Benzonaphthalene derivatives and compositions

A benzonaphthalene compound has the formula ##STR1## wherein R.sub.1 represents (i) ##STR2## or (ii) --CH.sub.2 OH; R.sub.6 represents ##STR3## or OR.sub.7 wherein R.sub.7 represents hydrogen, alkyl having 1-20 carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r' or r" represent hydrogen, lower alkyl, mono or polyhydroxyalkyl, aryl or a residue of an amino acid or a sugar, or together form a heterocycle; R.sub.2 represents hydrogen, alkyl having 1-15 carbon atoms, alkoxy having 1-4 carbon atoms or a cycloaliphatic radical; R.sub.3 represents hydrogen, hydroxy, alkyl having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a cycloaliphatic radical, a thiocycloaliphatic radical or --O--Si(CH.sub.3).sub.2 --R.sub.8 wherein R.sub.8 represents lower alkyl; and R.sub.4 and R.sub.5 represent hydrogen, lower alkyl, hydroxy or lower acyloxy. This compound is useful in the topical and systemic treatment of dermatologic diseases and in the treatment of the degeneration of conjuctive tissues. The compound also possesses anti-tumor activity.

The present invention relates to benzonaphthalene derivatives, to a process 
for preparing them and to their use in therapeutic and cosmetic 
compositions. 
These new benzonaphthalene derivatives are usefully employed in the topical 
and systemic treatment of dermatological diseases linked to keratinization 
disorders (differentiation-proliferation) and dermatological diseases, or 
others, with inflammatory and/or immunoallergic components and in the 
treatment of diseases attributable to the degeneration of conjuctive 
tissue. The benzonaphthalene derivatives of the present invention also 
exhibit anti-tumor activity. Moreover, these derivatives can be employed 
in the treatment of atrophy be it cutaneous or respiratory. 
The benzonaphthalene derivatives of the present invention are also usefully 
employed in the field of ophthalmology and principally in the treatment of 
corneopathies. 
A number of compounds have already been proposed for the various treatments 
noted above and principally compounds known under the designation of 
"retinoids" of which the most well-known ones are the trans and cis 
retinoic acids (tretinoin and isotretinoin) and etretinate. 
Compared to these known compounds, the benzonaphthalene derivatives 
according to the present invention exhibit a strong activity and better 
stability to light and to oxygen of the air. 
The benzonaphthane derivatives of the present invention can be represented 
by the following formula: 
##STR4## 
wherein 
R.sub.1 represents: 
(i) 
##STR5## 
or (ii) --CH.sub.2 OH, 
R.sub.6 represents 
##STR6## 
or --OR.sub.7 wherein R.sub.7 represents hydrogen, alkyl having 1-20 
carbon atoms, monohydroxyalkyl or polyhydroxyalkyl, r' and r" represent 
hydrogen, lower alkyl, mono- or polyhydroxyalkyl, aryl optionally 
substituted or a residue of an amino acid or aminated sugar or r' and r" 
taken together form a heterocycle, 
R.sub.2 represents hydrogen, branched or straight chain alkyl having 1-15 
carbon atoms, alkoxy having 1-4 carbon atoms or a cycloaliphatic group, 
R.sub.3 represents hydrogen, hydroxy, straight or branched chain alkyl 
having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a cycloaliphatic 
group substituted or not, a thio-cycloaliphatic group or a group of the 
formula --O--Si(CH.sub.3).sub.2 --R.sub.8 wherein R.sub.8 represents 
linear or branched lower alkyl, 
R.sub.4 and R.sub.5 each independently represent hydrogen, lower alkyl, 
hydroxy or a lower acyloxy group, and the salts of the said 
benzonaphthalene derivatives of Formula I. 
By the expression "lower alkyl" is meant alkyl radicals having from 1-6 
carbon atoms and principally methyl, ethyl, isopropyl, butyl and 
tert.butyl. 
The term "alkoxy" is intended to include radicals having 1-10 carbon atoms 
and principally methoxy, ethoxy, isopropoxy, hexyloxy and decyloxy 
radicals. 
By the expression "lower acyloxy" is meant radicals having 1-4 carbon atoms 
and principally acetyloxy and propionyloxy radicals. 
By the term "monohydryoxyalkyl" is meant a monohydroxy substituted radical 
having 2 or 3 carbon atoms, principally, 2-hydroxy ethyl and 
2-hydroxypropyl. 
Representative residues of aminated sugars include those derived from 
glucosamine, galactosamine and mannosamine. 
By the term "polyhydroxyalkyl" is meant an alkyl radial having 3-6 carbon 
atoms substituted 2-5 hydroxyl groups, such as 2,3-dihydroxy propyl, 
1,3dihydroxy propyl, or the residue of pentaerythritol. 
The term "cycloaliphatic" is meant to include a mono or polycyclilc radical 
such as, for example, 1-methyl cyclohexyl or 1-adamantyl. 
The preferred thiocycloaliphatic radical is, principally, 1-adamantylthio. 
When r' and r" together form a heterocycle, it is preferably a piperidino, 
piperazino, morpholino or pyrrolidion radical. 
The preferred compounds of Formula I are more particularly those having the 
following formula 
##STR7## 
wherein 
R'.sub.6 represents 
##STR8## 
or --OR'.sub.7, 
r' and r" each independently represent hydrogen or lower alkyl, or r' and 
r" taken together form a morpholino radical, 
R'.sub.7 represents hydrogen or lower alkyl, 
R'.sub.2 represents hydrogen, alkyl, alkoxy or 1-adamantyl, and 
R'.sub.3 represents hydrogen, hydroxy, alkyl, alkoxy or 1-adamantylthio. 
Representative compounds of the present invention include: 
(1) 6-(3-methylphenyl)-2-naphthoic acid and its methyl ester, 
(2) 6-(4-tert.butyl phenyl)-2-naphthoic acid and its methyl ester, 
(3) 6-(3-tert.butyl phenyl)-2-naphthoic acid and its methyl ester, 
(4) 6-(3,4-dimethoxy phenyl)-2-naphthoic acid and its methyl ester, 
(5) 6-[p-(l-adamantylthio)phenyl]-2-naphthoic acid and its methyl ester, 
(6) 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid and its methyl 
ester, 
(7) the methyl ester of 
6-[3-(1-adamantyl)-4-tert.butyldimethylsilyloxyphenyl]-2-naphthoic acid, 
(8) the methyl ester of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic 
acid, 
(9) 6-[3-(1-adamantyl-4-hydroxyphenyl]-2-naphthoic acid, 
(10) the methyl ester of 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic 
acid, 
(11) 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid, 
(12) the methyl ester of 6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic 
acid, 
(13) 6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid, 
(14) the methyl ester of 
6-[3-(1-adamantyl)-4-methoxyphenyl]-4-acetoxy-1-methyl-2-naphthoic acid, 
(15) 6-[3-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy-1-methyl-2-naphthoic 
acid, 
(16) the methyl ester of 
6-[3-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy-1-methyl-2-naphthoic acid, 
(17) the methyl ester of 
6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid, 
(18) 6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid, 
(19) 6-[3-(1-adamantyl-4-methoxyphenyl]-2-naphthalene methanol, 
(20) the ethylamide of 6-[3-(1-adamantyl)-4-methoxyphenyl]2-naphthoic acid, 
(21) the morpholide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic 
acid, 
(22) the methyl ester of 6-[3-tert.-4-methoxyphenyl]-2-naphthoic acid, 
(23) 6-(3-tert.butyl-4-methoxyphenyl)-2-naphthoic acid, 
(24) the methyl ester of 
6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid, and 
(25) 6-[3-(1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid. 
The present invention also relates to a process for preparing the compounds 
of Formula I. 
According to this process the compounds of Formula I are obtained by a 
coupling reaction between a halogenated compound of Formula III and a 
halogenated derivative of naphthalene of Formula IV: 
##STR9## 
wherein 
R.sub.1 to R.sub.5 have the same meanings as those given above for Formula 
I and 
X and Y represent Cl, Br, F or I. 
According to this coupling reaction, the halogenated compound of Formula 
III is transformed into its magnesium, lithium or zinc form in accordance 
with methods described in the literature and is coupled with the 
halogenated naphthalene derivative of Formula IV by employing, as a 
reaction catalyst, a transition metal or one of its complexes. 
Particularly preferred catalysts are those derived from nickel or palladium 
and more particularly the compounds of Ni.sub.II (NiCl.sub.2) with various 
phosphines. 
The coupling reaction is generally carried out at a temperature between 
-20.degree. and +30.degree. C. in an anhydrous solvent such as, for 
example, dimethylformamide or tetrahydrofuran. 
The resulting product can be purified by recrystallization or silica column 
chromatography. 
Obviously, the choice of the halogenated naphthalene derivative of Formula 
IV, for use in the coupling reaction with the halogenated compound of 
Formula III, must be such that it can lead, by subsequent reaction, to the 
various meanings of the R.sub.1 radical given above. 
When the compounds according to the present invention are provided in salt 
form, it is a question of salts of an alkali or alkaline earth metal or of 
an organic amine when the compounds have at least one free acid function. 
The present invention also relates to a medicinal composition comprising as 
the active principle thereof the compounds of Formula I as defined above. 
These compounds exhibit excellent activity in the test for inhibiting 
ornithine decarboxylase after induction, by "tape stripping" the body of a 
nude rat. This test is considered a measure of the activity of the 
retinoids with regard to cellular proliferation phenomenon. 
For instance, it has been noted that in this test, 
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid exhibits an effective 
dose between 5 and 25 nmoles applied per cm.sup.2. 
The compounds according to the invention also exhibit a strong activity in 
the differentiation test of embryonic tetracarcinoma F9 rat cells (Cancer 
Research 43, page 5268, 1983). 
As an illustration, 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthoic acid, at 
a 0.01 micromolar concentration induces the differentiation of F9 
carcinoma cells in endoderm cells. 
6-(3-tert.butyl phenyl)-2-naphthoic acid acts in the same fashion at a 
concentration of 1 micromolar. 
Moreover, the irritation test carried out on a rabbit has shown that the 
compounds of Formula I are less irritating than known retinoids of 
analogous structure. Moreover, their acute toxicity is weaker. 
The compounds of the present invention are indeed particularly suitable for 
the treatment of dermatological diseases linked to a k eratinization 
disorder (differentiation, proliferation), as well as dermatological 
diseases or others with inflammatory and/or immunoallergic components such 
as principally: 
acne vulgaris, comedons or polymorphs, solar acne seniles and medicamental 
or professional acne; 
extensive and/or severe forms of psoriasis, and other keratinization 
disorders, and principally ichtyosis and ichtyosiform states; 
Darier disease; 
palmo-plantary keratodermy; 
leucoplasies and leucoplasiform states, lichen plan; 
all dermatological proliferations, benign or malignant, severe or extended. 
They are also active for certain rheumatic diseases principally psoriasic 
rheumatism, for cutaneous or respiratory atrophies, as well as for certain 
ophthalmologic disorders relative to the corneopathies. 
The present invention also relates to medicinal compositions containing at 
least one compound of Formula I, as defined above and/or a salt thereof. 
The present invention thus relates to a new medicinal composition, intended 
principally for the treatment of the abovementioned diseases, comprising 
in a pharmaceutically acceptable support, at least one compound of Formula 
I and/or a salt thereof. 
As has been indiated previously, the benzonaphthalene derivatives according 
to the present invention, relative to known retinoids, exhibit better 
stability against light and oxygen, this being essentially due to the fact 
that they do not possess any easily isomerized double bonds. 
The compounds according to the present invention are generally administered 
at a daily dosage of about 2 .mu.g/kg to 2 mg/kg of body weight. 
As vehicles or supports for these compositions, there can be employed any 
conventional support, the active compound being found either in the 
dissolved state or in the dispersed state in the vehicle or support. 
The composition can be administered enterally, parenterally, topically or 
ocularly. When administered enterally, the medicinal composition can be 
provided in the form of tablets, gelules, lozenges, syrups, suspension, 
solution, powders, granules or emulsions. When administered parenterally 
the medicinal composition can be provided in the form of solutions or 
suspensions for perfusion or injection. 
When administered topicallY, the pharmaceutical compositions based on the 
compounds in accordance with the present invention can be provided in the 
form of ointments, tinctures, creams, pommades, powders, impregnated pads, 
buffers, solutions, lotions, gels, sprays or even suspensions. 
These compositions for topical application or administration can be 
provided either under anhydrous form, or in aqueous form according to 
clinical indications. When administered ocularly, the compositions are 
principally eyewashes. 
The topical or ocular composition contains preferably between 0.0005 and 5 
weight percent of the active compound based on the total weight of the 
composition. 
The compounds of Formula I, according to the present invention also find 
use in the cosmetic field, in particular in body and hair hygiene and 
principally for acne, hairgrowth, preventing hair fallout, to combat 
against the oily appearance of the skin or hair, in the protection against 
harmful effects of the sun or in the treatment of physiologically dry 
skin. 
The present invention then also envisages a cosmetic composition containing 
in a cosmetically acceptable support at least one compound of Formula I 
and/or a salt thereof, this composition being provided principally in the 
form of a lotion, gel, soap or shampoo. 
The concentration of the compound(s) of Formula I in the cosmetic 
compositions is between 0.0005 and 2 weight percent, preferably between 
0.01 and 1 weight percent, based on the total weight of the composition. 
The medicinal and cosmetic compositions according to the present invention 
can contain inert or even pharmacodynamic or cosmetically active adjuvants 
and principally: hydrating agents such as thiamorpholinone and its 
derivatives or urea; antiseborrheic agents such as 
S-carboxymethylcysteine, S-benzyl cysteamine and their derivatives, or 
tioxolone; antibiotics such as erythromycin, neomycin or the 
tetracyclines; agents favoring hair growth such as "Minoxidil" 
(2,4-diamino-6-piperidinopyrimidine-3-oxide) and its derivatives, 
Diazoxide and Phenytoin, steroidal anti-inflammatory agents; carotenoids 
and principally .beta.-carotene; and antipsoriasic agents such as 
anthralin and its derivatives, 5,8,11,14-eicosatetranoic acid and 
5,8,11-triynoic acid. 
The compositions according to the present invention can also contain flavor 
improving agents, preservatives, stabilizers, humidity regulating agents, 
pH regulating agents, osmotic pressure modifying agents, emulsifiers, UV-A 
and UV-B filters and antioxidants such as .alpha.-tocopherol, butylhydroxy 
anisole or butylhydroxy toluene.

The following non-limiting examples illustrate several examples for the 
preparation of the active compounds of Formula I according to the present 
invention, as well as examples of compositions containing these active 
compounds. 
EXAMPLE 1 
Methyl ester of 6-(3-methylphenyl)-2-naphthoic acid. Compound of Formula II 
wherein R'.sub.3 =H and R'.sub.2 =--CH.sub.3 and R'.sub.6 =--OCH.sub.3 
342 mg (2 mmol) of 3-bromotoluene in 4 ml of THF are converted into the 
corresponding magnesium form and then treated with an equivalent of zinc 
chloride to provide the corresponding zinc derivative. There are 
successively added 310 mg (1.17 mmol) of methyl 6-bromo-2-naphthoate and 
10 mg (0.02 mmol) of NiCl.sub.2 /1,2-(diphenylphosphino)ethane-DPPE-as the 
catalyst. The reaction mixture is stirred at ambient temperature for 30 
minutes and the mineral salts are then removed by passing the reaction 
mixture through a 2.times.3 cm silica column. The reaction mixture is then 
evaporated to dryness and the residue is chromatographed (HPLC 
column-Zorbax sil), using as the eluant, a mixture of cyclohexane (75%) 
and ether (25%). The product thus recovered has an Rf=0.45 (silica plate, 
eluant: hexane 50%, dichloromethane 50%) and crystallizes on evaporation 
of the chromatography solvents. The yield is 84%. Melting 
point-107.degree. C. 
EXAMPLE 2 
Methyl ester of 6-(4-tert.butyl phenyl)-2-naphthoic acid 
Compound of Formula II wherein R'.sub.2 =H, R'.sub.3 =--C(CH.sub.3).sub.3 
and R'.sub.6 =--OCH.sub.3 
In a manner analogous to Example 1, starting with 639 mg (3.0 mmol) of 
4-bromo tert.butyl benzene and 465 mg (1.75 mmol) of methyl 
6-bromo-2-naphthoate, 0.30 g of the expected product is obtained. 
Yield--54%. Melting point--154.degree. C. 
EXAMPLE 3 
Methyl ester of 6-(3-tert.butyl phenyl)-2-naphthoic acid 
Compound of Formula II wherein R'.sub.3 =H, R'.sub.2 =--C(CH.sub.3).sub.3 
and R'.sub.6 =--OCH.sub.3 
3.50 g (16.4 mmol) of 3-tert.butyl bromobenzene are added to a suspension 
of magnesium (0.44 g-18 m Atg) in 20 ml of dry tetrahydrofuran. The 
reaction is initiated by addition of an iodine crystal and continued at 
50.degree. C. for 30 minutes. 
2.46 g (18 mmol) of anhydrous zinc chloride dissolved in 20 ml of dry 
tetrahydrofuran are then added and after 15 minutes, the reaction mixture 
is cooled to 0.degree. C. At this point, 3.63 g (13.7 mmol) of methyl 
6-bromo-2-naphthoate and 86 mg (0.26 mmol) of the NiCl.sub.2 /DPPE complex 
are added to the reaction mixture. 
After stirring for 1 hour at ambient temperature, 100 ml of water are added 
and the mixture is extracted with ether. After washing the organic phase 
with a saturated solution of sodium bicarbonate, and water, then drying 
(sodium sulfate) and evaporating the solvents, the resulting residue is 
recrystallized in heptane. 3.12 g of the methyl ester of 6-(3-tert.butyl 
phenyl)-2-naphthoic acid which melts at 138.degree. C. are obtained. 
EXAMPLE 4 
6-(3-tert.butyl phenyl)-2-naphthoic acid 
Compound of Formula II wherein R'.sub.3 =H, R'.sub.2 =--C(CH.sub.3).sub.3 
and R'.sub.6 =OH 
1.0 g (3.14 mmol) of the methyl ester of 6-(3-tert.butyl 
phenyl)-2-naphthoic acid obtained in Example 3 is added to a mixture of 
95% ethanol (40 ml) and soda (4 ml, 5N). 
The mixture is heated at 60.degree. C. for 2 hours at which point 50 ml of 
water are added and the mixture is acidified to pH 1 with 2N HCl. The 
acidified mixture is then extracted with ether and the organic phase is 
washed with water until neutral. After drying (sodium sulfate) and 
evaporation of the solvent, 6-(3tert.butyl phenyl)-2-naphthoic acid (900 
mg) which sublimes at 190.degree. C. is obtained. 
EXAMPLE 5 
Methyl ester of 6-[p-(1-adamantylthio)phenyl]-2-naphthoic acid 
Compound of Formula II wherein R'.sub.2 =H, R'.sub.3 =1-adamantylthio and 
R'.sub.6 =--OCH.sub.3 
(a) p-(1-adamantylthio) bromobenzene. 
3.78 g (20 mmol) of p-bromothiophenol, 3.04 g (20 mmol) of 1-adamantanol 
and 10 ml of trifluoroacetic acid are stirred at ambient temperature for 8 
hours and then poured into water. Sodium bicarbonate is added until the 
mixture is neutral at which time it is extracted with methylene chloride. 
The organic phase is dried and evaporated. After recrystallization in 
isooctane, 5.9 g of the expected product are obtained. Yield--92%. Melting 
point: 121.degree.-122.degree. C. 
(b) Methyl ester of 6-[p-(1-adamantylthio)phenyl]-2-naphthoic acid 
0.64 g (26.5 m Atg) of magnesium suspended in 10 ml of tetrathydrofuran 
(THF) are treated slowly with 5.7 g (17.6 mmol) of p-(1-adamantylthio) 
bromobenzene. After heating at reflux for 2 hours and cooling to 
20.degree. C., 2.4 g (17.6 mmol) of anhydrous Zn Cl.sub.2 are added. The 
mixture is stirred for one hour at 20.degree. C. at which point 2.8 g 
(10.4 mmol) of methyl 6-bromo-2-naphthoate are added and then 92 mg of 
NiCl.sub.2 /1,2-(diphenylphosphino)ethane-DPPE complex are added. 
The mixture is stirred at ambient temperature for 2 hours, poured into 
water, extracted with methylene chloride, washed with sodium bicarbonate, 
dried and then evaporated. The residue is recrystallized in a mixture of 
diisopropyl oxide ans ethyl acetate. 3.7 g of the expected product are 
obtained. Yield--84%. Melting point: 189.degree.-190.degree. C. 
EXAMPLE 6 
6-[p-(1-adamantylthio)phenyl]-2-naphthoic acid 
Compound of Formula II wherein R'.sub.2 =H, R'.sub.6 =OH and R'.sub.3 
=1-adamantylthio 
3 g (7 mmol) of the ester obtained in Example 5(b) are treated with a 
solution of soda in methanol (150 ml, 5N). The reaction mixture is heated 
at reflux for 12 hours, evaporated, taken up in water and acidified with 
concentrated HCl. The resulting solid is filtered and dried under a vacuum 
on phosphoric anhydride. The resulting white solid is pulversized in 
methanol at relfux, cooled and filtered. 2.5 g of the expected product are 
thus obtained. Yield--86%. Melting point: 334.degree.-336.degree. C. 
EXAMPLE 7 
Methyl ester of 6-(3,4-dimethoxy phenyl)-2-naphthoic acid 
Compound of Formula II wherein R'.sub.2 =R'.sub.3 =R'.sub.6 =--OCH.sub.3. 
0.93 g (38.3 mAtg) of magnesium in 20 ml of THF are slowly treated with 5.5 
g (25.5 mmol) of 4-bromove ratrole. At the end of the addition, the 
mixture is heated at reflux for two hours, and then cooled. At this point 
3.48 (25.5 mmol of anhydrous ZnCl.sub.2 are added and the mixture is 
stirred one hour at ambient temperature. 3.98 g (15 mmol) of methyl 
6-bromo-2-naphthoate are then added followed by the addition of 130 mg of 
NiCl.sub.2 /DPPE complex. The mixture is stirred for two hours at ambient 
temperature and then poured into water and extracted with dichloromethane. 
The organic phase is dried and evaporated. The residue is recrystallized 
in a mixture of isopropyl ether and ethyl acetate. 3.4 g of the expected 
product are obtained. Yield--70%. Melting point: 147.degree.-148.degree. 
C. 
EXAMPLE 8 
6-(3,4-dimethoxyphenyl-2-naphthoic acid 
Compound of Formula II wherein R'.sub.2 =R'.sub.3 =--OCH.sub.3 and R'.sub.6 
=OH 
2.6 g (8 mmol) of the ester obtained in Example 7 are treated with a 
solution of soda in methanol (200 ml, 2N). The reaction mixture is heated 
at reflux for 8 hours, evaporated, taken up in water, acidified with 
concentrated HCl, and filtered. The solid thus obtained is dried under a 
vacuum (on P.sub.2 O.sub.5). The resulting white solid is pulverized in 
methanol at reflux, cooled and then filtered. 2.3 g of the expected 
product are obtained. Yield--92%. Melting point: 241.degree.-243.degree. 
C. 
EXAMPLE 9 
Methyl ester of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid 
Compound of Formula II wherein R'.sub.3 --OCH.sub.3, R'.sub.2 =1-adamantyl 
and R'.sub.6 =OCH.sub.3 
(a) 2-(1-adamantyl)-4-bromophenol. 
34.6 g (200 mmol) of p-bromophenol and 30.4 g (200 mmol) of 1-adamantanol 
are dissolved in 100 ml of dichloromethane. To the resulting solution 
there are slowly added 10 ml of concentrated sulfuric acid. The mixture is 
stirred for 8 hours at ambient temperature, poured into water, neutralized 
with sodium bicarbonate, extracted with methylene chloride, dried and 
evaporated. After recrystallization in isooctane 52.8 g of the expected 
product are obtained. Yield--86%. Melting point: 140.degree.-141.degree. 
C. 
(b) 2-(1-adamantyl)-4-bromoanisole. 
To a suspension of sodium hydride (80% in oil, 4.32 g, 144 mmol) in 50 ml 
of THF, there are slowly added, while maintaining the temperature at 
20.degree. C., 36.8 g (120 mmol) of 2-(1-adamantyl)-4-bromophenol. The 
mixture is stirred for 1 hour at ambient temperature at which point 9 ml 
(144 mmol) of methyl iodide are added. The mixture is then stirred for 2 
hours at 20.degree. C., poured into water, extracted with ether, dried and 
evaporated. The product is purified by passage through a silica column 
(10.times.30 cm), eluting with a mixture of hexane (90%) and 
dichloromethane (10%). On evaporation, 26.2 g of a white solid are 
obtained. Yield-68%. Melting point: 138.degree.-139.degree. C. 
(c) Methyl ester of 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid. 
To a suspension of magnesium (1.64 g, 67.5 m Atg) in 30 ml of THF, there is 
added a solution of 1.4 g (4.5 mmol) of 2-(1-adamantyl)-4-bromoanisole and 
0.39 ml of dibromoethane in 10 ml of THF. The mixture is stirred until the 
reaction is initiated and then there is slowly added a solution of 13.1 g 
(40.8 mmol) of 2-(1-adamantyl)-4-bromoanisole in 90 ml of THF. The mixture 
is heated at reflux for 2 hours, and then cooled to 20.degree. C. There 
are then added 6.2 g (45 mmol) of anhydrous ZnCl.sub.2. The mixture is 
stirred for 1 hour at 20.degree. C. at which point 7.95 g (30 mmol) of 
methyl 6-bromo-2-naphthoate are added followed by the addition of 300 g of 
NiCl.sub.2 /DPPE complex. The mixture is stirred again for 2 hours at 
20.degree. C., poured into water, extracted with CH.sub.2 Cl.sub.2, dried 
and evaporated. The product is isolated by column chromatography, eluting 
with a mixture of heptane (70%) and dichloromethane (30%) and then 
recrystallized in ethyl acetate. 12.2 g of the expected product are 
obtained. Yield--78%. Melting point: 222.degree.-223.degree. C. 
EXAMPLE 10 
6-[3-(1-adamantyl)-4-methoxy phenyl]-2-napthoic acid 
Compound of Formula II wherein R'.sub.3 =OCH.sub.3, R'.sub.2 =1-adamantyl 
and R'.sub.6 =OH. 
10.5 g of the ester obtained in Example 9(c) are treated with a solution of 
soda in methanol (200 ml, 4.2 N). The mixture is heated at reflux for 48 
hours. The solvents are evaporated and the resulting residue is taken up 
in water and acidified with concentrated HCl. The solid is filtered and 
dried under a vacuum over phosphoric anhydride. 
The resulting white solid is recrystallized in a mixture of THF and ethyl 
acetate. 8.2. g of the expected product are obtained. Yield--81%. Melting 
point: 325.degree.-327.degree. C. 
EXAMPLE 11 
Methyl ester of 6-[3-(1-adamantyl)-4-tert.butyl 
dimethylsilyloxylphenyl]-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =1-adamantyl, 
R.sub.3 =OSi(CH.sub.3).sub.2 C.sub.3 H.sub.7 and 
##STR10## 
(a) 2-(adamantyl)-4-bromo-1-tert.butyldimethylsilyloxybenzene. 
30.7 g of 2-adamantyl-4-bromophenol (100 mmol) are dissolved in DMF (200 
ml). There are then added triethylamine (15.4 ml, 110 mmol) and 
4-N,N-dimethylaminopyridine (DMAP, 500 mg, 4 mmol). 
To the resulting solution there is slowly added a solution of 
tert.butyldimethylsilyl chloride (15.7 g, 104 mmol) in DMF (100 ml). The 
mixture is stirred at ambient temperature for 4 hours, poured into water, 
extracted with ether, dried (MgSO.sub.4) and evaporated. The residue is 
dissolved in hexane and purified by passage through a silica column 
(eluant: hexane). 36.2 g (86%) of 
2-adamantyl-4-bromo-1-tert.butyldimethylsilyloxybenzene are obtained. 
Melting point--111.degree. C. 
(b) Methyl ester of 
6-]3-(1-adamantyl)-4-tert.butyldimethylsiloxyphenyl]-2-naphthoic acid. 
33.3 g (79 mmol) of the compound produced in part (a) above, dissolved in 
200 of THF are slowly added to a suspension of magnesium (2.9 g, 118 Atg) 
in 60 ml of THF. Once the addition is complete, the mixture is heated at 
reflux for 2 hours at which point the temperature of the mixture is 
permitted to return to ambient temperature. 10.8 g (79 mmol) of anhydrous 
zinc chloride are added and the mixture is stirred for one hour at ambient 
temperature, at which point 10.5 g (39.5 mmol) of methy 
6-bromo-2-naphthoate and 500 mg of NiCl.sub.2 /DPPE complex are added. 
This mixture is then stirred for 2 hours at ambient temperature, poured 
into water, extracted with CH.sub.2 Cl.sub.2, dried and evaporated. The 
residue is chromatographed on a silica column (eluant: mixture of heptane 
(70%) and ether (30%). 18.5 (90%) of the methyl ester of 
6-[3-(1-adamantyl)-4-tert.butyldimethylsilyoxyphenyl] -2-naphthoic acid 
are obtained. Melting point: 152.degree.-153.degree. C. 
EXAMPLE 12 
Methyl ester of 6[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =1-adamantyl, 
R.sub.3 =OH and R.sub.1 COOCH.sub.3 
17.5 g (33 mmol) of the ester produced in Example 11 are dissolved in 300 
ml of THF. To this solution there is added 36.6 ml of a molar solution of 
tetrabutylammonium fluoride in THF. The mixture is stirred fOr 2 hours at 
ambient temperature, poured into water and extracted with CH.sub.2 
Cl.sub.2. The organic phase is recovered, dried (MgSO.sub.4), and the 
solvents evaporated. The resulting residue is recrystallized in a mixture 
of ethylacetate (70%) and THF (30%) to give the expected ester. 11 g 
(81%). Melting point--266.degree. C. 
EXAMPLE 13 
6-[3-(1-adamantyl)-4-hydroxyphenyl-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =(1-adamantyl, 
R.sub.3 =OH and R.sub.1 =COOH 5 g (12 mmol) of the ester obtained in 
Example 12 are treated with 200 ml of methanolic soda (2N), under 
nitrogen, for 8 hours. The solvents are evaporated and the residue taken 
up in water and acidified to pH 1 (concentrated HCl). The reaction mixture 
is filtered, washed with water, the solid product is extracted with ethyl 
ether, dried (MgSO.sub.4) and evaporated. The residue is recrystallized in 
isopropylether, yielding 3.8 g (79%) of the expected acid. Melting point: 
270.degree.-271.degree. C. 
EXAMPLE 14 
Methyl ester of 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =1-adamantyl, 
R.sub.3 =--OC.sub.10 H.sub.21 and R.sub.1 =COOCH.sub.3 
(a) 2-(1-adamantyl)-4-bromo-1-decyloxy benzene. 
To a suspension of sodium hydride (80% in oil, 3.2 g, 104 mmol) in 100 ml 
of THF, there is slowly added a solution of 2-(1-adamantyl)-4-bromophenol 
(29 g, 95 mmol) in 200 ml of THF. The mixture is stirred until the 
evolution of gas ceases at which point 27.8 g (23 ml, 104 mmol) of 
1-iododecane and 100 ml of DMF are added. The mixture is stirred for 12 
hours at ambient temperature, poured into water, extracted with ether, 
dried and the solvents evaporated. The resulting residue is purified by 
passage through a silica column (eluant: heptane), yielding 40.7 g (96%) 
of 2-(1-adamantyl)-4-bromo-1-decyloxybenzene. Melting point: 
69.degree.-70.degree. C. 
(b) Methyl ester of 6-[3-(1adamantyl)-4-decyloxyphenyl]-2- naphthoic acid. 
In a manner analogous to Example 9c, starting with 17.9 g (40 mmol) of the 
brominated derivative obtained in part (a) above, and 5.3 g of methyl 
6-bromo-2-naphthoate, 7.4 g (67%) of the expected ester are obtained. 
Melting point: 113.degree.-114.degree. C. 
EXAMPLE 15 
6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =1-adamantyl, 
R.sub.3 =--OC.sub.10 H.sub.21 and R.sub.1 =COOH 
6.3 g (11 mmol) of the ester obtained in Example 14 dissolved in 200 ml of 
THF are treated at reflux with 200 ml of 2M methanolic soda for 4 hours. 
The solvents are evaporated and the residue is taken up in water, 
acidified to pH 1 (concentrated HCl), filtered, washed with water and the 
solid is extracted with ether. The extract is dried and the solvent 
evaporated. The resulting residue is treated with 700 ml of ethyl acetate 
at reflux. On cooling 5.9 g (97%) of the expected acid are obtained. 
Melting point: 214.degree.-215.degree. C. 
EXAMPLE 16 
Methyl ester of 6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid. 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =1-adamantyl, 
R.sub.3 =--OC.sub.6 H.sub.13 and R.sub.1 =--COOCH.sub.3 
5.3 g (13 mmol) of the ester obtained in Example 12 are dissolved in 100 ml 
of DMF and added to a suspension of NaH (80% in oil; 0.46 g; 15.4 mmol) in 
DMF (50 ml). The mixture is stirred at ambient temperature until the 
evolution of gas ceases, at which point 1-iodohexane (3.26 g; 2.3 ml; 15.4 
mmol) is added. This mixture is then stirred for 4 hours at ambient 
temperature, poured into water, extracted with ether, dried and 
evaporated. The residue is purified by passage through a silica column 
(eluant: mixture of dichloromethane - 50% and hexane - 50%), then 
recrystallized in isooctane to give 5.5 g (87%) of the expected pure 
product. Melting point: 129.degree.-130.degree. C. 
EXAMPLE 17 
6-[3-(1-admantyl)-4-hexyloxyphenyl]-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =1-adamantyl, 
R.sub.3 =--OC.sub.6 H.sub.13 and R.sub.1 =--COOH 
In a manner analogous to Example 15, starting with 4.2 g (8.4 mmol) of the 
ester obtained in Example 16, 3.8 g (95%) of 
6-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid are obtained. Melting 
point: 260.degree.-261.degree. C. 
EXAMPLE 18 
Methyl ester of 6-[3-(1-adamantyl)-4-methoxy 
phenyl]-4-acetoxy-1-methyl-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =CH.sub.3, R.sub.5 =--OCOCH.sub.3, 
R.sub.2 =1-adamantyl, R.sub.3 =--OCH.sub.3 and R.sub.1 =--COOCH.sub.3 
47.6 g (148 mmol) of 2-(1-adamantyl)-4-bromoanisole and 13.9 g (6.3 ml, 74 
mmol) of dibromoethane, dissolved in 100 ml of THF are added slowly to a 
suspension of magnesium (5.4 g, 222 mmol) in the THF (1000 ml). The 
mixture is brought to reflux for 2 hours at which point zinc chloride 
(20.2 g, 148 mmol) is added. The mixture is stirred for 1 hour and there 
are successively added 24.9 g (74 mmol) of methyl 
4-acetoxy-6-bromo-1-methyl-2-naphthoate and 500 mg of NiCl.sub.2 /DPPE 
complex. This mixture is stirred for 8 hours at ambient temperature, 
poured into a saturated aqueous solution of ammonium chloride, extracted 
with CH.sub.2 Cl.sub.2, dried and the solvents evaporated. The resulting 
residue is purified by passage through a silica column (eluant: mixture of 
hexane, 40%, and CH.sub.2 Cl.sub.2, 60%). The resulting product is 
recrystallized in isopropyl ether, yielding 23.5 g (64%) of the expected 
ester. Melting point: 201.degree.-202.degree. C. 
EXAMPLE 19 
6-[3-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy-1methyl -2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =CH.sub.3, R.sub.5 =OH, R.sub.2 
=1-adamantyl, R.sub.3 =OCH.sub.3 and R.sub.1 =COOH 
23 g (46 mmol) of the ester obtained in Example 18 are treated at reflux 
for 12 hours with 300 ml of methanolic soda (2N). The solvents are 
evaporated and the residue is taken up in water and acidified to pH 1 
(concentrated HCl). The solid is filtered, washed with water, dissolved in 
ethyl ether, dried (MgSO.sub.4) and evaporated. The resulting residue is 
recrystallized in ethyl acetate to 18.7 g (92%) of the expected acid. 
Melting point: 281.degree.-283.degree. C. 
EXAMPLE 20 
Methyl ester of 
6-[3-(1-adamantyl)-4-methoxy-phenyl]-4-hydroxy-1-methyl-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =CH.sub.3, R.sub.5 =OH, R.sub.2 
=1-adamantyl, R.sub.3 =OCH.sub.3 and R.sub.1 =COOCH.sub.3 
17 g (38 mmol) of the acid obtained in Example 19 are treated for 12 hours 
at reflux with 200 ml of methanol containing 2 ml of sulfuric acid. The 
solvents are evaporated and the residue is taken up in water, extracted 
with ether, dried and evaporated. The residue is purified by passage 
through a silica column using as the eluant a 90:10 mixture of ether/THF. 
The product is recrystallized in ethyl acetate to obtain the expected pure 
ester - 15 g (86%). Melting point: 272.degree.-274.degree. C. 
EXAMPLE 21 
Methyl ester of 6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic 
acid 
Compound of Formula I wherein R.sub.4 =CH.sub.3, R.sub.5 =H, R.sub.2 
=1-adamantyl, R.sub.3 =OCH.sub.3 and R.sub.1 =--COOCH.sub.3 
(a) Methyl 
6-[3-(1-adamantyl)-4-methoxyphenyl]-4-dimethylaminothiocarbonyloxy-1-methy 
l-2-naphoate 
4.56 g of the ester obtained in Example 20, dissolved in THF (100 ml) are 
slowly added to a suspension of sodium hydride (80% in oil, 360 mg, 12 
mmol) in DMF (50 ml). The mixture is stirred for 1 hour at ambient 
temperature and then for 1 hour at 40.degree. C. There are then added 1.75 
g (14 mmol) of dimethylthiocarbamoyl chloride, and the mixture is stirred 
initially at ambient temperature for 2 hours and then at 40.degree. C. for 
2 hours. The reaction mixture is poured into water, extracted with ether, 
dried, and the solvents evaporated. The product is purified by passage 
through a silica column (eluant: CH.sub.2 Cl.sub.2), yielding 4 g (74%) of 
the expected intermediate product. Melting point: 137.degree.-138.degree. 
C. 
(b) Methyl 
6-[3-(1-adamantyl)-4-methoxyphenyl]-4-dimethylcarbonythio-1-methyl-2-napht 
hoate. 
3.8 g (7 mmol) of the ester obtained above in part (a) are heated under 
nitrogen at 260.degree. C. for 0.5 hour. The residue is taken up in 
methylene chloride and purified by passage through a silica column 
(eluant: CH.sub.2 Cl.sub.2). The resulting gum is taken up in isopropyl 
ether, yielding 3.3 g (87%) of the desired intermediate. Melting point: 
201.degree.-202.degree. C. 
(c) Methyl ester of 
6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid. 
The intermediate obtained above in part (b) - (11 g, 20 mmol) is dissolved 
in 500 ml of ethanol. 20 g of Raney nickel are added and the reaction 
mixture is heated at reflux for 4 hours. 20 g of nickel are then added and 
the mixture is heated again for 1 hour, at which point the mixture is 
cooled, concentrated and taken up in CH.sub.2 Cl.sub.2 (1000 ml). The 
precipitate is filtered and the filtrate is recovered, dried and 
evaporated. The product is purified by passage through a silica column 
(eluant: CH.sub.2 Cl.sub.2) and recrystallized in a mixture of ethyl 
acetate (90%) and THF (10%), yielding 8 g (90%) of the methyl ester of 
6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid. Melting 
point: 238.degree.-239.degree. C. 
EXAMPLE 22 
6-[3-(1-adamantyl)-4-methoxyphenyl]-1-methyl-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =CH.sub.3, R.sub.5 =H, R.sub.2 
=1-adamantyl, R.sub.3 =OCH.sub.3 and R.sub.1 =COOH. 
6.8 g (15.4 mmol) of the ester obtained in Example 21(c) are treated as in 
Example 10 to give 5.8 g (88%) of the corresponding acid. Melting point: 
300.degree.-302.degree. C. 
EXAMPLE 23 
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalene methanol 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =1-adamantyl, 
R.sub.3 =OCH.sub.3 and R.sub.1 =--CH.sub.2 OH 
1.3 g (3 mmol) of the ester obtained in Example 9 dissolved in THF (5 ml) 
are treated with 171 mg (4.5 mmol) of LiAlH.sub.4. The mixture is heated 
at reflux, cooled and treated with a saturated aqueous solution of the 
double tartrate of sodium and potassium. The reaction mixture is filtered, 
evaporated to dryness, and the residue is recrystallized in cyclohexane, 
yielding 1.0 g (83%) of the 
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalene methanol. Melting point: 
163.degree.-164.degree. C. 
EXAMPLE 24 
Ethylamide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 =1-adamantyl, 
R.sub.3 =OCH.sub.3 and R.sub.1 =--CONHC.sub.2 H.sub.5. 
(a) 6-[3-(1-adamantyl)-4-methoxy phenyl]-2-naphthoic acid chloride. 
4.75 g (1.15 mmol) of the acid obtained in Example 10 in 200 ml of 
dichloromethane are treated with 2.08 g (2.3 ml, 1.15 mmol) of 
dicyclohexamine. The mixture is stirred at ambient temperature until 
dissolution. The solvents are evaporated and the residue taken up in 
ether. The solid thus formed is filtered (6.8 g) and then taken up in 
methylene chloride (50 ml). 1.37 g (0.84 ml, 1.15 mmol) of thionyl 
chloride are added. The salt forced is filtered and the filtrate is 
recovered, evaporated and dried. The resulting solid (3.9 g) is used as 
such in the following step. 
(b) Ethylamide of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid. 
1.3 g (3 mmol) of the acid chloride produced in (a) above are dissolved in 
20 ml of THF. 405 mg (600 .mu.l, 9 mmol) of ethylamine are added and the 
mixture is stirred for 2 hours at ambient temperature. The mixture is then 
poured into water, extracted with CH.sub.2 Cl.sub.2, dried and evaporated. 
The residue is recrystallized in ethyl acetate, yielding 1.1 g (85%) of 
the expected ethylamide. Melting point: 220.degree.-221.degree. C. 
EXAMPLE 25 
Morpholide of 6-[3-(1-adamantyl)-4-methoxyphenyl]2-naphthoic acid 
In a manner analogous to Example 24, starting with 1.3 g of acid chloride 
produced in part (a) of Example 24 and 780 mg (780 ml, 9 mmol) of 
morpholine, there are obtained 1.3 g (91%) of the expected morpholide. 
Melting point: 212.degree.-213.degree. C. 
EXAMPLE 26 
Methyl ester of 6-[3-tert.butyl-4-methoxy phenyl]2-naphthoic acid 
Compound of Formula II wherein R'.sub.2 =tert.butyl, R'.sub.3 =R'.sub.6 
=OCH.sub.3. 
(a) 4-bromo-2-tert.butyl anisole. 
3.10 g (22.6 mmol) of aluminum chloride are added all at once to a mixture 
of 63.5 g (339 mmol) of p-bromoanisole and 31.4 g (330 mmol) of tert.butyl 
chloride. The mixture is stirred at ambient temperature until the 
evolution of gas ceases (about 15 minutes). The mixture is then heated at 
80.degree. C. for 15 minutes and poured into ice. 300 ml of water are 
added and the mixture is extracted with ether. 
The organic phase is dried (MgSO.sub.4), the solvents evaporated and the 
residue purified by chromatography on a silica column (eluant: mixture of 
methylene chloride - 10% and hexane - 90%). After evaporation of the 
solvents, 4-bromo-2-tert.butyl anisole under the form of a colorless oil 
which crystallized on cooling is obtained. 31.9 g (39%). 
(b) Methyl ester of 6-[3-tert.butyl-4-methoxy phenyl]-2-naphthoic acid. 
There is slowly added, drop by drop, a solution of 18.8 g (77 mmol) of 
4-bromo-2-tert.butyl anisole to 2.26 g (93 mmol) of magnesium turnings and 
a crystal of iodine. The mixture is heated until the Grignard begins to 
form, at which point the remainder of the solution containing the 
brominated derivative is poured in a manner to maintain a regular reflux. 
Once the addition is complete, the mixture is heated at 40.degree. C. for 
30 minutes, diluted with 200 ml of THF and cooled to ambient temperature. 
12.7 g (93 mmol) of dry zinc chloride in solution in 20 ml of THF are 
added and the mixture is stirred for 30 minutes at ambient temperature. 
There are then successively added 12.1 g (46 mmol) of methyl 
6-bromo-2-naphthoate and 300 mg of NiCl.sub.2 /DPPE complex. 
The mixture is stirred for 10 hours at ambient temperature. 300 ml of water 
are added and the THF is evaporated. The remainder is extracted with 
methylene chloride. The organic phase is dried (MgSO.sub.4), filtered, 
evaporated and purified by passage through a silica column (eluant: 
mixture of 50% dichloromethane and 50% hexane). After evaporation of the 
solvents, the resulting residue is recrystallized in hexane to give the 
expected ester: 11.5 g (72%). Melting point - 160.degree. C. 
EXAMPLE 27 
6-(3-tert.butyl-4-methoxyphenyl)-2-naphthoic acid 
Compound of Formula II wherein R'.sub.2 =tert.butyl, R'.sub.3 =OCH.sub.3 
and R'.sub.6 =OH 
In a manner analogous to Example 15, starting with 7.0 g (20 mmol of the 
ester obtained in Example 26, 6.0 g (90%) of the expected acid are 
obtained. Melting point: 268.degree. C. 
EXAMPLE 28 
Methyl ester of 6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 
=C(CH.sub.3).sub.2 C.sub.9 H.sub.19, R.sub.3 =OCH.sub.3 and R.sub.1 
=--COOCH.sub.3 
A solution of 16 g (45 mmol) of 2-(1,1-dimethyldecyl)-4-bromo anisole in 60 
ml of THF is slowly added to 1.3 g (54 mmol) of magnesium and a crystal of 
iodine. The mixture is slightly heated at the beginning of the addition 
until the reaction of formation of the Grignard is initiated. Then the 
remainder of the solution containing the brominated derivative is added in 
a manner to maintain a regular reflux. Once the addition is complete, the 
mixture is stirred for 30 minutes at 50.degree. C. and then cooled to 
ambient temperature. 7.4 g (54 mmol) of zinc chloride in solution in 50 ml 
of THF are added. The mixture is stirred for 30 minutes at ambient 
temperature, 6.6 g (25 mmol) of methyl 6-bromo-2-naphthoate are added and 
then 175 mg of NiCl.sub.2 /DPPE complex. The mixture is stirred for 3 
hours at ambient temperature at which point 250 ml of water are added. The 
THF is evaporated under reduced pressure and the residue is extracted with 
dichloromethane, dried and the solvent evaporated. The residue is purified 
by passage through a silica column (eluant: mixture of 60% dichloromethane 
and 40% hexane). On evaporation, a solid is obtained which is 
recrystallized twice in hexane to give the methyl ester of 
6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid: 7.05 g (61%). 
Melting point: 92.degree. C. 
EXAMPLE 29 
6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid 
Compound of Formula I wherein R.sub.4 =R.sub.5 =H, R.sub.2 
=C(CH.sub.3).sub.2 C.sub.9 H.sub.19, R.sub.3 =OCH.sub.3 and R.sub.1 =COOH 
In a manner analogous to Example 15, starting with 3.6 g of the ester 
obtained in Example 28, 3 g (87%) of 
6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid are obtained. 
Melting point: 180.degree. C. 
EXAMPLES OF COMPOSITIONS 
EXAMPLE A 
Fatty cream wherein the active principle is in suspension 
______________________________________ 
6-[3-(10-adamantyl)-4-methoxy phenyl]- 
0.001 g 
2-naphthoic acid 
A combination of nonionic E/H emulsifiers 
25.00 g 
and a fatty body of mineral origin sold 
by Goldschmidt under the trade name 
"Protegin X" 
Petrolatum oil 10.00 g 
Preservatives, sufficient amount 
Water, sufficient amount for 
100.00 g 
______________________________________ 
In that example, the active compound can be replaced by the same amount of 
6-[3-(1-adamantyl)-4-methoxy phenyl]-1-methyl 2-2-naphthoic acid. 
EXAMPLE B 
Skin cream--A fluid cream wherein the active principle is in suspension 
______________________________________ 
Methyl ester of 6.(4-tert.butyl phenyl)-2- 
0.02 g 
naphthoic acid 
Sorbitan stearate polyoxyethylenated 
5.00 g 
with 20 moles of ethylene oxide sold 
by Atlas under the trade name "Tween 60" 
Sorbitan monostearate sold by Atlas under 
2.00 g 
the trade name "Span 60" 
Cetyl alcohol 5.00 g 
Triglycerides of capric and caprylic 
10.00 g 
acids sold by Dynamit Nobel under the 
trade name "Miglyol 812" 
Preservatives, sufficient amount 
Water, sufficient amount for 
100.00 g 
______________________________________ 
EXAMPLE C 
Gel for the skin or scalp wherein the active principle is in suspension. 
______________________________________ 
Methyl ester of 6-(4-t.butyl phenyl)-2- 
0.10 g 
naphthoic acid 
Ethanol 20.00 g 
Hydroxypropyl cellulose, sold by Hercules 
2.00 g 
under the trade name "Klucel HF" 
Preservative, sufficient amount 
Water, sufficient amount for 
100.00 g 
______________________________________ 
EXAMPLE D 
Lotion for the skin 
______________________________________ 
6-[3-(1-adamantyl)-4-methoxyphenyl]-1- 
0.1 g 
methyl-2-naphthoic acid 
Polyethylene glycol 400 70.0 g 
Ethanol 29.9 g 
______________________________________ 
In that example, the active compound can be replaced by the same amount of 
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid. 
EXAMPLE E 
Unguent for the skin 
______________________________________ 
6-[3-(1-adamantyl)-4-methoxyphenyl]-2- 
0.001 g 
naphthoic acid 
Lanolin 50 g 
Vaseline, sufficient amount for 
100 g 
______________________________________ 
EXAMPLE F 
Oral composition--0.30 g gelule. 
______________________________________ 
6-[3-(1-adamantyl)-4-methoxy phenyl]-2- 
0.003 g 
naphthoic acid 
Cornstarch 0.060 g 
Lactose, sufficent amount for 
0.300 g 
______________________________________ 
The resulting powder is packaged in a gelule whose wall is made of gelatin, 
TiO.sub.2 and a preservative. 
EXAMPLE G 
Capsule containing 0.400 g of the following suspension 
______________________________________ 
Ethylamide of 6-[3-(1-adamantyl)-4-methoxy- 
0.005 g 
phenyl]-2-naphthoic acid 
Glycerine 0.200 g 
Sucrose 0.050 g 
Polyethylene glycol 400 0.050 g 
Purified water, sufficient amount for 
0.400 g 
______________________________________ 
This suspension is packaged in a capsule made of gelatin, glycerin titanium 
dioxide and water.