U.S. patent application number 09/833047 was filed with the patent office on 2002-01-17 for long-acting, chemical-resistant skin emollients, moisturizers, and strengtheners.
Invention is credited to Chow, Carmen, Hartman, Rosemarie F., Rose, Cathryn M., Rose, K. Daniel, Rose, Seth D..
Application Number | 20020006421 09/833047 |
Document ID | / |
Family ID | 22079442 |
Filed Date | 2002-01-17 |
United States Patent
Application |
20020006421 |
Kind Code |
A1 |
Rose, Seth D. ; et
al. |
January 17, 2002 |
Long-acting, chemical-resistant skin emollients, moisturizers, and
strengtheners
Abstract
The present invention relates to compounds that are two-part
molecules, and compositions containing such compounds, in which one
part is designed to become covalently bonded to the skin (bonding
agent) and the other part (a characteristic use agent) is designed
to impart some characteristic use, such as emolliency, moisturizing
effect, anti-acne, anti-wrinkle, anti-pain, antimicrobial,
antifungal, antiviral, anti-irritation, skin tanning and skin
lightening effects, extended protection of the skin (e.g., from
ultraviolet light, by incorporation of a sunscreen component; from
toxic and/or irritating substances; from insects and skin
parasites, by incorporation of insecticides and/or insect
repellants; from free radicals or other agents, as in aging, by
incorporation of antioxidants), or dyeing of hair, skin nails, wool
or fur. The covalently bonded part may also be useful to impart
skin strengthening effect (e.g., from shear forces) or as wound
healing agents.
Inventors: |
Rose, Seth D.; (Tempe,
AZ) ; Hartman, Rosemarie F.; (Tempe, AZ) ;
Chow, Carmen; (Gilbert, AZ) ; Rose, Cathryn M.;
(Healdsburg, CA) ; Rose, K. Daniel; (Healdsburg,
CA) |
Correspondence
Address: |
BAKER & BOTTS
30 ROCKEFELLER PLAZA
NEW YORK
NY
10112
|
Family ID: |
22079442 |
Appl. No.: |
09/833047 |
Filed: |
April 11, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09833047 |
Apr 11, 2001 |
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09151360 |
Sep 10, 1998 |
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6284258 |
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60067943 |
Dec 8, 1997 |
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Current U.S.
Class: |
424/401 ;
424/59 |
Current CPC
Class: |
A61K 8/46 20130101; A61Q
17/00 20130101; A61Q 17/02 20130101; A61Q 17/04 20130101; A61P
17/10 20180101; A61K 2800/94 20130101; A61Q 19/08 20130101; A61Q
19/00 20130101; A61K 2800/522 20130101; Y10S 514/844 20130101; A61P
39/06 20180101; C08G 65/334 20130101; A61Q 19/04 20130101; A61K
8/86 20130101 |
Class at
Publication: |
424/401 ;
424/59 |
International
Class: |
A61K 007/42; A61K
007/00 |
Claims
We claim:
1. A skin care compound comprising at least one bonding agent and
at least one characteristic use agent, wherein said bonding agent
is selected from the group consisting of crotonyl thiol esters,
sorbyl thiol esters, and mixtures thereof, and wherein said
characteristic use agent is a chemical moiety selected from the
group consisting of emollients and skin soothing agents,
moisturizers, sunscreens, insecticides, antibacterials, fungicides,
skin lightening agents, artificial tanning agents, free-radical
scavengers, antivirals, anti-acne agents, artificial tanning
agents, anti wrinkle and anti-skin atrophy agents, antioxidants,
and mixtures thereof.
2. A skin care compound according to claim 1 wherein said bonding
agent is selected from the group consisting of crotonyl thiol
esters, sorbyl thiol esters, and mixtures thereof; and wherein said
characteristic use agent is selected from the group consisting of
emollients and skin soothing agents, moisturizers, sunscreens,
insecticides, antibacterials, fungicides, skin lightening agents,
artificial tanning agents, free-radical scavengers, antivirals,
anti-acne agents, artificial tanning agents, anti wrinkle and
anti-skin atrophy agents, antioxidants, and mixtures thereof.
3. A skin care compound according to claim 1 wherein said skin care
compound is characterized by the formula 33wherein y is 1 or 2; and
X is the characteristic use agent.
4. A skin care compound according to claim 1 wherein said skin care
compound is characterized by the formula 34wherein each y is
independently 1 or 2; and X is the characteristic use agent.
5. A skin care composition comprising: a cosmetically acceptable
carrier; and a skin care compound comprising at least one bonding
agent and at least one characteristic use agent, wherein said
bonding agent is selected from the group consisting of crotonyl
thiol esters, sorbyl thiol esters, and mixtures thereof, and
wherein said characteristic use agent is a chemical moiety selected
from the group consisting of emollients and skin soothing agents,
moisturizers, sunscreens, insecticides, antibacterials, fungicides,
skin lightening agents, artificial tanning agents, free-radical
scavengers, antivirals, anti-acne agents, artificial tanning
agents, anti wrinkle and anti-skin atrophy agents, antioxidants,
and mixtures thereof.
6. A skin care composition according to claim 5 wherein said
bonding agent is selected from the group consisting of crotonyl
thiol esters, sorbyl thiol esters, and mixtures thereof; and
wherein said characteristic use agent is selected from the group
consisting of emollients and skin soothing agents, moisturizers,
sunscreens, insecticides, antibacterials, fungicides, skin
lightening agents, artificial tanning agents, free-radical
scavengers, antivirals, anti-acne agents, artificial tanning
agents, anti wrinkle and anti-skin atrophy agents, antioxidants,
and mixtures thereof.
7. A skin care composition according to claim 5 wherein said skin
care compound is characterized by the formula 35wherein y is 1 or
2; and X is the characteristic use agent.
8. A skin care composition according to claim 5 wherein said skin
care compound is characterized by the formula 36wherein each y is
independently 1 or 2; and X is the characteristic use agent.
9. A skin care composition according to claim 5 further comprising
a catalytic amount of base.
10. A skin care composition according to claim 9, wherein said base
is selected from the group consisting of aliphatic, heterocyclic
and aromatic amines, imines, salts of organic and inorganic acids,
and mixtures thereof.
11. A skin care composition according to claim 10 wherein said base
is selected from the group consisting of
1,5-diazabicyclo[4.3.0]non-5-ene, bicarbonate, carbonate,
triethanolamine, phosphate, and mixtures thereof.
12. A method of conferring a skin care benefit by applying to
mammalian skin a skin care compound comprising at least one bonding
agent and at least one characteristic use agent, wherein said
bonding agent is selected from the group consisting of crotonyl
thiol esters, sorbyl thiol esters, and mixtures thereof, and
wherein said characteristic use agent is selected from the group
consisting of emollients and skin soothing agents, moisturizers,
sunscreens, insecticides, antibacterials, fungicides, skin soothing
agents, skin lightening agents, artificial tanning agents,
free-radical scavengers, antivirals, anti-acne agents, artificial
tanning agents, anti wrinkle and anti-skin atrophy agents,
antioxidants, and mixtures thereof.
13. A method according to claim 12 wherein said skin care compound
is selected from the group consisting of 37and mixtures thereof;
wherein each y is independently 1 or 2; and X is the characteristic
use agent.
Description
FIELD OF THE INVENTION
[0001] This invention relates to compounds that are two-part
molecules in which one part is designed to become covalently bonded
to skin (bonding agent) and the other part (a characteristic use
agent) is designed to impart some characteristic use, such as
emolliency, moisturizing effect, anti-acne, anti-wrinkle,
anti-pain, antibacterial, antifungal, antiviral, anti-irritation,
skin tanning and skin lightening effects, extended protection of
the skin (e.g., from ultraviolet light, by incorporation of a
sunscreen component; from toxic and/or irritating substances; from
insects and skin parasites, by incorporation of insecticides and/or
insect repellants; from free radicals or other agents, as in aging,
by incorporation of antioxidants), or dyeing of hair, skin, nails,
wool or fur. The covalently bonded part may also be useful to
impart skin strengthening effect (e.g., from shearing forces) or as
wound healing agents. The invention also relates to a method of
attaching the characteristic use agent to a water insoluble
substrate such as fibers that contain or have been modified to
contain a chemical group that can covalently react with the bonding
agent.
BACKGROUND OF THE INVENTION
[0002] The entire surface of the human body is covered by a layer
of skin, which is considered to be the largest organ in the body.
It serves as a barrier between the internal organism and the
external environment, to prevent toxic materials from entering into
the body and to retard excessive body water loss. In addition, it
also plays a major role in temperature regulation, vitamin
synthesis, excretion, sensory perception, and processing of
antigenic substances.
[0003] The skin consists of three major layers of tissue. From
inside out, the layers are the subcutaneous tissue, the dermis, and
the epidermis.
[0004] The epidermis is the most superficial layer of the skin. It
is divided into a living inner layer of viable cells (stratum
Malpighii) and an outermost laminated sheet of dry anucleate
flattened horny cells (stratum corneum or horny layer).
[0005] The lowermost cell layer of the epidermis (stratum basale or
stratum germinativum) consists of the basal cells. Basal cells are
continually moving up to the surface of the skin and undergo
modification in a process called keratinization, and are eventually
shed. The normal cell turnover time from the stratum basale to the
skin surface and shedding is approximately twenty-eight days. The
stratum spinosum lies immediately over the basal layer. This
stratum consists of several layers of cells, and the shape of these
spinous cells becomes progressively more flattened in a plane
parallel to the surface of the skin as they move outward. Above the
spinous cells is the stratum granulosum, which consists of one to
three layers of cells. The granular layer is most highly developed
in the regions where abundant keratin is produced. Keratins are
fibrous and insoluble proteins which are largely responsible for
the toughness of the protective outer covering of the skin. The
next stratum is the stratum lucidum, which consists of cells that
are on the way to becoming the flat, anucleate and dead cells that
constitute the stratum corneum. The stratum corneum is formed and
continuously replenished by the slow upward migration of cells from
the germinative basal layer of the epidermis. The entire stratum
corneum is replaced about every two weeks in mature adults.
[0006] The condition of dry and chapped skin, which afflicts
everyone at some time, is visually characterized as a slight
roughening and less flexibility in the feel of the skin surface.
Among dermatologists, this condition is called xerosis, in which
the skin loses its suppleness, forming cracks and fissures.
Environmental factors play an important role in bringing about this
condition. Decreased humidity contributes to water loss from the
skin surface, dry and cold winds increase evaporation by
convection, and low temperatures decrease stratum corneum
extensibility. The increased use of synthetic detergents also helps
to dehydrate the stratum corneum.
[0007] The physical appearance of the skin is solely governed by
the state of the stratum corneum. It has been demonstrated that the
prime factor responsible for dry skin is the lowered moisture
content of the stratum corneum. The factors that influence the
state of hydration of the stratum corneum can be classified into
three general categories: the rate at which water reaches the
stratum corneurn from layers beneath it; the rate at which water
leaves the skin surface by evaporation; and the ability of the
stratum corneum to hold moisture.
[0008] The stratum corneum receives water from the sweat glands and
from the underlying tissues by diffusion. At the same time, it
loses water to the environment by evaporation. Under normal
conditions, the rate at which water diffuses from the underlying
tissues to the skin surface is slow and uniform. Experiments
indicate that the major barrier against water loss over most areas
of the body is a very thin barrier at the base of the stratum
corneum, which separates the stratum corneum from the easily
available water of the underlying tissues and makes it dependent
upon the surrounding environment for the moisture. As a result, at
low relative humidity, when water tends to be lost from the surface
at a more rapid rate, the stratum corneum will tend to dry out.
[0009] The softness and flexibility of the skin is determined by
the moisture content of the stratum corneum. Contrary to older
beliefs, the amount of oil in the stratum corneum is not the
essential factor in controlling the physical appearance of the
skin. Thus pieces of hardened stratum corneum immersed in various
oils do not regain their flexibility, whereas immersion in water
increases their flexibility. However, the removal of the surface
lipids of the skin after organic solvent treatment also brings
about the feeling of dryness. This phenomenon demonstrates the
water-holding ability of the skin lipids.
[0010] Various kinds of lipids are located in the intercellular
region of the stratum corneum, which are called the intercellular
lipids or the stratum corneum lipids. Stratum corneum lipids are
composed mainly of ceramides, free fatty acids, and cholesterol,
with small proportions of triglycerides, sterol esters, and
cholesterol sulfate. The sphingolipid content is reported to reveal
a direct relationship with permeability to water, while the neutral
lipids are also suggested to make a definite contribution to the
water-retention properties of the stratum corneum. Lipid
compositions of different cell populations in pig epidermis are
disclosed by Goldsmith, ed., Biochemistry and Physiology of the
Skin, Oxford University Press, New York and Oxford, 1983, 364.
[0011] Dermal components of humans and animals have received much
attention in the hope of identifying markers of biologic aging. The
dermis is composed mainly of highly stable fibers, predominantly
collagen and about 5% elastin fibers. Collagen has high tensile
strength and prevents the skin from being torn by overstretching.
Elastin is an elastic protein that maintains normal skin tension.
It is the collagen-elastin fiber network that gives the skin its
strength and elasticity. Hall (1976) The Aging of Connective
Tissue, Academic Press, New York used "the rods and elastic band"
model to demonstrate the network of the collagen bundles in human
skin. The collagen bundles are loosely arranged in a rhomboid
network with individual bundles lying at angles to one another.
Intertwined amongst the collagen bundles lie single elastin fibers.
The network of collagen bundles can be distorted by the application
of a force in one direction, but it returns to its original form
when the force is removed, in exactly the same fashion that a
network of rigid rods will resume its shape if each crossing point
is restricted by an elastic band.
[0012] Both the collagen bundles and the elastin fibers seem to
undergo characteristic changes with time. Imayama and Braverman
(1989) Am. J. Pathol. 134:1019 reported that there is a dynamic
rearrangement of the collagen and elastic fibers during the growth
period of rats. The collagen bundles uncoil, thicken and develop a
lattice pattern of relatively straight bundles with age. As the
collagen bundles straighten, however, they bend and dislocate the
elastin fibers. During adulthood, elastin fibers become
increasingly tortuous and impart a frayed or porous appearance to
the skin surface. The elastin fibers become more stretched and
therefore a decrease in their original elasticity results. These
phenomena lead to the looseness, sagging and wrinkling of aged
skin.
[0013] Skin care products can be used to prevent excessive water
loss or to restore the high moisture content of the stratum
corneum. There are two groups of cosmetic products available for
the treatment of dry skin conditions, emollients and
moisturizers.
[0014] Emollients, often termed skin conditioners, increase and
maintain hydration by lubricating or occluding the skin surface.
They reduce the evaporative loss of water from the outside of the
skin and cause a buildup of water in the stratum corneum.
Emollients include a very wide range of compounds. They are all
water-insoluble materials. Petrolatum is the most efficient
emollient for protecting dry skin. Lanolin (a fatty secretion from
sheep's wool, which consists of a mixture of fatty acid esters of
the sterols, lanosterol and agnosterol), fatty acids, fatty
alcohols, triglyceride esters, wax esters, and esters of polyhydric
alcohols are all common emollients. Idson (1992) Cosm. & Toil.
107: 69.
[0015] Moisturizers are composed of hygroscopic substances. They
often contain humectants, substances that attract moisture to the
skin, such as urea, glycerin, propylene glycol, sorbitol,
pyrrolidone carboxylic acid (PCA), or sodium lactate, to impart or
restore moisture to the stratum corneum. Loden et al. (1994)
"Product Testing--Testing of Moisturizers" in Bioengineering of the
Skin: Water and the Stratum Corneum, Elsner et al., eds., CRC
Press, Boca Raton, Fla., 275.
[0016] In order to evaluate moisturizer efficacy, and the
irritation and barrier destruction potentials of soaps and
solvents, the term "transepidermal water loss" (TEWL) was
introduced. It is used to indicate the amount of water vapor
passing through the stratum corneum by passive diffusion. In other
words, TEWL is a true reflection of stratum corneum barrier
function for water only in the absence of sweat gland activity.
Rothman, "Insensible Water Loss" in Physiology and Biochemistry of
the Skin, University of Chicago, 1954, 233.
[0017] The mathematical principle governing the diffusion of water
through stratum corneum is Fick's law. TEWL is calculated according
to the following integrated form:
J.sub.s=K.sub.MD (c.sub.s/.delta.) eqn. 1
[0018] where J.sub.2=steady state flux of water (g
cm.sup.-2s.sup.-1);
[0019] K.sub.m=partition coefficient;
[0020] D=diffusion coefficient of water (cm.sup.2 s.sup.-1);
[0021] .delta.=thickness of the membrane (cm);
[0022] c.sub.s=concentration gradient of water across the stratum
corneum (g cm.sup.-3).
[0023] The water content of the innermost layer of the stratum
corneum is in equilibrium with the adjacent moist granular layer,
which is in turn in equilibrium with the drier environment
surrounding the skin. Thus, there exists a concentration gradient
of water within the stratum corneum that results in a continuous
diffusion of water from within the body through the skin and into
the environment. The wetter the surface layer, the smaller the
concentration gradient and the smaller should be the TEWL.
[0024] Upon hydration, the stratum corneum thickness .delta.
increases due to swelling of the tissue; the diffusivity D also
increases with increasing water content. Thus, the net result of a
change in stratum corneum hydration on TEWL is not always
predictable. However, in healthy skin, D usually predominates and
TEWL increases.
[0025] The introduction of the partition coefficient K.sub.m into
equation 1 takes account of the fact that in the diffusion process
the concentrations at the surfaces of the membrane are not
necessarily equal to the concentrations in the external solutions.
K.sub.m is defined as K.sub.m=c.sub.m/c.sub.s, where
c.sub.m=concentration of H.sub.2O in the membrane (g H.sub.2O
cm.sup.-3 of wet tissue); and c.sub.5=concentration of H.sub.2O in
the solution (g H.sub.2O cm.sup.-3 of solution). Blank et al.
(1984) J. Invest. Dermatol. 188.
[0026] It is an objective of the present invention to provide a
compound that is capable of conferring a long-lasting skin care
benefit. Currently available skin care products do not offer the
convenient, long-term effects of the present invention. It is a
further object of the present invention to provide a long-lasting
compound that can be used in treating and preventing a dry skin
condition, strengthening skin, or providing protection against UV
light, for example by inducing a nucleophilic addition reaction to
occur between the skin and the agent that provides these
emolliency, moisturizing, strengthening or UV-protective effects.
As a result, the agent is covalently bonded to skin proteins.
Because new cells are continually being produced from the stratum
basale to be shed, eventually, from the surface the binding period
may last for possibly weeks to maintain the hydration and
strengthening of the skin. Periodic application of the agent
affords a virtually continuous maintenance of the beneficial
effects, as the modified proteins work their way to the surface and
reside in all the upper layers.
SUMMARY OF INVENTION
[0027] The present invention provides compounds that comprise at
least one bonding agent and at least one characteristic use agent.
The bonding agent is a chemical moiety which is capable of
covalently bonding to one or more proteins in skin. The
characteristic use agent is a chemical moiety which is capable of
providing a skin care benefit. Skin care benefit, as used herein,
means a cosmetic effect imparted by a particular characteristic use
agent, such as but not limited to, the ability to provide
emolliency, moisturing effect, or skin protectant effect, etc.
[0028] In certain embodiments, the bonding agent is selected from
the group consisting of a crotonyl thiol ester, a sorbyl thiol
ester or any other suitable .alpha., .beta.-unsaturated ester or
thiol ester, and mixtures thereof; and the characteristic use agent
is selected from the group consisting of emollients and skin
soothing agents, moisturizers, sunscreens, insecticides,
antibacterial agents, fungicides, antiviral agents, skin lightening
agents, anti-acne agents, artificial tanning agents, free-radical
scavengers, antioxidants, and mixtures thereof.
[0029] In a further embodiment the characteristic use agent can be
connected to the bonding agent by a labile or cleavable linkage,
resulting in a slow or long-term release of the characteristic use
agent into the skin.
[0030] Exemplary compounds include octadecyl
S-sorbyl-3-mercaptopropionate (hereinafter "OSM"), octadecyl
S-crotonyl-3-mercaptopropionate (hereinafter "OCM"),
S-crotonyl-.omega.-mercapto[poly(ethylene glycol)] (hereinafter
"CPEG"), S,S'-dicrotonyl-.alpha.-thio-.omega.-mercapto[poly(-
ethylene glycol)] (hereinafter "DCPEG"),
S-sorbyl-.omega.-mercapto[poly(et- hylene glycol)] (hereinafter
"SPEG"), and S,S'-disorbyl-.alpha.-thio-.omeg-
a.-mercapto[poly(ethylene glycol)] (hereinafter "DSPEG"),
S-crotonyl-2-mercaptoethyl 4-methoxycinnamate (hereinafter "CMC"),
and S-sorbyl-2-mercaptoethyl 4-methoxycinnamate (hereinafter
"SMC").
[0031] The present invention further provides compositions
comprising the compounds of the present invention and a
cosmetically acceptable carrier. The present invention also
encompasses methods of conferring a skin care benefit by applying
to mammalian skin the compounds and compositions containing
compounds of the present invention.
[0032] In an alternate embodiment one or more characteristic use
agents can be bound to fibers that contain, or have been modified
to contain, a suitable nucleophilic group that can react with the
bonding agent.
[0033] The present compounds and compositions impart long-lasting
skin care benefits, e.g., suppleness, emolliency and moisturizing
effects, to skin and hair. The bonding agent is capable of
covalently bonding to proteins in skin, thereby maintaining the
characteristic use agent effects for possibly weeks by preventing
loss of the characteristic use agents (e.g., by washing). Thus, the
compounds and compositions containing the compounds of the
invention help skin to resist the irritating effects of substances
that remove skin lipids, such as detergents and organic solvents,
help to resist the drying effect that results from skin exposure to
the environment, or provide long-term sunscreen protection,
depending upon the particular characteristic use agent present in
the compound.
DESCRIPTION OF THE DRAWING
[0034] FIG. 1 is a diagrammatic illustration showing the anatomy of
human skin including the sulfhydryl-rich region.
DETAILED DESCRIPTION OF INVENTION
[0035] The present invention provides compounds that are two part
molecules comprising a bonding agent and a characteristic use
agent.
[0036] The compounds of the present invention have the generic
formula 1
[0037] or 2
[0038] wherein each y is independently 1 or 2. The crotonyl thiol
ester or sorbyl thiol ester moiety 3
[0039] s the bonding agent and "X" is the characteristic use
agent.
[0040] The characteristic use agent is selected from the group
consisting of emollients and skin soothing agents, moisturizers,
sunscreens, insecticides, antibacterial agents, fungicides, skin
lightening agents, antiviral agents, anti-acne agents, artificial
tanning agents, free-radical scavengers, antioxidants, and mixtures
thereof. Suitable characteristic use agents, for use herein, can be
found in the CTFA Cosmetic Ingredient Dictionary (3.sup.rd ed.,
1982) and the CTFA Cosmetic Ingredient Handbook, (2nd ed., 1992),
both published by The Cosmetic, Toiletry & Fragrance
Association, Inc., which references are incorporated herein by
reference in their entirety.
[0041] Emollients and skin soothing agents are known in the art and
include, for example, oils, petrolatum, lanolin, fatty acids, fatty
alcohols, triglyceride esters, wax esters, and esters of polyhydric
alcohols. Suitable emollients and oils are disclosed by Idson
(1992) Cosm. & Toil., 107:69 and U.S. Pat. No. 5,607,980,
incorporated herein by reference. Skin soothing agents include
bisabolol and non-steroidal, anti-inflammatory actives (NSAIDS)
such as anesthetics. Examples of NSAIDS include propionic acid
derivatives; acetic acid derivatives; fenamic acid derivatives
biphenylcarboxylic acid derivatives; and oxicams. All of these
NSAIDS are fully described in U.S. Pat. No. 4,985,459 to Sunshine
et al., issued Jan. 15, 1991, incorporated by reference herein in
its entirety. Examples of specific NSAIDS include acetyl salicylic
acid, ibuprofen, naproxen, benoxaprofen, flurbioprofen, fenoprofen,
fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin,
pranoprofen, microprofen, tioxaprofen, suprofen, alminoprofen,
tiaprofenic acid, fluprofen and bucloxic acid. Also useful are the
steroidal anti-inflammatory drugs including hydrocortisone and the
like.
[0042] Examples of topical anesthetic drugs include benzocaine,
lidocaine, buviacaine, chlorprocaine, dibucaine, etidocaine,
mepivacaine, tetracaine, dyclonine, hexyclaine, procaine, cocaine,
ketamine, pramoxine, phenol, and pharmaceutically acceptable salts
thereof.
[0043] Moisturizers or humectants are known in the art and include,
for example, materials selected from the group consisting of
glycerol; guanidine; glycolic acid and glycolate salts (e.g.,
ammonium and quaternary alkyl ammonium); lactic acid and lactate
salts (e.g., ammonium and quaternary alkyl ammonium); aloe vera in
any of its variety of forms (e.g., aloe vera gel); polyhydroxy
alcohols such as sorbitol, glycerol, hexanetriol, propylene glycol,
butylene glycol, hexylene glycol and the like; polyethylene
glycols; sugars and starches including sorbitol; sugars and starch
derivatives (e.g., alkoxylated glucose); hyaluronic acid;
pyrrolidone carboxylic acid; lactamide monoethanolamine; acetamide
monoethanolamine; and mixtures thereof.
[0044] Also, useful are propoxylated glycerols as described in U.S.
Pat. No. 4,976,953, to Orr et al., issued Dec. 11, 1990, which is
incorporated by reference herein in its entirety. Suitable
moisturizers are also disclosed by Loden et al. (1994), "Product
Testing--Testing of Moisturizers," in Bioengineering of the Skin:
Water and the Stratum Corneum, Elsner et al., eds, CRC Press, Boca
Raton, Fla., 275.
[0045] Skin protecting agents are known in the art and are useful
herein as a characteristic use agent and include sunscreens,
insecticides, insect repellants, anti-acne additives, anti-wrinkle
and anti-skin atrophy additives.
[0046] A wide variety of sunscreening agents are described in U.S.
Pat. No. 5,087,445, to Haffey et al., issued Feb. 11, 1992; U.S.
Pat. No. 5,073,372, to Turner et al.. issued Dec. 17, 1991; U.S.
Pat. No. 5,073,371, to Turner et al., issued Dec. 17. 1991; and
Segarin, et al., at Chapter VIII, pages 189 et seq., of Cosmetic
Science and Technology, all of which are incorporated herein by
reference in their entirety. Nonlimiting examples of sunscreens
which are useful in the compositions of the present invention are
those selected from the group consisting of 2-ethylhexyl
p-methoxycinnamate, 2-ethylhexyl N,N-dimethyl-p-aminobenzoat- e,
p-aminobenzoic acid, 2-phenylbenzimidazole-5-sulfonic acid,
octocrylene, oxybenzone, homomenthyl salicylate, octyl salicylate,
4,4'-methoxy-t-butyldibenzoylmethane, 4-isopropy dibenzoylmethane,
3-benzylidene camphor, 3-(4-methylbenzylidene) camphor,
anthanilates, ultrafine titanium dioxide, zinc oxide, silica and
iron oxide and mixtures thereof. Still other useful sunscreens are
those disclosed in U.S. Pat. No. 4,937,370, to Sabatelli, issued
Jun. 26, 1990; and U.S. Pat. No. 4,999,186, to Sabatelli et al.,
issued Mar. 12, 1991; these two references are incorporated by
reference herein in their entirety. The sunscreening agents
disclosed therein have, in a single molecule, two distinct
chromophore moieties which exhibit different ultraviolet radiation
absorption spectra. One of the chromophore moieties absorbs
predominantly in the UVB radiation range and the other absorbs
strongly in the UVA radiation range. These sunscreening agents
provide higher efficacy, broader UV absorption, lower skin
penetration and longer lasting efficacy relative to conventional
sunscreens. Examples of these sunscreens include those selected
from the group consisting of 4-N,N-(2-ethylhexyl)methylaminobenzoic
acid ester of 2,4-dihydroxybenzophenone,
4-N,N-(2-ethylhexyl)-methylaminobenzoic acid ester with
4-hydroxydibenzoylmethane, 4-N,N-(2-ethylhexyl)-methylaminoben-
zoic acid ester of 2-hydroxy-4-(2-hydroxyethoxy)benzophenone,
4-N,N(2-ethylhexyl)-methylaminobenzoic acid ester of
4-(2-hydroxyethoxy)dibenzoylmethane, and mixtures thereof.
[0047] Nonlimiting examples of anti wrinkle and anti-skin atrophy
actives include retinoic acid and its derivatives (e.g., cis and
trans); retinol, retinyl esters, salicylic acid and derivatives
thereof; sulfur-containing D and L amino acids other than cysteine
and their derivatives and salts, particularly the N-acetyl
derivatives; alpha-hydroxy acids, e.g., glycolic acid, and lactic
acid; phytic acid, lipoic acid, lysophosphatidic acid, and skin
peel agents (e.g., phenol and the like).
[0048] Nonlimiting examples of insecticides, insect repellants and
anti-arthropod agents include N,N-diethyl-m-toluamide, N-aryl and
N-cycloalkyl neoalkonamide compounds as desecribed in U.S. Pat. No.
5,434,190 incorporated by reference herein, terpenoids, especially
terpenoid alcohols and terpenoid-esters, aldehyde and ketones of
terpenes as described in U.S. Pat. No. 5,411,992 incorporated by
reference herein, oils of citronella, cedar and wintergreen as
described in U.S. Pat. No. 5,106,622 incorporated by reference
herein, 1-nonen-3-ol, and pyrethrum/pyrethoids as described in U.S.
Pat. No. 4,668,666 incorporated by reference herein.
[0049] Antibacterial agents such as antibiotics and bactericides,
and fungicides are known in the art and are useful herein as a
characteristic use agent. Nonlimiting examples of useful
antibacterial agents and fungicides include, .beta.-lactam drugs,
quinolone drugs, ciprofloxacin, norfloxacin, tetracycline,
erythromycin, amikacin, 2,4,4'-trichloro-2'-hydroxy diphenyl ether,
3,4,4'-trichlorobanilide, phenoxyethanol, phenoxy propanol,
phenoxyisopropanol, doxycycline, capreomycin, chlorhexidine,
chloretracycline, oxytetracycline, clindamycin, ethambutol,
hexamidine isethionate, metronidazole, pentamidine, gentamicin,
kanamycin, lineomycin, methacycline, methenamine, minocycline,
neomycin, netilmicin, paromomycin, streptomycin, tobramycin,
miconazole, tetracycline hydrochloride, erythromycin, zinc
erythromycin, erythromycin estolate, erythromycin stearate,
amikacin sulfate, doxycycline hydrochloride, capreomycin sulfate,
chlorhexidine gluconate, chlorhexidine hydrochloride,
chlortetracycline, hydrochloride, oxytetracycline hydrochloride,
clindamycin hydrochloride, ethambutol hydrochloride, metronidazole
hydrochloride, pentamidine hydrochloride, gentamicin sulfate,
kanamcyin sulfate, lineomycin hydrochloride, methacycline
hydrochloride, methenamine hippurate, methenamine mendelate,
minocycline hydrochloride, neomycin sulfate, netilmicin sulfate,
paromomycin sulfate, streptomycin sulfate, tobramycin sulfate,
miconazole hydrochloride, amanfadine hydrochloride, amanfadine
sulfate, octopirox, parachlorometa xyleneol, nystatin, tolnaftate
and clotrimazole.
[0050] Skin lightening agents are known in the art and are useful
herein as a characteristic use agent. Nonlimiting examples of
useful skin lightening agents include glycosides of
hydroxysalicylic acid and/or the glycosides of aliphatic esters of
hydroxysalicylic acid as described in U.S. Pat. No. 5,700,784
incorporated by reference herein, hydroquinone, kojic acid or a
derivative thereof, especially the salts or esters thereof as
described in U.S. Pat. No. 5,279,834 incorporated by reference
herein, 3-hydroxy-4(H)-pyran-4-one and its 3-acyl derivatives as
described in U.S. Pat. No. 4,545,982 incorporated by reference
herein, and 4-hydroxy-5-methyl-3[2H]-furanone.
[0051] Artificial tanning agents and accelerators are known in the
art and are useful herein as a characteristic use agent.
Nonlimiting examples of useful artificial tanning agents and
accelerators include dihydroxyacetone, tyrosine, tyrosine esters
such as ethyl tyrosinate, and phospho-DOPA.
[0052] Anti-Acne Actives are known in the art and are useful herein
as a characteristic use agent. Nonlimiting examples of useful
anti-acne actives include the keratolytics such as salicylic acid
(o-hydroxy-benzoic acid), derivatives of salicylic acid such as
5-octanoyl salicylic acid, and resorcinol; retinoids such as
retinoic acid and its derivatives (e.g., cis and trans);
sulfur-containing D and L amino acids other than cysteine and their
derivatives and salts, particularly their N-acetyl derivatives;
lipoic acid; antibiotics and antimicrobials such as benzoyl
peroxide, octopirox, tetracycline,
2,4,4'-trichloro-2'-hydroxydiphenyl ether,
3,4,4'-trichlorobanilide, azelaic acid and its derivatives,
phenoxyethanol, phenoxypropanol, phenoxisopropanol, ethyl acetate,
clindamycin and melclocycline; sebostats such as flavonoids; and
bile salts such as scymnol sulfate and its derivatives,
deoxycholate, and cholate.
[0053] Antiviral agents are also known in the art and useful herein
as a characteristic use agent. Nonlimiting examples of antiviral
agents include acyclovir, vidarabine, penciclovir, trifluridine,
idoxuridine, podophyllotoxin and carbenoxolone.
[0054] Free radical scavengers and antioxidants are known in the
art and are useful herein as a characteristic use agent.
Nonlimiting examples of useful free-radical scavengers and
antioxidants include butylated hydroxytoluene (BHT), butylated
hydroxyanisole (BHA), tocopherols and their derivatives, ascorbic
acid, its salts, derivatives such as ascorbyl palmitate and their
salts, retinol and related carotenoids, bioflavonoids such as
hesperitin, naringen, rutin, and quercetin, indole-3-carbinol,
pycnogenol, melatonin, sulforaphane, pregnenolone, lipoic acid,
amide and derivatives, 4-hydroxy-5-methyl-3[2H]-furanone,
ferruginol type compounds as described in U.S. Pat. No. 5,552,158
and esters of cinnamic acid as described in U.S. Pat. No.
5,536,500, Galey incorporated by reference herein.
[0055] The aforementioned characteristic use agents can bound to
fibers and other insoluble substrates as described in WO 98/18447
which either contain, or have been modified to contain, a
nucleophilic group which can react with the bonding agent.
[0056] The compounds of the present invention may be synthesized by
application of known organic chemical synthetic methods. Exemplary
compounds include the following: 4
[0057] wherein n is primarily 8 to 9; 5
[0058] wherein n is primarily 7 to 8; 6
[0059] wherein n is primarily 8 to 9; 7
[0060] wherein m is primarily 7 to 8; 8
[0061] The compounds of the present invention covalently bond to
skin by a reaction of the bonding agent of the present compounds
with a nucleophilic group (Nu.sup.-) of a skin protein without
requiring an enzyme to catalyze the reaction. As used herein, the
designation Nu.sup.- refers to nucleophilic groups contained in the
skin including but not limited to sulfhydryl groups of cysteine
residues, both in the neutral (--SH) and ionized forms (--S.sup.-),
including cysteine residues formed in situ by reduction of skin
cystine residues, the --NH.sub.2 of lysine residues and the
N-terminus of proteins, the imidazole side chain of histidine
residues, and the hydroxyl group of tyrosine residues, both in the
neutral (--OH) and ionized (--O.sup.-) forms.
[0062] The skin is rich in these nucleophilic groups. Free --SH
residues of proteins are concentrated in the cell membrane or
intracellular spaces in the junctional zone of living keratinocytes
and the dead horny layer of human epidermis. The stratum
spinosum--stratum granulosum boundary is rich in the neutral (--SH)
and ionized (--S.sup.-) forms of sulfhydryl groups of cysteine,
shown diagramatically in FIG. 1. In the horny layer, the
distribution of --SH groups is moderately high in the mid-stratum
corneum, and then decrease gradually on the way up to the surface
of the skin. Ogawa et al. (1979) J. Histochem. Cytochem.
27:942.
[0063] The reactivities of the compounds of the present invention
are optimal in that the compounds are not so reactive as to induce
skin irritation, nor damage essential biomolecules, nor produce
harmful byproducts, whereas the compounds have sufficient
reactivity to undergo reaction with skin nucleophiles (e.g.
--S.sup.-) under relatively mild conditions. The invention employs
a novel kind of reaction, namely the conjugate addition reaction,
in which nucleophiles attack a C.dbd.C that is conjugated to a
thiol ester functional group. The addition reaction does not
produce any by-products, as would have been generated by a
nucleophilic substitution reaction (e.g.,
Nu.sup.-+R-X-Nu-R+X.sup.-, where X.sup.- is a potentially
undesirable by-product). The other novel aspect of the present
compounds is the use of a thiol ester group, because it enhances
the reactivity of the C.dbd.C that it is conjugated to more than an
ordinary ester group does. Thus, for example, the .alpha., .beta.,
.gamma., .delta.-unsaturated thiol ester group of OSM
[C--C.dbd.C--C.dbd.C--C(.dbd.O)--S--R] and the .alpha.,
.beta.-unsaturated thiol ester groups of OCM, CPEG and CMC
[C--C.dbd.C--C(.dbd.O)--S--R] are novel groups that are ideally
suited for the desired reaction with skin nucleophiles.
[0064] To enhance the reaction between the present compounds and
skin nucleophiles, a base, such as bicarbonate or triethanolamine,
may be used in combination with the present compounds to convert
the less nucleophilic --SH groups into the more nucleophilic
--S.sup.- groups. The base converts some weak nucleophiles into
strong nucleophiles (e.g., --SH into --S.sup.-, tyrosine's --OH
into --O.sup.-, and reveals --NH.sub.2 from the nonnucleophilic
--NH.sub.3.sup.- form).
[0065] Exemplary compounds of the present invention include OSM,
OCM, CPEG, DCPEG, SPEG, DSPEG, CMC and SMC. The compound OSM
consists of a two-part molecule. One part is designed to impart
emolliency/moisturizing effects to skin, whereas the other part is
designed to become covalently bonded to skin. An illustrative
method of synthesizing OSM is provided at Example 1 hereinbelow.
The part of the molecule designed to react with skin can do so with
two different skin protein molecules or different regions of the
same molecule, thereby crosslinking skin and adding to the skin's
strength, and thus providing an important benefit for elderly
individuals, who often have fragile, easily torn skin.
[0066] The covalent bonding of OSM to skin is based upon the
nucleophilic attack of Nu.sup.- groups in skin. A representative
chemical reaction is as follows: 9
[0067] in which Nu.sup.- in the chemical equation is as defined
hereinabove. This chemical reaction describes one of the ways
covalent attachment of OSM to skin can occur in water, although
other solvents and other modes of covalent attachment are
possible.
[0068] As a model for skin-bound sulfhydryl groups (--SH) of
cysteine residues in skin proteins, the compound N-acetylcysteamine
was allowed to react with OSM in the presence of a catalytic amount
of the base 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in chloroform
solution. The addition of N-acetylcysteamine to OSM, in a manner
that is expected to parallel the addition of skin-bound
nucleophiles (e.g., cysteine residues in skin proteins) to OSM,
showed that covalent bond formation occurred, giving the compound
shown below, or a related adduct. 10
[0069] Covalent attachment also occurs between OSM and cysteine
ethyl ester, another model for skin-bound cysteine residues in skin
proteins, under similar conditions. The addition of cysteine ethyl
ester to OSM in a manner that is expected to parallel the addition
of skin-bound nucleophiles (e.g., cysteine residues of skin
proteins) to OSM is thought to occur as shown below, or by a
similar adduct formation path. 11
[0070] In the case of skin nucleophiles, the reaction shown below
or an analogous adduct formation is expected to occur, in which a
skin-bound sulfhydryl group (here illustrated with a cysteine
sulfhydryl group) is the nucleophile illustrated to react with OSM.
12
[0071] The compound OCM consists of a two-part molecule. One part
is designed to impart emolliency/moisturizing effects to skin,
whereas the other part is designed to become covalently bonded to
skin. An illustrative method of synthesizing OCM is provided at
Example 2 hereinbelow.
[0072] The covalent bonding of OCM to skin is based on the
nucleophilic attack of Nu.sup.- groups in skin. A representative
chemical reaction is as follows: 13
[0073] in which the Nu.sup.- in the chemical equation is as defined
hereinabove. This chemical reaction describes one of the ways
covalent attachment of OCM to skin can occur in water, although
other solvents and other modes of covalent attachment are
possible.
[0074] As a model for skin-bound sulfhydryl groups (--SH) of
cysteine residues in skin proteins, the compound N-acetylcysteamine
was allowed to react with OCM in the presence of a catalytic amount
of the base 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in chloroform
solution. The addition of N-acetylcysteamine to OCM, in a manner
that is expected to parallel the addition of skin-bound
nucleophiles (e.g., cysteine residues in skin proteins) to OCM,
showed that covalent bond formation occurred, giving the compound
shown below, or a related adduct. 14
[0075] The reaction also occurred between OCM and cysteine ethyl
ester, another model for skin-bound cysteine residues in skin
proteins, under similar conditions. Addition of cysteine ethyl
ester to OCM in a manner that is expected to parallel the addition
of skin-bound nucleophiles (e.g., cysteine residues in the skin
proteins) to OCM is thought to occur as shown below, or by a
similar adduct formation path: 15
[0076] In the case of skin, the addition of skin-bound nucleophiles
is expected to occur as shown below or as an analogous adduct
formation, in which a skin-bound sulfhydryl group is the
nucleophile illustrated to react with the OCM. 16
[0077] Exposure of skin to the environment or removal of skin
lipids by detergents and organic solvents results in a skin-drying
effect and irritation. The OSM and OCM molecules have lipid-like
characteristics, principally due to the (CH.sub.2).sub.17CH.sub.3
group, that combat the drying effect and irritancy that the loss of
skin lipids induces. Because of the covalent attachment of the
lipid-like group to skin components such as proteins, which are not
readily removed by detergents and organic solvents, the lipid-like
portion resists removal by detergents and organic solvents, and
imparts a protective effect to skin exposed to these agents.
[0078] To the extent that the binding of OSM and OCM to skin occurs
at the deeper I layers, e.g., the spinosum-granulosum boundary,
over time these layers that contain the bound lipid-like group of
OSM and OCM will evolve to the surface layers of the skin, through
normal growth process of the skin. This may produce an even more
beneficial protective effect on the skin, because the lipid-like
bound groups will be in an outer layer of the skin. Thus, the
repeated application of OSM and OCM to skin might result, over a
period of time, in virtually all layers of skin from relatively
deep (e.g., spinosum-granulosum boundary) to the surface (e.g.,
stratum corneum) being chemically modified with the lipid-like
chains of OSM or OCM.
[0079] Besides imparting chemical resistance and long-term
emolliency/moisturizing effects to skin, the compounds of the
invention may impart a skin-strengthening effect. This is a
consequence of the potential of OSM to crosslink skin components,
for example to link together different protein molecules in skin or
different parts of the same protein molecule in skin. The potential
beneficial effect of this is the strengthening effect that
crosslinking has on polymers, such as skin proteins. Thus, for the
elderly, who typically have easily torn and injured skin, the
application of OSM might result in a strengthening of the skin and
a decreased propensity for skin injury. As described above, this
effect might increase over time with repeated application of the
invention, as the lower layers of the skin bearing the crosslinked
protein molecules evolve to the surface of the skin.
[0080] In addition to the uses described above, suitable sorbate
thiol esters and crotonate thiol esters of a design apparent to
those skilled in the art, having regard for this disclosure, have
utility in the extended protection of skin, hair, nails, wool, and
fur (e.g., from ultraviolet light, by incorporation of sunscreens
into the thiol ester; from toxic and/or irritating substances, such
as urushiol or urinary by-products; or from insects and parasites,
by incorporation of insecticides and/or insect repellants), dyeing
of hair, skin (e.g., tanning or marking, as with reflectant or
colored substances), nails, wool, fur, and other substances with
native nucleophilic groups or nucleophilic groups that can be added
or revealed by suitable chemical and/or physical treatments.
[0081] The compounds CPEG, DCPEG, SPEG and DSPEG are two part
molecules. One part is designed to become covalently bonded to
skin, whereas the other part is designed to impart moisturizing
effects or humectancy to the skin. Similar compounds that would
accomplish substantially the same results are readily apparent to
one skilled in the art, having regard for this disclosure. An
illustrative method of synthesizing DCPEG is provided at Example 3
herein below.
[0082] As a model for skin bound sulfhydryl groups (--SH) of
cysteine residues in skin proteins, the compound N-acetylcysteamine
was allowed to react with DCPEG in the presence of a catalytic
amount of the base 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in
chloroform solution. The addition of N-acetylcysteamine to DCPEG in
a manner that is expected to parallel the addition of skin-bound
nucleophiles (e.g., cysteine residues in skin proteins) to DCPEG,
showed that covalent bond formation occurred, giving the compound
shown below, or a related adduct. 17
[0083] The covalent bonding of CPEG, DCPEG, SPEG, and DSPEG to skin
is based upon the nucleophilic attack of Nu.sup.- groups in skin. A
representative chemical reaction using CPEG is as follows: 18
[0084] in which the Nu.sup.- in the chemical equation is as defined
hereinabove. This chemical reaction describes one of the ways
covalent attachment of CPEG to skin can occur in water, although
other solvents and other modes of covalent attachment are possible.
A representative chemical reaction using DCPEG is as follows:
19
[0085] in which the Nu.sup.- in the chemical equation is as defined
hereinabove. This chemical reaction describes one of the ways
covalent attachment of DCPEG to skin can occur in water, although
other solvents and other modes of covalent attachment are possible.
In this case, two skin-bound nucleophiles can become attached to
one DCPEG molecule resulting in cross-linking of skin. This has the
beneficial effect of strengthening skin, such as the fragile skin
of the elderly.
[0086] A representative chemical reaction using SPEG is as follows:
20
[0087] in which the Nu.sup.- in the chemical equation is as defined
hereinabove. This chemical reaction describes one of the ways
covalent attachment of SPEG to skin can occur in water, although
other solvents and other modes of covalent attachment are possible.
Both of the reactive sites on SPEG need not necessarily react with
skin nucleophiles for there to be a beneficial effect on skin.
[0088] A representative chemical reaction using DSPEG is as
follows: 21
[0089] in which the Nu.sup.- in the chemical equation is as defined
hereinabove. This chemical reaction describes one of the ways
covalent attachment of DSPEG to skin can occur in water, although
other solvents and other modes of covalent attachment are possible.
DSPEG can cross-link skin via the nucleophiles. However, not all
four of the reactive sites of DSPEG need necessarily react with
skin nucleophiles in order for there to be a beneficial effect on
skin.
[0090] To enhance the reaction between CPEG, DCPEG, SPEG and DSPEG
with skin nucleophiles, a base may be used in combination with
CPEG, DCPEG, SPEG and DSPEG to convert the less nucleophilic --SH
groups into the more nucleophilic --S.sup.- groups. The base
converts some weak nucleophiles into strong nucleophiles (e.g.,
--SH into --S.sup.-, tyrosine's --OH into --O.sup.-, and reveals
--NH.sub.2 from the nonnucleophilic --NH.sub.3.sup.+ form).
[0091] For example, in the case of skin nucleophiles, the reaction
shown below or an analogous adduct formation is expected to occur,
in which a skin-bound sulfhydryl group is the nucleophile
illustrated to react with the CPEG: 22
[0092] Loss of skin moisture through the action of detergents and
organic solvents or exposure to the environment results in a skin
drying effect (e.g., flaking) and irritation or aged appearance.
The CPEG, DCPEG, SPEG and DSPEG molecules have a humectant or
hydrophilic chain derived from poly(ethylene glycol) that resists
the loss of skin moisture and assists the accumulation of moisture
by the skin, i.e., rehydration of skin, thereby combating the
irritancy and other effects that drying induces. The humectancy is
presumably derived from the polyether chain (--CH.sub.2
CH.sub.2--O--) augmented by the terminal hydroxyl group in the
cases of CPEG and SPEG. Because of the covalent attachment of the
hydrophilic, moisture-holding group to the skin components such as
proteins, which are not readily removed by detergents and organic
solvents, a protective and restorative effect is imparted to skin
exposed to these agents.
[0093] To the extent that the binding of one or more of CPEG,
DCPEG, SPEG, and DSPEG to skin occurs at the deeper layers, e.g.,
the spinosum-granulosum boundary, over time these layers that
contain one or more of the bound humectant group of CPEG, DCPEG,
SPEG, and DSPEG will evolve to the surface layers of the skin
though the normal growth processes of the skin. This may produce an
even more beneficial protective effect on the skin, because the
bound humectant groups will be in an outer layer of the skin. Thus,
the repeated application of one or more of CPEG, DCPEG, SPEG, and
DSPEG to skin might result, over a period of time, in virtually all
layers of skin from relatively deep (e.g. spinosum-granulosum
boundary) to the surface (e.g., stratum corneum) being chemically
modified with the humectant part of CPEG, DCPEG, SPEG, and
DSPEG.
[0094] The compounds CMC and SMC are two part molecules. One part
is designed to become covalently bonded to skin, whereas the other
part is designed to act as a sunscreen and impart protection to the
skin against the harmful effects of exposure to ultraviolet light.
Similar compounds that would accomplish substantially the same
results are readily apparent to one skilled in the art, having
regard for this disclosure.
[0095] French Patent No. 2,566,400, incorporated here by reference,
describes the production of sulfur containing p-methoxycinnamates
for use as sunscreens. The addition of a bonding agent as described
by this invention forms CMC or SMC.
[0096] An illustrative method of synthesizing CMC is as follows.
23
[0097] Similarly, an illustrative method of synthesizing SMC is as
follows. 24
[0098] The covalent bonding of CMC and SMC to skin is based on the
nucleophilic attack of Nu.sup.- groups in skin. A representative
chemical reaction using CMC is as follows: 25
[0099] in which the Nu.sup.- in the chemical equation is as defined
hereinabove. This chemical reaction describes one of the ways
covalent attachment of CMC to skin can occur in water, although
other solvents and other modes of covalent attachment are
possible.
[0100] A representative chemical reaction using SMC is as follows:
26
[0101] in which the Nu.sup.- in the chemical equation is as defined
hereinabove. This chemical reaction describes one of the ways
covalent attachment of SMC to skin can occur in water, although
other solvents and other modes of covalent attachment are possible.
Both of the reactive sites of SMC need not necessarily react with
the skin nucleophiles for there to be a beneficial effect on
skin.
[0102] To enhance the reaction between CMC and SMC with skin
nucleophiles, a base may be used in combination with CMC and SMC to
convert the less nucleophilic --SH groups into the more
nucleophilic --S.sup.- groups. The base converts some weak
nucleophiles into strong nucleophiles (e.g., --SH into --S.sup.-,
tyrosine's --OH into --O.sup.-, and reveals --NH.sub.2 from the
nonnucleophilic --NH.sub.3.sup.- form).
[0103] For example, in the case of skin nucleophiles, the reaction
shown below or an analogous adduct formation is expected to occur,
in which a skin bound sulfhydryl group is the nucleophile
illustrated to react with the CMC: 27
[0104] A similar reaction or formation of an analogous adduct would
occur in the case of skin nucleophiles and SMC.
[0105] Exposure of the skin to ultraviolet light has been
implicated as a possible factor in the induction of a number of
harmful biological effects, such as skin aging and cancer. The CMC
and SMC molecules have an ultraviolet light-absorbing group
(4-methoxycinnamate) that imparts protection from effects of
ultraviolet exposure. Because the ultraviolet light-absorbing group
is covalently attached via the bonding agent to skin components,
such as proteins which are not readily removed by detergents and
organic solvents or exposure to the environment (e.g, water, wind,
and abrasion), the ultraviolet light-absorbing portion resists
removal by these agents.
[0106] To the extent that the binding of one or more of CMC and SMC
to skin occurs at the deeper layers, e.g., the spinosum-granulosum
boundary, over time these layers that contain one or more of the
bound ultraviolet light-absorbing group of SMC and CMC will evolve
to the surface layers of the skin though the normal growth
processes of the skin. This may produce an even more beneficial
protective effect on the skin, because the ultraviolet light
absorbing groups will be in an outer layer of the skin. Thus, the
repeated application of one or more of CMC and SMC to skin might
result, over a period of time, in virtually all layers of skin from
relatively deep (e.g. spinosum-granulosum boundary) to the surface
(e.g., stratum corneum) being chemically modified with the
ultraviolet light-absorbing sunscreen group of CMC and SMC.
[0107] From the foregoing it becomes readily apparent new and
useful long-acting, chemical-resistant skin emollients,
moisturizers, sunscreens and strengtheners and their preparations
have been herein described and illustrated which fulfill all of the
aforestated objectives. It is of course understood that such
modifications, alterations and adaptations as will readily occur to
the artisan confronted with this disclosure are intended within the
scope of the invention.
[0108] The present invention further provides compositions
comprising one or more compounds of the present invention and a
cosmetically acceptable carrier which is compatible with the
compound of the invention. Cosmetically acceptable carriers include
water, alcohols, oils, and other carriers suitable for dissolving
or dispersing the active ingredient. The compositions may further
contain additional ingredients, such as fluidity promoters,
colorants, perfumes, and the like. Suitable cosmetically acceptable
carriers and additional ingredients, for use herein, can be found
in the CTFA Cosmetic Ingredient Dictionary (3.sup.rd ed., 1982) and
the CTFA Cosmetic Ingredient Handbook, (2nd ed., 1992), both
published by The Cosmetic, Toiletry & Fragrance Association,
Inc., which references are incorporated herein by reference in
their entirety. The compositions are useful for application to the
skin or hair as moisturizers, emollients, sunscreens or skin
strengtheners, depending upon the particular characteristic use
agent present in the compound of the invention.
[0109] Methods for the formulation of cosmetic compounds are well
known to those of skill in the art. The compositions may take a
form suitable for topical application, including for example a
lotion, cream, gel, or solid, e.g. stick form, composition. The
cosmetic compositions contain the compound of the invention in an
amount that will be dependent upon the characteristic use agent
portion of the two-part compound and the intended use of the
composition. The compositions may contain the compound of the
invention in an amount of about 0.1% to 35% by weight of the
composition. For example, a compound of the present invention in
which the characteristic use agent is a sunscreen agent will
preferably be present in an amount of 0.1% to 15%, and more
preferably 1% to 10% by weight of the composition. A compound of
the present invention in which the characteristic use agent is an
emollient will preferably be present in an amount of 1% to 35%, and
more preferably 5% to 20% by weight of the composition. A compound
of the present invention in which the characteristic use agent is a
humectant will preferably be present in an amount of 1% to 20%, and
more preferably 5 to 15% by weight of the composition. Formulations
are described in Examples 4 and 5 herein below.
[0110] The following examples serve to further illustrate the
present invention.
EXAMPLE 1
Synthesis and Characterization of OSM and n-Octadecyl Sorbate
(OS)
[0111] Material and Methods
[0112] All reagents used in the synthesis of the sorbate-based
esters and thiol esters were purchased from Aldrich Chemical Co. or
Lancaster Chemical Co., except octadecyl 3-mercaptopropionate was
obtained from Hampshire Chemical Corp. Solvents were distilled
prior to use. Evaporation of solvents was performed under reduced
pressure on a Buchi rotary evaporator. THF refers to
tetrahydrofuran, DBN to 1,5-diazabicyclo[4.3.0] non-5-ene and TEA
to triethylamine. The THF was predried by refluxing over sodium and
benzophenone until permanently purple and distilled under an
N.sub.2 atmosphere immediately before use. Analtech silica gel GF
(0.25 mm) plates were used for thin-layer chromatography (TLC) and
developed with a variety of solvents. A fluorescent indicator or an
iodine chamber was employed for visualization of spots. Preparative
silica gel thin layer chromatography plates (10 cm.times.20 cm,
1000 microns) were obtained from Analtech. Stationary phases used
for gravity column chromatography were Baxter 70-230 mesh silica
gel (VMR Scientific Co.). Tetramethylsilane and residual CHCl.sub.3
(7.256 ppm) were used as internal references in all nuclear
magnetic resonance measurements, which were determined with a
Varian AM 300 Gemini spectrometer. Chemical shifts were recorded in
ppm, and peak abbreviations for spin multiplicities are: s,
singlet; d, doublet; t, triplet; dd, doublet of doublets; dt,
doublet of triplets; m, multiplet; br, broad. Deuteriochloroform
was used as an NMR solvent. Confirmation of structural data was
given by the 2D COSY experiments. Melting points were measured on a
Electrothermal Meltemp apparatus and are uncorrected.
[0113] Time-course NMR spectral study
[0114] A solution of octadecyl S-sorbyl-3 -mercaptopropionate (10.9
mg, 0.024 mmol) in 0.3 mL of CDCl.sub.3 was added to a solution of
N-acetylcysteamine (5.2 .mu.L, 0.048 mmol) and DBN (3.1 .mu.L,
0.025 mmol) in 0.3 mL of CDCl.sub.3. The mixture was immediately
transferred to an NMR tube and the first spectrum was recorded at
time=0. The reaction solution was allowed to stand at room
temperature in the NMR tube for two days, and the course of the
reaction was monitored by periodically recording the .sup.1H NMR
spectrum. A total often .sup.1H NMR experiments were performed at
time=0, 0.25, 0.5, 1, 1.5, 4.5, 12, 20.5, 26, and 39 hours.
[0115] Synthesis
[0116] Sorboyl chloride (1).
[0117] To a 500-mL round-bottom flask containing 110 mL of
cyclohexane, 3.85 g of sorbic acid was added at room temperature.
The temperature was increased to 60.degree. C. and 8.9 mL of
thionyl chloride was added dropwise over a 1-hour period. The
mixture was heated under reflux for 17 hours, after which the
solvent and the unreacted thionyl chloride were evaporated in
vacuo, and the mixture was concentrated to a brown residue: 4.05 g
(90%) yield,
[0118] .sup.1H NMR (300 MHz) .delta. 7.30 and 7.70 (total 1 H, m,
HC.dbd.CCOCl), 5.8-6.6 (3 H, m, olefinic), and 1.9 (total 3 H, d,
J=5 Hz, CH.sub.3CH.dbd.).
[0119] n-Octadecyl sorbate (OS).
[0120] A solution of 0.9 g (6.9 mmol) of sorboyl chloride in 6 mL
of THF was added slowly with stirring to a mixture of 1.87 g (6.9
mmol) of n-octadecanol in 10 mL of THF at 40.degree. C. The
resulting mixture was refluxed for 16 hours. The solvent was
evaporated under reduced pressure and the crude product was
purified by column chromatography on silica gel using chloroform as
eluent. The appropriate fractions were combined and evaporated to
dryness in vacuo to give a white solid product: 1.04 g (42%) yield.
TLC (CHCl.sub.3) R.sub.f=0.75.
[0121] .sup.1H NMR (300 MHz) .delta. 0.89 [3H, t,
--(CH.sub.3).sub.15CH.su- b.3)], 1.25 [30H, br m,
--(CH.sub.3).sub.15--], 1.62 [2H, t, --OCH.sub.2CH.sub.2--], 1.86
[3H, d, CH.sub.3CH.dbd.], 4.14 [2H, t, --OCH.sub.2--],5.79 [1H, d,
OCCH.dbd.], 6.19 [2H, m, CH.sub.3CH=CH--], 7.22 [1H, m,
CH.sub.3CH.dbd.CH--CH.dbd.].
[0122] Octadecyl S-sorbyl-3-mercaptopropionate (OSM).
[0123] To a solution of 11.1 g (31.1 mmol) of octadecyl
3-mercaptopropionate dissolved in 30 mL of cyclohexane, at
45.degree. C. was slowly added 4.05 g (31.0 mmol) of sorboyl
chloride in 35 mL of cyclohexane. The resulting mixture was stirred
and refluxed for 15 hours. The solvent was evaporated in vacuo,
leaving a brown liquid. The resulting residue was applied to a
column of silica gel and product was eluted with 10% ethyl acetate
in hexanes solution. The appropriate fractions were combined and
concentrated to give a white solid: 7.5 g (67%) yield. TLC (ethyl
acetate/hexanes [10:90]) R.sub.f=0.55.
[0124] .sup.1H NMR (300 MH.sub.z) .delta. 0.89 [3H, t,
--(CH.sub.2).sub.15-CH.sub.3], 1.24 [30H, broad m,
--(CH.sub.2).sub.15--], 1.61 [2H, t, --OCH.sub.2CH.sub.2--], 1.94
[3H, d, CH.sub.3CH.dbd.], 2.63 [2H, t, --SCH.sub.2CH.sub.2--], 3.20
[2H, t, --SCH.sub.2--], 4.08 [2H, t, --OCH.sub.2--], 6.02 [H, d,
OCCH.dbd.]1, 6.20 [2H, m, CH.sub.3CH.dbd.CH--], 7.20 [1H, m,
OCCH.dbd.CH--].
[0125] n-Octadecyl sorbate-N-acetyleysteamine monoadduct (2).
[0126] To a solution of 109 mg (0.30 mmol) of n-octadecyl sorbate
dissolved in 6 mL of cyclohexane/chloroform (50:50) was added 31.9
.mu.L (0.30 mmol) of N-acetylcysteamine and 18 .mu.L (0.15 mmol) of
DBN. The mixture was heated at reflux for 15 hours, after which the
solvent was evaporated in vacuo. The residue was placed onto a
column of silica gel and product was eluted with 5% methanol in
chloroform. The appropriate fractions were combined and
concentrated to give a colorless oil (0.056 g, 39%). TLC
(cyclohexane/chloroform [50:50])R.sub.f=0.66,
[0127] .sup.1H NMR (300 MHz) .delta. 0.89 [3H, t,
CH.sub.3CH.sub.2).sub.15- --], 1.22 [30H, br m,
CH.sub.3(CH.sub.2).sub.15--], 1.31 [3H, d,
CH.sub.3CH(S--)CH.sub.2--], 1.61 [2H, t, --OCH.sub.2CH.sub.2--],
2.00 [3H, s, acetyl], 2.44-2.72 [2H, two dd, --NHCHH'--], 3.16 [2H,
d, O.dbd.CCH.sub.2--], 3.31-3.42 [3H, m,
CH.sub.3CH(SCH.sub.2--)CH.dbd.], 4.08 [2H, t, --OCH.sub.2--], 5.40
[1H, dd, C(3) olefinic], 5.55 [1H, dd, C(4) olefinic], 6.02 [1H, br
s, amide proton].
[0128] Octadecyl S-sorbyl-3-mercaptopropionate-N-acetylcysteamine
monoadducts (3 and 4).
[0129] In a 50-mL round-bottom flask, 181 mg (0.40 mmol) of OSM was
dissolved in 10 mL of chloroform, which was purged with nitrogen
for 15 minutes prior to use. 30 .mu.L (0.28 mmol) of
N-acetylcysteamine and 39 .mu.L (0.28 mmol) of triethylamine were
added, and the solution was stirred under reflux in a nitrogen
atmosphere for 2 hours. The solvent was evaporated and the mixture
of monoadducts was isolated by preparative TLC with 3% methanol in
chloroform. Rf=0.66. The isolated monoadducts mixture was spotted
onto another preparative TLC plate, and the monoadducts were
separated by repetitive developments with 3% methanol in
chloroform.
[0130] .sup.1H NMR (300 MHz) (monoadduct 3) .delta. 0.89 [3H, t,
--(CH.sub.2).sub.15CH.sub.3], 1.30 (30H, br m,
--(CH.sub.2).sub.15--], 1.31 [3H, d, CH.sub.3CH(S--)CH.dbd.], 1.61
(2H, t, --OCH.sub.2CH.sub.2--), 2.00 (3H, s, acetyl], 2.55 [1H, m,
--NHCH.sub.2CHH'--], 2.62 [2H, t,OC(O)CH.sub.2], 2.65 [1H,
m,--NHCH.sub.2CHH'--], 3.12 [2H, t, O.dbd.CSCH.sub.2--], 3.32 [3H,
m, CH.sub.3CH(SCH.sub.2CH.sub.2)CH.dbd.], 3.29 [2H, d,
--SC(O)CH.sub.2--], 4.10 [2H, t, --OCH.sub.2(CH.sub.2).sub.16--],
5.42-5.62 [2H, m, olefinic], 6.00 [1H, br s, amide proton]. COSY
Correlations: .delta.
0.89/1.30,1.30/1.61,1.31/3.44,1.61/4.10,2.55/2.65,2.62/3.12,
3.29/5.52,3.32/5.35, 5.35/5.52.
[0131] .sup.1H NMR(300 MHz) (monoadduct 4) .delta. 0.89 [3H,t,
--(CH.sub.2).sub.15CH.sub.3], 1.30 [30H, br m,
--CH.sub.2).sub.15--], 1.61 [2H, t, --OCH.sub.2CH.sub.2--], 1.71
(3H, d, CH.sub.3CH.dbd.], 2.00 [3H, s, acetyl], 2.55 [1H, m,
--SCHH'CH.sub.2NH--], 2.65 [1H, m, --SCHH'CH.sub.2NH--], 2.61 [2H,
t, --OC(O)CH.sub.2--], 2.79[2H d, --SC(O)CH.sub.2--], 3.18 [2H, t,
O.dbd.CSCH.sub.2--], 3.40 [1H, dt, --NHCHH'--], 3.42 [1H, dt,
--NHCHH'--], 3.63 [1H, m, CH.sub.3CH.dbd.CHCH(S--)CH.sub.2--], 4.08
[2H, t, --OCH.sub.2(CH.sub.2).s- ub.16--], 5.28 [1H, m, C(4)
olefinic], 5.55 [1H, m, C(5) olefinic], 6.00 [1H, br s, amide
proton]. COSY correlations: .delta. 0.89/1.30, 1/30/1.61,
1.61/4.10, 1.71/5.55, 2.55/2.65, 2.61/3.18, 2.55-2.65/3.40-3.42,
2.79/3.63, 3.40/3.42, 3.63/5.28, 5.28/5.55.
[0132] Reaction by-products formation.
[0133] To a 25-mL round-bottom flask equipped with a drying tube,
45.2 mg (0.10 mmol) of OSM, 21.3 .mu.L (0.20 mmol) of
N-acetylcysteamine and 12.3 .mu.L (0.10 mmol ) of DBN were
dissolved in 5 mL of CHCl.sub.3. The reaction mixture was allowed
to stir at room temperature for 6 hours and was periodically
monitored by TLC (ethyl acetate/hexanes [50:50]) for the
disappearance of starting material. The solvent was evaporated
under reduced pressure and the reaction crude mixture was purified
by column chromatography on silica gel using 3% hexanes in
methylene chloride solution. The isolated products were
individually identified by NMR spectroscopy and their spectral data
were summarized as follows:
[0134] Bis(octadecyl 3-mercaptopropionyl) disulfide (6).
[0135] TLC (ethyl acetate/hexanes [50:50]) Rf=0.93.
[0136] .sup.1H NMR (300 MHz) .delta. 0.89 [6H, t, methyl], 1.23
[60H, br m, --(CH.sub.2).sub.15--], 1.61 [4H, t,
--OCH.sub.2CH.sub.2--], 2.72 [4H, t, --SCH.sub.2CH.sub.2--], 2.94
[4H, t, --SCH.sub.2--], 4.09 [4H, t, --OCH.sub.2--].
[0137] N-Acetylcysteamino octadecyl 3-mercaptopropionyl disulfide
(7).
[0138] TLC (ethyl acetate/hexanes [50:50]) Rf=0.67,
[0139] .sup.1H NMR (300 MHz) .delta.0.89 [3H, t, methyl], 1.25
[30H, br m, --(CH.sub.2).sub.15--], 1.62 [2H, t
--OCH.sub.2CH.sub.2--], 2.00 [3H, s, acetyl], 2.74 [2H, t,
--OC(O)CH.sub.2--], 2.81 [2H, t, --NHCH.sub.2CH.sub.2--], 2.94 [2H,
t, --OC(O)CH.sub.2CH.sub.2--], 3.60 [2H, q, --NHCH.sub.2--], 5.89
[1 H, br s, amide proton].
[0140] S-sorbyl 2-mercapto(N-acetyl)ethylamine (8).
[0141] TLC (ethyl acetate/hexanes [50:50]) Rf=0.48, .sup.1H NMR
(300 MHz) .delta. 1.87 [3H, d, methyl], 1.99 [3H, s, acetyl], 3.11
[2H, t, --SCH.sub.2--], 3.44 [2H, t, --SCH.sub.2CH.sub.2--], 5.89
[1 H, br s, amide proton], 6.09 [1 H, d, OCCH.dbd.], 6.21 [2H, m,
CH.sub.3CH.dbd.CH--], 7.20 (1H, m, CH.sub.3CH.dbd.].
[0142] As described above, OSM and OS were synthesized via the
nucleophilic acyl substitution reaction of the sorboyl chloride
with the corresponding thiol or alcohol, respectively. The route
for the preparation of these compounds is as follows. 28
[0143] Sorboyl chloride was chosen based upon the fact that sorbic
acid has been considered to be harmless and is included in the list
of GRAS chemicals (generally regarded as safe). The preparation of
sorboyl chloride starting material 1 was achieved by refluxing a
cyclohexane solution of sorbic acid and thionyl chloride according
to the procedure of MacMilan et al. (1973) J. Org Chem., 2982,
except that the volatiles were removed by rotary evaporation
instead of distillation. The yield of sorboyl chloride (90%) was
the same as that reported by MacMilan et al. OS was prepared in 42%
yield by treatment of 1 with 1 equiv of n-octanol in THF at reflux
for 16 hours as described by Tieke (1995) Colloid Poly. Sci.
236:966. A similar procedure as that used in the preparation of OS
was employed to prepare OSM; treatment of 1 with 1 equiv of
octadecyl 3-mercaptopropionate in refluxing cyclohexane for 16
hours gave a 67% of OSM.
[0144] The study of the reaction between OSM and OS with the model
skin protein, N-acetylcysteamine, demonstrated that both of the
prospective emollient agents, OSM and OS, can be attached to the
skin covalently via a nucleophilic addition as follows: 29
[0145] OS was allowed to react with 1 equiv of N-acetylcysteamine
in the presence of 0.5 equiv of the base DBN in refluxing
cyclohexane/chloroform mixture; the reaction gave the corresponding
monoadduct 2 in 39% yield. Structural assignment of the monoadduct
2 was clearly made on the basis of its .sup.1H NMR spectral data
and 2D COSY correlations. The formation of the 2,5-addition product
was confirmed.
[0146] The reaction of OSM with 0.7 equiv of N-acetylcysteamine in
the presence of 0.7 equiv of triethylamine in chloroform at reflux,
under an N.sub.2 atmosphere, for 2 hours gave a mixture of two
isomeric monoadducts, 3 and 4. The crude reaction mixture was
concentrated to a small volume, which was subjected to column
chromatography on silica gel for isolation. The method of column
chromatography alone was insufficient to achieve a high level of
purification; the two monoadducts eluted together. To separate the
monoadducts 3 and 4, we employed the repetitive preparative TLC
purification procedure. By analogy to the reaction of OS with
N-acetylcysteamine, OSM would be expected to give monoadduct 3. In
addition, monoadduct 4 was also obtained.
[0147] The .sup.1H NMR spectra of both of the two monoadducts 3 and
4 exhibited the corresponding olefinic protons as a pair of
multiplets at .delta. 5.6-5.4 and .delta. 5.6-5.2, respectively,
and no signal assignable to olefinic protons at .delta. 6.2-6.0 and
.delta. 7.2, attributable to the original dienyl portion of the
sorbate group, --CH.dbd.CH--CH.dbd.CH--. The assignment of the
olefinic proton signals was made on the basis of correlations in
the 2D COSY spectra. These correlations indicated that the signals
at .delta. 5.35 and .delta. 5.52 are due to the olefinic protons
H-3 and H-4 of monoadduct 3; and the signals at .delta. 5.28 and
.delta. 5.55 are due to the olefinic protons H-4 and H-5 of
monoadduct 4. The upfield-shifted olefinic proton signal for C-4 in
monoadduct 3 correlates with the multiplet signal at .delta. 3.32
for C-5, which in turn correlates with the methyl signal at .delta.
1.31 for C-6. The methyl doublet at .delta. 1.71 for C-6 correlates
with the downfield-shifted olefinic signal at .delta. 5.55 for C-5
in monoadduct 4; and the aliphatic signals at .delta. 3.63 for C-3
correlates with the upfield-shifted olefinic signal at .delta. 5.28
for C-4 as well as the doublet at .delta. 2.79 for C-2. The .sup.1H
NMR spectral results, together with the correlations in the 2D COSY
spectra, demonstrated that both of the 2,5-addition product, 3, and
the 2,3-addition product, 4, were formed in the reaction.
[0148] The time course of the reaction of OSM with 2 equiv of
N-acetylcysteamine in the presence of 1 equiv of DBN in 0.6 mL of
CDCl.sub.3 was studied by recording .sup.1H NMR spectra at various
times for 39 hours. The signals of the olefinic protons due to the
sorbate group of OSM (.delta. 6.2-6.0 and .delta. 7.2) and that of
the newly formed C.dbd.C bond of the monoadducts (.delta. 5.6-5.2)
were monitored in particular. In the course of these experiments,
it was observed that the signals at .delta. 6.2-6.0 and .delta. 7.2
disappeared, while those at .delta. 5.6-5.2 appeared over the first
1.5 hours of the reaction, which indicated the formation of the
monoadducts. The olefinic protons signals of the monoadducts
started to fade away gradually after 1.5 hours and became very weak
by approximately 39 hours. These spectra may imply the formation of
the diadduct.
[0149] Only one monoadduct 2 was isolated in the reaction of OS
with N-acetylcysteamine, while two different monoadducts 3 and 4
were obtained in the reaction of N-acetylcysteamine with OSM. The
varying reactivity of the C.dbd.C of the sorbate group of the
different agents towards nucleophilic attack may account for the
differences.
[0150] When reactions were carried out in the absence of an
N.sub.2/inert gas atmosphere, as an attempt to bind together the
protein bound sulfhydryl groups with OSM, a range of side products
were isolated by column chromatography, as shown below. 30
[0151] Two molecules of octadecyl-3-mercaptopropionate were
oxidized to form a symmetrical Bis(octadecyl 3-mercaptopropionyl)
disulfide 6. The unsymmetrical N-acetylcysteamino octadecyl
3-mercaptopropionyl disulfide 7 was made when one molecule of
octadecyl 3-mercaptopropionate and one molecule of
N-acetylcysteamine were oxidized and coupled. The by-product
S-sorbyl 2-mercapto(N-acetyl)ethylamine 8 was also obtained in the
reaction mixture. It was formed possibly from the attack of the
carbonyl carbon of OSM followed by the displacement of the group
octadecyl 3-mercaptopropionate of OSM by the deprotonated
N-acetylcysteamine thiolate anion. In contrast, the formation of
the disulfide by-products was impossible in similar reactions with
OS.
[0152] The proposed mechanism for the reactions is summarized
below. 31
[0153] The nucleophilic attack by the thiolate anion (--RS--) at
the .delta.-carbon atom of the sorbate group of OS or OSM results
in an enolate intermediate, which protonates at the C-2 position to
give a 2,5-addition monoadduct 2 or 3 (route 1). The 2,5-addition
monoadduct has a double bond that is not conjugated to the carbonyl
group and cannot undergo a farther nucleophilic addition reaction
to yield the desired diadduct compound. According to the results of
the NMR spectral study of the time course of the reaction, the
formation of the diadduct is of the greatest likelihood. In order
to account for the observation, route 2 that leads to the formation
of the 4,5-addition monoadduct suggests a better explanation for
the possibility of the formation of the reaction diadduct. The
resulting enolate intermediate protonates at the C-4 position and
forms a monoadduct.that has a double bond that is conjugated to the
carbonyl group and is capable of reacting further in a nucleophilic
reaction. Subsequent attack by the thiol anion nucleophile at the
3-carbon of the 4,5-addition monoadduct would give the desired
diadduct. Khandelwal (1990) Food Chemistry 37:159 suggested that,
in the presence of a strong base, the 2,5-addition monoadduct may
be converted to the 4,5-addition monoadduct by the abstraction of
the .alpha.-proton and consequent protonation at the .gamma.-carbon
atom in the 2,5-addition monoadduct. However, the attempt to
convert the isolated 2,5-addition monoadduct 3 to the 4,5-addition
monoadduct in the presence of DBN was unsuccessful as determined by
means of .sup.1H NMR analysis. Moreover, the 2,3-addition
monoadduct 4 from the reaction between OSM and N-acetylcysteamine
(route 3) that was isolated was believed to be unreactive to
nucleophiles; thus, the formation of diadduct from 4 is not likely.
The differences in the aforementioned results and the experimental
observation of the time course .sup.1H NMR spectral study may be
accounted for by differences in the experimental conditions.
[0154] The formation of the 4,5-addition monoadduct was not
detected by .sup.1H NMR analysis in this reaction; Khandelwal et
al. have reported similar results for reactions of other thiols
with ethyl and methyl sorbates. The 4,5-addition monoadduct is
believed to be the more stable reaction product as it contains a
C.dbd.C bond that is conjugated to the carbonyl group. No evidence
was obtained for the formation of this more stable monoadduct. One
explanation is that the 4,5-addition monoadduct may have been
formed during the course of the reaction, but it was immediately
attacked by the second equiv of the thiol anion to form the desired
diadduct.
[0155] The foregoing results demonstrate that both the selected
thiol ester OSM and the ordinary ester OS react with
N-acetylcysteamine, in the presence of a base, to form their
corresponding 2,5-monoadducts, and in addition OSM formed a
2,3-addition monoadduct. These reactions demonstrate the capability
of these prospective emollients to be attached to the sulfhydryl
group of the protein residues of the skin, thus giving long-lasting
emolliency effects.
EXAMPLE 2
Synthesis of OCM
[0156] Crotonyl chloride was obtained from Aldrich Chemical, and
octadecyl 3-mercaptopropionate (hereinafter "OMP") was obtained
from Evans Chemetics (Lexington, Mass.); both were used without
further purification. Pyridine was distilled from BaO and stored
over 3 .ANG. molecular sieves. Tetrahydrofuran (hereinafter "THF")
was freshly distilled from sodium/benzophenone. All glassware was
dried with a flame before use.
[0157] To a 1-liter flask containing 13.5 g (0.129 mol) crotonyl
chloride dissolved in approx. 250 mL THF was added dropwise a
solution of 35.2 g (0.098 moles) OMP and 7.7 g (0.097 moles)
pyridine in approx. 75 mL THF. Addition to the stirred solution was
carried out over a period of 10 minutes. A white solid formed
immediately and continued to form. After 1 hour of stirring at room
temperature, the mixture was filtered. The filtrate was rotavapped
by use of a 40.degree. C. bath to yield 35.6 g (88% yield) of a
slurry that solidified to a waxy white solid upon chilling. This
material was purified by silica gel chromatography. A dry column
(3.5 cm.times.60 cm) of 60 .ANG. silica, 230-400 mesh (Baxter) was
poured. Approximately 2.5 g of the solid reaction product was
dissolved in a small volume of chloroform. A small amount of silica
was added, and the mixture was rotavapped. The silica with the OCM
adsorbed was placed at the head of the column. Elution with 3%
(v/v) hexanes in methylene chloride was carried out to yield 1.0 g
of pure OCM as a crisp, white solid (R.sub.f=0.47 in the same
solvent). .sup.1H NMR (CDCl.sub.3) .delta. 0.90 ppm [t, 3 H,
--(CH.sub.2).sub.17CH.sub.3], 1.2-1.3 [s, 30 H,
CH.sub.3(CH.sub.2).sub.15--], 1.6 [m, 2 H, --OCH.sub.2CH.sub.2--],
1.9 [dd, 3 H, CH.sub.3CH.dbd.CH--], 2.6 [t, 2 H, --CH.sub.2C(O)--],
3.18 [t, 2H, --SCH.sub.2--], 4.10 [t, 2H --CO.sub.2CH.sub.2--],
6.09 [m, 1 H, CH.sub.3CH.dbd.CH--], 6.9 [m, 1H,
CH.sub.3CH.dbd.CH--].
[0158] The reaction of OCM with N-acetylcysteamine was carried out
at room temperature as follows: 22.0 mg of OCM was dissolved in 0.6
mL of CDCl.sub.3 and 5.7 .mu.L of N-acetylcysteamine (1 equivalent)
was added. The NMR spectrum was recorded and showed that no
reaction had occurred. Then a catalytic amount (0.1 equiv) of the
base DBN was added, and the NMR spectrum was recorded immediately
and again after 5 minutes. By 5 minutes, more than 60% of the OCM
had reacted as judged by the diminished integration of the
resonances at 6.9 ppm and 6.1 ppm due to the vinyl protons of the
crotonyl moiety of OCM. After 27 minutes, NMR showed that complete
reaction has occurred. A COSY spectrum confirmed that the expected
product, shown earlier herein, had been formed. Nucleophilic attack
by the sulfur atom of N-acetylcysteamine, presumably as the
thiolate anion, at the .beta.-position of the unsaturated thiol
ester generated the expected covalent adduct. NMR characteristics
of the product are as follows: .sup.1H NMR (CDCl.sub.3) .delta.
0.85 ppm [t, 3 H, CH.sub.3(CH.sub.2).sub.17--], 1.2-1.3 [m, 30 H,
--(CH.sub.2).sub.15--]1.24 [dd, 3 H, CH.sub.3CH(S--)CH.sub.2--],
1.6 [m, 2 H, --CO.sub.2CH.sub.2CH.sub.2--], 2.0 [s, 3 H, cysteamine
CH.sub.3], 2.6 [m, 2H, --C(O)SCH.sub.2CH.sub.2--], 2.65 [m, 2H,
cysteamine SCH.sub.2CH.sub.2--], 2.7 [m, 2 H,
CH.sub.3CH(S--)CH.sub.2--], 3.2 [t, 2H, --C(O)SCH.sub.2CH.sub.2--],
3.3 [q, 1 H, CH.sub.3CH(S--)CH.sub.2--], 3.45 [m, 2 H, cysteamine
--SCH.sub.2CH.sub.2NH--], 4.1 [t, 3 H,
--CO.sub.2CH.sub.2(CH.sub.2).sub.16CH.sub.3], 6.2 [br s, 1 H,
cysteamine NH].
EXAMPLE 3
Synthesis of DCPEG
[0159] DCPEG was synthesized according to the following scheme.
32
[0160] Poly(ethylene glycol) (hereinafter "PEG") with an average
molecular weight (M.sub.n) of about 400 was obtained from Aldrich
and was dried by heating at 70.degree. C. under vacuum for three
hours. Triethylamine, methylene chloride and pyridine were purified
by distillation. THF was distilled from Na/benzophenone.
[0161] Preparation of PEG dimesylate was carried out as follows.
PEG (3.65 g, 18 mmol OH-ends) and 3.95 g triethylamine were
dissolved in methylene chloride, chilled to 0.degree. C. and then a
five-fold excess of methanesulfonyl chloride dissolved in methylene
chloride was added dropwise. The solution was stirred at 0.degree.
C. for three hours and then it was rotavapped to a syrup, taken up
in water and the unreacted methanesulfonyl chloride was destroyed
by addition of NaHCO.sub.3. The product was then extracted into
chloroform, dried with MgSO.sub.4 and rotavapped to yield 9.96 g of
a light yellow oil (95% yield).
[0162] .sup.1H NMR (CDCl.sub.3) .delta. 3.07 ppm [s, 6 H,
CH.sub.3SO.sub.2--], 3.6 [m, 28 H, --OCH.sub.2CH.sub.2O--], 3.8 [m,
4 H, --SO.sub.3CH.sub.2CH.sub.2--], 4.4 [m, 4 H,
--SO.sub.3CH.sub.2CH.sub.2--]- .
[0163] To prepare the PEG dithiol, 5.0 g of the PEG dimesylate was
added to an aqueous solution containing 53.8 mg
diethylenetriaminepentaacetic acid and 2.85 g (2 equivalents) of
thiourea. The pH was adjusted to 6.7, and the reaction was refluxed
for 2.5 hours. The reaction was then cooled and the isothiouronium
salt was hydrolyzed by addition of 2.35 g of NaHCO.sub.3 (1.5
equivalents) followed by 1.5 hours of reflux. The solution was
neutralized with 1 M H.sub.2SO.sub.4 and the PEG dithiol was
extracted into chloroform, dried with MgSO.sub.4 and rotavapped to
yield 2.18 g of a light amber oil.
[0164] Coupling of the PEG dithiol with crotonyl chloride to give
DCPEG was carried out as follows. A solution of 2.1 g PEG dithiol
(9.0 mmol SH-ends) and 0.656 g (8.3 mmol) pyridine in 10 mL THF was
placed in an addition funnel and added dropwise to a stirred
solution of 0.857 g (8.5 mmol) crotonyl chloride in 20 mL THF. The
solution instantly became cloudy. After 16 hours the reaction was
rotavapped to dryness and the residue was taken up in chloroform,
washed extensively with aqueous NaHCO.sub.3 and dried to give 1.7 g
of an amber oil (70% yield).
[0165] .sup.1H NMR (CDCl.sub.3) .delta. 1.88 ppm, [dd, J=7.6, 1.7
Hz, 6 H, 2 CH.sub.3--], 2.88 [t, J=6.6 Hz, 4 H, CH.sub.2--], 3.15
[t, J=6.6 Hz, 4H, --CH.sub.2--], 3.6-3.75 [m,
--OCH.sub.2CH.sub.2O--], 6.14 [m, 2 H, 2 CH.sub.3CH.dbd.CH--], 6.91
[m, 2 H, 2 CH.sub.3CH.dbd.CH--].
[0166] The reaction of DCPEG with N-acetylcysteamine was followed
by NMR: 35.6 mg of DCPEG was dissolved in 0.7 mL CDCl.sub.3 and the
spectrum was recorded before and after addition of
N-acetylcysteamine (1 equivalent per crotonyl moiety). Then 0.1
equivalent of DBN was added. The reaction was found to be complete
after 5 minutes, as evidenced by the disappearance of the
resonances at 6.14 and 6.91 ppm which correspond to the protons on
the crotonyl double bond. NMR of the covalent N-acetylcysteamine
adduct confirmed that addition to the .beta.-position of the
.alpha., .beta.-unsaturated thiol ester had occurred.
[0167] The synthesis of DSPEG can be carried out by a procedure
analogous to that described for DCPEG above, except that sorboyl
chloride is used in place of crotonyl chloride.
[0168] CPEG and SPEG can be synthesized by a procedure analogous to
that described for DCPEG above, except the amount of
methanesulfonyl chloride is reduced from a 5-fold excess to
approximately one half equivalent (per OH-ends) to yield a mixture
of unmodified PEG, PEG monomesylate and PEG dimesylate. The
purified PEG monomesylate can then be treated with
diethylenetriaminepentaacetic acid and thiourea, followed by
NaHCO.sub.3, to yield PEG monothiol. PEG monothiol can be coupled
to crotonyl chloride to yield CPEG, or to sorboyl chloride to yield
SPEG.
EXAMPLE 4
Preparation of Compositions
[0169] A suitable cream containing OCM for application to the skin
was formulated as follows.
1 Ingredient Percent by weight (wt. %) A: Water 67.7 Aculyn 33 2.5
B: Mineral Oil 20.0 Lanolin 4.0 Petrolatum 4.0 Ethomeen C-25 0.7 C:
Triethanolamine 1.1
[0170] Mixing procedure:
[0171] First, 86 mg of OCM and 287 mg of part B were gently warmed
for a few seconds until OCM dissolved. Second, the solution was
placed in a 60-70.degree. C. bath for approximately 5 seconds.
Then, 702 mg of part A also at 60-70.degree. C. was added to the
solution. After addition of 11 mg of part C, the sample was quickly
vortex-mixed and chilled to yield a cream. The pH was found to be
8.2, in the range desired for deprotonation of cysteine sulfhydryl
groups, tyrosine's --OH group, and protein --NH.sub.3.sup.+
groups.
EXAMPLE 5
Preparation of Composition
[0172] A suitable cream for application to the skin is formulated
as follows:
2 Ingredient Percent by weight (wt. %) A: Water 67.7 Aculyn 33 2.5
B: Mineral Oil 20.0 Lanolin 4.0 Petrolatum 4.0 Ethomeen C-25 0.7 C:
Triethanolamine 1.1
[0173] Mixing procedure:
[0174] A suitable quantity of CPEG, DCPEG, SPEG, DSPEG, OSM, OCM,
CMC or SMC or some combination thereof is added to part B and the
mixture is brought to 60-70.degree. C. After addition of part A,
also at 60-70.degree. C., part C is added and the sample is mixed
and quickly chilled to yield a cream. The amount of part C is
adjusted to produce a pH of approximately 8.2, in the range desired
for deprotonation of cysteine sulfhydryl groups, tyrosine hydroxyl
groups, and --NH.sub.3.sup.+ groups of lysine and the N-terminus of
proteins.
[0175] All of the references cited herein are incorporated herein
in their entirety.
* * * * *