U.S. patent application number 10/338313 was filed with the patent office on 2003-06-19 for methods and compositions for inhibiting free radical polymerization in skin and hair.
This patent application is currently assigned to Fan Tech, Ltd.. Invention is credited to O'Lenick, Anthony J. JR., Wohlman, Alan.
Application Number | 20030114532 10/338313 |
Document ID | / |
Family ID | 22750389 |
Filed Date | 2003-06-19 |
United States Patent
Application |
20030114532 |
Kind Code |
A1 |
Wohlman, Alan ; et
al. |
June 19, 2003 |
Methods and compositions for inhibiting free radical polymerization
in skin and hair
Abstract
A method is provided for inhibiting free radical degradation in
the skin of a human or nonhuman animal comprising contacting the
skin with a skin treatment composition having a concentration of a
1-(3-methoxybenzyl)-3-s- ubstituted thiourea compound effective for
inhibiting free radical generation. Skin protecting compositions
comprising a free radical inhibiting concentration of a
1-(3-methoxybenzyl)-3-substituted thiourea compound, and optionally
a sunscreeen composition, are also provided.
Inventors: |
Wohlman, Alan; (Northbrook,
IL) ; O'Lenick, Anthony J. JR.; (Dacula, GA) |
Correspondence
Address: |
Keith D. Parr
LORD, BISSELL & BROOK
115 South LaSalle Street
Chicago
IL
60603
US
|
Assignee: |
Fan Tech, Ltd.
|
Family ID: |
22750389 |
Appl. No.: |
10/338313 |
Filed: |
January 8, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10338313 |
Jan 8, 2003 |
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09725560 |
Nov 29, 2000 |
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6545052 |
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60202562 |
May 10, 2000 |
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Current U.S.
Class: |
514/585 ;
514/587 |
Current CPC
Class: |
A61Q 17/00 20130101;
A61K 2800/522 20130101; A61Q 5/00 20130101; A61Q 19/00 20130101;
C11B 5/0042 20130101; A61K 8/46 20130101; A61Q 17/04 20130101 |
Class at
Publication: |
514/585 ;
514/587 |
International
Class: |
A61K 031/17 |
Claims
We claim:
1. A method for inhibiting free radical degradation of skin or hair
of a human or nonhuman animal comprising contacting the skin or
hair with a composition comprising a
1-(3-methoxybenzyl)-3-substituted thiourea compound of formula I
4in a concentration which is effective to inhibit free radical
polymerization, wherein R is selected from the group consisting of
C.sub.1-C.sub.20 linear or branched alkyl; C.sub.5-C.sub.7
cycloalkyl; alkoxy-substituted C.sub.5-C.sub.7 cycloalkyl;
hydroxy-substituted C.sub.5-C.sub.7 cycloalkyl; C.sub.6-C.sub.7
aryl; hydroxy-substituted C.sub.6-C.sub.7 aryl; and
alkoxy-substituted C.sub.6-C.sub.7 aryl.
2. A method according to claim 1 wherein the composition comprises
between about 0.01% and 5% by weight of a compound of formula
I.
3. A method according to claim 2 wherein the composition comprises
between about 0.1% and 2% by weight of a compound of formula I.
4. A method according to claim 1 wherein the composition comprises
an oil that contains at least one compound of formula I.
5. A method according to claim 4 wherein the composition is an
emulsion.
6. A method according to claim 4 wherein the oil is meadowfoam seed
oil.
7. A method according to claim 1 wherein R is selected from the
group consisting of (i) C.sub.1-C.sub.20 linear alkyl, (ii)
hydroxy-substituted C.sub.6-C.sub.7 aryl and (iii)
alkoxy-substituted C.sub.6-C.sub.7 aryl moieties.
8. A method according to claim 1 wherein the compound of formula I
is selected from the group consisting of 1,3-di(3-methoxybenzyl)
thiourea; 1-(3-methoxybenzyl)-3-ethyl-2-thiourea;
1-(3-methoxybenzyl)-3-propyl-2-th- iourea;
1-(3-methoxybenzyl)-3-hexyl-2-thiourea; 1-(3-methoxybenzyl)-3-dode-
cyl-2-thiourea; 1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea;
and 1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea.
9. A method according to claim 1 wherein the compound of formula I
is 1,3-di(3-methoxybenzyl) thiourea.
10. A method according to claim 1 wherein the composition is a skin
treatment composition.
11. A method according to claim 1 wherein the composition is hair
treatment composition.
12. A composition for inhibiting free radical degradation of skin
or hair of a human or nonhuman animal comprising a base composition
and an amount of a 1-(3-methoxybenzyl)-3-substituted thiourea
compound of formula I 5which is sufficient to provide a
concentration of the compound of formula I effective to inhibit
free radical polymerization, wherein R is selected from the group
consisting of C.sub.1-C.sub.20 linear or branched alkyl;
C.sub.5-C.sub.7 cycloalkyl; alkoxy-substituted C.sub.5-C.sub.7
cycloalkyl; hydroxy-substituted C.sub.5-C.sub.7 cycloalkyl;
C.sub.6-C.sub.7 aryl; hydroxy-substituted C.sub.6-C.sub.7 aryl; and
alkoxy-substituted C.sub.6-C.sub.7 aryl.
13. A composition according to claim 12 which comprises between
about 0.01% and 5% by weight of a compound of formula I.
14. A composition according to claim 12 which comprises between
about 0.1% and 2% by weight of a compound of formula I.
15. A composition according to claim 12 which comprises an oil that
contains at least one compound of formula I.
16. A composition according to claim 15 wherein the composition is
an emulsion.
17. A composition according to claim 15 wherein the oil is
meadowfoam seed oil.
18. A composition according to claim 12 wherein R is selected from
the group consisting of (i) C.sub.1-C.sub.20 linear alkyl, (ii)
hydroxy-substituted C.sub.6-C.sub.7 aryl and (iii)
alkoxy-substituted C.sub.6-C.sub.7 aryl moieties.
19. A composition according to claim 12 which is selected from the
group consisting of 1,3-di(3-methoxybenzyl) thiourea;
1-(3-methoxybenzyl)-3-eth- yl-2-thiourea;
1-(3-methoxybenzyl)-3-propyl-2-thiourea;
1-(3-methoxybenzyl)-3-hexyl-2-thiourea;
1-(3-methoxybenzyl)-3-dodecyl-2-t- hiourea;
1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea; and
1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea.
20. A composition according to claim 12 which is a skin treatment
composition.
21. A composition according to claim 12 which is a hair treatment
composition.
22. A composition according to claim 12 which further comprises an
effective concentration of a sunscreen compound.
23. A composition according to claim 12 wherein the compound of
formula I is 1,3-di(3-methoxybenzyl) thiourea.
24. A composition according to claim 22 which comprises an oil
containing the compound of formula I.
25. A composition according to claim 24 wherein the composition is
an emulsion.
26. A composition according to claim 24 wherein the oil is
meadowfoam seed oil.
27. A composition according to claim 24 which further comprises an
effective concentration of a sunscreen compound.
Description
FIELD OF THE INVENTION
[0001] This invention relates to novel thiourea compounds for use
in personal care product applications, such as skin care and hair
care products, to protect the skin and hair from degradation caused
by free radical polymerization and oxidation.
BACKGROUND OF THE INVENTION
[0002] This is a continuation-in-part of U.S. Provisional
Application Serial No. 60/202,562, filed May 10, 2000, which is
incorporated herein by reference.
[0003] Skin and hair are exposed to a variety of environmental
factors that tend to degrade it. These include but are not limited
to sun exposure, exposure to ozone, smog and other airborne
pollutants. These conditions cause the skin to wrinkle, dry out,
turn scaly and in extreme cases develop disease states like
melanoma. Hair becomes brittle and dry and is cosmetically
unappealing. The present invention relates to a new series of free
radical inhibitors that protect the skin and hair from the
deleterious effects of these environmental conditions.
[0004] The ultraviolet (UV) wavelengths of sunlight can cause
sunburn (erythema) and blistering (edema). Exposure to ultraviolet
light can also cause the skin to feel dry and taut in moderate
doses, and to peel if exposed to higher doses. These acute, or
short term, effects are readily perceptible and oftentimes
uncomfortable and painful. While the exposure of the skin to the
damaging effects of the sun can cause potential health problems,
the exposure of hair to the sun can cause the hair to become
dehydrated, weakened, and, in some instances, bleached. Hair that
is damaged by sun exposure may become cosmetically
unacceptable.
[0005] Human skin can be protected from some of these environmental
effects. Moisturizers can readily reverse the appearance of dryness
regardless of whether it results from low humidity conditions or UV
light, and relieve the tautness of the skin caused by UV light
exposure. These products either attract moisture from the
environment to the skin's surface, or reduce the amount of
evaporative loss from the surface of the skin. These products also
add needed moisture to the skin from the formulation itself, and
add a layer of emollients on the skin surface to leave it softer
and more supple.
[0006] According to the free radical theory of premature aging of
the skin, ultraviolet light can produce reactive oxygen species
(ROS) that damage the skin. ROS are a collection of reactive free
radicals produced from the oxygen molecule, and include singlet
oxygen, the superoxide radical, hydrogen peroxide, and the hydroxyl
radical, as well as the reaction products produced by these free
radicals. Due to their reactivity, ROS relatively indiscriminately
react with other molecules, and generate a cascade of harmful free
radical reactions in the skin.
[0007] The skin possesses certain defense mechanisms against the
generation of ROS. These defenses include the presence of enzymes
such as superoxide dismutase, catalase, glutathione transferase,
glutathione peroxidase and glutathione reductase, as well as
antioxidants such as tocopherols, ubiquinone, ubiquinol, ascorbic
acid and dehydroascorbic acid. Unfortunately, ultraviolet light
entering the skin can easily overwhelm these defense systems, such
that the amount of superoxide dismutase and glutathione transferase
in the skin declines significantly upon irradiation with solar
ultraviolet light. Simultaneous with the loss of these reducing
enzymes, there is a dramatic increase in conjugated double bonds
formed in the skin from the linoleates present in cell membranes.
There is also an increase in thiobarbituric acid reactive
substances present in the skin, which represent a collection of
molecules that are formed from ROS.
[0008] Since sunscreens are unable to completely protect the skin
against the adverse effects of ultraviolet radiation, alternative
modes of protection have been proposed. Vitamins, such as Vitamin E
acetate, have been shown to make the skin softer and smoother after
topical application, which can offset some of the damaging effects
of the sun. Vitamin A palmitate has been shown to create smoother
skin and help enhance the process of cellular turnover. This
enhancement rids the skin of the outermost dead layer of skin by
bringing more youthful appearing skin cells to the surface. Other
materials, such as hyaluronic acid and pyrrolidone carboxylic acid
(PCA), have also been used for their ability to enhance the
moisture binding capacity of the skin and therefore lead to
smoother, softer skin.
[0009] Compositions that incorporate Vitamins A or E, or their
derivatives, in sunscreen compositions, are shown in U.S. Pat. Nos.
4,454,112; 5,532,805; and 5,378,461. The use of Vitamin C in
combination with Vitamins A, E, B and other agents in a skin
protectant composition, is described in U.S. Pat. No. 4,938,960. An
antioxidant preparation that is said to protect the skin against
harmful ultraviolet radiation is disclosed in U.S. Pat. No.
5,607,921, and contains Vitamin C, in combination with Vitamins A
and E, and monosaccharide or amide precursors. Sunscreen
compositions containing panthenol and other agents are disclosed in
U.S. Pat. Nos. RE 33,845; 5,505,935; 5,445,823; and 5,573,754. The
antioxidant effect of superoxide dismutase when externally applied
to the skin to protect against the effects of ultraviolet radiation
is also described in U.S. Pat. No. 5,601,806.
[0010] In spite of advances in recent years in the protection of
skin from harmful ultraviolet radiation, the epidemic of skin
cancer and skin damage from the effects of this radiation has
continued unabated. The loss of portions of the ozone layer from
environmental pollution is believed to have contributed to an
increase in ambient ultraviolet radiation that reaches exposed
skin. There is a significant need for commercially acceptable or
improved preparations that can be topically applied expecially to
human and animal skin, to offset the harmful effects of ultraviolet
radiation.
SUMMARY OF THE INVENTION
[0011] The present invention relates to the discovery that certain
1-(3-methoxybenzyl)-3-substituted thiourea compounds and
compositions containing same, when applied topically to the skin or
hair of a human or nonhuman animal, inhibit free radical
degradation (i.e., degradation caused by free radical
polymerization of natural compounds present in skin tissue or
hair), and oxidation of the skin or hair. The
1-(3-methoxybenzyl)-3-substituted thiourea compounds are soluble in
oils and alcohols and the like, and may desirably be provided in an
oil based composition, or in the oil phase of an emulsion, which
can be applied to the skin or hair.
[0012] The present invention thus entails a method for protecting
skin or hair from free radical polymerization and degradation,
which comprises contacting the skin or hair with a concentration of
a 1-(3-methoxybenzyl)-3-substituted thiourea compound of formula I
which is effective to inhibit free radical polymerization, 1
[0013] wherein R is a C.sub.1-C.sub.20 linear or branched alkyl
such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl, pentyl, hexyl, octyl, decyl, nonyl, dodecyl, and the
like, C.sub.5-C.sub.7 cycloalkyl, such as cyclopentyl, cyclohexyl
or cycloheptyl and the like, C.sub.6-C.sub.7 aryl such as phenyl or
benzyl and the like, hydroxy- or alkoxy-substituted C.sub.6-C.sub.7
aryl such as hydroxyphenyl, methoxyphenyl, etboxyphenyl,
hydroxybenzyl, methoxybenzyl, ethoxybenzyl. Among compounds of the
formula I, a presently preferred free radical inhibiting compound
is 1,3-di(3-methoxybenzyl) thiourea, i.e., a compound of formula I
wherein R is a 3-methoxybenzyl moiety. The compound,
1,3-di(3-methoxybenzyl) thiourea, has been identified as an
antioxidant in meadowfoam seed oil as disclosed in U.S. Provisional
Patent Application No. 60/202562, filed May 10, 2000, which is
incorporated herein by this reference.
[0014] The present invention also provides skin treatment
compositions comprising between about 0.01 wt. % and about 5 wt. %,
preferably between about 0.1 wt. % and about 2 wt. %, of a free
radical inhibiting compound of formula I in an appropriate base
composition such as a moisturizing composition, skin lotion,
sunscreen lotion, sunblock lotion, or the like. Hair treatment
compositions are also provided which comprise between about 0.01
wt. % and about 5 wt. %, preferably between about 0.1 wt. % and
about 2 wt. %, of a free radical inhibiting compound of formula I
in an appropriate base composition such as a hairspray, gel, mousse
or the like. As used herein, the term "base composition" includes
cosmetic base compositions for skin and base compositions for hair
which may be conventionally provided as oils, oil-in-water
emulsions, water-in-oil emulsions, oil-in-water-in-oil (O/W/O)
emulsions, microemulsions, gels or the like.
[0015] Presently preferred compounds of formula I for use in
accordance with the present inventions are 1,3-di(3-methoxybenzyl)
thiourea; 1-(3-methoxybenzyl)-3-ethyl-2-thiourea;
1-(3-methoxybenzyl)-3-propyl-2-th- iourea;
1-(3-methoxybenzyl)-3-hexyl-2-thiourea; 1-(3-methoxybenzyl)-3-dode-
cyl-2-thiourea; 1-(3-methoxybenzyl)-3-(4-hydroxyphenyl)-2-thiourea;
and 1-(3-methoxybenzyl)-3-(3-methoxyphenyl)-2-thiourea. The free
radical inhibiting activity of the compounds of formula I diminish
the deleterious effects of environmental factors when applied to
the skin alone, or desirably in combination with one or more
sunscreen compositions. 1,3-di(3-methoxybenzyl) thiourea is a
particularly preferred free radical inhibitor compound. Meadowfoam
seed oil may be used as an ingredient in emulsion or the like to
provide an effective free radical inhibitor concentration of 1,3
di(3-methoxybenzyl) thiourea.
DETAILED DESCRIPTION OF THE INVENTION
[0016] In one of its aspects, the present invention entails a
method of protecting the skin or hair of a human or nonhuman animal
from free radical degradation comprising contacting the skin or
hair with an amount of a 1-(3-methoxybenzyl)-3-substituted thiourea
compound of the formula I 2
[0017] in a concentration which is sufficient to inhibit free
radical degradation wherein R is selected from the group consisting
of C.sub.1-C.sub.20 linear or branched alkyl; C.sub.5-C.sub.7
cycloalkyl; alkoxy-substituted C.sub.5-C.sub.7 cycloalkyl;
hydroxy-substituted C.sub.5-C.sub.7 cycloalkyl; C.sub.6-C.sub.7
aryl; hydroxy-substituted C.sub.6-C.sub.7 aryl; and
alkoxy-substituted C.sub.6-C.sub.7 aryl. In a particularly
preferred embodiment, the substituted aryl moiety is a
3-hydroxy-substituted or 3-alkoxy-substituted aryl compound.
[0018] In another of its aspects, the present invention entails a
skin treatment composition or hair treatment composition capable of
inhibiting free radical degradation of the skin or hair, which
comprises a skin cosmetic base composition or hair cosmetic base
composition, which contains a concentration of a
1-(3-methoxybenzyl)-3-substituted thiourea compound of the formula
I 3
[0019] which is effective to inhibit free radical degradation of
the skin or hair, wherein R is selected from the group consisting
of C.sub.1-C.sub.20 linear or branched alkyl; C.sub.5-C.sub.7
cycloalkyl; hydroxy- or alkoxy-substituted C.sub.5-C.sub.7
cycloalkyl; C.sub.6-C.sub.7 aryl; and hydroxy- or
alkoxy-substituted C.sub.6-C.sub.7 aryl. The skin or hair treatment
composition of the invention may optionally be supplemented with
one or more conventional sunscreen compositions, vitamins, or other
compounds useful for protecting skin or hair from the degradative
effects of ultraviolet radiation. The novel thiourea derivatives
according to formula I are described in U.S. Provisional Patent
Application No. 60/202562, filed May 10, 2000, which is
incorporated herein by this reference.
[0020] As used herein, "C.sub.1-C.sub.20 linear or branched alkyl"
shall include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, 2-methyl-pentyl, 3-methyl-penyl, hexyl, octyl,
decyl, dodecyl, and the like. The term "C.sub.5-C.sub.7 cycloalkyl"
shall include cyclopentyl, cyclohexyl and cycloheptyl. The term
"hydroxy- or alkoxy-substituted C.sub.5-C.sub.7 cycloalkyl" shall
include cyclopentyl, cyclohexyl and cycloheptyl moieties that are
substituted with an hydroxy, methoxy, ethoxy, or propoxy group or
the like. The term "C.sub.6-C.sub.7 aryl" shall include phenyl and
benzyl. The term "hydroxy- or alkoxy-substituted C.sub.6-C.sub.7
aryl" shall include phenyl and benzyl moieties that are substituted
with an hydroxy, methoxy, ethoxy, or propoxy group or the like.
[0021] Compounds of the formula I may be synthesized by reacting
3-methoxybenzylamine and an appropriately selected isothiocyanate
compound of the formula II S.dbd.C.dbd.N--R, wherein R is defined
the same as for compounds of formula I. The reaction may be carried
out by slowly adding the isothiocyanate to an aqueous solution of
3-methoxybenzylamine, preferably under a nitrogen atmosphere. The
thiourea product of the reaction, which is a compound of formula I,
may be recovered and purified by mixing the reaction products with
a solvent that is not miscible with water but one that is a solvent
for the thiourea, such as methylene chloride, chloroform, toluene
or diethyl ether. The water layer may or may not be acidified to
enhance separation and recovery of the thiourea compound of the
invention. The thiourea, dissolved in the solvent layer can be
drawn off from the water layer, dried and the resulting crude
thiourea purified by recrystallization in an appropriate solvent
such as ethanol. See, Example 1. See also, generally, the procedure
of Moore and Crossley, Organic Synthesis 2, 617-618 (note 4).
[0022] The reactants, 3-methoxybenzylamine and an appropriate
isothiocyanate compound as defined above, may be obtained
commercially or synthesized by routine methods known in the art,
and the resultant product compounds of formula I may be readily
isolated by routine methods well-known to those having ordinary
skill in the art. Suitable isothiocyanate reactants for
synthesizing compounds of the present invention may be obtained as
well-known in the art from degradation of glucosinolates present in
seed oils and other lipids. In an aqueous solution containing the
enzyme thioglucosidase, glucosinolate compounds are degraded into
isothiocyanates and other degradation products. See, Vaughn, et
al., J. Chem. Ecol. 22, 1939-49 (1996); and C. VanEtten and H.
Tookey, (1983) Glucosinolates, pp. 15-30 in M. Rechcigl (ed.)
"Naturally Occurring Food Toxicants," CRC Press, Boca Raton, Fla.
The isothiocyanate fraction of the glucosinolate breakdown products
thus may be isolated and reacted with 3-methoxybenzylamine as
described above to provide compounds of the present invention.
Approximately 100 glucosinolate compounds have been identified in
plants from 11 different plant families including mustard,
rapeseed, cabbage, garlic mustard and crambe (S. F. Vaughn, 1999.
Glucosinolates as Natural Pesticides in Biologically Active Natural
Products: Agrochemicals, H. G. Cutler and S. J. Cutler, Eds, CRC
Press, Boac Raton, Fla.) Oils isolated from glucosinolate
containing plants are normally deodorized by steam sparging to
remove volatile compounds which includes isothiocyanates and
amines. Thus, a variety of isothiocyanate compounds and benzylamine
compounds may be obtained from the waste distillation product
generated in the process of purifying such oils and employed as
reactants in synthesizing compounds of the present invention.
[0023] 3-methoxybenzylamine may be purchased commercially or may be
isolated from meadowfoam seed oil by extraction into an immiscible
acidified aqueous layer which is separated from the oil, washed
with a nonpolar solvent, treated with a base to lower pH, and the
amine extracted into an immiscible solvent. The
3-methoxybenzylamine compound may be further purified by
crystallization from ethanol or similar solvent and/or purified by
reverse-phase HPLC using a C18 column, eluting with a gradient
starting at 100% methanol and proceeding to about 80% methanol:20%
chloroform. The peak containing 3-methoxybenzylamine may be
identified by its retention time on the HPLC column in comparison
to the retention time for a known standard sample of
3-methoxybenzylamine. Other natural amines may be purchased
commercially or may be similarly extracted from natural sources and
purified with reference to known standard samples and/or identified
by standard chemical methods for identification of amines (e.g.,
chromatography, infrared spectroscopy, mass spectroscopy, elemental
analysis, nuclear magnetic resonance analysis and the like).
[0024] The phrase "an effective concentration of a free radical
inhibitor" or "concentration which is effective to inhibit free
radical degradation" as used herein means a concentration of a free
radical inhibitor compound that is capable of reducing the amount
of free radical polymerization of a polymerizable compound as
compared to the amount of free radical polymerization obtained in
the absence of the free radical inhibitor compound. Methods of
determining the ability of a compound to inhibit a free radical
polymerization reaction are well known in the art.
[0025] A presently preferred method for determining the free
radical inhibitory capacity of a compound is based on the ability
of such a compound to inhibit free radical polymerization of
acrylic acid to polyacrylic acid. A suitable assay for
demonstrating an effective concentration of a selected free radical
inhibitor compound is an assay which determines the ability of such
a compound to inhibit the polymerization of a 30% aqueous solution
of acrylic acid at 85.degree. C. after initiation with 0.1%
azobisisobutyrylnitrile. The inhibitory capacity of such a compound
is determined by comparing the percent of polyacrylic acid formed
in the presence and absence of a predetermined concentration of the
selected free radical inhibitor compound, with inhibition being
demonstrated by a detectable decrease in the amount of polyacrylic
acid formed in the reaction mixture containing the inhibitor as
compared to the amount of polyacrylic acid formed in the reaction
mixture to which an inhibitor was not added. As will be
appreciated, the amount of polyacrylic acid formed is inversely
related to the amount of acrylic acid (i.e., monomer) remaining in
the reaction mixture at the end of the assay. The amount of acrylic
acid may be routinely determined by measuring the iodine value of
the reaction mixture or by other methods known in the art for
determinating unsaturation. A well-known free radical inhibitor
compound such as hydroquinone mono methyl ether (HQMME) may be used
as a standard inhibitor compound in the assay.
[0026] The compounds of formula I herein are potent inhibitors of
free radical polymerization, as well as scavengers of
hydroperoxides which are known precursors to free radicals. The
compounds of formula I also desirably absorb UV radiation at a
wavelength of 280 nm. Due to their ability to inhibit free radical
degradation, the compounds of formula I are capable of imparting
free radical inhibition activity to the skin or hair in accordance
with the methods of the present invention. Free radical degradation
can be initiated and propagated even in the presence of an
effective sunscreen composition. Thus, in one embodiment of the
present invention, skin care compositions contain an effective
concentration of a compound of formula I sufficient to inhibit free
radical degradation, as well as an effective concentration of a
sunscreen composition for absorbing UV light. The free radical
inhibitor compounds of formula I and the sunscreen compounds have
activities that are complementary to one another. Among the well
known sunscreen compositions (and the preferred percentages (w/w)
that provide effective sunscreen protection), which may be used in
accordance with the present invention, are UVA absorbers, including
oxybenzone (2-6%), sulisobenzone (5-10%), dioxybenzone (3%), methyl
anthranilate (3.5-5%), UVB absorbers, including aminobenzoic acid
(5-15%), amyldimethyl PABA (1-5%), 2-ethoxyethyl p-methoxycinnamate
(1-3%), diethanolamine p-methoxycinnamate (8-10%), digalloyl
trioleate (2-5%), ethyl 4-bis(hydroxypropyl) aminobenzoate (1-5%),
2-ethylhexyl-2-cyano-3,3-diphenylacrylate (7-10%), ethylhexyl
p-methoxycinnamate (2-7.5%), 2-ethylhexyl salicylate (3-5%),
glyceryl aminobenzoate (2-3%), homomenthyl salicylate (4-15%),
lawsone with dihydroxyacetone (0.25% with 33%), octyldimethyl PABA
(1.4-8%), 2-phenylbenzimidazole-5-sulfonic acid (1-4%),
triethanolamine salicylate 5-12%), and the physical UV absorbers,
red patrolatum (30-100%) and titanium dioxide (2-25%).
[0027] The free radical inhibiting compounds, alone or in
combination with a suitable suncreen compound, may be included into
a variety of skin care or hair care compositions. It is presently
contemplated that the free radical inhibitor compounds of formula I
will be dissolved in an oil, lipid or alcohol which is used to
prepare a skin treatment composition or a hair treatment
composition of the invention. Suitable base compositions for
preparing the skin or hair treatment compositions of the invention
include lotions, liquids, creams, ointments, and the like, which
may be conventionally provided as oils, oil-in-water emulsions,
water-in-oil emulsions, oil-in-water-in-oil emulsions,
microemulsions, liposomes or the like as are well known in the art.
Various compositions useful for skin treatment or for hair
treatment, which can be used (with or without the sunscreen
compositions being added) to deliver compounds of formula I to the
skin or hair may be prepared from the disclosures in for example,
U.S. Pat. Nos. 4,115,547; 4,172,122; 4,454,112; 4,567,038;
4,592,906; 4,663,157; 4,847,267; 4,938,960 and 5,980,871. The
Examples that follow provide skin treatment compositions of the
invention including free radical inhibitor compounds of the formula
I.
[0028] The following nonlimiting examples are illustrative of the
invention.
EXAMPLE 1
[0029] This example demonstrates the synthesis of
1,3-di-(3-methoxybenzyl) thiourea. To a three neck, 100-ml flask
fitted with a condenser, a rubber syringe septum and a nitrogen
inlet was added 20-ml water and 3.6 g (25.8 mmol) of
3-methoxybenzyl amine. The reaction vessel was purged with nitrogen
and stirred with a Teflon-coated magnetic stir bar. 3-methoxybenzyl
isothiocyanate 2.59 ml (3.0 g, 16.7 mmol) was then added dropwise
(approx. 1 drop/5-10 sec) from a glass syringe. A separate layer
forms and the mixture was stirred for 1 additional hour at room
temperature. The water layer was acidified with 1 M HCl (about 10
ml) to pH 5.5. Methylene chloride, (15 ml) was then added and the
two layers transferred to a separator funnel. The lower layer
(methylene chloride) was removed. The water layer was washed with
methylene chloride twice more with 10 ml of methylene chloride. The
methylene chloride layers were combined and washed with 0.1 M HCl
and then water. The methylene chloride solution was dried over 3A
molecular sieves and then evaporated to dryness in a rotating
solvent evaporator. The resulting viscous liquid was taken up in 20
ml ethanol that had been heated to 35.degree. C. and the product
recrystallized by cooling in a refrigerator twice from ethanol as
white crystals, dried in vacuum at room temperature and weighed. A
second recrystallization was made from the mother liquor to
retrieve additional product for a yield of 79.8% in the first
crystal batch and 83.2% for the combined batches of crystals.
Analysis of the product by NMR, mass spectroscopy and elemental
analysis revealed the product to be 1,3-di-(3methoxybenzyl)
thiourea.
EXAMPLE 2
[0030] The method described in example 1 is repeated except that
0.8 grams of methylamine is substituted for the
3-methoxybenzylamine.
EXAMPLE 3
[0031] The method described in example 1 is repeated except that
1.1 grams of ethylamine is substituted for the
3-methoxybenzylamine.
EXAMPLE 4
[0032] The method described in example 1 is repeated except that
2.6 grams of hexylamine is substituted for the
3-methoxybenzylamine.
EXAMPLE 5
[0033] The method described in example 1 is repeated except that
4.1 grams of decylamine is substituted for the
3-methoxybenzylamine.
EXAMPLE 6
[0034] The method described in example 1 is repeated except that
4.8 grams of dodecylamine is substituted for the
3-methoxybenzylamine.
EXAMPLE 7
[0035] The method described in example 1 is repeated except that
5.5 grams of CH.sub.3(CH.sub.2).sub.13NH.sub.2 is substituted for
the 3-methoxybenzylamine.
EXAMPLE 8
[0036] The method described in example 1 is repeated except that
6.9 grams of CH.sub.3(CH.sub.2).sub.17NH.sub.2 is substituted for
the 3-methoxybenzylamine.
EXAMPLE 9
[0037] The method described in example 1 is repeated except that
7.7 grams of CH.sub.3(CH.sub.2).sub.19NH.sub.2 is substituted for
the 3-methoxybenzylamine
EXAMPLE 10
[0038] This example demonstrates the free radical inhibitor
activity of 1,3-di(3-methoxybenzyl)thiourea. Into each of three 250
ml beakers, labeled "1," "2," and "3" respectively, is added 200 ml
of a 30% solution of acrylic acid (in water). One-tenth gram of
1,3-di(3-methoxybenzyl)thio- urea was dissolved 9.9 grams isopropyl
alcohol to give a 1% (w/w) solution of the free radical inhibitor
compound. One-tenth gram of the known free radical inhibitor
hydroquinone mono methyl ether was dissolved in 9.9 grams isopropyl
alcohol to give a 1% solution to be used as a positive control to
demonstrate that the assay is capable of detecting inhibition of
free radical polymerization. One-tenth gram of
azobisisobutyronitrile (a free radical initiator) was dissolved in
9.9 grams of isopropyl alcohol to provide a 1% solution of the free
radical initiator. To beaker 1, containing 200 ml of the acrylic
acid solution was added 0.6 ml of the 1% solution of
1,3-di(3-methoxybenzyl)thiourea. To beaker 2, containing 200 ml of
the acrylic acid solution was added 0.6 ml of the 1% solution of
hydroquinone mono methyl ether. To beaker 3 was added 0.6 ml of
isopropyl alcohol (no inhibitor). Beakers 1, 2 and 3 containing the
acrylic acid solution, with or without inhibitor compound added
thereto, were heated to 85.degree. C. on a hot plate and 0.2 ml of
the 0.1% solution of azobisisobutyrlnitrile was then added to each
beaker to initiate the free radical polymerization reaction. After
3 hours, the beakers were removed from the hot plate to stop the
reaction from progressing further, and the amount of acrylic acid
which remained in the reaction mixture was determined by measuring
the iodine value of an aliquot of the reaction mixture using the
A.O.C.S. Method Tg 1a-64T in Official Methods And Recommended
Practices Of The AOCS, by American Oil Chemists' Society,
Champaign, Ill. The results showed that the free radical
polymerization reaction was strongly inhibited by
1,3-di(3-methoxybenzyl)thiourea.
1 Beaker % Polymerization No. Inhibitor Compound (after 3 hours at
85.degree. C.) 1 1,3-di(3-methoxybenzyl)- thiourea 48.6% 2
hydroquinone mono methyl ether 78.6% 3 Control (no inhibitor)
84.8%
EXAMPLE 11
[0039] The free radical inhibition assay described in Example 10 is
carried out as described except that the
1-(3-methoxybenzyl)-3-substitute- d thiourea compounds of Examples
2-9 are separately tested, and the results show that the compounds
of Examples 2-9 are effective inhibitors of free radical
polymerization.
EXAMPLE 12
[0040] A skin treatment composition containing 1,3
di-(3-methoxybenzyl)thi- ourea as the free radical inhibitor is
prepared by blending 66 grams of mineral oil (B.P.) with 2.0 grams
of 1,3-di-(3-methoxybenzyl) thiourea, 3.0-grams of 2-ethylhexyl
palmitate, 27.0 grams of isopropyl myristate and an effective
amount of a suitable fragrance.
EXAMPLE 13
[0041] A skin treatment composition containing 1,3
di-(3-methoxybenzyl)thi- ourea as the free radical inhibitor is
prepared by blending 66 grams of meadowfoam seed oil, 3.0-grams of
2-ethylhexyl palmitate, 27.0 grams of isopropyl myristate and an
effective amount of a suitable fragrance.
EXAMPLE 14
[0042] Example 13 is repeated except that the meadowfoam seed oil
is supplemented with 1.0 gram of exogenously added 1,3
di-(3-methoxybenzyl)thiourea that is conventionally blended into
the meadowfoam seed oil prior to preparing the skin treatment
composition.
EXAMPLE 15
[0043] A skin treatment composition containing a free radical
inhibitor and a sunscreen compound (homosalate) is prepared from
Preparation A and Preparation B as follows.
2 Preparation A Preparation B Lanolin 5.00 g Methylparaben 0.10 g
Homosalate 8.00 g Edetate Disodium 0.05 g White Petrolatum 2.50 g
Propylene Glycol 5.00 g Stearic Acid 4.00 g Triethanolamine 1.00 g
Propylparaben 0.50 g Purified Water U.S.P. 74.30 G 1,3-di
(3-methoxybenzyl)- 2.00 g thiourea
[0044] Preparation A and Preparation B are heated separately to 77
to 82.degree. C. with constant stirring until the content of each
are solubilized. Then Preparation A is added slowly to Preparation
B with constant stirring. Stirring is continued at room temperature
(15 to 30.degree. C.) until the emulsion formed is cooled to room
temperature. Purified water is added to obtain 100 gram of the skin
treatment composition.
[0045] The present invention has been described herein with some
specificity and with reference to certain preferred embodiments
thereof. Those persons having ordinary skill in the art will
appreciate variations, modifications and substitutions which may be
made to what has been described without departing from the scope
and spirit of the invention which is defined by the following
claims. The publications, technical specifications and patents
which have been cited herein are hereby incorporated into this
document by this reference.
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