U.S. patent application number 12/866472 was filed with the patent office on 2010-12-23 for whitening agent and skin external preparation.
This patent application is currently assigned to SHISEIDO COMPANY LTD.. Invention is credited to Naoto Hanyu, Kimihiro Ogino, Tomoko Saito, Kiyoshi Sato, Takako Shibata.
Application Number | 20100324096 12/866472 |
Document ID | / |
Family ID | 40952264 |
Filed Date | 2010-12-23 |
United States Patent
Application |
20100324096 |
Kind Code |
A1 |
Hanyu; Naoto ; et
al. |
December 23, 2010 |
Whitening Agent And Skin External Preparation
Abstract
The present invention provides a compound having an excellent
inhibitory action on melanin production and being useful as a
whitening agent, and a skin external preparation containing the
compound. The whitening agent of the present invention comprises,
as an active ingredient, a heterocyclic compound represented by
formula (1) or a pharmacologically acceptable salt thereof:
##STR00001## wherein A is C.sub.1-6 alkyl, C.sub.5-6 cycloalkyl,
benzyl, benzylcarbonyl, benzoyl, phenyl, pyridyl or pyrimidyl; Ra
is H, C.sub.1-6 alkyl, or C.sub.2-6 alkenyl; "" represents a single
bond or a double bond wherein n=1 or 2; Y is S or O; and R.sub.3
and R.sub.4 are each independently H, C.sub.1-6 alkyl,
hydroxy-C.sub.1-6 alkyl, C.sub.2-7 acyl, phenyl, pyridyl,
pyrimidyl, etc.;with the proviso that at least one R.sub.3 is a
group other than C.sub.1-3 alkyl in the case where: the hetero ring
containing Y is a thiazoline ring; R.sub.4.dbd.Ra.dbd.H;
X.sub.1.dbd.X.sub.2.dbd.CH; and either p =0 or
R.sub.5.dbd.C.sub.1-6 alkyl.
Inventors: |
Hanyu; Naoto; (Kanagawa,
JP) ; Saito; Tomoko; (Kanagawa, JP) ; Shibata;
Takako; (Kanagawa, JP) ; Sato; Kiyoshi;
(Kanagawa, JP) ; Ogino; Kimihiro; (Kanagawa,
JP) |
Correspondence
Address: |
RANKIN, HILL & CLARK LLP
23755 Lorain Road - Suite 200
North Olmsted
OH
44070-2224
US
|
Assignee: |
SHISEIDO COMPANY LTD.
Chuo-ku, Tokyo
JP
|
Family ID: |
40952264 |
Appl. No.: |
12/866472 |
Filed: |
February 6, 2009 |
PCT Filed: |
February 6, 2009 |
PCT NO: |
PCT/JP2009/052079 |
371 Date: |
August 6, 2010 |
Current U.S.
Class: |
514/342 ;
514/370; 546/270.7; 548/190 |
Current CPC
Class: |
A61K 31/506 20130101;
A61P 1/00 20180101; A61P 17/00 20180101; A61K 8/4946 20130101; A61Q
19/02 20130101; A61P 19/02 20180101; A61P 17/16 20180101; A61K
31/4439 20130101 |
Class at
Publication: |
514/342 ;
548/190; 514/370; 546/270.7 |
International
Class: |
A61K 8/49 20060101
A61K008/49; C07D 277/18 20060101 C07D277/18; C07D 417/12 20060101
C07D417/12; A61Q 19/02 20060101 A61Q019/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 8, 2008 |
JP |
2008-029106 |
Aug 1, 2008 |
JP |
2008-199606 |
Claims
1-19. (canceled)
20. A whitening agent comprising, as an active ingredient, a
heterocyclic compound represented by formula (1) or a
pharmacologically acceptable salt thereof: ##STR00027## wherein A
is selected from the group consisting of (a) C.sub.1-6 alkyl, (b)
C.sub.5-6 cycloalkyl, (c) benzyl, (d) benzylcarbonyl, which may be
substituted with C.sub.2-6 alkylene at the benzyl position, (d)
benzoyl, which may be substituted with C.sub.1-6 alkyl, and (e) a
group represented by formula (A1): ##STR00028## wherein X.sub.1 is
CR.sub.1 or N, wherein R.sub.1 is H, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or OH; X.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or OH; R.sub.5 is C.sub.1-6
alkyl, C.sub.1-6 alkoxy, or OH; and p is an integer of 0 to 3,
wherein when p is 2 or 3, the groups R.sub.5 may be the same or
different; Ra is H, C.sub.1-6 alkyl, or C.sub.2-6 alkenyl; ""
represents a single bond making n=2 or a double bond making n=1,
wherein when n=2, two groups R.sub.3 may be the same or different,
and two groups R.sub.4 may also be the same or different; Y is S or
O; and R.sub.3 and R.sub.4 are each independently H, C.sub.1-6
alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.2-7 acyl, or the group (A1),
or one R.sub.3 and one R.sub.4 may together form a saturated or
unsaturated 5- or 6-membered hydrocarbon ring condensed with the
hetero ring to which R.sub.3 and R.sub.4 are bound, wherein the 5-
or 6-membered hydrocarbon ring may be substituted with C.sub.1-6
alkyl, or C(R.sub.3).sub.2 or C(R.sub.4).sub.2 may each
independently be C.dbd.CH.sub.2; with the proviso that at least one
R.sub.3 is a group other than C.sub.1-3 alkyl in the case where the
hetero ring containing Y is a thiazoline ring;
R.sub.4.dbd.Ra.dbd.H; X.sub.1.dbd.X.sub.2.dbd.CH; and p=0 or
R.sub.5.dbd.C.sub.1-6 alkyl.
21. The whitening agent of claim 20, wherein Y is S.
22. The whitening agent of claim 20, wherein A is the group
(A1).
23. The whitening agent of claim 20, wherein is a single bond.
24. The whitening agent of claim 23, wherein the heterocyclic
compound is represented by formula (1-1): ##STR00029## wherein
R.sub.3, R.sub.4, R.sub.5, p, and Ra are as defined in formula
(1).
25. The whitening agent of claim 24, wherein each group R.sub.3 is
independently H or C.sub.1-6 alkyl.
26. The whitening agent of claim 23, wherein each group R.sub.4 is
independently H or C.sub.1-6 alkyl, or C(R.sub.4).sub.2 is
C.dbd.CH.sub.2.
27. The whitening agent of claim 23, wherein the heterocyclic
compound is represented by formula (1-2): ##STR00030## wherein
R.sub.3, R.sub.4, R.sub.5, p, and Ra are as defined in formula
(1).
28. The whitening agent of claim 27, wherein R.sub.3 and R.sub.4
are each independently H or C.sub.1-6 alkyl.
29. The whitening agent of claim 20, wherein is a double bond.
30. The whitening agent of claim 29, wherein the heterocyclic
compound is represented by formula (1-3): ##STR00031## wherein,
R.sub.3, R.sub.4, R.sub.5, p, and Ra are as defined in formula
(1).
31. The whitening agent of claim 29, wherein the heterocyclic
compound is represented by formula (1-4): ##STR00032## wherein,
R.sub.3, R.sub.4, R.sub.5, p, and Ra are as defined in formula
(1).
32. The whitening agent of claim 30, wherein R.sub.3 is C.sub.1-6
alkyl or the group (A1).
33. The whitening agent of claim 30, wherein R.sub.4 is H or
C.sub.1-6 alkyl.
34. The whitening agent of claim 20, wherein Ra is H.
35. The whitening agent of claim 20, wherein R.sub.5 is C.sub.1-6
alkyl.
36. The whitening agent of claim 20, wherein the active ingredient
inhibits melanin production.
37. A skin external preparation comprising (i) a dermatologically
acceptable carrier or adjuvant, and (ii) a heterocyclic compound
represented by formula (1) or a pharmacologically acceptable salt
thereof: ##STR00033## wherein A is selected from the group
consisting of (a) C.sub.1-6 alkyl, (b) C.sub.5-6 cycloalkyl, (c)
benzyl, (d) benzylcarbonyl, which may be substituted with C.sub.2-6
alkylene at the benzyl position, (e) benzoyl, which may be
substituted with C.sub.1-6 alkyl, and (f) a group represented by
formula (A1): ##STR00034## wherein X.sub.1 is CR.sub.1 or N,
wherein R.sub.1 is H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or OH;
X.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, C.sub.1-6 alkyl,
C.sub.i-6 alkoxy, or OH; R.sub.5 is C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or OH; and p is an integer of 0 to 3, wherein when p is 2
or 3, the groups R.sub.5 may be the same or different; Ra is H,
C.sub.1-6 alkyl, or C.sub.2-6 alkenyl; "" represents a single bond
making n=2 or a double bond making n=1, wherein when n=2, two
groups R.sub.3 may be the same or different, and two groups R.sub.4
may also be the same or different; Y is S or O; and R.sub.3 and
R.sub.4 are each independently H, C.sub.1-6 alkyl,
hydroxy-C.sub.1-6 alkyl, C.sub.2-7 acyl, or the group (A1), or one
R.sub.3 and one R.sub.4 may together form a saturated or
unsaturated 5- or 6-membered hydrocarbon ring condensed with the
hetero ring to which R.sub.3 and R.sub.4 are bound, wherein the 5-
or 6-membered hydrocarbon ring may be substituted with C.sub.1-6
alkyl, or C(R.sub.3).sub.2 or C(R.sub.4).sub.2 may each
independently be C.dbd.CH.sub.2; with the proviso that at least one
R.sub.3 is a group other than C.sub.1-3 alkyl in the case where the
hetero ring containing Y is a thiazoline ring;
R.sub.4.dbd.Ra.dbd.H; X.sub.1.dbd.X.sub.2.dbd.CH; and p=0 or
R.sub.5=C.sub.1-6 alkyl.
38. The skin external preparation of claim 37, wherein the
preparation is a cosmetic.
39. The whitening agent of claim 31, wherein R.sub.3 is C.sub.1-6
alkyl or the group (A1).
40. The whitening agent of claim 31, wherein R.sub.4 is H or
C.sub.1-6 alkyl.
41. A method for inhibiting melanin production comprising topically
applying to the skin of a subject in need thereof a preparation
comprising an effective amount of a heterocyclic compound
represented by formula (1) or a pharmacologically acceptable salt
thereof: ##STR00035## wherein A is selected from the group
consisting of (a) C.sub.1-6 alkyl, (b) C.sub.5-6 cycloalkyl, (c)
benzyl, (d) benzylcarbonyl, which may be substituted with C.sub.2-6
alkylene at the benzyl position, (e) benzoyl, which may be
substituted with C.sub.1-6 alkyl, and (f) a group represented by
formula (A1): ##STR00036## wherein X.sub.1 is CR.sub.1 or N,
wherein R.sub.1 is H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or OH;
X.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, or OH; R.sub.5 is C.sub.1-6 alkyl, C.sub.1-6
alkoxy, or OH; and p is an integer of 0 to 3, wherein when p is 2
or 3, the groups R.sub.5 may be the same or different; Ra is H,
C.sub.1-6 alkyl, or C.sub.2-6 alkenyl; "" represents a single bond
making n=2 or a double bond making n=1, wherein when n=2, two
groups R.sub.3 may be the same or different, and two groups R.sub.4
may also be the same or different; Y is S or O; and R.sub.3 and
R.sub.4 are each independently H, C.sub.1-6 alkyl,
hydroxy-C.sub.1-6 alkyl, C.sub.2-7 acyl, or the group (A1), or one
R.sub.3 and one R.sub.4 may together form a saturated or
unsaturated 5- or 6-membered hydrocarbon ring condensed with the
hetero ring to which R.sub.3 and R.sub.4 are bound, wherein the 5-
or 6-membered hydrocarbon ring may be substituted with C.sub.1-6
alkyl, or C(R.sub.3).sub.2 or C(R.sub.4).sub.2 may each
independently be C.dbd.CH.sub.2; with the proviso that at least one
R.sub.3 is a group other than C.sub.1-3 alkyl in the case where the
hetero ring containing Y is a thiazoline ring;
R.sub.4.dbd.Ra.dbd.H; X.sub.1.dbd.X.sub.2.dbd.CH; and p=0 or
R.sub.5.dbd.C.sub.1-6 alkyl.
42. The method of claim 41, wherein the heterocyclic compound acts
as a skin-whitening agent.
Description
RELATED APPLICATIONS
[0001] This application claims the priority of Japanese Patent
Application No. 2008-29106 filed on Feb. 8, 2008 and Japanese
Patent Application No. 2008-199606 filed on Aug. 1, 2008, which are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a whitening agent and a
skin external preparation, and particularly, to an active
ingredient thereof.
BACKGROUND OF THE INVENTION
[0003] Pigmentation in the skin such as pigmented spots and
freckles are resulted from hyperpigmentation of melanin in the
epidermis. The hyperpigmentation is caused by acceleration of
melanin production in epidermal melanocytes triggered by hormone
abnormality or UV stimulation.
[0004] A whitening agent has been mixed into a skin external
preparation with an aim to prevent and improve such abnormal
melanin pigmentation. At present, as ingredients that are mixed
into a skin external preparation as a whitening agent, there are
vitamin C derivative, kojic acid, arbutin
(4-hydroxyphenyl-.beta.-D-glucopyranoside), Rucinol
(4-n-butylresorcinol), ellagic acid, etc., which are known to have
an inhibitory action on melanin production.
[0005] However, a whitening agent fully satisfactory in terms of
the effect, safety, and the like has not yet been obtained, and
therefore development of a new whitening agent has been
demanded.
[0006] On the other hand, Patent Literature 1 describes a
2-aminothiazole compound having an antibacterial or bactericidal
effect.
[0007] Also, Patent Literature 2 describes a thiazole compound
having a C17,20-lyase inhibitory effect.
[0008] Further, Patent Literature 3 describes a thiazoline compound
having a pest control effect on a harmful organism.
[0009] However, these literatures are totally silent on an
inhibitory action on the melanin production and a whitening
effect.
[0010] Patent Literature 1: Japanese Patent No. 3033178
[0011] Patent Literature 2: Japanese Unexamined Patent Publication
No. 2005-532983
[0012] Patent Literature 3: Japanese Unexamined Patent Publication
No. H6-25197
DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
[0013] The present invention has been accomplished in view of the
aforementioned problem of the conventional art. An object of the
present invention is to provide a compound having an excellent
inhibitory action on melanin production and being useful as a
whitening agent, and a skin external preparation containing the
compound.
Means to Solve the Problem
[0014] The present inventors conducted thorough research to solve
the aforementioned problem. As a result, they have found that a
specific thiazoline or oxazoline compound has an excellent
inhibitory action on melanin production and also has extremely low
cytotoxicity, thereby completing the present invention.
[0015] That is, the whitening agent of the present invention
comprises, as an active ingredient, a heterocyclic compound
represented by the following formula (1) or a pharmacologically
acceptable salt thereof:
##STR00002##
wherein
[0016] A is C.sub.1-6 alkyl, C.sub.5-6 cycloalkyl, benzyl,
benzylcarbonyl, benzoyl, or a group represented by formula
(A1):
##STR00003##
[0017] wherein
[0018] X.sub.1 is CR.sub.1 or N, wherein R.sub.1 is H, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, or OH;
[0019] X.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, or OH;
[0020] R.sub.5 is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or OH; and
[0021] p is an integer of 0 to 3, wherein when p is 2 or 3, R.sub.5
may be the same or different;
[0022] Ra is H, C.sub.1-6 alkyl, or C.sub.2-6 alkenyl;
[0023] "" represents a single bond that leads n=2 or a double bond
that leads n=1, wherein when n=2, two R.sub.3 may be the same or
different, and two R.sub.4 may also be the same or different;
[0024] Y is S or O; and
[0025] R.sub.3 and R.sub.4 are each independently H, C.sub.1-6
alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.2-7 acyl, or the group (A1),
or
[0026] one R.sub.3 and one R.sub.4 may together form a saturated or
unsaturated 5- or 6-membered hydrocarbon ring condensed with the
hetero ring to which R.sub.3 and R.sub.4 are bound, or
[0027] C(R.sub.3).sub.2 or C(R.sub.4).sub.2 may each independently
be C.dbd.CH.sub.2;
[0028] with the proviso that at least one R.sub.3 is a group other
than C.sub.1-3 alkyl in the case where: the hetero ring containing
Y is a thiazoline ring; R.sub.4.dbd.Ra.dbd.H;
X.sub.1.dbd.X.sub.2.dbd.CH; and p=0 or R.sub.5.dbd.C.sub.1-6
alkyl.
[0029] The present invention also provides the whitening agent,
wherein Y is S.
[0030] The present invention also provides the whitening agent,
wherein A is the group (A1).
[0031] The present invention also: provides the whitening agent,
wherein is a single bond.
[0032] The present invention also provides the whitening agent,
wherein is represented by formula (1-1):
##STR00004##
wherein R.sub.3, R.sub.4, R.sub.5, and Ra are as defined in the
formula (1).
[0033] The present invention also provides the whitening agent,
wherein R.sub.3 in the formula (1-1) is each independently H or
C.sub.1-6 alkyl.
[0034] The present invention also provides the whitening agent,
wherein R.sub.4 in the formula (1-1) is each independently H or
C.sub.1-6 alkyl, or C(R.sub.4).sub.2 is C.dbd.CH.sub.2.
[0035] The present invention also, provides the whitening agent,
wherein is represented by formula (1-2):
##STR00005##
wherein R.sub.3, R.sub.4, R.sub.5, and Ra are as defined in the
formula (1).
[0036] The present invention also provides the whitening agent,
wherein R.sub.3 and R.sub.4 in the formula (1-2) are each
independently H or C.sub.1-6 alkyl.
[0037] The present invention also provides the whitening agent,
wherein is a double bond.
[0038] The present invention also provides the whitening agent,
wherein is represented by formula (1-3):
##STR00006##
wherein, R.sub.3, R.sub.4, R.sub.5, and Ra are as defined in the
formula (1).
[0039] The present invention also provides the whitening agent,
wherein is represented by formula (1-4):
##STR00007##
wherein, R.sub.3, R.sub.4, R.sub.5, and Ra are as defined in the
formula (1).
[0040] The present invention also provides the whitening agent,
wherein R.sub.3 in the formula (1-3) or (1-4) is C.sub.1-6 alkyl or
the group (A1).
[0041] The present invention also provides the whitening agent,
wherein R.sub.4 in the formula (1-3) or (1-4) is H or C.sub.1-6
alkyl.
[0042] The present invention also provides the whitening agent,
wherein Ra is H.
[0043] The present invention also provides the whitening agent,
wherein R.sub.5 is C.sub.1-6 alkyl.
[0044] The present invention also provides the whitening agent,
wherein the active ingredient inhibits melanin production.
[0045] The present invention also, provides a skin external
preparation or a cosmetic comprising any of the aforementioned
heterocyclic compounds or a pharmacologically acceptable salt
thereof.
Effect of the Invention
[0046] The whitening agent of the present invention has an
excellent inhibitory action on melanin production and also has
extremely low cytotoxicity; therefore, it can be suitably mixed
into a skin external preparation as a whitening agent.
BEST MODE FOR CARRYING OUT THE INVENTION
[0047] The whitening agent of the present invention is represented
by the following formula (1):
##STR00008##
[0048] In the formula (1), A is C.sub.1-6 alkyl, C.sub.5-6
cycloalkyl, benzyl, benzylcarbonyl, benzoyl, or a group represented
by the following formula (A1):
##STR00009##
[0049] In the group (A1), X.sub.1 is CR.sub.1 or N, wherein R.sub.1
is H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or OH.
[0050] X.sub.2 is CR.sub.2 or N, wherein R.sub.2 is H, C.sub.1-6
alkyl, C.sub.1-6 alkoxy, or OH.
[0051] Accordingly, an unsaturated 6-membered ring containing
X.sub.1 and X.sub.2 is a benzene ring, a pyridine ring, or a
pyrimidine ring.
[0052] R.sub.5 is C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or OH, and
preferred examples thereof include C.sub.1-6 alkyl.
[0053] p is an integer of 0 to 3. When p is 2 or 3, R.sub.5 can be
the same or different.
[0054] Ra is H, C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, and
preferred examples thereof include H.
[0055] "" represents a single bond or a double bond. When it is a
single bond, n=2, When it is a double bond, n=1. When n=2, two
R.sub.3 may be the same or different, and two R.sub.4 may also be
the same or different.
[0056] Y is S or O. Accordingly, in the formula (1), an unsaturated
5-membered hetero ring containing Y is thiazole, thiazoline,
oxazole, or oxazoline.
[0057] R.sub.3 and R.sub.4 can each independently be H, C.sub.1-6
alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.2-7 acyl, or the
aforementioned group (A1). Also, one R.sub.3 and one R.sub.4 may
together form a saturated or unsaturated 5- or 6-membered
hydrocarbon ring condensed with the hetero ring to which R.sub.3
and R.sub.4 are bound. Alternatively, C(R.sub.3).sub.2 or
C(R.sub.4).sub.2 may each independently be C.dbd.CH.sub.2.
[0058] However, in the present invention, at least one R.sub.3 is a
group other than C.sub.1-3 alkyl, in the case where: a hetero ring
containing Y is a thiazoline ring; R.sub.4.dbd.Ra.dbd.H;
X.sub.1.dbd.X.sub.2.dbd.CH; and either p=0 or R.sub.5.dbd.C.sub.1-6
alkyl.
[0059] An example of the preferred compound represented by the
formula (1) is a compound wherein Y.dbd.S.
[0060] Another example of the preferred compound represented by the
formula (1) is a compound wherein A is the group (A1).
[0061] An example of the preferred compound wherein A is a group
(A1) is a compound wherein is a single bond. Preferred examples of
such a compound include a compound represented by the following
formula (1-1) or formula (1-2).
##STR00010##
[0062] In the formula (1-1) and formula (1-2), R.sub.3, R.sub.4,
R.sub.5, and Ra are as defined in the formula (1).
[0063] A preferred example of the compound represented by the
formula (1-1) is a compound wherein R.sub.3 is each independently H
or C.sub.1-6 alkyl.
[0064] Another preferred example of the compound represented by the
formula (1-1) is a compound wherein R.sub.4 is each independently H
or C.sub.1-6 alkyl, or a compound wherein C(R.sub.4).sub.2 is
C.dbd.CH.sub.2.
[0065] A preferred example of tho compound represented by the
formula (1-2) is a compound wherein R.sub.3 and R.sub.4 are each
independently H or C.sub.1-6 alkyl.
[0066] It is to be noted that compounds of the formula (1) wherein
is a single bond and Ra.dbd.H can be tautomers as shown below. In
the present invention, such tautomers are also included in the
compound of the formula (1).
##STR00011##
[0067] Also, a preferred example of the compound wherein A is the
group (A1) is a compound wherein is a double bond. Preferred
examples of such a compound include a compound represented by the
following formula (1-3) or formula (1-4).
##STR00012##
[0068] In the formula (1-3) and formula (1-4), R.sub.3, R.sub.4,
R.sub.5, and Ra are as defined in the formula (1).
[0069] A preferred example of the compound represented by the
formula (1-3) or formula (1-4) is a compound wherein R.sub.3 is
C.sub.1-6 alkyl or the group (A1).
[0070] Another preferred example of the compound represented by the
formula (1-3) or (1-4) is a compound wherein R.sub.4 is H or
C.sub.1-6 alkyl.
[0071] The compound of the formula (1) can be synthesized by a
known method or commercially available.
[0072] In the case of synthesis, when the molecule has a functional
group which blocks or might block a reaction, an appropriate
protecting group is preferably used to allow the reaction to
proceed efficiently. The use of the protecting group can be carried
out according to, for example, Protective Groups in Organic
Synthesis by Theodora W. Greene and Peter G. M. Wuts.
[0073] Further, when an isomer such as a conformational isomer, a
geometric isomer, and an optical isomer is present, a pure isomer
or geometric isomer can be obtained by appropriately selecting a
raw material and a reaction condition and performing a separation
operation. In the present invention, a pure isomer of the compound
of the formula (1) as well as a mixture thereof are also
included.
[0074] A compound wherein is a single bond and Ra.dbd.H in the
formula (1) can be obtained by, for example, a reaction shown in
the following scheme 1.
##STR00013##
[0075] In scheme 1, a reaction of an iso(thio)cyanate compound (2)
with an ethanolamine compound (3) can be carried out, for example,
in an appropriate solvent such as chloroform, while heating as
needed. A ring closure reaction of the (thio)urea compound (4) thus
obtained can be carried out, for example, in the presence of an
acid catalyst, while heating. The above reaction can be carried out
according to, for example, a method described in Japanese
Unexamined Patent Publication No. S62-228089.
[0076] Alternatively, as a method described in Japanese Unexamined
Patent Publication No. H6-25197, a reaction of 2-imino (or 2-amino)
thiazoline compound (or oxazoline compound) with a compound
represented by A-X (X is a halogen) can also be adopted. This
reaction can typically be carried out in an appropriate solvent in
the presence of a base such as triethylamine, while heating as
needed.
[0077] A compound wherein is a double bond and Ra.dbd.H in the
formula (1) can be obtained by, for example, a reaction shown in
the following scheme 2.
##STR00014##
[0078] In scheme 2, a reaction of a (thio)urea compound (5) with a
.alpha.-haloketone compound (6) can be carried out in an
appropriate solvent such as methanol, at room temperature or while
heating, in the presence of a base such as triethylamine as needed.
This reaction can be carried out according to, for example, a
method described in Japanese Unexamined Patent. Publication No.
2005-532983 and Japanese Patent No. 3023178.
[0079] Alternatively, as a method described in Japanese Patent No.
3023178, a reaction of 2-aminothiazole compound (or 2-aminooxazol
compound) with a compound represented by A-X (X is a halogen) can
also be adopted. This reaction can typically be carried out in an
appropriate solvent in the presence of a base such as
triethylamine, while heating as needed.
[0080] The compound of the formula (1) can be converted into an
acid-addition salt by an ordinary method as needed. Examples of
acid in the acid-addition salt include an inorganic salt such as
hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric
acid, and an organic acid such as acetic acid, propionic acid,
citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid,
succinic acid, tartaric acid, and methanesulfonic acid.
[0081] Many of the compounds of the formula (1) are commercially
available and can be obtained from various suppliers such as
Enamine Ltd. (Ukraine), Pharmeks Ltd. (Russia), Labotest (Germany),
Scientific Exchange Inc. (U.S.A), Life Chemicals Inc. (Ukraine),
Asinex Ltd. (Russia), Vitas-M Laboratory Ltd. (Russia), ACB Blocks
Ltd. (Russia), Bionet (U.S.A), and Princeton Biomolecular Research
Inc. (U.S.A).
[0082] The compound of the formula (1) has an excellent inhibitory
action on melanin production while exhibiting extremely low
eytotoxieity. Therefore, the present compound is useful as a
whitening agent and can be suitably mixed into various skin
external preparations, particularly a skin external preparation
intended to improve or prevent pigmented spots, freckles, skin
dullness, and the like.
[0083] When the compound of the formula (1) is mixed into the skin
external preparation as the whitening agent, the compound amount
is, in the total amount of the external agent, typically 0.0002% by
mass or more, preferably 0.002% by mass or more. When it is too
low, the effect cannot be fully exerted. Although no limitation is
imposed on the upper limit, it is typically 30% by mass or less,
preferably 20% by mass or less, and more preferably 5% by mass or
less. When the compound is excessively mixed in, not only a
remarkable effect reasonably expected from the increased amount may
not be obtained but also formulation designing and usability may be
affected.
[0084] Other than adding the compound of the formula (1), the skin
external preparation of the present invention can be produced by an
ordinary method.
[0085] In addition to the compound of the formula (1), other
ingredients normally used in a skin external preparation such as a
cosmetic product and a pharmaceutical product can be appropriately
added to the skin external preparation of the present invention as
needed as far as the effect of the present invention is not
adversely affected. Examples of such an ingredient include oil, a
humectant, an ultraviolet protective agent, an antioxidant, a metal
ion chelating agent, a surfactant, a preservative, a moisturizer, a
fragrance, water, an alcohol, a thickener, powder, a colorant, a
crude drug, and various kinds of medicinal ingredients.
[0086] Further, other whitening agents such as vitamin C, magnesium
ascorbyl phosphate, ascorbyl glucoside, arbutin, kojic acid,
Rucinol, ellagic acid, tranexamic acid, and linoleic acid can be
appropriately added.
[0087] The skin external preparation of the present invention is
widely applicable to the fields of cosmetics, drugs, and quasi
drugs. No particular limitation is imposed on the form of the skin
external preparation as long as it is applicable to the skin. Any
form such as a solution, an emulsion, a solid, a semi-solid, a
powder, a powder dispersion, a water-oil-separated two-phase
liquid, a water-oil-powder-separated three-phase liquid, an
ointment, a gel, an aerosol, a mousse, and a stick can be applied.
Further, the skin external preparation can be provided in any use
form including a facial cosmetic such as a lotion, an emulsion, a
cream, a pack, an essence, and a gel, and a makeup cosmetic such as
a foundation, a makeup base, and a concealer.
[0088] Hereinbelow, the present invention will be further described
with specific examples. However, the present invention is not
limited thereto.
Examples
[0089] A test for melanin production inhibition by the compounds of
the formula (1) was conducted. The test method is as follows.
[0090] Melanin Production Inhibition Test
(1) Inoculation of Cells and Addition of Test Substances
[0091] Mouse B16 melanoma cells were inoculated in a six well plate
at 100,000 cells/well. The next day, test substance solutions
(solvent: DMSO) were added.
(2) Cell Proliferation Test
[0092] Three days after the addition of the test substance
solution, the medium was removed by aspiration. Then 1 ml of EMEM
medium containing 10% Alamar Blue solution was added, and a
reaction was allowed to proceed at 37.degree. C. After 30 minutes,
100 .mu.L of the reaction mixture was transferred to a 96 well
plate and fluorescence was measured at an excitation wavelength of
544 nm and a measurement wavelength of 590 nm. Using the value thus
measured as a relative value of cell count, a ratio of the cell
count (% cell count) of the test substance-added group to the test
substance-absent group (group in which only the solvent was added)
was calculated. The higher the % cell count, the lower the
cytotoxicity. It was determined that a compound having the % cell
count of 80% or more was non-cytotoxic, and that a compound having
the % cell count of less than 80% was cytotoxic.
(3) Quantification of Melanin
[0093] The cells after the cell proliferation test were washed with
PBS three times, and then lysed by addition of 200 .mu.L of 1M NaOH
to measure an absorbance at 475 nm. Using the value thus measured
as a relative value of the melanin amount, a ratio of the melanin
amount (%) of the test substance-added group to the test
substance-absent group (group in which only the solvent was added)
was calculated. The lower the ratio of the melanin amount, the
higher the melanin production-inhibitory effect. In the final
concentrations of the test substances at which the compound was
determined to be non-cytotoxic, the minimum final concentration of
the test substance at which the ratio of the melanin amount (%) was
80% or less was provided as a minimum concentration for inhibition
of melanin production (ppm). The inhibitory effect on melanin
production was evaluated according to the following criteria.
[0094] .circleincircle.: the minimum concentration for inhibition
of melanin production was 1 ppm or less.
[0095] .largecircle.: the minimum concentration for inhibition of
melanin production was more than 1 ppm and 10 ppm or less.
[0096] .times.: no inhibitory effect on melanin production was
exhibited at 10 ppm or less [0097] (the ratio of the melanin amount
was not 80% or less even at 10 ppm or less).
[0098] The results of melanin production inhibition test using the
compounds of the present invention are shown in Table 1.
[0099] Any of the compounds shown in Table 1 was acknowledged to
have an inhibitory effect on melanin production, and most of them
exhibited the effect at such an extremely low concentration as 1
ppm or less.
[0100] It is to be noted that symbols in Tables represent the
following groups. [0101] Me: Methyl, Et: Ethyl, tBu: tert-Butyl,
Phe: Phenyl, Ac: Acetyl
TABLE-US-00001 [0101] TABLE 1 ##STR00015## Inhibitory effect on
melanin No. R.sub.3 R.sub.4 R.sub.5a R.sub.5b R.sub.5c R.sub.5d
R.sub.5e Ra production 1 pyridin-4-yl H Me H H H H H
.circleincircle. 2 pyridin-2-yl H Me H H H H H .circleincircle. 3
pyridin-2-yl H Et H H H H H .circleincircle. 4 pyridin-2-yl H H H H
H H H .circleincircle. 5 tBu H Me H Me H H H .circleincircle. 6 Me
Ac Me H H H H H .smallcircle. 7 4-methoxyphenyl Me Me H H H Me H
.circleincircle. 8 Phe H Me H H H Me H .circleincircle. 9
3,4-dihydroxyphenyl H Et H H H H H .circleincircle. 10
2,4-dihydroxyphenyl H Et H H H H H .circleincircle. 11
--(CH.sub.2).sub.4-- Me H H H H H .circleincircle.
TABLE-US-00002 TABLE 2 ##STR00016## Inhibitory effect on melanin
No. R.sub.3 R.sub.4 A1 Ra production 12 Phe H pyridin-2-yl H
.circleincircle. 13 Phe H 3-methylpyridin-2-yl H .circleincircle.
14 pyridin-4-yl H pyridin-2-yl H .circleincircle. 15 pyridin-4-yl H
3-methylpyridin-2-yl H .circleincircle. 16 pyridin-2-yl H 5
-methylpyridin-2-yl H .circleincircle. 17 pyridin-3-yl H
pyridin-2-yl H .circleincircle. 18 pyridin-4-yl H pyridin-3-yl H
.circleincircle.
TABLE-US-00003 TABLE 3 ##STR00017## Inhibitory effect on melanin
No. R.sub.3 R.sub.4 R.sub.5a R.sub.5b R.sub.5c R.sub.5d R.sub.5e Ra
production 19 H, Et H, H H H H H H H .circleincircle. 20 H, H H, H
H H H H H H .smallcircle. 21 H, H H, Me H H H H H H
.circleincircle. 22 H, H H, H Me H H H H H .circleincircle. 23 H, H
H, H O--Me H H H H H .circleincircle. 24 Me, Me H, H H H O--Me H H
H .smallcircle. 25 Me, Me H, H H O--Me H H H H .smallcircle. 26 Me,
Me H, H O--Me H H H H H .smallcircle. 27 H, Me H, H Me H Me H H H
.smallcircle. 28 H, H Me, Me Me H H H H H .circleincircle. 29
CH.sub.2OH, CH.sub.2OH H, H H H H H H H .smallcircle. 30
CH.sub.2OH, CH.sub.2OH H, H Me H Me H Me H .smallcircle. 31
##STR00018## .circleincircle. 32 ##STR00019## .circleincircle.
TABLE-US-00004 TABLE 4 ##STR00020## Inhibitory effect on melanin
No. R.sub.3 R.sub.4 A Y Ra production 33 Me Phe t-Bu S H
.circleincircle. 34 Me H 4-methylbenzoyl S H .smallcircle. 35
--(CH.sub.2).sub.4-- benzoyl S H .circleincircle. 36 ##STR00021##
.circleincircle. 37 ##STR00022## .smallcircle.
TABLE-US-00005 TABLE 5 ##STR00023## Inhibitory effect on melanin
No. R.sub.3 R.sub.4 A Ra production 38 H, H Me, Me pyridin-3-yl H
.smallcircle. 39 H, H Me, Me cyclohexyl H .smallcircle. 40 H, H Me,
Me benzyl H .smallcircle.
[0102] Hereinbelow, representative Synthesis Examples of the
heterocyclic compounds used for the whitening agent of the present
invention will be shown. Various heterocyclic compounds can be
obtained by carrying out a reaction according to the
below-described Synthesis Examples using a corresponding raw
material.
Synthesis Example 1-1
Synthesis of 4-(5,5-dimethyl-4,5-dihydrothiazol-2-yl amino)phenol
(Compound 41)
[0103] To p-anisidine (0.60 g, 4.86 mmol) and methanol (4.0 mL) in
a 50 mL recovery flask was added methallyl isothiocyanate (0.50 g,
4.42 mmol) dropwise at room temperature, and then the resulting
mixture was stirred for 12 hours at room temperature. Upon
completion of the reaction, the mixture was extracted with ethyl
acetate once. The organic phase thus obtained was washed with
saturated brine and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure and the
residue was recrystallized from a mixed solvent of ethyl acetate
and hexane to give 0.79 g of 1-(4-methoxyphenyl)-3-(2-
methylallyl)thiourea (yield 76%).
[0104] 1-(4-Methoxyphenyl)-3-(2-methylallyl)thiourea (0.50 g, 2.11
mmol) and 35% hydrochloric acid (5.0 mL) were added in a pressure
resistant reaction container, and the resulting mixture was stirred
at 140.degree. C. for five hours in the sealed container. Upon
completion of the reaction, a 3N aqueous solution of sodium
hydroxide was added to the reaction mixture to adjust the pH up to
14, and the resulting mixture was extracted with ethyl acetate
twice. The organic phase was washed with saturated brine and then
dried over anhydrous magnesium sulfate. The solvent was distilled
off under reduced pressure, and the residue was purified by silica
gel column chromatography (hexane:ethyl acetate=1:2) to give 0.19 g
of 4-(5,5-dimethyl-4,5-dihydrothiazol-2-ylamino)phenol (Compound
41) (yield 40%).
Synthesis Example 1-2
Synthesis of (hetero)arylaminothiazolines
[0105] (Hetero)arylaminothiazolines as shown in Table 6 were each
synthesized in the same manner as in Synthesis Example 1-1 except
that raw material A was used instead of anisidine.
TABLE-US-00006 TABLE 6 No. Structure Raw material A NMR Yield 41
##STR00024## p-anisidine .sup.1H-NMR (DMSO-d6): 1.46 (6 H, s), 3.51
(2 H, br-s), 6.61 (2 H, dd), 7.07 (2 H, br-s), 8.67 (2 H, br-s) 40%
42 ##STR00025## m-anisidine .sup.1H-NMR (DMSO-d6): 1.47 (6 H, s),
3.64 (2 H, br-s), 6.31 (1 H, d), 6.83 (2 H, br-s), 6.97 (1 H, t),
9.17 (2 H, br-s) 34% 38 ##STR00026## 3-aminopyridine .sup.1H-NMR
(DMSO-d6): 1.49 (6 H, s), 3.53 (2 H, br-s), 7.23 (1 H, dd), 7.66 (1
H, br-s), 8.12 (1 H, dd), 8.35 (1 H, br-s), 9.10 (1 H, br-s)
56%
Synthesis Example 2
Synthesis of 4-(pyridin-2-yl)-N-o-toluylthiazol-2-amine (Compound
2)
[0106] To 975 mL of methanol were added triethylamine (14.0 g, 137
mmol), o-toluylthiourea (11.54 g, 69.4 mmol), and
2-(bromoacetyl)pyridine hydrobromide (19.5 g, 69.4 mmol), and the
resulting mixture was stirred for 15 hours at room temperature.
Upon completion of the reaction, 1,950 mL of water was added to the
mixture and precipitated crystals were collected by filtration. The
solid thus collected was crystallized from a mixed solvent of water
and methanol to give the title compound (14.0 g, 76%).
[0107] .sup.1H-NMR (DMSO-d.sub.6): 2.30(3H, s), 7.01-7.04(1H, m),
7.22-7.30(3H, m), 7.46(1H, s), 7.82-7.91(2H, m), 7.97(1H, d),
8.56(1H, d), 9.32(1H, s)
Reference Example 1
Synthesis of 4,4-dimethyl-N-phenyl-4,5-dihydrothiazol-2-amine
[0108] In 500 g of chloroform was dissolved
2-amino-2-methyl-1-propanol (61.6 g, 0.69 moL). Then, 300 g of
chloroform solution containing phenyl isothiocyanate (81.6 g, 0.6
moL) was slowly added dropwise to the mixture over one hour, while
stirring. Upon completion of the addition, the resulting mixture
was stirred for 12 hours at room temperature. The precipitated
crystals were refluxed with heat to be dissolved and then
recrystallized. The crystals thus obtained were collected by
filtration, washed with 20 mL of diethyl ether three times, and
then dried under reduced pressure at room temperature to give 80.1
g of N-(1-hydroxy-2-methylpropan-2-yl)-N'-phenylthiourea (yield
60%).
[0109] N-(1-hydroxy-2-methylpropan-2-yl)-N'-phenylthiourea (80.1 g,
0.36 mol) was dissolved in 2,400 mL of 35% HCl, and the resulting
mixture was stirred while heating at 90.degree. C. for 1.5 hours.
After cooling, the mixture was neutralized with NaOH and extracted
with diethyl ether. The extract was washed with saturated brine and
then anhydrous sodium sulfate was added. The organic phase was
distilled off under reduced pressure and the residue was washed
three times with hexane. The crystals thus obtained were dried
under reduced pressure at room temperature, and then recrystallized
from methanol twice to give 22.4 g of the title compound (yield
18%).
[0110] .sup.1H-NMR (CDCl.sub.3): 1.39(6H, s), 3.08(2H, s),
7.01-7.09(3H, m), 7.26-7.30(2H, m)
[0111] Hereinbelow, Formulation Examples of the skin external
preparation of the present invention are shown. In each Formulation
Example, one or more compounds of the present invention can be
used. Any of the skin external preparations shown in Formulation
Examples below exerts a whitening effect because of the by the
addition of the compound of the present invention.
Formulation Example 1
Cream
(Formulation)
TABLE-US-00007 [0112] Stearic acid 5.0% by mass Stearyl alcohol 4.0
Isopropyl myristate 18.0 Glyceryl monostearate 3.0 Propylene glycol
10.0 Compound of the present invention 0.1 Caustic potash 0.2
Sodium bisulfite 0.05 Preservative q.s. Fragrance q.s.
Ion-exchanged water balance
[0113] (Production Method)
[0114] Propylene glycol and caustic potash were dissolved in
ion-exchanged water, and the resulting mixture was heated to and
maintained at 70.degree. C. (aqueous phase). Other components were
mixed and melted by heat, and maintained at 70.degree. C. (oil
phase). The oil phase was gradually added to the aqueous phase, and
after the complication of the addition, the resulting mixture was
maintained at 70.degree. C. for some time to allow a reaction to
proceed. Subsequently, the mixture was homogeneously emulsified by
a homomixer, and cooled to 30.degree. C. while thoroughly
stirring.
Formulation Example 2
Cream
(Formulation)
TABLE-US-00008 [0115] Stearic acid 5.0 by mass % Sorbitan
monostearate 2.5 Polyoxyethylene (20) sorbitan monostearate 1.5
Arbutin 7.0 Sodium bisulfite 0.03 Propylene glycol 10.0 Compound of
the present invention 0.05 Glyceryl trioctanoate 10.0 Squalene 5.0
Octyl p-dimethylaminobenzoate 3.0 Disodium
ethylenediaminetetraacetate 0.01 Ethylparaben 0.3 Fragrance q.s.
Ion-exchanged water balance
[0116] (Production Method)
[0117] Propylene glycol and disodium ethylenediaminetetraacetate
were dissolved in ion-exchanged water and the resulting mixture was
maintained at 70.degree. C. (aqueous phase). Other components were
mixed and melted by heat, and maintained at 70.degree. C. (oil
phase). The oil phase was gradually added to the aqueous phase. The
mixture was preliminarily emulsified at 70.degree. C.,
homogeneously emulsified by a homomixer, and then cooled to
30.degree. C. while thoroughly stirring.
Formulation Example 3
Cream
(Formulation)
TABLE-US-00009 [0118] Solid paraffin 5.0% by mass Beeswax 10.0
Petrolatum 15.0 Liquid paraffin 41.0 Glyceryl monostearate 2.0 POE
(20) sorbitan monolaurate 2.0 Soap powder 0.1 Borax 0.2 Compound of
the present invention 0.05 Sodium bisulfite 0.03 Ethylparaben 0.3
Fragrance q.s. Ion-exchanged water balance
[0119] (Production Method)
[0120] Powder soap and borax were added to ion-exchanged water and
dissolved with heat, and the resulting mixture was maintained at
70.degree. C. (aqueous phase). Other components were mixed and
melted by heat, and maintained at 70.degree. C. (oil phase). While
stirring, the oil phase was gradually added to the aqueous phase to
allow a reaction to proceed. Upon completion of the reaction, the
mixture was homogeneously emulsified by a homomixer, and then
cooled to 30.degree. C. while thoroughly stirring.
Formulation Example 4
Milky Lotion
(Formulation)
TABLE-US-00010 [0121] Stearic acid 2.5% by mass Cetyl alcohol 1.5
Petrolatum 5.0 Liquid paraffin 10.0 POE (10) monooleate 2.0
Polyethylene glycol 1500 3.0 Triethanolamine 1.0 Carboxyvinyl
polymer 0.05 Compound of the present invention 0.01 Sodium
bisulfite 0.01 Ethylparaben 0.3 Fragrance q.s. Ion-exchanged water
balance
[0122] (Production Method)
[0123] Carboxyvinyl polymer was dissolved in a small amount of
ion-exchanged water (phase A). Polyethylene glycol 1500 and
triethanolamine were added to the remaining ion-exchanged water and
dissolved with heat, and the resulting mixture was maintained at
70.degree. C. (aqueous phase). Other components were mixed and
melted by heat, and maintained at 70.degree. C. (oil phase). The
oil phase was added to the aqueous phase and preliminarily
emulsified. After addition of phase A, the resulting mixture was
homogeneously emulsified by a homomixer and then cooled to
30.degree. C. while thoroughly stirring.
Formulation Example 5
Milky Lotion
(Formulation)
TABLE-US-00011 [0124] Microcrystalline wax 1.0% by mass Beeswax 2.0
Lanolin 20.0 Liquid paraffin 10.0 Squalane 5.0 Sorbitan
sesquioleate 4.0 POE (20) sorbitan monooleate 1.0 Propylene glycol
7.0 Compound of the present invention 1.0 Sodium bisulfite 0.01
Ethylparaben 0.3 Fragrance q.s. Ion-exchanged water balance
[0125] (Production Method)
[0126] Propylene glycol was added to ion-exchanged water, and the
resulting mixture was heated and maintained at 70.degree. C.
(aqueous phase). Other components were mixed and melted by heat,
and maintained at 70.degree. C. (oil phase). While stirring the oil
phase, the aqueous phase was gradually added to the oil phase. The
resulting mixture was homogeneously emulsified by a homomixer and
then cooled to 30.degree. C. while thoroughly stirring.
Formulation Example 6
Jelly
(Formulation)
TABLE-US-00012 [0127] 95% Ethanol 10.0% by mass Dipropylene glycol
15.0 POE (50) oleyl ether 2.0 Carboxyvinyl polymer 1.0 Caustic soda
0.15 L-arginine 0.1 Compound of the present invention 5.0 Sodium
2-hydroxy-4-methoxybenzophenone sulfonate 0.05 Trisodium
ethylenediaminetetraaceate dihydrate 0.05 Methylparaben 0.2
Fragrance q.s. Ion-exchanged water balance
[0128] (Production Method)
[0129] Carboxyvinyl polymer was homogeneously dissolved in
ion-exchanged water. Separately, the compound of the present
invention and POE (50) oleyl ether were dissolved in 95% ethanol
and then added to the aqueous phase. After addition of the
remaining components, the resulting mixture was neutralized by
caustic soda and L-arginine to increase the viscosity.
Formulation Example 7
Essence
(Formulation)
TABLE-US-00013 [0130] (Phase A) Ethyl alcohol (95%) 10.0% by mass
POE (20) octyldodecanol 1.0 Pantothenyl ethyl ether 0.1 Compound of
the present invention 2.0 Methylparaben 0.15 (Phase B) Potassium
hydroxide 0.1 (Phase C) Glycerol 5.0 Dipropylene glycol 10.0 Sodium
bisulfite 0.03 Carboxyvinyl polymer 0.2 Purified water balance
[0131] (Production Method)
[0132] Each of Phase A and Phase C was homogeneously dissolved, and
Phase A was added to Phase C to be solubilized. After addition of
Phase B, the resulting mixture was packed in a container.
Formulation Example 8
Pack
(Formulation)
TABLE-US-00014 [0133] (Phase A) Dipropylene glycol 5.0% by mass POE
(60) hydrogenated castor oil 5.0 (Phase B) Compound of the present
invention 0.05 Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben
0.2 Fragrance 0.2 (Phase C) Sodium bisulfite 0.03 Polyvinyl alcohol
13.0 (saponification degree of 90 and polymerization degree of
2,000) Ethanol 7.0 Purified water balance
[0134] (Production Method)
[0135] Each of Phase A, Phase B, and Phase C was homogeneously
dissolved, and Phase B was added to Phase A to be solubilized.
After addition of Phase C, the resulting mixture was packed in a
container.
Formulation Example 9
Solid Foundation
(Formulation)
TABLE-US-00015 [0136] Talc 43.1% by mass Kaolin 15.0 Sericite 10.0
Zinc oxide 7.0 Titanium dioxide 3.8 Yellow iron oxide 2.9 Black
iron oxide 0.2 Squalane 8.0 Isostearic acid 4.0 POE sorbitan
monooleate 3.0 Isocetyl octanoate 2.0 Compound of the present
invention 0.5 Preservative q.s. Fragrance q.s.
[0137] (Production Method)
[0138] Powdery components from talc to black iron oxide shown above
were thoroughly mixed by a blender. To this mixture were added oily
components from squalane to isocetyl octanoate shown above, the
compound of the present invention, preservative, and fragrance. The
resulting mixture was thoroughly kneaded, packed in a container,
and then formed.
Formulation Example 10
Emulsion Foundation (Cream-Type)
(Formulation)
TABLE-US-00016 [0139] (Powder part) Titanium dioxide 10.3% by mass
Sericite 5.4 Kaolin 3.0 Yellow iron oxide 0.8 Red iron oxide 0.3
Black iron oxide 0.2 (Oil phase) Decamethylcyclopentasiloxane 11.5
Liquid paraffin 4.5 Polyoxyethylene-modified 4.0
dimethylpolysiloxane Compound of the present invention 0.5 (Aqueous
phase) Purified water 50.0 1,3-Butylene glycol 4.5 Sorbitan
sesquioleate 3.0 Preservative q.s. Fragrance q.s.
[0140] (Production Method)
[0141] The aqueous phase was stirred with heat and then the powder
part, which had been fully mixed and pulverized, was added. The
mixture was treated with a homomixer and then the oil phase, which
had been mixed with heat, was added. The mixture was treated with a
homomixer and then fragrance was added while stirring. The mixture
thus obtained was cooled to room temperature.
Formulation Example 11
Lotion
TABLE-US-00017 [0142] (1) Compound of the present invention 0.05%
by mass (2) Aspartic acid 1.0 (3) Tocopherol acetate 0.01 (4)
Glycerol 4.0 (5) 1,3-Butylene glycol 4.0 (6) Ethanol 8.0 (7) POE
(60) hydrogenated castor oil 0.5 (8) Methylparaben 0.2 (9) Citric
acid 0.05 (10) Sodium citrate 0.1 (11) Fragrance 0.05 (12) Purified
water balance
[0143] (Production Method)
[0144] (2), (4), (5), (9), and (10) were dissolved in (12) to
provide a purified water solution, Separately, (1), (3), (7), (8),
and (11) were dissolved in (6), and the resulting mixture was added
to the aforementioned the purified water solution to be
solubilized. The mixture thus obtained was filtrated to provide a
lotion.
Formulation Example 12
Lotion
TABLE-US-00018 [0145] A: Alcohol phase Ethanol 5.0% by mass POE
oleyl ether 2.0 2-Ethylhexyl-p-dimethylaminobenzoate 0.18 Compound
of the present invention 0.1 Fragrance 0.05 B: Aqueous phase
1,3-Butylene glycol 9.5 2-O-Ethyl ascorbic acid 0.5 Sodium
pyrrolidonecarboxylate 0.5 Whey extract 5.0 Nicotinamide 0.3
Glycerol 5.0 Hydroxypropyl-.beta.-cyclodextrin 1.0 Trisodium
hydroxyethylethylenediamine triacetate 1.0 Lysine 0.05 Tranexamic
acid 1.0 Purified water balance
[0146] (Production Method)
[0147] Alcohol phase A was added to Aqueous phase B and solubilized
to provide a lotion.
Formulation Example 13
Cream (Whitening)
TABLE-US-00019 [0148]
Trans-4-(trans-aminomethylcyclohexanecarbonyl) 1.0% by mass
aminomethylcyclohexanecarboxylic acid hydrochloride Potassium
4-methoxysalicylate 1.0 3-O-Ethylascorbic acid 1.0 Linoleic acid
0.3 Sodium lipoate 1.0 Compound of the present invention 3.0
Coenzyme Q10(CoQ10) 0.03 Petrolatum 2.0 Dimethylpolysiloxane 2.0
Ethanol 5.0 Behenyl alcohol 0.5 Batyl alcohol 0.2 Glycerol 7.0
1,3-Butylene glycol 5.0 Polyethylene glycol 20000 0.5 Jojoba oil
3.0 Squalane 2.0 Phytosteryl hydroxystearate 0.5 Pentaerythritol
tetra(2-ethylhexanoate) 1.0 Polyoxyethylene hydrogenated castor oil
1.0 Potassium hydroxide 0.1 Sodium pyrosulfite 0.01 Sodium
hexametaphosphate 0.05 Stearyl glycyrrhetinate 0.1 Pantothenyl
ethyl ether 0.1 Arbutin 7.0 Tranexamic acid 2.0 Tocopherol acetate
0.1 Sodium hyaluronate 0.05 p-Hydroxybenzoate ester q.s. Trisodium
edetate 0.05 4-t-Butyl-4'-methoxydibenzoylmethane 0.1 Glyceryl
diparamethoxycinnamate mono-2- 0.1 ethylhexanoate Yellow iron oxide
q.s. Xanthan gum 0.1 Carboxyvinyl polymer 0.2 Purified water
balance
Formulation Example 14
Two-Phase Cream (Sunscreen)
TABLE-US-00020 [0149] Tranexamic acid 2.0% by mass Potassium
4-methoxysalicylate 1.0 Compound of the present invention 0.03
Dimethylpolysiloxane 5.0 Decamethylcyclopentasiloxane 25.0
Trimethylsiloxysilicate 5.0 Polyoxyethylene/methylpolysiloxane
copolymer 2.0 Dipropylene glycol 5.0 Dextrin palmitate-coated
fine-particle zinc oxide (60 nm) 15.0 Dipotassium glycyrrhizinate
0.02 Glutathione 1.0 Thiotaurine 0.05 Sophora flavescens extract
1.0 Paraben q.s. Phenoxyethanol q.s. Trisodium edetate q.s.
2-Ethylhexyl p-methoxycinnamate 7.5 Dimethyldistearylammonium
hectorite 0.5 Spherical poly(alkyl acrylate) powder 5.0
Butylethylpropanediol 0.5 Purified water balance Fragrance q.s.
Formulation Example 15
Gel (Whitening)
TABLE-US-00021 [0150] Potassium 4-methoxysalicylate 0.1% by mass
Rucinol 0.3 Dihydrolipoic acid 1.0 Lamium album var. barbatum 0.1
Dimethylpolysiloxane 5.0 Glycerol 2.0 1,3-Butylene glycol 5.0
Polyethylene glycol 1500 3.0 Polyethylene glycol 20000 3.0 Cetyl
octanoate 3.0 Citric acid 0.01 Sodium citrate 0.1 Sodium
hexametaphosphate 0.1 Compound of the present invention 1.0
Dipotassium glycyrrhizinate 0.1 Ascorbyl glucoside 2.0 Tocopherol
acetate 0.1 Scutellaria baicalensis extract 0.1 Saxifraga
stolonifera extract 0.1 Trisodium edetate 0.1 Xanthan gum 0.3
Acrylic acid/alkyl methacrylate copolymer 0.05 (Pemulen TR-2) Agar
powder 1.5 Phenoxyethanol q.s. Dibutylhydroxytoluene q.s. Purified
water balance
Formulation Example 16
Pack (Moisturizing)
TABLE-US-00022 [0151] Trans-4-aminomethylcyclohexanecarboxylic acid
10.0% by mass methylamide hydrochloride Dihydrolipoamide 1.0 Rosa
multiflora fruit extract 0.1 Ethanol 10.0 1,3-Butylene glycol 6.0
Polyethylene glycol 4000 2.0 Olive oil 1.0 Macadamia nut oil 1.0
Phytosteryl hydroxystearate 0.05 Lactic acid 0.05 Sodium lactate
0.1 Disodium L-ascorbyl sulfate 0.1 Compound of the present
invention 0.5 Potassium 2-L-Ascorbyl .alpha.-tocopheryl phosphate
0.1 Vitamin E acetate 0.1 Fish collagen 0.1 Sodium chondroitin
sulfate 0.1 Sodium carboxymethyl cellulose 0.2 Polyvinyl alcohol
12.0 p-Hydroxybenzoate q.s. Purified water balance Fragrance
q.s.
Formulation Example 17
Lotion (Moisturizing)
TABLE-US-00023 [0152] Tranexamic acid 1.0% by mass Potassium
4-methoxysalicylate 1.0 Lipoic acid 10.0 Hamamelis 0.1
Silica-coated zinc oxide 0.1 Hypotaurine 0.1 Sophora flavescens
extract 0.1 Peach kernel extract 0.1 Beech sprout extract 0.1
Retinol 0.1 Compound of the present invention 0.01 Ethyl alcohol
5.0 Glycerol 1.0 1,3-Butylene glycol 5.0 Polyoxyethylene
polyoxypropylene decyltetradecyl ether 0.2 Sodium hexametaphosphate
0.03 Trimethylglycine 1.0 Sodium polyaspartate 0.1 Potassium
2-L-Ascorbyl .alpha.-tocopheryl phosphate 0.1 Thiotaurine 0.1 Green
tea extract 0.1 Peppermint extract 0.1 Iris root extract 1.0
Trisodium EDTA 0.1 Carboxyvinyl polymer 0.05 Potassium hydroxide
0.02 Phenoxyethanol q.s. Purified water balance Fragrance q.s.
* * * * *