naphthyl]benzoate. 3 g (6.1 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid and 61 100 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. 200 mg (6.7 mmol) of sodium hydride (80 % in oil) are added portionwise and stirring is carried out until gas evolution has ceased. 500 jj.1 (6.1 mmol) of iodopropane are then added and the reaction mixture is stirred for one hour. The reaction mixture is poured into water and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (80/20). 1 g (33 %) of the propyl ester is collected, which ester has the melting point 121-2°C.

EXAMPLE 33 4-[7- (1-Adamantyl) - 6-methoxye thoxyme thoxy-2-naphthyl]phenyl acetate.

Analogously to Example 1(c), by reaction of 5 g (12.8 mmol) of 7-(1-adamantyl)-6-methoxyethoxyme thoxy-2 -naph thy Iboronic acid with 2.7 g (10.1 mmol) of 4-iodophenyl acetate, 2.88 g (57 %) of the expected 62 product are obtained, which product has the melting point 117-8°C.

EXAMPLE 34 4-[7- (1-Adamantyl) - 6-me thoxye thoxyme thoxy-2-naphthyl J phenol.

Analogously to Example 1(d), from 2.5 g (5 mmol) of 4-[7-(1-adamantyl) -6-methoxyethoxymethoxy-2-naphthyl]phenyl acetate, 2.2 g (97 %) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]phenol are obtained, which product has the melting point 126-7°C.

EXAMPLE 35 4-[7- (1-Adamantyl) - 6-me thoxye thoxyme thoxy-2-naphthyl] phenoxyethyhnorpholine hydrochloride. 600 mg (1.32 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]phenol, 550 mg (3.96 mmol) of potassium carbonate, 4 mg of potassium iodide and 60 ml of methyl ethyl ketone are introduced into a round-bottomed flask under a stream of nitrogen. 270 mg (1.45 mmol) of 4-(2-chloroethyl)morpholine 63 hydrochloride are added and the reaction mixture is heated at reflux for twelve hours. The reaction mixture is poured into IN hydrochloric acid and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with ethyl acetate. After evaporation of the solvents, an oil is collected. The hydrochloride is formed by dissolving the oil in ethyl ether and by then adding 1 ml of a saturated solution of HC1 in methanol. The salt is filtered and dried and 350 mg (44 %) of the expected hydrochloride are collected, which product has the melting point 123-4°C.

EXAMPLE 36 4-[7- (1 -Adama.n tyl) - 6 -me thoxye thoxyme thoxy-2-naphthyl] phenoxyethylpiperidine hydrochloride.

Analogously to Example 35, by reaction of 600 mg (1.32 mmol) of 4-[7-(1-adamantyl)-6-methoxy-ethoxymethoxy-2-naphthyl]phenol with 310 mg (1.7 mmol) of 1-(2-chloroethyl)piperidine hydrochloride, 770 mg 64 (85 %) of the expected hydrochloride are obtained, which product has the melting point 126-7°C.

EXAMPLE 37 Hexyl 4-[7- (1-adamnntyl) -6-me thoxye thoxyme thoxy -2-naphthyl]benzoate.

Analogously to Example 32, by reaction of 1.35 g (2.8 mmol) of 4-[7-(1-adamantyl)-6-methoxy-e thoxyme thoxy-2 -naphthyl] benzoic acid with 800 }il (5.6 mmol) of iodohexane, 980 mg (62 %) of the hexyl ester are obtained, which ester has the melting point 73-4°C.

EXAMPLE 38 N-[[4-[7-(1-Adamantyl)- 6-methoxyethoxymethoxy-2-naphthyl]benzoyl] ]glutam-i c acid. (a) diethyl N-[[4-[7-(1-adamantyl)-6-methoxyethoxyme thoxy-2 -naph thyl] benzoyl]]glutamate. 1.93 g (7.8 mmol) of diethyl L-glutamate hydrochloride, 1.13 g (9.24 mmol) of 4-dimethylamino-pyridine and 100 ml of THF are introduced into a round-bottomed flask. A solution of 3.59 g (7.1 mmol) of 65 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid chloride in THF is added dropwise and the reaction mixture is stirred at room temperature for four hours. The reaction mixture is 5 poured into water and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (70/30). 2.8 g (58 %) of the expected product are collected in the form of an oil. (b) N-[[4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoyl]]glutamic acid.

Analogously to Example 1(d), from 2.7 g (4.2 mmol) of the above diester, 1.45 g (56%) of N-[[4-[7-(1-adamantyl)-6-methoxyethoxyme thoxy-2-naphthyl]benzoyl]]glutamic acid are obtained, which acid has the melting point 137-8°C. 66 EXAMPLE 39 4- [7- (1-Adamantyl) - 6-methoxyhexyloxy-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-methoxyhexyloxy-2-naphthyl]benzoate.

Analogously to Example 12(a), by reaction of 870 mg (1.7 mmol) of methyl 4-[7-(1-adamantyl)— 6-hydroxyhexyloxy-2-naphthyl]benzoate with 160 p.1 (1.7 mmol) of dimethyl sulphate, 100 mg (14%) of the expected product are obtained, which product has the melting point 141-3°C. (b) 4-[7-(1-adamantyl)-6-methoxyhexyloxy-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 95 mg (0.18 mmol) of the above ester, 61 mg (66%) of the expected acid are obtained, which acid has the melting point 267-9°C. 67 EXAMPLE 40 4-[7-(1-Adamantyl)- 6-methoxymethoxypropyl-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-methoxymethoxypropyl-5 2-naphthyl]benzoate. 541 mg (1.2 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxypropyl-2-naphthyl]benzoate and 5 ml of dimethoxymethane are introduced into a round-bottomed flask and 5 drops of trimethylsilyl 10 iodide are added. The reaction mixture is stirred at room temperature for 24 hours, is poured into water and extracted with ethyl ether and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by 15 chromatography on a silica column eluted with a mixture of dichloromethane and heptane (70/30). 355 mg (59%) of the expected product are collected, which product has the melting point 137-8°C. (b) 4-[7-(1-adamantyl)-6-methoxymethoxypropyl-2-naphthyl]benzoic acid. 68 Analogously to Example 1(d), from 345 mg (0.69 mmol) of the above ester, 280 mg (83%) of the expected acid are obtained, which acid has the melting point 237-8°C.

EXAMPLE 41 4-[7-(1 -Adamantyl)- 6-methoxymethoxyethyl-2-naphthyl]benzoic acid. (a) methyl 4-[7-(1-adamantyl)-6-methoxymethoxyethyl-2-naphthyl]benzoate.

Analogously to Example 40(a), from 200 mg (0.47 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-ethyl-2-naphthyl]benzoate, 156 mg (68%) of the expected product are obtained, which product has the melting point 145-6°C. (b) 4-[7-(1-adamantyl)-6-methoxymethoxyethyl-2-naphthyl]benzoic acid.

Analogously to Example 1(d), from 149 mg (0.3 mmol) of the above ester, 101 mg (70%) of the expected acid are obtained, which acid has the melting point 225-7°C. 69 EXAMPLE 42 The antagonist activity of the compounds of formula (I) is evaluated in the test of differentiation of embryonic teratocarcinoma F9 cells in mice (Cancer Research 43, p. 5268, 1983).

These compounds, tested at 10 Si, are inactive as agonists in this test and partially or completely inhibit the effect produced by an agonist retinoid on the morphology and on the secretion of the activator of plasminogen according to the following protocol.

The F9 cells are inoculated in 12-well -9 -5 clusters and the compounds are tested from 10 to 10 M in the presence of all-trans-retinoic acid or of a synthetic agonist retinoid (compound A): 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- —8 2-naphthylaminomethyl]benzoic acid (BASF) at 10 M.

After incubating for three days, the morphological observations are carried out and the concentration of the tested compound (IC50) which inhibits the effect of the agonist on the secretion of the activator of plasminogen by 50% is determined. 70 Ex. No.

Antagonist against compound A (10 nM) Test of differentiation of F9 cells IC50 (nM) 1 3 2 180 6 500 14 250 100 39 450 EXAMPLE 43 In this example, various concrete formulations based on the compounds according to the invention have been illustrated.

A- ORAL ROUTE (a) 0.2 g tablet 71 Compound prepared in Example 6 Starch Dicalcium phosphate Silica Lactose Talc Magnesium stearate (b) Drinkable suspension in Compound prepared in Example 5 Glycerol 70% Sorbitol Sodium saccharinate Methyl para-hydroxybenzoate Flavour q.s.

Purified water q.s. for 0.001 0 .114 0 . 020 0.020 0.030 0 . 010 0.005 ml phials 0.001 0.500 0.500 0 . 010 0.040 m (c) 0.8 g tablet Compound of Example 2 0.500 72 - Pregelatinized starch - Microcrystalline cellulose - Lactose - Magnesium stearate (d) Drinkable suspension in 10 - Compound of Example 4 - Glycerol - 70% Sorbitol - Sodium saccharinate - Methyl para-hydroxybenzoate - Flavour q.s.

- Purified water q.s. for B- TOPICAL ROUTE (a) Ointment - Compound of Example 6 - Isopropyl myristate - Fluid paraffin oil 0.100 0.115 0.075 0.010 ml phials 0.200 1.000 1.000 0.010 0.080 m 0.020 81.700 9.100 73 Silica ("Aerosil 200" sold by Degussa) 9.180 (b) Ointment Compound of Example 2 0.300 g Pharmaceutical-grade white petroleum jelly q.s. for 100 g (c) Non-ionic water-in-oil cream Compound of Example 7 0.100 Mixture of emulsified lanolin alcohols, of waxes and of oils ("Anhydrous eucerin" sold by BDF) 39.900 Methyl para-hydroxybenzoate 0.075 Propyl para-hydroxybenzoate 0.075 Sterile demineralized water <3-S- for 100 (d) Lotion Compound of Example 8 0.100 Polyethylene glycol (PEG 400) 69.900 95% Ethanol 30.000 (e) Hydrophobic ointment 74 Compound of Example 10 0.300 Isopropyl myristate 36.400 Silicone oil ("Rhodorsil 47 V 300" sold b Rhone-Poulenc) 36.400 Beeswax 13.600 Silicone oil ("Abil 300.000 est" sold by Goldschmidt)q.s. for 100 (f) Non-ionic oil-in-water cream Compound of Example 5 1.000 Cetyl alcohol 4.000 Glyceryl monostearate 2.500 PEG 50 stearate 2.500 Karite butter 9.200 Propylene glycol 2.000 Methyl para-hydroxybenzoate 0.075 Propyl para-hydroxybenzoate 0.075 Sterile demineralized water q.s. for 100

Claims (17)

75 WHAT//WE CLAIM IS <^.1 a Tcrf fa J <S P) A compound having a general formula (I): in which: - Rx represents (i) the -CH3 radical (ii) the -CH2OH radical (iii) the -0-R3 radical INTELLECTUAL PROPjkTY OFFICE OF N.Z. 1 6 MAR 2001 ^ KDECUEiQ) 76 (iv) the -CO-R4 radical R3 and R4 having the meanings given below, Ar is a radical of formula: FL F // A\ 'o' //A\ 's' (a) (b) (c) Rs having the meaning given below, ~ r2 is a polyether radical having carbon in the position a . to the carbon which is in the 6 position of the naphthyl radical, 10 it being understood that: 15 - R3 represents a hydrogen atom, a lower alkyl radical or a - (CH2) m- (CO) n-Ra radical, Rs, m and n having the meanings given below, 20 - R4 represents: (a) a hydrogen atom, intellectual property office of n.z. 1 2 APR 2001 RECEIVED 78 41 ■? g (b) a lower alkyl radical, (c) a radical of formula: (d) an -0R9 radical, R', R" and Rg having the meanings given below, 10 - R5 represents a hydrogen or halogen atom, a linear or branched alkyl radical having from 1 to 20 carbon atoms, a hydroxyl radical or an -OR10 or -OCOR10 radical, 15 R10 having the meaning given below, INTELLECTUAL PROPZRYY OFFICE OF N.Z. 1 6 MAR 2C01 l^E(S2!l¥C[D - Ra represents a lower alkyl radical or a saturated heterocycle, - R9 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 residue or an amino acid or peptide residue, - R10 represents a lower alkyl radical, intellectual property office of n.z. 1 2 APR 2001 RECEIVED 80 - R' and R", which are identical or different, represent a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkyl radical, an optionally 5 substituted aryl radical or an amino acid, peptide or sugar residue or alternatively, taken together, form a saturated heterocycle, - m is an integer between 1 and 3 inclusive, 10 15 20 intellectual property office of n.z.

1 2 APR 2001 received as well as their salts and their chiral analogues.

2 . A compound according to Claim 1 in the form of a salt of an alkali metal or alkaline-earth 5 metal or alternatively of zinc or of an organic amine.

3 . A compound according to either of Claims 1 and 2, characterized in that the lower alkyl radicals are chosen from the group comprising the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.

4. A compound according to any one of the preceding claims, characterized in that the linear or branched alkyl radicals having from 1 to 20 carbon atoms are chosen from the group comprising the methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl 15 and octadecyl radicals.

5. A compound according to any one of the preceding claims, characterized in that the monohydroxyalkyl radicals are chosen from the group comprising the hydroxymethyl, 2-hydroxyethyl, 20 2-hydroxypropyl or 3-hydroxypropyl radicals.

6. A compound according to any one of the preceding claims, characterized in that the ll-TEIJ.ECT'JAL PROPERTY OFFICE OF N.Z. 1 6 MAR 2001 EHEO^GVEiD) polyhydroxyalkyl radicals are chosen from the group comprising the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals or the pentaerythritol residue.

^ 7. A compound according to any one of the preceding claims, characterized in that the aryl radicals are a phenyl radical optionally substituted by at least one halogen atom, one hydroxyl or one nitro functional group. 10

8. A compound according to any one of the preceding claims, characterized in that the aralkyl radical is chosen from the group comprising the benzyl or phenethyl radicals optionally substituted by at least one halogen atom, one hydroxyl or one nitro 15 functional group.

9. A compound according to any one of the preceding claims, characterized in that the alkenyl radicals are chosen from the group comprising the radicals containing from 2 to 5 carbon atoms and having 2 0 one or a number of ethylenic unsaturations, in particular the allyl radical.

10. A compound according to any one of the preceding claims, characterized in that the sugar INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 S MAR 2001 ^E^EC^EE) 83 residues are chosen from the group comprising the glucose, galactose, mannose or glucuronic acid residues.

11. A compound according to any one of the 5 preceding claims, characterized in that the amino acid residues are chosen from the group comprising the residues deriving from lysine, from glycine or from aspartic acid.

12. A compound according to any one of the 10 preceding claims, characterized in that the peptide residues are chosen from the group comprising the dipeptide or tripeptide residues.

13 . A compound according to any one of the preceding claims, characterized in that the saturated 15 heterocyclic radicals are chosen from the group comprising the piperidino, morpholino, pyrrolidino or piperazino radicals, optionally substituted in the 4 position by a C^-Cg alkyl or mono- or polyhydroxyalkyl radical. INTELLECTUAL PROPZkVY OFFICE OF N.Z. 1 6 MAR 2001 K E (E I; G E E)

14. A compound according to any one of the preceding claims, characterized in that the halogen atoms are chosen from the group comprising fluorine, chlorine and bromine.

15. A compound according to Claim 1 characterised in that the compounds are chosen from the group comprising 4- [7- (1-adamantyl) -6-methoxymethoxypropyl-2-naphthyl]benzoic acid and 4-[7-(l- adamantyl)-6-methoxymethoxyethyl-2-naphthyl]benzoic acid.

16. A compound according to Claim 1, characterized in that the compounds correspond to tne formula (X) in which: Rx is the -CO-R4 radical, Ar represents the radical of formula (a) or (b) , and wherein R4, R2 / defined in claim 1. and b are as

17. A compound of formula I as defined in claim 1 substantially as herein described with reference to any example thereof. INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 APR 2001 RECEIVED END