U.S. patent number RE34,440 [Application Number 07/913,897] was granted by the patent office on 1993-11-09 for benzonaphthalene derivatives, a process for their preparation and their use in therapeutic and cosmetic compositions.
This patent grant is currently assigned to Centre International de Recherches Dermatologiques (C.I.R.D.). Invention is credited to Jean-Michel Bernardon, Jacques Eustache, Braham Shroot.
United States Patent |
RE34,440 |
Shroot , et al. |
November 9, 1993 |
Benzonaphthalene derivatives, a process for their preparation and
their use in therapeutic and cosmetic compositions
Abstract
A benzonaphthalene compound has the formula ##STR1## wherein
R.sub.1 represents ##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 radial; 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 conjunctive tissues. The compound
also possesses anti-tumor activity.
Inventors: |
Shroot; Braham (Antibes,
FR), Eustache; Jacques (Grasse, FR),
Bernardon; Jean-Michel (Nice, FR) |
Assignee: |
Centre International de Recherches
Dermatologiques (C.I.R.D.) (Valbonne, FR)
|
Family
ID: |
19730438 |
Appl.
No.: |
07/913,897 |
Filed: |
July 16, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
120958 |
Nov 16, 1987 |
4940696 |
|
|
|
850145 |
Apr 10, 1986 |
4717720 |
|
|
Reissue of: |
502122 |
Mar 30, 1990 |
05098895 |
Mar 24, 1992 |
|
|
Foreign Application Priority Data
Current U.S.
Class: |
514/62; 514/859;
514/700; 514/682; 514/718; 514/717; 514/712; 514/845; 514/844;
514/319; 514/237.5; 514/63; 514/622; 514/620; 514/619; 514/618;
514/617; 514/732; 514/730; 514/721; 514/719; 514/863; 514/913;
514/914; 514/533; 514/559; 514/544; 514/569; 514/621;
514/255.01 |
Current CPC
Class: |
C07C
65/11 (20130101); A61P 27/14 (20180101); A61K
8/37 (20130101); A61K 31/165 (20130101); C07C
65/24 (20130101); C07C 69/76 (20130101); C07C
69/94 (20130101); A61P 27/02 (20180101); A61P
37/08 (20180101); A61P 11/00 (20180101); C07C
323/62 (20130101); C07C 63/36 (20130101); A61K
8/368 (20130101); A61P 35/00 (20180101); C07C
39/42 (20130101); A61P 29/00 (20180101); A61Q
5/00 (20130101); A61Q 19/00 (20130101); C07C
235/66 (20130101); A61K 31/235 (20130101); C07C
65/17 (20130101); A61Q 7/00 (20130101); A61P
37/00 (20180101); C07F 7/1804 (20130101); A61K
8/42 (20130101); C07C 65/26 (20130101); A61P
17/00 (20180101); A61Q 19/008 (20130101); C07D
295/192 (20130101); C07D 295/185 (20130101); Y10S
514/912 (20130101); Y10S 514/859 (20130101); Y10S
514/845 (20130101); Y10S 514/913 (20130101); Y10S
514/885 (20130101); Y10S 514/886 (20130101); Y10S
514/88 (20130101); Y10S 514/887 (20130101); Y10S
514/863 (20130101); A61K 2800/92 (20130101); C07C
2603/74 (20170501); Y10S 514/914 (20130101); A61K
2800/75 (20130101); Y10S 514/844 (20130101) |
Current International
Class: |
A61K
31/235 (20060101); A61K 31/165 (20060101); A61K
31/21 (20060101); A61K 031/435 (); A61K 031/19 ();
B01J 029/04 (); B01J 029/06 () |
Field of
Search: |
;514/63,237.5,533,544,569,718 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Ramsuer; Robert W.
Attorney, Agent or Firm: Cushman, Darby & Cushman
Parent Case Text
This is a division of application Ser. No. 07/120,958, filed Nov.
16, 1987, now U.S. Pat. No. 4,940,696, which is a division of Ser.
No. 06/850,145, filed Apr. 10, 1986, now U.S. Pat. No.
4,717,720.
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 inflammator and/or
immunoallergic components and in the treatment of diseases
attributable to the degeneration of conjuctive tissue, The
benzonophthalene derivatives of the present invention also exhibit
anti-tumor activity. Moreover, these derivatives can be employed in
the treatment of atopy 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 retonic 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; ##STR5## or (ii) --CH.sub.2 OH,
R.sub.6 represents ##STR6## or --OR.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.carbon atoms, alkoxy having 1-4 carbon atoms or a
cycoaliphatic 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 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 "monohydroxyalkyl" 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 terms "polyhydroxyalkyl" is meant an alkyl radical having
3-6 carbon atoms substituted 2-5 hydroxyl groups, such as
2,3-dihydroxy propyl, 1,3-dihydroxy propyl, or the residue of
pentaerythritol.
The term "cycloaliphatic" is meant to include a mono or polycyclic
radical such as, for example, 1-methyl cyclohexyl or
1-adamantyl.
The preferred thiocycloaliphatic radical is, principally,
1-adamantylthio.
r' and r" together form a heterocycle, it is preferably a
piperidino, piperazino, morphilino or pyrrolidino 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 represent 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 -maphtoic 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-(1-adamantylthio)phenyl]-2-naphthoic acid and its methyl
ester,
(6)-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid and its
methyl ester,
(7) the methyl ester of 6-[3-(1-adamantyl)-4-tert.butyl
dimethylsilyloxyphenyli-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-decyloxy-phenyl]-2-naphthoic acid,
(11) 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphtoic 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-methoxy
phenyl]-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-adamanty)-4-methoxyphenyl]-2-naphthalene methanol.
(20) the ethylamide of 6-[3-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.butyl-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-(1,1-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 NiII (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 22 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]2-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
keratinization 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;
leucplasies 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 atopies, 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 above-mentioned
diseases, comprising in a pharmaceutically acceptable support, at
least one compound of Formula I and/or a salt thereof.
As has been indicated 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
isimerized 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 of 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, solutions, 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, pomrades,
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 ad3uvants and principally: hydrating agents such as
thiamorpholinone and its derivatives or urea; antiserbottheic
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-piperdinopyrimidine-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-eicosatetrainoic acid and 5,8,11-triynoic acid.
The compositions according to the present invention can also
contain flavor improving agent, 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.
Claims
What is claimed is:
1. A process for the treatment of a dermatologic, rheumatismal,
respiratory or ophtalmologic disease comprising administering to a
person suffering from said disease an effective amount of a
composition containing, in a pharmaceutically acceptable vehicle,
as the active ingredient thereof a benzonaphthalene compound of the
formula ##STR11## wherein R.sub.1 represents ##STR12## or
(ii)--CH.sub.2 OH, R.sub.6 represents ##STR13## 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 or a residue of an amino
acid, glucosamine, galactosamine or mannosamine, or together form a
heterocycle selected from the group consisting of piperidino,
piperazino, morpholino and pyrrolidino,
R.sub.2 represents hydrogen, branched or straight chain alkyl
having 1-15 carbon atoms, alkoxy having 1-4 carbon atoms or a
cycloaliphatic radical,
R.sub.3 represents hydrogen, hydroxy, branched or straight chain
alkyl having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a
cycloaliphatic radical selected from the group consisting of 1-
methylcyclohexyl and 1-adamantyl, a thiocycloaliphatic radical, or
--O--Si(CH.sub.3).sub.2 --R.sub.8 wherein R.sub.8 represents linear
or branched alkyl,
R.sub.4 and R.sub.5 each independently represent hydrogen, lower
alkyl.Iadd., hydroxy .Iaddend.or lower acyloxy. or salt
thereof.
2. A cosmetic composition for both and hair hygiene comprising a
cosmetically acceptable vehicle and an effective amount of as the
active ingredient at least one benzonaphthalene compound of the
formula ##STR14## wherein R.sub.1 represents ##STR15## or (ii)
--CH.sub.2 OH, R.sub.6 represents ##STR16## 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 or a residue of an
amino acid, glucosamine, galactosamine or mannosamine, or together
form a heterocycle selected from the group consisting of
piperidino, piperazino, morpholino and pyrrolidino,
R.sub.2 represents hydrogen, branched or straight chain alkyl
having 1-15 carbon atoms, alkoxy having 1-4 carbon atoms or a
cycloaliphatic radical.
R.sub.3 represents hydrogen, hydroxy, branched or straight chain
alkyl having 1-4 carbon atoms, alkoxy having 1-10 carbon atoms, a
cycloaliphatic radical selected from the group consisting of
1-methylcyclohexyl and 1- adamantyl, a thiocycloaliphatic radical,
or --O--Si(CH.sub.3).sub.2--R.sub.8 wherein R.sub.8 represents
linear or branches alkyl,
R.sub.4 and R.sub.5 each independently represent hydrogen, lower
alkyl.Iadd., hydroxy .Iaddend.or lower acyloxy, or a salt
thereof.
3. The cosmetic composition of claim 2 wherein said active
ingredient is present in an amount ranging from 0.0005 to 2 weight
percent based on the total weight of said composition.
4. The cosmetic composition of claim 2 wherein said active
ingredient is present in an amount ranging from 0.01 to 1 weight
percent based on the total weight of said composition.
Description
EXAMPLE 1
Methyl ester of 6-(3-methylphenyl)-2-naphtholic acid. Compound of
Formula II wherein R'.sub.3 .dbd.H and R'.sub.2 .dbd.--CH.sub.3 and
R'.sub.6 .dbd.--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 successfully 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.dbd.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 .dbd.H. R'.sub.3
.dbd.--C(CH.sub.3).sub.3 and R'.sub.6 .dbd.--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 .dbd.H. R'.sub.2
.dbd.--C(CH.sub.3).sub.3 and R'.sub.6 .dbd.--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-napthoate 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 recystallized in heptane, 3.12 g
of the methyl ester of 6-(1-tert.butyl phenyl)-2-napthoic 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 .dbd.H. R'.sub.2 .dbd.--C(CH.sub.3).sub.3 and
R'.sub.6 .dbd.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-(3-tert.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 .dbd.H, R'.sub.3
.dbd.1-adamantylthio and R'.sub.6 .dbd.--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 re 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 (2.65 m Atg) of magnesium suspended in 10 ml of
tetrathydrofuran (THF) are treated slowly with 5.7 g (17.6 mmol) of
p-(1-adamanthylthio) 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 and 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 .dbd.H, R'.sub.6 .dbd.OH and R'.sub.3
.dbd.1-adamantylthio
3 g (7mmol) 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 vacuo of phosphoric anhydride. The resulting
white solid is pulverized in methanol at reflux, 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 .dbd.R'.sub.3 .dbd.R'.sub.6
.dbd.--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-bromoveratrole. At the end of the
addition, the mixture is heated at reflux for two hours, and then
cooled. At this point 3.48 g (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 recyrstallized 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 .dbd.R'.sub.3 .dbd.-- OCH.sub.3 and R'.sub.6
.dbd.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.
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
.dbd.1-adamantyl and R'.sub.6 .dbd.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-adamanyl)-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-9
-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 of 10
ml of THF. The mixture is stirred until the reaction is initiated
and then there is slowly added a solution of 13.3 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-naphthoic acid. Compound of
Formula II wherein R'.dbd.OCH.sub.3, R'.sub.2 .dbd.1-adamantyl and
R'.sub.6 .dbd.OH.
10.5 g of the ester obtained in Example 9(c) are treated with a
solution of soda in methanol (200 ml, 4.2N). 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
the ethylacetate. 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 .dbd.R.sub.5 .dbd.H, R.sub.2 .dbd.2-adamantyl,
R.sub.3 .dbd.OSi(CH.sub.3).sub.2 C.sub.3 H.sub.7 and ##STR10##
(a) 2-(adamantyl)-4-bromo-1-tert.butyldimethylsilyloxy-benzene 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 print. 111.degree. C.
(b) Methyl ester of 6-[3-(1-adamantyl)-4-tert.butyldimethyl
siloxyphenyl]-2-naphthoic acid 33.3 g (79 mmol) of the compound
produced in part (a) above, dissolved in 200 ml 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 anydrous 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 methyl
6-bromo-2-naphthoate and 500 g 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.butyldimethylsilyloxyphenyl]-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 .dbd.R.sub.5 .dbd.H, R.sub.2
.dbd.1-adamantyl, R.sub.3 .dbd.OH and R.sub.1 .dbd.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 flouoride 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 .dbd.R.sub.5 .dbd.H, R.sub.2
.dbd.1-adamantyl, R.sub.3 .dbd.OH and R.sub.1 .dbd.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 isoproplether, 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 .dbd.R.sub.5 .dbd.H,
R.sub.2 .dbd.1-adamantyl, R.sub.3 .dbd.--OC.sub.10 H.sub.21 and
R.sub.1 .dbd.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 it 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-(1-adamantyl)-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 .dbd.R.sub.5 .dbd.H, R.sub.2
.dbd.1-adamantyl, R.sub.3 .dbd.--OC.sub.10 H.sub.21 and R.sub.1
.dbd.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 or 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 .dbd.R.sub.5 .dbd.H,
R.sub.2 .dbd.1-adamantyl, R.sub.3 .dbd.--OC.sub.6 H.sub.13 and
R.sub.1 .dbd.--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, as 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-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid. Compound of
Formula I wherein R.sub.4 .dbd.R.sub.5 .dbd.H, R.sub.2
.dbd.1-adamantyl, R.sub.3 .dbd.--OC.sub.6 H.sub.13 and R.sub.1
.dbd.--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 .dbd.CH.sub.3. R.sub.5 .dbd.--OCOCH.sub.3, R.sub.2
.dbd.1-adamantyl, R.sub.3 .dbd.--OCH.sub.3 and R.sub.1
.dbd.--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 a 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 2.9 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 crystallized 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-1-methyl-2-naphthoic
acid. Compound of Formula I wherein R.sub.4 .dbd.CH.sub.3, R.sub.5
.dbd.OH, R.sub.2 .dbd.1-adamantyl, R.sub.3 .dbd.OCH.sub.3 and
R.sub.1 .dbd.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 HCl1). 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 give 18.7 g (92%) of the expected acid. Melting point:
281.degree.-283.degree. C.
EXAMPLE 20
Methyl ester of
6-(1-adamantyl)-4-methoxyphenyl]-4-hydroxy-1-methyl-2-naphthoic
acid Compound of Formula I wherein R.sub.4 .dbd.CH.sub.3, R.sub.5
.dbd.OH, R.sub.2 .dbd.1-adamantyl, R.sub.3 .dbd.OCH.sub.3 and
R.sub.1 .dbd.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 .dbd.CH.sub.3, R.sub.5
.dbd.H, R.sub.2 .dbd.1-adamantyl, R.sub.3 .dbd.OCH.sub.3 and
R.sub.1 .dbd.--COOCH.sub.3 (a) Methyl
6-[3-(1-adamantyl)-4-methoxyphenyl]-4-dimethylaminothiocarbonyloxy-1-methy
l-2-naphthoate
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-dimethyl-carbonythio-1-methyl-2-naph
thoate
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-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 .dbd.CH.sub.3, R.sub.5
.dbd.H,R.sub.2 .dbd.1-adamantyl, R.sub.3 .dbd.OCH.sub.3 and R.sub.1
.dbd.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-napthalene methanol. Compound
of Formula I wherein R.sub.4 .dbd.R.sub.5 .dbd.H, R.sub.2
.dbd.1-adamantyl, R.sub.3 .dbd.OCH.sub.3 and R.sub.1 .dbd.CH.sub.20
H
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 6-13-(1-adamantyl)-4-methoxyphenyl]-2-naphthalene methanol.
Melting point: 163.degree.-164.degree. C.
EXAMPLE 24
6-[3-(1-adamantyl)-4-methoxyphenyl-9 -2-naphthoic acid. Compound of
Formula I wherein R.sub.4 .dbd.R.sub.5 .dbd.H, R.sub.2
.dbd.1-adamantyl, R.sub.3 .dbd.OCH.sub.3 and R.sub.1
.dbd.--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 either. The solid thus formed is filtered (6.8 g) and
then taken up in methylene chloride (50 ml). 1.37 g (0.85 ml, 1.15
mmol) of thionyl chloride are added. The salt formed 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 morphine, 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 .dbd.tert.butyl, R'.sub.3
.dbd.R'.sub.6 .dbd.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 of 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 30minutes, 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 .dbd.tert.butyl, R'.sub.3
.dbd.OCH.sub.3 and R'.sub.6 .dbd.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 .dbd.R.sub.5 .dbd.H, R.sub.2
.dbd.C(CH.sub.3).sub.2 C.sub.9 H.sub.19, R.sub.3 .dbd.OCH.sub.3 and
R.sub.1 .dbd.--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 eva-porated
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%
dichlorlmethane 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: 705 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 .dbd.R.sub.5 .dbd.H, R.sub.2
.dbd.C(CH.sub.3).sub.2 C.sub.9 H.sub.19, R.sub.3 .dbd.OCH.sub.3 and
R.sub.1 .dbd.COOH.
In a manner anologous to Example 15, starting with 3.6 g of the
ester obtained in Example 28, 3 (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-(1-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 Preservative, 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
2-2naphthoic 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- 0.3 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,
sufficient 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, glycerine
titanium dioxide and water.
* * * * *