U.S. patent application number 09/987439 was filed with the patent office on 2002-08-08 for galenical formulation.
Invention is credited to Buchholz, Herwig, Buenger, Joachim, Driller, Hans-Juergen, Pfluecker, Frank, Rosskopf, Ralf.
Application Number | 20020106338 09/987439 |
Document ID | / |
Family ID | 7663259 |
Filed Date | 2002-08-08 |
United States Patent
Application |
20020106338 |
Kind Code |
A1 |
Pfluecker, Frank ; et
al. |
August 8, 2002 |
Galenical formulation
Abstract
The invention relates to compounds of the formula I 1 where
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the meanings
given in claim 1. The compound is suitable in particular for use in
skin care compositions. They protect, firstly, against harmful
oxidation reactions and, secondly, also act as UV filters.
Inventors: |
Pfluecker, Frank;
(Darmstadt, DE) ; Buenger, Joachim;
(Gross-Umstadt, DE) ; Driller, Hans-Juergen;
(Gross-Umstadt, DE) ; Buchholz, Herwig;
(Frankfurt, DE) ; Rosskopf, Ralf; (Muenster,
DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
7663259 |
Appl. No.: |
09/987439 |
Filed: |
November 14, 2001 |
Current U.S.
Class: |
424/59 ; 546/153;
546/159; 548/305.1; 549/23; 549/401; 549/404 |
Current CPC
Class: |
A23V 2002/00 20130101;
A61K 8/498 20130101; A61P 29/00 20180101; A61P 37/08 20180101; A23V
2250/2116 20130101; A61K 8/49 20130101; A23L 33/10 20160801; A61Q
19/08 20130101; C07D 405/12 20130101; C07D 311/30 20130101; A61P
39/06 20180101; A61K 2800/522 20130101; A61Q 17/04 20130101; A23V
2002/00 20130101; A61P 17/16 20180101 |
Class at
Publication: |
424/59 ; 546/153;
546/159; 548/305.1; 549/23; 549/401; 549/404 |
International
Class: |
A61K 007/42; C07D 49/02;
C07D 41/02; C07D 47/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 14, 2000 |
DE |
10056400.3 |
Claims
1. A compounds of the formula I 16where X is O, S or NH; Y is O, S
or NH; a single or double bond may be provided between carbons C-2
and C-3, R.sup.1 and R.sup.2, and R.sup.3 and R.sup.4 may be
provided at any positions on the ring, and also R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 may be identical or different and
independently of one another are --H, --OH or --OA, and A is a
group which absorbs UV radiation selected from the group formed
from: 17and at least one of the groups R.sup.1, R.sup.2, R.sup.3,
R.sup.4 or R.sup.5 is formed by --OA.
2. A compound of formula I 18where X is O, S or NH; Y is O, S or
NH; a single or double bond may be provided between carbons C-2 and
C-3, R.sup.1 and R.sup.2, and R.sup.3 and R.sup.4 may be provided
at any positions on the ring, and also R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 may be identical or different and independently
of one another are --H, --OH or --OA, in addition R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5, independently of one another, can
stand for a straight-chain or branched oxyalkyl or carboxyalkyl
group having 1 to 12 carbon atoms, straight-chain or branched
oxyalkenyl or carboxyalkenyl group having 2 to 12 carbon atoms,
straight-chain or branched hydroxyoxyalkyl group having 1 to 12
carbon atoms, where the hydroxyl group may be bonded to a primary
or secondary carbon atom and, furthermore, the alkyl chain can also
be interrupted by oxygen, sulphate group, phosphate group and a
mono- or oligoglycosyl radical, and A is a group which absorbs UV
radiation selected from the group formed from: 19and at least one
of the groups R.sup.1, R.sup.2, R.sup.3, R.sup.4 or R.sup.5 is
formed by --OA.
3. A compound according to claim 1, wherein said compound is of
formula II 20
4. A compound according to claim 2, wherein said compound is of
formula II 21
5. In a cosmetic or pharmaceutical formulation comprising an active
ingredient and a physiologically acceptable carrier, the
improvement wherein said formulation comprises at least one
compound according to claim 1.
6. In a cosmetic or pharmaceutical formulation comprising an active
ingredient and a physiologically acceptable carrier, the
improvement wherein said formulation comprises at least one
compound according to claim 2.
7. In a cosmetic or pharmaceutical formulation comprising an active
ingredient and a physiologically acceptable carrier, the
improvement wherein said formulation comprises at least one
compound according to claim 3.
8. In a cosmetic or pharmaceutical formulation comprising an active
ingredient and a physiologically acceptable carrier, the
improvement wherein said formulation comprises at least one
compound according to claim 4.
9. A cosmetic formulation according to claim 5, where the
formulation comprises one or more additional UV filters and/or
antioxidants.
10. A cosmetic formulation according to claim 6, where the
formulation comprises one or more additional UV filters and/or
antioxidants.
11. A method for protecting the body's cells of a patient against
oxidative stress, in particular for reducing skin ageing,
comprising administering to said patient a formulation according to
claim 5.
12. A method for protecting the body's cells of a patient against
oxidative stress, in particular for reducing skin ageing,
comprising administering to said patient a formulation according to
claim 6.
13. An enriched foodstuff comprising a foodstuff and at least one
compound according to claim 1.
14. An enriched foodstuff comprising a foodstuff and at least one
compound according to claim 2.
15. A compound according to claim 1 as medicaments.
16. A compound according to claim 2 as medicaments.
17. Use of a compound according to claim 2 for the preparation of a
medicament against oxidative stress, in particular for reducing
skin ageing.
18. Use of a compound according to claim 2 for the preparation of a
medicament for the treatment of inflammations or allergic
reactions.
19. Use of a compound according to claim 2 as antioxidant, in
particular for cosmetic formulations.
20. Use of compounds according to claim 2 for the stabilization of
UV filters, in particular dibenzoylmethane and derivatives of
dibenzoylmethane.
Description
[0001] The invention relates to compounds of the formula I 2
[0002] where X, Y, R.sup.1, R.sup.2 R.sup.3, R.sup.4 and R.sup.5
have the meanings defined herein.
[0003] A suntan of the skin to whatever degree is regarded in
today's society as attractive and as an expression of vigour and
sportiness. As well as this desired effect of the sun on the skin,
a number of undesired secondary effects arise, such as sunburn or
premature skin ageing and the formation of wrinkles. In the
meantime, a number of performance UV filters have been developed
which, applied to the skin in the form of creams, lotions or gels,
can effectively delay the development of sunburn even when the
incidence of solar rays is relatively high. The UV filter present
in the pharmaceutical or cosmetic preparation forms a film or a
layer on the surface of the skin and does not penetrate into deeper
skin layers with other care substances present in the preparation.
Known UV filters or sun protection agents thus act only by
absorbing certain regions of sunlight, meaning that this radiation
cannot penetrate into deeper layers of the skin. As is known, the
most hazardous part of solar radiation is formed by the ultraviolet
rays having a wavelength of less than 400 nm. The lower limit of
the ultraviolet rays which reach the surface of the earth is
limited by the absorption in the ozone layer to about 280 nm. The
sun protection filters which are nowadays customary in cosmetics
absorb in a wavelength range from 280 to 400 nm. This range
includes UV-B rays having a wavelength between 280 and 320 nm,
which play a decisive role in the formation of a solar erythema,
and also UV-A rays, having a wavelength between 320 and 400 nm,
which tan the skin but also age it, favour the triggering of an
erythematous reaction or can exacerbate this reaction in certain
people or even trigger phototoxic or photoallergic and irritative
reactions.
[0004] Skin damage is caused not only by sunlight, but also by
other external influences, such as cold or warmth. In addition the
skin is subject to natural ageing, as a result of which wrinkles
appear and the elasticity of the skin decreases.
[0005] The object of care cosmetics is, wherever possible, to
obtain the impression of a youthful skin. In principle, there are
various ways of achieving this object. For example, existing skin
damage, such as irregular pigmentation or the formation of wrinkles
can be smoothed out by concealing powders or creams. Another
approach is to protect the skin against environmental influences
which lead to permanent damage and thus ageing of the skin. The
idea is therefore to intervene in a preventative manner and thus to
delay the ageing process. One example of this is the UV filters
already mentioned which, by absorbing certain wavelength regions,
prevent or at least reduce skin damage. While in the case of UV
filters, the harmful phenomenon, the UV radiation, is screened from
the skin, in another way, attempts have been made to support the
natural defence or repair mechanisms of the skin against the
harmful phenomenon. Finally, another approach involves compensating
for the defence functions of the skin toward harmful influences,
which weaken with increasing age, by externally applying substances
which are able to compensate for this diminishing defence or repair
function. For example, the skin has the ability to scavenge free
radicals which are produced by external or internal stress factors.
This ability decreases with increasing age, as a result of which
the ageing process accelerates with increasing age.
[0006] Substances which are to support or compensate for defence
and repair functions in the skin must be able to be transported to
their site of activity. In principle, there are two ways of
achieving this. Either the substance is applied to the skin and
penetrates through the external layers into the deeper layers of
the skin, or the active ingredient is, for example, following oral
administration, transported via the bloodstream to the site of
activity.
[0007] A further difficulty associated with the preparation of
cosmetics is the fact that active ingredients which are to be
incorporated into cosmetic formulations are often unstable and may
become damaged in the formulation. The damage can be caused, for
example, as a result of a reaction with atmospheric oxygen or as a
result of the absorption of UV rays. The molecules damaged in this
way can, as a result of a change in their structure, for example,
change their colour and/or lose their effectiveness.
[0008] DE 195 08 608 describes an unstable cosmetic composition for
protection against UV rays of wavelength between 280 and 400 nm
which comprises at least one tetraalkylquercetin in a cosmetically
acceptable oil-based medium, and novel tetraalkylquercetins.
[0009] FR 2 687 572 describes the use of flavonoids which do not
have a double bond at position 2, 3 or do not simultaneously have a
double bond at position 2, 3 and a hydroxyl group at position 3,
for the preparation of cosmetic compositions, and as active
ingredients for protecting the skin, the hair or cosmetic
compositions against singlet oxygen.
[0010] EP 0 716 847 A1 describes a cosmetic or dermatological
active ingredient combination of cinnamic acid derivatives and
flavone glycosides. The active ingredient combination here acts as
an antioxidant. It is suitable for the combating or the prophylaxis
of skin ageing. The active ingredient combination may also comprise
UV filter substances as a further constituent.
[0011] U.S. Pat. No. 5,665,367 describes a skincare composition
which comprises retinol or a retinyl ester and a flavonoid chosen
from the group consisting of naringenin and quercetin, which
comprises a suitable cosmetic carrier. The composition can also
comprise UV filters as a further component.
[0012] FR 2 708 851 describes a cosmetic composition which
comprises nanopigments and, as antioxidants, flavonoids. A further
ingredient which may be present is also UV-A or UV-B filters.
[0013] An object of the invention is to provide compounds which
both act as antioxidants and also are able to effect protection
against UV radiation.
[0014] Upon further study of the specification and appended claims,
further objects and advantages of this invention will become
apparent to those skilled in the art.
[0015] These objects are achieved by compounds of the formula I
3
[0016] where X is O, S or NH;
[0017] Y is O, S or NH
[0018] a single or a double bond may be provided between carbon
atoms C-2 and C-3,
[0019] where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may be
identical or different and, independently of one another are --H,
--OH or --OA, and A is a group which absorbs UV radiation,
preferably in the UV-A and/or UV-B region, which is chosen from the
group formed from 4
[0020] and at least one of the groups R.sup.1, R.sup.2, R.sup.3,
R.sup.4 or R.sup.5 is formed by --OA.
[0021] The compounds preferably have a structure of the formula II
5
[0022] where R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the meanings given above and below.
[0023] The flavonoids which form the base substance of the
compounds of the formula I have activity as antioxidants and/or
free-radical scavengers. Their combination with groups which
exhibit a suitable absorption in the UV region provides a new class
of compound which has very interesting properties.
[0024] As well as their action as antioxidant, the flavonoids used
as base substances themselves exhibit a certain protective action
against UVA radiation. Therefore, by combining them with
UV-absorbing groups, it is possible to provide UVA/B broad-band
filters which also have an antioxidative effect. In this
connection, the groups are chosen such that they exhibit an
absorption maximum in particular in the wavelength ranges of UVA
and of UVB radiation which are particularly harmful for the skin.
The UVB portion of sunlight covers the range from 280 to 320 nm,
and the UVA radiation the range >320 nm, which directly borders
the visible light region. UV broad-band filters of this type can be
used, for example, in a large number of cosmetics.
[0025] As a result of their antioxidative effect, compounds of the
formula I also have a stabilizing action on formulations which are
used for cosmetics. By adding compounds of the formula I to the
corresponding products, the latter thus remain stable for longer
and do not change their appearance. In particular, in cases of
longer-lasting application or prolonged storage, the effectiveness
of the ingredients, e.g. vitamins, is also retained. This is
particularly advantageous in the case of sunscreen compositions
since these cosmetics are subjected to particularly high stresses
by UV rays.
[0026] The substances of the formula I generally act as
free-radical scavengers. Such free radicals are produced not only
as a result of sunlight, but are formed under a variety of
conditions. Examples are anoxia which block the electron flow
upstream of the cytochrome oxidases and bring about the formation
of superoxide radical anions; inflammations which are associated
inter alia with the formation of superoxide anions as a result of
membrane NADPH oxidase of leukocytes which, however, are also
associated with the formation (as a result of disproportionation in
the presence of iron(II) ions) of hydroxyl radicals and other
reactive species normally involved in the phenomenon of
phagocytosis; and lipid autoxidation which is generally initiated
by a hydroxyl radical and produces lipidic alkoxy radicals and
hydroperoxides.
[0027] The compounds of the formula I also act as enzyme
inhibitors. For example, they inhibit histidine decarboxylase,
protein kinases, elastase, aldose reductase and hyaluronidase,
which would make it possible to maintain the entirety of the base
substance of vascular sheaths. In addition, they do not
specifically inhibit catechol O-methyltransferase, as a result of
which the amount of available catecholamines and, consequently,
vascular strength can be increased. As a further effect, they
inhibit AMP phosphodiesterase, as a result of which the substances
may have potential for inhibiting platelet aggregation.
[0028] These properties permit, for example, a use of compounds of
the formula I for a large number of therapeutic applications. They
are, for example, suitable for protecting DNA. Further uses arise
from their effect as an antiviral agent, in particular as an agent
against herpes. In addition, they can be used as bacteriostatic or
bactericidal agents or else as antiinflammatory agents.
[0029] Compounds of the formula I are in most cases not used
without a diluent, but are incorporated into suitable formulations,
such as creams, ointments or lotions. The compounds can be used by
application to the skin, but systemic transportation is also
conceivable. For this purpose, the properties of the compounds of
the formula I have to be matched to the conditions in question.
Modification of the solubility in oil or water is possible by
introducing corresponding groups into the molecule. Compounds which
have been found to be suitable are those where in addition R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5, independently of one
another, have the meanings of --H, --OH, --OA, with A having the
meaning given above, or one of the following meanings:
[0030] straight-chain or branched oxalkyl or carboxyalkyl group
having 1 to 12 carbon atoms,
[0031] straight-chain or branched oxalkenyl or carboxyalkenyl group
having 2 to 12 carbon atoms,
[0032] straight-chain or branched hydroxyoxalkyl group having 1 to
12 carbon atoms, where the hydroxyl group may be bonded to a
primary or secondary carbon atom and, furthermore, the alkyl chain
may also be interrupted by oxygen,
[0033] sulphate group,
[0034] phosphate group
[0035] and a mono- or oligoglycosyl radical,
[0036] where these groups may be substituted by alkyl, hydroxyl,
alkoxy, amino, mono- and dialkylamino, sulphonic acid, carboxyl
and/or halogen groups,
[0037] and wherein at least one of the groups is an --OA group.
[0038] To improve the solubility in oil, the hydroxyl groups of the
flavonoid base substance are etherified with suitable alcohols. A
particularly suitable alkyl group is the 2-ethylhexyl group.
[0039] The solubility in oil can also be improved by, for example,
esterifying the hydroxyl groups of the flavonoid base substance
with 2-ethylhexanecarboxylic acid.
[0040] Further suitable radicals are obtained by esterification
with monocarboxylic acids, such as butyric acid, valeric acid,
hexanoic acid, sorbic acid, ascorbic acid or lauric acid. These
radicals promote the transportation of the compound through
biological membranes. In the cell, the base substance can then be
liberated by cleaving off the carboxylic acids using esterases.
[0041] The solubility in water can be improved by introducing
sulphate or phosphate groups into the molecule. Suitable for this
are either compounds with one, two or three sulphate groups in the
molecule, or mixtures of different sulphates or phosphates.
[0042] Preference is also given to choosing those structures in
which at least one of the radicals R.sup.1, R.sup.2, R.sup.3,
R.sup.4. and R.sup.5 is formed by a mono- or oligosaccharide.
Preference is given here to hexosyl radicals, in particular
rhamnosyl radicals and glucosyl radicals. However, other hexosyl
radicals, for example allosyl, altrosyl, galactosyl, gulosyl,
idosyl, mannosyl and talosyl, can also be used advantageously in
some instances. It may also be advantageous to use pentosyl
radicals. The glucosyl radicals can be bonded to the base substance
by means of .alpha.- or .beta.-glycoside bonds. A preferred
disaccharide is, for example,
6-0-(6-deoxy-.alpha.-L-mannopyranosyl)-.bet-
a.-D-glucopyranoside.
[0043] The compounds of the formula I are prepared by methods known
per se to the person skilled in the art and are described in
standard works such as Houben-Weyl, "Methoden der organischen
Chemie" [Methods of Organic Chemistry], Georg-Thieme-Verlag,
Stuttgart.
[0044] The radicals can be introduced, for example, starting from
the known flavonoid base substances. Thus, alkyl chains can be
introduced by reacting the base substance with the corresponding
alkyl halides under the action of a strong base in a suitable
solvent, for example dimethylformamide. If the radicals R.sup.1 to
R.sup.5 bind as esters, this can be carried out, for example, by
reaction with a corresponding acid chloride. Scheme I shows
examples of a few precursors of radicals which are suitable for
introduction of the radicals in the respective base substance.
Here, --X is a suitable leaving group, for example a halide. This
list is only given by way of example and shows only a small
fraction of the number of possible precursors. It is directly
possible for the person skilled in the art to assign other suitable
leaving groups, for example a tosylate group or a triflate group,
instead of the halides. For example, introduction of the radicals
bonded via an ester function is also possible via corresponding
transesterification reactions. 6
[0045] The compounds of the formula I can either be used as pure
compounds, or it is also possible to use mixtures, this term here
being understood as meaning both isomeric mixtures and also
mixtures of compounds of the formula I which have different
substitution patterns, i.e. carry, for example, a different number
of substituents --OA.
[0046] The reaction of the flavonoid base substances with the
corresponding reactive precursors of the radicals R.sup.1 to
R.sup.5 is carried out by methods known to the person skilled in
the art and in customary solvents. Suitable solvents are, for
example, chlorinated hydrocarbons, dimethyl sulphoxide,
dimethylformamide etc.
[0047] The compounds of the formula I may display an advantageous
effect on the skin. The invention thus also provides a cosmetic or
pharmaceutical formulation comprising at least one compound of the
formula I.
[0048] The positive effect of the cosmetic or pharmaceutical
preparation according to the invention is presumably based on the
effect of the compounds of the formula I as antioxidants or
free-radical scavengers in combination with an action as UV
filters. In order to be able to develop their positive effect on
the skin, the compounds of the formula I should be able to
penetrate into deeper layers of the skin. For this, a number of
possibilities are available. Firstly, the compounds of the formula
I can have sufficient lipophilicity in order to be able to
penetrate through the outer layer of the skin into epidermal
layers. Another possibility involves also providing corresponding
transportation agents, for example liposomes, which permit
transportation of the compounds of the formula I through the
external layers of skin, in the preparation. Finally, a systemic
transportation of the compounds of the formula I is also
conceivable. The preparation is then formulated, for example, such
that it is suitable for oral administration.
[0049] The one or more compounds of the formula I can be
incorporated into cosmetic formulations in the customary manner.
For internal use, administration forms such as capsules,
sugar-coated tablets, powders, tablet solutions or solutions are
suitable.
[0050] Examples which may be mentioned of administration forms of
the cosmetic or pharmaceutical formulations according to the
invention for external use are: solutions, suspensions, emulsions,
PIT emulsions, pastes, ointments, gels, creams, lotions, powders,
soaps, surfactant-containing cleansing preparations, oils, aerosols
and sprays. Further application forms are, for example, sticks,
shampoos and shower preparations. Customary carriers, auxiliaries
and optionally further active ingredients may be added to the
formulation.
[0051] Preferred auxiliaries originate from the group of
preservatives, antioxidants, stabilizers, solubility promoters,
vitamins, colorants, odour improvers.
[0052] Ointments, pastes, creams and gels may comprise the
customary carriers, e.g. animal and vegetable fats, waxes,
paraffins, starch, tragacanth, cellulose derivatives, polyethylene
glycols, silicones, bentonites, silica, talc and zinc oxide or
mixtures of these substances.
[0053] Powders and sprays may comprise the customary carriers, e.g.
lactose, talc, silica, aluminium hydroxide, calcium silicate and
polyamide powder or mixtures of these substances. Sprays can
additionally comprise customary propellants, e.g.
chlorofluorocarbons, propane/butane or dimethyl ether.
[0054] Solutions and emulsions can comprise the customary carriers,
such as solvents, solubility promoters and emulsifiers, e.g. water,
ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils,
in particular cottonseed oil, peanut oil, maize germ oil, olive
oil, castor oil and sesame oil, glycerol fatty acid esters,
polyethylene glycols and fatty acid esters of sorbitan or mixtures
of these substances.
[0055] Suspensions can comprise the customary carriers such as
liquid diluents, e.g. water, ethanol or propylene glycol,
suspending agents, e.g. ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester,
microcrystalline cellulose, aluminium metahydroxide, bentonite,
agar agar and tragacanth or mixtures of these substances.
[0056] Soaps can comprise the customary carriers, such as alkali
metal salts of fatty acids, salts of fatty acid monoesters, fatty
acid protein hydrolysates, isethionates, lanolin, fatty alcohol,
plant oils, plant extracts, glycerol, sugars or mixtures of these
substances.
[0057] Surfactant-containing cleansing products can comprise the
customary carrier substances, such as salts of fatty alcohol
sulphates, fatty alcohol ether sulphates, sulphosuccinic
monoesters, fatty acid protein hydrolysates, isethionates,
imidazolinium derivatives, methyl taurates, sarcosinates, fatty
acid amide ether sulphates, alkylamidobetaines, fatty alcohols,
fatty acid glycerides, fatty acid diethanolamides, vegetable and
synthetic oils, lanolin derivatives, ethoxylated glycerol fatty
acid esters or mixtures of these substances.
[0058] Face and body oils can comprise the customary carrier
substances such as synthetic oils, such as fatty acid esters, fatty
alcohols, silicone oils, natural oils, such as vegetable oils and
oily plant extracts, paraffin oils, lanolin oils or mixtures of
these substances.
[0059] Further typically cosmetic application forms are also
lipsticks, lipcare sticks, mascara, eyeliner, eyeshadow, blusher,
powder make-up, emulsion make-up and wax make-up, and sunscreen,
presun and aftersun preparations.
[0060] All compounds or components which can be used in the
cosmetic formulations are either known and available commercially
or can be synthesized by known processes.
[0061] The cosmetic preparation according to the invention is
particularly suitable for protecting human skin against ageing
processes and against oxidative stress, i.e. against damage caused
by free radicals, as are produced, for example, by solar
irradiation, heat or other influences. In this connection, they are
in various administration forms customarily used for this
application. For example, it may in particular be in the form of a
lotion or emulsion, such as in the form of a cream or milk (O/W,
W/O, O/W/O, W/O/W), in the form of oily-alcoholic, oily-aqueous or
aqueous-alcoholic gels or solutions, in the form of solid sticks or
may be formulated as an aerosol.
[0062] The formulation may comprise cosmetic auxiliaries which are
customarily used in this type of preparation, such as, for example,
thickeners, emollients, moisturizers, interface-active agents,
emulsifiers, preservatives, antifoams, perfumes, waxes, lanolin,
propellants, dyes and/or pigments which colour the composition
itself or the skin, and other ingredients customarily used in
cosmetics.
[0063] As dispersant or solubilizer it is possible to use an oil,
wax or other fatty substance, a lower monoalcohol or a lower polyol
or mixtures thereof. Particularly preferred monoalcohols or polyols
include ethanol, isopropanol, propylene glycol, glycerol and
sorbitol.
[0064] A preferred embodiment of the invention is an emulsion in
the form of a protective cream or milk and which, apart from the
compound(s) of the formula I, comprises, for example, fatty
alcohols, fatty acids, fatty acid esters, in particular
triglycerides of fatty acids, lanolin, natural and synthetic oils
or waxes and emulsifiers in the presence of water.
[0065] Further preferred embodiments are oily lotions based on
natural or synthetic oils and waxes, lanolin, fatty acid esters, in
particular triglycerides of fatty acids, or oily-alcoholic lotions
based on a lower alcohol, such as ethanol, or a glycerol, such as
propylene glycol, and/or a polyol, such as glycerol, and oils,
waxes and fatty acid esters, such as triglycerides of fatty
acids.
[0066] The cosmetic preparation according to the invention can also
be in the form of an alcoholic gel which comprises one or more
lower alcohols or polyols, such as ethanol, propylene glycol or
glycerol, and a thickener, such as siliceous earth. The
oily-alcoholic gels also comprise natural or synthetic oil or
wax.
[0067] The solid sticks consist of natural or synthetic waxes and
oils, fatty alcohols, fatty acids, fatty acid esters, lanolin and
other fatty substances. If a preparation is formulated as an
aerosol, the customary propellants, such as alkanes, fluoroalkanes
and chlorofluoroalkanes are usually used.
[0068] The cosmetic formulation can also be used to protect the
hair against photochemical damage in order to prevent changes of
colour shades, decoloration or damage of a mechanical nature. In
this case, a suitable formulation is in the form of a shampoo,
lotion, gel or emulsion for rinsing out, the formulation in
question being applied before or after shampooing, before or after
colouring or bleaching or before or after permanent waving. It is
also possible to choose a formulation in the form of a lotion or
gel for styling or treating the hair, in the form of a lotion or
gel for brushing or blow-waving, in the form of a hair lacquer,
permanent waving composition, colorant or bleach for the hair.
Apart from the compound(s) of the formula I, the cosmetic or
pharmaceutical formulation may comprise various adjuvants used in
this type of composition, such as interface-active agents,
thickeners, polymers, emollients, preservatives, foam stabilizers,
electrolytes, organic solvents, silicone derivatives, oils, waxes,
antigrease agents, dyes and/or pigments which colour the
composition itself or the hair, or other ingredients customarily
used for hair care.
[0069] The cosmetic preparations according to the invention can be
prepared using techniques which are well known to the person
skilled in the art.
[0070] To protect the skin and/or natural or sensitized hair
against solar rays, a cosmetic preparation comprising one or more
compounds of formula I is applied to the skin or the hair.
Sensitized hair is understood here as meaning hair which has been
subjected to a chemical treatment, such as a permanent waving
treatment, a colouring process or bleaching process.
[0071] The protective action against UV radiation can be improved
if the formulation comprises one or more UV filters.
[0072] In principle, all UV filters are suitable for a combination.
Particular preference is given to those UV filters whose
physiological safety has already been demonstrated. There are many
tried and tested substances known from the specialist literature
both for UVA and also UVB filters, e.g.
[0073] benzylidenecamphor derivatives, such as
[0074] 3-(4'-methylbenzylidene)-dl-camphor (e.g. Eusolex.RTM.
6300),
[0075] 3-benzylidenecamphor (e.g. Mexoryl.RTM. SD),
[0076] polymers of N-{(2 and
4)-[(2-oxoborn-3-ylidene)methyl]benzyl}acryla- mide (e.g.
Mexoryl.RTM. SW),
[0077] N,N,N,-trimethyl-4-(2-oxoborn-3-ylidenemethyl)anilinium
methylsulphate (e.g. Mexoryl.RTM. SK) or
[0078] .alpha.-(2-oxoborn-3-ylidene)toluene-4-sulfonic acid (e.g.
Mexoryl.RTM. SL),
[0079] benzoylmethanes or dibenzoylmethanes, such as
[0080] -1-(4-tert-butylphenyl)-3-(4-methoxyphenyl)propane-1,3-dione
(e.g. Eusolex.RTM. 9020) or
[0081] -4-isopropyldibenzoylmethane, (e.g. Eusolex.RTM. 8020),
[0082] benzophenones, such as
[0083] 2-hydroxy-4-methoxybenzophenone (e.g. Eusolex.RTM. 4360)
or
[0084] 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and its
sodium salt (e.g. Uvinul.RTM. MS-40),
[0085] methoxycinnamic esters, such as
[0086] octyl methoxycinnamate (e.g. Eusolex.RTM. 2292),
[0087] isopentyl 4-methoxycinnamate, e.g. as a mixture of the
isomers (e.g. Neo Heliopan.RTM. E 1000),
[0088] salicylate derivatives, such as
[0089] 2-ethylhexyl salicylate (e.g. Eusolex.RTM. OS),
[0090] 4-isopropylbenzyl salicylate (e.g. Megasol.RTM.) or
[0091] 3,3,5-trimethylcyclohexyl salicylate (e.g. Eusolex.RTM.
HMS),
[0092] 4-aminobenzoic acid and derivatives, such as
[0093] 4-aminobenzoic acid,
[0094] 2-ethylhexyl 4-(dimethylamino)benzoate (e.g. Eusolex.RTM.
6007),
[0095] ethoxylated ethyl 4-aminobenzoate (e.g. Uvinul.RTM.
P25),
[0096] and further substances, such as
[0097] 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (e.g. Eusolex.RTM.
OCR),
[0098] 2-phenylbenzimidazole-5-sulphonic acid, and its potassium,
sodium and triethanolamine salts (e.g. Eusolex.RTM. 232),
[0099]
3,3'-(1,4-phenylenedimethylene)-bis(7,7-dimethyl-2-oxobicyclo-[2.2.-
1]hept-1-ylmethanesulphonic acid and salts thereof (e.g.
Mexoryl.RTM. SX) and
[0100]
2,4,6-trianilino(p-carbo-2'-ethylhexyl-1'-oxy)-1,3,5-triazine (e.g.
Uvinul.RTM. T 150)
[0101] 4,4-diaryl butadienes.
[0102] The compounds given in the list are only to be regarded as
examples. It is of course also possible to use other UV
filters.
[0103] These organic UV filters are usually incorporated into
cosmetic formulations in an amount of from 0.5 to 10% by weight,
preferably 1-8%.
[0104] Examples of further suitable organic UV filters are
[0105]
2-(2H-benzotriazol-2-yl)-4-methyl-6-(2-methyl-3-(1,3,3,3-tetramethy-
l-1-(trimethylsilyloxy)disiloxanyl)propyl)phenol (e.g.
Silatriazole.RTM.),
[0106] bis(2-ethylhexyl)
4,4'-[(6-[4-((1,1,-dimethylethyl)aminocarbonyl)ph-
enylamino]-1,3,5-triazine-2,4-diyl)diimino]bis(benzoate) (e.g.
Uvasorb.RTM. HEB),
[0107]
.alpha.-(trimethylsilyl)-.omega.-[(trimethylsilyl)oxy]poly[oxy(dime-
thyl [and approximately 6%
methyl[2-[p-[2,2-bis(ethoxycarbonyl]vinyl]pheno-
xy]-1-methyleneethyl] and about 1.5%
methyl[3-[p-2,2-bis(ethoxycarbonyl)vi- nyl)phenoxy)propenyl) and
0.1 to 0.4% (methylhydrogen)silylene]] (n.apprxeq.60) (CAS No. 207
574-74-1),
[0108]
2,2'-methylenebis(6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbu-
tyl)phenol) (CAS No.103 597-45-1),
[0109] 2,2'-(1,4-phenylene)bis (1H-benzimidazole-4,6-disulphonic
acid, monosodium salt) (CAS No.180 898-37-7) and
[0110]
2,4-bis{[4-(2-ethylhexyloxy)-2-hydroxy]phenyl}-6-(4-methoxyphenyl
)-1,3,5-triazine (CAS No.187 393-00-6).
[0111] These organic UV filters are usually incorporated into
cosmetic formulations in an amount of from 0.5 to 20% to 20% by
weight, preferably 1-15%.
[0112] Conceivable inorganic UV filters are those from the group of
titanium dioxides, such as, for example, coated titanium dioxide
(e.g. Eusolex.RTM. T-2000, Eusolex.RTM. T-AQUA), zinc oxides (e.g.
Sachtotec.RTM.), iron oxides and also cerium oxides. These
inorganic UV filters are usually incorporated into cosmetic
formulations in an amount of from 0.5 to 20% by weight, preferably
2-10%.
[0113] Preferred compounds with UV-filtering properties are
3-(4'-methylbenzylidene)-dl-camphor,
1-(4-tert-butylphenyl)-3-(4-methoxyp- henyl)propane-1,3-dione,
4-isopropyldibenzoylmethane, 2-hydroxy-4-methoxy-benzophenone,
octyl methoxy-cinnamate, 3,3,5-trimethylcyclohexyl salicylate,
2-ethylhexyl 4-(dimethylamino)-benzoate, 2-ethylhexyl
2-cyano-3,3-diphenylacrylate, 2-phenylbenzimidazole-5-sulphonic
acid, and its potassium, sodium and triethanolamine salts.
[0114] The organic or inorganic UV filters can be combined as
desired with the compounds of the formula I. Based on the weight,
the ratio of UV filters to the compounds of the formula I is
preferably chosen between 1:10 and 10:1, in particular between 1:5
and 5:1.
[0115] By combining one or more compounds of the formula I with
further UV filters, the protective action against harmful effects
of UV radiation can be optimized. The combination then demonstrates
both a protective action as antioxidant and also against burns by
UV radiation.
[0116] The protecting action against oxidative stress or against
the effect of free radicals can be further improved if the
formulation comprises one or more further antioxidants.
[0117] There are many tried and tested substances known from the
specialist literature which can be used, e.g. amino acids (e.g.
glycine, histidine, tyrosine, tryptophan) and derivatives thereof,
imidazoles (e.g. urocanic acid) and derivatives thereof, peptides,
such as D,L-carnosine, D-carnosine, L-carnosine and derivatives
thereof (e.g. anserine), carotenoids, carotenes (e.g.
.alpha.-carotene, .beta.-carotene, lycopene) and derivatives
thereof, chlorogenic acid and derivatives thereof, lipoic acid and
derivatives thereof (e.g. dihydrolipoic acid), aurothioglucose,
propylthiouracil and other thiols (e.g. thioredoxin, glutathione,
cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl,
ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl,
.gamma.-linoleyl, cholesteryl and glyceryl esters thereof), and
salts thereof, dilauryl thiodipropionate, distearyl
thiodipropionate, thiodipropionic acid and derivatives thereof
(esters, ethers, peptides, lipids, nucleotides, nucleosides and
salts), and sulphoximine compounds (e.g. buthionine-sulphoximine,
homocysteine-sulphoximine, buthionine-sulphones, penta-, hexa- and
heptathionine-sulphoximine) in very low tolerated doses (e.g. pmol
to pmol/kg), and also (metal) chelating agents, (e.g.
.alpha.-hydroxy fatty acids, palmitic acid, phytic acid,
lactoferrin), .alpha.-hydroxy acids (e.g. citric acid, lactic acid,
malic acid), humic acid, bile acid, bile extracts, bilirubin,
biliverdin, EDTA, EGTA and derivatives thereof, unsaturated fatty
acids and derivatives thereof, vitamin C and derivatives (e.g.
ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl
acetate), tocopherols and derivatives (e.g. vitamin E acetate),
vitamin A and derivatives (e.g. vitamin A palmitate), and coniferyl
benzoate of benzoin resin, rutinic acid and derivatives thereof,
.alpha.-glycosyl rutin, ferulic acid, furfurylideneglucitol,
carnosine, butylhydroxytoluene, butylhydroxyanisole,
nordihydroguaiaretic acid, trihydroxy-butyrophenone, quercetin,
uric acid and derivatives thereof, mannose and derivatives thereof,
zinc and derivatives thereof (e.g. ZnO, ZnSO.sub.4), selenium and
derivatives thereof (e.g. selenomethionine), stilbenes and
derivatives thereof (e.g. stilbene oxide, trans-stilbene
oxide).
[0118] Mixtures of antioxidants are likewise suitable for use in
the cosmetic formulations according to the invention. Known and
commercial mixtures are, for example, mixtures comprising, as
active ingredients, lecithin, L-(+)-ascorbyl palmitate and citric
acid (e.g. Oxynex.RTM. AP), natural tocopherols, L-(+)-ascorbyl
palmitate, L-(+)-ascorbic acid and citric acid (e.g. Oxynex.RTM. K
LIQUID), tocopherol extracts from natural sources, L-(+)-ascorbic
acid and citric acid (e.g. Oxynex.RTM. L LIQUID),
DL-.alpha.-tocopherol, citric acid and lecithin (e.g. Oxynex.RTM.
LM) or butylhydroxytoluene (BHT), L-(+)-ascorbyl palmitate and
citric acid (e.g. Oxynex.RTM. 2004).
[0119] The antioxidants can be combined as desired with the
compounds of the formula I. Based on the weight, the ratio of the
antioxidant to the compounds of the formula I is preferably chosen
between 1:10 and 10:1, in particular between 1:5 and 5:1.
[0120] The formulations according to the invention can comprise
vitamins as further ingredients. Preferably, vitamins and vitamin
derivatives chosen from vitamin A, vitamin A propionate, vitamin A
palmitate, vitamin A acetate, retinol, vitamin B, thiamine chloride
hydrochloride (vitamin B.sub.1), riboflavin (vitamin B.sub.2)
nicotinamide, vitamin C (ascorbic acid), vitamin D, ergocalciferol
(vitamin D.sub.2), vitamin E, DL-.alpha.-tocopherol, tocopherol E
acetate, tocopherol hydrogensuccinate, vitamin K.sub.1, esculin
(vitamin P active ingredient), thiamine (vitamin B.sub.1) nicotinic
acid (niacin), pyridoxine, pyridoxal, pyridoxamine, (vitamin
B.sub.6), pantothenic acid, biotin, folic acid and cobalamine
(vitamin B.sub.12) are present in the cosmetic formulations
according to the invention, particularly preferably vitamin A
palmitate, vitamin C, DL-.alpha.-tocopherol, tocopherol E acetate,
nicotinic acid, pantothenic acid and biotin.
[0121] Furthermore, the formulation according to the invention may
also comprise, as ingredient, ectoin
(2-methyl-1,4,5,6-tetrahydropyrimidine-4-- carboxylic acid) and in
that case effects protection of the Langerhans cells. By adding
1-(2-hydroxyphenyl)alkan-1-one oxime, the formulation according to
the invention develops an antiinflammatory action.
[0122] The cosmetic or pharmaceutical formulation comprising at
least one compound of the formula I is suitable particularly for
protecting the body's cells against oxidative stress, in particular
for reducing skin ageing.
[0123] Also to be regarded as positive are the properties of
compounds having the formula I for use in foodstuffs or as food
supplements or as "functional food". The explanations below given
for foodstuffs also apply analogously to food supplements and to
"functional food".
[0124] The foodstuffs which can be enriched according to the
present invention with one or more compounds of the formula I
include all materials which are suitable for consumption by animals
or for consumption by humans, for example vitamins and provitamins
thereof, fats, minerals or amino acids. (The foodstuffs may be
solid, or else liquid, i.e. be in the form of a drink). Foodstuffs
which can be enriched according to the present invention with one
or more compounds of the formula I are, for example, also
foodstuffs which originate from a single natural source, such as,
for example, sugars, unsweetened juice, nectar or puree from a
single plant species, such as, for example, unsweetened apple juice
(e.g. also a mixture of different types of apple juice), grapefruit
juice, orange juice, stewed apples, apricot nectar, tomato juice,
tomato sauce, tomato puree, etc. Further examples of foodstuffs
which can be enriched according to the present invention with one
or more compounds of the formula I are corn or cereals of a single
plant species and materials which are prepared from such plant
species, such as, for example, cereal syrup, rye flour, wheatmeal
or oat bran. Mixtures of such foodstuffs are also suitable for
being enriched according to the present invention with one or more
compounds of the formula I, for example multivitamin preparations,
mineral substance mixtures or sugared juice. Further examples which
may be mentioned of foodstuffs which can be enriched according to
the present invention with one or more compounds of the formula I
are foodstuff preparations, for example prepared cereals, bakery
products, mixed drinks, foodstuffs prepared specifically for
children, such as yoghurt, diet foodstuffs, low-calorie foodstuffs
or animal feed.
[0125] The foodstuffs which can be enriched according to the
present invention with one or more compounds of the formula I thus
include all palatable combinations of carbohydrates, lipids,
proteins, inorganic elements, trace elements, vitamins, water or
active metabolytes of plants and animals.
[0126] The foodstuffs which can be enriched according to the
present invention with one or more compounds of the formula I are
preferably used orally, e.g. in the form of foods, pills, tablets,
capsules, powders, syrup, solutions or suspensions.
[0127] The foodstuffs according to the invention enriched with one
or more compounds of the formula I can be prepared by techniques
which are well known to the person skilled in the art.
[0128] As a result of their advantageous action, in particular as
antioxidants or as free-radical scavengers, compounds of the
formula I are also suitable as medicaments. In this connection,
they have a supporting or substituting action for natural
mechanisms which scavenge free radicals within the body. With
regard to their activity, the compounds of the formula I may
sometimes be compared with free-radical scavengers such as vitamin
C. Compounds of the formula I can be used, for example, for the
preventative treatment of inflammation and allergies of the skin,
and in certain cases for preventing certain types of cancer.
[0129] Because of their antiallergic, antiinflammatory and
antiirritative effects, compounds of the formula I are suitable in
particular for the preparation of a medicament for the treatment of
inflammations, allergies and irritations, in particular of the
skin.
[0130] In addition, it is possible to prepare medicaments which act
as vein tonics, as agents for increasing the strength of blood
capillaries, as inhibitants for cuperose, as inhibitors of
chemical, physical or actinic erythemas, as agents for treating
sensitive skin, as decongestants, as dehydrating agents, as
weight-loss agents, as antiwrinkle agents, as stimulators of the
synthesis of components of the extracellular matrix, as
strengthening agents for improving elasticity of the skin and as
anti-ageing agents.
[0131] A further subject-matter of the invention relates to the
stabilization of UV filters. A known and high-performance class of
light protection filter substances is formed by the
dibenzoylmethane derivatives. However, a disadvantage is that these
substances are very readily decomposed by UV light and thus lose
their protective properties. One example which may be mentioned of
a commercially available light protection filter from this class of
compound is 4-(tert-butyl)-4'-methox- ydibenzoylmethane, which has
the structure shown below. 7
[0132] Surprisingly, it has now been found that compounds with the
formula I have a very good stabilizing action for the
dibenzoylmethanes, in particular
4-(tert-butyl)-4-methoxybenzoylmethane. A particularly high
stabilizing action has been found for a compound of the formula I
where X=--CH.sub.2-- and R.sup.1=R.sup.2=R.sup.3=R.sup.4=H. By
incorporating mixtures of these compounds into cosmetics, it is now
possible to prepare light protection compositions using
dibenzoylmethanes which, even when subjected to prolonged periods
of solar irradiation, for example during sunbathing for a number of
hours, have no or only a very low reduction in the protective
action against UV rays.
[0133] The invention is illustrated in more detail using
examples.
[0134] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0135] The entire disclosures of all applications, patents and
publications, cited above or below, and of corresponding German
patent application No. 10056400.3, filed Nov. 14, 2000, are hereby
incorporated by reference.
EXAMPLES
Example 1
[0136] Introduction of a protective group on quercetin: 8
[0137] A mixture of quercetin (604 mg, 2 mmol) and diphosphorus
pentoxide (284 mg) in dichloromethane (10 ml) is heated to
75.degree. C. Acetone (0.3 ml) is added dropwise to the suspension,
and the mixture is stirred for a further hour at 75.degree. C.
Following removal of an oily residue, NaOH (25%, 1.5 ml) is added
to the reaction mixture. The isolated organic phase is then washed
with water and obtained by removal of the solvent under reduced
pressure.
Example 2
[0138] 9
[0139] a) Chlorination of 2-phenylbenzimidazole-5-sulphonic
Acid:
[0140] Dimethylformamide Chloride Synthesis:
[0141] Equimolar amounts of thionyl chloride and DMFA are mixed
with cooling. The mixture is left to stand for 30 min at room
temperature and is then evaporated to constant weight at
30-40.degree. C. with the exclusion of moisture in a water-jet
vacuum. This gives a pale yellow-coloured crystal sludge which is
washed with ether.
[0142] Dimethylformamide chloride with
2-phenylbenzimidazole-5-sulphonic acid: 6.2 g of dimethylformamide
chloride and 5 g of 2-phenylbenzimidazole-5-sulphonic acid are
reacted in 120 ml of DMFA at 20.degree. C. for 24 h. Ice is added
to the mixture, which is then extracted with toluene. Following
removal of the solvent, the desired product is obtained by
recrystallization from CH.sub.2Cl.sub.2/hexane.
[0143] b) Reaction of 2-phenylbenzimidazole-5-sulphonyl Chloride
with acetone-protected Quercetin:
[0144] 2-phenylbenzimidazole-5-sulphonyl chloride (2 mol) and
3',4',7-tribenzylquercetin (1 mol) are refluxed in toluene. The
organic phase is then washed with an aqueous solution of potassium
carbonate. Following separation of the organic phase, the desired
product is obtained by removing the solvent under reduced
pressure.
Example 3
[0145] Synthesis of 2-ethylhexyl 4-(dimethylamino)benzoate 10
[0146] Iodine (0.1 mol) and diiodosilane (0.1 mol) are added to a
solution of 2-ethylhexyl 4-(dimethylamino)benzoate (0.1 mol) in
chloroform (5 ml). The reaction mixture is then stirred at
50.degree. C. for 1.5 hours. Removal of the solvent gives
4-(dimethylamino)-2-acyliodide-benzene.
Example 4
[0147] 11
[0148] a) Chlorination of
1-(4-tert-butylphenyl)-3-(4-methoxyphenyl)propan- e-1,3-dione
(Eusolex 9020)
[0149] 1-(4-tert-butylphenyl)-3-(4-methoxyphenyl)propane-1,3-dione
(2.48 g) and acetyl chloride are added to a suspension of zinc (130
mg) in ether (20 ml) under protective gas, and the mixture is
stirred for a further 1.5 hours. The reaction mixture is then
quenched with water. After solid zinc has been removed by means of
filtration, the reaction mixture is washed with ether (5.times.5
ml). The combined organic phases are washed with sodium carbonate
and sodium chloride solution and dried under reduced pressure.
[0150] b) Synthesis of the Ether:
[0151] A mixture of 3',4',7-tribenzylquercetin (3 g),
1-(4-tert-butylphenyl)-3-(4-chlorophenyl)propane-1,3-dione and
K.sub.2CO.sub.3 (30 g) is refluxed in dried acetone (300 ml) for 21
hours. The solution is then suction-filtered, and washing is
carried out a number times with warm acetone. The acetone is
removed from the filtrate under reduced pressure to give the
desired product.
[0152] c) Deprotection:
[0153]
3',4',7-tribenzyl-2-(1-(4-tert-butylphenyl)-3-(4-oxophenyl)propane--
1,3-dione)quercetin is dissolved in 200 ml of methanol and
hydrogenated using 0.3 g of 10% Pd/carbon at 1 bar. Removal of the
catalyst and of the solvent used gives the desired product.
Example 5
[0154] 12
[0155] 1 g of luteolin was introduced into 50 ml of pyridine and 50
ml of CH.sub.2Cl.sub.2, and, at room temperature, 100 ml of
cinnamyl chloride, dissolved in 25 ml of CH.sub.2Cl.sub.2, were
slowly added dropwise. When the addition was complete, the mixture
was stirred for a further 3 hours at room temperature. 100 ml of
H.sub.2O and 50 ml of CH.sub.2Cl.sub.2 were then added, the organic
phase was separated off and the aqueous phase was extracted with
CH.sub.2Cl.sub.2. The combined organic phases were washed with
water, 2N hydrochloric acid and aqueous sodium carbonate solution,
and then dried. Following distillation of the solvent and
recrystallization from toluene, fine white crystals were
obtained.
[0156] Yield: 2.16 g (83% of theory)
Example 6
[0157] 13
[0158] 1 g of troxeluteolin and 50 ml of pyridine were introduced
into 70 ml of CH.sub.2Cl.sub.2. A solution of 10 ml of cinnamyl
chloride in 50 ml of CH.sub.2Cl.sub.2 was then slowly added
dropwise at room temperature. When the addition was complete, the
reaction mixture was stirred for a further 3 hours. 50 ml of water
were added, and the organic phase was separated off and washed with
water, 2N hydrochloric acid and again with water and then aqueous
calcium carbonate solution. The organic phase was dried and then
the solvent was distilled off under reduced pressure.
Recrystallization from toluene gave a pale beige powder.
[0159] Yield: 1.09 g (67.3% of theory).
Example 7
[0160] 14
[0161] 0.5 g of luteolin and 50 ml of pyridine were introduced into
25 ml of CH.sub.2Cl.sub.2, and 1.026 g of trans-p-methoxycinnamyl
chloride in 25 ml of CH.sub.2Cl.sub.2 was slowly added dropwise at
room temperature. When the addition was complete, the reaction
mixture was stirred for a further 8 hours. 100 ml of water and 200
ml of CH.sub.2Cl.sub.2 were added, the organic phase was separated
off and the aqueous phase was extracted with CH.sub.2Cl.sub.2. The
combined organic phases were washed with water, 2N hydrochloric
acid and saturated sodium chloride solution.
[0162] The solvent was distilled off under reduced pressure.
Recrystallization from toluene gave a pale yellow powder.
[0163] Yield: 0.48 g (39% of theory).
Example 8
[0164] 15
[0165] 0.5 g of troxeluteolin and 25 ml of pyridine were introduced
into 20 ml of CH.sub.2Cl.sub.2 and then 0.9838 g of
trans-methoxycinnamyl chloride in 20 ml of CH.sub.2Cl.sub.2 were
slowly added dropwise at room temperature. When addition was
complete, the mixture was stirred for a further 8 hours. 100 ml of
H.sub.2O and 50 ml of CH.sub.2Cl.sub.2 were added, the organic
phase was separated off and the aqueous phase was extracted with
CH.sub.2Cl.sub.2. The combined organic phases were washed with
water, 2N hydrochloric acid and again with water. Following drying,
the solvent was distilled off under reduced pressure.
Recrystallization from toluene gave a pale yellow powder.
[0166] Yield: 0.63 g (59% of theory).
[0167] Exemplary compositions of cosmetic formulations are given
below.
[0168] The compounds prepared in Examples 2 and 7 are used for the
preparation of the compositions. Here, "compound 2" means the
compound prepared in Example 2 and "compound 7" means the compound
prepared in Example 7.
Example 1
[0169]
1 Care lotion (W/O) for application to the skin % by wt A Compound
7 1.00 Polyglyceryl-2 dipolyhydroxystearate 5.00 Beeswax 0.50 Zinc
stearate 0.50 Hexyl laurate 9.00 Cetyl isononanoate 6.00 Shea
butter 0.50 DL-.alpha.-Tocopherol acetate 1.00 B Glycerol 5.00
Magnesium sulphate heptahydrate 1.00 Preservative q.s. Water,
demineralized ad 100.00
[0170] Preparation:
[0171] Phase A is heated to 75.degree. C. and phase B is heated to
80.degree. C. With stirring, phase B is slowly added to phase A.
Following homogenization, the mixture is cooled with stirring. At a
temperature of 40.degree. C., perfume substances are added.
[0172] The preservatives used are:
[0173] 0.05% of propyl 4-hydroxybenzoate
[0174] 0.15% of methyl 4-hydroxybenzoate
Example 2
[0175]
2 Care lotion (W/O) for application to the skin % by wt A
Polyglyceryl-2 dipolyhydroxystearate 5.00 Beeswax 0.50 Zinc
stearate 0.50 Hexyl laurate 9.00 Cetyl isononanoate 6.00 Shea
butter 0.50 DL-.alpha.-Tocopherol acetate 1.00 B Compound 2 1.00
Glycerol 5.00 Magnesium sulphate heptahydrate 1.00 Preservative
q.s. Water, demineralized ad 100.00
[0176] Preparation:
[0177] Phase A is heated to 75.degree. C. and phase B is heated to
80.degree. C. With stirring, phase B is slowly added to phase A.
Following homogenization, the mixture is cooled with stirring. At a
temperature of 40.degree. C., perfume substances are added.
[0178] The preservatives used are:
[0179] 0.05% of propyl 4-hydroxybenzoate
[0180] 0.15% of methyl 4-hydroxybenzoate
Example 3
[0181]
3 Skin cream (O/W) % by wt A Paraffin 2.00 Isohexadecane 2.00
Isopropyl palmitate 3.00 Soya oil 0.50 Dimethicone 1.00 Cetyl
alcohol 1.00 Sorbitol stearate 1.50 Cetyl alcohol (and) cetyl
glucoside 4.00 (-)-.alpha.-Bisabolol 0.30 B Water, demineralized ad
100.00 Compound 2 1.00 Glycerol 87% 10.00 D-Panthenol 0.50
(D+)-Biotin 0.05 Preservative q.s. C Xanthan gum 0.30 D Perfume
0.20
[0182] Preparation:
[0183] Phase A and phase B are heated separately to 75.degree. C.
Phase C is then slowly added to phase B and stirred until
homogenized. The resulting B/C mixture is added to phase A at a
temperature of 75.degree. C., and the mixture is homogenized.
Perfume substances are added after cooling to 35.degree. C.
[0184] The preservatives used are:
[0185] 0.05% of propyl 4-hydroxybenzoate
[0186] 0.15% of methyl 4-hydroxybenzoate
[0187] 0.30% of Germall 115 (ISP, Frechen)
Example 4
[0188]
4 A Compound 7 1.00 Paraffin 2.00 Isohexadecane 2.00 Isopropyl
palmitate 3.00 Soya oil 0.50 Dimethicone 1.00 Cetyl alcohol 1.00
Sorbitol stearate 1.50 Cetyl alcohol (and) cetyl glucoside 4.00
(-)-.alpha.-Bisabolol 0.30 B Water, demineralized ad 100.00
Glycerol 87% 10.00 D-Panthenol 0.50 (D+)-Biotin 0.05 Preservative
q.s. C Xanthan gum 0.30 D Perfume 0.20
[0189] Preparation:
[0190] Phase A and phase B are heated separately to 75.degree. C.
Phase C is then slowly added to phase B and stirred until
homogenized. The resulting B/C mixture is added to phase A at a
temperature of 75.degree. C. and the mixture is homogenized. After
cooling to 35.degree. C., perfume substances are added.
[0191] The preservatives used are:
[0192] 0.05% of propyl 4-hydroxybenzoate
[0193] 0.15% of methyl 4-hydroxybenzoate
[0194] 0.30% of Germall 115 (ISP, Frechen)
Example 5
[0195]
5 Sunscreen spray (O/W) % by wt A Compound 7 1.00 Eusolex .RTM.
2292 (Art. No. 105382) 7.50 Eusolex .RTM. HMS (Art. No. 111412)
7.00 Steareth-2 0.40 Steareth-10 0.80 Pemulen .RTM. TR-2 1.18
Propylene glycol isoceteth-3 acetate 5.00 Performa .RTM. V 825 0.80
Dimethicone 1.00 Oxynex .RTM. K (Art. No. 108324) 0.10 B Eusolex
.RTM. 232 (Art. No. 105372) 1.00 Triethanolamine 0.90
1,2-propanediol 2.00 Preservative 0.50 Water, demineralized ad
100.00 Eusolex .RTM. 2292, Eusolex .RTM. HMS and Eusolex .RTM. 232
are UV filters which are sold by Merck KGaA, Darmstadt. Pemulen
.RTM. TR-2 is an acrylate alkyl acrylate polymer which is sold by
Goodrich, Neuss, Performa .RTM. V825 is a synthetic wax which is
sold by New Phase, NJ08554, Oxynex .RTM. K is a mixture of PEG-8,
tocopherol, ascorbyl palmitate, ascorbic acid and citric acid and
is sold by Merck KGaA, Darmstadt.
[0196] Preparation:
[0197] Phase B:
[0198] The water is mixed with the triethanolamine and then
Eusolex.RTM. 232 is added with stirring. As soon as everything has
dissolved, the further constituents of phase B are added and then
the mixture is heated to 80.degree. C.
[0199] Phase A:
[0200] The constituents of phase A, with the exception of
Pemulen.RTM. TR-2, are combined and heated to 80.degree. C. The
Pemulen.RTM. TR-2 is then added with stirring.
[0201] Preparation of the Sunscreen Composition:
[0202] Phase B is slowly added with stirring to phase A. Following
homogenization, the mixture is cooled with stirring.
[0203] The preservatives used were:
[0204] 0.05% of propyl 4-hydroxybenzoate
[0205] 0.15% of methyl 4-hydroxybenzoate
Example 6
[0206]
6 Sunscreen spray (O/W) % by wt A Eusolex .RTM. 2292 (Art. No.
105382) 7.50 Eusolex .RTM. HMS (Art. No. 111412) 7.00 Steareth-2
0.40 Steareth-10 0.80 Pemulen .RTM. TR-2 0.18 Propylene glycol
isoceteth-3 acetate 5.00 Performa .RTM. V 825 0.80 Dimethicone 1.00
Oxynex .RTM. K (Art. No. 108324) 0.10 B Compound 2 1.00 Eusolex
.RTM. 232 (Art. No. 105372) 1.00 Triethanolamine 0.90
1,2-propanediol 2.00 Water, demineralized ad 100.00
[0207] Preparation:
[0208] Phase B:
[0209] The water is mixed with the triethanolamine and then
Eusolex.RTM. 232 is added with stirring. As soon as everything has
dissolved, the further constituents of phase B are added and then
the mixture is heated to 80.degree. C.
[0210] Phase A:
[0211] The constituents of phase A, with the exception of
Pemulen.RTM. TR-2, are combined and heated to 80.degree. C. The
Pemulen.RTM. TR-2 is then added with stirring.
[0212] Preparation of the Sunscreen Composition:
[0213] Phase B is slowly added to phase A with stirring. Following
homogenization, the mixture is cooled with stirring.
[0214] The preservatives used are:
[0215] 0.05% of propyl 4-hydroxybenzoate
[0216] 0.15% of methyl 4-hyrdoxybenzoate
Example 7
[0217]
7 Sunscreen gel (aqueous) % by wt A Compound 7 1.00 Eusolex .RTM.
232 (Art. No. 105372) 4.00 Sodium hydroxide solution 6.00 Glycerol
3.00 1,2-propanediol 2.00 Preservative q.s. Water, demineralized ad
100.00 B Carbomer Ultrez-10 0.70 Water, demineralized 60.00 C
Sodium hydroxide solution (10%) 1.50 Water, demineralized 4.00
Carbomer Ultrez-10 is supplied by Goodrich, Neuss, Germany.
[0218] Preparation:
[0219] Carbomer Ultrez-10 is completely dispersed in the water of
phase B. Phase C is then slowly added and homogenized.
[0220] For phase A, the water is firstly added to the sodium
hydroxide solution and then the Eusolex.RTM. 232 is added and
completely dissolved with stirring. After a clear solution has been
obtained, the further constituents of phase A are added. Phase A is
then added in portions to the mixture of phases B and C, the
mixture being homogenized after each addition.
[0221] The preservative used is:
[0222] 0.20% of methyl 4-hydroxybenzoate
Example 8
[0223]
8 Sunscreen gel (O/W) % by wt A Compound 7 1.00 Eusolex .RTM. 6300
(Art. No. 5385) 0.75 Luvitol .RTM. EHO 10.00 Dimethicone 2.00 Shea
butter 5.00 Antaron .RTM. V-220 2.00 Oxynex .RTM. K 1.00 B Eusolex
.RTM. 232 (Art. No. 5372) 0.75 Tris(hydroxymethyl)aminome- thane
0.33 Preservative q.s. Water, demineralized 20.00 C
Tris(hydroxymethyl)aminomethane 1.20 Water, demineralized 10.00 D
Pemulen .RTM. TR-1 0.60 Water, demineralized ad 100.00 Pemulen
.RTM. TR-1 is an acrylate/C.sub.[lacuna]-- C.sub.[lacuna]-alkyl
acrylate polymer which is sold by Goodrich, Neuss, Germany, Eusolex
.RTM. 6300 is a UV filter which is sold by Merck KGaA, Darmstadt,
Germany, Luvitol .RTM. EHO is sold by BASF AG, Ludwigshafen,
Germany, Antaron .RTM. V-220 is sold by GAF, Frechen, Germany.
[0224] Preparation:
[0225] The Pemulen.RTM. TR-1 is dissolved in the water of phase D.
The tris(hydroxymethyl)aminomethane is dissolved in the water of
phase C and the solution is added to phase D. The
tris(hydroxymethyl)aminomethane is dissolved in the water of phase
B and then the Eusolex.RTM. 232 is added with stirring. After an
aqueous solution has been obtained, the further constituents of
phase B are added and then phase B is added to the mixture of
phases C and D and homogenized. The constituents of phase A are
combined and heated. Phase A is then added to the mixture of the
other phases with homogenization.
[0226] The preservatives used are:
[0227] 0.05% of propyl 4-hydroxybenzoate
[0228] 0.15% of methyl 4-hydroxybenzoate
Example 9
[0229]
9 Sunscreen gel (O/W) % by wt A Eusolex .RTM. 6300 (Art. No. 5385)
0.75 Luvitol .RTM. EHO 10.00 Dimethicone 2.00 Shea butter 5.00
Antaron .RTM. V-220 2.00 Oxynex .RTM. K liquid (Art. No. 8324) 1.00
B Compound 2 1.00 Eusolex .RTM. 232 (Art. No. 5372) 0.75
Tris(hydroxymethyl)aminomethane 0.33 Preservative q.s. Water,
demineralized 20.00 C Tris(hydroxymethyl)aminomethane 1.20 Water,
demineralized 10.00 D Pemulen .RTM. TR-1 0.60 Water, demineralized
ad 100.00
[0230] Preparation:
[0231] The Pemulen.RTM. TR-1 is dissolved in the water of phase D.
The tris(hydroxymethyl)aminomethane is dissolved in the water of
phase C and the solution is added to phase D. The
tris(hydroxymethyl)aminomethane is dissolved in the water of phase
B and then the Eusolex.RTM. 232 is added with stirring. After a
clear solution has been obtained, the further constituents of phase
B are added and then phase B is added to the mixture of phases C
and D and homogenized. The constituents of phase A are combined and
heated. Phase A is then added to the mixture of the other phases
with homogenization.
[0232] The preservatives used are:
[0233] 0.05% of propyl 4-hydroxybenzoate
[0234] 0.15% of methyl 4-hydroxybenzoate
Example 10
[0235]
10 Sunscreen lotion (W/O) with UVA/B protection % by wt A Compound
7 1.00 Eusolex .RTM. 2292 (Art. No. 1.05382) 3.00 Eusolex .RTM.
4360 (Art. No. 1.05376) 2.00 Dehymuls .RTM. E 6.00 Hydrogenated
castor oil 1.00 Beeswax 2.00 Oleyl erucate 6.00 Decyl oleate 6.00
Dicapryl ether 5.00 Dimethicone 1.00 B Glycerol (87%) 5.00
Magnesium sulphate heptahydrate 1.00 Preservative q.s. Water,
demineralized ad 100.00 Dehymuls .RTM. E is a mixture of dicocoyl
pentaerythrityl citrate, sorbitol sesquioleate, beeswax and
aluminium stearate and is sold by Henkel KGaA, Dusseldorf,
Germany.
[0236] Preparation:
[0237] The constituents of phases A and B are mixed in each case.
Phase A is heated to 75.degree. C. and phase B is heated separately
to 80.degree. C. Phase B is added to phase A with homogenization.
The mixture is then cooled with stirring.
[0238] The preservatives used are:
[0239] 0.05% of propyl 4-hydroxybenzoate
[0240] 0.15% of methyl 4-hydroxybenzoate
Example 11
[0241]
11 Sunscreen lotion (W/O) with UVA/B protection % by wt A Eusolex
.RTM. 2292 (Art. No. 1.05382) 3.00 Eusolex .RTM. 4360 (Art. No.
1.05376) 2.00 Dehymuls .RTM. E 6.00 Hydrogenated castor oil 1.00
Beeswax 2.00 Oleyl erucate 6.00 Decyl oleate 6.00 Dicapryl ether
5.00 Dimethicone 1.00 B Compound 2 1.00 Glycerol (87%) 5.00
Magnesium sulphate heptahydrate 1.00 Preservative q.s. Water,
demineralized ad 100.00
[0242] Preparation:
[0243] The constituents of phases A and B are mixed in each case.
Phase A is heated to 75.degree. C. and phase B is heated separately
to 80.degree. C. Phase B is added to phase A with homogenization.
The mixture is then cooled with stirring.
[0244] The preservatives used are:
[0245] 0.05% of propyl 4-hydroxybenzoate
[0246] 0.15% of methyl 4-hydroxybenzoate
[0247] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0248] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *