NOVEL BENZOIC ACID AMlDE COMPOUND
5 [Technical Field]
The present disclosure relates to a novel benzamide compound.
[Background Art]
Melanin protects skin organs beneath the dermis by blocking UV at the
10 epidermis and also protects the skin by scavenging free radicals. Also, melanin is
the primary determinant of skin color and is the cause of pigmentation such as
freckles, dark spots, etc. when existing in excess.
Melanin is produced by melanocytes, which are found in the basal layer of
the epidermis. It is known that the production of melanin is promoted by stimuli
15 such as UV or inflammation. Accordingly, the melanin production can be reduced
by decreasing external stimulation, blocking signal transduction or inhibiting
synthesis of the melanin-producing enzyme tyrosinase or inhibiting activity thereof.
Until now, kojic acid, hydroquinone, arbutin, azelaic acid, aloesin,
4-butylresorcinol, resveratrol, ceramide, sphingosine-I-phosphate,
20 sphingosylphosphorylcholline, etc. are known to be able to regulate melanin
production by promoting tyrosinase breakdown or regulating glycosylation.
However, these substances are not used widely due to unsatisfactory skin whitening
effect and stability as well as skin irritation. Accordingly, development of a
substance that provides superior skin whitening effect with less side effects is
5 necessary.
[Disclosure]
[Technical Problem]
The present disclosure is directed to providing a novel benzamide derivative
10 compound. The present disclosure is also directed to providing a composition
containing a benzamide derivative compound exhibiting skin whitening effect.
[Technical Sol~~tionl
In a general aspect, there is provided a compound of Chemical Formula 1, an
15 isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a
hydrate ,thereof or a solvate thereof:
[Chemical Formula I]
Wherein each of Rl, R3 and R4 is independently selected from a group
consisting of hydrogen, hydroxy, C1-C5 alkoxy, C3-Cs cycloalkoxy, aryloxy and C1-C5
haloalkoxy;
RP is selected from a group consisting of hydrogen, C1-C5 alkyl, C3-C6
5 cycloalkyl, aryl and CI-C5 haloalkyl; and
n is an integer selected from I to 5.
In another general aspect, there is provided a composition for skin whitening,
containing the compound of Chemical Formula I the isomer thereof, the
pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof or
10 the solvate thereof.
[Advantageous Effects]
A novel compound, an isomer thereof, a pharmaceutically acceptable salt
thereof, a prodrug thereof, a hydrate thereof or a solvate thereof according to the
15 present disclosure has superior skin whitening effect by reducing melanin production
and inhibiting the activity of tyrosinase.
[Best Model
In order to develop substances exhibiting improved skin whitening effect
20 while having less side effects, the inventors of the present disclosure have
synthesized polyhydroxybenzarnide derivative compounds having kazinol as a
backbone structure. Among them, the compounds having adamantane substituents
have been found to exhibit superior effect of reducing melanin production and
inhibiting tyrosinase activity. The superior effect of reducing melanin production
and inhibiting tyrosinase activity may be attributable to increased absorption owing to
5 increased oleophilicity provided by the adamantane group.
Definition
As used herein, "skin" refers to the tissue that covers the body surface of an
animal, including not only the face or body but also the scalp and hair, in the
10 broadest concept.
As used herein, "alkyl" refers to a monovalent saturated aliphatic
hydrocarbon chain. The hydrocarbon chain may be either straight or branched. In
an exemplary embodiment of the present disclosure, the "alkyl" may have 1-5 carbon
atoms ('lCl'C5 alkyl"). In another exemplary embodiment, it may have 1-4 carbon
15 atoms ("CI-C4 alkyl"). In another exemplary embodiment, it may have 1-3 carbon
atoms ("CI-C3 alkyl"). Specifically, the "alkyl" includes methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl or t-amyl, but is not limited thereto.
As used herein, "alkoxy" refers to an -OR group, where R is an alkyl group
defined above. Specifically, the "alkoxy" includes methoxy, ethoxy, n-propoxy,
20 isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy or 1,2-dimethylbutoxy, but
is not limited thereto.
As used herein, "cycloalkyl" refers to a cyclic saturated aliphatic hydrocarbon
group. The number following C means the number of carbon atoms that form a
ring. For example, lqC3-C6c ycloalkyl" refers to cycloalkyl having 3-6 ring-forming
carbon atoms. In an exemplary embodiment of the present disclosure, examples of
the "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, but are not
5 limited thereto. In another exemplary embodiment of the present disclosure, the
"cycloalkyl" group may be substituted with one or more alkyl group, for example, with
a C1-C6 alkyl group, specifically with a C1-C3 alkyl group, more specifically with a
methyl group. If the "cycloalkyl" has more than one substituent, the substituents
may be identical or different.
As used herein, "cycloalkoxy" refers to an -OR group, where R is a
"cycloalkyl" group defined above.
As used herein, "halo" or "halogen" includes fluoro, chloro, bromo or iodo.
In an exemplary embodiment of the present disclosure, the halo group may be fluoro
or chloro.
As used herein, "haloalkyl" refers to an "alkyl" group defined above which is
substituted with one or more identical (e.g., trifluoromethyl or pentafluoroethyl) or
different halogen.
As used herein, "aryl" refers to an aromatic hydrocarbon radical. The "aryl"
group may be, for example, phenyl, naphthyl, indenyl, azulenyl or anthracenyl,
20 specifically phenyl.
As used herein, "hydroxy" refers to an -OH radical.
As used herein, "isomer" includes not only optical isomers (e.g., essentially
pure enantiomers, essentially pure diastereomers or mixtures thereof) but also
conformation isomers (i.e., isomers different only in angles of one or more chemical
bonds), constitutional isomers (especially, tautomers) or geometric isomers (i.e.,
cis-trans isomers).
5 As used herein, "essentially pure" means, for example, when used in
connection with enantiomers or diastereomers, that the specific compound as an
example of the enantiomer or the diastereomer is present in about 90% (wlw) or
more, specifically about 95% or more, more specifically about 97% or more or about
98% or more, further more specifically about 99% or more, even more specifically
10 about 99.5% or more.
As used herein, "pharmaceutically acceptable" means approved by a
regulatory agency of the government or an international organization or listed in the
Pharmacopoeia or other generally recognized pharmacopoeia for use in animals,
more specifically in humans, since significant toxic effect can be avoided when used
15 with a common medicinal dosage.
As used herein, "pharmaceutically acceptable salt" refers to a salt which is
pharmaceutically acceptable and exhibits the desired pharmacological activity of its
parent compound. The salt may be (1) an acid addition salt formed from an
inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
20 phosphoric acid, etc., or an organic acid such as acetic acid, propionic acid,
hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid,
malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane disulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid,
2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,
5 4-methylbicyclo[2,2,2]-oct-2-ene-I -carboxylic acid, glucoheptonic acid,
3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid,
gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid or
muconic acid or (2) a salt formed as an acidic proton present in the parent
compound is replaced.
10 As used herein, "prodrug" refers to a drug whose physical and chemical
properties have been changed such that it does not exhibit physiological activity as it
is but exerts medicinal effect after it is converted to the original drug through
chemical or enzymatic action in vivo.
As used herein, "hydrate" refers to a compound bound with water. It is used
15 in a broad sense, including an inclusion compound which lacks chemical bonding
with water.
As used herein, "solvate" refers to a higher-order compound formed between
a solute molecule or ion, and a solvent molecule or ion.
Detailed description
In an aspect, the present disclosure provides a compound of Chemical
Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug
thereof, a hydrate thereof or a solvate thereof:
[Chemical Formula I ]
Wherein each of R1, R3 and R4 is independently selected from a group
5 consisting of hydrogen, hydroxy, C1-C3 alkoxy, C3-C6 cycloalkoxy, aryloxy and C1-C3
haloalkoxy ;
R2 is selected from a group consisting of hydrogen, C1-C3 alkyl, C3-Cs
cycloalkyl, aryl and C1-C3 haloalkyl; and
n is an integer selected from I to 3.
In an exemplary embodiment of the present disclosure, each of RI, R3 and R4
may be independently selected from a group consisting of hydrogen, hydroxy and
C1-C3 alkoxy, R2 may be hydrogen or C1-C3 alkyl and n may be 1 or 2.
In another exemplary embodiment of the present disclosure, the compound,
the isomer thereof, the pharniaceutically acceptable salt thereof, the prodrug thereof,
15 the hydrate thereof or the solvate thereof may be selected from a group consisting of
5-adamantan-1 -yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-2,4-dihydroxybenzamide1
5-adamantan-I -yl-N-[2-(3,4-dihydroxyphenyl)-ethy~]-2-hydroxy-4-methoxybenzamide
,5-adamantan-I -yl-N-(3,4-dihydroxybenzyl)-2,4-dihydroxybenzamide,
5-adamantan-1 -yl-N-(3,4-dihydroxybenzyl)-2-hydroxy-4-methoxybenzamidel
5-adamantan-1 -yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxybenzamide and
In another aspect, the present disclosure provides a method for preparing the
adamantane-substituted benzamide compound, including:
20 i) synthesizing adamantanyl hydroxybenzoic acid by reacting hydroxybenzoic
acid with adamantane compound in the presence of an acid catalyst;
ii) synthesizing adamantanyl alkoxybenzoic acid by reacting the adamantanyl
hydroxybenzoic acid with alkyl sulfate; and
iii) synthesizing the adamantane-substituted benzamide compound by
reacting the adamantanyl alkoxybenzoic acid with hydroxy-substituted
alkylp henylamine.
5 The method for preparing the adamantane-substituted benzamide compound
according to the present disclosure may be represented by Scheme 1.
[Scheme I]
In Scheme 1,
each of R1, R3 and Rq is independently selected from a group consisting of
hydrogen, hydroxy, CI-C5 alkoxy, C3-Cs cycloalkoxy, aryloxy and C1 -C5 haloalkoxy;
R2 is selected from a group consisting of hydrogen, C1'C5 alkyl, C3-C6
cycloalkyl, aryl and C1-C5 haloalkyl; and
n is an integer selected from 1 to 5.
In another aspect, the present disclosure provides a method for preparing the
adamantane-substituted benzamide compound, including:
i) synthesizing adamantanyl dihydroxybenzoic acid by reacting
dihydroxybenzoic acid with adamantane compound in the presence of an acid
catalyst;
20 ii) synthesizing adamantanyl hydroxyalkoxybenzoic acid or adamantanyl
10
dialkoxybenzoic acid by reacting the adamantanyl dihydroxybenzoic acid with dialkyl
sulfate in the presence of hydroxide; and
iii) synthesizing the adamantane-substituted benzamide - compound by
reacting the adamantanyl hydroxyalkoxybenzoic acid or adamantanyl
5 dialkoxybenzoic acid with hydroxy-substituted benzylamine or phenethylamine.
In another aspect, the present disclosure provides a method for preparing the
adamantane-substituted benzamide compound, including:
i) synthesizing 5-adamantanyl-2,4-dihydroxybenzoic acid by reacting
2,4-dihydroxybenzoic acid with I-adamantanol at room temperature in a
10 dichloromethane solvent in the presence of acetic acid and sulfuric acid catalysts;
ii) synthesizing 5-adamantanyl-2-hydroxy-4-methoxybenzoic acid or
5-adamantanyl-2,4-dimethoxybenzoic acid by reacting the
5-adamantanyl-2,4-dihydroxybenzoiac cid with dimethyl sulfate in the presence of
sodium hydroxide or potassium hydroxide; and
15 iii) synthesizing the adamantane-substituted benzamide compound by
reacting the 5-adamantanyl-2-hydroxy-4-methoxybenzoic acid or
5-adamantanyl-2,4-dimethoxybenzoic acid with hydroxy-substituted benzylamine or
phenethylamine in the presence of N-hydroxysuccinimide (HOSu) or
N,N'-dicyclohexylcarbodiimide (DCC).
20 In another aspect, the present disclosure provides a composition for skin
whitening containing the compound, the isomer thereof, the pharmaceutically
acceptable salt thereof, the prodrug thereof, the hydrate thereof or the solvate
thereof as an active ingredient. The compound, the isomer thereof, the
pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof or
the solvate thereof may exhibit superior skin whitening effect by reducing melanin
production and inhibiting tyrosinase activity.
5 In an exemplary embodiment, the composition according to the present
disclosure may contain the compound, the isomer thereof, the pharmaceutically
acceptable salt thereof, the prodrug thereof, the hydrate thereof or the solvate
thereof in an amount of 0.01-20 wt%, specifically 0.1-10 wt%, more specifically 0.5-5
wt%, based on the total weight of the composition. When the active ingredient is
10 contained in the above-described amount, the effect desired by the present
disclosure can be achieved adequately while satisfying stability and safety of the
composition and cost effectiveness. Specifically, if the compound, the isomer
thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the
hydrate thereof or the solvate thereof is contained in an amount less than 0.01 wt%,
15 skin whitening effect may be insufficient. And, if it is contained in an amount
exceeding 20 wt%, cost effectiveness may be not good.
In another aspect, the present disclosure provides a composition for external
application to skin, containing the compound, the isomer thereof, the
pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof or
20 the solvate thereof as an active ingredient. In another aspect, the present
disclosure provides a cosmetic composition containing the compound, the isomer
thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the
hydrate thereof or the solvate thereof as an active ingredient. The cosmetic
composition may exhibit superior skin whitening effect and, specifically, may improve
or prevent freckles, dark spots or pigmentation.
The composition according to the present disclosure may be provided as any
5 formulation suitable for topical application. For example, it may be provided in the
form of solution, oil-in-water emulsion, water-in-oil emulsion, suspension, solid, gel,
powder, paste, foam or aerosol. These formulations may be prepared by a method
commor~lye mployed in the art.
The composition according to the present disclosure may further contain
10 other ingredients that may provide synergic effect without negatively affecting the
desired effect. Specifically, the composition according to the present disclosure
may further contain arbutin or ascorbic acid derivatives that can enhance skin
whitening effect. Also, the composition according to the present disclosure may
further contain moisturizer, emollient, surfactant, UV absorbent, antiseptic, fungicide,
15 antioxidant, pH adjuster, organic or inorganic pigment, flavor, cooling agent or
antiperspirant. The content of these ingredients may be determined within ranges
not negatively affecting the purpose and effect of the present disclosure by those
skilled in the art. The content of these ingredients may be 0.01-5 wt%, specifically
0.01-3 wt%, based on the total weight of the composition.
20 In another aspect, the present disclosure provides a pharmaceutical
composition containing the compound, the isomer thereof, the pharmaceutically
acceptable salt thereof, the prodrug thereof, the hydrate thereof or the solvate
thereof as an active ingredient. The pharmaceutical composition may exhibit
excellent skin whitening effect and, specifically, may improve or prevent freckles,
dark spots or pigmentation.
The pharmaceutical corr~positiona ccording to the present disclosure may be
5 administered orally or parenterally, rectally, topically, transdermally, intravenously,
intramuscularly, intraperitoneally or subcutaneously. Formulations for oral
administration may be in the form of tablet, pill, soft and hard capsule, granule,
powder, fine granule, liquid, emulsion or pellet, but are not limited thereto.
Formulations for parenteral administration may be in the form of solution,
10 suspension, emulsion, gel, injection, medicinal drip, suppository, patch or spray, but
are not limited thereto. These formulations may be prepared easily by a method
commonly employed in the art and surfactant, vehicle, hydrating agent,
emulsification accelerator, suspension, salt or buffer for osmotic pressure control,
colorant, flavor, stabilizer, antiseptic, preservative or other commonly used adjuvants
15 may be used adequately.
The administration dosage of the active ingredient will vary depending on the
age, gender and body weight of a subject, pathological condition and severity
thereof, admir~istration route and discretion of a diagnoser. Determination of the
administration dosage considering these factors is in the level of those skilled in the
20 art. A daily dosage may be, for example, 0.1-1 00 mglkglday, more specifically 5-50
mglkglday, but is not limited thereto.
[Mode for Invention]
Hereinafter, the present disclosure will be described in detail through
examples and test examples. However, the following examples and test examples
are for illustrative purposes only and it will be apparent to those of ordinary skill in
5 the art that the scope of the present disclosure is not limited thereby.
[Example 1 1 Preparation
5-adamantan-I -yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-2,4-dihydroxybenzamide
(1) Preparation of 5-adamantan-I-yl-2,4-dihydroxybenzoic acid
2,4-Dihydroxybenzoic acid (9.24 g) and I-adamantanol (9.14 g) are dissolved
in dichloromethane (200 mL) and then stirred. After adding acetic acid (17.1 mL)
mixed with concentrated sulfuric acid (3.3 mL) dropwise, the mixture is stirred at
room temperature for 12 hours. After adding water (200 mL), sodium bicarbonate is
added until the pH of the solution becomes 6. The produced solid is filtered to
15 obtain 8.82 g of 5-adamantan-I-yl-2,4-dihydroxybenzoic acid as solid of a light color.
'H NMR (300 MHz, DMSO-ds) 12.40 (brs, 'IH), 10.17 (s, IH), 7.47 (s, AH),
6.27 (s, IH), 2.00 (s, 9H), 1.70 (s, 6H).
(2) Preparation of
5-adamantan-I -yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-2,4-dihydroxybenzamide
5-Adamantan-I-yl-2,4-dihydroxybenzoic acid (0.606 g) obtained in (I),
N-hydroxysuccinimide (0.24 g) and N,N1-dicyclohexylcarbodiimide (0.43 g) are
dissolved in dioxane (10 mL) and then stirred for 12 hours. The produced solid is
filtered and the filtrate is added dropwise to a mixture solution of dopamine bromate
5 (0.54 g), sodium bicarbonate (0.18 g) and water (2 rnL). After stirring at 50 OC for 2
hours, the solution is cooled to room temperature, neutralized with 10% HCI solution
and washed with ethyl acetate (50 mL). The organic layer is dried with anhydrous
magnesium sulfate, filtered, concentrated under reduced press[-lre and separated by
column chromatography to obtain 0.2 g of the target compound as white solid.
10 'H NMR (300 MHz, DMSO-d6) 12.63 (s, AH), 9.90 (s, AH), 8.74 (s, AH), 8.63
(s, AH), 8.58 (m, IH), 7.38 (m, IH), 6.63 (m, 2H), 6.47 (dl lHl J = 7.5 Hz), 6.25 (s,
AH), 3.32 (m, 2H), 2.63 (t, 2H, J = 7.2 Hz), 2.03 (s, 9H), 1.72 (s, 6H).
[Example 21 Preparation of
0.12 g of the target compound is obtained as white solid in sl~bstantiallyth e
same manner as in (2) of Example 1, except for using
5-adamantan-1 -yl-2-hydroxy-4-methoxybenzoic acid instead of
20 5-adamantan-1-yl-2,4-dihydroxybenzoiacc id.
'H NMR (300 MHz, DMSO-dB) 12.89 (s, AH), 8.76 (s, IH), 8.70 (m, AH), 8.65
(s, IH), 7.43 (s, AH), 6.62 (m, 2H), 6.45 (m, 2H), 3.79 (s, 3H), 3.36 (m, 2H), 2.64 (t,
2H, J = 7.2 Hz), 2.01 (s, 9H), 1.72 (s, 6H).
5 [Example 31 Preparation
5-adamantan-I -yl-N-(3,4-dihydroxybenzyl)-2,4-dihydroxybenzamide
0.09 g of the target compound is obtained as white solid in substantially the
same manner as in (2) of Example 1, except for using 3,4-dihydroxybenzylamine
10 instead of dopamine.
'H NMR (300 MHz, DMSO-d6) 12.74 (s, IH), 9.95 (s, AH), 8.98 (m, IH), 8.85
(s, IH), 8.71 (s, IH), 7.44 (s, IH), 6.67 (m, 2H), 6.56 (d, IH, J = 7.8 Hz), 6.26 (s,
AH), 4.28 (dl 2H, J = 5.4 Hz), 2.03 (s, 9H), 1.71 (s, 6H).
15 [Example 41 Preparation of
5-adamantan-I -yl-N-(3,4-dihydroxybenzyl)-2-hydroxy-4-methoxybenzamide
0.17 g of the target compound is obtained as white solid in substantially the
17
same manner as in (2) of Example 1, except for using
5-adamantan-I -yl-2-hydroxy-4-methoxybenzoic acid instead of
5-adamantan-I-yl-2,4-dihydroxybenzoic acid and using 3,4-dihydroxybenzylamine
instead of dopamine.
5 'H NMR (300 MHz, DMSO-d6) 12.99 (s, IH), 9.09 (m, IH), 8.85 (s, IH), 8.72
(s, AH), 7.48 (s, IH), 6.67 (m, 2H), 6.57 (d, IH, J = 8.1 Hz), 6.43 (s, IH), 4.30 (dl 2H,
J = 5.4 Hz), 3.79 (s, 3H), 2.00 (s, 9H), 1.71 (s, 6H).
[Example 51 Preparation
0.2 g of the target compound is obtained as white solid in substantially the
same manner as in (2) of Example 1, except for using tyramine instead of dopamine.
1 H NMR (300 MHz, DMSO-de) 12.59 (s, I H), 9.91 (s, 1 H), 9.16 (s, 1 H), 8.60
15 (s, IH), 7.38 (s, AH), 7.02 (dl 2H, J = 8.1 Hz), 6.68 (dl 2H, J = 8.1 Hz), 6.25 (s, IH),
3.37 (m, 2H), 2.70 (t, 2H, J =7.2 Hz), 2.03 (s, 9H), 1.72 (s,6H).
[Example 61 Preparation of
5-adamantan-1 -yl-2-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxybenzamide
0.15 g of the target compound is obtained as solid of a light color in
substantially the same manner as in' (2) of Example 1, except for usirlg
5-adamantan-I -yl-2-hydroxy-4-methoxybenzoic acid instead of
5 5-adamantan-I-yl-2,4-dihydroxybenzoic acid and using tyramine instead of
dopamine.
'H NMR (300 MHz, DMSO-ds) 12.85 (s, IH), 9.17 (s, 'IH), 8.70 (m, AH), 7.42
(s, IH), 7.02 (d, 2H, J = 8.1 Hz), 6.68 (d, 2H, J = 8.1 Hz), 6.41 (s, IH), 3.78 (s, 3H),
3.39 (m, 2H), 2.71 (m, 2H), 2.00 (s, 9H), 1.72 (s, 6H).
10
[Example 71 Preparation
5-Adamantan- I -yl-2,4-dimethoxybenzoic acid (0.32 g) is dissolved in
15 dichloromethane (5 mL). After adding thionyl chloride (0.08 mL), followed by
refluxing for 3 hours, the mixture is cooled to room temperature and concentrated
under reduced pressure. Then, 0.28 g of the target compound is obtained as white
plate-shaped solid in substantially the same manner as in (2) of Example 1, except
19
for using tyrarr~inein stead of dopamine.
'H NMR (300 MHz, DMSO-d6) 9.20 (s, 'IH), 7.94 (m, AH), 7.73 (s, 1 H), 7.04
(d, 2H, J = 8.1 Hz), 6.70 (dl 2H, J = 8.1 Hz), 6.63 (s, IH), 3.87 (s, 3H), 3.84 (s, 3H),
3.44 (m, 2H), 2.69 (t, 2H, J = 7.1 Hz), 1.99 (s, 9H), 1.71 (s, 6H).
5
[Example 81 Preparation
0.24 g of the target compound is obtained as white solid in substantially the
10 same manner as in (2) of Example 1, except for using 2,4-dihydroxybenzylamine
instead of dopamine.
'H NMR (300 MHz, DMSO-d6) 12.41 (s, AH), 9.91 (s, AH), 9.40 (s, 'IH), 9.09
(s, 'IH), 8.83 (m, AH), 7.47 (s, AH), 6.89 (d, IH, J = 8.1 Hz), 6.26 (s, 2H), 6.16 (dl 'lH,
J = 8.1 Hz), 4.29 (m, 2H), 2.02 (s, 9H), 1.70 (s, 6H).
[Example 91 Preparation
0.14 g of the target compound is obtained as solid of a light color in
substantially the same manner as in (2) of Example 1, except for using
5-adamantan-I -yl-2-hydroxy-4-methoxybenzoic acid instead of
5-adamantan-I-yl-2,4-dihydroxybenzoica cid and using 2,4-dihydroxybenzylamine
5 instead of dopamine.
'H NMR (300 MHz, DMSO-d6) 12.73 (s, IH), 9.40 (s, IH), 9.11 (s, IH), 8.95
(m, IH),7.52(s, IH),6.90(d, IH,J=8.4Hz),6.43(~,IH ),6.28(s, IH),6.17(d, IH,
J = 8.4 Hz), 4.31 (d, 2H, J = 5.4 Hz), 3.79 (s, 3H), 2.00 (s, 9H), 1.71 (s, 6H).
'i
10 [Example 1 01 Preparation
5-adamantan-I -yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxybenzamide
OMe 0
Me0
0.03 g of the target compound is obtained as white solid in substantially the
same manner as in (2) of Example 1, except for using
15 5-adamantan-I -yl-2,4-dimethoxybenzoic acid instead of
5-adamantan-I-yl-2,4-dihydroxybenzoic acid and using 2,4-dihydroxybenzylamine
instead of dopamine.
'H NMR (300 MHz, DMSO-d6) 9.67 (s, 'IH), 9.13 (s, IH), 8.51 (m, 'IH), 7.78
(m, IH), 6.92 (d, IH, J = 8.1 Hz), 6.66 (s, AH), 6.27 (s, IH), 6.16 (d, IH, J = 8.1 Hz),
20 4.30 (dl 2H, J = 5.4 Hz), 3.93 (s, 3H), 3.88 (s, 3H), I .98 (s, 9H), 1.71 (s, 6H).
[Example 111 Preparation
3-adamantan-I -yl-N-(3,4-dihydroxybenzy1)-4-hydroxybenzamide
5 3-Adamantan-I -yl-4-hydroxybenzoic acid (0.286 g), N-hydroxysuccinimide
(0.12 g) and N,N1-dicyclohexylcarbodiimide (0.22 g) are dissolved in dioxane (5 mL)
and stirred for 12 hours. The produced solid is filtered and the filtrate is added
dropwise to a mixture solution of 3,4-dihydroxybenzylamine bromate (0.25 g),
sodium bicarbonate (0.09 g) and water (1 mL). After stirring at 50 O C for 2 hours,
10 the solution is cooled to room temperature, neutralized with 10% HCI solution and
washed with ethyl acetate (30 mL). The organic layer is dried with anhydrous
magnesium sulfate, filtered, concentrated under reduced pressure and separated by
column chromatography to obtain 0.03 g of the target compound as white solid.
'H NMR (300 MHz, DMSO-d~) 9.82 (s, AH), 8.75 (m, 2H), 8.62 (m, AH), 7.63
15 (s, IH), 7.56 (m, AH), 6.77 (dl AH, J = 8.4 Hz), 6.69 (s, AH), 6.64 (d, 'IH, J =8.1 Hz),
6.53(m1 IH), 4.26 (dl 2H, J =6.0 Hz),2.07 (s, 9H), 1.72(sI6H).
[Example 1 21 Preparation
3-adamantan-1 -yl-N-(3,4-dihydroxybenzy1)-4-methoxybenzamide
0.02 g of the target compound is obtained as solid of a light color in
substantially the same manner as in (2) of Example 1, except for using
3-adamantan-I -yl-4-methoxybenzoic acid instead of
5 5-adamantan-I-yl-2,4-dihydroxybenzoic acid and using 3,4-dihydroxybenzylamine
instead of dopamine.
1 H NMR (300 MHz, DMSO-dB) 8.74 (m, 3H), 7.75 (d, 'I H, J = 7.8 Hz), 7.70 (s,
IH), 7.01 (d, IH, J = 8.4 Hz), 6.70 (s, IH), 6.64 (d, IH, J = 8.1 Hz), 6.54 (d, IH, J =
7.5 Hz), 4.27 (d, 2H, J = 6.0 Hz), 3.84 (s, 3H), 2.05 (s, 9H), 1.73 (s, 6H).
[Example 1 31 Preparation of
0.25 g of the target compound is obtained as white solid in substantially the
15 same manner as in (2) of Example 1, except for using
3-adamantan-I -yl-4-hydroxybenzoic acid instead of
5-adamantan-I-yl-2,4-dihydroxybenzoic acid.
1 H NMR (300 MHz, DMSO-d~) 9.78 (s, IH), 8.71 (brs, AH), 8.64 (brs, IH),
23
8.21 (m, AH), 7.56 (m, 1H), 7.50 (m, lH), 6.76 (m, 1H), 6.62 (m, 2H), 6.45 (m, 1H),
3.34 (m, 2H), 2.62 (m, 2H), 2.07 (s, 9H), 1.73 (s, 6H).
[Example 141 Preparation
5 3-adamantan-1-yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-4-methoxybenzamide
0.19 g of the target compound is obtained as white solid in substantially the
same manner as in (2) of Example 1, except for using
3-adamantan-1 -yl-4-methoxybenzoic acid instead of
1 0 5-adamantan- 1 -yl-2,4-di hydroxybenzoic acid.
'H NMR (300 MHz, DMSO-ds) 8.73 (brs, IH), 8.63 (brs, 1H), 8.34 (m, IH),
7.66(m,2H),7.00(d,'lH1 J=8.7Hz),6.63(ml2H),6.46(d, 1H, J=8.1 Hz),3.80(s1
3H), 3.32 (m, 2H), 2.62 (t, 2H, J = 8.1 Hz), 2.05 (s, 9H), 1.73 (s, 6H).
15 [Example 1 51 Preparation
3-adamantan-1 -yl-4-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]benzamide
0.03 g of the target compound is obtained as white solid in substantially the
24
same manner as in Example 11, except for using tyramine instead of
'H NMR (300 MHz, DMSO-d6) 9.78 (s, IH), 9.14 (s, 'IH), 8.33 (m, IH), 7.56
(dl IH, J = 8.4 Hz), 7.01 (dl 2H, J = 8.1 Hz), 6.76 (dl IH, J = 8.4 Hz), 6.67 (dl 2H, J =
[Example 161 Preparation
3-adamantan-I -yl-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxybenzamide
10 0.03 g of the target compound is obtained as white solid in substantially the
same manner as in Example 11, except for using
3-adamantan-I -yl-4-methoxybenzoic acid instead of
3-adamantan-I-yl-4-hydroxybenzoic acid and using tyramine instead of
3,4-dihydroxybenzylamine.
15 1 H NMR (300 MHz, DMSO-d6) 9.14 (s, IH), 8.33(t,lHI J = 5.4 Hz), 7.65 (m,
2H), 7.00 (m, 3H), 6.67 (m, 2H), 3.83 (s, 3H), 3.35 (m, 2H), 2.69 (t, 2H, J = 7.7 Hz),
2.05 (s, 9H), 1.74 (s, 6H).
[Example 1 71 Preparation
20 3-adamantan-l-yl-N-(2,4-dihydroxybenzyl)-4-hydroxybenzamide
25
0.04 g of the target compound is obtained as white solid in substantially the
same manner as in Example 11, except for using 2,4-dihydroxybenzylamine instead
of 3,4-dihydroxybenzylamine.
5 'H NMR (300 MHz, DMSO-d6) 9.87 (s, AH), 9.64 (s, IH), 9.09 (s, IH), 8.73
(m, IH), 7.58 (m,2H), 6.89 (dl IH, J = 8.1 Hz), 6.77 (d, IH, J = 7.8 Hz), 6.18 (m, 2H),
4.25 (m, 2H), 2.07 (s, 9H), 1.72 (s, 6H).
[Example 181 Preparation
10 3-adamantan-I -yl-N-(2,4-dihydroxybenzyl)-4-methoxybenzamide
0.03 g of the target compound is obtained as white solid in substantially the
same manner as in Example 11, except for using
3-adamantan-I -yl-4-methoxybenzoic acid instead of
15 3-adamantan-I -yl-4-hydroxybenzoic acid and using 2,4-dihydroxybenzylamine
instead of 3,4-di hydroxybenzylamine.
1 H NMR (300 MHz, DMSO-ds) 9.58 (s, AH), 9.09 (s, IH), 8.81 (t, IH, J = 5.4
Hz), 7.73 (m,2H), 7.02 (dl IH, J = 8.4 Hz), 6.90 (d, IH, J = 8.1 Hz), 6.18 (m, 2H),
26
4-26 (dl 2H, J = 5.7 Hz), 3.84 (s, 3H), 2.05 (s, 9H), 1.73 (s, 6H).
[Example 191 Preparation
5-adamantan-1 -yl-N-(2,5-dimethoxybenzyl)-2,4-dihydroxybenzamide
5-Adamantan-1 -yl-2,4-di hydroxy-benzoic acid (1.2 1 g), N-hydroxysuccinimide
(0.48 g) and N,N1-dicyclohexylcarbodiimide (0.86 g) are dissolved in dioxane (20 mL)
and stirred for 12 hours. The produced solid is filtered and the filtrate is added
dropwise to a mixture solution of 2,5-dimethoxybenzylamine (0.77 g), sodium
10 bicarbonate (0.36 g) and water (4 mL). After stirring at 50 O C for 2 hours, the
solution is cooled to room temperature, neutralized with 10% HCI solution and
washed with ethyl acetate (100 mL). The organic layer is dried with anhydrous
magnesium sulfate, concentrated under reduced pressure and separated by column
chromatography to obtain 0.43 g of the target compound as white solid.
15 'H NMR (300 MHz, DMSO-ds) 12.39 (s, IH), 9.94 (s, AH), 8.90 (m, AH), 7.50
(s, IH), 6.92 (dl 'IH, J = 8.7 Hz), 6.80 (m, IH), 6.73 (m, IH), 6.28 (s, lH), 4.44 (d,
2H, J =5.7 Hz), 3.77 (s, 3H), 3.65(s, 3H), 2.04(s, 9H), 1.71 (s,6H).
[Example 201 Preparation
20 5-adamantan-1 -yl-N-(2,5-dihydroxybenzyl)-2,4-dihydroxybenzamide
27
5-Adamantan-1-yl-N-(2,5-dimethoxybenzyl)-2,4-dihydroxybenzam(0id.2e7 g)
is dissolved in dichloromethane (3 mL). After adding BBr3 (1.7 mL in CH2C12 1.0 M
solution, 3 eq.) and stirring at room temperature for 2 hours, methanol (5 rnL) is
5 added and extraction is carried out using water and dichloromethane. The organic
layer is dried with anhydrous magnesium sulfate, filtered, concentrated under
reduced pressure and separated by column chromatography to obtain 0.02 g of the
target compound as white solid.
'H NMR (300 MHz, DMSO-d6) 12.50 (s, IH), 9.94 (s, AH), 8.93 (m, 'IH), 8.81
10 (s, 1H),8.59(s, IH),7.50(s, IH),6.58(m,2H),6.44(m, IH),6.28(s, IH),4.34(m,
2H), 2.04 (s, 9H), 1.71 (s, 6H).
[Example 211 Preparation
5-adamantan-l-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxybenzamide
0.31 g of the target compound is obtained as solid of a light color in
substantially the same manner as in (2) of Example 1, except for using
3,5-dimethoxybenzylamine instead of dopamine.
'H NMR (300 MHz, DMSO-dB) 12.55 (s, IH), 9.96 (s, IH), 9.02 (m, AH), 7.46
(s, IH), 6.46(m,2H),6.38(sI 1H),6.27(sI 1H),4.39(d,2HI J=5.4Hz), 3.71 (s,
6H), 2.04 (s, 9H), 1.71 (s, 6H).
5 [Example 221 Preparation of
5-adamantan-1 -yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)benzamide
5-Adamantan-l-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxybenzamide (0.27 g)
is dissolved in dichloromethane (3 mL) . After adding BBr3 (1.7 mL in CH2CI2 1.0 M
10 solution, 3 eq.) and stirring at room temperature for 2 hours, methanol (5 mL) is
added and extraction is carried out using water and dichloromethane. The organic
layer is dried with anhydrous magnesium sulfate, filtered, concentrated under
reduced pressure and separated by column chromatography to obtain 0.045 g of the
target compound as white solid.
15 1 H NMR (300 MHz, DMSO-d~) 12.45 (s, AH), 9.95 (s, IH), 9.35 (m, IH), 9.01
(m, IH), 7.46 (s, IH), 6.31 (m, 3H), 6.19 (s, IH), 4.34 (m, 2H), 3.67 (s, 3H), 2.04 (s,
9H), 1.71 (s, 6H).
[Test Example I ] Effect of reducing melanin production in melanocytes
20 The effect of reducing melanin production of the benzamide derivative
29
compounds prepared in Examples in melanocytes was measured according to the
Dooley's method. Mouse-derived B16F10 melanoma cells acquired from the
Korean Cell Line Bank were used. DMEM (Cat No. 11995), FBS (Cat No.
16000-044), and antibiotic and antifungal agents (Cat No. 15240-062) necessary for
5 cell culturing were purchased from Invitrogen(GIBC0). -The cells were cultured
under the condition of 37 OC and 5% COz. The cultured B16F10 cells were
detached using 0.05% trypsin-EDTA and seeded onto a 48-well plate with the same
cell number (1% lo4c ells/well). From the next day, the culture medium was replaced
with one containing 10 ppm of the compound of Examples for three consecutive
10 days. Kojic acid and rucinol were used as positive control. After 5 days, melanin
was extracted from the cells by treating with 1 N NaOH at 60 OC for 2 hours, which
was quantitated by measuring absorbance at 405 nm. The concentration required
to reduce melanin production in melanocytes to half (1C5~w) as calculated and is
given in Table 1.
15 [Table 11
Compounds
Kojic acid
Rucinol
Example 1
Example 5
Example 8
lc50
IC50 = 300 pM
1C50= 10 pM
IC50= 1.2 pM
1C50= 1.1 pM
1C50= 1.2 pM
As seen from above, the compounds of Examples can reduce melanin
production at much lower concentration as compared to kojic acid and rucinol.
Example 9
Example 10
Example 12
Example 13
Example 20
Example 21
Accordingly, it can be seen that the benzamide derivative compounds according to
1C50 = 1.8 IJM
1C50= 1.1 (JM
ICs0 = 1.9 pM
lC50 = 3.0 pM
IC50 = 2.9 pM
IC50 = 2.0 pM
the present disclosure have excellent skin whitening effect by reducing melanin
5 production.
[Test Example 21 Effect of inhibitins mushroom tyrosinase activity
The effect of inhibiting mushroorn tyrosinase activity of the benzamide
derivative compounds of Examples was measured according to the method of Vanni,
et al. Specifically, 49.5 pL of 0.1 M potassium phosphate buffer (pH 6.8), 45 pL of
10 distilled water (DW), 0.5 pL (10 units) of mushroom tyrosinase (SIGMAT-7755) and 5
pL of the benzamide derivative compound of Examples were mixed and reacted at
37 O C for 10 minutes by mixing with 50 pL of 0.3 mg1mL tyrosine aqueous solution in
a 96-well plate (total volume: 150 pL). Kojic acid and rucinol were used as positive
control. Absorbance of the reaction solution was measured at 480 nm and the
15 concentration required to inhibit tyrosinase activity to 50% (IC5~w) as calculated and
is given in Table 2.
[Table 21
As seen from above, the benzamide derivative compounds of Examples have
Compounds
Kojic acid
Rucinol
Example 8
Example 9
Example 10
Example 17
Example 18
excellent effect of inhibiting mushroom tyrosinase activity, even better than kojic acid
and rucinol. Accordingly, it can be seen that the benzamide derivative compounds
5 according to the present disclosure have excellent skin whitening effect by inhibiting
tyrosinase activity.
Ic50
30 pM
1.3 pM
1.1 pM
0.8 pM
0.9 pM
0.9 I.IM
1.4 pM
Hereinafter, formulation examples of a composition containing the
compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the
10 prodrug thereof, the hydrate thereof or the solvate thereof according to the present
disclosure will be described in detail. However, the following formulation examples
are for illustrative purposes only and it will be apparent to those of ordinary skill in
the art that the scope of the present disclosure is not limited thereby.
[Formulation Example I] Skin lotion
A lotion is prepared according to a commonly employed method with ,the
composition described in Table 3.
[Table 31
5 [Formulation Example 21 Nourishing cream
A nourishing cream is prepared according to a commonly employed method
with the composition described in Table 4.
[Table 41
Ingredients
Compound of Example
Glycerine
Butylene glycol
Propylene glycol
Carboxyvinyl polymer
PEG 12 nonyl phenyl ether
Polysorbate 80
Ethanol
Triethanolamine
Antiseptic, pigment and flavor
Purified water
Contents (wt%)
0.1
3.0
2.0
2.0
0.1
0.2
0.4
10.0
0.1
adequate
balance
[Formulation Example 33 Massage cream
A massage cream is prepared according to a commor~ly employed method
with the composition described in Table 5.
[Table 51
Ingredients
Compound of Example
Polysorbate 60
Sorbitan sesquioleate
PEG 60 hydrogenated castor oil
Liquid paraffin
Squalane
Capryliclcapric triglyceride
Glycerine
Butylene glycol
Propylene glycol
Triethanolamine
Antiseptic, pigment and flavor
Purified water
Contents (wt%)
2.0
1.5
0.5
2.0
10.0
5.0
5.0
5.0
3.0
3.0
0.2
adequate
balance
Ingredients
Compound of Example
Contents (wt%)
1 .O
Beeswax 10.0
Polysorbate 60 1.5
PEG 60 hydrogenated castor oil 2.0
Sorbitan sesquioleate 0.8 1
Liquid paraffin
Capryliclcapric triglyceride
40.0
Squalane 5.0
I
Glycerine
Butylene glycol
5.0
3.0
1
Propylene glycol 3.0
Triethanolamine
Purified water I balance
0.2
Antiseptic, pigment and flavor
~ ~ - - - - ~~ - - ~ ~ ~ [Formulation Example 41 Pack
A pack is prepared according to a commonly employed method with the
composition described in Table 6.
[Table 61
adequate
-
Ingredients
Compound of Example
Polyvinyl alcohol
Contents (wtOh)
0.2
13.0
[Formulation Example 51 Gel
A gel is prepared according to a commonly employed method with the
composition described in Table 7.
(Table 71
Sodium carboxymethylcellulose
Glycerine
Allantoin
Ethanol
PEG 12 nonyl phenyl ether
Polysorbate 60
Antiseptic, pigment and flavor
Purified water
0.2
5.0
0.1
6.0
0.3
0.3
adequate
balance
Ingredients
Compound of Example
Sodium ethylenediaminetetraacetate
Glycerine
Carboxyvinyl polymer
Ethanol
PEG 60 hydrogenated castor oil
Triethanolamine
Contents (wt%)
0.5
0.05
5.0
0.3
5.0
0.5
0.3
[Formulation Example 61 Ointment
-
Antiseptic, pigment and flavor
Purified water
An ointment is prepared according to a commonly employed method with the
adequate
balance
composition described 'in Table 8.
[Table 81
Ingredients Contents (wt%)
L
Compound of Example 1.5
I I
Liquid paraffin
Glycerine
Butylene glycol
8.0
4.0
Carbomer 0.1
Capryliclcapric triglyceride 3.0
Squalane
I Sorbitan stearate I 0.4 I
I .O
Cetearyl glucoside 1.5
Cetearyl alcohol I .O
Beeswax 4.0
Antiseptic, pigment and flavor adequate
'Purified water balance
[CLAIMS]
[Claim 1 I
A compound of Chemical Formula 1, an isomer thereof, a pharmaceutically
acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof:
5 [Chemical Formula I ]
wherein each of R1, R3 and R4 is independently selected from a group
consisting of hydrogen, hydroxy, C1'C5 alkoxy, C3-C6 cycloalkoxy, aryloxy and c1-C~
haloalkoxy;
R2 is selected from a group consisting of hydrogen, C1-C5 alkyl, C3-Cs
cycloalkyl, aryl and C1-C5 haloalkyl; and
n is an integer selected from 1 to 5.
[Claim 21
15 The compound, the isomer thereof, the pharmaceutically acceptable salt
thereof, the prodrug thereof, the hydrate thereof or the solvate thereof according to
claim 1,
wherein each of R1, R3 and R4 is independently selected from a group
consisting of hydrogen, hydroxy, C1-C3 alkoxy, C3'C6 cycloalkoxy, aryloxy and C1-C3
haloalkoxy;
RZ is selected from a group consisting of hydrogen, C1-C3 alkyl, C3-Cs
cycloalkyl, aryl and C1-C3 haloalkyl; and
5 n is an integer selected from 1 to 3.
[Claim 31
The compound, the isomer thereof, the pharmaceutically acceptable salt
thereof, the prodrug thereof, the hydrate thereof or the solvate thereof according to
10 claim 1,
wherein the compound is selected from a group consisting of
5-adamantan-I -yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-2,4-dihydroxybenzamidel
5-adamantan-I -yl-N-[2-(3,4-dihydroxyphenyl)-ethyl]-2-hydroxy-4-metho~ben
zamide,
15 5-adamantan-I -yl-N-(3,4-dihydroxybenzyl)-2,4-dihydroxybenzamidel
5-adamantan-I -yl-N-(3,4-dihydroxybenzyl)-2-hydroxy-4-methoxybenzamidel
5-adamantan-I -yl-2,4-di hydroxy-N-[2-(4-hydroxypheny1)-ethyl] benzamide,
5-adamantan-? -yl-2-hydroxy-N-[2-(4-hydroxyphenyl)-ethyl]-4-methoxybenza
mide,
20 5-adamantan-1 -yl-N-[2-(4-hydroxyphenyl)-ethyl]-2,4-dimethoxybenzamidel
5-adamantan-1 -yl-N-(2,4-dihydroxybenzyl)-2,4-dihydroxybenzamidel
5-adamantan-I -y\-N-(2,4-dihydroxybenzyl)-2-hydroxy-4-methoxybenzamidel
40
3-adamantan-I -yl-N-(2,4-dihydroxybenzy1)-4-methoxybenzamide,
5-adamantan-I -yl-N-(2,5-dimetho~benzyl)-2,4-dihydroxybenzamidel
5-adamantan-1 -yl-N-(2,5-dihydroxybenzyl)-2,4-dihydroxybenzamide,
5-adamantan-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxybenzamide and
5-adamantan-1 -yl-2,4-dihydroxy-N-(3-hydroxy-5-methoxybenzyl)benzamide.
15 [Claim 41
A composition for skin whitening, comprising the compound, the isomer
thereof, the pharmacel~tically acceptable salt thereof, the prodrug thereof, the
hydrate thereof or the solvate thereof according to any one of claims 1 to 3.
20 [Claim 51
The composition according to claim 4, which comprises the compound, the
4 1
isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the
hydrate thereof or the solvate thereof according to any one of claims I to 3 in an
amount of 0.01-20 wtOh based on the total weight of the composition.
5 [Claim 61
The composition according to claim 4, which is a composition for external
application to skin.
[Claim 71
10 The composition according to claim 4, which is a cosmetic composition.