U.S. patent application number 09/788469 was filed with the patent office on 2002-01-24 for stilbene compounds comprising an adamantyl group, compositions and methods thereof.
Invention is credited to Bernardon, Jean-Michel, Charpentier, Bruno.
Application Number | 20020010337 09/788469 |
Document ID | / |
Family ID | 9499383 |
Filed Date | 2002-01-24 |
United States Patent
Application |
20020010337 |
Kind Code |
A1 |
Bernardon, Jean-Michel ; et
al. |
January 24, 2002 |
Stilbene compounds comprising an adamantyl group, compositions and
methods thereof
Abstract
The invention relates to novel stilbene compounds having the
general formula (I): 1 as well as to pharmaceutical compositions
for use in human or veterinary medicine, including dermatological,
rheumatic, respiratory, cardiovascular and ophthalmic conditions
and cosmetic compositions and methods of use thereof.
Inventors: |
Bernardon, Jean-Michel; (Le
Rouet, FR) ; Charpentier, Bruno; (Biot, FR) |
Correspondence
Address: |
Norman H. Stepno
BURNS, DOANE, SWECKER & MATHIS, L.L.P.
P.O. Box 1404
Alexandria
VA
22313-1404
US
|
Family ID: |
9499383 |
Appl. No.: |
09/788469 |
Filed: |
February 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09788469 |
Feb 21, 2001 |
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09002040 |
Dec 31, 1997 |
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6214878 |
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Current U.S.
Class: |
546/285 ;
548/528; 549/497; 549/498; 549/78; 568/326 |
Current CPC
Class: |
A61P 25/04 20180101;
C07C 2603/74 20170501; C07C 43/315 20130101; C07C 323/62 20130101;
A61P 29/00 20180101; A61P 37/08 20180101; A61P 37/00 20180101; C07C
43/313 20130101; A61P 17/00 20180101; C07D 213/80 20130101; A61P
17/16 20180101; C07D 213/79 20130101; C07C 65/28 20130101 |
Class at
Publication: |
546/285 ;
548/528; 549/78; 549/497; 549/498; 568/326 |
International
Class: |
C07D 333/16; C07D
211/80; C07D 27/32 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 31, 1996 |
FR |
96-16311 |
Claims
What is claimed is:
1. A stilbene compound, corresponding to formula (I): 5wherein:
R.sub.1 represents (i) the --CH.sub.3 radical, (ii) the radical
--CH.sub.2--O-R.sub.6, (iii) the radical --O--R.sub.6, or (iv) the
radical --CO--R.sub.7, wherein the radicals R.sub.6 and R.sub.7
having the meanings given below, Ar represents a radical comprising
one of the radicals of formulae (a) to (f): 6wherein R.sub.8 and
R.sub.9 having the meanings given below, R.sub.2 and R.sub.3, which
may be identical or different, represent a hydrogen atom or a lower
alkyl radical, R.sub.4 represents the radical
--(X).sub.m--(CH.sub.2).sub.n--Y--(CH.sub.2).sub.p- --R.sub.10 the
values m, n and p and the radicals X, Y and R.sub.10 having the
meanings given below, R.sub.5 represents a hydrogen or halogen
atom, a lower alkyl radical or a radical --O--R.sub.6, R.sub.6
represents a hydrogen atom, a lower alkyl radical or a radical
--CO--R.sub.11, R.sub.7 represents a hydrogen atom, a lower alkyl
radical, a radical --OR.sub.12 or a radical 7wherein R' and R",
which may be identical or different, represent a hydrogen atom, a
lower alkyl radical, a mono- or polyhydroxyalkyl radical, an
optionally substituted aryl radical or an amino acid or peptide or
sugar residue, or alternatively, taken together, form a
heterocycle, wherein m is an integer equal to 0 or 1 n is an
integer ranging from 1 to 6, inclusive, p is an integer ranging
from 1 to 6, inclusive, X represents O or S(O).sub.q, Y represents
O, S(O).sub.q or N--R.sub.9, q is an integer ranging from 0 to 2,
inclusive, R.sub.8 represents a hydrogen or halogen atom, a lower
alkyl radical or a radical --O--R.sub.6, R.sub.9 represents a
hydrogen atom, a lower alkyl radical or a radical --CO--R.sub.11,
R.sub.10 represents a mono- or polyhydroxyalkyl radical wherein the
hydroxyls are optionally protected in the form of methoxy, ethoxy,
acetoxy or acetonide, a radical --CO--R.sub.7 or an optionally
substituted aryl or aralkyl radical, R.sub.11 represents a lower
alkyl radical, R.sub.12 represents a hydrogen atom, an alkyl
radical, an alkenyl radical, a mono- or polyhydroxyalkyl radical in
which the hydroxyls are optionally protected in the form of
methoxy, ethoxy, acetoxy or acetonide, an optionally substituted
aryl or aralkyl radical, a sugar residue or an amino acid or
peptide residue, or salts thereof or optical or geometrical isomers
thereof.
2. The compound as defined by claim 1, which is in the form of a
salt of an alkali metal or alkaline earth metal, of zinc, of an
organic amine or of an inorganic or organic acid.
3. The compounds as defined by claim 1, wherein the lower alkyl
radical comprises a methyl, ethyl, propyl, isopropyl, tert-butyl or
hexyl radical.
4. The compound as defined by claim 1, wherein the polyhydroxyalkyl
radical comprises 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, or
2,3,4,5-tetrahydroxypentyl radical or the pentaerythritol
residue.
5. The compound as defined by claim 1, wherein the aryl radical
comprises a phenyl radical optionally substituted with at least one
halogen atom, a hydroxyl radical, an alkyl radical, a nitro
function, a methoxy group or an optionally substituted amine
function.
6. The compound as defined by claim 1, wherein the aralkyl radical
comprises benzyl or phenethyl radicals, optionally substituted with
at least one halogen atom, a hydroxyl, a nitro function or a
methoxy group.
7. The compound as defined by claim 1, wherein the alkenyl radical
comprises radicals containing from 2 to 5 carbon atoms and having
one or more ethylenic unsaturations, and in particular the allyl
radical.
8. The compound as defined by claim 7, wherein the alkenyl radical
comprises an allyl radical.
9. The compound as defined by claim 1, wherein the sugar residue
comprises a glucose, galactose, mannose or glucuronic acid
residue.
10. The compound as defined by claim 1, wherein the amino acid
residue comprises a residue derived from lysine, glycine or
aspartic acid.
11. The compound as defined by claim 1, wherein the peptide residue
comprises dipeptide or tripeptide residues.
12. The compound as defined by claim 1, wherein the heterocyclic
radical comprises piperidino, morpholino, pyrrolidino and
piperazino radicals optionally substituted in position 4 with a
C.sub.1-C.sub.6 alkyl or polyhydroxyalkyl radical.
13. The compound as defined by claim 1, wherein the halogen atom
comprises fluorine, bromine or chlorine.
14. The compound as defined by claim 1, comprising: Ethyl
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)ethenyl]benzoate;
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)ethenyl]benzoic
acid; Ethyl
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-pr-
openyl]benzoate;
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)--
1-propenyl]benzoic acid;
4-[(Z)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy--
phenyl)-1-propenyl]benzoic acid; Methyl
5-{2-[3-adamant-1-yl-4-(2-methoxye-
thoxy-methoxy)phenyl]propen-(E)-yl}pyridine-2-carboxylate;
5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}pyri-
dine-2-carboxylic acid;
5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-ph-
enyl]propen-(Z)-yl}pyridine-2-carboxylic acid; Ethyl
6-{2-[3-adamant-1-yl-4-(2-methoxy-ethoxymethoxy)phenyl]propen-(E)-yl}nico-
tinate;
6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)--
yl}nicotinic acid;
6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]-
propen-(Z)-yl}nicotinic acid; Methyl
4-{2-[3-adamant-1-yl-4-(2-methoxyetho-
xy-methoxy)phenyl]propen-(Z)-yl}-2-methoxybenzoate;
4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}-2-m-
ethoxybenzoic acid;
4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl-
]propen-(Z)-yl}-2-methoxybenzoic acid; Ethyl
4-{2-[3-adamant-1-yl-4-(3-eth-
oxy-methoxypropyl)phenyl]propen-(E/Z)-yl}benzoate;
4-{2-[3-Adamant-1-yl-4--
(3-ethoxymethoxy-propyl)phenyl]propen-(E)-yl}benzoic acid;
4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]propen-(Z)-yl}benzoi-
c acid; Ethyl
4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen-(E/-
Z)-yl}-benzoate;
4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen--
(E)-yl}-benzoic acid;
4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-pr-
open-(Z)-yl}benzoic acid; Ethyl
4-{2-[3-adamant-1-yl-4-(3-diethylcarbamoyl-
-methoxypropyl)phenyl]propenyl}benzoate;
4-{2-[3-Adamant-1-yl-4-(3-diethyl-
carbamoylmethoxy-propyl)phenyl]propenyl}benzoic acid; Ethyl
4-{2-[3-adamant-1-yl-4-(3-carboxymethoxypropyl)phenyl]propenyl}benzoate;
4-{2-[3-Adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propenyl}benzoic
acid; Ethyl
4-{2-[3-adamant-1-yl-4-(3-carbamoylmethoxy-propyl)phenyl]prop-
enyl}benzoate;
4-{2-[3-Adamant-1-yl-4-(3-carbamoylmethoxypropyl)-phenyl]pr-
openyl}benzoic acid;
N-Ethyl-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-met-
hoxyphenyl)-1-propenyl]benzamide;
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethox-
ymethoxy-phenyl)-1-propenyl]benzamide;
N-4-(Hydroxyphenyl)-4-[(E)-2-(3-(1--
adamantyl)-4-methoxyethoxymethoxyphenyl)-1-propenyl]benzamide;
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benze-
nemethanol;
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-pro-
penyl]benzaldehyde;
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-pheny-
l)-1-propenyl]phenol;
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phe-
nyl)-1-propenyl]benzoic acid morpholide; or
4-[(E)-2-(3-(1-Adamantyl)-4-me-
thoxyethoxymethyl-sulphanylphenyl)-1-propenyl]benzoic acid; or
mixtures thereof.
15. The compound as defined by claim 1, having at least one of the
following characteristics: R.sub.1 is the radical --CO--R.sub.7, Ar
represents the radicals of formulae (a) or (b), X and Y, which may
be identical or different, independently represent an oxygen or
sulfur atom, R.sub.3 represents a lower alkyl radical.
16. A pharmaceutical composition comprising at least one stilbene
compound as defined by claim 1 and pharmaceutically acceptable
carrier therefor.
17. The pharmaceutical composition as defined by claim 16, wherein
said stilbene compound ranges from 0.01% to 5% by weight relative
to the weight of the entire composition.
18. A cosmetic composition comprising at least one stilbene
compound as defined by claim 1 and a cosmetically acceptable
carrier therefor.
19. The cosmetic composition as defined by claim 18, wherein said
stilbene compound ranges from 0.001% to 3% by weight relative to
the weight of the entire composition.
20. The cosmetic composition as defined by claim 18, which is
applied to the body or the hair.
21. A method for the prevention or treatment of a dermatological
condition at least one compound as defined by claim 1, to a patient
in need of such prevention or treatment.
22. The method as defined by claim 21, wherein said dermatological
condition comprises a condition involving at least one of common
acne, comedones, polymorphonuclear leukocytes, acne rosacea,
nodulocystic acne, acne conglobata, senile acne, secondary acnes,
medication-induced acne, occupational acne, ichthyosis,
ichthyosiform states, Darrier's disease, palmoplantar keratoderma,
leucoplasia, a leucoplasiform state, cutaneous or mucous (buccal)
lichen, keratinization disorder having an inflammatory and/or
immunoallergic component, cutaneous, mucous or ungual psoriasis,
psoriatic rheumatism, cutaneous atopy, eczema, respiratory atopy,
gingival hypertrophy; inflammatory complaints which do not exhibit
a disorder of keratinization; dermal or epidermal proliferations,
common warts, flat warts and verruciform epidermodysplasia, oral or
florid papillomatoses, basocellular and spinocellular epitheliomas;
bullosis and collagen diseases; ophthalmological disorders,
corneopathies; light-induced and chronological aging of the skin,
actinic keratoses and pigmentations; stigmata of epidermal and/or
dermal atrophy induced by local or systemic corticosteroids, skin
atrophy; cicatrization disorders, stretch marks; sebaceous
functioning, hyperseborrhoea of acne or simple seborrhoea;
cancerous or precancerous states, promyelocytic leukemias;
inflammatory complaints, arthritis; viruses; alopecia;
dermatological complaints having an immunological component;
complaints of the cardiovascular system, arteriosclerosis,
hypertension, insulin-independent diabetes; or skin disorders due
to exposure to UV radiation.
Description
BACKGROUND OF THE INVENTION
TECHNICAL FIELD OF THE INVENTION
[0001] The invention relates to stilbene compounds containing an
adamantyl group which are novel and useful industrial products. The
invention also relates to the use of these novel compounds in
pharmaceutical compositions intended for use in human or veterinary
medicine, or alternatively, in cosmetic compositions.
SUMMARY OF THE INVENTION
[0002] The compounds according to the present invention have
pronounced activity in the fields of cell proliferation and
differentiation, and find application more particularly in the
topical and systemic treatment of dermatological complaints
associated with a keratinization disorder, dermatological (or
other) complaints with an inflammatory and/or immunoallergic
component, and dermal or epidermal proliferations, whether benign
or malignant. These compounds can also be used in the treatment of
degenerative diseases of connective tissue, to combat aging of the
skin, both light-induced and chronological aging, and to treat
cicatrization disorders. They also find application in the
ophthalmic field, in particular, in the treatment of
corneopathies.
[0003] The compounds according to the present invention can also be
used in cosmetic compositions for body and hair hygiene.
[0004] The compounds according to the invention can be represented
by the general formula (I) below: 2
[0005] wherein:
[0006] R.sub.1 represents
[0007] (i) the --CH.sub.3 radical,
[0008] (ii) the radical --CH.sub.2--O--R.sub.6,
[0009] (iii) the radical --O--R.sub.6, or
[0010] (iv) the radical --CO--R.sub.7,
[0011] wherein the radicals R.sub.6 and R.sub.7 have the meanings
given below,
[0012] Ar represents a radical of formulae (a) to (f) below: 3
[0013] wherein R.sub.8 and R.sub.9 have the meanings given
below,
[0014] R.sub.2 and R.sub.3 which may be identical or different,
independently represent a hydrogen atom or a lower alkyl
radical,
[0015] R.sub.4 represents the radical
--(X).sub.m--(CH.sub.2).sub.n--Y--(C- H.sub.2).sub.p--R.sub.10,
[0016] wherein the values m, n and P and the radicals X, Y and
R.sub.10 having the meanings given below,
[0017] R.sub.5 represents a hydrogen or halogen atom, a lower alkyl
radical or a radical --O--R.sub.6,
[0018] R.sub.6 represents a hydrogen atom, a lower alkyl radical or
a radical --CO--R.sub.11,
[0019] R.sub.7 represents a hydrogen atom, a lower alkyl radical, a
radical --OR.sub.12 or a radical 4
[0020] wherein R' and R", which may be identical or different,
independently represent a hydrogen atom, a lower alkyl radical, a
mono- or polyhydroxyalkyl radical, an optionally substituted aryl
radical or an amino acid or peptide or sugar residue, or
alternatively, taken together, form a heterocycle, it being
understood that, in all of the text hereinabove:
[0021] m is an integer ranging from 0 to 1,
[0022] n is an integer ranging from 1 to 6, inclusive,
[0023] p is an integer ranging from 1 to 6, inclusive,
[0024] X represents O or S(O).sub.q,
[0025] Y represents O, S(O).sub.q or N--R.sub.9,
[0026] g is an integer ranging from 0 to 2, inclusive,
[0027] R.sub.8 represents a hydrogen or halogen atom, a lower alkyl
radical or a radical --O--R.sub.6,
[0028] R.sub.9 represents a hydrogen atom, a lower alkyl radical or
a radical --CO--R.sub.11,
[0029] R.sub.10 represents a mono- or polyhydroxyalkyl radical
wherein the hydroxyls are optionally protected in the form of
methoxy, ethoxy, acetoxy or acetonide, a radical --CO--R.sub.7 or
an optionally substituted aryl or aralkyl radical,
[0030] R.sub.11 represents a lower alkyl radical,
[0031] R.sub.12 represents a hydrogen atom, an alkyl radical, an
alkenyl radical, a mono- or polyhydroxyalkyl radical in which the
hydroxyls are optionally protected in the form of methoxy, ethoxy,
acetoxy or acetonide, an optionally substituted aryl or aralkyl
radical, a sugar residue or an amino acid or peptide residue, and
the optical and geometrical isomers of the compounds of formula
(I), as well as the salts thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0032] FIG. 1 is a schematic diagram of a process for preparing the
compounds of formulae I(a), I(b) and I(c).
[0033] FIG. 2 is a schematic diagram of a process for preparing a
halogenated compound of the present invention.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
[0034] When the compounds according to the invention are in the
form of salts resulting from the addition of an acid, the salts are
pharmaceutically or cosmetically acceptable salts obtained by
addition of an inorganic or organic acid, in particular,
hydrochloric acid, sulfuric acid, acetic acid, citric acid, fumaric
acid, hemisuccinic acid, maleic acid or mandelic acid. When the
compounds according to the invention are in the form of salts
resulting from the addition of a base, those salts are preferably
salts of an alkali metal or alkaline earth metal, or alternatively,
salts of zinc or of an organic amine.
[0035] According to the present invention, the term alkyl radical
is understood to refer to a linear or branched radical optionally
substituted with one or more halogen atoms having from 1 to 20,
preferably from 1 to 12, carbon atoms, advantageously the methyl,
ethyl, isopropyl, butyl, tert-butyl, hexyl, nonyl and dodecyl
radicals. When it is lower, the alkyl radical generally comprises
from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms.
Exemplary lower alkyl comprise methyl, ethyl, propyl, isopropyl,
tert-butyl and hexyl radicals.
[0036] Exemplary linear alkyl radicals having from 1 to 20 carbon
atoms comprise methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl,
hexadecyl and octadecyl radicals.
[0037] Exemplary branched alkyl radicals having from 1 to 20 carbon
atoms comprise 2-methylpentyl, 1-methylhexyl and 3-methylheptyl
radicals.
[0038] By the term "alkenyl radical" is intended a linear or
branched radical having from 2 to 20 carbon atoms containing one or
more double bonds.
[0039] The preferred alkenyl radical is a radical ranging from 2 to
5 carbon atoms and having one or more ethylenic unsaturations, more
preferably the allyl radical.
[0040] By the term "monohydroxyalkyl or polyhydroxyalkyl radical"
is intended a radical containing from 1 to 6 carbon atoms and from
1 to 5 hydroxyl groups.
[0041] The preferred monohydroxyalkyl radical comprises a radical
ranging from 1 to 3 carbon atoms, in particular the hydroxymethyl,
2-hydroxyethyl and 2-or 3-hydroxypropyl radicals.
[0042] The preferred polyhydroxyalkyl radical comprises a radical
having from 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups,
for example, the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or
2,3,4,5-tetrahydroxypen- tyl radicals or the pentaerythritol
residue.
[0043] The preferred aryl radical comprises a phenyl radical
optionally substituted with at least one halogen atom, a hydroxyl
radical, an alkyl radical, a nitro function, a methoxy group or an
optionally substituted amine function.
[0044] The preferred aralkyl radical comprises the benzyl or
phenethyl radical optionally substituted with at least one halogen
atom, a hydroxyl radical, a nitro function or a methoxy group.
[0045] By the term "sugar residue" is intended a residue derived in
particular from glucose, galactose or mannose, or alternatively
from glucuronic acid.
[0046] By the term "amino acid residue" is intended a residue
derived from one of the amino acids, for example, lysine, glycine
or aspartic acid, and by the term "peptide residue" is intended a
dipeptide or tripeptide residue resulting from the combination of
amino acids.
[0047] By the term "heterocycle" is intended a piperidino,
morpholino, pyrrolidino or piperazino radical, optionally
substituted in position 4 with a C.sub.1-C.sub.6 alkyl or
polyhydroxyalkyl radical as defined above.
[0048] When the radicals R.sub.5 and R.sub.8 represent a halogen
atom, the halogen atom is preferably a fluorine, bromine or
chlorine atom.
[0049] Particular compounds of formula (I) according to the present
invention comprise:
[0050] Ethyl
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)ethen-
yl]benzoate.
[0051]
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)ethenyl]ben-
zoic acid.
[0052] Ethyl
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-pr-
openyl]benzoate.
[0053]
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl-
]benzoic acid.
[0054]
4-[(Z)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl-
]benzoic acid.
[0055] Methyl
5-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]prope-
n-(E)-yl}pyridine-2-carboxylate.
[0056]
5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-y-
l}pyridine-2-carboxylic acid.
[0057]
5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-y-
l}pyridine-2-carboxylic acid.
[0058] Ethyl
6-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-
-(E)-yl}nicotinate.
[0059]
6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)yl-
}nicotinic acid.
[0060]
6{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl-
}nicotinic acid.
[0061] Methyl
4-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]prope-
n-(Z)-yl}-2-methoxybenzoate.
[0062]
4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-y-
l}-2-methoxybenzoic acid.
[0063]
4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-y-
l}-2-methoxybenzoic acid.
[0064] Ethyl
4-{2-[3-adamant-1-yl-4-(3-ethoxymethoxypropyl)-phenyl]propen--
(E/Z)-yl}benzoate.
[0065]
4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]-propen-(E)-yl-
}benzoic acid.
[0066]
4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]-propen-(Z)-yl-
}benzoic acid.
[0067] Ethyl
4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen-(E/Z-
)-yl}benzoate.
[0068]
4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(E)-yl}ben-
zoic acid.
[0069]
4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(Z)-yl}ben-
zoic acid.
[0070] Ethyl
4-{2-[3-adamant-1-yl-4-(3-diethylcarbamoyl-methoxypropyl)phen-
yl]propenyl}benzoate.
[0071]
4-{2-[3-Adamant-1-yl-4-(3-diethylcarbamoylmethoxypropyl)phenyl]prop-
enyl}benzoic acid.
[0072] Ethyl
4-{2-[3-adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propen-
yl}benzoate.
[0073]
4-{2-[3-Adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propenyl}ben-
zoic acid.
[0074] Ethyl
4-{2-[3-adamant-1-yl-4-(3-carbamoylmethoxy-propyl)phenyl]prop-
enyl}benzoate.
[0075]
4-{2-[3-Adamant-1-yl-4-(3-carbamoylmethoxypropyl)-phenyl]propenyl}b-
enzoic acid.
[0076]
N-Ethyl-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-l--
propenyl]benzamide.
[0077]
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl-
]benzamide.
[0078]
N-4-(Hydroxyphenyl)-4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxymethox-
y-phenyl)-1-propenyl]benzamide.
[0079]
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl-
]benzenemethanol.
[0080] 4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1
-propenyl]benzaldehyde.
[0081]
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl-
]phenol.
[0082]
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl-
]benzoic acid morpholide.
[0083]
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethyl-sulphanylphenyl)-1--
propenyl]benzoic acid.
[0084] According to the present invention, the preferred compounds
of formula (I) are those for which at least one, and more
preferably all, of the conditions below apply:
[0085] R.sub.1 is the radical --CO--R.sub.7,
[0086] Ar represents the radicals of formula (a) or (b),
[0087] X and Y, which may be identical or different, independently
represent oxygen or sulfur atoms,
[0088] R.sub.3 represents a lower alkyl radical.
[0089] The subject of the present invention is also a process for
the preparation of the compounds of formula (I), in particular,
according to the reaction schemes set forth in FIGS. 1 and 2.
[0090] Thus, the compounds of formula I(a), I(b) and I(c) can be
obtained (FIG. 1) by reacting, in an anhydrous medium in an organic
solvent, preferably THF, an aromatic aldehyde derivative (1) (when
R.sub.3 is a hydrogen atom) or an aromatic ketone derivative (2)
(when R.sub.3 is a lower alkyl radical) in a Horner-Emmons or
Wittig type reaction with aromatic phosphonate derivatives (3) or
aromatic phosphine derivatives (4) in the presence of sodium
hydride or potassium tert-butoxide.
[0091] In these olefination reactions, the geometrical isomer
having an E configuration can also be obtained by conversion of the
isomer, having a Z configuration by irradiation under UV light.
[0092] When R.sub.4 represents the radicals
--(CH.sub.2).sub.n--Y--(CH.sub- .2).sub.p--R.sub.10, the compounds
can be obtained (FIG. 2) from phenol derivatives (5) which are
converted into triflate derivatives (6), followed by a reaction
with a tin derivative (7) in the presence of a palladium catalyst
(for example bis(-triphenyl-phosphine)palladium(II) chloride
according to M. Echavarren and J. K. Stille, J. Am. Chem. Soc.,
109, 5478-86 (1987)). The alcohol derivatives (9) are obtained by
reaction of the ethylenic derivatives (8) with
9-borabicyclo[3.3.1]nonane- , followed by oxidation with aqueous
hydrogen peroxide solution, according to E. F. Knights et al., J.
Am. Chem. Soc., 90, 5281 (1968). By alkylation with a halogenated
derivative (10), the derivatives (11) are obtained. When R.sub.1
represents the --COOH radical, the compounds are prepared by
protecting R.sub.1 with a protecting group of the alkyl, allylic or
tert-butyl type. Passage to the free form can be carried out:
[0093] in the case of an alkyl protecting group, using sodium
hydroxide or lithium hydroxide in an alcoholic solvent, such as
methanol, or in THF,
[0094] in the case of an allylic protecting group, using a
catalyst, such as certain transition metal complexes, in the
presence of a secondary amine such as morpholine,
[0095] in the case of a protecting group of tert-butyl type, using
trimethylsilyl iodide.
[0096] When R.sub.1 is an alcohol radical, the compounds can be
obtained from the acid by reduction in the presence of lithium
aluminum hydride.
[0097] When R.sub.1 is an aldehyde radical, the compounds can be
obtained from the alcohol by oxidation with manganese oxide or
pyridinium dichromate.
[0098] When R.sub.1 is a radical of the amide type, the compounds
can be prepared by conversion of the acid into the acid chloride,
for example, with thionyl chloride, followed by reaction with
aqueous ammonia or a suitable amine.
[0099] The products of general formula (I) can serve as starting
materials for the manufacture of other compounds of formula (I)
according to the invention. These compounds are obtained according
to the standard synthetic methods used in chemistry, such as those
described in "Advanced Organic Chemistry" by J. March; John Wiley
and Sons (1985).
[0100] For example, functional modifications of the group R.sub.1
can be carried out as indicated below:
1 carboxylic acid .fwdarw. ester ester .fwdarw. carboxylic acid
acid .fwdarw. acid chloride acid chloride .fwdarw. amide acid
.fwdarw. amide acid .fwdarw. alcohol alcohol .fwdarw. aldehyde
amide .fwdarw. amine thiol .fwdarw. thioether thioether .fwdarw.
sulfoxide thioether .fwdarw. sulfone sulfonic acid .fwdarw.
sulfonic ester sulfonic acid .fwdarw. sulfonamide sulfinic acid
.fwdarw. sulfinic ester
[0101] The compounds according to the invention show activity in
the test of differentiation of mouse embryonic teratocarcinoma
cells (F9) (Cancer Research, 43, 5268 (1983)) and/or in the test of
inhibition of ornithine decarboxylase after induction with TPA in
mice (Cancer Research, 38, 793-801 (1978)). These tests show the
activities of these compounds in the fields of cell differentiation
and cell proliferation, respectively. In the test of cell (F9)
differentiation, an agonist activity may be evaluated as an
antagonist activity to retinoic acid receptors. This is because an
antagonist is inactive when it is alone in this test, but partially
or totally inhibits the effect produced by a retinoid which is an
agonist towards the morphology and secretion of the plasminogen
activator. Some of these compounds are thus also active in a test
which is used to identify molecules which are RAR antagonists, as
described in French patent application No. 95/07302 filed on Jun.
19, 1995 by the same Assignee as the present invention, which is
incorporated by reference in its entirety herein. This test
comprises the following steps: (i) a sufficient amount of an
RAR-agonist molecule is applied topically to a part of the skin of
a mammal, (ii) a molecule capable of exhibiting RAR-antagonist
activity is administered systemically or topically to this same
mammal or to this same part of the skin of the mammal, before,
during or after step (i), and (iii) the response on that part of
the mammal's skin which has been treated is evaluated. Thus, the
response to a topical application, to the ear of a mammal, of an
RAR-agonist molecule, which corresponds to an increase in the
thickness of this ear, may be inhibited by the systemic or topical
administration of an RAR-antagonist molecule. In addition, some of
these compounds may provide synergism to the biological activity of
products binding to the nuclear receptors.
[0102] The subject of the present invention is also, a
pharmaceutical or cosmetic composition comprising the compounds of
formula (I) as defined above in combination with a pharmaceutically
or cosmetically acceptable carrier therefor.
[0103] The compounds according to the present invention are
particularly useful in the following fields of treatment:
[0104] (1) for treating dermatological conditions associated with a
keratinization disorder which has a bearing on cell differentiation
and on proliferation, in particular for treating common acne,
comedones, polymorphonuclear leucocytes, acne rosacea, nodulocystic
acne, acne conglobata, senile acne and secondary acnes such as
solar acne, medication-induced acne or occupational acne,
[0105] (2) for treating other types of keratinization disorders, in
particular ichthyosis, ichthyosiform states, Darrier's disease,
palmoplantar keratoderma, leucoplasias and leucoplasiform states,
and cutaneous or mucous (buccal) lichen,
[0106] (3) for treating other dermatological complaints associated
with a keratinization disorder having an inflammatory and/or
immunoallergic component and, in particular, all forms of
psoriasis, whether it is cutaneous, mucous or ungual psoriasis, and
even psoriatic rheumatism, or alternatively cutaneous atopy, such
as eczema, or respiratory atopy or alternatively gingival
hypertrophy; the compounds may also be used in certain inflammatory
complaints which do not exhibit a disorder of keratinization,
[0107] (4) for treating all dermal or epidermal proliferations,
whether benign or malignant and whether or not they are of viral
origin, such as common warts, flat warts and verruciform
epidermodysplasia, it being also possible for the oral or florid
papillomatoses and the proliferations to be induced by ultraviolet
radiation, in particular in the case of basocellular and
spinocellular epitheliomas,
[0108] (5) for treating other dermatological disorders such as
bullosis and collagen diseases,
[0109] (6) for treating certain ophthalmological disorders, in
particular corneopathies,
[0110] (7) for repairing or combating both light-induced and
chronologic aging of the skin or for reducing actinic keratoses and
pigmentations, or any pathology associated with chronological or
actinic ageing,
[0111] (8) for preventing or curing the stigmata of epidermal
and/or dermal atrophy induced by local or systemic corticosteroids,
or any other form of skin atrophy,
[0112] (9) for preventing or treating cicatrization disorders or
for preventing or repairing stretch marks,
[0113] (10) for combating disorders of sebaceous functioning such
as the hyperseborrhea of acne or simple seborrhea,
[0114] (11) in the treatment or prevention of cancerous or
precancerous states,
[0115] (12) in the treatment of inflammatory complaints such as
arthritis,
[0116] (13) in the treatment of any complaint of viral origin on
the skin or generally, such as Kaposi's syndrome,
[0117] (14) in the prevention or treatment of alopecia,
[0118] (15) in the treatment of dermatological or general
complaints having an immunological component,
[0119] (16) in the treatment of complaints of the cardiovascular
system such as arteriosclerosis or hypertension, as well as
insulin-independent diabetes,
[0120] (17) in the treatment of skin disorders due to exposure to
UV radiation.
[0121] In the therapeutic fields mentioned above, the compounds
according to the invention may advantageously be employed in
combination with other compounds having retinoid-type activity,
with D vitamins or derivatives thereof, with corticosteroids, with
anti-free-radical agents, a-hydroxy or a-keto acids or derivatives
thereof, or alternatively with ion-channel blockers. The expression
D vitamins or derivatives thereof is understood to refer, for
example, to vitamin D2 or D3 derivatives and in particular
1,25-dihydroxy vitamin D3. The expression anti-free-radical agent
is understood to refer, for example, to .alpha.-tocopherol,
superoxide dismutase, ubiquinol or certain metal-chelating agents.
The expression .alpha.-hydroxy or .alpha.-keto acids or derivatives
thereof is understood to refer, for example, to lactic acid, malic
acid, citric acid, glycolic acid, mandelic acid, tartaric acid,
glyceric acid or ascorbic acid or salts, amides or esters thereof.
Lastly, the expression ion-channel blockers is understood to refer,
for example, to minoxidil (2,4-diamino-6-piperidinopyrimidine
3-oxide) and derivatives thereof.
[0122] The subject of the present invention is also a medicinal
composition comprising at least one compound of formula (I) as
defined above, one of the optical or geometrical isomers thereof or
one of the salts thereof, in combination with a pharmaceutically or
cosmetically acceptable carrier therefor.
[0123] The subject of the present invention is thus a novel
medicinal composition intended in particular for treating the
above-mentioned complaints, and which comprises, in a
pharmaceutically acceptable support or carrier which is compatible
with the mode of administration selected for this composition, at
least one compound of formula (I), one of the optical or
geometrical isomers thereof or one of the salts thereof.
[0124] The compounds according to the invention may be administered
enterally, parenterally, topically or ocularly.
[0125] Via the enteral route, the medicinal products may be in the
form of tablets, gelatin capsules, sugar-coated tablets, syrups,
suspensions, solutions, powders, granules, emulsions, microspheres
or nanospheres or polymeric or lipid vesicles which allow
controlled release. Via the parenteral route, the compositions may
be in the form of solutions or suspensions for infusion or for
injection.
[0126] The compounds according to the invention are generally
administered at a daily dose of about 0.01 mg/kg to 100 mg/kg of
body weight, taken in 1 to 3 doses.
[0127] Via the topical route, the pharmaceutical compositions based
on compounds according to the invention are more particularly
intended for treating the skin and mucous membranes and may, in
this case, be in the form of an ointment, cream, milk, salve,
powder, impregnated pad, solution, gel, spray, lotion or
suspension. They may also be in the form of microspheres or
nanospheres or polymeric or lipid vesicles or polymeric patches and
hydrogels which allow controlled release. These topical route
compositions may moreover be either in anhydrous form or in an
aqueous form, depending on the clinical indication.
[0128] Via the ocular route, they are primarily administered as
eyedrops.
[0129] The compositions for topical or ocular use contain at least
one compound of formula (I) as defined above, or one of the optical
or geometrical isomers thereof, or alternatively one of the salts
thereof, at a concentration preferably ranging from 0.001% to 5% by
weight relative to the total weight of the composition.
[0130] The compounds of formula (I) according to the invention also
find an application in the cosmetics field, in particular, for body
or hair hygiene and especially for treating skin types with a
tendency towards acne, for promoting the regrowth of hair, for
combating hair loss, for controlling the greasy appearance of the
skin or the hair, in protecting against the harmful effects of
sunlight or in the treatment of physiologically dry skin types, and
for preventing and/or combating light-induced or chronologic
aging.
[0131] In the cosmetics field, the compounds according to the
invention may also advantageously be employed in combination with
other compounds having retinoid-type activity, with D vitamins or
derivatives thereof, with corticosteroids, with anti-free-radical
agents, .alpha.-hydroxy or .alpha.-keto acids or derivatives
thereof, or alternatively with ion-channel blockers, all of these
different products being as defined above or having an
art-recognized definition.
[0132] The present invention is thus also directed to a cosmetic
composition which comprises, in a cosmetically acceptable support
or carrier which is suitable for topical application, at least one
compound of formula (I) as defined above, or one of the optical or
geometrical isomers thereof or one of the salts thereof. The
cosmetic composition is preferably in the form of a cream, a milk,
a lotion, a gel, microspheres or nanospheres or polymeric or lipid
vesicles, a soap or a shampoo.
[0133] The concentration of compound of formula (I) in the cosmetic
composition according to the present invention preferably ranges
from 0.001% to 3% by weight relative to the composition as a
whole.
[0134] The medicinal and cosmetic compositions according to the
invention may also contain inert additives or even
pharmacodynamically or cosmetically active additives or
combinations of these additives and, in particular, wetting agents;
depigmenting agents such as hydroquinone, azelaic acid, caffeic
acid or kojic acid; emollients; moisturizing agents such as
glycerol, PEG 400, thiamorpholinone and derivatives thereof, or,
alternatively, urea; anti-seborrhea or anti-acne agents such as
S-carboxymethylcysteine, S-benzylcysteamine, the salts and the
derivatives thereof, or benzoyl peroxide; antibiotics such as
erythromycin and esters thereof, neomycin, clindamycin and esters
thereof, and tetracyclines; anti-fungal agents such as ketoconazole
or 4,5-polymethylene-3-isothiazolidones; agents for promoting the
regrowth of hair, such as minoxidil
(2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives
thereof, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiaz- ine
1,1-dioxide) and phenytoin (5,4-diphenylimidazolidine-2,4-dione);
non-steroidal anti-inflammatory agents; carotenoids and, in
particular, .beta.-carotene; anti-psoriatic agents such as
anthraline and derivatives thereof and, lastly,
eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-trynoic acid,
the esters and the amides thereof.
[0135] The compositions according to the invention may also contain
flavor enhancing agents, preservatives such as para-hydroxybenzoic
acid esters, stabilizing agents, moisture regulators, pH
regulators, osmotic pressure modifiers, emulsifying agents, UV-A
and UV-B screening agents, and antioxidants such as
.alpha.-tocopherol, butylhydroxyanisole or butylhydroxytoluene.
[0136] In order to further illustrate the present invention and the
advantages thereof, the following specific examples of the
production of active compounds of formula (I) according to the
invention, as well as various solid formulations based on such
compounds are given, it being understood that same are intended
only as illustrative and in nowise limitative.
[0137] A. EXAMPLES OF COMPOUNDS
EXAMPLE 1
Ethyl
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)ethenyl]benz-
oate
[0138] (a)
3-(1-Adamantyl)-1-bromo-4-methoxyethoxymethoxy-benzene.
[0139] 3.8 g (0.13 mol) of sodium hydride (80% in oil) and 50 ml of
DMF were introduced into a three-necked flask under a stream of
nitrogen. A solution of 40.0 g (0.13 mol) of
2-(1-adamantyl)-4-bromophenol dissolved in 100 ml of DMF was added
dropwise and the mixture was stirred until the evolution of gas had
ceased. A solution of 18 ml (0.15 mol) of 2-methoxy-ethoxymethyl
chloride in 20 ml of DMF was then added dropwise and the mixture
was stirred for four hours at room temperature. The reaction medium
was poured into water and extracted with ethyl ether. The organic
phase was separated out after settling had taken place, washed with
water, dried over magnesium sulfate and evaporated. The residue was
purified by chromatography on a column of silica eluted with a
mixture of dichloromethane and hexane (50/50). After evaporation of
the solvents, 40.1 g (78%) of the expected product, with a melting
point of 69-70.degree. C., was collected.
[0140] (b)
3-(1-Adamantyl)-4-methoxyethoxymethoxyphenyl-carboxaldehyde.
[0141] 34.0 g (89.0 mmol) of
3-(1-adamantyl)-1-bromo-4-methoxyethoxymethox- ybenzene and 250 ml
of THF were introduced into a three-necked flask under a stream of
nitrogen. 43 ml (106 mmol) of a solution of n-butyllithium (2.5M in
hexane) was added dropwise at -78.degree. C. and the mixture was
stirred for 30 minutes. 8.3 ml (106 mmol) of DMF was then added
dropwise and the mixture was allowed to warm to room temperature.
The reaction medium was poured into an aqueous ammonium chloride
solution and extracted with ethyl ether. The organic phase was
separated out after settling had taken place, dried over magnesium
sulfate and evaporated. The residue obtained was purified by
chromatography on a column of silica eluted with dichloromethane.
After evaporation of the solvents, 17.6 g (58%) of the expected
aldehyde, with a melting point of 63-64.degree. C., was
collected.
[0142] (c) Ethyl
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)e-
thenyl]benzoate.
[0143] 360 mg (12 mmol) of sodium hydride (80% in oil) and 20 ml of
THF were introduced into a three-necked flask under a stream of
nitrogen. A solution of 70 ml of THF containing 3.44 g (10 mmol) of
3-(1-adamantyl)-4-methoxyethoxymethoxyphenylcarbox-aldehyde, 3.6 g
(12 mmol) of diethyl 4-ethoxycarbonyl-benzylphosphonate and 440 mg
of crown ether (15-crown-5) were added dropwise. The reaction
medium was stirred at room temperature for four hours and was then
poured into water and extracted with ethyl ether. The organic phase
was separated out after settling has taken place, dried over
magnesium sulfate and evaporated. The residue obtained was
triturated from hexane, filtered and dried. 4.55 g (93%) of the
expected ethyl ester, with a melting point of 87-88.degree. C., was
collected.
EXAMPLE 2
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)ethenyl]benzoic
acid.
[0144] 2.0 g (4.0 mmol) of ethyl
4-[(E)-2-[3-(1-adamantyl)-4-methoxyethoxy-
methoxyphenyl)ethenyl]-benzoate and methanolic sodium hydroxide
solution (1.6 g of sodium hydroxide in 50 ml of methanol) were
introduced into a round-bottomed flask. The mixture was refluxed
for four hours and evaporated to dryness, and the residue was taken
up in water and acidified to pH 1. The aqueous phase was extracted
with ethyl acetate and the organic phase was separated out after
settling had taken place, dried over magnesium sulfate and
evaporated. The residue obtained was triturated from the minimum
amount of ethyl ether, filtered and dried. 1.4 g (74%) of the
expected acid, with a melting point of 207-208.degree. C., was
collected.
EXAMPLE 3
Ethyl
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)-1-propenyl]-
benzoate
[0145] (a) 3-(1-Adamantyl)-4-methoxyethoxymethoxybenzoic acid
[0146] 3-(1-Adamantyl)-1-bromo-4-methoxyethoxy-methoxybenzene (28.5
g, 72 mmol) was dissolved in 200 ml of THF. The solution obtained
was added dropwise onto magnesium (2.4 g, 100 mmol) and a crystal
of iodine. After introduction, the mixture was refluxed for two
hours, cooled to -78.degree. C. and a stream of CO.sub.2 was passed
through for one hour. The reaction medium was allowed to warm to
room temperature and was then poured into saturated aqueous
ammonium chloride solution and extracted with ethyl ether. The
organic phase was separated out after settling had taken place,
dried over magnesium sulfate and evaporated. The residue obtained
was triturated from hexane, filtered and dried. 15.5 g (60%) of the
expected acid, with a melting point of 115-116.degree. C., was
collected.
[0147] (b) 3-(1-Adamantyl)-4-methoxyethoxymethoxyacetophenone
[0148] 15.5 g (43 mmol) of
3-(1-adamantyl)-4-methoxyethoxymethoxybenzoic acid and 300 ml of
anhydrous ethyl ether were introduced into a three-necked flask
under a stream of nitrogen. 80 ml (0.13 mol) of methyllithium (1.6M
in ether) was added dropwise at -20.degree. C. and the mixture was
then stirred at room temperature for three hours. The reaction
medium was poured into saturated aqueous ammonium chloride solution
and the organic phase was separated out after settling had taken
place, dried over magnesium sulfate and evaporated. 15.4 g (100%)
of the expected acetophenone was collected in the form of a pale
yellow oil.
[0149] (c) Ethyl
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxy-methoxyphenyl)--
1-propenyl]benzoate
[0150] In a similar manner to Example 1(c), by reaction of 3.58 g
(10 mmol) of 3-(1-adamantyl)-4-methoxyethoxymethoxyacetophenone
with 3.13 g (12 mmol) of diethyl 4-ethoxycarbonylbenzylphosphonate,
and after chromatography on a column of silica eluted with a
mixture of heptane and ethyl acetate (90/10), 2.5 g (50%) of ethyl
ester was obtained in the form of a mixture of (E) and (Z)
isomers.
EXAMPLE 4
4-[(E)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoi-
c acid
[0151] In a similar manner to Example 2, starting with 2.5 g (5
mmol) of an (E/Z) mixture of ethyl
4-[2-(3-(1-adamantyl)-4-methoxyethoxymethoxyphe-
nyl)-1-propenyl]benzoate and after recrystallization from ethanol,
150 mg (13%) of
4-[(E)-2-(3-(1-adamantyl)-4-methoxyethoxymethoxyphenyl)-1-propen-
yl]benzoic acid, with a melting point of 177-178.degree. C., was
collected.
EXAMPLE 5
4-[(Z)-2-(3-(1-Adamantyl)-4-methoxyethoxymethoxy-phenyl)-1-propenyl]benzoi-
c acid
[0152] The recrystallization filtrate obtained in Example 4 was
evaporated to dryness. The solid obtained was recrystallized from
ethanol and, after filtration, 140 mg (12%) of
4-[(Z)-2-(3-(1-adamantyl)-4-methoxy-ethoxymet-
hoxyphenyl)-1-propenyl]benzoic acid, with a melting point of
198-199.degree. C., was collected.
EXAMPLE 6
Methyl
5-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(E)-y-
l}pyridine-2-carboxylate
[0153] (a) 2-Bromo-5-methylpyridine
[0154] 500 ml of aqueous hydrobromic acid (47%) was mixed with 50.0
g (462 mmol) of 2-amino-5-methyl-pyridine in a two-liter reactor.
The solution obtained was cooled to -20.degree. C. and 206.9 g (1.3
mol) of bromine was then run in over ten minutes, while keeping the
temperature between -15.degree. C. and -25.degree. C. The reaction,
medium was stirred for one hour at -20.degree. C., after which a
solution composed of 82.7 g (1.2 mol) of sodium nitrite dissolved
in 300 ml of water was run in dropwise over twenty minutes.
[0155] The reaction medium was stirred for four hours at room
temperature and was then cooled to -10.degree. C., 800 ml of
aqueous sodium hydroxide solution (pH 10) was added and the mixture
was stirred for five minutes and extracted with ethyl ether. The
organic phase was separated out after settling had taken place,
washed with water and then with Na.sub.2S.sub.2O.sub.3 solution,
dried over magnesium sulfate and evaporated. 75.2 g (94%) of the
expected compound was collected in the form of orange crystals with
a melting point of 38-42.degree. C.
[0156] (b) 2-Bromo-5-bromomethylpyridine
[0157] 10.0 g (58.0 mmol) of the bromo compound obtained in Example
4(a) and 70 ml of carbon tetrachloride were mixed together in a 250
ml three-necked flask. The mixture was heated to about 35.degree.
C. and a ground mixture composed of 10.32 g (58.0 mmol) of
N-bromosuccinimide and 421 mg (1.74 mmol) of benzoyl peroxide were
introduced in a single portion. The reaction medium was refluxed
under light irradiation (1000 W) for three hours. The mixture was
cooled and filtered, the filtrate was evaporated to dryness, the
residue was taken up in dichloromethane and washed with saturated
sodium bicarbonate solution and the organic phase was then dried
over magnesium sulfate and evaporated. The residue obtained was
purified by chromatography on a column of silica eluted with a
mixture composed of dichloromethane and heptane (1/1). After
evaporation of the solvents, 2.9 g (20%) of the expected compound
was collected in the form of beige-colored crystals.
[0158] (c) Diethyl (6-bromopyrid-3-ylmethyl)phosphonate
[0159] 3.0 g (11.9 mmol) of the compound obtained in Example 6(b)
and 10 ml of triethyl phosphite were mixed together in a 100 ml
round-bottomed flask. The mixture was refluxed for thirty minutes,
cooled and evaporated to dryness. The residue obtained was purified
by chromatography on a column of silica eluted with a mixture of
ethyl acetate and heptane (6/4). After evaporation of the solvents,
3.12 g (80%) of the expected compound was collected in the form of
a pale yellow oil.
[0160] (d)
5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(-
E)-yl}-2-bromopyridine
[0161] 2.6 g (8.4 mmol) of the compound obtained in Example 6(c), 5
ml of DMPU and 5 ml of THF were mixed together in a 100 ml
round-bottomed flask. 250 mg (8.4 mmol) of 80% sodium hydride were
added in a single portion and the mixture was stirred at room
temperature for thirty minutes and then at 40.degree. C. for
fifteen minutes. A solution of 2.5 g (7.0 mmol) of the ketone
obtained in Example 3(b) dissolved in 10 ml of THF was added
dropwise. The reaction medium was stirred for four hours at room
temperature, after which saturated citric acid solution was added.
The mixture was extracted with ethyl ether and the organic phase
was separated out after settling had taken place, washed with
water, dried over magnesium sulfate and evaporated. The residue
obtained was purified by chromatography on a column of silica
eluted with a mixture of ethyl acetate and heptane (2/8). 2.69 g
(75%) of the expected compound was collected in the form of a
yellow oil.
[0162] (e) Methyl
5-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]p-
ropen-(E)/(Z)-yl}pyridine-2-carboxylate
[0163] 4.1 g (8.0 mmol) of the bromo compound obtained in Example
6(d), 890 mg (1.6 mmol) of 1,1'-bis(diphenylphosphino)ferrocene,
180 mg (0.8 mmol) of palladium acetate, 20 ml of DMF, 2.23 ml (16.0
mmol) of triethylamine and 3.24 ml (80 mmol) of methanol were
introduced into a hydrogenation bomb. The reaction medium was
confined under a pressure of three bar of carbon monoxide and
heated at 100.degree. C. for three hours. The mixture was cooled,
taken up in water, extracted with ethyl acetate and washed with
water. The organic phase was then dried over magnesium sulfate and
evaporated. The residue obtained was purified by chromatography on
a column of silica eluted with a mixture of ethyl acetate and
heptane (2/8). After evaporation of the solvents, 1.3 g (33%) of
the (Z) isomer in the form of a yellow oil and 1.16 g (29%) of the
(E) isomer in the form of a pale yellow powder with a melting point
of 96-102.degree. C. were collected.
EXAMPLE 7
5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxlmethoxy)-phenyl]propen-(E)-yl}pyrid-
ine-2-carboxylic acid.
[0164] In a similar manner to Example 2, starting with 1.16 g (2.36
mmol) of the (E) isomer of methyl
5-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethox-
y)phenyl]-propen-yl}pyridine-2-carboxylate obtained in Example
6(e), and after purification by trituration from a mixture of ethyl
ether and heptane (5/5), 0.98 g (86%) of
5-{2-[3-adamant-1-yl-4-(2-methoxyethoxymet-
hoxy)-phenyl]propen-(E)-yl}pyridine-2-carboxylic acid was collected
in the form of a beige-colored powder with a melting point of
91-95.degree. C.
EXAMPLE 8
5-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}pyrid-
ine-2-carboxylic acid.
[0165] In a similar manner to Example 2, starting with 1.30 g (2.64
mmol) of the (Z) isomer of methyl
5-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethox-
y)phenyl]-propen-yl}pyridine-2-carboxylate obtained in Example
6(e), and after trituration from heptane, 1.05 g (83%) of
5-{2-[3-adamant-1-yl-4-(2-
-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}pyridine-2-carboxylic
acid was collected in the form of a white powder with a melting
point of 91-95.degree. C.
EXAMPLE 9
Ethyl
6-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl-
}nicotinate
[0166] (a) Ethyl 6-hydroxymethylnicotinate
[0167] 45.77 g (205 mmol) of ethyl 2,5-pyridine-dicarboxylate was
dissolved in 410 ml of absolute ethanol in a one-liter
round-bottomed flask. The reaction medium was cooled to -5.degree.
C. and 5.04 g (133.2 mmol) of sodium borohydride was added,
followed by portionwise addition of 14.79 g (133.2 mmol) of calcium
chloride, while keeping the temperature below -5.degree. C. The
reaction medium was stirred at -5.degree. C. for two hours and
poured into water. The product was extracted with ethyl ether and
washed with water and the organic phase was then dried over
magnesium sulfate and evaporated. The residue obtained was purified
by chromatography on a column of silica eluted with ethyl ether, in
order to obtain 31.33 g (84%) of a white crystalline solid.
[0168] (b) Ethyl 6-bromomethylnicotinate
[0169] 10.0 g (55.2 mmol) of the compound obtained in Example 9(a),
36.6 g (110 mmol)of carbon tetrabromide and 100 ml of ethyl ether
were dissolved in a 500 ml round-bottomed flask. The reaction
medium was cooled to 0.degree. C. and 40.78 g (110 mmol) of
trioctylphosphine was then added over ten minutes. The reaction
medium was stirred for fifteen minutes at room temperature and
poured into water. The product was extracted with ethyl ether and
washed with water and the organic phase was then dried over
magnesium sulfate and evaporated. The residue obtained was purified
by chromatography on a column of silica eluted with ethyl ether, in
order to obtain 11.70 g (87%) of a red oil.
[0170] (c) Ethyl 6-(diethoxyphosphoryl)nicotinate
[0171] 11.0 g (45.0 mmol) of the compound obtained in Example 9(b)
and 100 ml of triethyl phosphite were mixed together in a 100 ml
round bottomed flask. The mixture was refluxed for five minutes,
cooled and evaporated to dryness. The residue obtained was purified
by chromatography on a column of silica eluted with a mixture of
ethyl acetate and heptane (8/2). After evaporation of the solvents,
9.7 g (71%) of the expected compound was collected in the form of a
yellow oil.
[0172] (d) Ethyl
6-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]pr-
open-(E)-yl}nicotinate
[0173] 0.5 g (1.66 mmol) of the compound obtained in Example 9(c),
5 ml of DMPU and 5 ml of THF were mixed together in a 50 ml
round-bottomed flask. 50 mg (1.66 mmol) of 80% sodium hydride was
added in a single portion and the mixture was stirred at room
temperature for fifteen minutes and then at 40.degree. C. for an
additional fifteen minutes. A solution of 496 mg (1.4 mmol) of the
ketone obtained in Example 3(b) dissolved in 5 ml of THF is added
dropwise. The reaction medium was stirred for four hours at room
temperature, saturated citric acid solution was then added. The
mixture was extracted with ethyl ether and the organic phase was
separated out after settling had taken place, washed with water,
dried over magnesium sulfate and evaporated. The residue obtained
was purified by chromatography on a column of silica eluted with a
mixture of ethyl acetate and heptane (2/8). 60 mg (7%) of the
expected (E) compound was collected in the form of a yellow solid
with a melting point of 78.degree. C., along with a fraction
corresponding to the (Z) compound, which would be directly reacted
in order to obtain the corresponding acid (Example 11).
EXAMPLE 10
6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(E)-yl}nicot-
inic acid
[0174] In a similar manner to Example 2, starting with 1.30 g (2.57
mmol) of the (E) isomer of ethyl
6-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy-
)-phenyl]propen-yl}nicotinate obtained in Example 9(d), and after
purification by chromatography on a column of silica eluted with a
mixture of ethyl acetate and heptane (5/5), 0.98 g (80%) of the
expected compound was collected in the form of an off-white powder
with a melting point of 86-90.degree. C.
EXAMPLE 11
6-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}nicot-
inic acid.
[0175] In a similar manner to Example 2, starting with 463 mg (0.92
mmol) of the (Z) isomer of ethyl
6-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethoxy-
)-phenyl]propenyl}nicotinate obtained in Example 9(d), and after
crystallization from a mixture of ethyl ether and heptane (5/5),
350 mg (80%) of the expected compound was collected in the form of
an off-white powder with a melting point of 191-195.degree. C.
EXAMPLE 12
Methyl
4-{2-[3-adamant-1-yl-4-(2-methoxyethoxy-methoxy)phenyl]propen-(Z)-y-
l}-2-methoxybenzoate
[0176] In a similar manner to Example 6(d), starting with 13.96 g
(50.9 mmol) of diethyl 4-methoxycarbonyl-benzylphosphonate and 9.13
g (25.45 mmol) of the ketone obtained in Example 3(b), 8.25 g (62%)
of the (Z) compound in the form of a white crystalline solid and
3.00 g (23%) of the (Z) compound in the form of a colorless oil
were collected.
EXAMPLE 13
4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenol]propen-(E)-yl}-2-me-
thoxybenzoic acid.
[0177] In a similar manner to Example 2, starting with 3.00 g (5.76
mmol) of the (E) isomer of methyl
4-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethox- y)
phenyl]-propen-yl}-2-methoxybenzoate obtained in Example 12, and
after crystallization from methanol, 2.80 g (96%) of the expected
compound was collected in the form of yellow crystals.
EXAMPLE 14
4-{2-[3-Adamant-1-yl-4-(2-methoxyethoxymethoxy)-phenyl]propen-(Z)-yl}-2-me-
thoxybenzoic acid.
[0178] In a similar manner to Example 2, starting with 7.60 g (14.6
mmol) of the (Z) isomer of methyl
4-{2-[3-adamant-1-yl-4-(2-methoxyethoxymethox-
y)-phenyl]propen-yl}-2-methoxybenzoate obtained in Example 12, and
after crystallization from a mixture of ethyl ether and hexane
(10/90), 7.39 g (100%) of the expected compound was collected in
the form of white crystals with a melting point of 113.degree.
C.
EXAMPLE 15
Ethyl
4-{2-[3-adamant-1-yl-4-(3-ethoxymethoxpropyl)-phenyl]propen-(E/Z)-yl-
}benzoate
[0179] (a) Methyl
3-adamant-1-yl-4-trifluoromethane-sulphonyloxybenzoate.
[0180] 28.6 g (100.0 mmol) of methyl
3-(1-adamantyl)-4-hydroxybenzoate was mixed with 122 mg (1.0 mmol)
of N,N-dimethylaminopyridine, 200 ml of dichloromethane and 28 ml
of pyridine in a one liter three-necked flask under a nitrogen
atmosphere. The mixture was cooled to -78.degree. C. and 20.19 ml
(120.0 mmol) of triflic anhydride was added dropwise. The
temperature was raised to room temperature and the mixture was
continuously stirred for two hours. The reaction medium was poured
into 1N hydrochloric acid solution, extracted with ethyl ether,
washed with water, dried over magnesium sulfate, filtered and
evaporated to dryness. 41.5 g (99%) of the expected compound was
collected in the form of a pale orange powder with a melting point
of 95.degree. C.
[0181] (b) Methyl 3-adamant-1-yl-4-allylbenzoate
[0182] 23.06 g (55.1 mmol) of the compound obtained in Example
15(a) was mixed with 4.66 g (110.0 mmol) of lithium chloride, 5.8 g
(8.3 mmol) of bis(triphenylphosphine)palladium(II) chloride, 21.89
g (66.0 mmol) of allyltributyltin and 300 ml of
N,N-dimethylformamide in a one liter three-necked flask under a
nitrogen atmosphere. The mixture was heated at 100.degree. C. for
two hours and was then poured into 1N hydrochloric acid solution,
extracted with ethyl ether, washed with water, dried over magnesium
sulfate, filtered and evaporated to dryness. The residue obtained
was purified by distillation of tin salts (108-116.degree. C. at
8'10.sup.-2 bar) followed by chromatography on a column of silica
eluted with heptane. After evaporation of the solvents, 12.75 g
(74%) of the expected compound was collected in the form of a
yellow oil.
[0183] (c) Methyl 3-adamant-1-yl-4-(3-hydroxypropyl)benzoate
[0184] 12.40 g (40.0 mmol) of the compound obtained in Example
15(b) was dissolved in 250 ml of tetrahydrofuran in a 250 ml
three-necked flask under a nitrogen atmosphere. The mixture was
cooled to 0.degree. C. and 240 ml (120.0 mmol) of
9-borabicyclo[3.3.1]nonane (9-BBN) was then run in dropwise and the
mixture was stirred at room temperature for two hours. The reaction
medium was again cooled to 0.degree. C. and 124 ml (124 mmol) of
aqueous sodium hydroxide solution (1M) was then run in dropwise,
followed, while maintained at 0.degree. C., by 102 ml (1 mol) of
30% aqueous hydrogen peroxide solution. The reaction medium was
stirred for thirty minutes at room temperature and was then poured
into 1N hydrochloric acid solution, extracted-with ethyl ether,
washed with water, dried over magnesium sulfate, filtered and
evaporated to dryness. The residue was purified by chromatography
on a column of silica eluted with a mixture composed of 30% ethyl
acetate and 70% heptane. 9.4 g (71%) of the expected compound were
collected in the form of a white powder with a melting point of
77.degree. C.
[0185] (d) Methyl
3-adamant-1-yl-4-(3-ethoxymethoxypropyl)-benzoate.
[0186] 8.00 g (24.3 mmol) of the compound obtained in Example 15(c)
was dissolved in 200 ml of toluene in a 500 ml three-necked flask
under a nitrogen atmosphere. 577 mg (1.7 mmol) of tetrabutylamine
hydrogen sulfate was added, the mixture was cooled to 0.degree. C.
and 6.78 ml (73.0 mmol) of ethoxymethyl chloride and 120 ml of
aqueous 10 M sodium hydroxide were then run in dropwise. The
reaction medium was stirred at 0.degree. C. for thirty minutes and
then poured into 1N hydrochloric acid solution, extracted with
ethyl ether, washed with water, dried over magnesium sulfate,
filtered and evaporated to dryness. 9.39 g (100%) of the expected
compound were collected in the form of a pale yellow oil.
[0187] (e) 3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)benzoic acid
[0188] In a similar manner to Example 2, starting with 9.39 g (24.3
mmol) of the compound obtained in Example 15(d), 8.52 g (94%) of
the expected compound was collected in the form of a white powder
with a melting point of 115.degree. C.
[0189] (f)
1-[3-Adamant-1-yl-4-(3-ethoxymethoxypropyl)phenyl]-ethanone
[0190] In a similar manner to Example 3(b), starting with 8.00 g
(21.5 mmol) of the compound obtained in Example 15(e), 5.34 g (67%)
of the expected compound was collected in the form of a colorless
oil.
[0191] (g) Ethyl
4-{2-[3-adamant-1-yl-4-(3-ethoxymethoxy-propyl)phenyl]pro-
pen-(E/Z)-yl}benzoate
[0192] In a similar manner to Example 1(c), by reaction of 5.00 g
(13.5 mmol) of the compound obtained in Example 15(f) with 8.10 g
(27.0 mmol) of diethyl 4-ethoxycarbonylbenzylphosphonate, and after
chromatography on a column of silica eluted with a mixture of
heptane and ethyl acetate (90/10), 6.3 g (90%) of the ethyl ester
was obtained in the form of a mixture of (E) and (Z) isomers.
EXAMPLE 16
4-{2-[3-Adamant-1-yl-4-(3-ethoxymethoxpropyl)-phenyl]propen-(E/Z)-yl}benzo-
ic acids.
[0193] In a similar manner to Example,2, starting with 1.00 g (1.9
mmol) of the mixture of (E) and (Z) compounds obtained in Example
15(g), and after chromatography on a column of silica eluted with a
mixture of heptane and ethyl acetate (80/20), 330 mg (34%) of the
expected compound (Z isomer) in the form of a white powder with a
melting point of 161.degree. C., and 70 mg (7%) of the expected
compound (E isomer) in the form of a white powder with a melting
point of 165.degree. C., were collected.
EXAMPLE 17
Ethyl
4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen-(E/Z)-yl}be-
nzoate
[0194] (a) Ethyl
4-{2-[3-adamant-1-yl-4-(3-hydroxypropyl)-phenyl]propen-(E-
/Z)-yl}benzoate
[0195] 5.00 g (9.68 mmol) of the compound obtained in Example 15(g)
was dissolved in 50 ml of absolute ethanol in a 250 ml three-necked
flask under a nitrogen atmosphere. 5.18 ml (96.8 mmol) of
concentrated sulfuric acid was added dropwise. The reaction medium
was stirred at room temperature for 24 hours and then at 40.degree.
C. for 5 hours, it was poured into water, extracted with ethyl
ether, washed with water, dried over magnesium sulfate, filtered
and evaporated to dryness. 4.40 g (99%) of the expected compound
was collected in the form of a pale yellow oil.
[0196] (b) Ethyl
4-{2-[3-adamant-1-yl-4-(3-benzyloxypropyl)-phenyl]propen--
(E/Z)-yl}benzoate
[0197] In a similar manner to Example 15(d), starting with 1.00 g
(2.18 mmol) of the compound obtained in Example 17(a) and 0.78 ml
(6.54 mmol) of benzyl bromide, 1.19 g (100%) of the expected
compound was collected in the form of a yellow oil.
EXAMPLE 18
4-{2-[3-Adamant-1-yl-4-(3-benzyloxypropyl)phenyl]-propen-(E/Z)-yl}benzoic
acids
[0198] In a similar manner to Example 2, starting with 1.00 g (1.82
mmol) of the mixture of (E) and (Z) compounds obtained in Example
17 (b), and after chromatography on a column of silica eluted with
a mixture of heptane and ethyl acetate (90/10), 480 mg (50%) of the
expected compound (Z isomer) in the form of a white powder with a
melting point of 166.degree. C., and 175 mg (18%) of the expected
compound (E isomer) in the form of a white powder with a melting
point of 243.degree. C., were collected.
EXAMPLE 19
Ethyl
4-{2-[3-adamant-1-yl-4-(3-diethylcarbamoyl-methoxypropyl)phenyl]prop-
enyl}benzoate
[0199] In a similar manner to Example 15(d), starting with 1.00 g
(2.18 mmol) of the compound obtained in Example 17(a) and 0.83 ml
(6.54 mmol) of N,N-diethylchloroacetamide, 1.00 g (80%) of the
expected compound was collected in the form of a pale yellow
oil.
EXAMPLE 20
4-{2-[3-Adamant-1-yl-4-(3-diethylcarbamoylmethoxy-propyl)phenyl]propenyl}b-
enzoic acid.
[0200] In a similar manner to Example 2, starting with 1.00 g (1.75
mmol) of the mixture of (E) and (Z) compounds obtained in Example
19(a), and after chromatography on a column of silica eluted with a
mixture of heptane and ethyl acetate (90/10), 480 mg (50%) of the
mixture (Z+E) of the expected compounds was collected.
EXAMPLE 21
Ethyl
4-{2-[3-adamant-1-yl-4-(3-carboxymethoxy-propyl)phenyl]propenyl}benz-
oate
[0201] (a) Ethyl
4-{2-[3-adamant-1-yl-4-(3-tert-butoxy-carbonylmethoxyprop-
yl)phenyl]propenyl}benzoate
[0202] In a similar manner to Example 15(d), starting with 2.45 g
(5.34 mmol) of the compound obtained in Example 17(a) and 2.59 ml
(16.0mmol) of tert-butyl bromoacetate, and after chromatography on
a column of silica eluted with a mixture of heptane and ethyl
acetate (90/10), 2.65 g (86%) of the mixture (Z+E) of the expected
compounds was collected in the form of a colorless oil.
[0203] (b) Ethyl
4-{2-[3-adamant-1-yl-4-(3-carboxymethoxy-propyl)phenyl]pr-
openyl}benzoate
[0204] 2.60 g (4.54 mmol) of the compound obtained in Example 21(a)
was dissolved in 45 ml of dichloromethane in a 100 ml
round-bottomed flask under a nitrogen atmosphere, and 3.50 ml (45.4
mmol) of trifluoroacetic acid was added dropwise. The reaction
medium was stirred at room temperature for 16 hours and then at
reflux for 8 hours. It was poured into water, extracted with
dichloromethane, washed with water, dried over magnesium sulfate,
filtered and evaporated to dryness. 2.35 g (100%) of the expected
compound was collected in the form of a pale yellow oil.
EXAMPLE 22
4-{2-[3-Adamant-1-yl-4-(3-carboxymethoxypropyl)-phenyl]propenyl}benzoic
acids
[0205] In a similar manner to Example 2, starting with 300 mg (0.60
mmol) of the mixture of (E) and (Z) compounds obtained in Example
21(b), and after trituration from a mixture composed of 20% ethyl
ether and 80% heptane, 150 mg (51%) of the mixture (Z+E) of the
expected compounds was collected.
EXAMPLE 23
Ethyl
4-{2-[3-adamant-1-yl-4-(3-carbamoylmethoxy-propyl)phenyl]propenyl}be-
nzoate
[0206] 1.00 g (1.93 mmol) of the compound obtained in Example 21(b)
was dissolved in 20 ml of dichloromethane in a 100 ml
round-bottomed flask under a nitrogen atmosphere, and 0.42 ml (2.13
mmol) of dicyclohexylamine was added dropwise. The reaction medium
was stirred at room temperature for five minutes, after which 0.14
ml (1.93 mmol) of thionyl chloride was added dropwise and the
mixture was stirred at room temperature for twenty minutes. The
reaction medium was evaporated to dryness, taken up in ethyl ether
and filtered and the filtrate was evaporated in order to obtain a
yellow oil which was taken up in 10 ml of THF in order to obtain a
solution. This solution was added dropwise to a solution composed
of 0.13 ml of 32% aqueous ammonia solution (2.13 mmol) in 20 ml of
THF and 0.32 ml (2.32 mmol) of triethylamine. The reaction medium
was stirred at room temperature for five minutes, poured into water
and the pH was adjusted to 2 by addition of 0.5N HCl. The product
was extracted with ethyl ether, washed with water, dried over
magnesium sulfate, filtered and evaporated to dryness. After
chromatography on a column of silica eluted with a mixture of
heptane and ethyl acetate (50/50), 650 mg (65%) of the mixture
(Z+E) of the expected compounds was collected.
EXAMPLE 24
4-{2-[3-Adamant-1-yl-4-(3-carbamoylmethoxypropyl)-phenyl]propenyl}benzoic
acids
[0207] In a similar manner to Example 2, starting with 650 mg (1.26
mmol) of the mixture of (E) and (Z) compounds obtained in Example
23, and after trituration from a mixture composed of 20% ethyl
ether and 80% heptane, 340 mg (55%) of the mixture (Z+E) of the
expected compounds was collected.
EXAMPLE 25
[0208] The antagonist activity of the compounds of formula (I) was
evaluated in the mouse embryonic teratocarcinoma F9 cell
differentiation test (Cancer Research, 43, 5268 (1983)).
[0209] These compounds tested at 10.sup.-6 M were inactive as
agonists in this test and partially or totally inhibit the effect
produced by an agonist retinoid on the morphology and secretion of
the plasminogen activator, according to the following
procedure.
[0210] The F9 cells were inoculated in 12-well clusters, the
compounds were tested at from 10.sup.-9 to 10.sup.-5 M in the
presence of all-trans-retinoic acid or of a synthetic agonist
retinoid,
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylaminomethyl)benzoic
acid (CD 2043), at 10.sup.-8 M. After incubation for three days,
the morphological observations were carried out and the
concentration of the test compound which inhibits the agonist
effect on the secretion of the plasminogen activator by 50% (IC50)
was determined.
2 Antagonist against CD 2043 (10 nM) F9 differentiation test
Example No. IC50 (nM) 2 310 4 9 5 630 10 35 7 600
[0211] B. FORMULATION EXAMPLES
[0212] (1) ORAL ROUTE
[0213] (a) The following composition was prepared in the form of a
0.8 g tablet:
3 Compound of Example 1 0.005 g Pregelatinized starch 0.265 g
Microcrystalline cellulose 0.300 g Lactose 0.200 g Magnesium
stearate 0.030 g
[0214] For the treatment of acne, 1 to 3 tablets will be
administered to an adult individual each day for 3 to 6 months
depending on the severity of the case being treated.
[0215] (b) A drinkable suspension intended to be packaged in 5 ml
ampules is prepared:
4 Compound of Example 2 0.050 g Glycerol 0.500 g 70% Sorbitol 0.500
g Sodium saccharinate 0.010 g Methyl parahydroxybenzoate 0.040 g
Flavoring qs Purified water qs 5 ml
[0216] For the treatment of acne, 1 ampule will be administered to
an adult individual each day for 3 months depending on the severity
of the case being treated.
[0217] (c) The following formulation intended to be packaged in
gelatin capsules is prepared:
5 Compound of Example 4 0.025 g Corn starch 0.060 g Lactose qs
0.300 g
[0218] The gelatin capsules used consist of gelatin, titanium oxide
and a preservative. In the treatment of psoriasis, 1 gelatin
capsule will be administered to an adult individual each day for 30
days.
[0219] 2) TOPICAL ROUTE
[0220] (a) The following nonionic water-in-oil cream is
prepared:
6 Compound of Example 1 0.100 g Mixture of emulsifying lanolin
39.900 g alcohols, waxes and refined oils, having the trademark
"Anhydrous Eucerin", by BDF Methyl para-hydroxybenzoate 0.075 g
Propyl para-hydroxybenzoate 0.075 g Sterile demineralized water qs
100.000 g
[0221] This cream will be applied to psoriatic skin once or twice a
day for 30 days.
[0222] (b) A gel is prepared by making the following
formulation:
7 Compound of Example 3 0.050 g Base erythromycin 4.000 g
Butylhydroxytoluene 0.050 g Hydroxypropylcellulose having the 2.000
g trademark "Klucel HF" by Hercules Ethanol (95%) qs 100.000 g
[0223] This gel will be applied to skin affected with dermatitis or
to acneic skin 1 to 3 times each day for 6 to 12 weeks depending on
the severity of the case being treated.
[0224] (c) An antiseborrheic lotion is prepared by mixing together
the following ingredients:
8 Compound of Example 20.030 g Propylene glycol 5.000 g
Butylhydroxytoluene 0.100 g Ethanol (95%) qs 100.000 g
[0225] This lotion will be applied twice each day to a seborrheic
scalp and a significant improvement is observed within a period of
2 to 6 weeks.
[0226] (d) A cosmetic composition to combat the harmful effects of
the sun is prepared by mixing together the following
ingredients:
9 Compound of Example 12 1.000 g Benzylidene camphor 4.000 g Fatty
acid triglycerides 31.000 g Glyceryl monostearate 6.000 g Stearic
acid 2.000 g Cetyl alcohol 1.200 g Lanolin 4.000 g Preservative
0.300 g Propylene glycol 2.000 g Triethanolamine 0.500 g Fragrance
0.400 g Demineralized water qs 100.000 g
[0227] This composition will be applied daily and makes it possible
to combat light-induced aging.
[0228] (e) The following nonionic oil-in-water cream is
prepared:
10 Compound of Example 14 0.500 g Vitamin D3 0.020 g Cetyl alcohol
4.000 g Glyceryl monostearate 2.500 g PEG 50 stearate 2.500 g
Karite butter 9.200 g Propylene glycol 2.000 g Methyl
parahydroxybenzoate 0.075 g Propyl parahydroxybenzoate 0.075 g
Sterile demineralized water qs 100.000 g
[0229] This cream will be applied to psoriatic skin once or twice
each day for 30 days.
[0230] (f) A topical gel is prepared by mixing together the
following ingredients:
11 Compound of Example 18 0.050 g Ethanol 43.000 g
.alpha.-Tocopherol 0.050 g Carboxyvinyl polymer, trademark 0.500 g
"Carbopol 941" by Goodrich Triethanolamine as an aqueous 3.800 g
solution containing 20% by weight Water 9.300 g Propylene glycol qs
100.000 g
[0231] This gel will be applied in the treatment of acne 1 to 3
times each day for 6 to 12 weeks depending on the severity of the
case being treated.
[0232] (g) A lotion for preventing hair loss and for promoting hair
regrowth is prepared by mixing together the following
ingredients:
12 Compound of Example 15 0.05 g Minoxidil 1.00 g Propylene glycol
20.00 g Ethanol 34.92 g Polyethylene glycol having a 40.00 g
molecular weight of 400 Butylhydroxyanisole 0.01 g
Butylhydroxytoluene 0.02 g Water qs 100.00 g
[0233] This lotion will be applied twice a day for 3 months to a
scalp which has lost a considerable amount of hair.
[0234] (h) An anti-acne cream is prepared by mixing together the
following ingredients:
13 Compound of Example 5 0.050 g Retinoic acid 0.010 g Mixture of
glyceryl stearates and 15.000 g polyethylene glycol (75 mol),
having the trademark "Gelot 64" by Gattefosse Polyoxyethylenated
kernel oil 8.000 g containing 6 mol of ethylene oxide, having the
trademark "Labrafil M2130 CS" by Gattefosse Perhydrosqualene 10.000
g Preservatives qs Polyethylene glycol having a 8.000 g molecular
weight of 400 Disodium salt of 0.050 g ethylenediaminetetra-acetic
acid Purified water qs 100.000 g
[0235] This cream will be applied to skin affected with dermatitis
or to acneic skin 1 to 3 times each day for 6 to 12 weeks.
[0236] (i) An oil-in-water cream is prepared by making the
following formulation:
14 Compound of Example 20 0.020 g Betamethasone 17-valerate 0.050 g
S-Carboxymethylcysteine 3.000 g Polyoxyethylene stearate (40 mol of
4.000 g ethylene oxide) having the trademark "Myrj 52" by Atlas
Sorbitan monolaurate 1.800 g polyoxyethylenated with 20 mol of
ethylene oxide, having the trademark "Tween 20" by Atlas Mixture of
glyceryl mono- and 4.200 g distearate, having the trademark "Glol"
by Gattefosse Propylene glycol 10.000 g Butylhydroxyanisole 0.010 g
Butylhydroxytoluene 0.020 g Cetostearyl alcohol 6.200 g
Preservatives qs Perhydrosqualene 18.000 g Mixture of
caprylic/capric 4.000 g triglycerides, having the trademark
"Miglyol 812" by Dynamit Nobel Triethanolamine (99% by weight)
2.500 g Water qs 100.000 g
[0237] This cream will be applied twice a day to skin affected with
dermatitis, for 30 days.
[0238] (j) The following cream of oil-in-water type is
prepared:
15 Lactic acid 5.000 g Compound of Example 23 0.020 g
Polyoxyethylene stearate (40 mol of 4.000 g ethylene oxide), having
the trademark "Myrj 52" by Atlas Sorbitan monolaurate 1.800 g
polyoxyethylenated with 20 mol of ethylene oxide, having the
trademark "Tween 20" by Atlas Mixture of glyceryl mono- and 4.200 g
distearate, having the trademark "Geleol" by Gattefosse Propylene
glycol 10.000 g Butylhydroxyanisole 0.010 g Butylhydroxytoluene
0.020 g Cetostearyl alcohol 6.200 g Preservatives qs
Perhydrosqualene 18.000 g Mixture of caprylic/capric 4.000 g
triglycerides, having the trademark "Miglyol 812" by Dynamit Nobel
Water qs 100.000 g
[0239] This cream will be applied once a day and helps to combat
aging, both light-induced and chronologic aging.
[0240] While the invention has been described in terms of various
preferred embodiments, the skilled artisan will appreciate that
various modifications, substitutions, omissions, and changes may be
made without departing from the spirit thereof. Accordingly, it is
intended that the scope of the present invention be limited solely
by the scope of the following claims, including equivalents
thereof.
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