U.S. patent application number 15/042918 was filed with the patent office on 2016-06-09 for compositions and methods for stimulating collagen synthesis in the skin.
This patent application is currently assigned to Avon Products, Inc.. The applicant listed for this patent is Avon Products, Inc.. Invention is credited to Hong Hu, Cheng S. HWANG, John W. Lyga.
Application Number | 20160158131 15/042918 |
Document ID | / |
Family ID | 48136459 |
Filed Date | 2016-06-09 |
United States Patent
Application |
20160158131 |
Kind Code |
A1 |
HWANG; Cheng S. ; et
al. |
June 9, 2016 |
Compositions and Methods for Stimulating Collagen Synthesis in the
Skin
Abstract
Cosmetic compositions comprising substituted carbamoyl
heterocyclic analogs and methods of using such compositions to
impart anti-aging benefits to the skin are disclosed. The
substituted carbamoyl heterocyclic analogs are believed to have
modulatory activity against one or more biochemical pathways
implicated in skin aging.
Inventors: |
HWANG; Cheng S.; (New
Milford, NJ) ; Lyga; John W.; (Basking Ridge, NJ)
; Hu; Hong; (Basking Ridge, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Avon Products, Inc. |
Suffern |
NY |
US |
|
|
Assignee: |
Avon Products, Inc.
Suffern
NY
|
Family ID: |
48136459 |
Appl. No.: |
15/042918 |
Filed: |
February 12, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13279605 |
Oct 24, 2011 |
9289365 |
|
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15042918 |
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Current U.S.
Class: |
514/236.5 ;
514/254.05; 514/254.07; 514/406 |
Current CPC
Class: |
A61K 31/496 20130101;
A61K 8/4946 20130101; A61K 31/5377 20130101; A61K 8/494 20130101;
A61K 31/4155 20130101; A61Q 19/06 20130101; A61K 2800/78 20130101;
A61Q 19/00 20130101; A61K 8/49 20130101; A61K 8/496 20130101; A61Q
19/02 20130101; A61Q 19/08 20130101; A61P 17/00 20180101 |
International
Class: |
A61K 8/49 20060101
A61K008/49; A61Q 19/08 20060101 A61Q019/08; A61Q 19/00 20060101
A61Q019/00 |
Claims
1. A cosmetic composition for improving the aesthetic appearance of
human skin comprising a cosmetically acceptable vehicle in the form
of a water-in-oil or oil-in-water emulsion, and an effective amount
of a collagen-stimulating compound of formula I: ##STR00061##
where: .epsilon..sub.1-.epsilon..sub.3 are independently selected
from CR.sub.a, N, or NR.sup.b, and wherein the ring A is optionally
aromatic or may comprise zero, one, or two double bonds; with the
proviso that at least one of .epsilon..sub.1, .epsilon..sub.2, or
.epsilon..sub.3 is NR.sup.b; and in the case where .epsilon..sub.3
is NR.sup.b, then .epsilon..sub.2 is a nitrogen atom, and the bond
between .epsilon..sub.1 and .epsilon..sub.2 is a double bond; in
the case where .epsilon..sub.2 is NR.sup.b, then .epsilon..sub.1 is
a nitrogen atom, and the bond between .epsilon..sub.1 and the
carbon atom to which R.sub.1 is attached is a double bond; and in
the case where .epsilon..sub.1 is NR.sup.b, then .epsilon..sub.2 is
a nitrogen atom, and the bond between .epsilon..sub.2 and
.epsilon..sub.3 is a double bond; R.sup.b is an aryl group of the
form, ##STR00062## R.sub.1 is selected from a group consisting of
H, or a C.sub.1-6 alkyl, alkenyl, alkynyl, aryl, or heteroaryl
group optionally substituted with one or more C.sub.1-6 alkyl,
alkenyl, alkynyl, aryl, or R.sub.a groups; R.sub.2 and R.sub.3 are
independently selected from the group consisting of C.sub.1-6
alkyl, alkenyl, alkynyl, and aryl, which could be optionally
connected to form together with the nitrogen atom to which they are
attached a 5, 6, or 7 membered ring, saturated or unsaturated,
which optionally further comprises one or more heteroatoms in the
ring, selected from oxygen, nitrogen, or sulfur, and wherein
R.sub.2 and R.sub.3 are optionally substituted with one or more
groups R.sub.a; R.sub.4-R.sub.8 are independently selected from the
group consisting of R.sub.a, C.sub.1-6 alkyl, alkenyl, alkynyl, and
aryl, each of which could be optionally further substituted with
one or more groups R.sub.a; wherein R.sub.a is independently, at
each occurrence, selected from hydrogen, halogen (F, Cl, Br, or I);
--OH; --NH.sub.2; --NR.sup.NR.sup.N; --SH; --CN; oxo; --CHO;
--CO.sub.2H; --O--(C.dbd.O)--H; --O--(C.dbd.O)--C.sub.1-10 alkyl;
--O--(C.dbd.O)-Ar; --(C.dbd.O)--O--C.sub.1-10 alkyl;
--(C.dbd.O)--O--Ar; --(C.dbd.O)--NR.sup.NR.sup.N; --O--C.sub.1-10
alkyl; --O--Ar; --S--C.sub.1-10 alkyl; --S--Ar; --Ar; --C.sub.1-10
alkyl; --NR.sup.N--CHO; --NR.sup.N--(C.dbd.O)--C.sub.1-10 alkyl;
--C.sub.1-10 alkyl-O--C.sub.1-10 alkyl; perfluoroalkyl; epoxy;
azido; thiocyanate; --SO.sub.2--R.sup.N; or nitro; wherein R.sup.N
is independently selected, at each occurrence, from hydrogen or a
C.sub.1-16 hydrocarbon radical, optionally substituted with a group
R.sub.a; and where any two adjacent groups R.sup.N may together
form a 5, 6, or 7 membered ring; or a cosmetically acceptable salt
thereof.
2. The cosmetic composition to claim 1, wherein said compound of
structure (I) is selected from the group of compounds consisting
of: (a) ##STR00063## (b) ##STR00064## (c) ##STR00065## (d)
##STR00066## and mixtures thereof, where R.sub.1, R.sub.4-R.sub.8,
R.sub.a, and R.sup.N are as defined in claim 22; and Q is a 3-7
membered heterocyclic ring, optionally aromatic, and which may
comprise zero, one, or two double bonds; X is selected from
CR.sub.a, C(R.sub.a).sub.2, N, O, S, NR.sup.N, or a bond (i.e.,
absent); and L.sub.1 and L.sub.2 are independently selected from a
bond or a group X.sub.1-(L.sub.3).sub.l-X.sub.2, where "l" is an
integer from 0 to 4; where L.sub.3 is selected from CR.sub.a,
C(R.sub.a).sub.2, or a bond; and X.sub.1 and X.sub.2 are
independently selected from N, NR.sup.N, O, S, or a bond; or a
cosmetically acceptable salt thereof.
3. The cosmetic composition according to claim 2, wherein L.sub.1
is --(CH.sub.2).sub.m--, and L.sub.2 is --(CH.sub.2).sub.n--,
wherein "m" and "n" are independently selected from integers from
1-3; and X is selected from N, NR.sup.N, S, O, or a bond; or a
cosmetically acceptable salt thereof.
4. The cosmetic composition according to claim 3, wherein ring Q is
a heterocycle selected from the group consisting of aziridine,
diaziridine, oxaziridine, azetidine, diazetidine, oxazetidine,
pyrrolidine, oxazolidine, thiazolidine, imidazolidine,
pyrazolidine, pyrrole, imidazole, pyrazole, 1,3,4-triazole,
1,2,3-triazole, piperidine, morpholine, piperazine, and
thiomorpholine, each being optionally substituted with one or more
groups R.sub.a.
5. The cosmetic composition according to claim 4, wherein ring Q is
a heterocycle selected from the group consisting of pyrrolidine,
morpholine, and piperazine, each being optionally substituted with
one or more groups R.sub.a.
6. The composition according to claim 5, wherein said compound has
the structure I.sub.a.
7. The composition according to claim 6, wherein R.sub.a is
hydrogen, methyl, ethyl, propyl, and R.sub.1 is hydrogen, methyl,
ethyl, or propyl.
8. The composition according to claim 7, wherein R.sub.4 to R.sub.8
are independently hydrogen, methyl, ethyl, propyl, chloro, or
bromo, with at least two of R.sub.4 to R.sub.8 being hydrogen.
9. The composition according to claim 6, wherein the heterocycle is
pyrrolidine.
10. The composition according to claim 6, wherein the heterocycle
is morpholine.
11. The composition according to claim 6, wherein the heterocycle
is piperazine.
12. The method according to claim 1, wherein the compound has the
structure: ##STR00067## and wherein R.sup.b, R.sub.a, R.sub.1, and
Q are as set forth below: TABLE-US-00006 R.sup.b R.sub.a R.sub.1
##STR00068## ##STR00069## ##STR00070## H ##STR00071## ##STR00072##
##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## H
##STR00078## ##STR00079## ##STR00080## H ##STR00081## ##STR00082##
##STR00083## H ##STR00084##
13. The method according to claim 1, wherein the compound has the
structure: ##STR00085## and wherein R.sup.b, R.sub.a, R.sub.1, and
Q are as set forth below: TABLE-US-00007 R.sup.b R.sub.a R.sub.1
##STR00086## ##STR00087## ##STR00088## H ##STR00089## ##STR00090##
##STR00091## H ##STR00092##
14. The cosmetic composition according to claim 1 wherein said
effective amount comprises from about 0.0001% to about 1% by weight
of the total composition.
15. The cosmetic composition according claim 14, wherein said
effective amount is between about 0.001% to about 0.5% by weight of
the total composition.
16. The cosmetic composition according to claim 14, wherein said
effective amount is between about 0.01% to about 0.2% by weight of
the total composition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/279,605, filed on Oct. 24, 2011, the entirety of which
is herein incorporated by reference in its entirety.
FIELD OF INVENTION
[0002] The present invention relates generally to compositions and
methods for topical application to the skin which comprise
substituted carbamoyl heterocyclic analogs and the use of such
compositions to improve the aesthetic appearance of the skin.
BACKGROUND OF THE INVENTION
[0003] Collagen is the body's major structural protein and is
composed of three protein chains wound together in a tight triple
helix. This unique structure gives collagen a greater tensile
strength than steel. Approximately 33 percent of the protein in the
body is collagen. This protein supports tissues and organs and
connects these structures to bones. In fact, bones are also
composed of collagen combined with certain minerals such as calcium
and phosphorus. Collagen plays a key role in providing the
structural scaffolding surrounding cells that helps to support cell
shape and differentiation, similar to how steel rods reinforce a
concrete block. The mesh-like collagen network binds cells together
and provides the supportive framework or environment in which cells
develop and function, and tissues and bones heal.
[0004] Collagen is created by fibroblasts, which are specialized
skin cells located in the dermis. Fibroblasts also produce other
skin structural proteins such as elastin (a protein which gives the
skin its ability to snap back) and glucosaminoglycans (GAGs). GAGs
make up the ground substance that keeps the dermis hydrated. In
order to signal or turn on the production of skin structural
proteins, fibroblast cells have specially shaped receptors on their
outside membranes that act as binding sites to which signal
molecules with a matching shape can fit. When the receptors are
bound by the correct combination of signal molecules (called
fibroblast growth factors, or FGFs), the fibroblast begins the
production of collagen. The stimulation of collagen gives the skin
its strength, durability, and smooth, plump appearance.
[0005] It is therefore an object of the invention to provide new
compositions and methods for stimulating collagen. It is a further
object of the invention to improve the overall appearance of skin,
including treating, reversing, and/or preventing signs of aging,
such as skin wrinkles, by stimulating collagen, with cosmetic
compositions comprising effective amounts of substituted carbamoyl
heterocyclic analogs.
[0006] The foregoing discussion is presented solely to provide a
better understanding of nature of the problems confronting the art
and should not be construed in any way as an admission as to prior
art nor should the citation of any reference herein be construed as
an admission that such reference constitutes "prior art" to the
instant application.
SUMMARY OF THE INVENTION
[0007] In accordance with the foregoing objectives and others, it
has surprisingly been found that substituted carbamoyl heterocyclic
analogs are stimulators of collagen, and thus are beneficial agents
against various signs of intrinsic aging and photo-aging of
skin.
[0008] In one aspect of the invention, a method is provided for
improving the aesthetic appearance of human skin comprising
topically applying to an area of the skin in need thereof an
effective amount of a substituted carbamoyl heterocyclic analog or
a cosmetically acceptable salt thereof in a cosmetically acceptable
vehicle.
[0009] In another aspect of the invention, cosmetic compositions
are provided for improving the aesthetic appearance of skin
comprising, in a cosmetically acceptable vehicle, an effective
amount of a substituted carbamoyl heterocyclic analog having the
structure of formula I:
##STR00001##
[0010] where .epsilon..sub.1-.epsilon..sub.3 are independently
selected from CR.sub.a, N, or NR.sup.b, and wherein the ring A is
optionally aromatic or may comprise zero, one, or two double
bonds;
[0011] with the proviso that at least one of .epsilon..sub.1,
.epsilon..sub.2, or .epsilon..sub.3 is NR.sup.b; and in the case
where .epsilon..sub.3 is NR.sup.b, then .epsilon..sub.2 is a
nitrogen atom, and the bond between .epsilon..sub.1 and
.epsilon..sub.2 is a double bond; in the case where .epsilon..sub.2
is NR.sup.b, then .epsilon..sub.1 is a nitrogen atom, and the bond
between .epsilon..sub.1 and the carbon atom to which R.sub.1 is
attached is a double bond; and in the case where .epsilon..sub.1 is
NR.sup.b, then .epsilon..sub.2 is a nitrogen atom, and the bond
between .epsilon..sub.2 and .epsilon..sub.3 is a double bond;
[0012] R.sup.b is an aryl group of the form,
##STR00002##
[0013] R.sub.1 is selected from a group consisting of H, or a
C.sub.1-20 hydrocarbons, independently selected from alkyl,
cycloalkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, alkylaryl,
heteroalkyl, heteroarylalkyl, arylalkyl, aryl, aminoalkyl,
aminoalkylheteroaryl, alkyloxyaryl, alkyloxyheteroaryl, or
heteroaryl group optionally substituted with one or more C.sub.1-20
alkyl, alkenyl, alkynyl, aryl, or R.sub.a groups;
[0014] R.sub.2 and R.sub.3 are independently selected from the
group consisting of C.sub.1-6 alkyl, alkenyl, alkynyl, and aryl,
which could be optionally connected to form together with the
nitrogen atom to which they are attached a 5, 6, or 7 membered
ring, saturated or unsaturated, which optionally further comprises
one or more heteroatoms in the ring, selected from oxygen,
nitrogen, or sulfur, and wherein R.sub.2 and R.sub.3 are optionally
substituted with one or more groups R.sub.a;
[0015] R.sub.4-R.sub.8 are independently selected from the group
consisting of R.sub.a, C.sub.1-6 alkyl, alkenyl, alkynyl, and aryl,
each of which could be optionally further substituted with one or
more groups R.sub.a;
[0016] wherein R.sub.a is independently, at each occurrence,
selected from hydrogen, halogen (F, Cl, Br, or I); --OH;
--NH.sub.2; --NR.sup.NR.sup.N; --SH; --CN; oxo; --CHO; --CO.sub.2H;
--O--(C.dbd.O)--H; --O--(C.dbd.O)--C.sub.1-10 alkyl;
--O--(C.dbd.O)-Ar; --(C.dbd.O)--O--C.sub.1-10 alkyl;
--(C.dbd.O)--O--Ar; --(C.dbd.O)--NR.sup.NR.sup.N; --O--C.sub.1-10
alkyl; --O--Ar; --S--C.sub.1-10 alkyl; --S--Ar; --Ar; --C.sub.1-10
alkyl; --NR.sup.N--CHO; --NR.sup.N--(C.dbd.O)--C.sub.1-10 alkyl;
--C.sub.1-10 alkyl-O--C.sub.1-10 alkyl; perfluoroalkyl; epoxy;
azido; thiocyanate; --SO.sub.2--R.sup.N; or nitro;
[0017] wherein R.sup.N is independently selected, at each
occurrence, from hydrogen or a C.sub.1-16 hydrocarbon radical,
optionally substituted with a group R.sub.a; and where any two
adjacent groups R.sup.N may together form a 5, 6, or 7 membered
ring;
[0018] and wherein any two adjacent R groups can be taken together
to form a 5-7 member ring, saturated or unsaturated, optionally
incorporating O, S, N heteroatoms or substituted with alkyl,
haloalkyl, or alkoxy groups;
[0019] or a cosmetically acceptable salt thereof.
[0020] Also provided is a method of treating one or more signs of
skin aging comprising topically applying to skin in need thereof a
collagen-stimulating substituted carbamoyl heterocyclic analog
according to formula I or a cosmetically acceptable salt
thereof.
[0021] In another aspect of the invention, a method of treating,
reducing, and/or preventing fine lines and/or wrinkles, sagging in
human skin, loss of elasticity and molting is provided, comprising
topically applying to skin in need thereof, including applying
directly to a wrinkle or fine line, a composition comprising a
collagen-stimulating substituted carbamoyl heterocyclic analog
according to formula I or a cosmetically acceptable salt
thereof.
[0022] These and other aspects of the present invention will be
better understood by reference to the following detailed
description.
DETAILED DESCRIPTION
[0023] All terms used herein are intended to have their ordinary
meaning unless otherwise provided. By "cosmetically acceptable" is
meant that a particular component is generally regarding as safe
and non-toxic at the levels employed. The term "prevent," as used
herein, includes delaying the onset or progression of a particular
sign of skin aging. The term "thin skin" includes skin that becomes
thinner with chronological aging as well as prematurely thinned
skin, which may be caused, for example, by photo-aging. The phrase
"individual in need thereof" refers to a human that could benefit
from improved dermal appearance or health, including males or
females. The term "skin" includes, without limitation, the lips,
skin of the face, hands, arms, neck, legs, in particular thighs,
and chest. As used herein, the term "consisting essentially of" is
intended to limit the invention to the specified materials or steps
and those that do not materially affect the basic and novel
characteristics of the claimed invention, as understood from a
reading of this specification.
[0024] The present invention provides compositions for topical
application which comprise an effective amount of substituted
carbamoyl heterocyclic analogs or a related compound to treat,
reverse, ameliorate and/or prevent signs of skin aging. Such signs
of skin aging include without limitation, the following: [0025] (a)
treatment, reduction, and/or prevention of fine lines or wrinkles,
[0026] (b) reduction of skin pore size, [0027] (c) improvement in
skin thickness, plumpness, and/or tautness; [0028] (d) improvement
in skin suppleness and/or softness; [0029] (e) improvement in skin
tone, radiance, and/or clarity; [0030] (f) improvement in
procollagen, collagen production, and/or elastin production; [0031]
(g) improvement in maintenance and remodeling of collagen and/or
elastin; [0032] (h) improvement in skin texture and/or promotion of
retexturization; [0033] (i) improvement in skin barrier repair
and/or function; [0034] (j) improvement in appearance of skin
contours; [0035] (k) restoration of skin luster and/or brightness;
[0036] (l) replenishment of essential nutrients and/or constituents
in the skin; [0037] (m) decreased by aging and/or menopause; [0038]
(n) improvement in skin moisturization; [0039] (o) increase in skin
elasticity and/or resiliency; [0040] (p) treatment, reduction,
and/or prevention of skin sagging; [0041] (q) reduction of pigment
spots; [0042] (s) improving the appearance of acne scars or marks;
[0043] (t) improving the appearance of stretch marks; and/or [0044]
(u) improvement in the appearance of cellulite.
[0045] In practice, the compositions of the invention are applied
to skin in need of treatment. That is, skin which suffers from a
deficiency or loss in any of the foregoing attributes or which
would otherwise benefit from improvement in any of the foregoing
skin attributes.
[0046] In certain preferred embodiments the compositions and
methods of the invention are directed to the prevention, treatment,
and/or amelioration of fine lines and/or wrinkles in the skin. In
this case, the compositions are applied to skin in need of
treatment, by which is meant skin having wrinkles and/or fine
lines. Preferably, the compositions are applied directly to the
fine lines and/or wrinkles. The compositions and methods are
suitable for treating fine lines and/or wrinkles on any surface of
the skin, including without limitation, the skin of the face, neck,
and/or hands.
[0047] The cosmetic compositions for treating a skin condition
associated with loss of collagen and/or elastin fiber comprise, in
a cosmetically acceptable vehicle, an amount of a substituted
carbamoyl heterocyclic analogs effective to enhance collagen. These
collagen enhancing/stimulating agents may have the structure of
formula (I):
##STR00003##
[0048] where .epsilon..sub.1-.epsilon..sub.3 are independently
selected from CR.sub.a, N, or NR.sup.b, and wherein the ring A is
optionally aromatic or may comprise zero, one, or two double
bonds;
[0049] with the proviso that at least one of .epsilon..sub.1,
.epsilon..sub.2, or .epsilon..sub.3 is NR.sup.b; and in the case
where .epsilon..sub.3 is NR.sup.b, then .epsilon..sub.2 is a
nitrogen atom, and the bond between .epsilon..sub.1 and
.epsilon..sub.2 is a double bond; in the case where .epsilon..sub.2
is NR.sup.b, then .epsilon..sub.1 is a nitrogen atom, and the bond
between .epsilon..sub.1 and the carbon atom to which R.sub.1 is
attached is a double bond; and in the case where .epsilon..sub.1 is
NR.sup.b, then .epsilon..sub.2 is a nitrogen atom, and the bond
between .epsilon..sub.2 and .epsilon..sub.3 is a double bond;
[0050] R.sup.b is an aryl group of the form,
##STR00004##
[0051] R.sub.1 is selected from a group consisting of H, or a
C.sub.1-20 hydrocarbons, independently selected from alkyl,
cycloalkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, alkylaryl,
heteroalkyl, heteroarylalkyl, arylalkyl, aryl, aminoalkyl,
aminoalkylheteroaryl, alkyloxyaryl, alkyloxyheteroaryl, or
heteroaryl group optionally substituted with one or more C.sub.1-20
alkyl, alkenyl, alkynyl, aryl, or R.sub.a groups;
[0052] R.sub.2 and R.sub.3 are independently selected from the
group consisting of C.sub.1-6 alkyl, alkenyl, alkynyl, and aryl,
which could be optionally connected to form together with the
nitrogen atom to which they are attached a 5, 6, or 7 membered
ring, saturated or unsaturated, which optionally further comprises
one or more heteroatoms in the ring, selected from oxygen,
nitrogen, or sulfur, and wherein R.sub.2 and R.sub.3 are optionally
substituted with one or more groups R.sub.a;
[0053] R.sub.4-R.sub.8 are independently selected from the group
consisting of R.sub.a, C.sub.1-6 alkyl, alkenyl, alkynyl, and aryl,
each of which could be optionally further substituted with one or
more groups R.sub.a;
[0054] wherein R.sub.a is independently, at each occurrence,
selected from hydrogen, halogen (F, Cl, Br, or I); --OH;
--NH.sub.2; --NR.sup.NR.sup.N; --SH; --CN; oxo; --CHO; --CO.sub.2H;
--O--(C.dbd.O)--H; --O--(C.dbd.O)--C.sub.1-10 alkyl;
--O--(C.dbd.O)-Ar; --(C.dbd.O)--O--C.sub.1-10 alkyl;
--(C.dbd.O)--O--Ar; --(C.dbd.O)--NR.sup.NR.sup.N; --O--C.sub.1-10
alkyl; --O--Ar; --S--C.sub.1-10 alkyl; --S--Ar; --Ar; --C.sub.1-10
alkyl; --NR.sup.N--CHO; --NR.sup.N--(C.dbd.O)--C.sub.1-10 alkyl;
--C.sub.1-10 alkyl-O--C.sub.1-10 alkyl; perfluoroalkyl; epoxy;
azido; thiocyanate; --SO.sub.2--R.sup.N; or nitro;
[0055] wherein R.sup.N is independently selected, at each
occurrence, from hydrogen or a C.sub.1-16 hydrocarbon radical,
optionally substituted with a group R.sub.a; and where any two
adjacent groups R.sup.N may together form a 5, 6, or 7 membered
ring;
[0056] and wherein any two adjacent R groups can be taken together
to form a 5-7 member ring, saturated or unsaturated, optionally
incorporating O, S, N heteroatoms or substituted with alkyl,
haloalkyl, or alkoxy groups;
[0057] and wherein any two adjacent R groups can be taken together
to form a 5-7 member ring, saturated or unsaturated, optionally
incorporating O, S, and/or N heteroatoms or substituted with alkyl,
haloalkyl, or alkoxy groups;
[0058] and wherein any R group may be optionally substituted with
one or more substituents selected independently at each occurrence
from hydrogen; --F; --Cl; --Br; --I; --OH, --OR*; --NH.sub.2;
--NHR*; --N(R*).sub.2; --N(R*).sub.3+; --N(R*)--OH;
--N(.fwdarw.O)(R*).sub.2; --O--N(R*).sub.2; --N(R*)--O--R*;
--N(R*)--N(R*).sub.2; --C.dbd.N--R*; --N.dbd.C(R*).sub.2;
--C.dbd.N--N(R*).sub.2; --C(.dbd.NR*)--N(R*).sub.2; --SH; --SR*;
--CN; --NC; --CHO; --CO.sub.2H; --CO.sub.2--; --CO.sub.2R*;
--(C.dbd.O)--S--R*; --O--(C.dbd.O)--H; --O--(C.dbd.O)--R*;
--S--(C.dbd.O)--R*; --(C.dbd.O)--NH.sub.2;
--(C.dbd.O)--N(R*).sub.2; --(C.dbd.O)--NHNH.sub.2;
--O--(C.dbd.O)--NHNH.sub.2; --(C.dbd.S)--NH.sub.2;
--(C.dbd.S)--N(R*).sub.2; --N(R*)--CHO; --N(R*)--(C.dbd.O)--R*;
--(C.dbd.NR)--O--R*; --O--(C.dbd.NR*)--R*, --SCN; --NCS; --NSO;
--SSR*; --N(R*)--C(.dbd.O)--N(R*).sub.2;
--N(R*)--C(.dbd.S)--N(R*).sub.2; --SO.sub.2--R*;
--O--S(.dbd.O).sub.2--R*; --S(.dbd.O).sub.2--OR*;
--N(R*)--SO.sub.2--R*; --SO.sub.2--N(R*).sub.2; --O--SO.sub.3--;
--O--S(.dbd.O).sub.2--OR*; --O--S(.dbd.O)--OR*; --O--S(.dbd.O)--R*;
--S(.dbd.O)--OR*; --S(.dbd.O)--R*; --NO; --NO.sub.2; --NO.sub.3;
--O--NO; --O--NO.sub.2; --N.sub.3; --N.sub.2--R*;
--N(C.sub.2H.sub.4); --Si(--R*).sub.3; --CF.sub.3; --O--CF.sub.3;
--(C.dbd.O)--R*; --PR*.sub.2; --O--P(.dbd.O)(OR*).sub.2;
--P(.dbd.O)(OR*).sub.2; .dbd.O; .dbd.S; .dbd.NR*; an aliphatic
C.sub.1-C.sub.20 hydrocarbon radical; a C.sub.1-C.sub.20 aromatic
hydrocarbon radical; or a C.sub.1-C.sub.20 heteroaryl radical;
where R* is independently at each occurrence hydrogen or a
saturated, partially saturated, or aromatic C.sub.1-C.sub.20
hydrocarbon radical (preferably a C.sub.1-C.sub.6 hydrocarbon, or a
C.sub.1-C.sub.3 hydrocarbon) or halogenated derivative thereof;
[0059] or a cosmetically acceptable salt thereof.
[0060] Any nitrogen atom may be optionally oxidized to the N-oxide
or can be quarternized, for example with lower alkyl halides, such
as methyl, ethyl, propyl, and butyl chloride, bromides, and
iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and
diamyl sulfates, long chain halides such as decyl, lauryl, myristyl
and stearyl chlorides, bromides and iodides, aralkyl halides such
as benzyl and phenethyl bromides, to name a few.
[0061] In one embodiment according to formula (I), .epsilon..sub.1
is preferably a nitrogen atom, .epsilon..sub.2 is a group NR.sup.b
when R.sup.b is a substituted aryl ring, and the
collagen-stimulating compound is a substituted carbamoyl
heterocyclic analog having the structure shown in formula (Ia):
##STR00005##
[0062] where, R.sub.1, and R.sub.4-R.sub.8, R.sub.a, and R.sup.N
are as defined as above;
[0063] Q is a 3-7 membered heterocyclic ring, optionally aromatic,
and which may comprise zero, one, or two double bonds;
[0064] X is selected from CR.sub.a, C(R.sub.a).sub.2, N, O, S,
NR.sup.N, or a bond (i.e. absent); and
[0065] L.sub.1 and L.sub.2 are independently selected from a bond
or a group X.sub.1-(L.sub.3).sub.l-X.sub.2, where "l" is an integer
from 0 to 4; where L.sub.3 is selected from CR.sub.a,
C(R.sub.a).sub.2, or a bond; and X.sub.1 and X.sub.2 are
independently selected from N, NR.sup.N, O, S, or a bond; or a
cosmetically acceptable salt thereof.
[0066] In one embodiment according to formula (Ia), L.sub.1 is
--(CH.sub.2).sub.m--, and L.sub.2 is --(CH.sub.2).sub.n--, wherein
"m" and "n" are independently selected from integers from 1-3; and
X is selected from N, NR.sup.N, S, O, or a bond; or a cosmetically
acceptable salt thereof.
[0067] In another embodiment according to formula (Ia), the Q is a
heterocycle selected from the group consisting of aziridine,
diaziridine, oxaziridine, azetidine, diazetidine, oxazetidine,
pyrrolidine, oxazolidine, thiazolidine, imidazolidine,
pyrazolidine, pyrrole, imidazole, pyrazole, 1,3,4-triazole,
1,2,3-triazole, piperidine, morpholine, piperazine, and
thiomorpholine, each being optionally substituted with one or more
groups R.sub.a, or a cosmetically acceptable salt thereof.
[0068] In a preferred embodiment according to formula (Ia), Q is a
heterocycle selected from the group consisting of pyrrolidine,
morpholino, and piperazine, each being optionally substituted with
one or more groups R.sub.a, or a cosmetically acceptable salt
thereof.
[0069] In another embodiment according to formula (I),
.epsilon..sub.2 is preferably a nitrogen atom, .epsilon..sub.3 is a
group NR.sup.b when R.sup.b is a substituted aryl ring, and the
collagen-stimulating compound is a substituted carbamoyl
heterocyclic analog having the structure shown in formula (Ib):
##STR00006##
[0070] where, R.sub.1, and R.sub.4-R.sub.8, R.sub.a, and R.sup.N
are as defined above;
[0071] Q is a 3-7 membered heterocyclic ring, optionally aromatic,
and which may comprise zero, one, or two double bonds;
[0072] X is selected from CR.sub.a, C(R.sub.a).sub.2, N, O, S,
NR.sup.N, or a bond (i.e. absent); and
[0073] L.sub.1 and L.sub.2 are independently selected from a bond
or a group X.sub.1-(L.sub.3).sub.l-X.sub.2, where "l" is an integer
from 0 to 4; where L.sub.3 is selected from CR.sub.a,
C(R.sub.a).sub.2, or a bond; and X.sub.1 and X.sub.2 are
independently selected from N, NR.sup.N, O, S, or a bond; or a
cosmetically acceptable salt thereof.
[0074] In one embodiment according to formula (Ib), L.sub.1 is
--(CH.sub.2).sub.m--, and L.sub.2 is --(CH.sub.2).sub.n--, wherein
"m" and "n" are independently selected from integers from 1-3; and
X is selected from N, NR.sup.N, S, O, or a bond; or a cosmetically
acceptable salt thereof.
[0075] In another embodiment according to formula (Ib), the Q is a
heterocycle selected from the group consisting of aziridine,
diaziridine, oxaziridine, azetidine, diazetidine, oxazetidine,
pyrrolidine, oxazolidine, thiazolidine, imidazolidine,
pyrazolidine, pyrrole, imidazole, pyrazole, 1,3,4-triazole,
1,2,3-triazole, piperidine, morpholine, piperazine, and
thiomorpholine, each being optionally substituted with one or more
groups R.sub.a, or a cosmetically acceptable salt thereof.
[0076] In a preferred embodiment according to formula (Ib), Q is a
heterocycle selected from the group consisting of pyrrolidine,
morpholino, and piperazine, each being optionally substituted with
one or more groups R.sub.a, or a cosmetically acceptable salt
thereof.
[0077] In another embodiment according to formula (I),
.epsilon..sub.1 and .epsilon..sub.2 are preferably nitrogen atoms,
.epsilon..sub.3 is a group NR.sup.b when R.sup.b is a substituted
aryl ring, and the collagen-stimulating compound is a substituted
carbamoyl heterocyclic analog having the structure shown in formula
(Ic):
##STR00007##
[0078] where, R.sub.1, and R.sub.4-R.sub.8, R.sub.a, and R.sup.N
are as defined as above;
[0079] Q is a 3-7 membered heterocyclic ring, optionally aromatic,
and which may comprise zero, one, or two double bonds;
[0080] X is selected from CR.sub.a, C(R.sub.a).sub.2, N, O, S,
NR.sup.N, or a bond (i.e. absent); and
[0081] L.sub.1 and L.sub.2 are independently selected from a bond
or a group X.sub.1-(L.sub.3).sub.l-X.sub.2, where "l" is an integer
from 0 to 4; where L.sub.3 is selected from CR.sub.a,
C(R.sub.a).sub.2, or a bond; and X.sub.1 and X.sub.2 are
independently selected from N, NR.sup.N, O, S, or a bond; or a
cosmetically acceptable salt thereof.
[0082] In one embodiment according to formula (Ic), L.sub.1 is
--(CH.sub.2).sub.m--, and L.sub.2 is --(CH.sub.2).sub.n--, wherein
"m" and "n" are independently selected from integers from 1-3; and
X is selected from N, NR.sup.N, S, O, or a bond; or a cosmetically
acceptable salt thereof.
[0083] In another embodiment according to formula (Ic), the Q is a
heterocycle selected from the group consisting of aziridine,
diaziridine, oxaziridine, azetidine, diazetidine, oxazetidine,
pyrrolidine, oxazolidine, thiazolidine, imidazolidine,
pyrazolidine, pyrrole, imidazole, pyrazole, 1,3,4-triazole,
1,2,3-triazole, piperidine, morpholine, piperazine, and
thiomorpholine, each being optionally substituted with one or more
groups R.sub.a, or a cosmetically acceptable salt thereof.
[0084] In a preferred embodiment according to formula (Ic), Q is a
heterocycle selected from the group consisting of pyrrolidine,
morpholino, and piperazine, each being optionally substituted with
one or more groups R.sub.a, or a cosmetically acceptable salt
thereof.
[0085] In another embodiment according to formula (I),
.epsilon..sub.2 and .epsilon..sub.3 are preferably nitrogen atoms,
.epsilon..sub.1 is a group NR.sup.b when R.sup.b is a substituted
aryl ring, and the collagen-stimulating compound is a substituted
carbamoyl heterocyclic analog having the structure shown in formula
(Id):
##STR00008##
[0086] where, R.sub.1, and R.sub.4-R.sub.8, R.sub.a, and R.sup.N
are as defined as above;
[0087] Q is a 3-7 membered heterocyclic ring, optionally aromatic,
and which may comprise zero, one, or two double bonds;
[0088] X is selected from CR.sub.a, C(R.sub.a).sub.2, N, O, S,
NR.sup.N, or a bond (i.e. absent); and
[0089] L.sub.1 and L.sub.2 are independently selected from a bond
or a group X.sub.1-(L.sub.3).sub.l-X.sub.2, where "l" is an integer
from 0 to 4; where L.sub.3 is selected from CR.sub.a,
C(R.sub.a).sub.2, or a bond; and X.sub.1 and X.sub.2 are
independently selected from N, NR.sup.N, O, S, or a bond; or a
cosmetically acceptable salt thereof.
[0090] In one embodiment according to formula (Id), L.sub.1 is
--(CH.sub.2).sub.m--, and L.sub.2 is --(CH.sub.2).sub.n--, wherein
"m" and "n" are independently selected from integers from 1-3; and
X is selected from N, NR.sup.N, S, O, or a bond; or a cosmetically
acceptable salt thereof.
[0091] In another embodiment according to formula (Id), the Q is a
heterocycle selected from the group consisting of aziridine,
diaziridine, oxaziridine, azetidine, diazetidine, oxazetidine,
pyrrolidine, oxazolidine, thiazolidine, imidazolidine,
pyrazolidine, pyrrole, imidazole, pyrazole, 1,3,4-triazole,
1,2,3-triazole, piperidine, morpholine, piperazine, and
thiomorpholine, each being optionally substituted with one or more
groups R.sub.a, or a cosmetically acceptable salt thereof.
[0092] In a preferred embodiment according to formula (Id), Q is a
heterocycle selected from the group consisting of pyrrolidine,
morpholino, and piperazine, each being optionally substituted with
one or more groups R.sub.a, or a cosmetically acceptable salt
thereof.
[0093] Other illustrative compounds according to the invention are
provided below.
##STR00009## ##STR00010## ##STR00011##
[0094] The invention embraces the use of cosmetically or
pharmaceutically acceptable (e.g., non-toxic and/or non-irritating)
salts. Examples of the salts of the compounds in the present
invention include salts with alkali metals such as sodium and
potassium; salts with alkaline-earth metals such as calcium and
magnesium; salts with amines such as monoethanolamine; salts with
inorganic acids such as hydrochloric acid and sulfuric acid; and
salts with organic acids such as citric acid and acetic acid.
Special mention may be made of hydrochloride salts.
[0095] The cosmetic compositions according to the invention can be
formulated in a variety of forms for topical application and will
comprise from about 0.0001% to about 1% by weight of one or more
compounds according to formula (I), and preferably will comprise
from about 0.001% to about 0.5% by weight, and more preferably from
about 0.01% to about 0.2% by weight. The compositions will comprise
an effective amount of the substituted carbamoyl heterocyclic
analog compounds according to formula (I), by which is meant an
amount sufficient to enhance collagen and/or stimulate collagen in
a given area of skin when topically applied thereto.
[0096] The composition may be formulated in a variety of product
forms, such as, for example, a lotion, cream, serum, spray,
aerosol, cake, ointment, essence, gel, paste, patch, pencil,
towelette, mask, stick, foam, elixir, concentrate, and the like,
particularly for topical administration. Preferably the composition
is formulated as a lotion, cream, ointment, or gel.
[0097] The compositions can include a cosmetically acceptable
vehicle. Such vehicles may take the form of any known in the art
suitable for application to skin and may include water; vegetable
oils; mineral oils; esters such as octal palmitate, isopropyl
myristate and isopropyl palmitate; ethers such as dicapryl ether
and dimethyl isosorbide; alcohols such as ethanol and isopropanol;
fatty alcohols such as cetyl alcohol, cetearyl alcohol, stearyl
alcohol and biphenyl alcohol; isoparaffins such as isooctane,
isododecane and is hexadecane; silicone oils such as
cyclomethicone, dimethicone, dimethicone cross-polymer,
polysiloxanes and their derivatives, preferably organomodified
derivatives; hydrocarbon oils such as mineral oil, petrolatum,
isoeicosane and polyisobutene; polyols such as propylene glycol,
glycerin, butylene glycol, pentylene glycol and hexylene glycol;
waxes such as beeswax and botanical waxes; or any combinations or
mixtures of the foregoing.
[0098] The vehicle may comprise an aqueous phase, an oil phase, an
alcohol, a silicone phase or mixtures thereof. The cosmetically
acceptable vehicle may also comprise an emulsion. Non-limiting
examples of suitable emulsions include water-in-oil emulsions,
oil-in-water emulsions, silicone-in-water emulsions,
water-in-silicone emulsions, wax-in-water emulsions,
water-oil-water triple emulsions or the like having the appearance
of a cream, gel or microemulsions. The emulsion may include an
emulsifier, such as a nonionic, anionic or amphoteric
surfactant.
[0099] The oil phase of the emulsion preferably has one or more
organic compounds, including emollients; humectants (such as
propylene glycol and glycerin); other water-dispersible or
water-soluble components including thickeners such as veegum or
hydroxyalkyl cellulose; gelling agents, such as high MW polyacrylic
acid, i.e. CARBOPOL 934; and mixtures thereof. The emulsion may
have one or more emulsifiers capable of emulsifying the various
components present in the composition.
[0100] The compounds suitable for use in the oil phase include
without limitation, vegetable oils; esters such as octyl palmitate,
isopropyl myristate and isopropyl palmitate; ethers such as
dicapryl ether; fatty alcohols such as cetyl alcohol, stearyl
alcohol and behenyl alcohol; isoparaffins such as isooctane,
isododecane and isohexadecane; silicone oils such as dimethicones,
cyclic silicones, and polysiloxanes; hydrocarbon oils such as
mineral oil, petrolatum, isoeicosane and polyisobutene; natural or
synthetic waxes; and the like. Suitable hydrophobic hydrocarbon
oils may be saturated or unsaturated, have an aliphatic character
and be straight or branched chained or contain alicyclic or
aromatic rings. The oil-containing phase may be composed of a
singular oil or mixtures of different oils.
[0101] Hydrocarbon oils include those having 6-20 carbon atoms,
more preferably 10-16 carbon atoms. Representative hydrocarbons
include decane, dodecane, tetradecane, tridecane, and C.sub.8-20
isoparaffins. Paraffinic hydrocarbons are available from Exxon
under the ISOPARS trademark, and from the Permethyl Corporation. In
addition, C.sub.8-20 paraffinic hydrocarbons such as C12
isoparaffin (isododecane) manufactured by the Permethyl Corporation
having the tradename Permethyl 99 ATM are also contemplated to be
suitable. Various commercially available C.sub.16 isoparaffins,
such as isohexadecane (having the tradename Permethyl.RTM.) are
also suitable. Examples of preferred volatile hydrocarbons include
polydecanes such as isododecane and isodecane, including for
example, Permethyl-99A (Presperse Inc.) and the C.sub.7-C.sub.8
through C.sub.12-C.sub.15 isoparaffins such as the Isopar Series
available from Exxon Chemicals. A representative hydrocarbon
solvent is isododecane.
[0102] The oil phase may comprise one or more waxes, including for
example, rice bran wax, carnauba wax, ouricurry wax, candelilla
wax, montan waxes, sugar cane waxes, ozokerite, polyethylene waxes,
Fischer-Tropsch waxes, beeswax, microcrystaline wax, silicone
waxes, fluorinated waxes, and any combination thereof.
[0103] Non-limiting emulsifiers included emulsifying waxes,
emulsifying polyhydric alcohols, polyether polyols, polyethers,
mono- or di-ester of polyols, ethylene glycol mono-stearates,
glycerin mono-stearates, glycerin di-stearates, silicone-containing
emulsifiers, soya sterols, fatty alcohols such as cetyl alcohol,
fatty acids such as stearic acid, fatty acid salts, and mixtures
thereof. The preferred emulsifiers include soya sterol, cetyl
alcohol, stearic acid, emulsifying wax, and mixtures thereof. Other
specific emulsifiers that can be used in the composition of the
present invention include, but are not limited to, one or more of
the following: sorbitan esters; polyglyceryl-3-diisostearate;
sorbitan monostearate, sorbitan tristearate, sorbitan sesquioleate,
sorbitan monooleate; glycerol esters such as glycerol monostearate
and glycerol monooleate; polyoxyethylene phenols such as
polyoxyethylene octyl phenol and polyoxyethylene nonyl phenol;
polyoxyethylene ethers such as polyoxyethylene cetyl ether and
polyoxyethylene stearyl ether; polyoxyethylene glycol esters;
polyoxyethylene sorbitan esters; dimethicone copolyols;
polyglyceryl esters such as polyglyceryl-3-diisostearate; glyceryl
laurate; Steareth-2, Steareth-10, and Steareth-20, to name a few.
Additional emulsifiers are provided in the INCI Ingredient
Dictionary and Handbook 11th Edition 2006, the disclosure of which
is hereby incorporated by reference.
[0104] These emulsifiers typically will be present in the
composition in an amount from about 0.001% to about 10% by weight,
in particular in an amount from about 0.01% to about 5% by weight,
and more preferably, below 1% by weight.
[0105] The oil phase may comprise one or more volatile and/or
non-volatile silicone oils. Volatile silicones include cyclic and
linear volatile dimethylsiloxane silicones. In one embodiment, the
volatile silicones may include cyclodimethicones, including
tetramer (D4), pentamer (D5), and hexamer (D6) cyclomethicones, or
mixtures thereof. Particular mention may be made of the volatile
cyclomethicone-hexamethyl cyclotrisiloxane,
octamethyl-cyclotetrasiloxane, and decamethyl-cyclopentasiloxane.
Suitable dimethicones are available from Dow Corning under the name
Dow Corning 200.RTM. Fluid and have viscosities ranging from 0.65
to 600,000 centistokes or higher. Suitable non-polar, volatile
liquid silicone oils are disclosed in U.S. Pat. No. 4,781,917,
herein incorporated by reference in its entirety. Additional
volatile silicones materials are described in Todd et al.,
"Volatile Silicone Fluids for Cosmetics", Cosmetics and Toiletries,
91:27-32 (1976), herein incorporated by reference in its entirety.
Linear volatile silicones generally have a viscosity of less than
about 5 centistokes at 25.degree. C., whereas the cyclic silicones
have viscosities of less than about 10 centistokes at 25.degree. C.
Examples of volatile silicones of varying viscosities include Dow
Corning 200, Dow Corning 244, Dow Corning 245, Dow Corning 344, and
Dow Corning 345, (Dow Corning Corp.); SF-1204 and SF-1202 Silicone
Fluids (G.E. Silicones), GE 7207 and 7158 (General Electric Co.);
and SWS-03314 (SWS Silicones Corp.). Linear, volatile silicones
include low molecular weight polydimethylsiloxane compounds such as
hexamethyldisiloxane, octamethyltrisiloxane,
decamethyltetrasiloxane, and dodecamethylpentasiloxane, to name a
few.
[0106] Non-volatile silicone oils will typically comprise
polyalkylsiloxanes, polyarylsiloxanes, polyalkylarylsiloxanes, or
mixtures thereof. Polydimethylsiloxanes are preferred non-volatile
silicone oils. The non-volatile silicone oils will typically have a
viscosity from about 10 to about 60,000 centistokes at 25.degree.
C., preferably between about 10 and about 10,000 centistokes, and
more preferred still between about 10 and about 500 centistokes;
and a boiling point greater than 250.degree. C. at atmospheric
pressure. Non limiting examples include dimethyl polysiloxane
(dimethicone), phenyl trimethicone, and diphenyldimethicone. The
volatile and non-volatile silicone oils may optionally be
substituted will various functional groups such as alkyl, aryl,
amine groups, vinyl, hydroxyl, haloalkyl groups, alkylaryl groups,
and acrylate groups, to name a few.
[0107] The water-in-silicone emulsion may be emulsified with a
nonionic surfactant (emulsifier) such as, for example,
polydiorganosiloxane-polyoxyalkylene block copolymers, including
those described in U.S. Pat. No. 4,122,029, the disclosure of which
is hereby incorporated by reference. These emulsifiers generally
comprise a polydiorganosiloxane backbone, typically
polydimethylsiloxane, having side chains comprising -(EO)m- and/or
--(PO)n- groups, where EO is ethyleneoxy and PO is
1,2-propyleneoxy, the side chains being typically capped or
terminated with hydrogen or lower alkyl groups (e.g., C.sub.1-6,
typically C.sub.1-3). Other suitable water-in-silicone emulsifiers
are disclosed in U.S. Pat. No. 6,685,952, the disclosure of which
is hereby incorporated by reference herein. Commercially available
water-in-silicone emulsifiers include those available from Dow
Corning under the trade designations 3225C and 5225C Formulation
Aid; Silicone SF-1528 available from General Electric; ABIL EM 90
and EM 97, available from Goldschmidt Chemical Corporation
(Hopewell, Va.); and the SILWET series of emulsifiers sold by OSI
Specialties (Danbury, Conn.).
[0108] Examples of water-in-silicone emulsifiers include, but are
not limited to, dimethicone PEG 10/15 crosspolymer, dimethicone
copolyol, cetyl dimethicone copolyol, PEG-15 lauryl dimethicone
crosspolymer, laurylmethicone crosspolymer, cyclomethicone and
dimethicone copolyol, dimethicone copolyol (and) caprylic/capric
triglycerides, polyglyceryl-4 isostearate (and) cetyl dimethicone
copolyol (and) hexyl laurate, and dimethicone copolyol (and)
cyclopentasiloxane. Preferred examples of water-in-silicone
emulsifiers include, without limitation, PEG/PPG-18/18 dimethicone
(trade name 5225C, Dow Corning), PEG/PPG-19/19 dimethicone (trade
name BY25-337, Dow Corning), Cetyl PEG/PPG-10/1 dimethicone (trade
name Abil EM-90, Goldschmidt Chemical Corporation), PEG-12
dimethicone (trade name SF 1288, General Electric), lauryl
PEG/PPG-18/18 methicone (trade name 5200 FORMULATION AID, Dow
Corning), PEG-12 dimethicone crosspolymer (trade name 9010 and 9011
silicone elastomer blend, Dow Corning), PEG-10 dimethicone
crosspolymer (trade name KSG-20, Shin-Etsu), and dimethicone
PEG-10/15 crosspolymer (trade name KSG-210, Shin-Etsu).
[0109] The water-in-silicone emulsifiers typically will be present
in the composition in an amount from about 0.001% to about 10% by
weight, in particular in an amount from about 0.01% to about 5% by
weight, and more preferably, below 1% by weight.
[0110] The aqueous phase of the emulsion may include one or more
additional solvents, including lower alcohols, such as ethanol,
isopropanol, and the like. The volatile solvent may also be a
cosmetically acceptable ester such as butyl acetate or ethyl
acetate; ketones such as acetone or ethyl methyl ketone; or the
like.
[0111] The oil-containing phase will typically comprise from about
10% to about 99%, preferably from about 20% to about 85%, and more
preferably from about 30% to about 70% by weight, based on the
total weight of the emulsion, and the aqueous phase will typically
comprise from about 1% to about 90%, preferably from about 5% to
about 70%, and more preferably from about 20% to about 60% by
weight of the total emulsion. The aqueous phase will typically
comprise from about 25% to about 100%, more typically from about
50% to about 95% by weight water.
[0112] The compositions may include liposomes. The liposomes may
comprise other additives or substances and/or may be modified to
more specifically reach or remain at a site following
administration.
[0113] The composition may optionally comprise other cosmetic
actives and excipients, obvious to those skilled in the art
including, but not limited to, fillers, emulsifying agents,
antioxidants, surfactants, film formers, chelating agents, gelling
agents, thickeners, emollients, humectants, moisturizers, vitamins,
minerals, viscosity and/or rheology modifiers, sunscreens,
keratolytics, depigmenting agents, retinoids, hormonal compounds,
alpha-hydroxy acids, alpha-keto acids, anti-mycobacterial agents,
antifungal agents, antimicrobials, antivirals, analgesics, lipidic
compounds, anti-allergenic agents, H1 or H2 antihistamines,
anti-inflammatory agents, anti-irritants, antineoplastics, immune
system boosting agents, immune system suppressing agents, anti-acne
agents, anesthetics, antiseptics, insect repellents, skin cooling
compounds, skin protectants, skin penetration enhancers,
exfollients, lubricants, fragrances, colorants, depigmenting
agents, hypopigmenting agents, preservatives, stabilizers,
pharmaceutical agents, photostabilizing agents, sunscreens, and
mixtures thereof. In addition to the foregoing, the cosmetic
compositions of the invention may contain any other compound for
the treatment of skin disorders.
[0114] Colorants may include, for example, organic and inorganic
pigments and pearlescent agents. Suitable inorganic pigments
include, but are not limited to, titanium oxide, zirconium oxide
and cerium oxide, as well as zinc oxide, iron oxide, chromium oxide
and ferric blue. Suitable organic pigments include barium,
strontium, calcium, and aluminium lakes and carbon black. Suitable
pearlescent agents include mica coated with titanium oxide, with
iron oxide, or with natural pigment.
[0115] Various fillers and additional components may be added.
Fillers are normally present in an amount of about 0 weight % to
about 20 weight %, based on the total weight of the composition,
preferably about 0.1 weight % to about 10 weight %. Suitable
fillers include without limitation silica, treated silica, talc,
zinc stearate, mica, kaolin, Nylon powders such as Orgasol.TM.,
polyethylene powder, Teflon.TM., starch, boron nitride, copolymer
microspheres such as Expancel.TM. (Nobel Industries), Polytrap.TM.
(Dow Corning) and silicone resin microbeads (Tospearl.TM. from
Toshiba), and the like.
[0116] In one embodiment of the invention, the compositions may
include additional skin actives such as, but are not limited to,
botanicals, keratolytic agents, desquamating agents, keratinocyte
proliferation enhancers, collagenase inhibitors, elastase
inhibitors, depigmenting agents, anti-inflammatory agents,
steroids, anti-acne agents, antioxidants, salicylic acid or
salicylates, thiodipropionic acid or esters thereof, and advanced
glycation end-product (AGE) inhibitors.
[0117] In a specific embodiment, the composition may comprise at
least one additional botanical, such as, for example, a botanical
extract, an essential oil, or the plant itself. Suitable botanicals
include, without limitation, extracts from Abies pindrow, Acacia
catechu, Anogeissus latifolia, Asmunda japonica, Azadirachta
indica, Butea frondosa, Butea monosperma, Cedrus deodara, Emblica
officinalis, Ficus benghalensis, Glycyrrhiza glabra, Ilex purpurea
Hassk, Innula racemosa, Ligusticum chiangxiong, Ligusticum lucidum,
Mallotus philippinensis, Mimusops elengi, Morinda citrifolia,
Moringa oleifera, Naringi crenulata, Nerium indicum, Psoralea
corylifolia, Stenoloma chusana, Terminalia bellerica, tomato
glycolipid, Sapindus rarak, Humulus japonicus, Eclipta prostrate,
Amorphophallus campanulatus, Sesbania grandiflora, Pouzolzia
pentandra, Melicope hayesii, Ixora chinensis, Erythina indica,
Medemia noblis, Tiliacora triandra, Derris scandens, Portulaca
oleracea, Alisma orientale, and mixtures thereof.
[0118] The composition may comprise additional active ingredients
having anti-aging benefits, as it is contemplated that synergistic
improvements may be obtained with such combinations. Exemplary
anti-aging components include, without limitation, botanicals
(e.g., Butea Frondosa extract); thiodipropionic acid (TDPA) and
esters thereof; retinoids (e.g., all-trans retinoic acid, 9-cis
retinoic acid, phytanic acid and others); hydroxy acids (including
alpha-hydroxyacids and beta-hydroxyacids), salicylic acid and
salicylates; exfoliating agents (e.g., glycolic acid,
3,6,9-trioxaundecanedioic acid, etc.), estrogen synthetase
stimulating compounds (e.g., caffeine and derivatives); compounds
capable of inhibiting 5 alpha-reductase activity (e.g., linolenic
acid, linoleic acid, finasteride, and mixtures thereof); barrier
function enhancing agents (e.g., ceramides, glycerides, cholesterol
and its esters, alpha-hydroxy and omega-hydroxy fatty acids and
esters thereof, etc.); collagenase inhibitors; and elastase
inhibitors; to name a few. Further additional actives useful for
topical application to skin include perilla oil, mangostine,
palmitoyl lysylaminovaleroyl lysine (palmitoyl K-ava-K), palmatoyl
tetrapeptide-10 (KTFK), L-4-thiazolylalanine, cis-6-nonenol,
desthiobiotin, N-(4-mesyloxybenzyl)-N-methoxyethyl-4-chlorobenzene
carboxamide, N-(4-mesyloxybenzyl)-N-isobutyl benzenesulfonamide,
retinyl oleate, carvacrol, and mixtures thereof.
[0119] Exemplary retinoids include, without limitation, retinoic
acid (e.g., all-trans or 13-cis) and derivatives thereof, retinol
(Vitamin A) and esters thereof, such as retinol palmitate, retinol
acetate and retinol propionate, and salts thereof.
[0120] In another embodiment, the topical compositions of the
present invention may also include one or more of the following: a
skin penetration enhancer, an emollient, a skin plumper, an optical
diffuser, a sunscreen, an exfoliating agent, and an
antioxidant.
[0121] An emollient provides the functional benefits of enhancing
skin smoothness and reducing the appearance of fine lines and
coarse wrinkles. Examples include isopropyl myristate, petrolatum,
isopropyl lanolate, silicones (e.g., methicone, dimethicone), oils,
mineral oils, fatty acid esters, or any mixtures thereof. The
emollient may be preferably present from about 0.1 wt % to about 50
wt % of the total weight of the composition.
[0122] A skin plumper serves as a collagen enhancer to the skin. An
example of a suitable, and preferred, skin plumper is palmitoyl
oligopeptide. Other skin plumpers are collagen and/or other
glycosaminoglycan (GAG) enhancing agents. When present, the skin
plumper may comprise from about 0.1 wt % to about 20 wt % of the
total weight of the composition.
[0123] An optical diffuser is a particle that changes the surface
optometrics of skin, resulting in a visual blurring and softening
of, for example, lines and wrinkles. Examples of optical diffusers
that can be used in the present invention include, but are not
limited to, boron nitride, mica, nylon, polymethylmethacrylate
(PMMA), polyurethane powder, sericite, silica, silicone powder,
talc, Teflon, titanium dioxide, zinc oxide, or any mixtures
thereof. When present, the optical diffuser may be present from
about 0.01 wt % to about 20 wt % of the total weight of the
composition.
[0124] A sunscreen for protecting the skin from damaging
ultraviolet rays may also be included. Preferred sunscreens are
those with a broad range of UVB and UVA protection, such as
octocrylene, avobenzone (Parsol 1789), octyl methoxycinnamate,
octyl salicylate, oxybenzone, homosylate, benzophenone, camphor
derivatives, zinc oxide, and titanium dioxide. When present, the
sunscreen may comprise from about 0.01 wt % to about 70 wt % of the
composition.
[0125] Suitable exfoliating agents include, for example,
alpha-hydroxyacids, beta-hydroxyacids, oxaacids, oxadiacids, and
their derivatives such as esters, anhydrides and salts thereof.
Suitable hydroxy acids include, for example, glycolic acid, lactic
acid, malic acid, tartaric acid, citric acid, 2-hydroxyalkanoic
acid, mandelic acid, salicylic acid and derivatives thereof. A
preferred exfoliating agent is glycolic acid. When present, the
exfoliating agent may comprise from about 0.1 wt % to about 80 wt %
of the composition.
[0126] An antioxidant functions, among other things, to scavenge
free radicals from skin to protect the skin from environmental
aggressors. Examples of antioxidants that may be used in the
present compositions include compounds having phenolic hydroxy
functions, such as ascorbic acid and its derivatives/esters;
beta-carotene; catechins; curcumin; ferulic acid derivatives (e.g.
ethyl ferulate, sodium ferulate); gallic acid derivatives (e.g.,
propyl gallate); lycopene; reductic acid; rosmarinic acid; tannic
acid; tetrahydrocurcumin; tocopherol and its derivatives; uric
acid; or any mixtures thereof. Other suitable antioxidants are
those that have one or more thiol functions (--SH), in either
reduced or non-reduced form, such as glutathione, lipoic acid,
thioglycolic acid, and other sulfhydryl compounds. The antioxidant
may be inorganic, such as bisulfites, metabisulfites, sulfites, or
other inorganic salts and acids containing sulfur. Compositions of
the present invention may comprise an antioxidant preferably from
about 0.001 wt % to about 10 wt %, and more preferably from about
0.01 wt % to about 5 wt %, of the total weight of the
composition.
[0127] Other conventional additives include: vitamins, such as
tocopherol and ascorbic acid; vitamin derivatives such as ascorbyl
monopalmitate; thickeners such as hydroxyalkyl cellulose; gelling
agents; structuring agents such as bentonite, smectite, magnesium
aluminum silicate and lithium magnesium silicate; metal chelating
agents such as EDTA; pigments such as zinc oxide and titanium
dioxide; colorants; emollients; and humectants.
[0128] It is preferred that the composition be essentially free of
components having a strong oxidizing potential, including for
example, organic or inorganic peroxides. By "essentially free of"
these components is meant that the amounts present are insufficient
to have a measurable impact on the collagen I, desmogleins, and/or
dermatopontin enhancing activity of the substituted carbamoyl
heterocyclic analog. In some embodiments, this will be, on a molar
basis in relation to the amount of substituted carbamoyl
heterocyclic analog, less than 1%.
[0129] In one embodiment, the composition of the invention
comprising a substituted carbamoyl heterocyclic analog may have a
pH between about 1 and about 8. In certain embodiments, the pH of
the composition will be acidic, i.e., less than 7.0, and preferably
will be between about 2 and about 7, more preferably between about
3.5 and about 5.5.
[0130] The invention provides a method for treating aging skin by
topically applying a composition comprising a substituted carbamoyl
heterocyclic analog, preferably in a cosmetically acceptable
vehicle, over the affected area for a period of time sufficient to
reduce, ameliorate, reverse or prevent dermatological signs of
aging. This method is particularly useful for treating signs of
skin photoaging and intrinsic aging.
[0131] Generally, the improvement in the condition and/or aesthetic
appearance is selected from the group consisting of: reducing
dermatological signs of chronological aging, photo-aging, hormonal
aging, and/or actinic aging; preventing and/or reducing the
appearance of lines and/or wrinkles; reducing the noticeability of
facial lines and wrinkles, facial wrinkles on the cheeks, forehead,
perpendicular wrinkles between the eyes, horizontal wrinkles above
the eyes, and around the mouth, marionette lines, and particularly
deep wrinkles or creases; preventing, reducing, and/or diminishing
the appearance and/or depth of lines and/or wrinkles; improving the
appearance of suborbital lines and/or periorbital lines; reducing
the appearance of crow's feet; rejuvenating and/or revitalizing
skin, particularly aging skin; reducing skin fragility; preventing
and/or reversing of loss of glycosaminoglycans and/or collagen, in
particular collagen I; ameliorating the effects of estrogen
imbalance; preventing skin atrophy; preventing, reducing, and/or
treating hyperpigmentation; minimizing skin discoloration;
improving skin tone, radiance, clarity and/or tautness; preventing,
reducing, and/or ameliorating skin sagging; improving skin
firmness, plumpness, suppleness and/or softness; improving
procollagen and/or collagen production; improving skin texture
and/or promoting retexturization; improving skin barrier repair
and/or function; improving the appearance of skin contours;
restoring skin luster and/or brightness; minimizing dermatological
signs of fatigue and/or stress; resisting environmental stress;
replenishing ingredients in the skin decreased by aging and/or
menopause; improving communication among skin cells; increasing
cell proliferation and/or multiplication; increasing skin cell
metabolism decreased by aging and/or menopause; retarding cellular
aging; improving skin moisturization; enhancing skin thickness;
increasing skin elasticity and/or resiliency; enhancing
exfoliation; improving microcirculation; decreasing and/or
preventing cellulite formation; and any combinations thereof.
[0132] Without wishing to be bound by any particular theory, it is
believed that the compositions of the present invention enhance and
improve the aesthetic appearance of skin by stimulation of
collagen.
[0133] The composition will typically be applied to the skin one,
two, or three times daily for as long as is necessary to achieve
desired anti-aging results. The treatment regiment may comprise
daily application for at least one week, at least two weeks, at
least four weeks, at least eight weeks, or at least twelve weeks.
Chronic treatment regimens are also contemplated.
[0134] The substituted carbamoyl heterocyclic analog active
component is topically applied to an "individual in need thereof,"
by which is meant an individual that stands to benefits from
reducing visible signs of skin damage or aging. In a specific
embodiment, the substituted carbamoyl heterocyclic analog component
is provided in a pharmaceutically, physiologically, cosmetically,
and dermatologically-acceptable vehicle, diluent, or carrier, where
the composition is topically applied to an affected area of skin
and left to remain on the affected area in an amount effective for
improving the condition and aesthetic appearance of skin.
[0135] In one embodiment, methods for treating fine lines and
wrinkles comprise topically applying the inventive substituted
carbamoyl heterocyclic analog compositions to the skin of an
individual in need thereof, e.g., topically application directly to
the fine line and/or wrinkle in an amount and for a time sufficient
to reduce the severity of the fine lines and/or wrinkles or to
prevent or inhibit the formation of new fine lines and/or wrinkles.
The effect of a composition on the formation or appearance of fine
lines and wrinkles can be evaluated qualitatively, e.g., by visual
inspection, or quantitatively, e.g., by microscopic or computer
assisted measurements of wrinkle morphology (e.g., the number,
depth, length, area, volume and/or width of wrinkles per unit area
of skin). This embodiment includes treatment of wrinkles on the
skin of the hands, arms, legs, neck, chest, and face, including the
forehead,
[0136] It is also contemplated that the compositions of the
invention will be useful for treating thin skin by topically
applying the composition to thin skin of an individual in need
thereof. "Thin skin" is intended to include skin that is thinned
due to chronological aging, menopause, or photo-damage. In some
embodiments, the treatment is for thin skin in men, whereas other
embodiments treat thin skin in women, pre-menopausal or
post-menopausal, as it is believed that skin thins differently with
age in men and women, and in particular in women at different
stages of life.
[0137] The method of the invention may be employed prophylactically
to forestall aging including in patients that have not manifested
signs of skin aging, most commonly in individuals under 25 years of
age. The method may also reverse or treat signs of aging once
manifested as is common in patients over 25 years of age.
[0138] The following examples are meant to demonstrate certain
aspects of the invention in a non-limiting fashion.
EXAMPLES
Example 1
[0139] The compounds 1-5, and 8-9 were assayed for stimulation of
collagen synthesis as follows. Human dermal fibroblasts (Cascade
Biologics, Portland, Oreg.) were plated at 10,000 cells/well in
96-well culture plates in supplemented medium (DMEM, 10% Fetal
Bovine Serum, 1% Penicillin/Streptomycin and 1% L-Glutamine)
overnight in humidified atmosphere of 10% CO.sub.2 at 37.degree. C.
The next day, the medium was replaced with fresh medium (DMEM, 1%
Penicillin/Streptomycin and 1% L-Glutamine) and the compounds
dissolved in DMSO were added to the wells in triplicate at a
concentration of 0.0005%. DMSO solution was used a control.
Following 48-hour incubation, the plates were removed from the
incubator and the medium from each well was collected for the
procollagen assay.
[0140] Collagen production was measured using procollagen type I
C-peptide (PIP) EIA kit (Takara Bio, Inc., Japan). Briefly, the
conditioned medium was diluted 1:10 in Sample Diluent. 20 .mu.l of
diluted conditioned medium and 100 .mu.l of antibody-POD conjugate
solution were added to the wells of the Takara ELISA plate. The
ELISA plate was incubated at 37.degree. C. for 3 hours before the
wells were washed four times with 400 .mu.l of 1.times.PBS. At the
end of wash, 100 .mu.l of substrate solution (supplied with kit)
was added to the wells and incubated at room temperature for 15
minutes. The reaction was stopped by adding 100 .mu.l of 1N
sulfuric acid to the wells. The absorbance was measured on a
spectrophotometer at 450 nm wavelength. The amount of procollagen
peptide in the conditioned medium was calculated from the standard
curve. The stimulation of collagen production was shown as an
increase in collagen over the control.
[0141] For compounds 1-5 the results were:
##STR00012##
TABLE-US-00001 TABLE 1 Compound R.sup.b R.sub.a R.sub.1
##STR00013## % Collagen Stimulation 1 ##STR00014## ##STR00015## H
##STR00016## 73.2% 2 ##STR00017## ##STR00018## ##STR00019##
##STR00020## 23.1% 3 ##STR00021## ##STR00022## H ##STR00023## 13.5%
4 ##STR00024## ##STR00025## H ##STR00026## 12.5% 5 ##STR00027##
##STR00028## H ##STR00029## 45.23%
[0142] For compounds 8-9 the results were:
##STR00030##
TABLE-US-00002 TABLE 2 Compound R.sup.b R.sub.a R.sub.1
##STR00031## % Collagen Stimulation 8 ##STR00032## ##STR00033## H
##STR00034## 83.7% 9 ##STR00035## ##STR00036## H ##STR00037##
62.2%
[0143] Results illustrate that the compounds included in Tables 1
and 2 are collagen stimulators, and that compounds 1, 8 and 9 are
potent stimulators of collagen synthesis.
Example 2
[0144] Other illustrative examples are shown below in Tables 3 and
4.
##STR00038##
TABLE-US-00003 TABLE 3 Compound R.sup.b R.sub.a R.sub.1
##STR00039## 6 ##STR00040## ##STR00041## H ##STR00042## 7
##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047##
TABLE-US-00004 TABLE 4 Compound R.sup.b R.sub.a R.sub.1
##STR00048## 10 ##STR00049## ##STR00050## H ##STR00051## 11
##STR00052## ##STR00053## H ##STR00054## 12 ##STR00055##
##STR00056## H ##STR00057## 13 ##STR00058## ##STR00059## H
##STR00060##
Example 3
Illustrative Compositions
[0145] The cosmetic compositions set forth in Table 5 are
illustrative of the invention and are useful for topical
application to the skin to enhance its aesthetic appearance.
TABLE-US-00005 TABLE 5 Composition 1 2 3 4 5 Components Weight %
Compound 1 of Table 1 0.01 0.05 -- -- -- Compound 5 of Table 1 --
-- 0.1 -- -- Compound 8 of Table 2 -- -- -- 0.05 -- Compound 9 of
Table 2 0.05 Acrylates/C10-30 Alkyl 1 1 1 1 1 Acrylate rosspolymer
Cetyl Ethylhexanoate 10 10 10 10 10 C12-15 Alkyl Benzoate 3.9 3.9
3.9 3.9 3.9 Isopropyl Isostearate 3 3 3 3 3 Diisopropyl dimer 0.1
0.1 0.1 0.1 0.1 dillinoleate Tocopheryl acetate 0.5 0.5 0.5 0.5 0.5
Butylene glycol 2 2 2 2 2 Propylene glycol 1 1 1 1 1 Dimethicone
PEG-7 0.5 0.5 0.5 0.5 0.5 isostearate Methyl gluceth-20 0.5 0.5 0.5
0.5 0.5 Triethanolamine 1 1 1 1 1 Acrylates/acrylamide 1.5 1.5 1.5
1.5 1.5 copolymer/mineral oil DMDM 0.4 0.4 0.4 0.4 0.4
Hydantoin/Iodopropynyl- tylcarbonate Deionized water q.s. q.s. q.s.
q.s. q.s. Total: 100 100 100 100 100
[0146] All references including patent applications and
publications cited herein are incorporated herein by reference in
their entirety and for all purposes to the same extent as if each
individual publication or patent or patent application was
specifically and individually indicated to be incorporated by
reference in its entirety for all purposes. Many modifications and
variations of this invention can be made without departing from its
spirit and scope, as will be apparent to those skilled in the art.
The specific embodiments described herein are offered by way of
example only, and the invention is to be limited only by the terms
of the appended claims, along with the full scope of equivalents to
which such claims are entitled.
* * * * *