U.S. patent application number 14/199873 was filed with the patent office on 2014-09-11 for resorcinol compounds for dermatological use.
The applicant listed for this patent is Ampere Life Sciences, Inc.. Invention is credited to Dana Davis, Andrew W. HINMAN, Viktoria Kheifets.
Application Number | 20140256830 14/199873 |
Document ID | / |
Family ID | 50424742 |
Filed Date | 2014-09-11 |
United States Patent
Application |
20140256830 |
Kind Code |
A1 |
HINMAN; Andrew W. ; et
al. |
September 11, 2014 |
RESORCINOL COMPOUNDS FOR DERMATOLOGICAL USE
Abstract
Provided herein are methods and compositions comprising
resorcinol derivatives for the use of treating, regulating or
preventing a skin condition characterized by oxidative stress or a
degenerative process. Methods of preventing, lightening or reducing
the appearance of visible discontinuities of the skin resulting
from skin pigmentation, skin aging, or other disorders are also
disclosed.
Inventors: |
HINMAN; Andrew W.; (San
Francisco, CA) ; Davis; Dana; (Sunnyvale, CA)
; Kheifets; Viktoria; (Mountain View, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ampere Life Sciences, Inc. |
Mountain View |
CA |
US |
|
|
Family ID: |
50424742 |
Appl. No.: |
14/199873 |
Filed: |
March 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61775384 |
Mar 8, 2013 |
|
|
|
Current U.S.
Class: |
514/729 ;
514/731; 514/736; 568/743; 568/744; 568/763 |
Current CPC
Class: |
C07C 2601/08 20170501;
A61Q 19/08 20130101; C07C 2601/14 20170501; A61Q 19/02 20130101;
A61Q 17/04 20130101; C07C 39/42 20130101; A61K 8/69 20130101; A61P
17/00 20180101; A61P 43/00 20180101; C07C 39/24 20130101; C07C
39/367 20130101; C07C 39/08 20130101; C07C 2601/02 20170501; C07C
39/17 20130101; A61P 3/02 20180101; A61P 17/18 20180101; A61K 8/37
20130101; C07C 39/15 20130101; A61K 8/347 20130101; A61K 8/70
20130101; A61K 2800/522 20130101 |
Class at
Publication: |
514/729 ;
514/731; 514/736; 568/743; 568/744; 568/763 |
International
Class: |
C07C 39/17 20060101
C07C039/17; C07C 39/10 20060101 C07C039/10; C07C 39/15 20060101
C07C039/15 |
Claims
1. A cosmetic or dermatological composition comprising one or more
resorcinols of formula I: ##STR00015## wherein R.sup.1 and R.sup.2
are independently alkyl, alkenyl, cycloalkyl, heterocycloalkyl,
aryl, heteroaryl, --F, or --Cl, each of which alkyl, alkenyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally
substituted with --OH, --OR.sup.3, --NR.sup.3R.sup.4,
--C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, or halo; and R.sup.3 and
R.sup.4 are independently hydrogen, alkyl, alkenyl, cycloalkyl,
heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
arylalkyl, heteroarylalkyl, aryl, or heteroaryl; or a
pharmaceutically acceptable salt thereof.
2. The composition of claim 1, comprising a compound of formula I
wherein R.sup.1 is alkyl, perhaloalkyl, --F, or --Cl; and R.sup.2
is alkyl or cycloalkyl.
3. The composition of claim 1, comprising a compound of formula I
wherein R.sup.1 is alkyl.
4. The composition of claim 3, comprising a compound of formula I
wherein R.sup.1 is methyl.
5. The composition of claim 1, comprising a compound of formula I
wherein R.sup.1 is trifluoromethyl.
6. The composition of claim 1, comprising a compound of formula I
wherein R.sup.1 is fluoro.
7. The composition of claim 1, comprising a compound of formula I
wherein R.sup.1 is chloro.
8. The composition of claim 1, comprising a compound of formula I
wherein R.sup.2 is alkyl.
9. The composition of claim 8, comprising a compound of formula I
wherein R.sup.2 is ethyl.
10. The composition of claim 8, comprising a compound of formula I
wherein R.sup.2 is hexyl.
11. The composition of claim 1, comprising a compound of formula I
wherein R.sup.2 is cycloalkyl.
12. The composition of claim 11, comprising a compound of formula I
wherein R.sup.2 is cyclohexyl.
13. The composition of claim 1, comprising a compound of formula I
wherein the compound is ##STR00016## ##STR00017## or a
pharmaceutically acceptable salt thereof.
14. A cosmetic or dermatological composition comprising a
therapeutically effective amount of the composition of claim 1 and
a pharmaceutically, dermatologically, or cosmetically acceptable
carrier.
15. A method of regulating or preventing a skin condition wherein
the skin condition is characterized by oxidative stress or a
degenerative process, comprising administering to a subject
exhibiting said skin condition an effective amount of the
composition of claim 1.
16. A method of reducing or treating the signs of skin aging or of
reducing the appearance of signs of skin aging comprising
administering to a subject exhibiting said skin condition an
effective amount of the composition of claim 1.
17. A method of regulating or preventing a skin condition
associated with visible discontinuities of the skin, comprising
administering to a subject exhibiting said skin condition an
effective amount of the composition of claim 1.
18. The method of claim 17, wherein the visible discontinuities are
associated with aging, age-related damage or damage resulting from
extrinsic factors.
19. The method of claim 17, wherein the visible discontinuities of
the skin are associated with pigmentation disorders.
20. The method of claim 19, wherein the pigmentation disorders are
selected from a group consisting of uneven pigmentation, age spots,
vitiligo and melasma.
21. A method for preventing, lightening or reducing the appearance
of visible discontinuities of the skin, comprising administering to
a subject exhibiting said skin conditions an effective amount of
the composition of claim 1.
22. A method of regulating or preventing a skin condition wherein
the skin condition is associated with visible discontinuities of
the skin, while concurrently reducing or treating the signs of skin
aging, comprising administering to a subject exhibiting said skin
condition an effective amount of the composition of claim 1.
23. The method of claim 22, wherein the visible discontinuities of
the skin are selected from uneven pigmentation, age spots, vitiligo
and melasma.
24. The method of claim 22, wherein the visible discontinuities of
the skin are a result of harmful ultraviolet radiation, pollution
or other environmental insults, stress, or fatigue.
25. A method of preventing, lightening, or reducing the appearance
of visible discontinuities of the skin, while concurrently reducing
or treating the signs of skin aging, comprising administering to a
subject exhibiting said skin condition an effective amount of the
composition of claim 1.
26. The method of claim 25, wherein the visible discontinuities of
the skin are selected from a group consisting of uneven
pigmentation, age spots, vitiligo and melasma.
27. The method of claim 26, wherein the visible discontinuities of
the skin are a result of harmful ultraviolet radiation, pollution
or other environmental insults, stress, or fatigue.
28. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims priority benefit of U.S.
Provisional Patent Application No. 61/775,384, filed Mar. 8, 2013.
The entire contents of that application are hereby incorporated by
reference herein.
TECHNICAL FIELD
[0002] Provided herein are cosmetic and dermatological
compositions, such as resorcinol derivatives, with anti-aging, skin
even-toning, and other useful properties for skin treatment.
BACKGROUND
[0003] Natural-looking skin is influenced by a number of
physiological and genetic factors. Standard definitions of
beautiful skin include skin having a transparent quality with
uniform undertones of color and no visible or tactile
discontinuities. The basis for this natural-looking appearance is
in the skin structure itself. The outer layer of human skin is a
semi-transparent layer known as the stratum corneum. The
transparency of the stratum corneum permits glimpses of the deeper
layers of skin, where blood vessels and pigments reside. The pale
reddish hue of the blood vessels' hemoglobin, and the brown/black
hue of melanin that is the primary skin pigment, combine to produce
the skin's color. Ideal skin should also be smooth and even, with
no apparent surface flaws in addition to having the transparent
look with uniform color distribution.
[0004] Skin is composed of a top layer, the epidermis, which is
approximately 20 cell layers or about 0.1 mm in thickness, and a
lower layer, the dermis, which is from about 1 to about 4 mm in
thickness and contains small blood vessels, collagen, elastin and
fibroblasts. The dermis provides structural support and nutrients
to the epidermis. Aging has been shown to increase cellular
heterogeneity of the epidermal layer. Aging does not affect the
number of cell layers in the epidermis, but the overall thickness
decreases. The supporting dermis is known to thin with age and
exposure to the sun and environmental contaminants. The dermal
layer provides the support and blood supply for the epidermis,
therefore the dermal layer is important in maintaining the
elasticity and appearance of the skin.
[0005] Considerable effort has been expended to find ways to
prevent adverse changes in the skin brought about by ultraviolet
(UV) exposure and other causes. Preventative approaches include
physically blocking or absorbing the UV radiation before it can
enter the skin using UV absorbing compounds. Skin problems in aging
individuals can result from a variety of extrinsic or intrinsic
factors such as harmful UV radiation from the sun, exposure to the
environment, stress, fatigue, disease, or a combination
thereof.
[0006] Many people at different stages of their life are concerned
with the degree of pigmentation of their skin and may wish to
reduce the skin darkening, or may wish to lighten or even-tone
their natural skin color. The mechanism by which skin pigmentation
is formed, melanogenesis, is particularly complex and schematically
involves the following main steps:
Tyrosine.fwdarw.L-Dopa.fwdarw.Dopaquinone.fwdarw.Dopachrome.fwdarw.Melani-
ns. The first two reactions in this series are catalyzed by the
enzyme tyrosinase. The activity of tyrosinase is promoted by the
action of .alpha.-melanocyte stimulating hormone or UV rays. It is
well established that a substance has a depigmenting effect if it
acts directly on the vitality of the epidermal melanocytes where
melanogenesis normally occurs and/or if it interferes with one of
the stages in melanin biosynthesis. Pigmentation disorders can take
a variety of forms like hyperpigmentation, hypopigmentation, and
uneven pigmentation, and include but are not limited to melasma
(mask of pregnancy or chloasma), liver spots (which often develop
with age) and leukoderma such as vitiligo. Some of the pigmentation
occurs as a side effect of birth control pills, as a result of skin
damage such as a persistent result of acne, burns, bites and other
skin injuries, as after-burn scars, as cicatrical spots, as stretch
mark scars, and as dark circles and puffiness under and around the
eyes. The degree of pigmentation disorders of the skin in many
cases increases with the age of the individuals. Because of the
involvement of tyrosinase in melanogensis, tyrosinase inhibition
assays are often used to screen potential skin lightening agents.
Some mushroom tyrosinases (such as that from Agaricus bisporus) are
homologous with mammalian tyrosinase, and mushroom tyrosinase is
often used in inhibition assays due to its ready commercial
availability. However, the enzyme inhibition assays may not be as
good an indicator of activity as assays which are more similar to
the intended clinical or cosmetic use, such as the MatTek
Corporation's MelanoDerm.TM. Skin Model (a system which consists of
normal, human-derived epidermal keratinocytes and melanocytes
formed into a multilayered model of human epidermis).
[0007] In the United States, the most commonly used treatment for
hyperpigmentation is 1,4-benzenediol, which is known as
hydroquinone. Treatment with hydroquinone interferes with the
action of tyrosinase, which is an enzyme used in the synthesis of
melanin, and compositions are sold across the counter at about 2%
hydroquinone and by prescription at higher concentrations.
Hydroquinone compositions are effective but have some undesirable
side effects. These can be burning, redness, sensitization and
irritation in some patients. U.S. Pat. No. 4,526,179 refers to
certain hydroquinone fatty esters that have good activity and are
less irritating and more stable than hydroquinone. Japanese Patent
Application No. 27909/86 (JP 61-27909) refers to other hydroquinone
derivatives that do not have the drawbacks of hydroquinone but that
have relatively poor efficacy. Other compounds with a hydroquinone
core structure have been described in the patent literature, for
example, U.S. Pat. No. 5,449,518 refers to 2,5-dihydroxyphenyl
carboxylic acid derivatives, and European Patent Application EP
341,664A1 and PCT International Publication WO 99/15148 refer to
certain resorcinol derivatives as tyrosinase inhibitors.
[0008] A variety of additional agents have been applied to the skin
to lighten the skin. Such agents include but are not limited to
kojic acid, licorice and its derivatives, ascorbic acid and its
derivatives, arbutin, bearberry, Glycyrrhiza glabra and its
derivatives, Chlorella vulgaris extract, perilla extract, and
coconut fruit extract. Perilla extract is disclosed as a whitening
agent in U.S. Pat. No. 5,980,904 and Japanese Publications Nos.
07-025742, 07-187989, 10-265322, 2001-163759 and 2001-181173.
Coconut fruit extract is disclosed as a whitening agent in Japanese
Patent No. 2896815 B2.
[0009] Resorcinol (1,3-benzenediol) derivatives have been used to
provide cosmetic benefits to skin and hair. 4-Substituted
resorcinol derivatives have been used for skin lightening; see, for
example, U.S. Pat. No. 4,959,393, U.S. Pat. No. 6,132,740, U.S.
Pat. No. 6,504,037, U.S. Patent Application Publication No.
2008/0131382, and Japanese Published Patent Application Nos. JP
2001-01 0925 and JP 2000-327557. Resorcinol derivative dimers which
are inhibitors of tyrosinase are disclosed in U.S. Pat. No.
5,399,785. Resorcinol-type skin lightening agents, which can be
synthesized using coumarin as starting material, are disclosed in
U.S. Patent Application Publication No. 2004/0042983. However, some
of these compounds can be difficult to formulate, or may cause skin
irritation.
[0010] It would be desirable to have a safe and non-toxic
composition for the treatment or prevention of the pigmentation
disorders. The compounds and compositions comprising resorcinols
described herein fill this need.
BRIEF DESCRIPTION
[0011] Provided herein are methods for reducing or improving the
appearance of visible discontinuities in skin associated with
age-related damage, or damage resulting from harmful ultraviolet
radiation, such as that contained in sunlight, pollution and other
environmental insults, stress, or fatigue. Also provided herein are
methods for reducing the appearance of coloration due to
pigmentation disorders. Also provided are compositions and methods
of improving skin appearance by alleviating skin discoloration
associated with age and reducing the appearance of coloration due
to pigmentation disorders simultaneously. Also provided are
resorcinol derivatives for reducing or preventing the appearance of
skin pigmentation and the skin problems arising with age, and
compositions comprising such resorcinol derivatives, such
pharmaceutically acceptable compositions, including topical
pharmaceutically acceptable compositions.
[0012] Also provided are methods for reducing or improving the
appearance of pigmentation or discoloration in skin. Also provided
are methods of reducing age spots, liver spots, and other
age-related pigmentation disorders, and method of treating
pigmentation disorders such as vitiligo and melasma. The methods
comprise applying a therapeutically or cosmetically effective
amount of the compounds to the skin in an amount sufficient to
reduce or improve the appearance of pigmentation or discoloration
in skin, or in an amount sufficient to reduce age spots, liver
spots, or other age-related pigmentation disorders, or in an amount
sufficient to treat a pigmentation disorder, such as vitiligo and
melasma. Also provided are compounds for use in reducing or
improving the appearance of pigmentation or discoloration in skin,
or for use in reducing age spots, liver spots, or other age-related
pigmentation disorders, or for use in treating a pigmentation
disorder, such as vitiligo and melasma.
[0013] The resorcinol derivatives provided herein, which are
defined below and used in the various methods provided herein, are
useful in the treatment or prevention of one or more dermatological
conditions as desired by the subject being treated, such as for
medicinal or cosmetic purposes, such as to prevent, lighten, reduce
or treat the signs or appearance of undesired pigmentation of skin
affected by the one or more conditions.
[0014] Provided herein is a cosmetic or dermatological composition
comprising one or more resorcinols of formula I:
##STR00001##
[0015] wherein R.sup.1 and R.sup.2 are independently alkyl,
alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or halo,
each of which alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl,
or heteroaryl is optionally substituted with --OH, --OR.sup.3,
--NR.sup.3R.sup.4, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, or halo;
and R.sup.3 and R.sup.4 are independently hydrogen, alkyl, alkenyl,
cycloalkyl, heterocycloalkyl, cycloalkyl-alkyl,
heterocycloalkyl-alkyl, arylalkyl, heteroarylalkyl, aryl, or
heteroaryl; or a pharmaceutically acceptable salt thereof. Also
provided are mixtures of two or more compounds of formula I. In
some variations, R.sup.1 is alkyl or halo, and R.sup.2 is alkyl or
cycloalkyl. In some variations, R.sup.1 is alkyl, such as methyl.
In some variations, R.sup.1 is haloalkyl, perhaloalkyl,
fluoroalkyl, or perfluoroalkyl, such as trifluoromethyl. In some
variations, R.sup.1 is halo, such as fluoro, chloro, bromo, or
iodo. In some variations, R.sup.1 is fluoro or chloro. In some
variations, R.sup.2 is alkyl, such as ethyl or hexyl. In some
variations, R.sup.2 is cycloalkyl, such as cyclohexyl.
[0016] In some variations, R.sup.1 is (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.3-C.sub.8)-cycloalkyl,
(C.sub.3-C.sub.8)-heterocycloalkyl, (C.sub.6-C.sub.12)-aryl,
(C.sub.3-C.sub.12)-heteroaryl, or halo, each of which
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.8)-heterocycloalkyl,
(C.sub.6-C.sub.12)-aryl, or (C.sub.3-C.sub.12)-heteroaryl is
optionally substituted with one, two, or three substituents
selected from the group consisting of --OH, --OR.sup.3,
--NR.sup.3R.sup.4, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, or halo;
and R.sup.2 is (C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.8)-heterocycloalkyl,
(C.sub.6-C.sub.12)-aryl, (C.sub.3-C.sub.12)-heteroaryl, or halo,
each of which (C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.8)-heterocycloalkyl,
(C.sub.6-C.sub.12)-aryl, or (C.sub.3-C.sub.12)-heteroaryl is
optionally substituted with one, two, or three substituents
selected from the group consisting of --OH, --OR.sup.3,
--NR.sup.3R.sup.4, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, or
halo.
[0017] In some variations, R.sup.1 is (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.3-C.sub.8)-cycloalkyl,
(C.sub.3-C.sub.8)-heterocycloalkyl, (C.sub.6-C.sub.12)-aryl,
(C.sub.3-C.sub.12)-heteroaryl, or halo, each of which
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.8)-heterocycloalkyl,
(C.sub.6-C.sub.12)-aryl, or (C.sub.3-C.sub.12)-heteroaryl is
optionally substituted with one, two, or three substituents
selected from the group consisting of --OH, --OR.sup.3,
--NR.sup.3R.sup.4, --C(O)OR.sup.3, --C(O)NR.sup.3R.sup.4, or halo;
and R.sup.2 is cycloalkyl, such as (C.sub.3-C.sub.8)-cycloalkyl,
such as cyclohexyl.
[0018] In some variations, R.sup.3 and R.sup.4 are independently
hydrogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.3-C.sub.8)-cycloalkyl, (C.sub.3-C.sub.8)-heterocycloalkyl,
(C.sub.3-C.sub.8)-cycloalkyl-(C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.8)-heterocycloalkyl-(C.sub.1-C.sub.6)-alkyl,
(C.sub.6-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.12)-heteroaryl-(C.sub.1-C.sub.6)-alkyl,
(C.sub.6-C.sub.12)-aryl, or (C.sub.3-C.sub.12)-heteroaryl.
[0019] In some variations, R.sup.1 is (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.3-C.sub.8)-cycloalkyl, or halo,
and R.sup.2 is (C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
or (C.sub.3-C.sub.8)-cycloalkyl.
[0020] In some variations, R.sup.1 is (C.sub.1-C.sub.6)-alkyl or
halo, and R.sup.2 is (C.sub.1-C.sub.6)-alkyl or
(C.sub.3-C.sub.8)-cycloalkyl.
[0021] In some variations, R.sup.1 is methyl, fluoro, or
trifluoromethyl, and R.sup.2 is ethyl, hexyl, or cyclohexyl.
[0022] In particular variations, the cosmetic or dermatological
composition contains one or more of the following compounds:
##STR00002## ##STR00003## ##STR00004##
or a pharmaceutically acceptable salt thereof.
[0023] In some variations, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used for the prophylaxis and treatment of cosmetic and
dermatological skin changes in a subject in need thereof, such as
undesirable skin pigmentation or changes in skin pigmentation or
skin tone, which is achieved by administering an effective amount
of one or more of the compositions to the subject. In some
variations, the skin changes are produced by oxidative or
degenerative processes.
[0024] In some variations, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used for preventing, lightening or reducing visible signs from
aging in a subject, which is achieved by administering an effective
amount of one or more of the compositions to the subject. In some
variations, the cosmetic and dermatological compositions comprising
one or more compounds of formula I may be used in a subject for
reducing the appearance of visible, tactile, and/or coloration
discontinuities in skin associated with aging, age-related damage,
or damage resulting from harmful factors, such as those contained
in sunlight, harmful ultraviolet radiation, pollution and other
environmental insults, stress, or fatigue, which is achieved by
administering an effective amount of one or more of the
compositions to the subject.
[0025] In some variations, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used in a subject for the prophylaxis or treatment of
dermatological conditions comprising unevenness or pigmentation of
the skin, which is achieved by administering an effective amount of
one or more of the compositions to the subject.
[0026] In some variations, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used in a subject for preventing, lightening or reducing the
appearance of visible and/or tactile discontinuities of the skin,
such as mottling, which is achieved by administering an effective
amount of one or more of the compositions to the subject.
[0027] In some variations, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used in a subject for preventing, lightening or reducing the
appearance of visible discontinuities of the skin resulting from
the aging processes, which is achieved by administering an
effective amount of one or more of the compositions to the
subject.
[0028] In some variations, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used in a subject for preventing, lightening or reducing the
appearance of visible discontinuities of the skin such as
pigmentation, age spots, vitiligo and melasma, which is achieved by
administering an effective amount of one or more of the
compositions to the subject.
[0029] In some variations, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used in a subject for preventing, lightening or reducing the
appearance of visible discontinuities of the skin such as
coloration, discoloration, or pigmentation resulting from stress,
fatigue, or extrinsic insults such as harmful factors contained in
sunlight, harmful ultraviolet radiation, pollution and other
environmental insults, which is achieved by administering an
effective amount of one or more of the compositions to the
subject.
[0030] In some variations, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used for preventing, lightening or reducing the appearance of dark
circles, dark spots and uneven skin tone, which is achieved by
administering an effective amount of one or more of the
compositions to the subject.
[0031] In another variation, the cosmetic and dermatological
compositions comprising one or more compounds of formula I may be
used for reducing the appearance of visible discontinuities in skin
associated with inflammation, which is achieved by administering an
effective amount of one or more of the compositions to the subject.
The visible discontinuities may be caused by post-inflammatory
hypopigmentation or hyperpigmentation. The inflammation may be due
to various causes. The inflammation may be caused by rosacea. The
inflammation may be caused by diaper rash. The inflammation may be
caused by acne. The inflammation may be caused by dermatitis such
as atopic dermatitis, contact dermatitis, or seborrheic dermatitis.
The inflammation may be caused by poison ivy or poison oak. The
inflammation may be caused by erythema. The inflammation may be
caused by psoriasis.
[0032] Also provided herein is a cosmetic composition comprising a
cosmetically acceptable or dermatologically acceptable carrier in
combination with any one or more of the compounds of formula I. The
carrier can be formulated for topical use.
[0033] Also provided herein is a cosmetic composition comprising a
pharmaceutically acceptable carrier in combination with any one or
more of the compounds of formula I.
[0034] In one variation, provided herein are methods for reducing
the appearance of visible discontinuities in skin, such as
coloration, discoloration, or pigmentation discontinuities, with a
composition comprising one or more compounds of formula I, wherein
the composition is included in a topical formulation, comprising
administering an effective amount of the composition to a
subject.
[0035] In one variation, provided herein are methods for reducing
the appearance of visible discontinuities in skin such as
coloration, discoloration, or pigmentation discontinuities, with a
composition comprising one or more compounds of formula I, wherein
the composition is included in a topical pharmaceutical
formulation, comprising administering an effective amount of the
one or more compounds of formula I to a subject. In further
embodiments, the administration is topical or dermatological
administration. The composition can comprise pharmaceutically
and/or dermatologically acceptable carriers and vehicles.
[0036] In one variation, provided herein are methods for reducing
the appearance of visible discontinuities in skin such as
coloration, discoloration, or pigmentation discontinuities, with a
composition comprising one or more compounds of formula I, wherein
the composition is formulated for transdermal administration,
comprising administering an effective amount of the one or more
compounds of formula I to the skin of a subject. The composition
can comprise pharmaceutically and/or dermatologically acceptable
carriers and vehicles.
[0037] Also provided herein is a method of lightening skin of a
subject while providing reduction or treatment or prevention of
signs of skin aging, comprising administering to said subject an
amount of one or more compounds of formula I effective for
even-toning, skin-lightening or pigmentation-reducing. In further
embodiments, the administration is topical or dermatological
administration. In a particular variation, provided herein is a
method of lightening skin of a subject in need of said treatment
while providing reduction or treatment or prevention of signs of
skin aging, comprising administering to said subject an amount of a
composition comprising a compound of formula I effective to
even-tone the skin, lighten the skin, or reduce pigmentation in the
skin. In further embodiments, the administration is topical or
dermatological administration. The composition can comprise
pharmaceutically and/or dermatologically acceptable carriers and
vehicles.
[0038] Further provided is a method of improving the appearance of
skin of a subject, comprising administering to said subject an
amount of a composition comprising a compound of formula I
effective to reduce pigmentation. In further embodiments, the
administration is topical or dermatological administration. In a
particular variation, provided herein is a method of reducing or
preventing the appearance of pigmentation in a subject in need of
said treatment, comprising administering to said subject an amount
of a composition comprising a compound of formula I effective to
reduce the appearance of pigmentation in a subject or to prevent
the appearance of pigmentation in a subject. The composition can
comprise pharmaceutically and/or dermatologically acceptable
carriers and vehicles. In some variations, provided is a method of
treating pigmentation or reducing the appearance of pigmentation or
prophylaxis against the appearance of pigmentation, by
administering an effective amount of a composition comprising a
compound of formula I. In some variations the subject has a
pigmentation disorder selected from age spots, vitiligo and
melasma.
[0039] In another variation, provided herein is a method of
treating or regulating a skin condition characterized by oxidative
stress comprising administering to a subject exhibiting said skin
condition a composition comprising one or more compounds of formula
I. The composition can comprise pharmaceutically and/or
dermatologically acceptable carriers and vehicles. In further
embodiments, the administration is topical or dermatological
administration.
[0040] In another variation, provided herein is a method of
regulating and/or preventing visible signs of skin aging comprising
administering to a subject exhibiting skin damage due to aging, a
composition comprising one or more compounds of formula I. The
composition can comprise pharmaceutically and/or dermatologically
acceptable carriers and vehicles. In further embodiments, the
administration is topical or dermatological administration.
[0041] In another variation, provided herein is a method of
regulating and/or preventing visible signs of skin damage due to
extrinsic factors comprising administering to a subject exhibiting
skin damage a composition comprising an effective amount of one or
more compounds of formula I. The composition can comprise
pharmaceutically and/or dermatologically acceptable carriers and
vehicles. In further embodiments, the administration is topical or
dermatological administration. The extrinsic factors can include,
but are not limited to, diaper rash, erythema, UV radiation damage,
sunburn, photoaging, contact dermatitis, and combinations
thereof.
[0042] Also provided herein is a method of reducing the appearance
of pigmentation and aging processes in the skin of a subject,
comprising administering to said subject an amount of a composition
comprising one or more compounds of formula I effective to reduce
the appearance of pigmentation, or to prevent the appearance of
pigmentation, in combination with another therapeutic agent. In one
variation, provided herein is a method of reducing the appearance
of pigmentation, or preventing the appearance of pigmentation, in
the skin of a subject, comprising administering to said subject an
effective amount of a composition comprising one or more compounds
of formula I in combination with an antioxidant. In one variation,
provided herein is a method of reducing the appearance of
pigmentation and aging processes, or preventing the appearance of
pigmentation and aging processes, in a subject in need of said
treatment, comprising administering to said subject an effective
amount of a composition comprising one or more compounds of formula
I in combination with ascorbic acid or derivatives thereof. In
another variation, provided herein is a method of reducing the
appearance of pigmentation and aging processes, or preventing the
appearance of pigmentation and aging processes, in a subject in
need of said treatment, comprising administering to said subject an
effective amount of a composition comprising one or more compounds
of formula I in combination with alpha-tocopherol or any mixture of
tocopherols or derivatives thereof. In another variation, provided
herein is a method of reducing the appearance of pigmentation and
aging processes, or preventing the appearance of pigmentation and
aging processes, in a subject in need of said treatment, comprising
administering to said subject an effective amount of a composition
comprising one or more compounds of formula I in combination with
alpha-tocotrienol or any mixture of tocotrienols or derivatives
thereof. In another variation, provided herein is a method of
reducing the appearance of pigmentation and aging processes, or
preventing the appearance of pigmentation and aging processes, in a
subject in need of said treatment, comprising administering to said
subject an effective amount of a composition comprising one or more
compounds of formula I in combination with any mixture of
tocopherols and tocotrienols or derivatives thereof. In yet another
variation, provided herein is a method of reducing the appearance
of pigmentation and aging processes, or preventing the appearance
of pigmentation and aging processes, in a subject in need of said
treatment, comprising administering to said subject an effective
amount of a composition comprising one or more compounds of formula
I in combination with ascorbic acid and alpha-tocopherol or
derivatives thereof. In other variations, provided herein is a
method of reducing the appearance of pigmentation and aging
processes, or preventing the appearance of pigmentation and aging
processes, in a subject in need of said treatment, comprising
administering to said subject an effective amount of a composition
comprising one or more compounds of formula I in combination with
retinoids or an exfoliating agent. When administered in
combination, the therapeutic agents can be formulated as separate
compositions that are given at the same time or different times, or
the therapeutic agents can be given as a single composition. The
composition can also comprise pharmaceutically and/or
dermatologically acceptable carriers and vehicles. In any of the
foregoing embodiments, the administration can be topical or
dermatological administration.
[0043] Also provided herein is a product comprising instructions
directing a user to apply a composition including a skin care
composition comprising one or more compounds of formula I. The
composition can comprise pharmaceutically and/or dermatologically
acceptable carriers and vehicles.
[0044] Also provided herein is a kit, comprising a container
comprising one or more specific compounds or dermatological
compositions described herein that lighten skin pigmentation. The
kit may further comprise printed instructions as a label or a
package insert directing the use of the enclosed compound or
composition to lighten skin pigmentation.
[0045] Also provided for herein is the use of a composition of any
of the foregoing variations in the manufacture of a cosmetic or
dermatological composition for treating a mammalian subject, such
as a human, having a dermatologic condition, where the treatment is
to prevent, reduce or treat signs of skin aging or skin
pigmentation, or to reduce the appearance of skin aging or skin
pigmentation.
[0046] For all compositions described herein, and all methods using
a composition described herein, the compositions can either
comprise the listed components or steps, or can "consist
essentially of" the listed components or steps. When a composition
is described as "consisting essentially of" the listed components,
the composition contains the components listed, and may contain
other components which do not substantially affect the skin or the
skin condition being treated, but do not contain any other
components which substantially affect the skin or the skin
condition being treated other than those components expressly
listed; or, if the composition does contain extra components other
than those listed which substantially affect the skin or the skin
condition being treated, the composition does not contain a
sufficient concentration or amount of the extra components to
substantially affect the skin or the skin condition being treated.
When a method is described as "consisting essentially of" the
listed steps, the method contains the steps listed, and may contain
other steps that do not substantially affect the skin or the skin
condition being treated, but the method does not contain any other
steps which substantially affect the skin or the skin condition
being treated other than those steps expressly listed.
DETAILED DESCRIPTION
Definitions
[0047] As used herein, a "subject" or "patient" is a mammal,
particularly a human. It is understood that use "in" a subject or
patient can comprise use "on" a subject or patient as well; that
is, use "in" a subject or patient can comprise either internal use,
external use, or both, according to the context of the use.
[0048] As used herein, the terms "even-toning", "whitening",
"lightening" and "depigmentation" agent are used interchangeably
throughout this document. For purposes of skin lightening, topical
application of skin lightening agent should have a lightening
effect on only the area to be treated, preferably produce no or
minimal irritation, preferably produce no or minimal
post-inflammatory secondary pigmentation, and preferably not cause
an allergic reaction. In addition, the skin lightening should be
effective for normal cutaneous pigmentation and its excesses,
including, but not limited to, lentigo senilis, chloasma,
cicatrical brown spots, and hyperpigmentation after use of
photosensitizing products. Preferably, the skin lightening should
be effective while simultaneously providing anti-aging skin
benefits.
[0049] As used herein, a "skin-lightening or pigmentation reducing
amount of a compound of formula I" means an amount or concentration
of the compound capable of detectably lightening skin or reducing
pigmentation in a subject, such as a human, as determined by any
standard assay. The active compound is typically administered in a
dermatological or pharmaceutical composition for a standard course
of treatment that produces the desired result of skin
depigmentation.
[0050] As used herein, "administering to skin in need of such
treatment" means contacting (e.g., by use of the hands or an
applicator such as, but not limited to, a wipe, tube, roller,
spray, or patch) the area of skin in need such treatment or an area
of skin proximate to the area of skin in need of such
treatment.
[0051] As used herein, "composition" means a composition suitable
for topical administration to the skin.
[0052] As used herein, the term "cosmetics" includes make-up,
foundation, and skin care products. The term "make-up" refers to
products that leave color on the face, including foundations,
blacks and browns, e.g., mascara, concealers, eye liners, brow
colors, eye shadows, blushers, lip colors, and so forth. The term
"foundation" refers to liquid, creme, mousse, pancake, compact,
concealer, or like products that even out the overall coloring of
the skin. Foundation is typically manufactured to work better over
moisturized and/or oiled skin. The term "skin care products" refers
to products used to treat or otherwise care for, moisturize,
improve, or clean the skin. Products contemplated by the phrase
"skin care products" include, but are not limited to, adhesives,
bandages, anhydrous occlusive moisturizers, antiperspirants, facial
wash cleaners, cold cream, deodorants, soaps, occlusive drug
delivery patches, powders, tissues, wipes, solid emulsion compact,
anhydrous hair conditioners, medicated shampoos, scalp treatments
and the like.
[0053] As used herein, the term "cosmetically-acceptable" or
"dermatologically-acceptable" means that the compositions or
components thereof so-described are suitable for use in contact
with skin, particularly human skin, without undue toxicity,
incompatibility, instability, irritation, or allergic response.
[0054] As used herein, the term "cosmetically acceptable carrier",
"cosmetically acceptable excipient", "dermatologically acceptable
carrier" or "dermatologically acceptable excipient" includes any
and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents and the
like, that are cosmetically acceptable or dermatologically
acceptable. The use of such media and agents for cosmetically
active substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the active
ingredient, its use in the cosmetic compositions is contemplated.
Supplementary active ingredients can also be incorporated into the
compositions. Dermatologically acceptable carriers are suitable for
topical application to the skin, have good aesthetic properties,
are compatible with the active agents described herein and any
other components, and cause minimal or no safety or toxicity
concerns. A safe and effective amount of carrier is from about 50%
to about 99.99% or about 50% to about 99%, preferably from about
80% to about 99.9% or about 75% to about 99%, more preferably from
about 90% to about 98%, and most preferably from about 90% to about
95% or about 85% to about 95% of the composition. The percentages
are preferably percent by weight.
[0055] As used herein, the term "effective amount" refers to that
amount of a compound described herein that is sufficient to effect
treatment, as defined below, when administered to a subject in need
of such treatment. The effective amount will vary depending upon
the subject and skin condition or disease condition being treated
and the like, all of which can readily be determined by one of
ordinary skill in the art.
[0056] As used herein, "regulating a skin condition" includes
regulating the appearance of a skin condition, including visible
discontinuities in skin such as, but not limited to, coloration,
discoloration, and unwanted pigmentation. Regulating a skin
condition includes even-toning the skin and reducing
pigmentation.
[0057] As used herein, "signs of skin aging" include, but are not
limited to, all outward manifestations of skin aging which are
visibly perceptible due to changes in skin pigmentation, skin
coloration, or skin discoloration. Such signs may be induced or
caused by intrinsic factors or extrinsic factors, e.g.,
chronological aging and/or environmental damage (e.g., sunlight;
UV; smoke, including cigarette, cigar or other tobacco product
smoke; ozone; pollutants; stress; etc.). These signs include, but
are not limited to, blotching (e.g., uneven red coloration due to,
e.g., rosacea), sallowness (pale color), discoloration caused by
telangiectasia or spider vessels; melanin-related hyperpigmented
(or unevenly pigmented) skin regions such as age spots (liver
spots, brown spots) and freckles; post-inflammatory
hyperpigmentation or hypopigmentation such as that which occurs
following an inflammatory event (e.g., as an acne lesion, in-grown
hair, insect/spider bite or sting, scratch, cut, wound, abrasion,
and the like); and tissue responses to insult such as itch or
pruritus.
[0058] As used herein, the terms "skin condition", "dermatologic
condition", and "dermatological condition" are used
interchangeably.
[0059] As used herein, the term "sunscreen" may include, but is not
limited to, organic or inorganic sunscreens, such as
methoxycinnamate, oxybenzone, avobenzone, and the like; sun blocks
such as titanium oxide and zinc oxide; and skin protectants; or
mixtures thereof.
[0060] As used herein, the term "topical application" means to
apply or spread the compositions described herein onto the surface
of the skin.
[0061] As used herein, the terms "treat" and "treating", and the
like refer to reversing, alleviating, or inhibiting the progress
of, the disorder or condition to which such term applies, or one or
more symptoms of such disorder or condition. The term "treatment",
as used herein, refers to the act of treating, as "treating" is
defined immediately above. The term "treatment" or "treating"
includes the reduction in appearance of skin imperfections
irrelevant of the mechanism of action. One of ordinary skill in the
art will appreciate that the endpoint of treatment chosen in a
particular case will vary according to the disease, condition, or
disorder being treated, the outcome desired by the patient,
subject, or treating physician, and other factors. Where the
composition is being used to lighten skin color such as, for
example, to reverse hyperpigmentation caused by, for example,
diseases such as melasma or age spots, any one of a number of
endpoints can be chosen. For example, endpoints can be defined
subjectively such as, for example, when the subject is simply
"satisfied" with the results of the treatment. For pharmacological
compositions, the endpoint can be determined by the patient's,
subject's, or the treating physician's, satisfaction with the
results of the treatment. Alternatively, endpoints can be defined
objectively. For example, the patient's or subject's skin in the
treated area can be compared to a color chart. Treatment is
terminated when the color of the skin in the treated area is
similar in appearance to a color on the chart. Alternatively, the
reflectance of the treated skin can be measured, and treatment can
be terminated when the treated skin attains a specified
reflectance. Alternatively, the melanin content of the treated skin
can be measured. Treatment can be terminated when the melanin
content of the treated skin reaches a specified value. Melanin
content can be determined in any way known to the art, including by
histological methods, with or without enhancement by stains for
melanin.
[0062] As used herein, "alkyl" is intended to embrace a saturated
linear or branched hydrocarbon chain having the number of carbon
atoms specified. In one embodiment, alkyl groups can have 1 to 12
carbon atoms. "Alkylene" is intended to embrace a divalent
saturated linear or branched hydrocarbon chain having the number of
carbon atoms specified. In one embodiment, alkylene groups can have
1 to 12 carbon atoms.
[0063] As used herein, "cycloalkyl" is intended to embrace a
saturated cyclic hydrocarbon chain having the number of carbon
atoms specified. In one embodiment, cycloalkyl groups can have 3 to
12 carbon atoms.
[0064] As used herein, "alkenyl" is intended to embrace a linear or
branched hydrocarbon chain having at least one carbon-carbon double
bond. In one embodiment, alkenyl groups can have 2 to 12 carbon
atoms. "Alkenylene" is intended to embrace a divalent linear or
branched hydrocarbon chain having at least one carbon-carbon double
bond, and having the number of carbon atoms specified. In one
embodiment, alkenylene groups can have 2 to 12 carbon atoms.
[0065] As used herein, "haloalkyl" indicates an alkyl group where
at least one hydrogen of the alkyl group has been replaced with a
halogen substituent, that is, a fluorine (F), chlorine (Cl),
bromine (Br), or iodine (I) substituent. "Perhaloalkyl" indicates
an alkyl group where all available valences have been substituted
with halogen. For example, "perhaloethyl" can refer to
--CCl.sub.2CF.sub.3, --CF.sub.2CBr.sub.3, or
--CCl.sub.2CCl.sub.3.
[0066] As used herein, "fluoroalkyl" indicates an alkyl group where
at least one hydrogen of the alkyl group has been replaced with a
fluorine substituent. "Perfluoroalkyl" indicates an alkyl group
where all available valences have been substituted with fluorine.
For example, "perfluoroethyl" refers to --CF.sub.2CF.sub.3.
[0067] As used herein, "chloroalkyl" indicates an alkyl group where
at least one hydrogen of the alkyl group has been replaced with a
chlorine substituent. "Perchloroalkyl" indicates an alkyl group
where all available valences have been substituted with chlorine.
For example, "perchloroethyl" refers to --CCl.sub.2CCl.sub.3.
[0068] As used herein, "aryl" is defined as an optionally
substituted aromatic ring system, such as phenyl or naphthyl. Aryl
groups include monocyclic aromatic rings and polycyclic aromatic
ring systems containing the number of carbon atoms specified. In
one embodiment, aryl groups can contain six to twenty carbon atoms.
In other embodiments, aryl groups can contain six to twelve carbon
atoms, or six to ten carbon atoms. In other embodiments, aryl
groups can be unsubstituted. In other embodiments, aryl groups can
be substituted.
[0069] As used herein, "heterocycloalkyl" is intended to embrace an
optionally substituted cyclic hydrocarbon chain having the number
of carbon atoms specified and one or more heteroatoms (such as one
to three heteroatoms, such as oxygen, nitrogen, sulfur, and
phosphorus). In one embodiment, heterocycloalkyl groups can have 3
to 12 carbon atoms and 1 to 3 heteroatoms. Examples of
heterocycloalkyl groups include, but are not limited to,
tetrahydrofuranyl, piperidinyl, and piperazinyl. In some
embodiments, heterocycloalkyl groups can be unsubstituted. In other
embodiments, heterocycloalkyl groups can be substituted.
[0070] As used herein, "heteroaryl" is defined as an optionally
substituted aromatic ring system which contains the number of
carbon atoms specified, and one or more heteroatoms (such as one to
three heteroatoms), where heteroatoms include, but are not limited
to, oxygen, nitrogen, sulfur, and phosphorus. In some embodiments,
heteroaryl groups can contain three to twelve carbon atoms and one
to three heteroatoms, or six to ten carbon atoms and one to three
heteroatoms. In some embodiments, heteroaryl groups can be
unsubstituted. In other embodiments, heteroaryl groups can be
substituted. Examples of heteroaryl groups include, but are not
limited to, imidazolyl, pyrrolyl, and pyridinyl.
[0071] As used herein, the term "tocopherols or tocotrienols"
encompasses a family of molecules characterized by a 6-chromanol
ring structure and a side chain at the 2-position. Tocopherols
possess a 4',8',12'-trimethyltridecyl phytol side chain, while
tocotrienols possess an unsaturated phytol side chain. As used
herein, the term tocopherol or tocotrienols means alpha-, beta-,
gamma- or delta-, epsilon- and zeta-tocopherol or tocotrienols (see
The Merck Index (1996), Merck & Co., Whitehouse Station, N.J.
1620-1621 and 1712, and references cited therein), as well as
Vitamin E. The term tocopherol also includes cosmetically
acceptable esters, for example tocopherol acetate, tocopherol
lineate, or tocopherol stearate. The term tocopherol also includes
mixtures of tocopherols, tocotrienols and/or stereoisomers as well
as enriched compositions comprising at least 50% of any tocopherol
or tocotrienol. The tocopherols and tocotrienols can be of natural
or synthetic origin.
[0072] As used herein, the term "retinoids" means retinol, retinal,
esters of retinol, retinyl palmitate, retinyl linoleate, retinoic
acid, or retinoic acid esters, as well as synthetic or natural
Vitamin A. The term "retinol" includes the following isomers of
retinol: all-trans-retinol, 13-cis-retinol, 11-cis-retinol,
9-cis-retinol, 3,4-didehydro-retinol. A retinyl ester is an ester
of retinol. Suitable retinyl esters are C.sub.1-C.sub.30 esters of
retinol, preferably C.sub.2-C.sub.20 esters, and most preferably
C.sub.2, C.sub.3, and C.sub.16 esters. Some esters may be selected
from retinyl palmitate, retinyl acetate, retinyl propionate, and
retinyl linoleate. Retinoyl ester is an ester of retinoic acid with
an alcohol. Suitable retinoyl esters include C.sub.1-C.sub.30
alcohol esters of retinoic acid, preferably C.sub.2-C.sub.20 esters
and most preferably C.sub.2-C.sub.3 and C.sub.16 esters. Some
retinoyl esters comprise the linoleyl alcohol ester of retinoic
acid, the hexanedecanol ester of retinoic acid, the oleic alcohol
ester of retinoic acid, retinoyl ascorbate, and the linolenyl
alcohol ester of retinoic acid.
[0073] While the compounds described herein can occur and can be
used as the neutral (non-salt) compound, the description is
intended to embrace all salts of the compounds described herein, as
well as methods of using such salts of the compounds. In one
embodiment, the salts of the compounds comprise pharmaceutically
acceptable salts and/or dermatologically acceptable salts.
Pharmaceutically acceptable salts are those salts which can be
administered as drugs or pharmaceuticals to humans and/or animals
and which, upon administration, retain at least some of the
biological activity of the free compound (neutral compound or
non-salt compound). Dermatologically acceptable salts are those
salts which can be applied as drugs or pharmaceuticals to the skin
of humans and/or animals and which, upon application, retain at
least some of the biological activity of the free compound (neutral
compound or non-salt compound). The desired salt of a basic
compound may be prepared by methods known to those of skill in the
art by treating the compound with an acid. Examples of inorganic
acids include, but are not limited to, hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
Examples of organic acids include, but are not limited to, formic
acid, acetic acid, propionic acid, glycolic acid, pyruvic acid,
oxalic acid, maleic acid, malonic acid, succinic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, sulfonic acids, and salicylic acid. Salts of basic
compounds with amino acids, such as aspartate salts and glutamate
salts, can also be prepared. The desired salt of an acidic compound
can be prepared by methods known to those of skill in the art by
treating the compound with a base. Examples of inorganic salts of
acid compounds include, but are not limited to, alkali metal and
alkaline earth salts, such as sodium salts, potassium salts,
magnesium salts, and calcium salts; ammonium salts; and aluminum
salts. Examples of organic salts of acid compounds include, but are
not limited to, procaine, dibenzylamine, N-ethylpiperidine,
N,N-dibenzylethylenediamine, and triethylamine salts. Salts of
acidic compounds with amino acids, such as lysine salts, can also
be prepared. Other pharmaceutically acceptable salts are described
in Bighley, "Salt Forms of Drugs," Encyclopedia of Pharmaceutical
Technology vol. 13 pp 453-499 (1996) (Swarbrick, Boylan, eds.), and
Berge, "Pharmaceutical Salts," J. Pharm. Sci. 66:1 (1977).
[0074] The invention also includes, if chemically possible, all
stereoisomers of the compounds, including diastereomers and
enantiomers. The invention also includes mixtures of possible
stereoisomers in any ratio, including, but not limited to, racemic
mixtures. Unless stereochemistry is explicitly indicated in a
structure, the structure is intended to embrace all possible
stereoisomers of the compound depicted. If stereochemistry is
explicitly indicated for one portion or portions of a molecule, but
not for another portion or portions of a molecule, the structure is
intended to embrace all possible stereoisomers for the portion or
portions where stereochemistry is not explicitly indicated.
[0075] The compounds can be administered in prodrug form. Prodrugs
are derivatives of the compounds, which are themselves relatively
inactive but which convert into the active compound when introduced
into the subject in which they are used by a chemical or biological
process in vivo, such as an enzymatic conversion. Suitable prodrug
formulations include, but are not limited to, peptide conjugates of
the compounds of the invention and esters of compounds of the
inventions. Further discussion of suitable prodrugs is provided in
H. Bundgaard, Design of Prodrugs, New York: Elsevier, 1985; in R.
Silverman, The Organic Chemistry of Drug Design and Drug Action,
Boston: Elsevier, 2004; in R. L. Juliano (ed.), Biological
Approaches to the Controlled Delivery of Drugs (Annals of the New
York Academy of Sciences, v. 507), New York: New York Academy of
Sciences, 1987; and in E. B. Roche (ed.), Design of
Biopharmaceutical Properties Through Prodrugs and Analogs
(Symposium sponsored by Medicinal Chemistry Section, APhA Academy
of Pharmaceutical Sciences, November 1976 national meeting,
Orlando, Fla.), Washington: The Academy, 1977.
[0076] The description of compounds herein also includes all
isotopologues, for example, partially deuterated or perdeuterated
analogs of all compounds herein.
Methods
[0077] Any of the compounds described herein can be mixed as
cosmetics, cosmeceuticals, quasi-drugs (where applicable), or
pharmaceutical drugs. The compounds can appropriately be mixed with
other components. Examples of such components include oily
components such as hydrocarbons, fats and oils such as liquid
paraffin, squalene, petroleum jelly such as Vaseline.RTM. (a
registered trademark of Conopco Corp., Englewood Cliffs, N.J.),
cetyl alcohol, isostearyl alcohol, cetyl-2-ethylhexanoate,
2-octyldodecyl alcohol, glycerin, glycerin triisostearate, nut
oils, and lanolin, as well as wax, silicone, surfactants,
thickeners, neutralizers, antiseptics, germicides, anti-oxidants,
powder components, pigments, perfumes, ultraviolet light
absorbents, drugs, metallic sealant, and pH modifiers.
[0078] Occurrences in the skin of noticeable but undesired
pigmentation as a result of overproduction or underproduction of
melanin or of noticeable uneven texture as a result of aging can be
reduced, treated or prevented using the methods described herein.
Cosmetic applications for methods described herein include the
topical application of compositions containing one or more of the
compounds describe herein to enhance or otherwise alter the visual
appearance of skin. The cosmetic compositions described herein are
also useful to provide a smoother or softer skin appearance.
[0079] The active compounds described herein can also be used in
combination with skin peeling agents (including glycolic acid or
trichloroacetic acid face peels) or skin exfoliating agents
(including retinoids, such as retinoic acid or retinol) to lighten
skin tone and prevent repigmentation. The appropriate dose regimen,
the amount of each dose administered, and specific intervals
between doses of the active compound will depend upon the
particular active compound employed, the condition of the patient
or subject being treated, and the nature and severity of the
disorder or condition being treated. Preferably, the active
compound is administered in an amount and at an interval that
results in the desired treatment of or improvement in the disorder
or condition being treated.
[0080] An active compound described herein can also be used in
combination with sun screens (UVA or UVB blockers) to prevent
repigmentation; to protect against sun or UV-induced skin
darkening, or to enhance their skin lightening or bleaching action
and to enhance their ability to reduce skin melanin. An active
compound described herein can also be used in combination with any
compounds that interact with retinoic acid receptors and accelerate
or enhance their ability to reduce skin melanin, accelerate or
enhance their skin lightening or bleaching action, or accelerate or
enhance their ability to prevent the accumulation of skin melanin.
An active compound described herein can also be used in combination
with 4-hydroxyanisole. An active compound described herein can also
be used in combination with ascorbic acid, its derivatives and
ascorbic-acid based products (such as magnesium ascorbate) or other
products with an anti-oxidant mechanism (such as resveratrol,
tocopherols, tocotrienols and derivatives) which accelerate or
enhance their ability to reduce skin melanin, or accelerate or
enhance their skin bleaching action.
[0081] In some variations, the composition further comprises a
soybean extract that is a blend of compounds isolated from soybean.
The soybean extract may contain only a portion of the soybean
(e.g., an extract of the soybean such as a lipid reduced soybean
powder or filtered soymilk) or may contain the entire soybean
(e.g., a ground powder of the soybean). The soybean extract may be
in the form of a fluid (e.g., soymilk) or a solid (e.g., a soybean
powder or soymilk powder).
[0082] One or more active compounds used in the methods described
herein may be used alone or in combination with one or more other
compounds known in the art. For example, any of the compounds
described herein may be used in combination with a tyrosinase
inhibitor or other skin-lightening, pigmentation-modifying, or
skin-whitening agent, including any one or more of those agents,
including compounds or extracts, described in the following patent
publications: U.S. Pat. No. 4,278,656 to Nagai et al.; U.S. Pat.
No. 4,959,393 to Torihara et al.; U.S. Pat. No. 5,164,182; U.S.
Pat. No. 5,580,549 to Fukuda et al.; U.S. Pat. No. 5,723,109 to
L'Oreal; U.S. Pat. No. 6,123,959 to Jones et al.; U.S. Pat. No.
6,132,740 to Hu; U.S. Pat. No. 6,159,482 to Tuloup et al.; U.S.
Pat. No. 6,365,135 to L'Oreal; U.S. Pat. No. 6,514,538 to Shiseido
Co. Ltd.; U.S. Pat. Publ, No. 2006188559 to Neis; WO 99/64025 by
Fytokem Prod. Inc.; U.S. Pat. No. 6,348,204 by L'Oreal; WO 00/56702
by Pfizer Inc.; JP 5221846 by Kunimasa Tomoji; JP 7242687 by
Shiseido Co. Ltd.; JP 7324023 by Itogawa H.; JP 8012552 by Shiseido
Co. Ltd.; JP 8012554 by Shiseido Co. Ltd.; JP 8012557 by Shiseido
Co. Ltd.; JP 8012560 by Shiseido Co. Ltd.; JP 8012561 by Shiseido
Co. Ltd.; JP 8134090 by Fujisawa; JP 8277225 by Kansai Koso K K; JP
9002967 by Sanki Shoji K K; JP 9295927 by Yagi Akir; JP 10072330 by
Kansai Kouso; JP 10081626 by Kamiyama K K; JP 10101543 by Kansai
Kouso K K; JP 11071231 by Maruzen Pharm.; JP 11079934 by Kyodo
Nyugyo; JP 11246347 by Shiseido Co. Ltd.; JP 11246344 by Shiseido
Co. Ltd.; JP 2000-080023 by Kanebo Ltd.; JP 2000-095663 by Kose K
K; JP 2000-159681 by Hai Tai Confectionery Co. Ltd.; JP-7206753 by
Nikken Food K K; JP-59157009 by Yakurigaku Chuou K E; JP
2001019618, by Shiseido; JP 2002029959 by Shiseido; JP 2004315534
by Access Business Group Int Llc; JP 2005041821 by Shiseido; JP
2007063224 by Kobayashi Pharma; JP 2007091635 by Maruzen Pharma; JP
2008013481 by Univ. of Tokushima; KR 20040078449 by Enbioeng Co
Ltd.; TW 281863 by Taiyen Biotech Co Ltd; and CN 101102746 by Young
Chung Se; among others. These patent publications are incorporated
herein by reference in their entireties.
[0083] Provided herein are methods of lightening or reducing the
pigmentation of skin and/or of reducing uneven texture in which an
active compound described herein, and one or more of the other
active ingredients, such as those referred to above, are
administered together as part of the same pharmaceutical
composition, as well as methods in which they are administered
separately as part of an appropriate dose regimen designed to
obtain the benefits of the combination therapy. The appropriate
dose regimen, the amount of each dose administered, and specific
intervals between doses of each active agent will depend upon the
specific combination of active agents employed, the condition of
the patient or subject being treated, and the nature and severity
of the disorder or condition being treated. Such additional active
ingredients can be administered in amounts less than or equal to
those for which they are effective as single topical therapeutic
agents.
[0084] An active compound will generally be administered in the
form of a dermatological or cosmetic composition comprising the
compound of formula I, together with a dermatologically acceptable
carrier or solvent. Alternatively, an active compound can be
administered in the form of a pharmaceutical composition comprising
the compound of formula I, together with a pharmaceutically
acceptable carrier or solvent.
[0085] In the depigmenting compositions provided herein, the
concentration of the active compound is generally between 0.01% and
10%, or between about 0.01% and about 10%, for example between 0.1%
and 5% or between about 0.1% and about 5%, or between 0.1% and 2%,
or between about 0.1% and about 2%, or between 0.1% and 1%, or
between about 0.1% and about 1%, relative to the total weight of
the composition.
[0086] The compositions described herein can be applied directly to
the skin. Alternatively, they can be delivered by various
transdermal drug delivery systems, such as transdermal patches as
known in the art. For example, for topical administration, the
active ingredient can be formulated in a solution, gel, lotion,
ointment, cream, suspension, paste, liniment, powder, tincture,
aerosol, patch, or the like in a pharmaceutically or cosmetically
acceptable form by methods known in the art. The composition can be
any of a variety of forms common in the pharmaceutical or cosmetic
arts for topical application to animals or humans, including
solutions, lotions, sprays, creams, ointments, salves, gels, etc.,
as described below. Exemplary agents are those that are viscous
enough to remain on the treated area, those that do not readily
evaporate, and/or those that are easily removed by rinsing with
water, optionally with the aid of soaps, cleansers and/or shampoos.
Actual methods for preparing topical formulations are known to
those skilled in the art, such as those described in Remington's
Pharmaceutical Sciences, (1990); and Pharmaceutical Dosage Forms
and Drug Delivery Systems, 6th ed., Williams & Wilkins
(1995).
[0087] The compositions may be made into a wide variety of product
types that include but are not limited to solutions, suspensions,
lotions, creams, gels, toners, sticks, sprays, ointments, cleansing
liquid washes and solid bars, shampoos and hair conditioners,
pastes, foams, powders, mousses, shaving creams, wipes, strips,
patches, electrically-powered patches, wound dressing and adhesive
bandages, hydrogels, film-forming products, facial and skin masks,
make-up such as foundations, eye liners, and eye shadows, and the
like. These product types may contain several types of
cosmetically-acceptable carriers including, but not limited to
solutions, suspensions, emulsions such as microemulsions and
nanoemulsions, gels, solids and liposomes.
[0088] The compositions can be formulated as solutions. Solutions
typically include an aqueous or organic solvent, e.g., from about
50% to about 99.99% or from about 90% to about 99% of a
cosmetically acceptable aqueous or organic solvent. Examples of
suitable organic solvents include: propylene glycol, polyethylene
glycol (200-600), polypropylene glycol (425-2025), glycerol,
1,2,4-butanetriol, sorbitol esters, 1,2,6-hexanetriol, ethanol, and
mixtures thereof. One example of such solvents is a mixture of
ethanol/polyethylene glycol (80/20).
[0089] A lotion can be made from such a solution. Lotions typically
contain from about 1% to about 20% (e.g., from about 5% to about
10%) of an emollient(s) and from about 50% to about 90% (e.g., from
about 60% to about 80%) of water.
[0090] Another type of product that may be formulated from a
solution is a cream. A cream typically contains from about 5% to
about 50% (e.g., from about 10% to about 20%) of an emollient(s)
and from about 45% to about 85% (e.g., from about 50% to about 75%)
of water.
[0091] Yet another type of product that may be formulated from a
solution is an ointment. An ointment may contain a simple base of
animal, vegetable, or synthetic oils or semi-solid hydrocarbons. An
ointment may contain from about 2% to about 10% of an emollient(s)
plus from about 0.1% to about 2% of a thickening agent(s). Examples
of thickening agents include, but are not limited to, those set
forth in the ICI Handbook (International Cosmetic Ingredient
Dictionary and Handbook) pp. 1693-1697.
[0092] The compositions described herein can also be formulated as
emulsions. If the carrier is an emulsion, from about 1% to about
10% (e.g., from about 2% to about 5%) of the carrier contains an
emulsifier(s). Emulsifiers may be nonionic, anionic or cationic.
Examples of emulsifiers include, but are not limited to, those set
forth in the ICI Handbook, pp. 1673-1686.
[0093] Lotions and creams can be formulated as emulsions. Typically
such lotions contain from 0.5% to about 5% of an emulsifier(s),
while such creams would typically contain from about 1% to about
20% (e.g., from about 5% to about 10%) of an emollient(s); from
about 20% to about 80% (e.g., from 30% to about 70%) of water; and
from about 1% to about 10% (e.g., from about 2% to about 5%) of an
emulsifier(s).
[0094] Single emulsion skin care preparations, such as lotions and
creams, of the oil-in-water type and water-in-oil type are
well-known in the art and are useful in compositions and methods
described herein. Multiphase emulsion compositions, such as the
water-in-oil-in-water type or the oil-in-water-in-oil type, are
also useful in the compositions and methods describe herein. In
general, such single or multiphase emulsions contain water,
emollients, and emulsifiers as essential ingredients.
[0095] The compositions described herein can also be formulated as
a gel (e.g., an aqueous, alcohol, alcohol/water, or oil gel using a
suitable gelling agent(s)). Suitable gelling agents for aqueous
and/or alcoholic gels include, but are not limited to, natural
gums, acrylic acid and acrylate polymers and copolymers, and
cellulose derivatives (e.g., hydroxymethyl cellulose and
hydroxypropyl cellulose). Suitable gelling agents for oils (such as
mineral oil) include, but are not limited to, hydrogenated
butylene/ethylene/styrene copolymer and hydrogenated
ethylene/propylene/styrene copolymer. Such gels typically contains
between about 0.1% and 5%, by weight, of such gelling agents.
[0096] One or more additional agents can be added in the topical
formulations in order to enhance the percutaneous absorption of the
active ingredients, including, but not limited to,
dimethylsulfoxide, dimethylacetamide, dimethylformamide,
surfactants, azone (laurocapram), alcohol, acetone, propylene
glycol and polyethylene glycol. Physical methods can also be used
to enhance transdermal penetration such as iontophoresis or
sonophoresis. Alternatively, or in addition, administration via
liposomes can be employed.
[0097] A topically applied composition provided herein contains a
pharmaceutically effective agent that has the desired effect on
skin as described herein, and those ingredients as are necessary
for use as a carrier, such as an emulsion, a cream, an ointment, an
aqueous solution, a lotion or an aerosol. Non-limiting examples of
such carriers may be found in U.S. Pat. No. 5,691,380 to Mason et
al., issued Nov. 25, 1997; and U.S. Pat. No. 5,968,528 to Deckner
et al., issued Oct. 19, 1999; which are incorporated herein by
reference. Suitable pharmaceutical carriers are further described
in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing
Company, Easton, Pa. (1990).
[0098] The carrier utilized in the compositions described herein
can be in a wide variety of forms. These include emulsion carriers,
including, but not limited to, oil-in-water, water-in-oil,
water-in-oil-in-water, and oil-in-water-in-silicone emulsions, a
cream, an ointment, an aqueous solution, a lotion or an aerosol. As
will be understood by the skilled artisan, a given component will
distribute primarily into either the water or oil/silicone phase,
depending on the water solubility/dispersibility of the component
in the composition.
[0099] Dermatological formulations provided herein may typically
comprise a derivative of any compound or composition described
herein and optionally, a polar solvent. Solvents suitable for use
in the formulations described herein include any polar solvent
capable of dissolving the derivative. Suitable polar solvents may
include: water; alcohols (such as ethanol, propyl alcohol,
isopropyl alcohol, hexanol, and benzyl alcohol); polyols (such as
propylene glycol, polypropylene glycol, butylene glycol, hexylene
glycol, maltitol, sorbitol, and glycerine); and panthenol dissolved
in glycerine, flavor oils and mixtures thereof. Mixtures of these
solvents can also be used. Exemplary polar solvents may be
polyhydric alcohols and water. Examples of solvents may include
glycerine, panthenol in glycerine, glycols such as propylene glycol
and butylene glycol, polyethylene glycols, water and mixtures
thereof. Additional polar solvents for use may be alcohols,
glycerine, panthenol, propylene glycol, butylene glycol, hexylene
glycol and mixtures thereof.
[0100] An emollient may also be added to the
cosmetic/dermatological compositions described herein. The
emollient component can comprise fats, oils, fatty alcohols, fatty
acids and esters which aid application and adhesion, yield gloss
and provide occlusive moisturization. Suitable emollients for use
may be isostearic acid derivatives, isopropyl palmitate, lanolin
oil, diisopropyl dimerate, maleated soybean oil, octyl palmitate,
isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopheryl
acetate, acetylated lanolin alcohol, cetyl acetate, phenyl
trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ
glycerides, arachidyl propionate, myristyl lactate, decyl oleate,
propylene glycol ricinoleate, isopropyl linoleate, pentaerythrityl
tetrastearate, neopentylglycol dicaprylate/dicaprate, hydrogenated
coco-glycerides, isononyl isononanoate, isotridecyl isononanoate,
myristyl myristate, triisocetyl citrate, cetyl alcohol, octyl
dodecanol, oleyl alcohol, panthenol, lanolin alcohol, linoleic
acid, linolenic acid, sucrose esters of fatty acids, octyl
hydroxystearate and mixtures thereof. Examples of other suitable
emollients can be found in the Cosmetic Bench Reference, pp.
1.19-1.22 (1996), or in the International Cosmetic Ingredient
Dictionary and Handbook, eds. Wenninger and McEwen, pp. 1656-61,
1626, and 1654-55 (The Cosmetic, Toiletry, and Fragrance Assoc.,
Washington, D.C., 7.sup.th Edition, 1997) (hereinafter "ICI
Handbook"), incorporated herein by reference. Suitable emollients
may include polar emollient emulsifiers (such as linear or branched
chained polyglycerol esters) and non-polar emollients. The
emollient component typically may comprise from about 1% to about
90%, preferably from about 10% to about 80%, more preferably from
about 20% to about 70%, and most preferably from about 40% to about
60%, of the cosmetic composition.
[0101] By "polar emollient," as used herein, is meant any emollient
emulsifier having at least one polar moiety and wherein the
solubility (at 30.degree. C.) of the cytoprotective derivative
compound in the polar emollient is greater than about 1.5%,
preferably greater than about 2%, more preferably greater than
about 3%. Suitable polar emollients may include, but are not
limited to, polyol ester and polyol ethers such as linear or
branched chained polyglycerol esters and polyglycerol ethers.
Non-limiting examples of such emollients may include PG3
diisostearate, polyglyceryl-2-sesquiisostearate,
polyglyceryl-5-distearate, polyglyceryl-10-distearate,
polyglyceryl-10-diisostearate, acetylated monoglycerides, glycerol
esters, glycerol tricaprylate/caprate, glyceryl ricinoleate,
glyceryl isostearate, glyceryl myristate, glyceryl linoleate,
polyalkylene glycols such as PEG 600, monoglycerides, 2-monolaurin,
sorbitan esters and mixtures thereof.
[0102] By "non-polar emollient," as used herein, means any
emollient emulsifier possessing no or minimal permanent electric
moments. Suitable non-polar emollients may include, but are not
limited to, esters and linear or branched chained hydrocarbons.
Non-limiting examples of such emollients may include isononyl
isononanoate, isopropyl isostearate, octyl hydroxystearate,
diisopropyl dimerate, lanolin oil, octyl palmitate, isopropyl
palmitate, paraffins, isoparaffins, acetylated lanolin, sucrose
fatty acid esters, isopropyl myristate, isopropyl stearate, mineral
oil, silicone oils, dimethicone, allantoin, isohexadecane,
isododecane, petrolatum, and mixtures thereof. The solubility of
the compound in polar or non-polar emollients may be determined
according to methods known in the art.
[0103] Suitable oils include esters, triglycerides, hydrocarbons
and silicones. These can be a single material or a mixture of one
or more materials. They may normally comprise from 0.1% to about
100%, preferably from about 5% to about 90%, and most preferably
from about 70% to about 90% of the emollient component.
[0104] Oils that act as emollients also impart viscosity,
tackiness, and drag properties to cosmetic compositions such as
lipstick. Examples of suitable oils may include acrylic
triglycerides; caprice triglyceride; isostearyl triglyceride;
atopic triglyceride; propylene glycol myristyl acetate; lanolin;
lanolin oil; polybutene; isopropyl palmitate; isopropyl myristate;
isopropyl isostearate; diethyl sebacate; diisopropyl adipate;
tocopheryl acetate; tocopheryl linoleate; hexadecyl stearate; ethyl
lactate; cetyl oleate; cetyl ricinoleate; oleyl alcohol; hexadecyl
alcohol; octyl hyroxystearate; octyl dodecanol; wheat germ oil;
hydrogenated vegetable oils; castor oil; petrolatum; modified
lanolins; branched-chain hydrocarbons; alcohols and esters; corn
oil; cottonseed oil; olive oil; palm kernel oil; rapeseed oil;
safflower oil; jojoba oil; evening primrose oil; avocado oil,
mineral oil, shea butter, octylpalmitate, maleated soybean oil,
glycerol trioctanoate, diisopropyl dimerate, and volatile and
non-volatile silicone oils including phenyl trimethicone.
[0105] Suitable oils for use herein may be acetylglycerides,
octanoates, and decanoates of alcohols and polyalcohols, such as
those of glycol and glycerol, the ricinoleates of alcohols and
polyalcohols such as cetyl ricinoleate, PG-3 diisostearate,
polyglycerol ethers, polyglyerol esters, caprylic triglycerides,
capric triglycerides, isostearic triglyceride, adipic triglyceride,
phenyl trimethicone, lanolin oil, polybutene, isopropyl palmitate,
isopropyl isostearate, cetyl ricinoleate, octyl dodecanol, oleyl
alcohol, hydrogenated vegetable oils, castor oil, modified
lanolins, octyl palmitate, lanolin oil, maleated soybean oil, cetyl
ricinoleate, glyceryl trioctanoate, diisopropyl dimerate, synthetic
lanolin derivatives and branched chain alcohols, sucrose esters of
fatty acids, octyl hydroxystearate and mixtures thereof.
[0106] Preferably, the oils used may be selected such that the
majority (at least about 75%, preferably at least about 80% and
most preferably at least about 99%) of the types of oils used have
solubility parameters that do not differ by more than from about 1
to about 0.1, preferably from about 0.8 to about 0.1.
[0107] A surfactant may also be added to compositions described
herein, in order to confer beneficial cosmetic or application
properties. Surfactants suitable for use may be those which can
form emulsions and/or association structures. Surfactant emulsifier
can be from 0% to about 20% of the formulation, preferably from 0%
to about 15% and most preferably from about 1% to about 10%.
Examples of suitable emulsifiers can be found in U.S. Pat. No.
5,085,856 to Dunphy et al., and U.S. Pat. No. 5,688,831 to
El-Nokaly et al. Examples of other suitable emulsifiers can be
found in Cosmetic Bench Reference, pp. 1.22, 1.24-1.26 (1996), all
of which are incorporated herein by reference.
[0108] Examples of surface active agents which may be used in the
compositions described herein include sodium alkyl sulfates, e.g.,
sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl
sarcosinates, e.g., sodium N-lauroyl sarcosinate and sodium
N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, sodium
hydrogenated coconut fatty acid monoglyceride sulfate, sodium
lauryl sulfoacetate and N-acyl glutamates, e.g., N-palmitoyl
glutamate, N-methylacyltaurin sodium salt, N-methylacylalanine
sodium salt, sodium alpha-olefin sulfonate and sodium
dioctylsulfosuccinate; N-alkylaminoglycerols, e.g.,
N-lauryl-diamino-ethylglycerol and N-myristyldiaminoethylglycerol,
N-alkyl-N-carboxymethylammonium betaine and sodium
2-alkyl-1-hydroxyethylimidazoline betaine; polyoxyethylenealkyl
ether, polyoxyethylenealkylaryl ether, polyoxyethylenelanolin
alcohol, polyoxyethyleneglyceryl monoaliphatic acid ester,
polyoxyethylenesorbitol aliphatic acid ester, polyoxyethylene
aliphatic acid ester, higher aliphatic acid glycerol ester,
sorbitan aliphatic acid ester, Pluronic type surface active agent,
and polyoxyethylenesorbitan aliphatic acid esters such as
polyoxyethylenesorbitan monooleate and polyoxyethylenesorbitan
monolaurate. Emulsifier-type surfactants known to those of skill in
the art can be used in the compositions described herein.
[0109] Also useful herein may be surfactants that form association
structures, preferably lamellar or hexagonal liquid crystals, at
ambient temperature when mixed with a polar solvent. In preparing a
sample combination of surfactant and polar solvent to demonstrate
the ability to form association structures, the surfactant needs to
be sufficiently soluble in the polar solvent such that an
association structure can form at ambient temperature. One of
ordinary skill in the art is capable of determining compatible
interactions.
[0110] Any surfactant which forms association structures at ambient
temperature and is suitable for use in cosmetics may be suitable
for use herein. Surfactants suitable for use in cosmetics present
no or minimal dermatological or toxicological problems. Anionic
surfactants, nonionic surfactants, cationic surfactants, amphoteric
surfactants and mixtures thereof may be suitable for use.
Preferably anionic surfactants, nonionic surfactants, cationic
surfactants, amphoteric surfactants and mixtures thereof having a
Krafft point at or below about ambient temperature are used. More
preferably, nonionic surfactants, cationic surfactants, amphoteric
surfactants and mixtures thereof having a Krafft point at or below
about ambient temperature are used.
[0111] The surfactants can be used at levels from about 4% to about
97%, preferably from about 5% to about 95%, more preferably from
about 20% to about 90% and most preferably from about 30% to about
70% of the association structure.
[0112] The cosmetic compositions described herein may contain one
or more materials, herein singly or collectively referred to as a
"solidifying agent", that are effective to solidify the particular
liquid base materials to be used in a cosmetic composition. (As
used herein, the term "solidify" refers to the physical and/or
chemical alteration of the liquid base material so as to form a
solid or semi-solid at ambient conditions, i.e., to form a final
composition that has a stable physical structure and can be
deposited on the skin under normal use conditions.) As is
appreciated by those skilled in the art, the selection of the
particular solidifying agent for use in the cosmetic compositions
will depend upon the particular type of composition desired, i.e.,
gel or wax-based, the desired rheology, the liquid base material
used and the other materials to be used in the composition. The
solidifying agent can be preferably present at a concentration of
from about 0.1% to about 90%, more preferably from about 1% to
about 50%, even more preferably from about 5% to about 40%, most
preferably from about 3% to about 20%.
[0113] The wax cosmetic stick variations provided herein preferably
may contain from about 5% to about 50% (by weight) of a waxy
solidifying agent. By the term "waxy solidifying agent," as used
herein, is meant a solidifying material having wax-like
characteristics. Such waxy materials may also serve as emollients.
Among the waxy materials useful herein are the high melting point
waxes, i.e., having a melting point of from about 65.degree. C. to
about 125.degree. C., such as beeswax, spermaceti, carnauba,
bayberry, candelilla, montan, ozokerite, ceresin, paraffin,
synthetic waxes such as Fisher-Tropsch waxes, microcrystalline wax,
and mixtures thereof. Ceresin, ozokerite, white beeswax, synthetic
waxes, and mixtures thereof, are among those useful herein;
additional useful waxes are disclosed in U.S. Pat. No. 4,049,792,
Elsnau, issued Sep. 20, 1977, herein incorporated by reference in
its entirety. Low melting waxes, having a melting point of from
about 37.degree. C. to about 75.degree. C., may be preferred for
use in the wax stick variations described herein. Wax stick
variations, which contain volatile silicone oils as a liquid base
material, preferably contain from about 10% to about 35%, more
preferably from about 10% to about 20% (by weight), of a
low-melting wax. Such materials include fatty acids, fatty
alcohols, fatty acid esters and fatty acid amides, having fatty
chains of from about 8 to about 30 carbon atoms, and mixtures
thereof. Wax-like materials include cetyl alcohol, palmitic acid,
stearyl alcohol, behenamide, sucrose esters of tallow fatty acids,
mono and di-fatty acid esters of polyethylene glycol, and mixtures
thereof. Stearyl alcohol, cetyl alcohol, and mixtures thereof, are
mostly used. Additional fatty acids, fatty alcohols, and other
wax-like materials are also well known in the art.
[0114] In addition, these compositions may include other medicinal
agents, therapeutic agents, carriers, adjuvants, and the like. Some
particular additional agents may include sunscreens; retinoids;
antioxidants; hydroxyacids; fatty acids, acceptable non-toxic metal
salts of naturally occurring amino acids or of hydroxyalkyl acids;
botanical extracts, salicylic acid, benzoyl peroxide, antibiotics,
antiandrogens, anti-inflammatory agents, antioxidants, ascorbic
acid, vitamins B, tocopherols or tocotrienols, corticosteroids,
moisteners, surfactants, keratolytic agents, complexing agents,
colorants, fragrances, and mixtures thereof.
Measurement of Skin Pigmentation and Coloration
[0115] Measurements of skin pigmentation and coloration can be
quantitated using a chromameter, colorimeter, or skin reflectance
instrument (see, for example, Clarys et al., Skin Res. Technol.
6(4):230-238 (2000)). Chromameters are commercially available from
vendors such as Konica Minolta (CR-400 or CR-410 Chroma Meter) or
Gigahertz-Optik (HCT-99D color meter). Baseline readings prior to
treatment are taken, and readings during treatment can be taken, at
one or more wavelengths. Skin coloration can be measured and
compared to assess treatment. Measurements can be taken at various
points, such as an area affected by discoloration and a surrounding
unaffected area.
Synthetic Methods
[0116] The resorcinol compounds described herein can be synthesized
by an appropriate combination of generally well-known synthetic
methods. Techniques useful in synthesizing the compounds herein are
both readily apparent and accessible to those of skill in the
relevant art in light of the teachings described herein. The
discussion below is offered to illustrate certain of the diverse
methods available for use in assembling the compounds herein.
However, the discussion is not intended to limit the scope of
reactions or reaction sequences that are useful in preparing the
compounds herein.
[0117] The resorcinol compounds described herein may be synthesized
according to Scheme 1. Reactant C(O)R.sup.2 indicates a reactant
having a carbonyl group; that is, the C.dbd.O group is a part of
R.sup.2, and not an additional moiety appended to R.sup.2.
Appropriate protecting groups (PG in the scheme below), such as
alkyl groups, may be used to protect certain functional groups from
reaction conditions, and such protecting groups are removed under
standard conditions when appropriate.
##STR00005##
[0118] Scheme 2 shows an exemplary synthesis of a 5-methyl
resorcinol compound described herein according to Scheme 1. R.sup.a
and R.sup.b are each hydrogen or substituted or unsubstituted
alkyl, wherein the substituted or unsubstituted alkyl groups may be
the same or different, or R.sup.a and R.sup.b, together with the
carbon to which they are attached, form a substituted or
unsubstituted cycloalkyl. Compound 1 (commercially available from
Sigma-Aldrich, St. Louis, Mo.) is brominated, for example with
N-bromosuccinimide, to afford compound 2, which is reacted with
magnesium to form Grignard reagent 3. Compound 3 is reacted with an
alkyl ketone in the presence of lanthanum salts, followed by
reduction by hydrogen over Pd/C to form compound 4. The alkoxy
groups are then converted to hydroxy groups to afford resorcinol
compound 5.
##STR00006##
[0119] Scheme 3 shows an exemplary synthesis of a 5-fluoro
resorcinol compound described herein according to Scheme 1. R.sup.c
and R.sup.d are each hydrogen or substituted or unsubstituted
alkyl, wherein the substituted or unsubstituted alkyl groups may be
the same or different, or R.sup.c and R.sup.d, together with the
carbon to which they are attached, form a substituted or
unsubstituted cycloalkyl. Compound 6 (commercially available from
Sigma-Aldrich, St. Louis, Mo.) is brominated to afford compound 7,
which is reacted with magnesium to form Grignard reagent 8.
Compound 8 is reacted with an alkyl ketone in the presence of
lanthanum salts to form compound 9, followed by reduction by
hydrogen over Pd/C to form compound 10. The alkoxy groups are then
converted to hydroxy groups to afford resorcinol compound 11.
Similar methods can be used to synthesize other 4-halo
resorcinols.
##STR00007##
[0120] Scheme 4 shows an exemplary synthesis of a
4-alkyl-5-trifluoromethyl resorcinol compound described herein
according to Scheme 1. R.sup.e is substituted or unsubstituted
alkyl. Bromide compound 12 is converted to the corresponding iodide
13, which is reacted with an acyl chloride to form ketone 14.
Compound 14 is reacted with difluoro-fluorosulfonyl-acetic acid
methyl ester (15) to form compound 16, followed by reduction by
zinc in the presence of acid (or other suitable reducing agent) to
form compound 17. The alkoxy groups are then converted to hydroxy
groups to afford resorcinol compound 18. Similar methods can be
used to synthesize other 4-alkyl-5-trifluoromethyl resorcinols.
##STR00008##
[0121] Scheme 5 shows an exemplary synthesis of a
4-cycloalkyl-5-trifluoromethyl resorcinol compound described herein
according to Scheme 1. A represents a substituted or unsubstituted
cycloalkenyl ring, and B represents the corresponding substituted
or unsubstituted cycloalkyl ring. Bromide compound 19 is converted
to the corresponding iodide 20. Compound 20 is reacted with
difluoro-fluorosulfonyl-acetic acid methyl ester to form compound
21, followed by bromination with NBS to form compound 22.
Cycloalkenyl A is installed using an appropriate dioxaborolane to
form compound 23, which is reduced in the presence of Pd/C (or
other suitable reducing agent) to form compound 24. The alkoxy
groups are then converted to hydroxy groups to afford resorcinol
compound 25. Similar methods can be used to synthesize other
4-cycloalkyl-5-trifluoromethyl resorcinols.
##STR00009##
EXAMPLES
Example 1
4-cyclohexyl-5-methylbenzene-1,3-diol (4,5CHMR)
##STR00010##
[0123] 4-bromo-1,5-bis(methoxymethoxy)-3-methylbenzene. 26.10 g of
orcinol and 19.10 g of ammonium bromide were weighed into a 2000 mL
3-neck round bottom flask fitted with a stir bar, thermometer, and
nitrogen bubbler. A nitrogen atmosphere was established and
maintained. 1000 mL of acetonitrile was added, and the mixture was
stirred rapidly to suspend the solids. The suspension was cooled to
10.degree. in an ice bath and 67.88 g of Oxone.TM. (OXONE is a
registered trademark of DuPont for a monopersulfate oxidizing
compound) was added in one portion. The ice bath was removed, and
the mixture was stirred at 20.degree. for 30 h. The solids were
removed by filtration. The solvent was removed from the filtrate to
obtain a dark orange solid. The solid was partitioned between 200
mL of 1.0 M hydrochloric acid and 400 mL tert-butyl methyl ether.
The phases were separated, and the aqueous phase was extracted with
200 mL tert-butyl methyl ether. The combined organic phases were
washed with 5.times.200 mL of 1.0 M pH 5.5 phosphate buffer and 200
mL of brine. 1.0 g of activated carbon was added to the solution,
and the solution was dried over sodium sulfate. The solution was
filtered through a 10 cm diameter Buchner funnel containing a
2-layer filter pad of 5 cm silica gel on top of 2 cm of Celite.TM.
(CELITE is a registered trademark of Imerys Minerals California,
Inc. for a diatomaceous earth-containing filter aid). The filter
pad was washed with 2.times.300 mL of tert-butyl methyl ether. The
solvent was removed from the filtrate to obtain 38.78 g of a
brown-orange solid. The solid was recrystallized from
1,2-dichloroethane and dried under vacuum to obtain 35.30 g of a
7:88:4 mixture of unbrominated:monobrominated:dibrominated orcinols
as brown crystals. 32.95 g of the crystals were dissolved in 100 mL
of anhydrous ethyl acetate, and the solution was added dropwise to
a solution of chloromethyl methyl ether prepared as described
below.
[0124] A three-necked 1000-mL flask was fitted with a magnetic stir
bar, thermometer, addition funnel, efficient reflux condenser with
nitrogen inlet, and gas outlet bubbler quenched into 1.0 M aqueous
sodium hydroxide. A nitrogen atmosphere was established and
maintained. The flask was charged with 46.65 g of dimethoxymethane
and 180 mL of anhydrous toluene. 16 mg of zinc bromide was added.
47.2 g of acetyl chloride was added dropwise over 10 minutes. The
addition funnel was rinsed with 20 mL of toluene directly into the
reaction mixture. The reaction mixture was stirred at 20.degree.
for 4.5 h. The resulting solution of chloromethyl methyl ether was
cooled with an ice bath, and 100 mL of N,N-diisopropylethylamine
was added dropwise over 20 min. The solution of 32.95 g of
brominated orcinols in 100 mL ethyl acetate prepared above was
added dropwise at a rate to maintain the reaction temperature below
10.degree.. A white precipitate formed during the addition. The ice
bath was removed, and the mixture was stirred at 20.degree. for 68
h. The reaction was quenched with 100 mL of saturated aqueous
ammonium chloride. 50 mL of water was added to bring all the salts
into solution. The biphasic mixture was stirred vigorously for 3 h
to ensure all residual chloromethyl methyl ether was decomposed.
The phases were separated, and the aqueous phase was extracted with
250 mL of ethyl acetate. The combined organic phases were washed
with 2.times.200 mL of 1.0 M aqueous citric acid, 3.times.200 mL of
1.0 M aqueous sodium hydroxide, and 250 mL of brine. The solution
was dried over sodium sulfate and the solvent was removed to obtain
47.87 g of a red liquid. 45.34 g of the crude was purified by
vacuum distillation to obtain 35.91 g [86% yield calculated from
orcinol] of the title compound as a pale yellow liquid, Bp
92-94.degree./0.046 Torr. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
6.69 (d, J=2.7 Hz), 6.64 (d, J=2.7 Hz), 5.20 (s, 2H), 5.11 (s, 2H),
3.50 (s, 3H), 3.45 (s, 3H), 2.37 (s, 3H).
4-cyclohexyl-1,5-bis(methoxymethoxy)-3-methylbenzene
[0125] 1.12 g of
2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl, 0.28
g of palladium(II)acetate, and 18.50 g of
4-bromo-1,5-bis(methoxymethoxy)-3-methylbenzene (1) were weighed
into a 1000 mL oven dried 3-neck round bottom flask fitted with a
stir bar, thermometer, addition funnel, and nitrogen bubbler. A
nitrogen atmosphere was established and maintained. 200 mL of
anhydrous THF was added, and the mixture was stirred to obtain a
clear ruby solution. The solution was cooled with an ice bath, 150
mL of a 0.5 M solution of cyclohexylzinc bromide in THF was added
over 60 min, keeping the reaction temperature below 5.degree. C.
The cooling bath was removed when the addition was complete, and
the mixture was stirred at ambient temperature for 4 h. The
solution was cooled in an ice bath and quenched with 350 mL of
saturated aqueous ammonium chloride. The phases were separated, and
the aqueous phase was extracted with 350 mL of cyclopentyl methyl
ether. The combined organic phases were filtered through Celite.TM.
to remove fine particulates. The filtrate was washed with
2.times.300 mL of 1.0 M citric acid, 300 mL of saturated aqueous
sodium bicarbonate, and 300 mL of brine, and dried over sodium
sulfate and removed the solvent to obtain a dark red liquid. The
liquid was diluted with 100 mL of heptane and filtered through a 5
cm thick.times.9.5 cm diameter silica gel pad. The product was
washed through with 1000 mL of 25% EtOAc/heptane. The solvent was
removed from the filtrate. The amber liquid was purified by vacuum
distillation to obtain 15.83 g [85% yield] of the title compound as
a clear colorless oil, Bp 114-116.degree. C./0.056 Torr.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.63 (d, J=2.5 Hz), 6.49
(d, J=2.5 Hz), 5.13 (s, 2H), 5.10 (s, 2H), 3.47 (s, 3H), 3.45 (s,
3H), 2.77 (br s, 1H), 2.29 (s, 3H), 2.10-1.95 (m, 2H), 1.83-1.75
(m, 2H), 1.73-1.66 (m, 1H), 1.59-1.52 (m, 2H), 1.37-1.18 (m,
3H).
4-cyclohexyl-5-methylbenzene-1,3-diol (4,5CHMR)
[0126] 15.78 g of
4-cyclohexyl-1,5-bis(methoxymethoxy)-3-methylbenzene (2) was
weighed into an oven dried 1000 mL flask fitted with a stir bar,
septum and nitrogen bubbler. A nitrogen atmosphere was established
and maintained. Added 400 mL of anhydrous methanol. Cooled the
solution below 5.degree. C. Added 7.7 mL of acetyl chloride over 30
min, keeping the reaction temperature below 5.degree. C. Removed
the cooling bath when the addition was complete and stirred at
20.degree. C. for 42 h. Removed the volatiles on a rotary
evaporator to obtain a yellow resin. Dissolved the resin in 75 mL
MTBE and diluted with 75 mL heptane. Removed baseline impurities by
passing the solution through 220 g of silica gel, washing the
product through with 800 mL of 50% MTBE/heptane. Removed the
solvent on a rotary evaporator to obtain a pale yellow solid. The
solid was recrystallized twice from 50 mL of 1,2-dichloroethane.
Dried under vacuum at 85.degree./0.05 Torr to obtain 9.33 g [84%
yield] of the title compound as fine white needles. 300 mg of this
material was purified by sublimation at 130.degree./0.03 Torr to
obtain an analytical standard. .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.74 (overlapping singlets, 2H), 6.07 (d, J=2.5 Hz), 5.98
(d, J=2.4 Hz), 2.64 (br s, 1H), 2.17-1.98 (methyl singlet at 2.12
overlaps multiplet, 5H), 1.77-1.68 (m, 2H), 1.68-1.60 (m, 1H),
1.46-1.34 (m, 2H), 1.34-1.10 (m, 3H).
Example 2
4-cyclohexyl-5-fluorobenzene-1,3-diol (4,5CHFR)
##STR00011##
[0127] 2-bromo-1-fluoro-3,5-dimethoxybenzene
[0128] 28.22 g of 3,5-dimethoxy-5-fluorobenzene was weighed into a
1,000 mL round bottom flask fitted with a stir bar, reflux
condenser, nitrogen inlet, and cap. A nitrogen atmosphere was
established and maintained throughout the reaction. 200 mL of
anhydrous CCl.sub.4 was added, followed by 32.61 g of
N-bromosuccinimide (NBS). The remaining NBS powder residue was
washed into the flask with 100 mL of CCl.sub.4. The reaction
mixture was stirred at reflux under N, for 4 h, during which time
the suspended yellow solids changed color to white. At completion,
the precipitated succinimide solids were filtered off and washed
thoroughly with 200 mL heptane. The CCl.sub.4 was removed from the
filtrate by rotary evaporation at 50.degree. C. More succinimide
precipitated from the heptane solution and was removed by
filtration while the solution was still warm. The remaining heptane
was removed in vacuo to obtain a clear, amber oil (40.67 g), which
solidified on standing. Purification of the crude material was
accomplished by distillation. The condenser was kept at 50.degree.
C. to prevent the product from solidifying before reaching the
collection flask. After a small impurity fraction was collected at
78.degree. C./8 torr, the product distilled at 123-125.degree. C./8
torr. The clear pale yellow liquid solidified to an off-white solid
on standing (37.88 g, 89%).
1-(2-fluoro-4,6-dimethoxyphenyl)cyclohexanol
[0129] 19.52 g of 2-bromo-1-fluoro-3,5-dimethoxybenzene was weighed
into an oven-dried 500 mL round bottom flask fitted with a stir
bar, septum, thermometer, and nitrogen inlet. A nitrogen atmosphere
was established and maintained. To the solution was slowly added
200 mL of a 0.5 M solution of lithium chloride in anhydrous THF.
The clear pale yellow solution was placed in a water ice/acetone
bath and the reaction temperature was maintained between
-15.degree. C. and -10.degree. C. To the reaction mixture was added
45 mL of a 2.0 M (iodometric titration) solution of isopropyl
magnesium chloride in diethyl ether, dropwise over 20 min using a
syringe pump. The reaction was stirred between -20.degree. C. and
-15.degree. C. for 60 min. The solution rapidly became colorless at
the start of addition, then slowly became a clear yellow color.
LC-MS analysis of an aliquot quenched in 5% H.sub.2O/MeOH at 60 min
indicated the reaction was 50% complete. At this point, 5 mL of a
2.0 M solution of isopropylmagnesium chloride in Et.sub.2O was
added via syringe. LC-MS analysis of an aliquot quenched in 5%
H.sub.2O/MeOH 60 min after the addition indicated the reaction was
80% complete. After waiting another 30 min, the clear yellow
solution was transferred into the next reaction via cannula.
[0130] 7.48 g of cyclohexanone was weighed into an oven-dried 1,000
mL 3-neck round bottom flask fitted with a stir bar, septum,
thermometer, and nitrogen inlet. A nitrogen atmosphere was
established and maintained. To the solids was added 125 mL of a 0.6
M solution of lanthanum trichloride complex with 2 equivalents of
lithium chloride in anhydrous THF. The solution was stirred at room
temperature for 2.5 h. Following this period, the clear amber
solution was cooled in a water ice/acetone bath and the solution
temperature was maintained between -5.degree. C. and 0.degree. C.
during addition. The above-described solution of
2,4-dimethoxy-6-methylphenyl magnesium chloride complex with
lithium chloride was transferred into the reaction mixture by
cannula. The amber reaction mixture was stirred between 0.degree.
C. and 5.degree. C. for 2 h. The reaction mixture was cooled to
-10.degree. and quenched by adding a mixture of 100 g of ice in 100
mL of saturated aqueous NH.sub.4Cl. A moderate exotherm raised the
temperature to 5.degree. C. before cooling down again. A white
emulsion formed in the aqueous layer. To the mixture was added 20
mL of concentrated hydrochloric acid. The emulsion did not
dissolve. The phases were separated, and the aqueous phase was
back-extracted with 2.times.200 mL of MTBE. The combined organics
were washed with 1.times.200 mL of a mixture of 1:1 brine and 1 M
aqueous NaOH. A small amount of gummy orange material separated at
the solvent interface and was discarded. The remaining organic
phase was washed with 200 mL brine and dried over Na.sub.2SO.sub.4.
Excess solvent was removed in vacuo to obtain 21.96 g of a dark
amber liquid. The liquid was diluted with 25 mL heptane and
purified by chromatography on a 450 g Supelco VersaPak.TM. silica
gel column (gradient elution from 0 to 33% ethyl acetate/heptane
over 15 column volumes). Isolated 13.14 g, pale yellow liquid (68%
yield).
2-cyclohexyl-1-fluoro-3,5-dimethoxybenzene
[0131] 13.04 g of 1-(2-fluoro-4,6-dimethoxyphenyl)cyclohexanol was
weighed into a 500 mL round bottom flask fitted with a stir bar and
septum cap. To the solids was added 250 mL of 9:1 EtOAc:HOAc. The
solution was sparged with nitrogen for 5 min and charged with 2.58
g of 10 wt % palladium on carbon. A hydrogen atmosphere over the
reaction mixture was established and maintained with a balloon. The
reaction was stirred at 70.degree. C. for 20 h, after which LC-MS
analysis indicated the reduction was complete. The catalyst was
removed by filtration through a Whatman GF/B glass fiber filter and
the solids washed thoroughly with 200 mL EtOAc. The filtrate was
poured into a separatory funnel and washed with 200 mL of 2.5 M
aqueous sodium hydroxide, 200 mL of water, and 200 mL of brine,
dried over Na.sub.2SO.sub.4, and concentrated by rotary evaporation
to obtain a clear, colorless liquid (11.67 g). The liquid was
diluted with heptane and purified by chromatography to obtain 8.67
g of a clear colorless oil (71%).
4-cyclohexyl-5-fluorobenzene-1,3-diol (4,5CHFR)
[0132] 8.51 g of 4-cyclohexyl-1,3-dimethoxy-5-fluorobenzene and
32.93 g of tetrabutylammonium iodide were weighed into an oven
dried 500 mL 2-neck round bottom flask fitted with a stir bar,
thermometer, nitrogen inlet, and septum. A nitrogen atmosphere was
established and maintained throughout the reaction. To the flask
was added 200 mL of anhydrous CH.sub.2Cl.sub.2. The mixture was
cooled to -78.degree. C. in a dry ice/acetone bath. To the rapidly
stirred mixture was added 90 mL of a 1.0 M solution of boron
trichloride in CH.sub.2Cl.sub.2 over 30 min using a syringe pump.
The mixture was stirred at -78.degree. C. for 15 min, then stirred
at -2.degree. C. for 3 h. LC-MS analysis at 2.5 h showed all the
starting material had converted to product. The reaction was
quenched by slow addition of 100 mL water and the mixture was
stirred at room temperature 15 min. At this point, 50 mL of
methanol was added to dissolve the solids, and the mixture was
stirred at room temperature for 30 min. Organic solvents were
removed by rotary evaporation at 50.degree. C. The remaining
aqueous mixture was diluted with 400 mL water and extracted with
MTBE (3.times.150 mL). The combined organic layers were extracted
with 3.times.150 mL of 1.0 M aqueous NaOH. The combined aqueous
extracts were made acidic by adding 40 mL concentrated hydrochloric
acid. The acidic solution was extracted with 3 portions of 150 mL
of MTBE. The combined extracts were washed with brine and dried
over Na.sub.2SO.sub.4. Excess solvent was removed on a rotary
evaporator. The residue was dissolved in 10% ethyl acetate/heptane
and purified by chromatography on a 330 g Isco RediSep.TM. silica
gel column (gradient elution from 10 to 50% ethyl acetate/heptane).
The collected fractions were concentrated and the resulting solids
recrystallized from 30 mL of hot 1:1 1,2-dichloroethane:heptane to
obtain 3.31 g of colorless orthorhombic crystals. After removal of
the solvent from the filtrate, the residue was recrystallized from
12 mL of hot 1:1 1,2-dichloroethane:heptane to obtain a second crop
of 2.76 g of small white crystals. A third crop of 472 mg of small
pink crystals (the mother liquor is red) was obtained in a similar
fashion. The first and second crops were identical by `H-NMR,
LC-MS, and TLC and were combined to give the product. White
crystalline solid, 6.07 g. 81% yield. .sup.1H NMR (DMSO-d.sub.6,
400 MHz) .delta.: 9.43 (d, J=1.4 Hz, 1H), 9.32 (d, J=0.5 Hz, 1H),
6.99 (dd, J=2.3, 1.2 Hz, 1H), 5.91 (dd, J=13, 2.3 Hz, 1H), 2.85
(tt, J=12, 3.3 Hz, 1H), 1.62-1.83 (m, 5H), 1.47-1.57 (m, 2H),
1.10-1.33 (m, 3H).
Example 3
2-Ethyl-1,5-dihydroxy-3-trifluoromethyl-benzene (4,5 ETFMR)
##STR00012##
[0133] 1-(2-Iodo-4,6-dimethoxy-phenyl)-ethanone
[0134] To a solution of acetyl chloride (3.12 g, 39 mmol) in
dichloromethane (100 mL) was added AlCl.sub.3 (6.34 g, 47 mmol) at
0.degree. C. over 30 min. 1-Iodo-3,5-dimethoxy-benzene (10.5 g, 39
mmol) was added to the mixture. The reaction mixture was stirred at
room temperature for 1 h. Then ice water (60 mL) was added. The
aqueous layer was extracted with dichloromethane (2.times.30 mL),
dried over sodium sulfate and concentrated, and purified by column
chromatography (eluted with petroleum ether/ethyl
acetate=20:1.about.1:1), to give the title compound (6 g, 50%).
1-(2,4-Dimethoxy-6-trifluoromethyl-phenyl)-ethanone
[0135] A mixture of 1-(2-iodo-4,6-dimethoxy-phenyl)-ethanone (3.17
g, 10.1 mmol), difluoro-fluorosulfonyl-acetic acid methyl ester
(7.9 g, 41.1 mmol) and CuI (3.8 g, 20 mmol) in NMP (50 mL) was
heated at 120.degree. C. under nitrogen overnight. The mixture was
filtered and diluted with water (200 mL), and extracted with ethyl
acetate (3.times.50 mL). The organic layers were washed with brine
(50 mL), dried over sodium sulfate and concentrated and purified
with column chromatography (eluted with petroleum ether: ethyl
acetate=20:1.about.10:1) to give the title compound (1.6 g,
64%).
2-Ethyl-1,5-dimethoxy-3-trifluoromethyl-benzene
[0136] Zinc (8.4 g, 0.13 mol) was added over 10 min to a solution
of 1-(2,4-Dimethoxy-6-trifluoromethyl-phenyl)-ethanone (1.6 g, 6.4
mmol) in ethyl ether (20 mL) and concentrated hydrogen chloride (20
mL) at 0.degree. C. The mixture was stirred at room temperature for
2 h. The mixture was filtered off, extracted with ethyl ether
(3.times.50 mL), washed with brine (30 mL), dried over sodium
sulfate and concentrated, and purified by column chromatography
(eluted with petroleum ether) to give the title compound (0.4 g,
27%).
2-Ethyl-1,5-dihydroxy-3-trifluoromethyl-benzene (4,5 ETFMR)
[0137] BBr.sub.3 (12 mL, 0.67 mol/L) was added to a mixture of
2-ethyl-1,5-dimethoxy-3-trifluoromethyl-benzene (0.4 g, 1.9 mmol)
in dichloromethane (10 mL), and the mixture was stirred at room
temperature for 4 h. Methanol (5 mL) was added slowly to the
mixture at 0.degree. C., and the mixture was concentrated to give
an oil residue, which was diluted with water (20 mL), extracted
with dichloromethane (4.times.10 mL), washed with brine (10 mL),
concentrated, and purified by pre-HPLC to give the title compound
(140 mg, 40%). LC-MS 205 (M-1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.6.69 (d, J=2.0 Hz, 1H), 6.48 (d, J=2.0 Hz, 1H), 5.06 (s,
1H), 4.99 (s, 1H), 2.70 (q, J=7.6 Hz, 2H), 1.16 (t, J=7.6 Hz, 3H).
.sup.19F NMR (400 MHz, CDCl.sub.3) .delta.-60.2 (s).
Example 4
4-cyclohexyl-3-trifluoromethyl benzene-1,3-diol (4,5CHTFMR)
##STR00013##
[0138] 1-iodo-3,5-dimethoxy-benzene
[0139] A mixture of 1-bromo-3,5-dimethoxy-benzene (9.6 g, 44 mmol),
CuI (0.7 g, 3.6 mmol), NaI (13.3 g, 88 mmol) and
MeNHCH.sub.2CH.sub.2NHMe (0.78 mL) in 1,4-dioxane (80 mL) was
degassed and filled with nitrogen in a sealed tube. The reaction
mixture was heated at 120.degree. C. for 20 h. The mixture was
cooled to room temperature. Water (100 mL) was added, and the
mixture was extracted with ethyl acetate (2.times.60 mL). The
organic layers were washed with brine (50 mL), dried over sodium
sulfate, and concentrated to give the title compound (10 g,
86%).
1,3-Dimethoxy-5-trifluoromethyl-benzene
[0140] A mixture of 1-iodo-3,5-dimethoxy-benzene (1.6 g, 6.0 mmol),
difluoro-fluorosulfonyl-acetic acid methyl ester (3.1 mL, 24 mmol),
and CuI (3.4 g, 18 mmol) in NMP (30 mL) was heated at 120.degree.
C. for 16 h, then the mixture was cooled to room temperature and
water (50 mL) was added. The mixture was extracted with ethyl
acetate (200 mL), washed with water (2.times.50 mL), and the
organic layer was dried over sodium sulfate and concentrated. The
crude product was purified by column chromatography (eluted with
petroleum ether) to give the title compound (0.54 g, 44%).
2-bromo-1,5-dimethoxy-3-trifluoromethyl-benzene
[0141] A mixture of NBS (2.75 g, 16.9 mmol) and
1,3-dimethoxy-5-trifluoromethyl-benzene (3.5 g, 16.9 mmol) in
dichloromethane was stirred at room temperature for 16 h. The
mixture was concentrated and purified by column chromatography
(eluted with petroleum ether:ethyl acetate=5:1) to obtain the title
compound (4 g, 83%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.6.84
(d, J=2.8 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 3.91 (s, 3H), 3.84 (s,
3H). .sup.19F NMR (360 MHz, CDCl.sub.3) .delta.-62.7 (s).
2-cyclohex-1-enyl-1,5-dimethoxy-3-trifluoromethyl-benzene
[0142] To a mixture of
2-bromo-1,5-dimethoxy-3-trifluoromethyl-benzene (50 mg, 0.175
mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (12 mg, 0.0175 mmol), and
K.sub.2CO.sub.3 (97 mg, 0.7 mmol) in mixed solvents (DMF/MeOH, 3:1,
1.2 mL) in a sealed tube was added
2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (73 mg,
0.35 mmol). The tube was degassed and back-filled with N.sub.2
(3.times.) and sealed under N.sub.2. The tube was heated on oil
bath to 100.degree. C. for 6 h. After being cooled to room
temperature, the reaction mixture was diluted with ethyl
acetate/hexane and water. The organic layer was washed with brine,
dried with Na.sub.2SO.sub.4, concentrated, and purified by prep TLC
(ethyl acetate/hexanes, 8:2) to give the title compound (22 mg,
44%).
2-cyclohexyl-1,5-dimethoxy-3-trifluoromethyl-benzene
[0143] 2-Cyclohex-1-enyl-1,5-dimethoxy-3-trifluoromethyl-benzene
(800 mg, 2.8 mmol) and MeOH (40 mL) were charged into a 200-mL
round bottom flask fitted with a stir bar and septum cap. The
solution was sparged with nitrogen for 5 min. To the mixture 10 wt
% palladium on carbon (400 mg) was added. The flask was vacuumed
and filled with a hydrogen balloon. The reaction mixture was
stirred at 50.degree. C. for 16 h. The reaction mixture was
filtered and concentrated to give a residue, which was purified by
silica gel column chromatography with ethyl acetate/hexanes to give
the title compound (480 mg, 59%) as a white solid.
4-cyclohexyl-3-trifluoromethyl benzene-1,3-diol (4,5CHTFMR)
[0144] To a solution of 4-cyclopentyl-1,3-dimethoxy-5-methylbenzene
(480 mg, 1.67 mmol) in anhydrous CH.sub.2Cl.sub.2 (15 mL) at
-78.degree. in a dry ice/acetone bath was added boron tribromide
(1.25 g, 5.0 mmol). The reaction mixture was stirred at -78.degree.
for 5 min and slowly warmed to room temperature overnight. The
reaction mixture was quenched by slow addition of water (50 mL).
The mixture was extracted with ether (3.times.). The combined
organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated to give a residue, which was
purified by silica gel column chromatography with ethyl
acetate/hexanes to give the title compound (300 mg, 69%). LC-MS:
259 (M-1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.6.69 (d, 1H),
6.40 (d, 1H), 5.11 (s, 1H), 5.07 (s, 1H), 2.88 (m, 1H), 1.99 (m,
2H), 1.69 (M, 4H), 1.29 (M, 4H).
Example 5
4-hexyl-5-methylbenzene-1,3-diol (4,5HMR)
[0145] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
LC-MS: 209.0 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.8.87
(s, 1H), 8.79 (s, 2H), 6.07 (d, 1H), 5.98 (d, 1H), 2.34 (s, 2H),
2.07 (s, 3H), 1.23 (m, 8H), 0.83 (t, 3H).
Example 6
4-isopropyl-5-methylbenzene-1,3-diol (4,5IPMR)
[0146] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.8.83 (s, 1H), 8.78 (s,
1H), 6.05 (d, 1H), 5.94 (d, 1H), 3.04 (m, 1H), 2.09 (s, 3H), 1.20
(s, 3H), 1.18 (s, 3H).
Example 7
4-butyl-5-methylbenzene-1,3-diol (4,5BMR)
[0147] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
LC-MS: 180.8 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.8.87
(s, 1H), 8.78 (s, 1H), 6.07 (d, 1H), 5.98 (d, 1H), 2.37 (t, 2H),
2.07 (s, 3H), 1.28 (m, 4H), 0.85 (t, 3H).
Example 8
4-benzyl-5-methylbenzene-1,3-diol (4,5BnMR)
[0148] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.27 (m, 2H), 7.17 (m,
3H), 6.30 (d, 1H), 6.22 (d, 1H), 4.73 (s, 1H), 4.68 (s, 1H), 3.97
(s, 2H), 2.21 (s, 3H).
Example 9
4-cyclopropyl-5-methylbenzene-1,3-diol (4,5CPrMR)
[0149] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.8.85 (s, 1H), 8.66 (s,
1H), 6.04 (d, 1H), 5.99 (d, 1H), 2.17 (s, 3H), 1.35 (m, 1H), 0.75
(m, 2H), 0.45 (m, 2H).
Example 10
4-cyclopentylmethyl-5-methylbenzene-1,3-diol (4,5MCPMR)
[0150] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
LC-MS: 207.0 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.8.85
(s, 1H), 8.79 (s, 1H), 6.08 (s, 1H), 5.99 (s, 1H), 2.39 (d, 2H),
2.08 (s, 3H), 1.99 (m, 1H), 1.52 (m, 6H), 1.18 (m, 2H).
Example 11
4-cyclopentyl-5-methylbenzene-1,3-diol (4,5CPMR)
[0151] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
LC-MS: 193.1 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.6.23
(d, 1H), 6.13 (d, 1H), 4.63 (s, 1H), 4.58 (s, 1H), 3.25 (m, 1H),
2.27 (s, 3H), 1.88 (m, 6H), 1.67 (m, 2H).
Example 12
4-ethyl-5-methylbenzene-1,3-diol (4,5EMR)
[0152] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
LC-MS: 152.8 (M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.8.87
(s, 1H), 8.76 (s, 1H), 6.08 (s, 1H), 5.99 (s, 1H), 2.38 (q, 2H),
2.08 (s, 3H), 0.93 (t, 3H).
Example 13
4-sec-butyl-5-methylbenzene-1,3-diol (4,5sBMR)
[0153] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
LC-MS: 181.15 (M+1). .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.6.21
(s, 1H), 6.11 (s, 1H), 4.80 (m, 2H), 2.92 (m, 1H), 1.80 (m, 2H),
1.26 (d, 3H), 0.82 (t, 3H).
Example 14
4-(1-phenylethyl)-5-methylbenzene-1,3-diol (4,5PEMR)
[0154] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes,
LC-MS: 229.0 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.32
(m, 3H), 7.25 (m, 2H), 6.29 (d, 1H), 6.13 (d, 1H), 4.64 (s, 1H),
4.50 (m, 2H), 2.32 (s, 3H), 1.63 (t, 3H).
Example 15
4-(2,2,2-trifluoroethyl)-5-methylbenzene-1,3-diol (4,5TFEMR)
[0155] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta.6.16 (s, 2H), 3.43 (q,
2H), 2.20 (s, 3H).
Example 16
4-cyclohexyl-5-fluorobenzene-1,3-diol (4,5EFR)
[0156] The title compound may be prepared using methods analogous
to those described in the Examples and general synthetic schemes.
.sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.: 9.48 (s, 1H), 9.33 (s,
1H), 6.12 (dd, J=2.3, 1.3 Hz, 1H), 5.96 (dd, J=12, 2.3 Hz, 1H),
2.85 (qd, J=7.4, 1.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H).
Example 17
2-Benzyl-1,5-dihydroxy-3-trifluoromethyl-benzene (4,5BNTFMR)
[0157] LC-MS: 267 (M-1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.7.14-7.28 (m, 5H), 6.81 (d, J=2.0 Hz, 1H), 6.52 (s, 1H),
5.11 (s, 1H), 4.98 (s, 1H), 4.11 (s, 2H). .sup.19F NMR (360 MHz,
CDCl.sub.3) .delta.-59.7 (s).
Example 18
Mushroom Tyrosinase Inhibition Assay
[0158] 10 .mu.M compound, 300 .mu.M L-Tyrosine, and 84 units/mL of
mushroom tyrosinase (Sigma T3824) were combined into 0.05 M
potassium monophosphate buffer at pH=6.5, and incubated for 15 min
at room temperature. Absorbance was recorded at 490 nm. %
tyrosinase inhibition was calculated as follows:
(Abs.sub.DMSO-Abs.sub.cmpd)/Abs.sub.DMSO.times.100. The assay was
performed for various compounds described herein, as well as for
control compounds 4-ethyl resorcinol (4ER), 4-isopropylresorcinol
(4IPR), 4-hexylresorcinol (4HR), 4-cyclohexylresorcinol (4CHR),
5-methylresorcinol (5MR), kojic acid (KA), and hydroquinone (HQ),
structures of which are shown below. Results are shown in Table
1.
##STR00014##
TABLE-US-00001 TABLE 1 Mushroom Tyrosinase (% remaining enzyme
activity) % TYR Compound Activity 4,5CHMR 22 4,5 BMR 18 4,5BnMR 97
4,5TFEMR 103 4,5sBMR 100 4,5HMR 10 4,5CPMR 71 4,5CPrMR 30 4,5PEMR
105 4,5EMR 93 4,5IPMR 108 4,5MCPMR 32 4,5ETFMR 102 4,5CHTFMR 100
4,5BnTFMR 93 4,5EFR 3 4,5CHFR 1 4ER 2 4IPR 1 4HR 1 4CHR 0 5MR 100
Hydroquinone 100 Kojic Acid 84
Example 19
Mammalian Tyrosinase Inhibition Assay
[0159] B16F1 cells are grown in Dulbecco's Modified Eagle Medium
(DMEM) 10% FBS, P/S at 10% CO.sub.2 and 37.degree. C. to 90%
confluency. Cell lysate is prepared with 150 mM NaCl; 20 mM
Tris-HCl, pH=7.4; and 1% Triton-X100. The assay is conducted in
buffer (0.05M potassium monophosphate buffer, pH=6.5, 600 uM
L-Tyrosine, 15 uM L-Dopa, 0.325 mg/mL B16F1 cell lysate) with 10
.mu.M compound. After mixing, the reaction mixture is incubated at
37.degree. C. for 8 h and absorbance measured at 490 nm. %
tyrosinase inhibition is calculated as follows:
(Abs.sub.DMSO-Abs.sub.cmpd)/Abs.sub.DMSO.times.100.
Example 20
B16 Melanin Assay
[0160] B16F1 cells were grown in phenol free DMEM 10% FBS, P/S at
10% CO.sub.2 and 37.degree. C. After trypsinization, cells were
seeded at 3,000 cells per well in a 96-well plate and allowed to
attach overnight. 1 mM Theophylline was used to stimulate
melanogenesis, and the compound of interest was added. After 72 h
growth at 10% CO.sub.2 and 37.degree. C., media absorbance was
measured at 405 nm and corrected for cellular viability measured
with Calcein-AM. % melanin content was calculated as follows:
(Abs.sub.DMSO/Calcein.sub.DMSO-Abs.sub.cmpd/Calcein.sub.cmpd)/Ab-
s.sub.DMSO/Calcein.sub.DMSO.times.100. The assay was performed for
various compounds described herein, as well as for control
compounds 4ER, 4IPR, 4HR, 4CHR, 5MR kojic acid, and hydroquinone.
Results are shown in Table 2.
TABLE-US-00002 TABLE 2 B16 Media Melanin (% Melanin) % Melanin
Compound B16 4,5CHMR 58 4,5 BMR 55 4,5BnMR 86 4,5TFEMR 90 4,5sBMR
76 4,5HMR 78 4,5CPMR 61 4,5CPrMR 62 4,5PEMR 87 4,5EMR 69 4,5IPMR 71
4,5MCPMR 90 4,5ETFMR 68 4,5CHTFMR 65 4,5BnTFMR 82 4,5EFR 87 4,5CHFR
51 4ER 48 4IPR 77 4HR 71 4CHR 63 5MR 100 Hydroquinone 100 Kojic
Acid 100
Example 21
Melanocyte-HaCaT Co-Culture Assay
[0161] Darkly pigmented human neonatal epidermal melanocytes
(HEMn-DP, Invitrogen) were grown in Medium 254 with HMGS-2
supplement and P/S at 37.degree. C. and 5% CO.sub.2. HaCaT cells
were grown in DMEM, 10% FBS, P/S at 37.degree. C., 5% CO.sub.2.
Co-culture was conducted in 50% melanocyte media+50% keratinocyte
media (EpiLife with EDGS, P/S). Cells were plated in the co-culture
media at 40K (HaCaT) and 30K (HEMn-DP) per well in a 24-well plate.
After 24 h of incubation at 37.degree. C. and 5% CO.sub.2, media
was changed to M153 (MCDB153 Sigma M7403 with NaHCO.sub.3 pH to
7.1, 2 mM Tyrosine, 10 nM NDP-aMSH, 3 ng/mL bFGF, 2.8 ug/mL
Hydrocortisone, 10 ug/mL Insulin, 10 ug/mL Transferrin, and P/S),
treated with compound, and incubated for 72 h at 37.degree. C. and
5% CO.sub.2. After measuring cellular viability with Calcein-AM
(RFU Ex/Em=488/525 nm), cells were lysed at 1 h at 65.degree. C.
with 1N NaOH+10% DMSO. Absorbance of cleared lysate was measured at
405 nm and 660 nm. % melanin was calculated as follows:
((Abs405.sub.DMSO-Abs660.sub.DMSO)/Calcein.sub.DMSO)-(Abs405.sub.comp-Abs-
660.sub.comp)/Calcein.sub.comp))/(Abs405.sub.DMSO-Abs660.sub.DMSO)/Calcein-
.sub.DMSO.times.100. At 10 .mu.M concentration, % cellular melanin
was 42% in the presence of compound 4,5CHMR.
Example 22
Mattek 3D Skin Equivalents
[0162] MelanoDerm (Mel-300-B) assay was conducted according to the
manufacturer's instruction (MatTek Corporation). Every other day,
the test articles were administered into the EPI-100-NMM-113
culture medium, and positive control, 25 uL of 2% Kojic acid was
applied topically. After 14 days, tissue viability and melanocyte
morphology were visually verified and tissue melanin was extracted
and quantitated against a standard curve. % melanin was calculated
as follows:
(Melanin.sub.DMSO-Melanin.sub.comp)/Melanin.sub.DMSO.times.100. The
assay was performed for various compounds described herein, as well
as for control compounds 4ER, 4IPR, 4HR, 4CHR, kojic acid, and
hydroquinone. Results are shown in Table 3.
TABLE-US-00003 TABLE 3 MatTek Assay (% Melanin) % Melanin 3D
EpiDerm Compound 30 .mu.M 10 .mu.M 4,5CHMR 44 66 4,5 BMR 64 81
4,5BnMR 61 82 4,5TFEMR 72 81 4,5sBMR 67 75 4,5HMR 68 77 4,5CPMR 55
65 4,5CPrMR 82 99 4,5PEMR 62 98 4,5EMR 79 102 4,5IPMR 72 102
4,5MCPMR 72 94 4,5ETFMR 66 81 4,5CHTFMR 89 4,5BnTFMR 75 93 4,5CHFR
81 87 4ER 61 84 4IPR 46 71 4HR 72 93 4CHR 36 65 Hydroquinone 92 94
Kojic Acid 100 100 KA topical 75
Example 23
Clinical Evaluation for Dark Circles
[0163] Female subjects with mild to moderate dark circles under
their edges are recruited for the study after providing informed
consent. The study is conducted in accordance with all applicable
government regulations and institutional policies. Both an expert
grader and the subjects evaluate the severity of the dark circles
under their eyes prior to application of test products. A
composition containing one or more compounds as described herein is
topically applied to the skin area around one eye and a composition
not containing the compounds described herein around the opposite
eye as a control. Treatment assignments are randomized across the
panel, and neither the subject nor the grader has knowledge of the
treatment code. One hour after product application, both the grader
and subject separately evaluate the appearance of the dark circles
under the eyes.
Example 24
Clinical Evaluation for Puffiness
[0164] A set of female subjects with puffiness under their eyes is
recruited after providing informed consent. The study is conducted
in accordance with all applicable government regulations and
institutional policies. A composition containing a compound
described herein is applied under one eye, and a composition with
no compound as described herein is applied under the other eye as a
control. The subjects use the product for 4 weeks, returning at
week 2 for another dermatological evaluation. After 2 and 4 weeks
of product use, both the subjects and the dermatologist evaluate
the improvement in the puffiness of the eyes compared with the
baseline observations.
Example 25
Clinical Evaluation for Aging Signs
[0165] A set of male and female subjects is recruited after
providing informed consent. The study is conducted in accordance
with all applicable government regulations and institutional
policies. Expert graders trained in visual and tactile evaluations
assess the different aging signs of the face of each subject by
grading on a semi-structured scale. Each subject is characterized
by a quantitative profile of his or her aging signs and two expert
graders evaluate each parameter at each time point. A composition
containing a compound described herein is applied to one section of
the face, and a composition with no compound as described herein is
applied to another section of the face as a control. The subjects
use the product for 4 weeks, returning at week 2 and week 4 for an
evaluation by the graders.
[0166] Mean values and standard deviation are calculated, as well
as variations of the parameter relative to before application
(expressed in percentage). A Paired Student's t test is used to
determine the significance of the results.
[0167] While the present compositions and methods have been
described with reference to the specific variations thereof, it
should be understood by those skilled in the art that various
changes may be made and equivalents may be substituted without
departing from the true spirit and scope of the compositions and
methods described herein. In addition, many modifications may be
made to adapt a particular situation, material, composition of
matter, process, process step or steps, to the objective, spirit
and scope of the compounds and methods described herein. All
patents and publications cited above are hereby incorporated by
reference.
* * * * *