U.S. patent application number 13/075776 was filed with the patent office on 2012-03-29 for use of piperidine derivatives as dermo-decontracting agents.
This patent application is currently assigned to L'OREAL. Invention is credited to Alexandre Cavezza, Roger Rozot.
Application Number | 20120077844 13/075776 |
Document ID | / |
Family ID | 34946773 |
Filed Date | 2012-03-29 |
United States Patent
Application |
20120077844 |
Kind Code |
A1 |
Cavezza; Alexandre ; et
al. |
March 29, 2012 |
USE OF PIPERIDINE DERIVATIVES AS DERMO-DECONTRACTING AGENTS
Abstract
The present invention relates to a cosmetic process for treating
wrinkled skin, in particular the skin of the face and/or of the
forehead, through a dermo-decontracting effect, comprising the
topical application to said skin of a composition comprising, in a
physiologically acceptable medium, at least one piperidine
derivative chosen from the compounds of formula (I): ##STR00001##
These compounds make it possible to combat expression wrinkles
according to a mechanism of dermo-decontraction.
Inventors: |
Cavezza; Alexandre;
(Pavillion sous Bois, FR) ; Rozot; Roger;
(Lagny/Marne, FR) |
Assignee: |
L'OREAL
Paris
FR
|
Family ID: |
34946773 |
Appl. No.: |
13/075776 |
Filed: |
March 30, 2011 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12607824 |
Oct 28, 2009 |
|
|
|
13075776 |
|
|
|
|
11631391 |
Feb 2, 2007 |
7629359 |
|
|
PCT/EP05/07975 |
Jun 15, 2005 |
|
|
|
12607824 |
|
|
|
|
60589563 |
Jul 21, 2004 |
|
|
|
Current U.S.
Class: |
514/317 ;
546/192 |
Current CPC
Class: |
A61K 8/4926 20130101;
A61Q 19/00 20130101; A61Q 19/08 20130101 |
Class at
Publication: |
514/317 ;
546/192 |
International
Class: |
A61K 8/49 20060101
A61K008/49; A61Q 19/08 20060101 A61Q019/08; C07D 211/14 20060101
C07D211/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 1, 2004 |
FR |
0451396 |
Claims
1. Cosmetic process for treating wrinkled skin, in particular the
skin of the face and/or of the forehead, through a
dermo-decontracting effect, comprising the topical application to
said skin of a composition comprising, in a physiologically
acceptable medium, at least one piperidine derivative chosen from
the compounds of formula (I): ##STR00005## in which: R.sub.1
denotes a halogen or a radical chosen from: a C.sub.1-C.sub.6 alkyl
radical, an OR group, an NRR' group, a CF.sub.3 group, an NHCOR
group or a CONRR' group; R.sub.2 denotes a linear or branched
C.sub.1-C.sub.20 alkyl or alkenyl radical optionally substituted
with at least one OR, COOR, .dbd.O, NRR', NHCOR or CONRR' group or
with a phenyl group optionally substituted with one or more
radicals R.sub.1; where R and R' denote, independently of one
another, a hydrogen atom or a C.sub.1-C.sub.6 alkyl radical, m
ranges from 0 to 5; n ranges from 0 to 5; and their salts and
optical isomers.
2. Process according to claim 1, characterized in that said salt is
a salt obtained by addition of the compound of formula (I) with an
inorganic acid chosen from hydrochloric acid, sulphuric acid and
phosphoric acid.
3. Process according to claim 1, characterized in that said salt is
a salt obtained by addition of the compound of formula (I) with an
organic acid chosen from acetic acid, propionic acid, succinic
acid, fumaric acid, maleic acid, lactic acid, glycolic acid, citric
acid and tartaric acid.
4. Process according to any one of claims 1 to 3, characterized in
that said derivative is such that m ranges from 0 to 3.
5. Process according to any one of claims 1 to 4, characterized in
that said derivative is such that R.sub.1 denotes a methoxy or
trifluoromethyl radical.
6. Process according to claim 4, characterized in that said
derivative is such that m is equal to 0.
7. Process according to any one of claims 1 to 6, characterized in
that said derivative is such that R.sub.2 denotes a linear or
branched C.sub.1-C.sub.6 alkyl or alkenyl radical optionally
substituted with a phenyl group.
8. Process according to any one of claims 1 to 7, characterized in
that said derivative is such that n is equal to 0.
9. Process according to any one of claims 1 to 8, characterized in
that said derivative is 4-phenyl-1-(4-phenylbutyl)piperidine or one
of its salts.
10. Process according to claim 9, characterized in that said
derivative is the maleic acid salt of
4-phenyl-1-(4-phenylbutyl)piperidine.
11. Process according to any one of claims 1 to 7, characterized in
that said derivative is such that n is equal to 1.
12. Process according to claim 11, characterized in that said
derivative is 4-benzyl-1-hexylpiperidine.
13. Process according to any one of claims 1 to 12, characterized
in that the composition is applied to the areas of the face and/or
of the forehead that are marked with expression wrinkles, and/or on
individuals with expression wrinkles.
14. Cosmetic use of at least one piperidine derivative as defined
in any one of claims 1 to 12, as a dermo-decontracting agent for
combating wrinkles, in particular expression wrinkles, and/or for
decontracting the skin and/or relaxing the features.
Description
[0001] The present invention relates to a cosmetic process for
treating wrinkled skin through a dermo-decontracting effect,
comprising the topical application to said skin of a composition
comprising, in a physiologically acceptable medium, at least one
piperidine derivative of specific formula.
[0002] Women, and even men, currently have a tendency to wish to
look youthful for as long as possible and consequently seek to fade
out the signs of age on the skin, which are reflected in particular
by wrinkles and fine lines. In this respect, advertising and the
fashion world talk about products intended to keep the skin radiant
and wrinkle-free, which are signs of youthful skin, for as long as
possible, and all the more so since the physical appearance has an
effect on the psyche and/or on the morale.
[0003] Up until now, wrinkles and fine lines were treated using
cosmetic products containing active agents acting on the skin, for
example by improving its cell renewal or alternatively by promoting
the synthesis of, or by preventing the degradation of, the elastic
fibres of which skin tissue is composed.
[0004] Although these treatments make it possible to act on the
wrinkles and fine lines caused by chrono-logical or intrinsic
ageing, and also on those caused by photoageing, they have no
effect on expression wrinkles, which require an intervention on the
muscular contractile component (via muscle-relaxing agents) or
dermal contractile component (via dermo-decontracting agents) of
wrinkles.
[0005] Expression wrinkles are in fact the result of mechanisms
that are different from those that generate wrinkles caused by
ageing.
[0006] Specifically, they are produced due to the effect of the
strain exerted on the skin by the skin muscles that allow facial
expressions. Depending on the shape of the face, the frequency of
facial expressions and possible tics, they may appear as early as
childhood. Age, along with certain environmental factors such as
exposure to sunlight, are not involved in generating them, but may
make them deeper and permanent.
[0007] Expression wrinkles are characterized by the presence of
grooves around the orifices formed by the nose (nasal grooves), the
mouth (perioral wrinkles and "sour-face" wrinkles) and the eyes
(crow's-feet wrinkles), around which are the skin muscles, and also
between the eyebrows (glabella wrinkles or lion wrinkles) and on
the forehead.
[0008] Until now, the only means commonly used for acting on
expression wrinkles is botulinum toxin, which is in particular
injected into the wrinkles of the glabella, which are wrinkles
between the eyebrows (see J. D. Carruters et al., J. Dermatol.
Surq. Oncol., 1992, 18, pp. 17-21).
[0009] The applicant has also proposed various compounds capable of
providing a muscle-relaxing effect when they are applied topically
to the skin, thus making it possible to act on expression wrinkles
via another route. Among these compounds, mention may in particular
be made of calcium channel-associated receptor antagonists, such as
verapamil (FR-2 793 681), and in particular manganese and its salts
(FR-2 809 005), and alverine (FR-2 798 590); chloride
channel-associated receptor agonists, including glycine (EP-0 704
210) and certain extracts of Iris pallida (FR-2 746 641); and
sapogenins (EP-1 352 643).
[0010] Along with these muscle-relaxing agents, the applicant has
described various dermo-decontracting compounds, and in particular
amine compounds (EP-1 405 633).
[0011] However, there is still a need for compounds that are more
effective than those of the prior art for smoothing or fading out
expression wrinkles.
[0012] Now, the applicant has discovered, surprisingly, that
certain piperidine derivatives can satisfy this need. Specifically,
it has been demonstrated that these compounds make it possible to
relax or decontract the dermal contractile cells that are supposed
to be involved in generating expression wrinkles. It is in fact
thought that the phenotype of certain fibroblasts located along the
tension lines created due to skin muscle contractions during facial
expressions is gradually modified under the effect of these
contractions, thus conferring specific contractile properties on
these fibroblasts. The decontraction of these cells will thus make
it possible to act on another component of expression wrinkles.
[0013] Among the compounds used according to the invention, several
have already been described as calcium channel inhibitors in
applications EP-0 542 846 and JP-61 027 963 and in U.S. Pat. No.
4,952,560.
[0014] However, the applicant had demonstrated that, while calcium
channel inhibitors are, a priori, muscle relaxing agents according
to the teaching of application FR-2 793 681, they are not all
dermo-decontracting agents. In particular, cinnarizine, diltiazem,
nitrendipine and diazepam, which are known anti-calcium compounds
(either because they act directly on calcium channels or because
they act on chloride channels and thus generate an anti-calcium
effect) and the muscle relaxing effect of which has--at least as
regards diazepam--been demonstrated, are not active as
dermo-decontracting agents in the test presented in Example 1
hereinafter. It was not therefore possible to predict that the
compounds used according to the present invention, also known as
calcium channel inhibitors, would have a dermo-decontracting
effect.
[0015] In addition, dermo-decontraction is a phenomenon that
results from the phosphorylation of the myosin light chain. This
phosphorylation is modulated by many factors, for instance the
activity of the myosin light chain-specific phosphatase. Now,
calcium channel inhibitors do not affect this pathway. There is
therefore nothing that implies that some of these inhibitors may
have a dermo-decontracting effect.
[0016] Among the compounds used according to the present invention,
ifenprodil has already been described as an anti-glycation agent
for the treatment of age-, diabetes- and smoking-related
complications (WO 03/032969), for promoting blood circulation and
moisturizing the skin (JP-62 226 909 and U.S. Pat. No. 4,952,560)
and in hair products (JP-62 270 514). Other piperidine derivatives
have been described as antibacterial agents (EP-0 308 328).
[0017] On the other hand, to the applicant's knowledge, the use of
these piperidine derivatives for combating wrinkles, in particular
expression wrinkles, and/or for decontracting the skin and/or
relaxing the features, has never been suggested.
[0018] A subject of the present invention is therefore a cosmetic
process for treating wrinkled skin, in particular the skin of the
face and/or of the forehead, through a dermo-decontracting effect,
comprising the topical application to said skin of a composition
comprising, in a physiologically acceptable medium, at least one
piperidine derivative chosen from the compounds of formula (I):
##STR00002##
in which: R.sub.1 denotes a halogen or a radical chosen from: a
C.sub.1-C.sub.6 alkyl radical, an OR group, an NRR' group, a
CF.sub.3 group, an NHCOR group or a CONRR' group; R.sub.2 denotes a
linear or branched C.sub.1-C.sub.20 alkyl or alkenyl radical
optionally substituted with at least one OR, COOR, .dbd.O, NRR',
NHCOR or CONRR' group or with a phenyl group optionally substituted
with one or more radicals R.sub.1;
[0019] where R and R' denote, independently of one
[0020] another, a hydrogen atom or a C.sub.1-C.sub.6 alkyl
radical,
m ranges from 0 to 5; n ranges from 0 to 5; and their salts and
optical isomers.
[0021] A subject of the invention is also the cosmetic use of at
least one piperidine derivative as defined above, as a
dermo-decontracting agent for combating wrinkles, in particular
expression wrinkles, and/or for decontracting the skin and/or
relaxing the features.
[0022] In formula (I), the alkyl groups may in particular be
chosen, according to the case, from the groups: methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl,
heptyl, octyl, nonyl, decyl, undecyl, dodecyl, myristyl, palmityl,
stearyl and arachidyl.
[0023] In addition, in the context of this application, the term
"alkenyl" is intended to mean radicals possibly comprising one or
more double bonds, that may or may not be conjugated. They may in
particular be chosen, according to the case, from the groups:
vinyl, allyl, butenyl or pentenyl.
[0024] As salts of the compound of formula (I), mention may be made
of the salts obtained by addition of the compound of formula (I)
with an inorganic acid, chosen in particular from hydrochloric
acid, sulphuric acid and phosphoric acid, or with an organic acid,
chosen in particular from acetic acid, propionic acid, succinic
acid, fumaric acid, maleic acid, lactic acid, glycolic acid, citric
acid and tartaric acid.
[0025] Preferably, the piperidine derivative according to the
invention is such that at least one, and preferably all, of the
following conditions are satisfied: [0026] m ranges from 0 to 3,
and is preferably equal to 0, [0027] n is equal to 0 or 1, [0028]
R.sub.1 denotes a methoxy radical or trifluoromethyl radical,
[0029] R.sub.2 denotes a linear or branched C.sub.1-C.sub.6 alkyl
or alkenyl radical optionally substituted with a phenyl group.
[0030] It is advantageously 4-phenyl-1-(4-phenylbutyl)piperidine or
one of its salts, such as its maleic acid salt (commercially
available), or else 4-benzyl-1-hexylpiperidine or one of its
salts.
[0031] The compounds of formula (I) can in particular be prepared
according to the following reaction scheme:
##STR00003##
by reacting one equivalent of substituted piperidine A with one
equivalent of B, where X denotes a leaving group of halogen or
sulphonate type, in the presence of K.sub.2CO.sub.3 in acetonitrile
at reflux overnight. The product obtained can be treated and
purified on a silica column.
[0032] The amount of piperidine derivative that can be used
according to the invention depends of course on the desired effect
and can therefore vary to a large extent.
[0033] To give an order of magnitude, these derivatives can be used
in an amount representing from 0.01% to 10% of the total weight of
the composition, preferably in an amount representing from 0.05% to
5% of the total weight of the composition, more preferably in an
amount representing from 0.1% to 2% of the total weight of the
composition.
[0034] The composition used according to the invention is suitable
for topical application to the skin, and it therefore contains a
physiologically acceptable medium, i.e. a medium that is compatible
with the skin and optionally with its integuments (eyelashes,
nails, hair) and/or the mucous membranes. This medium is
advantageously cosmetically acceptable, i.e. it does not result in
itching, stinging or redness that may put off the user of the
composition, and it has a pleasant appearance, smell and feel.
[0035] This composition may be provided in any of the
pharmaceutical forms normally used in the cosmetics field, and in
may in particular be in the form of an optionally gelled solution,
of a dispersion of the lotion type, optionally a two-phase lotion,
of an emulsion obtained by dispersion of a fatty phase in an
aqueous phase (O/W) or vice versa (W/O), or of a triple emulsion
(W/O/W or O/W/O) or of a vesicular dispersion of ionic and/or
non-ionic type. These compositions are prepared according to the
usual methods. According to this invention, it is preferable to use
a composition in the form of an oil-in-water emulsion.
[0036] This composition may be more or less fluid and may have the
appearance of a white or coloured cream, of an ointment, of a milk,
of a lotion, of a serum, of a paste or of a mousse. It may
optionally be applied in the form of an aerosol. It may also be
provided in solid form, in particular in the form of a stick. It
may be used as a care product and/or as a makeup product for the
skin.
[0037] In a known manner, the composition used according to the
invention may also contain the adjuvants that are usual in the
cosmetics field, such as hydrophilic or lipophilic gelling agents,
hydrophilic or lipophilic active agents, preserving agents,
antioxidants, solvents, fragrances, fillers, screening agents,
pigments, odour absorbers and dyes. The amounts of these various
adjuvants are those conventionally used in the field under
consideration, and for example from 0.01 to 20% of the total weight
of the composition. Depending on their nature, these adjuvants may
be introduced into the fatty phase, into the aqueous phase or into
the lipid vesicles. In any event, these adjuvants, and the
proportions thereof, will be chosen so as not to harm the desired
properties of the piperidine derivatives according to the
invention.
[0038] When the composition used according to the invention is an
emulsion, the proportion of the fatty phase may range from 5 to 80%
by weight, and preferably from 5 to 50% by weight, relative to the
total weight of the composition. The oils, the emulsifiers and the
co-emulsifiers used in the composition in the form of an emulsion
are chosen from those conventionally used in the field under
consideration. The emulsifier and the co-emulsifier are present in
the composition in a proportion ranging from 0.3 to 30% by weight,
and preferably from 0.5 to 20% by weight, relative to the total
weight of the composition.
[0039] As oils that may be used in the invention, mention may be
made of mineral oils (liquid petroleum jelly), oils of plant origin
(avocado oil, soybean oil), oils of animal origin (lanolin),
synthetic oils (perhydrosqualene), silicone oils (cyclomethicone)
and fluoro oils (perfluoropolyethers). Fatty alcohols (cetyl
alcohol), fatty acids or waxes (carnauba wax, ozokerite) may also
be used as fats.
[0040] As emulsifiers and co-emulsifiers that may be used in the
invention, mention may, for example, be made of fatty acid esters
of polyethylene glycol, such as PEG-100 stearate, and fatty acid
esters of glycerol such as glyceryl stearate.
[0041] As hydrophilic gelling agents/thickeners, mention may in
particular be made of carboxyl vinyl polymers (carbomer), acrylic
copolymers such as acrylate/alkyl acrylate copolymers,
polyacrylamides, polysaccharides, natural gums and clays, and as
lipophilic gelling agents/thickeners, mention may be made of
modified clays such as bentones, metal salts of fatty acids, and
hydrophobic silica.
[0042] As active agents, it will be advantageous to introduce into
the composition used according to the invention at least one
compound chosen from: desquamating agents; moisturizers;
depigmenting or propigmenting agents; anti-glycation agents;
NO-synthase inhibitors; agents for stimulating the synthesis of
dermal or epidermal macromolecules and/or for preventing their
degradation; agents for stimulating fibroblast and/or keratinocyte
proliferation or for stimulating keratinocyte differentiation; the
other muscle-relaxing agents and/or other dermo-decontracting
agents; tensioning agents; antipollution agents and/or free-radical
scavengers; agents that act on the microcirculation; agents that
act on the energy metabolism of cells; and mixtures thereof.
[0043] Examples of such additional compounds are: retinol and its
derivatives such as retinyl palmitate; ascorbic acid and its
derivatives such as magnesium ascorbyl phosphate and ascorbyl
glucoside; tocopherol and its derivatives such as tocopheryl
acetate; nicotinic acid and its precursors such as nicotinamide;
ubiquinone; glutathione and its precursors such as
L-2-oxothiazolidine-4-carboxylic acid; plant extracts and in
particular plant proteins and hydrolysates thereof, and also
phytohormones; marine extracts such as algal extracts; bacterial
extracts; sapogenins, such as diosgenin, and extracts of Wild Yam
containing them; ceramides; hydroxy acids; hydroxy acids such as
salicylic acid and 5-n-octanoylsalicylic acid; resveratrol;
oligopeptides and pseudopeptides and acylated derivatives thereof;
manganese salts and magnesium salts, in particular gluconates; and
mixtures thereof.
[0044] As indicated above, the composition according to the
invention may also contain photoprotective agents that are active
in the UVA and/or the UVB range, in the form of organic or
inorganic compounds, the latter being optionally coated in order to
make them hydrophobic.
[0045] The organic photoprotective agents can in particular be
chosen from: anthranilates, in particular menthyl anthranilate;
benzophenones, in particular benzophenone-1, benzophenone-3,
benzophenone-5, benzophenone-6, benzophenone-8, benzophenone-9,
benzophenone-12, and preferably benzophenone-3 (oxybenzone), or
benzophenone-4 (Uvinul MS40 available from BASF);
benzylidenecamphors, in particular 3-benzylidenecamphor,
benzylidenecamphorsulphonic acid, camphor
benzalkoniummethosulphate, polyacrylamidomethylbenzylidenecamphor,
terephthalylidinedicamphorsulphonic acid, and preferably
4-methylbenzylidenecamphor (Eusolex 6300 available from Merck);
benzimidazoles, in particular benzimidazilate (Neo Heliopan AP
available from Haarmann and Reimer), or
phenylbenzimidazolesulphonic acid (Eusolex 232 available from
Merck); benzotriazoles, in particular drometrizole trisiloxane, or
methylenebisbenzotriazolyltetramethylbutylphenol (Tinosorb M
available from Ciba); cinnamates, in particular cinoxate, DEA
methoxycinnamate, diisopropyl methylcinnamate, glyceryl
ethylhexanoate dimethoxycinnamate, isopropyl methoxycinnamate,
isoamyl cinnamate and, preferably, ethocrylene (Uvinul N35
available from BASF), octyl methoxycinnamate (Parsol MCX available
from Hoffmann La Roche), or octocrylene (Uvinul 539 available from
BASF); dibenzoylmethanes, in particular
butylmethoxydibenzoylmethane (Parsol 1789); imidazolines, in
particular ethylhexyl dimethoxybenzylidene dioxoimidazoline; PABAs,
in particular ethyl dihydroxypropyl PABA, ethylhexyldimethyl PABA,
glyceryl PABA, PABA, PEG-25 PABA and, preferably,
diethylhexylbutamidotriazone (Uvasorb HEB available from 3V Sigma),
ethylhexyltriazone (Uvinul T150 available from BASF) or ethyl PABA
(benzocaine); salicylates, in particular dipropylene glycol
salicylate, ethylhexyl salicylate, homosalate or TEA salicylate;
triazines, in particular anisotriazine (Tinosorb S available from
Ciba).
[0046] The inorganic photoprotective agents preferably consist of
zinc oxide and/or titanium dioxide, preferably of nanometric size,
optionally coated with alumina and/or stearic acid.
[0047] The composition according to the invention is advantageously
intended to be applied to areas of the face and/or of the forehead
that are marked with expression wrinkles, and/or on individuals
with expression wrinkles.
[0048] The wrinkles concerned are preferably those lying radially
around the mouth and/or the eyes, in particular the crow's-feet
wrinkles, and/or lying on the forehead, in particular the "lion"
wrinkle, located in the glabella, in between the eyebrows, and/or
lying horizontally on the forehead.
[0049] The invention will now be illustrated by means of the
following non-limiting examples. In these examples, the amounts are
indicated as percentages by weight.
EXAMPLES
Example 1
Demonstration of the Dermo-Decontracting Effect of the Piperidine
Derivatives According to the Invention
a) Principle of the Test
[0050] The principle of this test consists in studying the
decontracting effect of the maleic acid salt of
4-phenyl-1-(4-phenylbutyl)piperidine (commercially available from
one of the companies Biomol, ICN, Nacalai and Tocris), on a dermis
equivalent model consisting of a matrix of collagen seeded with
normal human fibroblasts.
[0051] These conditions are intended to mimic, in vitro, the dermal
contractile phenomena that occur during facial expressions. Under
these conditions, in fact, the cells spontaneously express tensile
forces that induce a retraction of the collagen gel. As a result of
this, there is a decrease in the total surface area of the dermis
equivalent over time. Measurement of this surface area makes it
possible to evaluate the relaxing effects of the substances brought
into contact with the dermis equivalent beforehand.
b) Protocol
[0052] Two series of attached dermis equivalents containing normal
human fibroblasts are prepared: a control series without any
treatment, and a series treated with the test compound (1 .mu.M).
The experiment is repeated three times.
[0053] The dermis equivalents are prepared as described in
Asselineau et al., Exp. Cell. Res., 1985, 159, 536-539; Models in
dermatology, 1987, Vol. 3 pp. 1-7, in the following
proportions:
TABLE-US-00001 MEM medium (1.76X) with or without compound 45%
Foetal calf serum: 10% NaOH (0.1N): 5% Acetic acid (1/1000): 4%
Collagen: 26% Fibroblasts: 11%
[0054] The treated dermis equivalent differs from the control
dermis equivalents in that 1 .mu.M of the test compound is added
thereto.
[0055] The collagen used is type I collagen (commercial solution).
It is extracted from rat tails or from calf skin by acid hydrolysis
and is conserved in an acidic medium at +4.degree. C.; it
polymerizes naturally by reheating to 37.degree. C. and by a
decrease in the degree of acidity. The collagen is dialysed
beforehand against successive baths of water+acetic acid.
[0056] The protocol is as follows: the 1.76.times.MEM medium in the
presence of additives (1% glutamine, 1% nonessential amino acids,
1% sodium pyruvate, 1% fungizone and 1% Penicillin/Streptomycin),
the foetal calf serum and the 0.1 N sodium hydroxide NaOH are
introduced into a 50 ml centrifuge tube kept in crushed ice. The
fibroblasts isolated form human skin explants are then added at a
concentration of 1.5.times.10.sup.5 cells per 1 ml of culture
medium.
[0057] A volume/volume mixture of collagen in acetic acid at 1/1000
is then added slowly, along the wall of the tube so as to observe
the appearance of a whitish cloud.
[0058] The entire combination is then carefully mixed and dispensed
into the wells of a 12-well culture plate (Costar type, reference
3512) in a proportion of 2 ml of mixture per well. The final cell
concentration is 3.times.10.sup.4 cells/dermis equivalent, with a
final collagen concentration of 1 mg/ml. The culture plate is then
placed in an incubator at 37.degree. C. with 5% CO.sub.2.
[0059] Once formed after polymerization of the collagen, the dermis
equivalents are left adherent to the culture support for 3 days and
are then detached from the support so that the contraction may
begin. These attached dermis equivalents are taken out of the
incubator in order to take the pictures for the purpose of
measuring their surface area, for each point of the contraction
kinetics (0, 4, 8 and 24 hours). They are immediately returned to
the incubator between each measurement point.
[0060] The spontaneous contraction of the dermis equivalent that is
treated (with the test compound) and the control dermis equivalent
(without test compound) is evaluated by measuring their surface
area, at various times after the beginning of the spontaneous
contraction.
[0061] For this, a digital image is acquired for each treated or
nontreated dermis equivalent, by means of a camera (CCD
camera--Iris Sony DXC--107P) and the surface area is then
calculated on each image by means of an image analysing system
(Zeiss Axiovision 3.0). Correspondent to this surface area
measurement is a percentage contraction equal to the ratio of the
surface areas according to the formula:
% contraction=(Sp-Si)/Sp.times.100
where: `Sp` represents the surface area of a well of the culture
plate; it corresponds to the total surface area of the dermis
equivalent before contraction, `Si` represents the surface area of
the dermis equivalent at the moment i of the contraction
kinetics.
c) Results
[0062] The maleic acid salt of 4-phenyl-1-(4-phenylbutyl)piperidine
reduces the contraction of the fibroblasts by 17%, on average, over
the duration of the experiment, compared with the control. This
compound therefore has a significant dermo-decontracting
effect.
Example 2
Synthesis of 4-phenyl-1-(4-phenylbutyl)piperidine
[0063] This compound was prepared according to the following
reaction scheme:
##STR00004##
[0064] 4-Phenylpiperidine (1 eq) was reacted with
4-phenylbromobutyl (1 eq) in the presence of K.sub.2CO.sub.3 in
acetonitrile at reflux overnight. The product obtained was treated
and purified on a silica column. The .sup.1H NMR at 500 MHz is in
accordance with the expected structure.
Example 3
Cosmetic Composition
[0065] This composition is prepared in a manner that is
conventional for those skilled in the art. The amounts given in
this example are indicated as percentages by weight.
TABLE-US-00002 4-Phenyl-1-(4-phenylbutyl)piperidine 0.10% Stearic
acid 3.00% Mixture of glyceryl monostearate and 2.50% polyethylene
glycol stearate (100 EO) Polyethylene glycol stearate (20 EO) 1.00%
Cyclopentadimethylsiloxane 10.00% Fillers 3.00% Plant oils 7.00%
Synthetic oils 6.00% Preserving agents 1.20% Oxyethylenated (16 EO)
dimethylsiloxane 1.00% with methoxy ends Silicone gum 0.20% Acrylic
copolymer in an inverse emulsion 1.70% (Simulgel 600 from Seppic)
Stearyl alcohol 1.00% Water qs 100%
[0066] This cream is intended to be applied to the face and the
forehead in order to relax the features and decontract the facial
skin.
* * * * *