Hair loss abstract
Hair growth-/hair loss-affecting cosmetic/therapeutic compositions
contain an effective amount of at least one 2-amino-4-alkylaminopyrimidine
3-oxide having the structural formula (I): ##STR1## in which R.sub.1
is an alkyl radical having from 5 to 20 carbon atoms, and Z is either
a hydrogen atom or a radical --OR.sub.2, wherein R.sub.2 is an alkyl
radical having from 1 to 12 carbon atoms, or an acyl derivative
or acid addition salt thereof.
Hair loss claims
What is claimed is:
1. The compound which is 2-amino-4-hexylaminopyrimidine 3-oxide;
2-amino-4-octylaminopyrimidine 3-oxide; or 2-amino-4-dodecylaminopyrimidine
3-oxide.
2. The compound as defined by claim 1, which is 2-amino-4-dodecylaminopyrimidine
3-oxide.
3. A process for the preparation of a compound as defined by claim
1, comprising: (a) reacting hexylanic, octylamine or dodecylamine,
respectively, with 2-amino-4,6-dichloropyrimidine in ethanol, to
afford 2-amino-4-hexylamino-6-chloropyrimidine, 2-amino-4-octylamino-6-chloropyrimidine
or 2-amino-4-decylamino-6-chloropyrimidine, respectively; (b) reacting
the resultant 2-amino-4-hexylamino-6-chloropyrimidine, 2-amino-4-octylamino-6-chloropyrimidine
or 2-amino-4-dodecylamino-6-chloropyrimidine, respectively, with
a urea/H.sub.2 O.sub.2 complex and phthalic anhydride in isopropanol,
to afford 2-amino-4-hexylamino-6-chloropyrimidine 3-oxide, 2-amino-4-octylamino-6-chloropyrimidine
3-oxide or 2-amino-4-dodecylamino-6-chloropyrimidine 3-oxide, respectively;
and (c) reacting the resultant 2-amino-4-hexylamino-6-chloropyrimidine
3-oxide, 2-amino-4-octylamino-6-chloropyrmidine 3-oxide or 2-amino-4-dodecylamino-6-chloropyrimidine
3-oxide, respectively, in the presence of potassium hydroxide and
palladium-on-charcoal, in ethanol, under a high hydrogen pressure,
to afford 2-amino-4-hexylaminopyrimidine 3-oxide, 2-amino-4-octylaminopyrimidine
3-oxide or 2-amino-4-dodecylaminopyrimidine 3-oxide, respectively.
4. A hair growth-/hair loss-affecting cosmetic/therapeutic composition
of matter, comprising an effective hair growth stimulating and/or
hair loss retarding amount of at least one compound as defined by
claim 1, formulated into a physiologically acceptable vehicle, diluent
or carrier therefor.
5. The cosmetic/therapeutic composition as defined by claim 4,
comprising from 0.001% to 10% by weight of said at least one compound.
6. The cosmetic/therapeutic composition as defined by claim 5,
comprising from 0.01% to 2% by weight of said at least one compound.
7. The cosmetic/therapeutic composition as defined by claim 4,
further comprising an effective amount of at least one antibacterial
agent, antiparasitic agent, antifungal agent, antiviral agent, anti-inflammatory
agent, antipruriginous agent, anaesthetic, keratolytic agent, anti-free-radical
agent, antiseborrhoeic agent, antidandruff agent, antiacne agent
or agent for reducing skin differentiation or proliferation or pigmentation,
extract of plant, marine or bacterial origin, or mixture thereof.
8. The cosmetic/therapeutic composition as defined by claim 7,
comprising an effective amount of at least one imidazole antifungal
agent.
9. The cosmetic/therapeutic composition as defined by claim 8,
comprising an effective amount of the imidazole antifungal agent
ketoconazole.
10. The cosmetic/therapeutic composition as defined by claim 4,
formulated for topical application.
11. The cosmetic/therapeutic composition as defined by claim 4,
formulated for oral administration.
12. The cosmetic/therapeutic composition as defined by claim 4,
formulated for systemic administration.
13. The cosmetic/therapeutic composition as defined by claim 4,
further comprising at least one hydrophilic or lipophilic gelling
agent, hydrophilic or lipophilic active agent, preservative, antioxidant,
solvent, fragrance, filler, sunscreen, odor absorber, dyestuff,
colorant or mixture thereof.
14. The cosmetic/therapeutic composition as defined by claim 4,
formulated as an aqueous or oily solution, dispersion, lotion, serum,
syrup, ointment, emulsion, suspension, cream, gel, mousse, spray,
soap or bar.
15. The cosmetic/therapeutic composition as defined by claim 4,
formulated as microcapsules, microparticles, a vesicle dispersion,
capsules, granules or tablets.
16. The cosmetic/therapeutic composition as defined by claim 4,
formulated as a shampoo, hairsetting lotion, hairstyling cream or
gel hair-restructuring lotion or permanent-wave formulation.
17. A method for inducing or stimulating the growth of hair or
limiting the loss of hair on an individual subject in need of such
treatment, comprising administering to said subject, for such period
of time as required to elicit the desired response, an effective
hair growth stimulating or hair loss retarding amount of at least
one compound as defined by claim 1, or of a cosmetic/therapeutic
composition comprising said effective amount of said at least one
compound formulated into a physiologically acceptable vehicle, diluent
or carrier therefor.
18. The method as defined by claim 17, comprising topically applying
said at least one compound or said composition comprising said at
least one compound, in said effective amount, onto the head and/or
hair of said subject.
Hair loss description
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The present invention relates to novel 2-amino-4-alkylaminopyrimidine
3-oxide chemical compounds, to compositions comprised thereof and
to the use of such novel compounds/compositions as active principles
for inducing and/or stimulating hair growth and/or for preventing
hair loss.
2. Description of the Prior Art
In human subjects the growth and renewal of the hair are principally
determined by the activity of the hair follicles. This activity
is cyclic and essentially entails three phases, i.e., the anagenic
phase, the catagenic phase and the telogenic phase.
The active anergenic phase, or growth phase, which lasts for several
years and during which the hair elongates, is followed by a very
short and transient catagenic phase which lasts for a few weeks,
and then a rest or quiescent phase, designated the telogenic phase,
which lasts for a few months.
At the end of the rest period, the hair falls out and another cycle
begins anew. The head of hair is thus under constant renewal, and
out of the approximately 150,000 hairs on a head of hair, at any
given instant approximately 10% are at rest and will thus be replaced
within a few months.
However, different causes can lead to a considerable, temporary
or permanent, loss of hair. Alopecia is essentially due to a disruption
in hair renewal which occasions, in a first stage, an acceleration
of the frequency of the cycles, at the expense of the quality of
the hair and then at the expense of its quantity. A gradual depletion
of the head of hair takes place by regression of the so-called "terminal"
hairs at the downy stage. Certain regions are preferentially affected,
in particular the temples or frontal bulbs in men, and in women,
diffuse alopecia of the vertex is observed.
By the term "alopecia" are intended the entire family
of afflictions of the hair follicle, the final consequence of which
is the partial or general permanent loss of the hair. In a large
number of cases, early loss of the hair arises in genetically predisposed
individuals and especially affects men. This more particularly applies
to androgenetic or androgenic or even androgeno-genetic alopecia.
Active substrates for suppressing or reducing alopecia, and in
particular for inducing or stimulating hair growth or reducing hair
loss, have long been considered desiderata in the cosmetics and
pharmaceutical industries.
In this respect, a large number of very diverse active compounds
have already been suggested for such purposes, for example, 2,4-diamino-6-piperidino-pyrimidine
3-oxide or "Minoxidil" described in U.S. Pat. Nos. 4,139,619
and 4,596,812, or the many 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.
Nonetheless, serious need continues to exist for yet other active
agents/species potentially more active and/or less toxic than those
active substrates to date characterizing the state of this art.
SUMMARY OF THE INVENTION
Accordingly, a major object of the present invention is the provision
of novel 2-amino-4-alkylaminopyrimidine 3-oxide compounds having
the structural formula (I): ##STR2##
in which R.sub.1 is an alkyl radical having from 5 to 20 carbon
atoms, and Z is either a hydrogen atom or a radical --OR.sub.2,
wherein R.sub.2 is an alkyl radical having from 1 to 12 carbon atoms,
as well as the acyl derivatives or acid addition salts thereof.
The subject compounds are well suited as active principles for
inducing and/or stimulating hair growth and/or preventing hair loss.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS
OF THE INVENTION
More particularly according to the present invention, it is known
to this art that certain polyunsaturated fatty acids, in particular
those having carbon atoms, such as arachidonic acid, dihomo-.gamma.-linolenic
acid and eicosapentaenoic acid, can be converted in vivo, under
the influence of certain specific enzymes contained in living cells,
in particular epithelial cells, into certain yet other compounds
of eicosanoid type which are useful to the body.
Thus, it is known to this art that the enzymes designated cyclooxygenated
generate, from the different fatty acids indicated above, particularly
from arachidonic acid, eicosanoids of prostaglandin and thromboxane
type, and that the enzymes deemed lipoxygenases are responsible
for the formation of eicosanoids of leukotriene type and other hydroxylated
acyclic acids containing 20 carbon atoms. Depending on the nature
of the enzyme with which it reacts first, the same given polyunsaturated
fatty acid (or substrate) may be responsible for the formation of
several different metabolites, namely, for example, prostaglandins
and leukotrienes.
Cyclooxygenase activity can be defined as the enzymatic activity
which converts certain polyunsaturated fatty acids into cyclized
oxygenated compounds which are, indeed, highly unstable endoperoxides
which thereafter enter the subsequent metabolic pathways.
Prostaglandin-endoperoxide synthase, or cyclooxygenase (or PGHS,
EC 1.14.99.1), which is a haemoprotein, is an example of these enzymes
exhibiting such activity. It is involved in one of the metabolic
pathways of prostaglandins.
It too is known that the enzymatic transformations indicated above
and the various reaction products resulting therefrom exert an appreciable
influence on the mechanisms of growth of body and/or head hair.
In this respect, it has now been shown that by promoting one or
other of the two enzymatic pathways, cyclooxygenated or lipoxygenated,
in skin and/or scalp cells, it is possible to substantially modify
the growth of body and/or head hair. Compare EP-94/402,055, assigned
to the assignee hereof.
Essentially, in the aforesaid patent application, promoting one
of the pathways over the other is described, by the administration
of a combination of compounds combining an inhibitor of one of the
pathways with a stimulator of the other pathway.
Even more specifically, it has now been shown that the growth of
body and/or head hair can be promoted and/or their loss can be controlled
by promoting the cyclooxygenase pathway, for example by activating
PGHS and inhibiting the lipoxygenase pathway.
The involvement of these enzymes in several metabolic pathways
and the consequences which may ensue from deregulating their functioning
are such that extensive research has been undertaken in order to
develop active agents with the capacity either of increasing or
of reducing the activity of these enzymes.
Arachidonic acid metabolites, nitrogen monoxide and nitrogen-monoxide-donating
compounds, stanozolol, glutathione-donating compounds, calcium aionophores,
anthocyanosides, bioflavonoids, platelet activating factors (PAF),
pro-inflammatory cytokines agents and bacterial endotoxins are recognized,
in particular, in the field of cyclooxygenase activators.
Similarly, illustrative is 6-chloro-2,3-dihydroxy-1,4-naphthoquinone
(CNDQ), which has the particular feature of being both a lipoxygenase
inhibitor and a cyclooxygenase stimulator (C. J. Bedord et al.,
The Journal of Investigative Dermatology, 81:566-571 (1983))
However, most of these species present the major drawback of having
a broad functional spectrum, which entails that, in general, they
have no genuine specificity for cyclooxygenase. In this regard,
the literature on this subject reflects a wide variety of interpretation.
These substrates can also be labile or their activity can depend
on their concentration, which makes them difficult to administer.
The present inventors have thus sought to develop novel compounds
which have activity at least on PGHS, and which would then be considered
cyclooxygenase activators.
After considerable research, it has now surprisingly and unexpectedly
been determined that the 2-amino-4-alkylaminopyrimidine 3-oxides
of the invention have the property of activating PGHS.
Furthermore, the presence of an alkyl chain in the 4-position imparts
to these compounds improved lipophilic properties.
This reinforces the advantage of these compounds as active agents
in the treatment of hair loss.
Accordingly, this invention features novel compounds corresponding
to the structural formula (I): ##STR3##
in which R.sub.1 is an alkyl group having from 5 to 20 carbon atoms,
and Z is either a hydrogen atom or a radical --OR.sub.2, wherein
R.sub.2 is an alkyl group having from 1 to 12 carbon atoms, as well
as the acyl derivatives and acid addition salts thereof.
Consistent herewith, by the term "alkyl radical" is intended
a linear or branched acyclic radical originating from the removal
of a hydrogen atom in a hydrocarbon molecule, such as, for example,
a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,
heptadecyl, octadecyl, nonadecyl or eicosadecyl radical.
In one preferred embodiment of the invention, R.sub.1 is an alkyl
radical having from 6 to 12 carbon atoms, such as, for example,
a hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl radicals.
In another preferred embodiment of the invention, R.sub.2 is an
alkyl radical having from 2 to 6 carbon atoms, such as, for example,
an ethyl, propyl, butyl, pentyl or hexyl radical.
Preferred compounds of the invention include: 2-amino-4-pentylaminopyrimidine
3-oxide; 2-amino-4-hexylaminopyrimidine 3-oxide; 2-amino-4-heptylaminopyrimidine
3-oxide; 2-amino-4-octylaminopyrimidine 3-oxide; 2-amino-4-nonylaminopyrimidine
3-oxide; 2-amino-4-decylaminopyrimidine 3-oxide; 2-amino-4-undecylaminopyrimidine
3-oxide; 2-amino-4-dodecylaminopyrimidine 3-oxide; 2-amino-4-tridecylaminopyrimidine
3-oxide; 2-amino-4-tetradecylaminopyrimidine 3-oxide; 2-amino-4-pentadecylaminopyrimidine
3-oxide; 2-amino-4-hexadecylaminopyrimidine 3-oxide; 2-amino-4-heptadecylaminopyrimidine
3-oxide; 2-amino-4-octadecylaminopyrimidine 3-oxide; 2-amino-4-nonadecylaminopyrimidine
3-oxide; 2-amino-4-eicosadecylaminopyrimidine 3-oxide; 2-amino-4-pentylamino-6-methoxypyrimidine
3-oxide; 2-amino-4-hexylamino-6-methoxypyrimidine 3-oxide; 2-amino-4-eptylamino-6-methoxypyrimidine
3-oxide ; 2-amino-4-octylamino-6-methoxypyrimidine 3-oxide; 2-amino-4-nonylamino-6-methoxypytimidine
3-oxide; 2-amino-4-decylamino-6-methoxypyrimidine 3-oxide; 2-amino-4-undecylamino-6-methoxypyrimidine
3-oxide; 2-amino-4-dodecylamino-6-methoxypyrimidine 3-oxide; 2-amino-4-tridecylamino-6-methoxypyrimidine
3-oxide; 2-amino-4-tetradecylamino-6-methoxypyrimidine 3-oxide;
2-amino-4-pentadecylamino-6-methoxypyrimidine 3-oxide; 2-amino-4-hexadecylamino-6-methoxypyrimidine
3-oxide; 2-amino-4-heptadecylamino-6-methoxypyrimidine 3-oxide;
2-amino-4-octadecylamino-6-methoxypyrimidine 3-oxide; 2-amino-4-nonadecylamino-6-methoxypyrimidine
3-oxide; 2-amino-4-eicosadecylamino-6-methoxypyrimidine 3-oxide;
2-amino-4-pentylamino-6-ethoxypyrimidine 3-oxide; 2-amino-4-hexylamino-6-ethoxypyrimidine
3-oxide; 2-amino-4-heptylamino-6-ethoxypyrimidine 3-oxide; 2-amino-4-octylamino-6-ethoxypyrimidine
3-oxide; 2-amino-4-nonylamino-6-ethoxypyrimidine 3-oxide; 2-amino-4-decylamino-6-ethoxypyrimidine
3-oxide; 2-amino-4-undecylamino-6-ethoxypyrimidine 3-oxide; 2-amino-4-dodecylamino-6-ethoxypyrimidine
3-oxide; 2-amino-4-tridecylamino-6-ethoxypyrimidine 3-oxide; 2-amino-4-tetradecylamino-6-ethoxypyrimidine
3-oxide; 2-amino-4-pentadecylamino-6-ethoxypyrimidine 3-oxide; 2-amino-4-hexadecylamino-6-ethoxypyrimidine
3-oxide; 2-amino-4-heptadecylamino-6-ethoxypyrimidine 3-oxide; 2-amino-4-octadecylamino-6-ethoxypyrimidine
3-oxide; 2-amino-4-nonadecylamino-6-ethoxypyrimidine 3-oxide; 2-amino-4-eicosadecylamino-6-ethoxypyrimidine
3-oxide; 2-amino-4-pentylamino-6-propyloxypyrimidine 3-oxide; 2-amino-4-hexylamino-6-propyloxypyrimidine
3-oxide; 2-amino-4-heptylamino-6-propyloxypyrimidine 3-oxide; 2-amino-4-octylamino-6-propyloxypyrimidine
3-oxide; 2-amino-4-nonylamino-6-propyloxypyrimidine 3-oxide; 2-amino-4-decylamino-6-propyloxypyrimidine
3-oxide; 2-amino-4-undecylamino-6-propyloxypyrimidine 3-oxide; 2-amino-4-dodecylamino-6-propyloxypyrimidine
3-oxide; 2-amino-4-tridecylamino-6-propyloxypyrimidine 3-oxide;
2-amino-4-tetradecylamino-6-propyloxypyrimidine 3-oxide; 2-amino-4-pentadecylamino-6-propyloxypyrimidine
3-oxide; 2-amino-4-hexadecylamino-6-propyloxypyrimidine 3-oxide;
2-amino-4-heptadecylamino-6-propyloxypyrimidine 3-oxide; 2-amino-4-octadecylamino-6-propyloxypyrimidine
3-oxide; 2-amino-4-nonadecylamino-6-propyloxypyrimidine 3-oxide;
2-amino-4-eicosadecylamino-6-propyloxypyrimidine 3-oxide; 2-amino-4-pentylamino-6-butyloxypyrimidine
3-oxide; 2-amino-4-hexylamino-6-butyloxypyrimidine 3-oxide; 2-amino-4-heptylamino-6-butyloxypyrimidine
3-oxide; 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide; 2-amino-4-nonylamino-6-butyloxypyrimidine
3-oxide; 2-amino-4-decylamino-6-butyloxypyrimidine 3-oxide; 2-amino-4-undecylamino-6-butyloxypyrimidine
3-oxide; 2-amino-4-dodecylamino-6-butyloxypyrimidine 3-oxide; 2-amino-4-tridecylamino-6-butyloxypyrimidine
3-oxide; 2-amino-4-tetradecylamino-6-butyloxypyrimidine 3-oxide;
2-amino-4-pentadecylamino-6-butyloxypyrimidine 3-oxide; 2-amino-4-hexadecylamino-6-butyloxypyrimidine
3-oxide; 2-amino-4-heptadecylamino-6-butyloxypyrimidine 3-oxide;
2-amino-4-octadecylamino-6-butyloxypyrimidine 3-oxide; 2-amino-4-nonadecylamino-6-butyloxypyrimidine
3-oxide; 2-amino-4-eicosadecylamino-6-butyloxypyrimidine 3-oxide;
and
Even more preferred compounds according to the invention are: 2-amino-4-hexaylaminopyrimidine
3-oxide; 2-amino-4-octylaminopyrimidine 3-oxide; 2-amino-4-dodecylaminooxpyrimidine
3-oxide; 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide;
and yet even more preferred are 2-amino-4-dodecylaminopyrimidine
3-oxide; and 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide.
This invention also features a process for preparing the 2-amino-4-alkylaminopyrimidine
3-oxides of formula (I).
This process comprises reacting an aliphatic amine with 2-amino-4,6-dichloropyrimidine
in a solvent such as ethanol. The compound thus obtained, after
purification, is then reacted with a urea/H.sub.2 O.sub.2 complex
and phthalic anhydride in a solvent such as isopropanol. After purification,
the compound obtained is reacted in the presence of potassium hydroxide
and palladium-on-charcoal in a solvent such as absolute ethanol,
under a hydrogen pressure in order to provide the corresponding
2-amino-4-alkylaminopyrimidine 3-oxides.
The present invention also features a process for preparing the
2-amino-4-alkylamino-6-alkyloxy-pyrimidine 3-oxides of formula (I).
This process comprises reacting an aliphatic amine with 2-amino-4,6-dichloropyrimidine
in a solvent such as ethanol. The compound thus obtained, after
purification, is then reacted with a urea/H.sub.2 O.sub.2 complex
and phthalic anhydride in a solvent such as isopropanol. After purification,
the compound obtained is reacted with an excess of sodium or potassium
alkoxide to provide the corresponding 2-amino-4-alkylamino-6-alkyl-oxypyrimidine
3-oxide.
Too, this invention features compositions which comprise at least
one compound of the 2-amino-4-alkylaminopyrimidine 3-oxides having
the structural formula (I).
It will of course be appreciated that the compositions according
to the invention can contain the compounds of formula (I) either
alone or as mixtures in all proportions.
Too, the "effective" amount of compound administered
corresponds to the amount required to elicit the desired result.
One skilled in this art is thus capable of easily evaluating this
effective amount, which depends on the nature of the compound used
and on the particular individual thus treated.
To provide an order of magnitude, in the compositions according
to the invention, the compounds of formula (I) are advantageously
present at a concentration ranging from 0.001% to 10% by weight
relative to the total weight of the composition and preferably from
0.01% to 2%.
The present invention also features formulating as an active principle,
in a physiologically acceptable medium (vehicle, diluent or carrier),
into a composition, of an effective amount of at least one compound
of formula (I); such compounds/compositions are well suited to induce
and/or stimulate hair growth and/or prevent hair loss.
The compositions according to the invention can be ingested, injected
or topically applied onto the skin and/or the hair. Depending on
the mode of administration, the compositions according to the invention
are formulated into any pharmaceutical form normally employed.
For topical application onto the skin or the hair, the composition
can be in the form, in particular, of an aqueous or oily solution
or a dispersion of the lotion or serum type, emulsions of liquid
or semi-liquid consistency of the milk type, obtained by dispersing
a fatty phase in an aqueous phase (O/W) or, conversely, (W/O), or
suspensions or emulsions of runny consistency of the cream or aqueous
or anhydrous gel type, or alternatively microcapsules or microparticles,
or vesicle dispersions of ionic and/or nonionic type. These compositions
are formulated via the usual techniques.
They can also be used for the hair in the form of aqueous, alcoholic
or aqueous-alcoholic solutions, or in the form of creams, gels,
ointments, emulsions or mousses or alternatively in the form of
aerosol compositions also comprising a propellant under pressure.
The compositions according to the invention can also constitute
a haircare composition, in particular a shampoo, a hairsetting lotion,
a treating lotion, a styling cream or gel, a dye composition (in
particular an oxidation dye composition) optionally in the form
of coloring shampoos, restructuring lotions for the hair, a permanent-waving
composition (in particular a composition for the first stage of
a permanent-waving operation), a lotion or gel for preventing hair
loss, an antiparasitic shampoo, etc.
For systemic injection, the subject compositions can be formulated
as an aqueous or oily lotion or in the form of a serum. For the
eyes, drops are well suited, and for ingestion, same can be formulated
as capsules, granules, syrups or tablets.
The amounts of the various constituents in the compositions according
to the invention are those conventional in the fields under consideration.
The compositions according to the invention can also be formulated
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 propellant under pressure.
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 relative to the total weight of the composition.
The oils, waxes, emulsifiers and co-emulsifiers included in the
composition in emulsion form are chosen from among those that are
conventional in the cosmetics field. The emulsifier and the co-emulsifier
are advantageously 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. The emulsion can
also contain 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 compositions can also contain additives
and adjuvants that are common in the cosmetics field, such as hydrophilic
or lipophilic gelling agents, hydrophilic or lipophilic additives
and active agents, preservatives, antioxidants, solvents, fragrances,
fillers, sunscreening agents, odor absorbers and dyestuffs and colorants.
The amounts of these various adjuvants are those conventionally
formulated in the cosmetics field, and, for,example, range from
0.01% to 10% of the total weight of the composition. Depending on
their nature, these additives and adjuvants can be introduced into
the fatty phase, into the aqueous phase and/or into the lipid spherules.
Exemplary oils or waxes according to the invention include mineral
oils. (liquid petroleum jelly), plant oils (liquid fraction of karite
butter or sunflower oil), animal oils (perhydrosqualene), synthetic
oils (purcellin oil), silicone oils or waxes (cyclomethicone) and
fluoro 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 glyceryl stearate, polysorbate-60 and the PEG-6/PEG-32/glycol
stearate mixture marketed under the trademark Tefose.RTM.63 by Gattefosse.
Exemplary solvents per this invention include the lower alcohols,
in particular ethanol and isopropanol, and propylene glycol.
And exemplary hydrophilic gelling agents include carboxyvinyl polymers
(carbomer), acrylic copolymers such as acrylate/alkylacrylate copolymers,
polyacrylamides, polysaccharides such as hydroxy-propylcellulose,
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
and polyethylene.
The subject compositions can contain other hydrophilic active agents,
such as proteins or protein hydrolysates, amino acids, polyols,
urea, allantoin, sugars and sugar derivatives, water-soluble vitamins,
plant extracts and hydroxy acids.
Lipophilic active agents which are suitable include retinol (vitamin
A) and derivatives thereof, tocopherol (vitamin E) and derivatives
thereof, essential fatty acids, ceramides, essential oils and salicylic
acid and its derivatives.
In one embodiment according to the invention, the subject compositions
comprise at least one compound of formula (I) in admixture with
other active agents. Among these active agents, particularly representative
are: (1) agents for improving the activity with regard to regrowth
of the hair and/or preventing hair loss, and which have already
been described for such activity, for example, nicotinic acid esters,
including, in particular, tocopheryl nicotinate, benzyl nicotinate
and C.sub.1 -C.sub.6 alkyl nicotinates such as methyl or hexyl nicotinates,
pyrimidine derivatives, such as 2,4-diamino-6-piperidinopyrimidine
3-oxide or "Minoxidil" described in U.S. Pat. Nos. 4,139,619
and 4,596,812, and agents for promoting regrowth of the hair, such
as those described in the European patent application published
under No. 0,648,488 and assigned to the assignee hereof; (2) agents
which reduce skin differentiation and/or-proliferation and/or pigmentation,
such as retinoic acid and its isomers, retinol and its esters, vitamin
D and derivatives thereof, estrogens such as estradiol, kojic acid
or hydroquinone; (3) antibacterial agents such as clindamycin phosphate,
erythromycin or antibiotics of the tetracyclene class; (4) antiparasitic
agents, in particular metronidazole, crotamiton or pyrethroids;
(5) antifungal agents, in particular compounds belonging to the
imidazole class, such as econazole, ketoconazole or miconazole or
their salts, polyene compounds, such as amphotericin B, compounds
of the allylamine family such as terbinafine, or alternatively octopirox;
(6) antiviral agents such as acyclovir; (7) steroidal anti-inflammatory
agents such as hydrocortisone, betamethasone valerate or clobetasol
propionate, or nonsteroidal anti-inflammatory agents such as, for
example, ibuprofen and its salts, diclofenac and its salts, acetylsalicylic
acid, acetaminophen or glycyrrhizic acid; (8) anaesthetics such
as lidocane hydrochloride and derivatives thereof; (9) anti-pruriginous
agents such as thenaldine, trimeprazine or cyproheptadine; (10)
keratolytic agents such as .alpha.- and .beta.-hydroxycarboxylic
or .beta.-ketocarboxylic acids, their salts, amides or esters and
more particularly hydroxy acids such as glycolic acid, lactic acid,
salicylic acid, citric acid and fruit acids in general, and 5-n-octanoylsalicylic
acid; (11) anti-free-radical agents such as .alpha.-tocopherol or
its esters, superoxide dismutases, certain metal-chelating agents
or ascorbic acid and its esters; (12) antiseborrhoeic agents such
as progesterone; (13) antidandruff agents such as octopirox or zinc
pyrithione; (14) antiacne agents such as retinoic acid or benzoyl
peroxide; (15) extracts of plant, marine or bacterial origin.
Other compounds may also be included, for example, Diazoxide, Spiroxazone,
phospholipids such as lecithin, linoleic acid, linolenic acid, salicylic
acid and derivatives thereof described in FR-2,581,542, e.g., salicylic
acid derivatives bearing an alkanoyl group containing from 2 to
12 carbon atoms in the 5-position of the benzene ring, hydroxycarboxylic
or ketocarboxylic acids and their esters, lactones and their corresponding
salts, anthralin, carotenoids, eicosatetraenoic and eicosatrienoic
acids or their esters and amides.
Thus, in one specific embodiment, the compositions according to
the invention also comprise at least one active agent or substrate
selected from among antibacterial agents, antiparasitic agents,
antifungal agents, antiviral agents, anti-inflammatory agents, antipruriginous
agents, anaesthetics, keratolytic agents, anti-free-radical agents,
antiseborrhoeic agents, antidandruff agents, antiacne agents and/or
agents for reducing skin differentiation and/or proliferation and/or
pigmentation, and extracts of plant, marine or bacterial origin.
It will also be appreciated that the subject compositions can comprise
at least one compound as described above in liposomal form, in particular
as described in WO-94/22468, filed Oct. 13, 1994 by Anti Cancer
Inc. Thus, the compound encapsulated in the liposomes can be delivered
selectively to the hair follicle.
The compositions according to the invention are topically applied
onto the alopecic areas of an individual subject's scalp and hair,
and is optionally maintained in contact with such areas for several
hours and optionally rinsed therefrom. In one embodiment, a composition
containing an effective amount of at least one compound as described
above is topically applied during the evening, maintained overnight
and optionally shampooed out in the morning. These applications
can be repeated daily for one or more months depending on the needs
of the individual.
Thus, the present invention also features a cosmetic treatment
for the hair and/or the scalp (regime or regimen), comprising topically
applying a composition containing an effective amount of at least
one compound as described above to the hair and/or the scalp, maintaining
this composition in contact with the hair and/or the scalp and optionally
rinsing same therefrom.
This treatment has the characteristics of a cosmetic regime/regimen
inasmuch as it improves the aesthetics of the hair by providing
more vitality and imparting an improved appearance thereto.
The compositions according to the invention are well suited for
cosmetic or pharmaceutical applications, in particular dermatological
application.
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.
EXAMPLE 1
Synthesis of 2-amino-4-hexylaminopyrimidine 3-oxide
##STR4##
(1) Preparation of 2-amino-4-hexylamino-6-chloropyrimidine
##STR5##
50 g of 2-amino-4,6-dichloropyrimidine were suspended in 350 ml
of absolute ethanol in a reactor. 181.5 ml of hexylamine (reagent
A) were added in a single portion and the mixture was refluxed for
3 h. The medium was evaporated under vacuum. The oil obtained was
taken up in 600 ml of water with stirring for 1 h, 30 min. The precipitate
was filtered off, washed and dried in a heated desiccator. 43.5
g of the expected compound were thus obtained, for a yield of 62%.
Analysis
*NMR spectrum: .sup.1 H (200 MHz; DMSO) .delta. ppm 0.8 (3H, t),
1.2 (6H, s), 1.4 (2H, t), 3(2H, s), 5.6 (1H, s), 6.2 (2H, s), 6.9
(1H, s).
(2) Preparation of 2-amino-4-hexylamino-6-chloropyrimidine 3-oxide
##STR6##
5.95 g of urea/H.sub.2 O.sub.2 complex and 9.07 g of phthalic anhydride
were suspended in 90 ml of isopropanol, in a three-necked flask.
The mixture was stirred for 30 min at room temperature (20-25.degree.
C.). 10 g of 2-amino-4-hexylamino-6-chloropyrimidine were then added
while controlling the exotherm at +30.degree. C. After reaction
for 3 hours, 100 ml of sodium hydrogen sulfite were poured thereinin
to destroy the residual oxidizing agents. The mixture was permitted
to separate out by settling and the upper phase was concentrated
under vacuum. The residue obtained was taken up in a water (80 ml)/30%
sodium hydroxide (20 ml) mixture. The solid obtained was reimpasted
in 150 ml of isopropyl ether. The solid was filtered off and washed.
It was dried in a heated desiccator. 4.52 g of the expected compound
were thus obtained, for a yield of 42%.
Analysis
*NMR spectrum .sup.1 H (200 MHz; DMSO) .delta. ppm 0.7 (3H, t),
1 (6H, s), 1.2 (2H, t), 3.1(2H, m), 6 (1H, s), 7.4 (2H, m), 7.7
(1H, t).
(3) Synthesis of 2-amino-4-hexylaminopyrimidine 3-oxide
##STR7##
0.7 g of potassium hydroxide was dissolved in 100 ml of absolute
ethanol, in a three-necked flask. 2.2 g of 2-amino-4-hexylamino-6-chloropyrimidine
3-oxide were then added. After complete dissolution, 0.5 g of palladium-on-charcoal
was added and the mixture was reacted in a hydrogenator at a hydrogen
pressure of 3 bar. After 2 hours, the medium was filtered through
filter paper and concentrated under vacuum. The pale yellow solid
obtained was recrystallized from 20 ml of acetonitrile. It was filtered
off and the filter cake was washed with 10 ml of water. The solid
was dried in a desiccator under vacuum. 1 g of the expected compound
was thus obtained, for a yield of 53%.
Analysis
*NMR spectrum: .sup.1 H (200 MHz; DMSO) .delta. ppm; 1.9 (3H, t),
2.2 (6H, s), 2.5 (2H, t), 4.3 (2H, m), 7.2 (1H, d), 8.1 (2H, s),
8.5 (1H, d), 8.6 (1H, m).
EXAMPLE 2
Synthesis of 2-amino-4-dodecylaminopyrimidine 3-oxide
##STR8##
(1) Preparation of 2-amino-4-dodecylamnino-6-chlororyrimidine
##STR9##
10 g of 2-amino-4,6-dichloropyrimidine were suspended in 100 ml
of absolute ethanol in a reactor. 33.9 g of dodecylamine (reagent
A) were added in a, single portion and the mixture was refluxed
for 2 h. The medium was evaporated under vacuum. The solid obtained
was taken up in 200 ml of acetone with stirring for 30 min. 200
ml of water were added and the mixture was maintained under stirring
for 2 h. The solid was filtered off, washed and dried in a heated
desiccator.
17.55 g of the expected compound were thus obtained, for a yield
of 92%.
Analysis
*NMR spectrum: .sup.1 H (200 MHz; DMSO) .delta. ppm; 0.8 (3H, t),
1.2 (18H, s), 1.3 (2H, t), 3 (2H,s), 5.6 (1H, s), 6.1 (2H, s), 6.8
(1H, s).
(2) Preparation of 2-amino-4-dodecylamino-6-chloropyrimidine 3-oxide
##STR10##
3.26 g of urea/H.sub.2 O.sub.2 complex and 4.97 g of phthalic anhydride
were suspended in 60 ml of isopropanol, in a three-necked flask.
The mixture was maintained under stirring for 30 min at room temperature.
10 g of 2-amino-4-dodecylamino-6-chloropyrimidine were then added
while controlling the exotherm at +25.degree. C. After reaction
for 2 hours, the medium was cooled to +4.degree. C. for 1 h. The
solid was filtered off and washed with 5 ml of ice-cold methanol.
The solid was taken up in a water (12 ml)/40% sodium hydroxide (3
ml) mixture. The solid was filtered off and washed. It was dried
in a heated desiccator.
3.3 g of the expected compound were thus obtained, for a yield
of 42%.
Analysis
*NMR spectrum .sup.1 H (200 MHz; DMSO) .delta. ppm; 0.7 (3H, t),
1.1 (18H, s), 1.3 (2H, t), 2.8 (2H,t), 5.5 (1H, s), 6.9. (3H, m).
(3) Synthesis of 2-amino-4-dodecylaminopyrimidine 3-oxide
##STR11##
0.7 g of potassium hydroxide was dissolved in 250 ml of absolute
ethanol, in a three-necked flask. 3.3 g of 2-amino-4-dodecylamino-6-chloropyrimidine
3-oxide were then added. Once dissolution was complete, 0.5 g of
palladium-on-charcoal was added and the mixture was reacted in a
hydrogenator at a hydrogen pressure of 3 bar. After 2 h, the medium
was filtered through filter paper and concentrated under vacuum.
The solid obtained was recrystallized from an ethanol (10 ml)/acetonitrile
(50 ml) mixture. It was filtered off and the filter cake was washed
with 10 ml of water. The solid was dried in a desiccator under vacuum.
0.8 g of the expected compound was thus obtained, for a yield of
27%.
Analysis
*NMR spectrum: .sup.1 H (200 MHz; DMSO) .delta. ppm; 0.9 (3H, t),
1.3 (18H, s), 1.7 (2H, t), 3.3 (2H, m), 6.3 (1H, d), 7.2 (2H, s),
7.6 (1H, d), 7.7 (1H, m).
EXAMPLE 3
Synthesis of 2-amino-4-octylaminopyrimidine 3-oxide
##STR12##
(1) Preparation of 2amino-4-octylamino-6-chloropyrimidine
##STR13##
20 g of 2-amino-4,6-dichloropyrimidine were suspended in 200 ml
of absolute ethanol in a reactor. 60 g of octylamine (reagent A)
were added in a single portion and the mixture was refluxed for
2 h. The medium was evaporated under vacuum. The oil obtained was
extracted with dichloromethane and was then purified on a column
of silica.
22.8 g of the expected compound were thus obtained, for a yield
of 71%.
Analysis
NMR: .sup.1 H (200 MHz; CDCl.sub.3) .delta. ppm; 1 (3H, t), 1.4
(10H, s), 1.7 (2H, t), 3.3 (2H, m), 5.1 (3H, d), 6 (1H, s).
(2) Preparation of 2-amino-4-octylamino-6-chloropyrimidine 3-oxide
##STR14##
6.8 g of urea/H.sub.2 O.sub.2 complex and 10.35 g of phthalic anhydride
were suspended in 100 ml of isopropanol, in a three-necked flask.
The mixture was maintained stirring for 30 min at room temperature.
10 g of 2-amino-4-octylamino-6-chloropyrimidine were then added,
while controlling the exotherm at +30.degree. C. After reaction
for 3 hours, 100 ml of sodium hydrogen sulfite were poured thereinin
to destroy the residual oxidizing agents. The mixture was permitted
to separate by settling and the upper phase was concentrated under
vacuum. The residue obtained was taken up in a water (80 ml)/30%
sodium hydroxide (20 ml) mixture. The solid was filtered off and
washed. This solid was dried in a heated desiccator.
6.3 g of the expected compound were thus obtained, for a yield
of 46%.
Analysis
NMR: .sup.1 H (200 MHz; DMSO) .delta. ppm; 0.7 (3H, t), 1.1 (10H,
s), 1.4 (2H, t), 3(2H, t), 6 (1H, s), 7.2 (3H, s).
(3) Synthesis of 2-amino-4-octylamino-pyrimidine 3-oxide
##STR15##
0.54 g of potassium hydroxide was dissolved in 100 ml of absolute
ethanol, in a three-necked flask. 2 g of 2-amino-4-octylamino-6-chloropyrimidine
3-oxide were then added. Once dissolution was complete, 0.5 g of
palladium-on-charcoal was added and the mixture was reacted in a
hydrogenator at a hydrogen pressure of 3 bar. After 2 hours, the
medium was filtered through filter paper and concentrated under
vacuum. The pale yellow solid obtained was recrystallized from 20
ml of acetonitrile. It was filtered off and the filter cake was
washed with 10 ml of water. The solid was dried in a desiccator
under vacuum.
0.5 g of the expected compound was thus obtained, for a yield of
29%.
Analysis
NMR: .sup.1 H (200 MHz; DMSO) .delta. ppm; 1.1 (3H, t), 1.4 (10H,
s), 1.8 (2H, t), 3.4 (2H, m), 6.1 (1H, d), 6.4 (2H, s), 7.3 (1H,
t), 7.7 (1H, d).
EXAMPLES 4-16
The following compounds of the invention listed below are obtained
via the same procedure as in Examples 1-3 and using the appropriate
reagent A in the first step of the process (see Table I below):
TABLE I Compound obtained Reagent A used 4 2-amino-4-pentylaminopyrimidine
3-oxide pentylamine 5 2-amino-4-heptylaminopyrimidine 3-oxide heptylamine
6 2-amino-4-nonylaminopyrimidine 3-oxide nonylamine 7 2-amino-4-decylaminopyrimidine
3-oxide decylamine 8 2-amino-4-undecylaminopyrimidine 3-oxide undecylamine
9 2-amino-4-tridecylaminopyrimidine 3-oxide tridecylamine 10 2-amino-4-tetradecylaminopyrimidine
3-oxide tetradecylamine 11 2-amino-4-pentadecylaminopyrimidine 3-oxide
pentadecylamine 12 2-amino-4-hexadecylaminopyrimidine 3-oxide hexadecylamine
13 2-amino-4-heptadecylaminopyrimidine 3-oxide heptadecylamine 14
2-amino-4-octadecylaminopyrimidine 3-oxide octadecylamine 15 2-amino-4-nonadecylaminopyrimidine
3-oxide nonadecylamine 16 2-amino-4-eicosadecylaminopyrimidine 3-oxide
eicosadecylamine
EXAMPLE 17
Synthesis of 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide
##STR16##
90 ml of butanol (reagent B) predried over K.sub.2 CO.sub.3 were
introduced into a 250 ml three-necked flask. 0.18 g of sodium in
kerosene was added portionwise under argon. The medium was then
heated at 60.degree. C. until the sodium has completely dissolved.
1.5 g of 2-amino-4-octylamino-6-chloro-pyrimidine 3-oxide, obtained
according to Example 3 (reagent C), was then introduced and the
mixture was heated at 90.degree. C. for 24 hours.
The medium was washed with aqueous 20% sodium chloride solution
and the butanol phase was then concentrated on a rotavapor. The
residue obtained was purified on a column of silica. The oily product
obtained at the column outlet was dissolved in 2.2 ml (2.5 eq) of
2N hydrochloric methanol solution and the solution was then evaporated
under reduced pressure. An off-white solid was obtained, which was
washed with 10 ml of isopropyl ether. 0.5 g of a white solid of
the expected compound was obtained, in a yield of 30%.
Analysis
NMR: .sup.1 H (200 MHz; DMSO) .delta. ppm; 1 (6H, m), 1.7 (2H,
s), 6.1 (16H, m), 3.4 (2H, q), 4.3 (2H;t), 5.7 (1H;s), 8.5 (4H;m).
Elemental Analysis (1 Hcl)
C H N O Cl Theoretical 55.40% 9.01% 16.15% 9.22% 10.22% Found 55.19%
8.88% 16.07% 9.94%
EXAMPLES 18 to 80
The following compounds of the invention listed below (Table II)
are obtained via the same procedure as in Example 17, but using
the appropriate reagent A in the first step of the process and the
appropriate reagents B and C in the 2nd step (see Table III below).
TABLE II Example Compound obtained 18 2-amino-4-pentylamino-6-methoxypyrimidine
3-oxide 19 2-amino-4-hexylamino-6-methoxypyrimidine 3-oxide 20 2-amino-4-heptylamino-6-methoxypyrimidine
3-oxide 21 2-amino-4-octylamino-6-methoxypyrimidine 3-oxide 22 2-amino-4-nonylamino-6-methoxypyrimidine
3-oxide 23 2-amino-4-decylamino-6-methoxypyrimidine 3-oxide 24 2-amino-4-undecylamino-6-methoxypyrimidine
3-oxide 25 2-amino-4-dodecylamino-6-methoxypyrimidine 3-oxide 26
2-amino-4-tridecylamino-6-methoxypyrimidine 3-oxide 27 2-amino-4-tetradecylamino-6-methoxypyrimidine
3-oxide 28 2-amino-4-pentadecylamino-6-methoxypyrimidine 3-oxide
29 2-amino-4-hexadecylamino-6-methoxypyrimidine 3-oxide 30 2-amino-4-heptadecylamino-6-methoxypyrimidine
3-oxide 31 2-amino-4-octadecylamino-6-methoxypyrimidine 3-oxide
32 2-amino-4-nonadecylamino-6-methoxypyrimidine 3-oxide 33 2-amino-4-eicosadecylamino-6-methoxypyrimidine
3-oxide 34 2-amino-4-pentylamino-6-ethoxypyrimidine 3-oxide 35 2-amino-4-hexylamino-6-ethoxypyrimidine
3-oxide 36 2-amino-4-heptylamino-6-ethoxypyrimidine 3-oxide 37 2-amino-4-octylamino-6-ethoxypyrimidine
3-oxide 38 2-amino-4-nonylamino-6-ethoxypyrimidine 3-oxide 39 2-amino-4-decylamino-6-ethoxypyrimidine
3-oxide 40 2-amino-4-undecylamino-6-ethoxypyrimidine 3-oxide 41
2-amino-4-dodecylamino-6-ethoxypyrimidine 3-oxide 42 2-amino-4-tridecylamino-6-ethoxypyrimidine
3-oxide 43 2-amino-4-tetradecylamino-6-ethoxypyrimidine 3-oxide
44 2-amino-4-pentadecylamino-6-ethoxypyrimidine 3-oxide 45 2-amino-4-hexadecylamino-6-ethoxypyrimidine
3-oxide 46 2-amino-4-heptadecylamino-6-ethoxypyrimidine 3-oxide
47 2-amino-4-octadecylamino-6-ethoxypyrimidine 3-oxide 48 2-amino-4-nonadecylamino-6-ethoxypyrimidine
3-oxide 49 2-amino-4-eicosadecylamino-6-ethoxypyrimidine 3-oxide
50 2-amino-4-pentylamino-6-propyloxypyrimidine 3-oxide 51 2-amino-4-hexylamino-6-propyloxypyrimidine
3-oxide 52 2-amino-4-heptylamino-6-propyloxypyrimidine 3-oxide 53
2-amino-4-octylamino-6-propyloxypyrimidine 3-oxide 54 2-amino-4-nonylamino-6-propyloxypyrimidine
3-oxide 55 2-amino-4-decylamino-6-propyloxypyrimidine 3-oxide 56
2-amino-4-undecylamino-6-propyloxypyrimidine 3-oxide 57 2-amino-4-dodecylamino-6-propyloxypyrimidine
3-oxide 58 2-amino-4-tridecylamino-6-propyloxypyrimidine 3-oxide
59 2-amino-4-tetradecylamino-6-propyloxypyrimidine 3-oxide 60 2-amino-4-pentadecylamino-6-propyloxypyrimidine
3-oxide 61 2-amino-4-hexadecylamino-6-propyloxypyrimidine 3-oxide
62 2-amino-4-heptadecylamino-6-propyloxypyrimidine 3-oxide 63 2-amino-4-octadecylamino-6-propyloxypyrimidine
3-oxide 64 2-amino-4-nonadecylamino-6-propyloxypyrimidine 3-oxide
65 2-amino-4-eicosadecylamino-6-propyloxypyrimidine 3-oxide 66 2-amino-4-pentylamino-6-butyloxypyrimidine
3-oxide 67 2-amino-4-hexylamino-6-butyloxypyrimidine 3-oxide 68
2-amino-4-heptylamino-6-butyloxypyrimidine 3-oxide 69 2-amino-4-nonylamino-6-butyloxypyrimidine
3-oxide 70 2-amino-4-decylamino-6-butyloxypyrimidine 3-oxide 71
2-amino-4-undecylamino-6-butyloxypyrimidine 3-oxide 72 2-amino-4-dodecylamino-6-butyloxypyrimidine
3-oxide 73 2-amino-4-tridecylamino-6-butyloxypyrimidine 3-oxide
74 2-amino-4-tetradecylamino-6-butyloxypyrimidine 3-oxide 75 2-amino-4-pentadecylamino-6-butyloxypyrimidine
3-oxide 76 2-amino-4-hexadecylamino-6-butyloxypyrimidine 3-oxide
77 2-amino-4-heptadecylamino-6-butyloxypyrimidine 3-oxide 78 2-amino-4-octadecylamino-6-butyloxypyrimidine
3-oxide 79 2-amino-4-nonadecylamino-6-butyloxypyrimidine 3-oxide
80 2-amino-4-eicosadecylamino-6-butyloxypyrimidine 3-oxide
TABLE III Example Reagent A Reagent B Reagent C 18 pentylamine
methanol 2-amino-4-pentylamino-6-chloro- pyrimidine 3-oxide 19 hexylamine
methanol 2-amino-4-hexylamino-6-chloro- pyrimidine 3-oxide 20 heptylamine
methanol 2-amino-4-heptylamino-6-chloro- pyrimidine 3-oxide 21 octylamine
methanol 2-amino-4-octylamino-6-chloro- pyrimidine 3-oxide 22 nonylamine
methanol 2-amino-4-nonylamino-6-chloro- pyrimidine 3-oxide 23 decylamine
methanol 2-amino-4-decylamino-6-chloro- pyrimidine 3-oxide 24 undecyl-
methanol 2-amino-4-undecylamino-6-chloro- amine pyrimidine 3-oxide
25 dodecyl- methanol 2-amino-4-dodecylamino-6- amine chloropyrimidine
3-oxide 26 tri- methanol 2-amino-4-tridecylamino-6-chloro- decylamine
pyrimidine 3-oxide 27 tetradecyl- methanol 2-amino-4-tetradecylamino-6-
amine chloropyrimidine 3-oxide 28 pentadecyl- methanol 2-amino-4-pentadecylamino-6-
amine chloropyrimidine 3-oxide 29 hexadecyl- methanol 2-amino-4-hexadecylamino-6-
amine chloro-pyrimidine 3-oxide 30 heptadecyl- methanol 2-amino-4-heptadecylamino-6-
amine chloropyrimidine 3-oxide 31 octadecyl- methanol 2-amino-4-octadecylamino-6-
amine chloro-pyrimidine 3-oxide 32 nonadecyl- methanol 2-amino-4-nonadecylamino-6-
amine chloro-pyrimidine 3-oxide 33 eicosadicyl- methanol 2-amino-4-eicosadecylamino-6-
amine chloropyrimidine 3-oxide 34 pentylamine ethanol 2-amino-4-pentylamino-6-chloro-
pyrimidine 3-oxide 35 hexylamine ethanol 2-amino-4-hexylamino-6-chloro-
pyrimidine 3-oxide 36 heptylamine ethanol 2-amino-4-heptylamino-6-chloro-
pyrimidine 3-oxide 37 octylamine ethanol 2-amino-4-octylamino-6-chloro-
pyrimidine 3-oxide 38 nonylamine ethanol 2-amino-4-nonylamino-6-chloro-
pyrimidine 3-oxide 39 decylamine ethanol 2-amino-4-decylamino-6-chloro-
pyrimidine 3-oxide 40 undecyl- ethanol 2-amino-4-undecylamino-6-chloro-
amine pyrimidine 3-oxide 41 dodecyl- ethanol 2-amino-4-dodecylamino-6-chloro-
amine pyrimidine 3-oxide 42 tri- ethanol 2-amino-4-tridecylamino-6-chloro-
decylamine pyrimidine 3-oxide 43 tetradecyl- ethanol 2-amino-4-tetradecylamino-6-
amine chloropyrimidine 3-oxide 44 pentadecyl- ethanol 2-amino-4-pentadecylamino-6-
amine chloropyrimidine 3-oxide 45 hexadecyl- ethanol 2-amino-4-hexadecylamino-6-
amine chloro-pyrimidine 3-oxide 46 heptadecyl- ethanol 2-amino-4-heptadecylamino-6-
amine chloropyrimidine 3-oxide 47 octadecyl- ethanol 2-amino-4-octadecylamino-6-
amine chloro-pyrimidine 3-oxide 48 nonadecyl- ethanol 2-amino-4-nonadecylamino-6-
amine chloro-pyrimidine 3-oxide 49 eicosadecyl- ethanol 2-amino-4-eicosadecylamino-6-
amine chloropyrimidine 3-oxide 50 pentylamine propanol 2-amino-4-pentylamino-6-chloro-
pyrimidine 3-oxide 51 hexylamine propanol 2-amino-4-hexylamino-6-chloro-
pyrimidine 3-oxide 52 heptylamine propanol 2-amino-4-heptylamino-6-chloro-
pyrimidine 3-oxide 53 octylamine propanol 2-amino-4-octylamino-6-chloro-
pyrimidine 3-oxide 54 nonylamine propanol 2-amino-4-nonylamino-6-chloro-
pyrimidine 3-oxide 55 decylamine propanol 2-amino-4-decylamino-6-chloro-
pyrimidine 3-oxide 56 undecyl- propanol 2-amino-4-undecylamino-6-chloro-
amine pyrimidine 3-oxide 57 dodecyl- propanol 2-amino-4-dodecylamino-6-chloro-
amine pyrimidine 3-oxide 58 tridecyl- propanol 2-amino-4-tridecylamino-6-chloro-
amine pyrimidine 3-oxide 59 tetradecyl- propanol 2-amino-4-tetradecylamino-6-
amine chloropyrimidine 3-oxide 60 pentadecyl- propanol 2-amino-4-pentadecylamino-6-
amine chloropyrimidine 3-oxide 61 hexadecyl- propanol 2-amino-4-hexadecylamino-6-
amine chloro-pyrimidine 3-oxide 62 heptadecyl- propanol 2-amino-4-heptadecylamino-6-
amine chloropyrimidine 3-oxide 63 octadecyl- propanol 2-amino-4-octadecylamino-6-
amine chloro-pyrimidine 3-oxide 64 nonadecyl- propanol 2-amino-4-nonadecylamino-6-
amine chloro-pyrimidine 3-oxide 65 eicosadecyl- propanol 2-amino-4-eicosadecylamino-6-
amine chloropyrimidine 3-oxide 66 pentylamine butanol 2-amino-4-pentylamino-6-chloro-
pyrimidine 3-oxide 67 hexylamine butanol 2-amino-4-hexylamino-6-chloro-
pyrimidine 3-oxide 68 heptylamine butanol 2-amino-4-heptylamino-6-chloro-
pyrimidine 3-oxide 69 nonylamine butanol 2-amino-4-nonylamino-6-chloro-
pyrimidine 3-oxide 70 decylamine butanol 2-amino-4-decylamino-6-chloro-
pyrimidine 3-oxide 71 undecyl- butanol 2-amino-4-undecylamino-6-chloro-
amine pyrimidine 3-oxide 72 dodecyl- butanol 2-amino-4-dodecylamino-6-chloro-
amine pyrimidine 3-oxide 73 tridecyl- butanol 2-amino-4-tridecylamino-6-chloro-
amine pyrimidine 3-oxide 74 tetradecyl- butanol 2-amino-4-tetradecylamino-6-
amine chloropyrimidine 3-oxide 75 pentadecyl- butanol 2-amino-4-pentadecylamino-6-
amine chloropyrimidine 3-oxide 76 hexadecyl- butanol 2-amino-4-hexadecylamino-6-
amine chloro-pyrimidine 3-oxide 77 heptadecyl- butanol 2-amino-4-heptadecylamino-6-
amine chloropyrimidine 3-oxide 78 octadecyl- butanol 2-amino-4-octadecylamino-6-
amine chloro-pyrimidine 3-oxide 79 nonadecyl- butanol 2-amino-4-nonadecylamino-6-
amine chloro-pyrimidine 3-oxide 80 eicosadecyl- butanol 2-amino-4-eicosadecylamino-6-
amine chloropyrimidine 3-oxide
EXAMPLE 81
Measurement of the prostaglandin-endoperoxide synthase (PGHS-1)
activating power.
General Measuring Principles
The amount of oxygen required for the oxidation of arachidonic
acid was measured by means of the cyclooxygenase activity of the
prostaglandin-endoperoxide synthase, in the presence or absence
of the test compound.
The oxygen consumption measurements were taken using a Clark electrode
connected to a YSI 5300 oxymeter marketed by Yellow Spring Instruments.
These measurements were taken in an open chamber with constant-stirring
at a temperature of 37.degree. C.
If a graph recorder was used, the oxygen consumption measurement
is expressed in the form of a curve, the maximum slope of which
makes it possible to determine the initial rate of the reaction,
and from which it is possible to calculate the period for which
the initial reaction rate is maintained.
The curve thus obtained, in the absence of any substance other
than the ingredients required for the enzymatic reaction, provides
the basal activity of the enzyme. The initial rate and the period
for which this rate is maintained can be determined under these
conditions in a reaction comprising only the enzyme and its substrate.
These data will serve as a reference in the study of the test compounds.
The activity of the test compounds was measured under the same
conditions, by adding the test compound to the reaction medium.
The activity of the test compound with respect to cyclooxygenase
was evaluated by means of the variation of the slope and the variation
of the period for which the maximum rate was maintained.
Formulation for the Measurements
A solution of 0.1 M Tris and 5 mM EDTA at pH=8.00 (TE solution)
was prepared.
The measurements were taken in a buffered solution (TEA buffer)
composed of 9 volumes of TE solution and 1 volume of 20% alcohol.
The substrate was formulated in the form of a stock solution of
potassium arachidonate according to the supplier's procedure (Interchim,
France).
The solution thus obtained had a 46 mM titre of arachidonic acid.
It can be stored at 4.degree. C. for 24 hours.
The enzyme employed was prostaglandin endoperoxidesynthase (PGHS-1),
isolated from sheep seminal glands, marketed by Cayman Chemical
under the reference 60100.
The test compounds were prepared in the form of a stock solution
with a titre of 5 mM, in a water/alcohol mixture (80/20) and were
tested with the same batch of enzyme.
Measurements
Basal Activities of the Enzyme
At t=0, 380 .mu.l of TEA buffer preheated to 37.degree. C. were
introduced into the measuring chamber and maintained to equilibrate
for at least one minute.
At t=1, 300 units of enzyme (PGHS) were introduced.
Recording was initiated, and the mixture was again permitted to
stabilize for one minute. The recording obtained provided the reaction
baseline.
After a further minute, 10 .mu.l of substrate were introduced and
the oxygen consumption was recorded for 2 to 3 minutes.
The initial reaction rate and the period for which this rate was
maintained were thus determined. These data served as a reference
for the measurements of the activity of the test compounds.
Activities of the Test Compounds
The experimental conditions were identical to those above, except
that the TEA buffer preheated to 37.degree. C. was replaced by an
identical buffer containing the test compound at a concentration
of 0.5 mM.
Results
The following results are expressed as a % relative to the values
obtained with the control.
TABLE IV Compounds Activation Control +0% Compound of Example 1
+37% Compound of Example 2 +11% Compound of Example 3 +14% Compound
of Example 17 Indomethacin.sup.1 -100% .sup.1 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic
acid, or indomethacin, is a known inhibitor of cyclooxygenase activity.
(H.P. Rang/M. M. Dale Pharmacology second edition 1991. Published
by Churchill Livingstone). This inhibitory effect was clearly evident
under the conditions of the experiment.
EXAMPLE 82
The following specific compositions containing at least one 2-amino4-alkylaminopyrimidine
3-oxide of the invention were formulated employing conventional
techniques in the cosmetics or pharmacy arts.
Lotion for Preventing Hair Loss
Compound of Example 2 0.5 g Propylene glycol 10.0 g Isopropyl alcohol
qs 100.0 g
1 ml of this lotion is applied to the scalp, at a frequency of
once or twice a day.
Niosomal Gel
Chimexane NS .RTM. 1.8 g Monosodium stearylglutamate 0.2 g Compound
of Example 17 2.0 g Carbomer 0.2 g Triethanolamine qs pH = 7 Preservatives
qs Fragrances qs Demineralized water qs 100.0 g
This gel is applied to the scalp once or twice a day.
Lotion for Preventing Hair Loss
Compound of Example 17 3.0 g Propylene glycol 30.0 g Ethyl alcohol
40.5 g Water qs 100.0 g
This lotion is applied to the scalp once or twice a day, at a rate
of 1 ml per application.
Thickened Lotion for Preventing Hair Loss
Compound of Example 2 1.0 g Kawain 2.0 g Hydroxypropylcellulose
marketed by 3.5 g Hercules under the trademark Klucel G Ethyl alcohol
qs 100.0 g
This thickened lotion is applied to the scalp once or twice a day,
at a rate of 1 ml per application.
Niosomal Lotion
Chimexane NL .RTM. 0.475 g Cholesterol 0.475 g Monosodium stearylglutamate
0.05 g Compound of Example 1 1.0 g Preservatives qs Dyes qs Fragrance
qs Demineralized water qs 100.0 g
This lotion is applied to the scalp once or twice a day, at a rate
of 1 ml per application.
Lotion for Preventing Hair Loss
Compound of Example 3 1.0 g Propylene glycol monomethyl ether 20.0
g marketed under the trademark Dowanol PM by Dow Chemical Hydroxypropylcellulose
marketed by 3.0 g Hercules under the trademark Klucel G Ethyl alcohol
40.0 g Water qs 100.0 g
This thickened lotion is applied to the scalp once or twice a day,
at a rate of 1 ml per application.
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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