Hair loss abstract
Novel N-aryl-2-hydroxyalkylamido compounds having the formula (I):
##STR1## are well suited for inducing/stimulating hair growth and/or
retarding hair loss and/or for therapeutically treating hyperseborrhea
and/or acne.
Hair loss claims
What is claimed is:
1. An N-aryl-2-hydroxyalkylamide compound having the structural
formula (I): ##STR6## in which R.sub.1 is a hydrogen atom, a halogen
atom, a cyano group (--CN), a C.sub.1 -C.sub.4 alkyl radical, a
perfluoroalkyl radical or an --OR.sub.6 radical, wherein R.sub.6
is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl radical; R.sub.2
is a nitro group (--NO.sub.2), a cyano group (--CN), a halogen atom,
an --SO.sub.2 R.sub.7 radical, a --COR.sub.7 radical or a --COOR.sub.7
radical, wherein R.sub.7 is a hydrogen atom, a C.sub.1 -C.sub.4
alkyl radical or a phenyl radical optionally substituted by at least
one halogen atom; R.sub.3 is a hydrogen atom, a halogen atom, a
cyano group (--CN), a C.sub.1 -C.sub.4 alkyl radical optionally
substituted by at least one halogen atom, or an --OR.sub.6 radical,
wherein R.sub.6 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl radical;
R.sub.4 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl radical optionally
substituted by at least one halogen atom; R.sub.5 is a C.sub.1 -C.sub.4
alkyl radical substituted by at least one halogen atom or a phenyl
radical optionally substituted by at least one halogen atom, a cyano
group (--CN) or a nitro group (--NO.sub.2); Y is an --OR radical
or an --NRR' radical; and R and R', which may be identical or different,
are each a hydrogen atom, a C.sub.1 -C.sub.8 alkyl radical optionally
substituted by at least one hydroxyl radical (--OH), or a --COOR.sub.6
radical; with the proviso that, when Y is --NRR', R and R', together
with the nitrogen atom from which they depend, can form a 5- or
6-membered heterocyclic ring member; or isomer, acylated derivative
or pharmaceutically acceptable salt thereof.
2. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.1 is a halogen atom.
3. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.1 is a C.sub.1 -C.sub.4 alkyl radical.
4. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.1 is a perfluoroalkyl radical.
5. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.1 is an --OR.sub.6 radical.
6. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.2 is a halogen atom.
7. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.2 is an --SO.sub.2 --R.sub.7 radical.
8. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.2 is a --COR.sub.7 radical.
9. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.2 is a --COOR.sub.7 radical.
10. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.3 is a halogen atom.
11. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.3 is a C.sub.1 -C.sub.4 alkyl radical
optionally substituted by at least one halogen atom.
12. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.3 is an --OR.sub.6 radical.
13. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.4 is a C.sub.1 -C.sub.4 alkyl radical.
14. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.4 is a C.sub.1 -C.sub.4 alkyl radical
substituted by at least one halogen atom.
15. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.5 is a C.sub.1 -C.sub.4 alkyl radical
substituted by at least one halogen atom.
16. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R.sub.4 and R.sub.5 are different.
17. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), Y is an --NHR radical.
18. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R is a C.sub.1 -C.sub.8 alkyl radical.
19. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1, wherein formula (I), R is a --COOR.sub.6 radical.
20. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: (4-cyano-3-(trifluoromethyl)phenyl)(3,3,3-trifluoro-2-hydroxy-2-methylprop
ionyl)carbamic acid.
21. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: the ethyl ester of (4-cyano-3-(trifluoromethyl)phenyl)(3,3,3-trifluoro-2-hydroxy-2-methylprop
ionyl)carbamic acid.
22. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: 1-(3,4-dichlorophenyl)-3-propyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropi
onyl)urea.
23. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: 1-(3,4-dichlorophenyl)-3-benzyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropi
onyl)urea.
24. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: 1-(3,4-dichlorophenyl)-3-piperidinyl-1-(3,3,3-trifluoro-2-hydroxy-2-methyl
propionyl)urea.
25. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: 1-(4-sulfonylphenyl)-3-propyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropion
yl)urea.
26. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: 1-(4-benzoylphenyl)-3-propyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropiony
l)urea.
27. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: the ethyl ester of (3,4-dichlorophenyl)(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)carbamic
acid.
28. The N-aryl-2-hydroxyalkylamide compound as defined by claim
1: 1-(3,4-dichlorophenyl)-3-(4-hydroxybutyl)-(3,3,3-trifluoro-2-hydroxy-2-met
hylpropionyl) urea.
29. A cosmetic/pharmaceutical composition suited for inducing/stimulating
hair growth and/or retarding hair loss and/or for treating hyperseborrhea
and/or acne, comprising an amount effective to elicit at least one
of the following activities: (i) inducing or stimulating hair growth;
(ii) retarding hair loss; (iii) treating hyperseborrhea and (iv)
treating acne, of at least one N-aryl-2-hydroxyalkylamide compound
as defined by claim 1, formulated into a cosmetically/pharmaceutically
acceptable vehicle, diluent or carrier therefor.
30. The cosmetic/pharmaceutical composition as defined by claim
29, comprising from 0.0001% to 5% by weight of said at least one
N-aryl-2-hydroxyalkylamide compound.
31. The cosmetic/pharmaceutical composition as defined by claim
29, comprising from 0.001% to 2% by weight of said at least one
N-aryl-2-hydroxyalkylamide compound.
32. The cosmetic/pharmaceutical composition as defined by claim
29, comprising from 0.001% to 10% by weight of said at least one
N-aryl-2-hydroxyalkylamide compound.
33. The cosmetic/pharmaceutical composition as defined by claim
29, comprising from 0.01% to 5% by weight of said at least one N-aryl-2-hydroxyalkylamide
compound.
34. The cosmetic/pharmaceutical composition as defined by claim
29, further comprising an effective amount of at least one active
agent selected from among antibacterial agents, agents for combating
parasites, antifungals, antivirals, anti-inflammatories, antipruritics,
anaesthetics, keratolytics, agents for combating free radicals,
antiseborrhoeics, antidandruff agents, antiacne agents, agents which
decrease cutaneous pigmentation and/or proliferation and/or differentiation,
extracts of plant or bacterial origin, or combination thereof.
35. The cosmetic/pharmaceutical composition as defined by claim
29, formulated for topical application onto the skin, hair and/or
scalp of a human subject.
36. The cosmetic/pharmaceutical composition as defined by claim
29, formulated for injection into a human subject.
37. The cosmetic/pharmaceutical composition as defined by claim
29, formulated for ingestion by a human subject.
38. The cosmetic/pharmaceutical composition as defined by claim
29, comprising a solution, dispersion, emulsion, gel, cream, milk,
serum, foam, aerosol, lotion, dye composition, shampoo, eyedrops,
syrup, capsules, granules, tablets, soap, microcapsules, microparticles,
or vesicular dispersion.
39. The cosmetic/pharmaceutical composition as defined by claim
29, further comprising an effective amount of an auxiliary active
agent also suited for inducing/stimulating hair growth and/or retarding
hair loss.
40. A regime or regimen for inducing/stimulating hair growth and/or
retarding hair loss on a human subject in need of such treatment,
comprising administering to said human subject an effective amount
of the cosmetic/pharmaceutical composition as defined by claim 29,
for a period of time sufficient to elicit said hair growth-/hair
loss-affecting response.
41. A regime or regimen for therapeutically treating hyperseborrhea
and/or acne afflicting a human subject, comprising administering
to said human subject an effective amount of the cosmetic/pharmaceutical
composition as defined by claim 29, for a period of time sufficient
to elicit said hyperseborrhea-/acne-affecting response.
42. A process for the preparation of the N-aryl-2-hydroxyalkylamide
compound as defined by claim 1, comprising first reacting an isocyanate
with a cyanohydrin in the presence of an amine, then treating the
mixture of reaction with hydrochloric acid, next adding an excess
of alcohol or amine to a solution of the N-aryl-2,4-dioxooxazolidine
thus formed, and thence heating such mixture for such period of
time as to convert same into said N-aryl-2-hydroxyalkylamide compound.
Hair loss description
CROSS-REFERENCE TO PRIORITY APPLICATION
This application claims priority under 35 U.S.C. .sctn.119 of FR-97/14241,
filed Nov. 13, 1997, assigned to the assignee hereof and hereby
expressly incorporated by reference.
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The present invention relates to novel N-aryl-2-hydroxyalkylamide
compounds, to a process for the synthesis thereof, and to the formulation
of at least one of said novel compounds into cosmetic/therapeutic
compositions well suited for inducing and/or stimulating hair growth
and/or retarding hair loss and/or for treating hyperseborrhoea and/or
acne.
2. Description of the Prior Art
In human subjects the growth of the hair and its renewal are principally
determined by the activity of the hair follicles. This activity
is cyclical and essentially comprises three phases, namely, the
anagen phase, the catagen phase and the telogen phase.
The active anagen phase, or growth phase, which lasts for several
years and during which the hairs lengthen, is succeeded by a very
short and transitory catagen phase, which lasts for a few weeks,
and then by a resting or quiescent phase, also designated the telogen
phase, which lasts for a few months.
At the end of the rest period, the hairs fall out and another cycle
begins anew. The head of hair is thus continuously renewed and,
out of the approximately 150,000 hairs on a human head, at each
instant approximately 10% of them are at rest in the telogen phase
and will thus be replaced in a few months.
However, various causes and challenges can result in a significant,
temporary or definitive, loss of hair. Alopecia is essentially due
to a disruption in hair renewal which initially gives rise to an
acceleration of the frequency of the cycles at the expense of the
quality of the hairs and then of their quantity. A progressive thinning
of the head of hair takes place by regression of the so-called "terminal"
hairs to the down stage. Certain regions are preferentially affected,
in particular the temporal or frontal bulbs in man and, in woman,
a diffuse alopecia of the vertex is observed.
By the term "alopecia" is intended an entire family of
conditions of the hair follicle having as final consequence the
partial or general definitive loss of the hair.
In a significant number of cases, early hair loss occurs in subjects
who are genetically predisposed and it affects men in particular.
It is more particularly androgenetic or androgenic alopecia or,
alternatively, androgeno-genetic alopecia.
Compositions that eliminate or reduce the effects of alopecia and,
in particular, that induce or stimulate hair growth or decrease
hair loss have long been considered desiderata in the cosmetic and
pharmaceutical industries.
In this regard, a large number of very diverse active compounds
have been suggested for such purposes, for example, 2,4-diamino-6-piperidinopyrimidine
3-oxide or "Minoxidil" described in U.S. Pat. Nos. 4,139,619
and 4,596,812 or numerous derivatives thereof, such as those described,
for example, in EP-0,353,123, EP-0,356,271, EP-0,408,442, EP-0,522,964,
EP-0,420,707, EP-0,459,890 and EP-0,519,819.
SUMMARY OF THE INVENTION
A major object of the present invention is the provision of yet
other such valuable active compounds, particularly those species
that are potentially more active and/or less toxic.
Briefly, the present invention features novel N-aryl-2-hydroxyalkylamido
compounds having the general formula (I): ##STR2## in which R.sub.1
is a hydrogen atom, a halogen atom, a cyano group (--CN), a C.sub.1
-C.sub.4 alkyl radical, a perfluoroalkyl radical or an --OR.sub.6
radical, wherein R.sub.6 is a hydrogen atom or a C.sub.1 -C.sub.4
alkyl radical; R.sub.2 is a nitro group (--NO.sub.2), a cyano group
(--CN), a halogen atom, an --SO.sub.2 R.sub.7 radical, a --COR.sub.7
radical or a --COOR.sub.7 radical, wherein R.sub.7 is a hydrogen
atom, a C.sub.1 -C.sub.4 alkyl radical or a phenyl radical optionally
substituted by at least one halogen atom; R.sub.3 is a hydrogen
atom, a halogen atom, a cyano group (--CN), a C.sub.1 -C.sub.4 alkyl
radical optionally substituted by at least one halogen atom, or
an --OR.sub.6 radical, wherein R.sub.6 is a hydrogen atom or a C.sub.1
-C.sub.4 alkyl radical; R.sub.4 is a hydrogen atom or a C.sub.1
-C.sub.4 alkyl radical optionally substituted by at least one halogen
atom; R.sub.5 is a C.sub.1 -C.sub.4 alkyl radical substituted by
at least one halogen atom or a phenyl radical optionally substituted
by at least one halogen atom, a cyano group (--CN) or a nitro group
(--NO.sub.2); Y is an --OR radical or an --NRR' radical; and R and
R', which may be identical or different, are each a hydrogen atom,
a C.sub.1 -C.sub.8 alkyl radical optionally substituted by at least
one hydroxyl radical (--OH), or a --COOR.sub.6 radical; with the
proviso that, when Y is --NRR', R and R', together with the nitrogen
atom from which they depend, can form a 5- or 6-membered heterocyclic
ring member.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS
OF THE INVENTION
More particularly according to the present invention, also featured
are the optical and/or geometrical isomers of the subject novel
compounds, alone or in admixture in all proportions, as well as
the acylated derivatives or the pharmaceutically acceptable salts
thereof.
Among the halogen atom substituents of the formula (I) compounds,
preferred are fluorine, chlorine, iodine or bromine and, more preferably,
fluorine.
By "C.sub.1 -C.sub.4 alkyl radical" preferably are intended
the acyclic radicals originating from the removal of a hydrogen
atom from the molecule of a linear or branched hydrocarbon having
from 1 to 4 carbon atoms and, in particular, the methyl, ethyl,
propyl, isopropyl, butyl, isobutyl or tert-butyl radicals and, more
particularly, the methyl radical.
By "alkyl radical optionally substituted by at least one halogen
atom" are preferably intended the radicals defined above in
which at least one hydrogen atom is substituted by a halogen atom,
including the perhalogenated radicals in which all of the hydrogen
atoms are replaced by an equal number of halogen atoms.
The "alkyl radicals substituted by at least one halogen atom"
are preferably substituted by at least one chlorine or fluorine
atom. The perhalogenated radicals are preferably perfluorinated
radicals, in particular perfluoromethyl radicals.
When R.sub.1 is a halogen atom, R.sub.1 is preferably a chlorine
atom.
When R.sub.1 is a C.sub.1 -C.sub.4 alkyl radical, R.sub.1 is preferably
a methyl radical.
When R.sub.1 is a perfluoroalkyl radical, R.sub.1 is preferably
a trifluoromethyl radical (--CF.sub.3).
When R.sub.1 is an --OR.sub.6 radical, R.sub.1 is preferably a
methoxy radical (--OCH.sub.3).
When R.sub.2 is a halogen atom, R.sub.2 is preferably a chlorine
atom.
When R.sub.2 is an --SO.sub.2 R.sub.7 radical, R.sub.7 is preferably
a phenyl radical.
When R.sub.2 is a --COR.sub.7 radical, R.sub.7 is preferably a
phenyl radical.
When R.sub.2 is a --COOR.sub.7 radical, R.sub.7 is preferably an
ethyl radical.
When R.sub.3 is a halogen atom, R.sub.3 is preferably a chlorine
atom.
When R.sub.3 is a C.sub.1 -C.sub.4 alkyl radical optionally substituted
by at least one halogen atom, R.sub.3 is preferably a trifluoromethyl
radical (--CF.sub.3).
When R.sub.3 is an --OR.sub.6 radical, R.sub.6 is preferably a
methyl radical (--CH.sub.3).
When R.sub.4 is a C.sub.1 -C.sub.4 alkyl radical, R.sub.4 is preferably
a methyl radical (--CH.sub.3).
When R.sub.4 is a C.sub.1 -C.sub.4 alkyl radical substituted by
at least one halogen atom, R.sub.4 is preferably a trifluoromethyl
radical (--CF.sub.3).
When R.sub.5 is a C.sub.1 -C.sub.4 alkyl radical substituted by
at least one halogen atom, R.sub.5 is preferably a trifluoromethyl
radical (--CF.sub.3).
R.sub.4 and R.sub.5 can be identical but R.sub.4 and R.sub.5 preferably
are different.
Y preferably represents an --NHR radical.
When R represents a C.sub.1 -C.sub.8 radical, R is preferably a
butyl radical.
When R represents a --COOR.sub.6 radical, R.sub.6 is preferably
a propyl radical.
Exemplary compounds of formula (I) include:
(4-cyano-3-(trifluoromethyl)phenyl)-(3,3,3-trifluoro-2-hydroxy-2-methylprop
ionyl)carbamic acid;
the ethyl ester of (4-cyano-3-(trifluoro-methyl)phenyl)(3,3,3-trifluoro-2-hydroxy-2-methylpro
pionyl)carbamic acid;
1-(3,4-dichlorophenyl)-3-propyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropio
nyl)urea;
1-(3,4-dichlorophenyl)-3-benzyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropio
nyl)urea;
1-(3,4-dichlorophenyl)-3-piperidinyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylp
ropionyl)urea;
1-(4-sulfonylphenyl)-3-propyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropiony
l)urea;
1-(4-benzoylphenyl)-3-propyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl
)urea;
the ethyl ester of (3,4-dichlorophenyl)(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)carbamic
acid;
1-(3,4-dichlorophenyl)-3-(4-hydroxybutyl)-1-(3,3,3-trifluoro-2-hydroxy-2-me
thylpropionyl)urea.
More particularly preferred are:
(4-cyano-3-(trifluoromethyl)phenyl)-(3,3,3-trifluoro-2-hydroxy-2-methylprop
ionyl)carbamic acid;
the ethyl ester of (4-cyano-3-(trifluoromethyl)phenyl)(3,3,3-trifluoro-2-hydroxy-2-methylprop
ionyl)carbamic acid;
1-(3,4-dichlorophenyl)-3-propyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropio
nyl)urea.
This invention also features a process for the preparation of the
compounds of formula (I).
This process is characterized in that, in a first stage, an N-aryl-2,4-dioxooxazolidine
derivative is prepared, according to the technique described by
Patton, T. L., J. Org. Chem., 32(2), 383-388 (1967), by reacting
an isocyanate with a cyanohydrin in an anhydrous solvent in the
presence of an amine. The mixture obtained is treated in the presence
of hydrochloric acid and then the N-aryl-2,4-dioxo-oxazolidine derivative
formed is extracted using an organic solvent and then dried and
purified by chromatography on a silica column. In a second stage,
an excess of alcohol or of amine is added to a solution of N-aryl-2,4-dioxooxazolidine
obtained in the first stage. The solution is heated to a temperature
of from 25.degree. C. to 70.degree. C. for 1 to 7 days and then
evaporated to dryness. The residue is purified by chromatography
on a silica column or recrystallized.
Specific examples of the preparation of the compounds according
to the invention are set forth in the examples to follow.
The present invention also features cosmetic or pharmaceutical
compositions, particularly dermatological compositions, which comprise
an effective amount of at least one of the compounds of formula
(I).
Of course, the compositions according to the invention can comprise
the compounds of formula (I) alone or in admixture in all proportions.
The amount of the compounds of formula (I) present in the compositions
of the invention is, of course, a function of the desired effect
and can thus vary to a great extent.
To provide an order of magnitude, if the composition is a cosmetic
composition, it advantageously comprises at least one compound of
formula (I) in an amount ranging from 0.0001% to 5% of the total
weight of the composition and, preferably, in an amount ranging
from 0.001% to 2% of the total weight of the composition.
To also provide another order of magnitude, if the composition
is a pharmaceutical composition, it advantageously comprises at
least one compound of formula (I) in an amount ranging from 0.001%
to 10% of the total weight of the composition and, preferably, in
an amount ranging from 0.01% to 5% of the total weight of the composition.
The subject compositions can be ingested, injected or topically
applied to human skin (over any cutaneous region of the body), hair,
nails or mucous membranes (buccal, jugal, gingival, genital or connective).
Depending on the mode of administration, the compositions according
to the invention can be provided in all of the pharmaceutical dosage
forms conventional to this art.
For topical application onto the skin, the subject compositions
can be formulated, in particular, as an aqueous or oily solution
or as a dispersion of the lotion or serum type, as emulsions having
a liquid or semi-liquid consistency of the milk type, obtained by
dispersion of a fatty phase in an aqueous phase (O/W) or vice versa
(W/O), or as suspensions or emulsions having a soft consistency
of the aqueous or anhydrous gel or cream type, or, alternatively,
as microcapsules or microparticles, or as vesicular dispersions
of ionic and/or nonionic type. These compositions are formulated
via conventional techniques.
The subject compositions can also be applied onto hair in the form
of aqueous, alcoholic or aqueous/alcoholic solutions, or in the
form of creams, gels, emulsions or foams, or, alternatively, in
the form of aerosol compositions also comprising a pressurized propellant.
The compositions according to the invention can also be formulated
as a hair care composition and, in particular, a shampoo, a hair
setting lotion, a treating lotion, a styling cream or gel, a dyeing
composition (in particular oxidation dyeing composition), optionally
in the form of coloring shampoos, hair restructuring lotions, a
permanent wave composition (in particular a composition for the
first step of permanent waving), a lotion or gel for combating hair
loss, an antiparasitic shampoo, and the like.
For injection, the subject compositions can be provided in the
form of an aqueous or oily lotion or in the form of a serum. For
the eyes, they can be provided in the form of drops and, for ingestion,
they can be provided in the form of capsules, granules, syrups or
tablets.
The amounts of the various constituents of the compositions according
to the invention are those conventionally formulated in the fields
under consideration.
The compositions according to the invention can also be provided
as solid preparations constituting cleansing soaps or bars.
The subject compositions can also be packaged in the form of an
aerosol composition also comprising a pressurized propellant.
When the composition is an emulsion, the proportion of the fatty
phase advantageously ranges from 5% to 80% by weight and preferably
from 5% to 50% by weight with respect to the total weight of the
composition. The oils, waxes, emulsifiers and coemulsifiers comprising
the composition in the form of an emulsion are selected from among
those conventionally employed in the cosmetics field. The emulsifier
and the coemulsifier are typically present in the composition in
a proportion ranging from 0.3% to 30% by weight and preferably from
0.5% to 20% by weight with respect to the total weight of the composition.
In addition, the emulsion can comprise lipid vesicles.
When the composition is an oily solution or gel, the fatty phase
can constitute more than 90% of the total weight of the composition.
In known fashion, the subject cosmetic compositions can also comprise
additives and adjuvants conventional in the cosmetics field, such
as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic
additives, preservatives, antioxidizing agents, solvents, fragrances,
fillers, screening agents, odor absorbers and colorants. The amounts
of these various additives and adjuvants are those conventionally
employed in the cosmetic field and, for example, range from 0.01%
to 10% of the total weight of the composition. These additives and
adjuvants, depending on their nature, can be formulated into the
fatty phase, into the aqueous phase and/or into the lipid spherules.
Exemplary oils or waxes which can be formulated into the compositions
of the invention include the mineral oils (liquid petrolatum), vegetable
oils (liquid fraction of karite butter, sunflower oil), animal oils
(perhydrosqualene), synthetic oils (purcellin oil), silicone oils
or waxes (cyclomethicone) and fluorinated oils (perfluoropolyethers),
beeswax, carnauba wax or paraffin wax. Fatty alcohols and fatty
acids (stearic acid) can be added to these oils.
Exemplary emulsifiers according to the invention include glycerol
stearate, polysorbate 60 and the PEG-6/PEG-32/Glycol Stearate mixture
marketed under the trademark Tefose.RTM. 63 by Gattefosse.
Exemplary solvents according to the invention include the lower
alcohols, in particular ethanol and isopropanol, or propylene glycol.
And exemplary hydrophilic gelling agents according to the invention
include carboxyvinyl polymers (carbomer), acrylic copolymers, such
as acrylate/alkyl acrylate copolymers, polyacrylamides, polysaccharides,
such as hydroxypropylcellulose, natural gums and clays and exemplary
lipophilic gelling agents include modified clays, such as bentones,
metal salts of fatty acids, such as aluminum stearates, and hydrophobic
silica, ethylcellulose or polyethylene.
The subject compositions can also comprise other hydrophilic active
agents and principles, such as proteins or protein hydrolysates,
amino acids, polyols, urea, allantoin, sugars and sugar derivatives,
water-soluble vitamins, plant extracts, hydroxyacids, etc.
Exemplary lipophilic active principles include retinol (vitamin
A) and derivatives thereof, tocopherol (vitamin E) and its derivatives,
essential fatty acids, ceramides, essential oils, or salicylic acid
and derivatives thereof.
According to the present invention, the subject compositions may
contain at least one compound of formula (I) and at least one other
active agent or principle. Representative such active agents/principles
are:
(a) agents which improve the activity with respect to hair regrowth
and/or with respect to retarding hair loss and which are already
known for this activity, such as, for example, nicotinic acid esters,
including, in particular, tocopherol nicotinate, benzyl nicotinate
and nicotinates of C.sub.1 -C.sub.6 alkyls, such as methyl or hexyl
nicotinates, pyrimidine derivatives, such as 2,4-diamino-6-piperidinopyrimidine
3-oxide or "Minoxidil", disclosed in U.S. Pat. Nos. 4,139,619
and 4,596,812, or agents which promote hair regrowth, such as those
described in the European patent application published under the
number 0,648,488 and assigned to the assignee hereof;
(b) agents which decrease cutaneous pigmentation and/or proliferation
and/or differentiation, such as retinoic acid and isomers thereof,
retinol and esters thereof, vitamin D and derivatives thereof, estrogens,
such as estradiol, kojic acid or hydroquinone;
(c) antibacterials, such as clindamycin phosphate, erythromycin
or antibiotics from the tetracycline class;
(d) agents for combating parasites, in particular metronidazole,
crotamiton or pyrethroids;
(e) antifungals, in particular compounds belonging to the imidazole
class, such as econazole, ketoconazole or miconazole or salts thereof,
polyene compounds, such as amphotericin B, compounds of the allylamine
family, such as terbinafine, or, alternatively, octopirox;
(f) antiviral agents, such as acyclovir;
(g) steroidal anti-inflammatory agents, such as hydrocortisone,
betamethasone valerate or clobetasol propionate, or nonsteroidal
anti-inflammatory agents, such as, for example, ibuprofen and salts
thereof, diclofenac and salts thereof, acetylsalicylic acid, acetaminophen
or glycyrrhizic acid;
(h) anaesthetic agents, such as lidocaine hydrochloride and derivatives
thereof;
(i) antipruriginous agents, such as thenaldine, trimeprazine or
cyproheptadine;
(j) keratolytic agents, such as .alpha.- and .beta.-hydroxycarboxylic
acids or .beta.-ketocarboxylic acids, their salts, amides or esters
and more particularly hydroxyacids, such as glycolic acid, lactic
acid, salicylic acid, citric acid and generally fruit acids, and
5-(n-octanoyl)salicylic acid;
(k) agents for combating or scavenging free radicals, such as .alpha.-tocopherol
and esters thereof, superoxide dismutases, certain metal chelating
agents or ascorbic acid and esters thereof;
(l) antiseborrhoeics, such as progesterone;
(m) antidandruff agents, such as octopirox or zinc pyrithione;
(n) antiacne agents, such as retinoic acid or benzoyl peroxide,
(o) extracts of plant or bacterial origin.
Other active agents/principles can also be included, for example
diazoxide, spiroxazone, phospholipids, such as lecithin, linoleic
and linolenic acids, salicylic acid and derivatives thereof described
in FR-2,581,542, such as salicylic acid derivatives bearing an alkanoyl
group having from 2 to 12 carbon atoms in the 5-position of the
benzene ring, hydroxycarboxylic or ketocarboxylic acids and esters
thereof, lactones and their corresponding salts, anthralin, carotenoids,
eicosatetrayenoic and eicosatriyenoic acids or their esters and
amides, vitamin D and derivatives thereof, or extracts of plant
or bacterial origin.
Thus, in one embodiment, the compositions according to the invention
also comprise at least one agent selected from among antibacterial
agents, agents for combating parasites, antifungals, antivirals,
anti-inflammatories, antipruritics, anaesthetics, keratolytics,
agents for combating free radicals, antiseborrhoeics, antidandruff
agents, antiacne agents and/or agents which decrease cutaneous pigmentation
and/or proliferation and/or differentiation, or extracts of plant
or bacterial origin.
The subject compositions may also comprise at least one compound
as indicated above that is in the liposomed form, such as described
in WO-94/22468, filed Oct. 13, 1994, by Anti-Cancer Inc. The compound
encapsulated in the liposomes can thus be delivered selectively
to hair follicles.
The pharmaceutical compositions according to the invention can
be administered parenterally, enterally or topically. Such pharmaceutical
compositions are preferably administered topically.
The present invention thus features formulating, into cosmetic/pharmaceutical
compositions comprising a physiologically acceptable medium therefor
(vehicle, diluent or carrier), an effective amount of at least one
compound of above formula (I).
This because the compounds of formula (I) are excellent potassium
channel openers, the principal property of Minoxidil, the only compound
currently recognized as effective in treatments for hair loss.
They are also excellent antagonists of androgen receptors, androgens
being responsible for a particularly widespread form of alopecia,
androgen-dependent alopecia. However, it is also known that androgens
are implicated in hyperseborrhoea and acne.
Thus, the compounds of formula (I) exhibit notable activities which
justify their use as medicaments, in particular for inducing and/or
stimulating hair growth and/or retarding hair loss and/or for the
treatment of hyperseborrhoea and/or acne.
To date, N-aryl-2-hydroxyalkylamide compounds having mixed potassium
channel opener/antiandrogen activity have not been employed for
combating hair loss and/or for treating hyperseborrhoea and/or acne.
Accordingly, this invention also features formulating an effective
active principle amount of at least one compound of formula (I)
into cosmetic/pharmaceutical compositions well suited to induce
and/or stimulate hair growth and/or retard hair loss and/or to treat
hyperseborrhoea and/or acne.
Of course, the subject compounds can be used either alone or as
a mixture.
The cosmetic compositions according to the invention are topically
applied to the regions of the body requiring such treatment, such
as, for example, the alopecic regions of the scalp or hair of an
individual. The cosmetic compositions can then optionally be maintained
in contact with the skin/hair/scalp for several hours and then optionally
rinsed therefrom. It is possible, for example, to topically apply
a composition comprising an effective active principle amount of
at least one compound as indicated above in the evening, to maintain
the composition in contact with the skin/hair/scalp overnight and
optionally to shampoo it therefrom in the morning. These applications
can be repeated daily over one or more months, depending on the
particular individual.
The present invention thus also features a regime or regimen for
cosmetically treating the hair and/or scalp and/or skin, comprising
topically applying, to the hair and/or scalp and/or skin, a cosmetic
composition comprising an effective active principle amount of at
least one compound of formula (I), maintaining such composition
in contact with the hair and/or scalp and/or skin, and, optionally,
rinsing same therefrom.
Such regime/regimen presents the characteristics of a cosmetic
treatment insofar as it permits the appearance of the hair and/or
skin to be improved by imparting a greater strength and an improved
appearance thereto.
In order to further illustrate the present invention and the advantages
thereof, the following specific examples are given, it being understood
that same are intended only as illustrative and in nowise limitative.
|