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): 1 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
5. A compound as defined by claim 4, selected from among 2-amino-4-hexylaminopyrimidine
3-oxide; 2-amino-4-octylaminopyrimidine 3-oxide; 2-amino-4-dodecylaminopyrimidine
3-oxide; and 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide.
6. A compound as defined by claim 5, comprising 2-amino-4-dodecylaminopyri-
midine 3-oxide or 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide.
7. A process for the preparation of the 2-amino-4-alkylaminopyrimidine
3-oxide compound of formula (I) as defined by claim 1, comprising
reacting an aliphatic amine with 2-amino-4,6-dichloropyrimidine
in a solvent medium, next reacting the compound thus obtained with
a urea/H.sub.2O.sub.2 complex and phthalic anhydride, also in a
solvent medium, and thence reacting the compound obtained, in the
presence of potassium hydroxide and palladium-on-charcoal, in a
solvent medium under a high hydrogen pressure.
8. A process for the preparation of the 2-amino-4-alkylamino-6-alkyloxypyr-
imidine 3-oxide compound of formula (I) as defined by claim 1, comprising
reacting an aliphatic amine with 2-amino-4,6-dichloropyrimidine
in a solvent medium, next reacting the compound thus obtained with
a urea/H.sub.2O.sub.2 complex and phthalic anhydride in the presence
of isopropanol, and thence reacting the compound obtained with an
excess of sodium alkoxide to provide the corresponding 2-amino-4-alkylamino-6-alkyl-
oxypyrimidine 3-oxide.
9. A hair growth-/hair loss-affecting cosmetic/therapeutic composition
of matter, comprising a hair growth stimulating and/or hair loss
retarding effective amount of at least one 2-amino-4-alkylamino-6-alkyloxypyrimidin-
e 3-oxide compound of formula (I), as defined in claim 1, formulated
into a physiologically acceptable vehicle, diluent or carrier therefor.
10. The cosmetic/therapeutic composition as defined by claim 9,
comprising from 0.001% to 10% by weight of said at least one 2-amino-4-alkylamino-6--
alkyloxypyrimidine 3-oxide compound of formula (I).
11. The cosmetic/therapeutic composition as defined by claim 10,
comprising from 0.01% to 2% by weight of said at least one 2-amino-4-alkylamino-6-alkyloxypyrimidine
3-oxide compound of formula (I).
12. The cosmetic/therapeutic composition as defined by claim 9,
further comprising effective amount(s) of at least one antibacterial
agent, antiparasitic agent, antifungal agent, antiviral agents,
anti-inflammatory agent, antipruriginous agent, anaesthetics, keratolytic
agent, anti-free-radical agent, antiseborrhoeic agent, antidandruff
agent, antiacne agent and/or agent for reducing skin differentiation
and/or proliferation and/or pigmentation, extract of plant, marine
or bacterial origin, or mixture thereof.
13. The cosmetic/therapeutic composition as defined by claim 12,
comprising an effective amount of at least one of an imidazole antifungal
agent, or the antifungal agent ketoconazole.
14. The cosmetic/therapeutic composition as defined by claim 9,
adopted for topical application.
15. The cosmetic/therapeutic composition as defined by claim 9,
adopted for oral administration.
16. The cosmetic/therapeutic composition as defined by claim 9,
adopted for systemic administration.
17. The cosmetic/therapeutic composition as defined by claim 9,
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.
18. The cosmetic/therapeutic composition as defined by claim 9,
comprising an aqueous or oily solution, dispersion, lotion, serum,
syrup, ointment, emulsion, suspension, cream, gel, mousse, spray,
soap, or bar.
19. The cosmetic/therapeutic composition as defined by claim 9,
comprising microcapsules, microparticles, a vesicle dispersion,
capsules, granules, or tablets.
20. The cosmetic/therapeutic composition as defined by claim 9,
comprising a shampoo, hairsetting lotion, hairstyling cream or gel
hair restructuring lotion, or permanent-wave formulation.
21. A regime or regimen 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 thereto, for such
period of time as required to elicit the desired response, an effective
amount of at least one 2-amino-4-alkylamino-6-alkyloxypyrimidine
3-oxide compound of formula (I) as defined by claim 1, or cosmetic/therapeutic
composition comprised thereof.
22. The regime or regimen as defined by claim 21, comprising topically
applying said at least one compound of formula (I), or composition
comprised thereof, onto the head and/or hair of said individual
subject in need of such treatment.
Hair loss description
CROSS-REFERENCE TO PRIORITY APPLICATION
[0001] This application claims priority under 35 U.S.C. .sctn.119
OF FR-98/09509, filed Jul. 24, 1998, assigned to the assignee hereof
and hereby expressly incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field of the Invention
[0003] The present invention relates to novel 2-amino-4-alkylaminopyrimidi-
ne 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.
[0004] 2. Description of the Prior Art
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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.
[0011] In this respect, a large number of very diverse active compounds
have already 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 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.
[0012] 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
[0013] 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): 2
[0014] 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.
[0015] 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
[0016] More particularly according to the present invention, it
is known to this art that certain polyunsaturated fatty acids, in
particular those having 20 carbon atoms, such as arachidonic acid,
dihomo-.gamma.-linoleni- c 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.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] Arachidonic acid metabolites, nitrogen monoxide and nitrogen-monoxide-donating
compounds, stanozolol, glutathione-donating compounds, calcium ionophores,
anthocyanosides, bioflavonoids, platelet activating factors (PAF),
pro-inflammatory cytokines agents and bacterial endotoxins are recognized,
in particular, in the field of cyclooxygenase activators.
[0026] Similarly, illustrative is 6-chloro-2,3-dihydroxy-1,4-naphthoquinon-
e (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)).
[0027] 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.
[0028] 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.
[0029] 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.
[0030] Furthermore, the presence of an alkyl chain in the 4-position
imparts to these compounds improved lipophilic properties.
[0031] This reinforces the advantage of these compounds as active
agents in the treatment of hair loss.
[0032] Accordingly, this invention features novel compounds corresponding
to the structural formula (I): 3
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] Preferred compounds of the invention include:
[0038] 2-amino-4-pentylaminopyrimidine 3-oxide;
[0039] 2-amino-4-hexylaminopyrimidine 3-oxide;
[0040] 2-amino-4-heptylaminopyrimidine 3-oxide;
[0041] 2-amino-4-octylaminopyrimidine 3-oxide;
[0042] 2-amino-4-nonylaminopyrimidine 3-oxide;
[0043] 2-amino-4-decylaminopyrimidine 3-oxide;
[0044] 2-amino-4-undecylaminopyrimidine 3-oxide;
[0045] 2-amino-4-dodecylaminopyrimidine 3-oxide;
[0046] 2-amino-4-tridecylaminopyrimidine 3-oxide;
[0047] 2-amino-4-tetradecylaminopyrimidine 3-oxide;
[0048] 2-amino-4-pentadecylaminopyrimidine 3-oxide;
[0049] 2-amino-4-hexadecylaminopyrimidine 3-oxide;
[0050] 2-amino-4-heptadecylaminopyrimidine 3-oxide;
[0051] 2-amino-4-octadecylaminopyrimidine 3-oxide;
[0052] 2-amino-4-nonadecylaminopyrimidine 3-oxide;
[0053] 2-amino-4-eicosadecylaminopyrimidine 3-oxide;
[0054] 2-amino-4-pentylamino-6-methoxypyrimidine 3-oxide;
[0055] 2-amino-4-hexylamino-6-methoxypyrimidine 3-oxide;
[0056] 2-amino-4-heptylamino-6-methoxypyrimidine 3-oxide;
[0057] 2-amino-4-octylamino-6-methoxypyrimidine 3-oxide;
[0058] 2-amino-4-nonylamino-6-methoxypyrimidine 3-oxide;
[0059] 2-amino-4-decylamino-6-methoxypyrimidine 3-oxide;
[0060] 2-amino-4-undecylamino-6-methoxypyrimidine 3-oxide;
[0061] 2-amino-4-dodecylamino-6-methoxypyrimidine 3-oxide;
[0062] 2-amino-4-tridecylamino-6-methoxypyrimidine 3-oxide;
[0063] 2-amino-4-tetradecylamino-6-methoxypyrimidine 3-oxide;
[0064] 2-amino-4-pentadecylamino-6-methoxypyrimidine 3-oxide;
[0065] 2-amino-4-hexadecylamino-6-methoxypyrimidine 3-oxide;
[0066] 2-amino-4-heptadecylamino-6-methoxypyrimidine 3-oxide;
[0067] 2-amino-4-octadecylamino-6-methoxypyrimidine 3-oxide;
[0068] 2-amino-4-nonadecylamino-6-methoxypyrimidine 3-oxide;
[0069] 2-amino-4-eicosadecylamino-6-methoxypyrimidine 3-oxide;
[0070] 2-amino-4-pentylamino-6-ethoxypyrimidine 3-oxide;
[0071] 2-amino-4-hetylamino-6-ethoxypyrimidine 3-oxide;
[0072] 2-amino-4-hexylamino-6-ethoxypyrimidine 3-oxide;
[0073] 2-amino-4-heptylamino-6-ethoxypyrimidine 3-oxide;
[0074] 2-amino-4-notylamino-6-ethoxypyrinidine 3-oxide;
[0075] 2-amino-4-nocylamino-6-ethoxypyrimidine 3-oxide;
[0076] 2-amino-4-udecylamino-6-ethoxypyrimidine 3-oxide;
[0077] 2-amino-4-nodecylamino-6-ethoxypyrimidine 3-oxide;
[0078] 2-amino-4-d.decylamino-6-ethoxypyrimidine 3-oxide;
[0079] 2-amino-4-tridecylamino-6-ethoxypyrimidine 3-oxide;
[0080] 2-amino-4-petadecylamino-6-ethoxypyrimidine 3-oxide;
[0081] 2-amino-4-pntadecylamino-6-ethoxypyrimidine 3-oxide;
[0082] 2-amino-4-hexadecylamino-6-ethoxypyrimidine 3-oxide;
[0083] 2-amino-4-heptadecylamnino-6-ethoxypyrimidine 3-oxide;
[0084] 2-amino-4-notadecylamino-6-ethoxypyrimidine 3-oxide;
[0085] 2-amino-4-ionadecylamino-6-ethoxypyrimidine 3-oxide;
[0086] 2-amino-4-peitadecylamino-6-ethoxypyrimidine 3-oxide;
[0087] 2-amino-4-pentylamino-6-propyloxypyrimidine 3-oxide;
[0088] 2-amino-4-hexpylamino-6-propyloxypyrimidine 3-oxide;
[0089] 2-amino-4-heptylamino-6-propyloxypyrimidine 3-oxide;
[0090] 2-amino-4-octylamino-6-propyloxypyrimidine 3-oxide;
[0091] 2-amino-4-nonylamino-6-propyloxypyrimidine 3-oxide;
[0092] 2-amino-4-undecylamino-6-propyloxypyrimidine 3-oxide;
[0093] 2-amino-4-dodecylamino-6-propyloxypyrimidine 3-oxide;
[0094] 2-amino-4-ddecylamino-6-propyloxypyrimidine 3-oxide;
[0095] 2-amino-4-tridecylamino-6-propyloxypyrimidine 3-oxide;
[0096] 2-amino-4-tetradecylamino-6-propyloxypyrimidine 3-oxide;
[0097] 2-amino-4-pentadecylamino-6-propyloxypyrimidine 3-oxide;
[0098] 2-amino-4-hexadecylamino-6-propyloxypyrimidine 3-oxide;
[0099] 2-amino-4-heptadecylamino-6-propyloxypyrimidine 3-oxide;
[0100] 2-amino-4-octadecylamino-6-propyloxypyrimidine 3-oxide;
[0101] 2-amino-4-nonadecylamino-6-propyloxypyrimidine 3-oxide;
[0102] 2-amino-4-eicosadecylamino-6-propyloxypyrimidine 3-oxide;
[0103] 2-amino-4-pentylamino-6-butyloxypyrimidine 3-oxide;
[0104] 2-amino-4-hexylamino-6-butyloxypyrimidine 3-oxide;
[0105] 2-amino-4-heptylamino-6-butyloxypyrimidine 3-oxide;
[0106] 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide;
[0107] 2-amino-4-nonylamino-6-butyloxypyrimidine 3-oxide;
[0108] 2-amino-4-decylamino-6-butyloxypyrimidine 3-oxide;
[0109] 2-amino-4-undecylamino-6-butyloxypyrimidine 3-oxide;
[0110] 2-amino-4-dodecylamino-6-butyloxypyrimidine 3-oxide;
[0111] 2-amino-4-tridecylamino-6-butyloxypyrimidine 3-oxide;
[0112] 2-amino-4-tetradecylamino-6-butyloxypyrimidine 3-oxide;
[0113] 2-amino-4-pentadecylamino-6-butyloxypyrimidine 3-oxide;
[0114] 2-amino-4-hexadecylamino-6-butyloxypyrimidine 3-oxide;
[0115] 2-amino-4-heptadecylamino-6-butyloxypyrimidine 3-oxide;
[0116] 2-amino-4-octadecylamino-6-butyloxypyrimidine 3-oxide;
[0117] 2-amino-4-nonadecylamino-6-butyloxypyrimidine 3-oxide;
[0118] 2-amino-4-eicosadecylamino-6-butyloxypyrimidine 3-oxide;
and
[0119] Even more preferred compounds according to the invention
are:
[0120] 2-amino-4-hexylaminopyrimidine 3-oxide;
[0121] 2-amino-4-octylamino pyrimidine 3-oxide;
[0122] 2-amino-4-dodecylaminooxpyrimidine 3-oxide;
[0123] 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide;
[0124] and yet even more preferred are
[0125] 2-amino-4-dodecylaminopyrimidine 3-oxide; and
[0126] 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide.
[0127] This invention also features a process for preparing the
2-amino-4-alkylaminopyrimidine 3-oxides of formula (I).
[0128] 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.2O.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.
[0129] The present invention also features a process for preparing
the 2-amino-4-alkylamino-6-alkyloxypyrimidine 3-oxides of formula
(I).
[0130] 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.2O.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-alkyloxypyrimidine 3-oxide.
[0131] Too, this invention features compositions which comprise
at least one compound of the 2-amino-4-alkylaminopyrimidine 3-oxides
having the structural formula (I).
[0132] 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.
[0133] 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.
[0134] 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%.
[0135] 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.
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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.
[0140] 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.
[0141] The amounts of the various constituents in the compositions
according to the invention are those conventional in the fields
under consideration.
[0142] The compositions according to the invention can also be
formulated as solid preparations constituting cleansing soaps or
bars.
[0143] The subject compositions can also be packaged in the form
of an aerosol composition also comprising a propellant under pressure.
[0144] 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.
[0145] When the composition is an oily solution or gel, the fatty
phase can constitute more than 90% of the total weight of the composition.
[0146] 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.
[0147] 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.
[0148] Exemplary solvents per this invention include the lower
alcohols, in particular ethanol and isopropanol, and propylene glycol.
[0149] And exemplary hydrophilic gelling agents include carboxyvinyl
polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate
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
and polyethylene.
[0150] 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.
[0151] 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.
[0152] 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:
[0153] (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;
[0154] (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;
[0155] (3) antibacterial agents such as clindamycin phosphate,
erythromycin or antibiotics of the tetracyclene class;
[0156] (4) antiparasitic agents, in particular metronidazole, crotamiton
or pyrethroids;
[0157] (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;
[0158] (6) antiviral agents such as acyclovir;
[0159] (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;
[0160] (8) anaesthetics such as lidocane hydrochloride and derivatives
thereof;
[0161] (9) anti-pruriginous agents such as thenaldine, trimeprazine
or cyproheptadine;
[0162] (10) keratolytic agents such as .alpha.- and .beta.-hydroxycarboxylic
or P-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;
[0163] (11) anti-free-radical agents such as .alpha.-tocopherol
or its esters, superoxide dismutases, certain metal-chelating agents
or ascorbic acid and its esters;
[0164] (12) antiseborrhoeic agents such as progesterone;
[0165] (13) antidandruff agents such as octopirox or zinc pyrithione;
[0166] (14) antiacne agents such as retinoic acid or benzoyl peroxide;
[0167] (15) extracts of plant, marine or bacterial origin.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] The compositions according to the invention are well suited
for cosmetic or pharmaceutical applications, in particular dermatological
application.
[0175] 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
[0176] Synthesis of 2-amino-4-hexylaminopyrimidine 3-oxide: 4
[0177] (1) Preparation of 2-amino-4-hexylamino-6-chloropyrimidine:
5
[0178] 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%.
[0179] Analysis:
[0180] *NMR spectrum: .sup.1H (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).
[0181] (2) Preparation of 2-amino-4-hexylamino-6-chloropyrimidine
3-oxide: 6
[0182] 5.95 g of urea/H.sub.2O.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%.
[0183] Analysis:
[0184] *NMR spectrum .sup.1H (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).
[0185] (3) Synthesis of 2-amino-4-hexylaminopyrimidine 3-oxide:
7
[0186] 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-chlorop-
yrimidine 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%.
[0187] Analysis:
[0188] *NMR spectrum: .sup.1H (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
[0189] Synthesis of 2-amino-4-dodecylaminopyrimidine 3-oxide: 8
[0190] (1) Preparation of 2-amino-4-dodeavlamino-6-chloropyrimidine:
9
[0191] 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.
[0192] 17.55 g of the expected compound were thus obtained, for
a yield of 92%.
[0193] Analysis:
[0194] *NMR spectrum: .sup.1H (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).
[0195] (2) Preparation of 2-amino-4-dodecylamino-6-chloropyrimidine
3-oxide: 10
[0196] 3.26 g of urea/H.sub.2O.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.
[0197] 3.3 g of the expected compound were thus obtained, for a
yield of 42%.
[0198] Analysis:
[0199] *NMR spectrum .sup.1H (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,
[0200] (3) Synthesis of 2-amino-4-dodecylaminopyrimidine 3-oxide:
11
[0201] 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-chlor-
opyrimidine 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.
[0202] 0.8 g of the expected compound was thus obtained, for a
yield of 27%.
[0203] Analysis:
[0204] *NMR spectrum: .sup.1H (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
[0205] Synthesis of 2-amino-4-octylaminolpyrimnidine 3-oxide: 12
[0206] (1) Preparation of 2-amino-4-octylamino-6-chloropyrimidine:
13
[0207] 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.
[0208] 22.8 g of the expected compound were thus obtained, for
a yield of 71%.
[0209] Analysis:
[0210] NMR: .sup.1H (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).
[0211] (2) Preparation of 2-amino-4-octylamino-6-chloropyrimidine
3-oxide: 14
[0212] 6.8 g of urea/H.sub.2O.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.
[0213] 6.3 g of the expected compound were thus obtained, for a
yield of 46%.
[0214] Analysis:
[0215] NMR: .sup.1H (200 MHz; DMSO) .delta. ppm; 0.7 (3H, t), 1.1
(10H, s), 1.4 (2H, t), 3(2H, t), 6 (lH, s), 7.2 (3H, s).
[0216] (3) Synthesis of 2-amino-4-octylaminopyrimidine 3-oxide:
15
[0217] 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-chloropyr-
imidine 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.
[0218] 0.5 g of the expected compound was thus obtained, for a
yield of 29%.
[0219] Analysis:
[0220] NMR: .sup.1H (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
[0221] 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):
1 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
eicosadecyl- amine
EXAMPLE 17
[0222] Synthesis of 2-amino -4-octylamino-6-butyloxyyrimidine 3-oxide:
16
[0223] 90 ml of butanol (reagent B) predried over K.sub.2CO.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.
[0224] 1.5 g of 2-amino-4-octylamino-6-chloropyrimidine 3-oxide,
obtained according to Example 3 (reagent C), was then introduced
and the mixture was heated at 90.degree. C. for 24 hours.
[0225] 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%.
[0226] Analysis:
[0227] NMR: .sup.1H (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).
[0228] Elemental analysis (1 Hcl):
2 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
[0229] 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).
3TABLE 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-pentadecylamine-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
[0230]
4TABLE 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 tridecyl- methanol 2-amino-4-tridecylamino-6-chloro-
amine pyrimidine 3-oxide 27 tetradecyl- methanol 2-amino-4-tetradecylami-
no-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 chloropyrimidine 3-oxide 30 heptadecyl- methanol 2-amino-4-heptadecylamino-6-
amine chloropyrimidine 3-oxide 31 octadecyl- methanol 2-amino-4-octadecylamino-6-
amine chloropyrimidine 3-oxide 32 nonadecyl- methanol 2-amino-4-nonadecylamino-6-
amine chloropyrimidine 3-oxide 33 eicosadecyl- 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 tridecyl- ethanol 2-amino-4-tridecylamino-6-chloro-
amine pyrimidine 3-oxide 43 tetradecyl- ethanol 2-amino-4-tetradecylamin-
o-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 chloropyrimidine 3-oxide 46 heptadecyl- ethanol 2-amino-4-heptadecylamino-6-
amine chloropyrimidine 3-oxide 47 octadecyl- ethanol 2-amino-4-octadecylamino-6-
amine chloropyrimidine 3-oxide 48 nonadecyl- ethanol 2-amino-4-nonadecylamino-6-
amine chloropyrimidine 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 chloropyrimidine 3-oxide 62 heptadecyl- propanol 2-amino-4-heptadecylamino-6-
amine chloropyrimidine 3-oxide 63 octadecyl- propanol 2-amino-4-octadecylamino-6-
amine chloropyrimidine 3-oxide 64 nonadecyl- propanol 2-amino-4-nonadecylamino-6-
amine chloropyrimidine 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-ch-
loro- 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-tetradecylamin-
o-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 chloropyrimidine 3-oxide 77 heptadecyl- butanol 2-amino-4-heptadecylamino-6-
amine chloropyrimidine 3-oxide 78 octadecyl- butanol 2-amino-4-octadecylamino-6-
amine chloropyrimidine 3-oxide 79 nonadecyl- butanol 2-amino-4-nonadecylamino-6-
amine chloropyrimidine 3-oxide 80 eicosadecyl- butanol 2-amino-4-eicosadecylamino-6-
amine chloropyrimidine 3-oxide
EXAMPLE 81
[0231] Measurement of the prostaglandin-endoperoxide synthase (PGHS-1)
activating power.
[0232] General Measuring Principles:
[0233] The amount of oxygen required for the oxidation of arachidonic
acid was measured by means of the cyclooxygenase activity of the
prostaglandin-endo-peroxide 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.
[0234] These measurements were taken in an open chamber with constant
stirring at a temperature of 37.degree. C.
[0235] 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.
[0236] 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.
[0237] These data will serve as a reference in the study of the
test compounds.
[0238] 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.
[0239] Formulation for the Measurements:
[0240] A solution of 0.1 M Tris and 5 mM EDTA at pH=8.00 (TE solution)
was prepared.
[0241] The measurements were taken in a buffered solution (TEA
buffer) composed of 9 volumes of TE solution and 1 volume of 20%
alcohol.
[0242] The substrate was formulated in the form of a stock solution
of potassium arachidonate according to the supplier's procedure
(Interchim, France).
[0243] The solution thus obtained had a 46 mM titre of arachidonic
acid. It can be stored at 4.degree. C. for 24 hours.
[0244] The enzyme employed was prostaglandin endo-peroxidesynthase
(PGHS-1), isolated from sheep seminal glands, marketed by Cayman
Chemical under the reference 60100.
[0245] 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.
[0246] Measurements:
[0247] Basal Activities of the Enzyme:
[0248] 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.
[0249] At t=1, 300 units of enzyme (PGHS) were introduced.
[0250] Recording was initiated, and the mixture was again permitted
to stabilize for one minute. The recording obtained provided the
reaction baseline.
[0251] After a further minute, 10 pl of substrate were introduced
and the oxygen consumption was recorded for 2 to 3 minutes.
[0252] 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.
[0253] Activities of the Test Compounds:
[0254] 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.
[0255] Results:
[0256] The following results are expressed as a % relative to the
values obtained with the control.
5 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 +8% 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
[0257] The following specific compositions containing at least
one 2-amino-4-alkylaminopyrimidine 3-oxide of the invention were
formulated employing conventional techniques in the cosmetics or
pharmacy arts.
[0258] Lotion for Preventing Hair Loss:
6 Compound of Example 2 0.5 g Propylene glycol 10.0 g Isopropyl
alcohol qs 100.0 g
[0259] 1 ml of this lotion is applied to the scalp, at a frequency
of once or twice a day.
[0260] Niosomal Gel:
7 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
[0261] This gel is applied to the scalp once or twice a day.
[0262] Lotion for Preventing Hair Loss:
8 Compound of Example 17 3.0 g Propylene glycol 30.0 g Ethyl alcohol
40.5 g Water qs 100.0 g
[0263] This lotion is applied to the scalp once or twice a day,
at a rate of 1 ml per application.
[0264] Thickened Lotion for Preventing Hair Loss:
9 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
[0265] This thickened lotion is applied to the scalp once or twice
a day, at a rate of 1 ml per application.
[0266] Niosomal Lotion:
10 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
[0267] This lotion is applied to the scalp once or twice a day,
at a rate of 1 ml per application.
[0268] Lotion for Preventing Hair Loss:
11 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
[0269] This thickened lotion is applied to the scalp once or twice
a day, at a rate of 1 ml per application.
[0270] 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. |