J6810
FORM - 2
THE PATENTS ACT,
1970 (39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
NOVEL SKIN LIGHTENING AGENTS, COMPOSITIONS
HINDUSTAN LEVER LIMITED, a company incorporated under the Indian Companies Act, 1913 and having its registered office at Hindustan Lever House, 165/166, Backbay Reclamation, Mumbai -400 020, Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed.
1 5 DEC 2006
GRANTED
18-12-2006

WO 2004/052316 PCT7EP2003/013704
The invention relates to cosmetic methods of using 4-. substituted resorcinol derivative compounds and cosmetic 5 compositions including the same, and more specifically 1,3-dithiane resorcinol derivatives, as skin lightening agents.
Many people are concerned with the degree of pigmentation of their skin. For example, people with age spots or freckles
10 may wish such pigmented spots to be less pronounced. Others may wish to reduce the skin darkening caused by exposure to sunlight, or to lighten their natural skin color. To meet this need, -many attempts have been made to develop products that reduce the pigment production in the melanocytes.
15 However, the substances identified thus far tend to have
either low efficacy or undesirable side effects, such as for example toxicity or skin irritation. Therefore, there is a continuing need for new skin lightening agents, with improved overall effectiveness.
20
Resorcinol derivatives have cosmetic skin and hair benefits. Certain resorcinol derivatives, particularly 4-substituted resorcinol derivatives, are useful in cosmetic compositions for skin lightening benefits. Resorcinol derivatives are
25 described in many publications, including Hu et al., U.S. Patent No. 6,132,740; Collington et al., PCT Patent Application WO 00/56702; Bradley et al., European Patent Application EP 1 134 207; Shinomiya et al., U.S. Patent No. 5,880,314; LaGrange et al., U.S. Patent No. 5,468,472;
30 Hiroaki et al., Japanese Patent Application JPll-255638 A2; Torihara et al., U.S. Patent No. 4,959,393; and Japanese
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published patent applications JP 2001-010925 and JP2000-327557. Resorcinol 'derivatives are known compounds and can be readily obtained by various means, including by a method wherein a saturated carboxylic acid and resorcinol are 5 condensed in the presence of zinc chloride, and the resultant condensate is reduced with zinc amalgam/hydrochloric acid {Lille, et al., Tr. Nauch-Issled. Inst. Slantsev 1969, No. 18:127-134), or by a method wherein resorcinol and a corresponding alkyl alcohol are reacted in the presence of an 10 alumina catalyst at a high temperature of from 200 to 400°C (British Patent No. 1,581,428). However, some of these compounds- can be irritating to the skin.
The applicants have now discovered novel 1,3-dithiane 15 resorcinol compounds, which possess skin lightening benefits. The general chemical formulas and structures of these compounds are discussed in more detail herein below. The 1,3- dithiane resorcinols have been found to be effective and possibly less irritating .to the skin, and are novel compounds 20 that have not been used for lightening skin.
In another aspect, the present invention relates to an inventive process for making the novel compounds of the present invention. 25
Compounds of the general formula I, and compositions including the same, deliver skin lightening benefits with potential reduced irritation. The present invention provides a cosmetic composition and method of skin lightening using, 30 in addition to a cosmetically acceptable vehicle, about
0.000001 % to about 50 % of a compound of general formula I,
3

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(I)

wherein: 10
each A1 and/or A2 independently is = H or COR (acyl group), CO2R, CONHR having the following formula A:
0 0 0
15 1L il 11
-CR, -COR, -CNHR
where R= C1-C18 saturated or unsaturated, linear or branched, 20 hydrocarbon;
each Y1 and/or Y2 independently is H; C1-C18 saturated or unsaturated hydrocarbon; or 02, where Z = H or COR , CO2R1 ,
CONHR of formula B:
25
0 0 ,0 (B)
-OR1, -C0R1 -CNHR1
and where R = C1-C18 saturated or unsaturated, linear or 30 branched, hydrocarbon;

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^
X is carbon, nitrogen, sulphur, or oxygen; preferably, carbon; and
N is in integer between 0 and 2.
When N = 0 (zero), X is disregarded, so that the dithiane structure is a 5-member ring, and the compound has the general formula II:


10
15

(II)

20

In a preferred embodiment, each or both A1 and/or A2
represents H and each Y1 and/or Y2 represents H. In a more
preferred embodiment, N is zero; both Ai and A2 represent H,
and both Y1 and Y2 represent H, so that the compound is of formula III as follows:

25
30

(III)

5

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In another aspect, the present invention relates to an inventive process for making the novel compounds of the present invention. The compounds of formula I, II and III are prepared by reacting 2,4-dihydroxy benzaldehyde with 5 1,2-Dimercaptoethane, 1.3-Diiaercaptopropane or 1,4-
dimercaptobutane, respectively, in the presence, of an acid catalyst such as methane sulfonic acid, p-toluene sulfonic acid, sulfuric acid, hydrochloric acid, acidic resins and mixtures thereof. Optionally, the hydroxy groups may be
10 further substituted by methods known in the art. For
example, the one or both hydroxy groups may be esterified with any or a combination of the following acids: ferulic acid, vanillic acid, sebacic acid, azaleic acid, benzoic acid, caffeic acid, coumaric acid, salicylic acid, cysteine,
15 cystine, lactic acid, and glycolic acid.
Further skin benefit agents may be included in the compositions useful for the inventive method. Organic and inorganic sunscreens may also be included. 20
The inventive compositions and methods have effective skin lightening properties, may be less irritating to the skin, and are cost-effective to prepare commercially.
25 As used herein, the term "cosmetic composition" is intended to describe compositions for topical application to human skin.
The term "skin" as used herein includes the skin on the face, 30 neck, chest, back, arms, axilla, hands, legs, and scalp.

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Except in the examples, or where otherwise explicitly indicated, all numbers in this description indicating amounts of material or conditions of reaction, physical properties of materials and/or use are to be understood as modified by the 5 word "about". All amounts are by weight of the composition, unless otherwise specified.
It should be noted that in specifying any range of concentration, any particular upper concentration can be 10 associated with any particular lower concentration.
For the avoidance of doubt the word "comprising" is intended to mean including but not necessarily consisting of or composed of. In other words the listed steps or options need 15 not be exhaustive.
The invention is concerned with compounds of general formula I, shown below,, compositions including the same, processes for making the same, and uses thereof as skin lightening
20 agents. A particular advantage of the inventive compounds,
compositions and methods is that compounds of general formula I can be less irritating to the skin than other known skin lightening compounds. The present invention provides a cosmetic composition and method of skin lightening using in
25 addition to a cosmetically acceptable vehicle, about
7
30

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0.000001 % to about 50 % of a compound of formula I,

(I)
5
wherein:
10 Ax^
each A1 and/or A2 independently is = H or COR, CO2R ,CONHR,
the latter three having the following formula A;
15
0 0 0
II II
-CR, -COR -CNHR
(A)
where R= C1-C18 saturated or unsaturated, linear or branched, 20 hydrocarbon; and
each Y1 and/or Y2 independently is H; C1-C18 saturated or
1 1 unsaturated hydrocarbon; or OZ, where Z = H or COR , CO2R ,
CONHR1 of formula B:
(B)
25 0 0 0
-CR1, -COR1 -CNHR1
and where R = C1-C18 saturated or unsaturated, linear or
branched, hydrocarbon; 30

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X is carbon, nitrogen, sulphur, or oxygen; preferably, carbon; and
N is in integer between 0 and 2.
When N = 0, X is disregarded, so that the dithiane structure is a 5-member ring, and the compound has the general formula II:


10
15

(ID

20
- 25

In a preferred embodiment, each or both A1 and/or A2
represents H and each Y1 and/or Y2 represents H. In a more
preferred embodiment, both A1 and A2 represent H, and both Y1
and Y2 represent H, so that the compound is of formula II as follows:

(III)

In the compound of general formula III, optionally, the 30 hydroxy groups (the hydrogen on one or both of the OH-groups)
9

PCT/EP2003/013704
may be further substituted by methods known in the art. For example, the one or both hydroxy groups may be esterified with any or a combination of the following acids; ferulic acid, vanillic acid, sebacic acid, azaleic acid, benzoic 5 acid, caffeic acid, coumaric acid, salicylic acid, cysteine, cystine, lactic acid, and glycolic acid.
Examples
10 Synthetic Processes
Thioacetalyzation of 2,4-Dihydroxybenzaldehyde
Alkyldithiol (1.2 eg) is added to a solution of 2,4-15 dihydroxybenzaldehyde (1.0 eq) and p-toluenesulfonic acid
monohydrate (0.1 eq) in tetrahydrofuran (0.4-0.5 M solution) at room temperature under a nitrogen atmosphere. Magnesium sulfate (1.0 weight eq) is added, and the reaction monitored by TLC until there is complete consumption of 2,4-20 dihydroxybenzaldehyde. The mixture is partitioned between ethyl acetate:saturated sodium bicarbonate, the organic layer washed with saturated sodium chloride and the solvent removed under reduced pressure. The crude material is purified by flash chromatography to afford pure product. 25
30

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Synthesis of 4-[2'{l' ,3' -dithiacyclohexy) 3-1,3-dihydroxybenzene



HS SH
THF, TsOH (cat) MgS04 R.T., 4h

(IV)

5 1,3-propanedithiol (872 uL; 8.69 mmol) was added to a
solution of 2,4-dihydroxybenzaldehyde (l.Og; 7.24 mmol) and p-toluenesulfonic acid monohydrate (140 mg; 0.72 mmol) in tetrahydrofuran (15 ml) at room temperature (R.T. of about 20°C to about 25°C) under a nitrogen atmosphere. After 10 10 minutes, magnesium sulfate (l.Og) was added, and the mixture stirred for 2 hours, at which point TLC (1:1 ethyl
acetate:hexanes) showed the clean formation of product (Rf =
0.37) and no starting aldehyde (Rf = 0.52). The mixture was
poured into ethyl acetate:saturated sodium bicarbonate 15 (25ml:25ml), the organic layer washed with saturated sodium chloride (2 X 25ml) and the solvent removed under reduced pressure to give a white solid. The crude product was washed with toluene (3X30ml) and purified by flash chromatography (silica gel; 1:1 ethyl acetaterhexanes) to 20 give pure product as a white solid (1.35g; 95 % yield).
11

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Synthesis of 4-[2' -d' ,3' -dithiacyclopenty) ]-l,3-dihydroxybenzene



HS SH
■>-
THF, TsOH (cat) MgS04 R.T.,4h

(III-A)

5 1,2-ethanedithiol (818 pi; 9.72 mmol) was added to a
• solution of 2,4-dihydroxybenzaldehyde (l.Og; 7.24 mmol) and. p-toluenesulfonic acid monohydrate (140 mg; 0.72 mmol) in tetrahydrofuran (15 ml) at room temperature under a nitrogen atmosphere. After 20 minutes, magnesium sulfate (l.Og) was 10 added, and the mixture stirred for 4 hours, at which point TLC (1:1 ethyl acetate:hexanes) showed the clean formation
of product (Rf - 0.42) and no starting aldehyde (Rf = 0.51).
The mixture was poured into ethyl acetate:saturated sodium bicarbonate (25ml:25ml), the organic layer washed with
15 saturated sodium chloride (2 X 25 ml) and the solvent
removed under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography (silica gel; 1:1 ethyl acetate:hexanes) to afford pure product as a faint pale yellow oil (1.40g; 90 %).
20 12

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Synthesis of 4- [2r - (lr , 3' -dithiacyclohepty) ] -1,3» dihydroxybenzene



THF, TsOH (cat) MgS04 R.T., 4h

(V)
10
1,4-butanedithiol (1.02mL; 8.69mmol) was added to a solution of 2,4-dihydroxybenzaldehyde (lg; 7.24mmol) and p-toluenesulfonic acid monohydrate (140mg; 0.72mmol) in tetrahydrofuran (15ml) at room temperature under a nitrogen atmosphere. After 10 minutes, magnesium sulfate (lg) was added, and the mixture stirred for 2 hours, at which point TLC (1:1 ethyl acetaterhexanes) showed the clean formation of product and no starting aldehyde. The mixture was poured into ethyl acetate:saturated sodium bicarbonate (25ml:25ml), 15 the organic layer washed with saturated sodium chloride (2 X 25ml), and the solvent removed under reduced pressure. The crude material was purified by flash chromatography (silica gel; 1:1 ethyl acetaterhexanes) to give pure product (1.57g, 90%) .
20
Compositions
The compounds of general formula I may be formulated in a cosmetic composition. The inventive compositions and 25 methods have effective skin lightening properties, may be
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WO 2004/052316 PCT/EP2003/013704
less irritating to the skin than other skin lightening actives, and are...relatively easy to manufacture and cost-effective.
5 The compositions generally contain about 0.000001 % to about 50 % of compounds of general formula I and/or II. Compounds of formula II are preferred. The amount of the inventive compound is preferably in the range of about 0.00001 % to about 10 %, more preferably about 0.001 % to about 7 %, most 10 preferably from 0.01 % to about 5 %, of the total amount of a cosmetic composition.
Preferred cosmetic compositions are those suitable for the application to human skin according to the method of the 15 present invention, which optionally, but preferably, include a skin benefit agent in addition to a compound of general formula I.
Suitable additional skin benefit agents include anti-ageing, 20 wrinkle-reducing, skin whitening, anti-acne, and sebum
reduction agents. Examples of these include alpha-hydroxy acids, beta-nydroxy acids, polyhydroxy acids, hydroquinone, t-butyl hydroquinone, vitamin C derivatives, dioic acids (e.g., malonic acid, sebacic acid), retinoids, and 25 resorcinol derivatives other than compound of formula I of the present invention.
The cosmetically acceptable vehicle may act as a dilutant, dispersant or carrier for the skin benefit ingredients in the 30 composition, so as to facilitate their distribution when the composition is applied to the skin.
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The vehicle may be aqueous, anhydrous or an emulsion. Preferably, the compositions are aqueous or an emulsion, especially water-in-oil or oil-in-water emulsion, preferably 5 oil in water emulsion. Water when present will typically be in amounts which may range from 5 % to 99 %, preferably from 20 % to 70 %, optimally between 40 % and 70 % by weight.
Besides water, relatively volatile solvents may also serve as 10 carriers within compositions of the present invention. Most preferred are monohydric C3.-C3 alkanols. These include ethyl alcohol, methyl alcohol and isopropyl alcohol. The amount of monohydric alkanol may range from 1 % to 70 %, preferably from 10 % to 50 %, optimally between 15 % to 40 % by weight.
Emollient materials may also serve as cosmetically acceptable carriers. These may be in the form of silicone oils and synthetic esters. Amounts of the emollients may range anywhere from 0.1 % to 50 %, preferably between 1 % and 20 % 20 by weight.
Silicone oils may be divided into the volatile and non¬volatile variety. The term "volatile" as used herein refers to those materials which have a measurable vapor pressure at
25 ambient temperature. Volatile silicone oils are preferably
chosen from cyclic or linear polydimethylsiloxanes containing from 3 to 9, preferably from 4 to 5, silicon atoms. Linear volatile silicone materials generally have viscosities less than about 5 centistokes at 25°C while cyclic materials
30 typically have viscosities of less than about 10 centistokes. Non-volatile silicone oils useful as an emollient material
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include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers. The essentially non-volatile polyalkyl siloxanes useful herein include, for example, polydimethyl siloxanes with viscosities of from about 5 to 5 about.25 million centistokes at 25°C. Among the preferred non-volatile emollients useful in the present compositions are the polydimethyl siloxanes having viscosities from about 10 to about 400 centistokes at 25°C.
10 Among the suitable ester emollients are:
(1) Alkenyl or alkyl esters of fatty acids having 10 to
20 carbon atoms. Examples thereof include
isoarachidyl neopentanoate, isononyl isonanonoate,
15 oleyl myristate, oleyl stearate, and oleyl oleate.
(2) Ether-esters such as fatty acid esters of
ethoxylated fatty alcohols.
20 (3) Polyhydric alcohol esters. Ethylene glycol mono and di-fatty acid esters, diethylene glycol mono-and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters,
25 polypropylene glycol 2000 monooleate, polypropylene
glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty esters, ethoxylated glyceryl mono-stearate, 1,3-butylene
30 glycol monostearate, 1,3-butylene glycol
distearate, polyoxyethylene polyol fatty acid

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ester, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyhydric alcohol esters.
5 (4) Wax esters such as beeswax, spermaceti, myristyl
myristate, stearyl stearate and arachidyl behenate.
(5) Sterol esters, of which cholesterol fatty acid esters are examples. 10
Fatty acids having from 10 to 30 carbon atoms may also be included as cosmetically acceptable carriers for compositions of this invention. Illustrative of this category are pelargonic, lauric, myristic, palmitic, stearic, isostearic, 15 hydroxystearic, oleic, linoleic, ricinoleic, arachidic, behenic and erucic acids.
Humectants of the polyhydric alcohol-type may also be employed as cosmetically acceptable carriers in compositions of this
20 invention. The humectant aids in increasing the effectiveness of the emollient, reduces scaling, stimulates removal of built-up scale and improves skin feel. Typical polyhydric alcohols include glycerol, polyalkylene glycols and more preferably alkylene polyols and their derivatives, including
25 propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof. For best results the. humectant is
30 preferably propylene glycol or sodium hyaluronate. The amount
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of humectant. may...range,anywhere from 0.5 % to 30 %, preferably between 1 % and 15 % by weight of the composition.
Thickeners may also be utilized as part of the cosmetically 5 acceptable carrier of compositions according to the present invention. Typical thickeners include crosslinked acrylates (e.g. Carbopol 982), hydrophobically-modified acrylates (e.g. Carbopol 1382), cellulosic derivatives and natural gums. Among useful cellulosic derivatives are sodium
10 carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose and hydroxymethyl cellulose. Natural gums suitable for the present invention include guar, xanthan, sclerotium, carrageenan, pectin and combinations of these gums. Amounts
15 of the thickener may range from 0.0001 % to 5 %, usually from 0.001 % to 1 %, optimally from 0.01 % to 0.5 % by weight.
Collectively the water, solvents, silicones, esters, fatty acids, humectants and/or thickeners will constitute the 20 cosmetically acceptable carrier in amounts from 1 % to 99.9 %, preferably from 80 % to 99 % by weight.
An oil or oily material may be present, together with an emulsifier to provide either a water-in-oil emulsion or an 25 oil-in-water emulsion, depending largely on the average hydrophilic-lipophilic balance (HLB) of the emulsifier employed.
Surfactants may also be present in cosmetic compositions of 30 the present invention. Total concentration of the surfactant will typically range from 0.1 % to 40 %, preferably from 1 %
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to 20 %, optimally from 1 % to 5 % by weight of the composition. The surfactant may be selected from the group consisting of anionic, nonionic, cationic and amphoteric actives. 5
Particularly preferred nonionic surfactants are those with a
C10-C20 fatty alcohol or acid hydrophobe condensed with from 2
to 100 moles of ethylene oxide or propylene oxide per mole of
hydrophobe; C2-C10 alkyl phenols condensed with from 2 to 20
10 moles of alkylene oxide; mono- and di- fatty acid esters of
ethylene glycol; fatty acid monoglyceride; sorbitan, mono- and
di- C8-C20 fatty acids; block copolymers (ethylene
oxide /propylene oxide); and polyoxyethylene sorbitan as well as combinations thereof. Alkyl polyglycosides and saccharide 15 fatty amides (e.g. methyl gluconamides) are also suitable nonionic surfactants.
Preferred anionic surfactants include soap, alkyl ether sulfate and sulfonates, alkyl sulfates and sulfonates, 20 alkylbenzene sulfonates, alkyl and dialkyl sulfosuccinates,
C8-C20 acy1 isethionates, acyl glutamates, C8-C20 alkyl ether phosphates and combinations thereof.
In the cosmetic compositions of the invention, there may be
25 added various other optional components such as thickeners,
calamine, pigments, antioxidants, and chelating agents; as
well as sunscreens, including organic and/or inorganic
sunscreens.
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Other adjunct minor components may also be incorporated into the cosmetic compositions. These ingredients may include coloring agents, opacifiers, and perfumes. Amounts of these . other adjunct minor components may range anywhere from 0.001 5 % up to 20 % by weight of the composition.
For use as sunscreens, metal oxides may be used alone or in mixture and/or in combination with organic sunscreens. Examples of organic sunscreens include but are not limited 10 those set forth in the table below:
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TABLE 1. Typical Organic Sunscreens

CTFA Name

Trade Name

Supplier

4-lsopropyl dibenzoyi methane EUSOLEX 8020
Butyl methoxy dibenzoyi methane PARSOL 1789
Etocrylene UVINUL N-35
10
15
20
25
30

Benzophenone-3 Chemical Co.
Benzophenone-8
DEA
Methoxycinnamate
Ethyl dihydroxypropyl-PABA
Glyceryl PABA
Homosalate
Methyl anthranilate
Octocrylene
Octyl dimethyl PABA
Octyl methoxycinnamate
Octyl salicylate
PABA
2-Phenylbenzimidazole-5-
suiphonic acid
TEA salicylate
3-(4-methylbenzyIidene)
-camphor
Benzophenone-1 Benzophenone-2 Benzophenone-6 Benzophenone-12

UVINUL M-40
UVMUL MS-40 SPECRA-SORB UV-24
BERNEL HYDRO AMERSCREEN P NIPA G.M.P A KEMESTER HMS SUNAROME UVA ' UVINUL N-539 AMERSCOL PARSOL MCX SUNAROME WMO PABA
EUSOLEX 232 SUNAROMEW
EUSOLEX 6300
UVINUL 400 UVINUL D-50 UVINUL D-49 UVINUL 408

BASF
BASF Ohemca) Co. American Cyanamide
Bernel Chemical Amerchol Corp. Nipa Labs. Hunko Chemical Felton Worldwide BASF Chemical Co. Amerchol Corp. Bemel Chemical Felton Worldwide National Starch
EM Industries Felton Worldwide
EM Industries
BASF Chemical Co. BASF Chemical Co. BASF Chemical Co. BASF Chemical Co.
EM Industries Givaudan Corp. BASF Chemical Co.

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The amount of the organic sunscreens in the cosmetic composition is preferably in the range of about 0.1 wt % to about 10 wt %, more preferably about 1 wt % to 5 wt %.
5 Preferred organic sunscreens are PARSOL MCX and Parsol 1789, due to their effectiveness and commercial availability.
Perfumes are fragrance compositions that are mixtures of components providing, usually, a pleasing sense of smell. 10 Terpenes and terpene derivatives are often an important
component of fragrances. Fragrance terpenes and derivatives are described in Bauer, K., et al., Common Fragrance and Flavor Materials, VCH Publishers (1990).
15 Terpenes and derivatives that may preferably be incorporated in the inventive cosmetic compositions are divided into three classes, including acyclic terpenoids, cyclic terpenoids, and cycloaliphatic compounds that are structurally related to terpenoids.
20
Terpene derivatives within each of the three classes include alcohols, ethers, aldehydes, acetals, acids, ketones, esters, and terpene compounds that contain heteroatoms such as nitrogen or sulfur.
25
Examples of terpenes and derivative that may be incorporated in the cosmetic compositions of the present invention are set forth in the tables below:
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TABLE 2. Acyclic Terpenes and Derivatives
HYDROCARBONS Myrcene Ocimene beta-Famesene

ALCOHOLS
Dihydromyrcenol 10 Geraniol
Nerol
Linalool
Myrcenol
Lavandulol 15 Citronellol
Trans-irans-Famesol
Trans-Nerolidol

(2,6-dimethyl-7-octen-2-ol) (3,7-dimethy!-trans-2,6-octadlen-1 -ol) (3,7-dimethyl-cis-2,6-octadien-1 -ol) (3,7-dimethyl-1 ,6-octadien-3-ol) (2-metiiyl-6-methylene-7-octen-2-ol)
(3,7-dimethyl-6-octen-1 -ol)
(3,7,11-trimethyl-2,6,10-dodecatrien-1-ol)
(3,7,11-trimethyl-1,6,10-dodecatrien-3-ol)

20

ALDEHYDES AND ACETALS
Citral (3,7-dimethyl-2,6-octadien-1-al)
Citral diethyl acetal (3,7-dlmethyl-2,6-octadien-1-al djethyl acetal)
Citronellal (3,7-dimethyl-6-octen-1-al)
Citronellyloxyacetaldehyde
2,6,10-Trimethyl-9-undecenal

25

KETONES Tagetone Solanone Geranylacetone

(6,10-dime1hyl-5,9-undecadien-2-one)

30

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TABLE 2. Acyclic Terpenes and Derivatives (cont'd)
ACIDS AND ESTERS C/s-Geranic acid 5 Citronelllc acid
Geranyl Esters, including Geranyl formate, Geranyl acetate, Geranyl propionate, Geranyl isobutyrate, Geranyl isovalerate Neryl Esters, including Neryl acetate
Linalyl Esters, including Lynalyl formate, Linalyl acetate, Linalyl propionate,
10 Linalyl butyrate, Linalyl isobutyrate,
Lavandulyl Esters, including Lavenduryl acetate
Citronellyl Esters, including Citroneliyi formate, Citronellyl acetate, Citronellyl propionate, Citronellyl isobutyrate, Citronellyl isovalerate, Citronellyl tigiate
15 NITROGEN CONTAINING UNSATURATED TERPENE DERIVATIVES C/s-Geranic acid nitrite Citronellic acid nitrile
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TABLE 3. Cyclic Terpenes and Derivatives

(1,8-p-menthadiene)
(1,4-p-menthadiene)
(1,5-p-menthadiene)
(2-pjnene) (2(10)-pinene)
HYDROCARBONS
Limonene 5 Alpha-Terpinene
Gamma-Terpinene
Terpinolene
Alpha-Phellandrene
Beta-Phellandrene 10 Alpha-Pinene
Beta-Pinene
Camphene
3-Carene
Caryophyflene 15 (+)-Valencene
Thujopsene
Alpha-Cedrene
Beta-Cedrene
Longifolene
20
ALCOHOLS AND ETHERS
(8-p-menten-3-ol) (1-p-menten-8-oI)
(+)-Neoiso-isopulegol
Isopulegol
Alpha-Terpineol
25 Beta-Terpineol
Gamma-Terpineol
Delta-Terpineol
(1-p-menten-4-ol)
1-Terpinen-4-ol

25

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.

TABLE 3. Cyclic Terpenes and Derivatives (cont'd)

(1,8-p-mantadien-6-one) (C13H20O) (C13H20O) (C13H20O)
(C14H22O)
10

ALDEHYDES AND KETONES
Carvone
Alpha-Ionone
Beta-lonone
Gamma-lonone
Irone, alpha-, beta-, gamma-
n-Methylionone, alpha-, beta-, gamma- (C14H22O)
Isomethylionone, alpha-, beta-, gamma- (C14H22O)
Allyllonone (C16H24O)
Pseudoionone
n-Methylpseudoionone
Isomethylpseudoionone

15

Nootkatone
Cedryl methyl ketone
20
25

Damascones 1-{2,6,6-trimethylcyclohexenyl)-2-buten-1-ones
Including beta-Damascenone 1-{2,6,6-trimethyl-1,3-cyclohadienyl>2-buten-1-
one
5,6-dimethyl-8-isopropenylbicyclo[4.4.0]-1-decen-3-one
(C17H260)

ESTERS
30 Alpha-Terpinyl acetate
Nopyl acetate acetate

(1-p-menthen-8-yl acetate) (-)-2-(6,6-dimethylbicyclo[3.1.1 ]hept-2-en-2-yl)ethyl

35 Khusymil acetate

26

WO 2004/052316 PCT/EP2003/013704
TABLE 4. Cycloallpnatic Compounds Structurally Related to
Terpenes
5
ALCOHOLS
5-(2,2,3-Trimethyl-3-cyc!openten-1-yl)-3-methylpentan-2-ol
ALDEHYDES 10 2,4-DimethyI-3-cyclohexene carboxaldehyde
4-(4-Methyl-3-penten-1-yl)-3-cyclohexene carboxaldehyde 4-(4-Hydroxy-4-methypentyl)-3-cyc!ohexene carboxaldehyde
KETONES 15 Civetone
Dihydrojasmone (3-methyI-2-pentyl-2-cyclopenten-1 -one)
Cis-Jasmone 3-methyl-2-{2-c/s-penten-1-yl)-2-cyc)openten-1-one
5-Cyclohexadecen-1-one
2,3,8,8-Tetramethyl-1>2,3,4>5,6,7,8-octahydro-2-napthalenyl methyl ketone 20 3-methyl-2-cyclopentei>2-oM-one
ESTERS
4,7-Methano-3a,4,5,6,7,7a-hexahydro-5-(or 6)-indenyl acetate Allyl 3-cyclohexylpropionate 25 Methyl dlhydrojasmonate methyl (3-oxo-2-pentylcyclopentyl)acetate
Preferably, the amount of terpenes and derivatives in the cosmetic composition is in the range of about 0.000001 % to about 10 %, more preferably about 0.00001 % to about 5 wt %, 30 most preferably about 0.0001 % to about 2 %.
27

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The method according to the invention is intended primarily as using a personal care product for topical application to human skin.
5 In use, a small quantity of the composition, for example from 1 to 5 ml, is applied to exposed areas of the skin, from a suitable container or applicator and, if necessary, it is then spread over and/or rubbed into the skin using the hand or fingers or a suitable device.
10
The cosmetic composition useful for the method of the invention can be formulated as a lotion having a viscosity of from 4,000 to 10,000 mPas, a fluid cream having a viscosity of from 10,000 to 20, 000 mPas or a cream having a
15 viscosity of from 20,000 to 100,000 mPas, or above, as measured at 25°C. The composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer. For example, a lotion or fluid cream can be packaged in a bottle or a roll-ball applicator or a
20 propellant-driven aerosol device or a container fitted with a pump suitable for finger operation. When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar. When the composition is a solid or semi-solid stick, it may
25 be packaged in a suitable container for manually or
mechanically pushing out.or extruding the composition.
The invention accordingly also provides a closed container containing a cosmetically acceptable composition as herein 30 defined.
28

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The following examples are by way of example, not by way of limitation, of the principles of the present invention, to illustrate the best mode of carrying out the invention.
5 Example 1
Procedure for making 1,3-dithiane resorcinol
The compound of formula III was prepared in accordance with 10 the process discussed hereinbelow and used throughout the examples that follow:


15

(III)

20 In a most preferred embodiment designated by the compound of formula III, N is zero; both A1 and A2 represent OH, both Y1
and Y2 represent H, because it is most cost-effective to manufacture. This most preferred embodiment, referred to herein as 1,3-dithiane resorcinol, may be prepared by
25 reaction of 2,4-dihydroxy benzaldehyde and 1,3-
Dimercaptoethane (both starting materials are available from Yick-Vic Chemicals & Pharmaceuticals (HK) Ltd/ Hong Kong), denoted by-the following formula III and catalyzed by an acid catalyst. Suitable catalysts include but are not
30 limited to methane sulfonic acid, p-toluene sulfonic acid,
29

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H2SO4 (sulfuric acid)/ HCl (hydrochloric acid) and acidic resins.
A three necked flask equipped with a Dean-Stark apparatus, 5 an additional funnel and a condenser is charged with 2, 4-dihydroxy benzaldehyde (1 equ.). To this was added toluene (500ml) and a catalytic amount of p-toluene sulfonic acid. The mixture was heated at 120°C. One equivalent of 1,3-dithioethane in toluene (100ml) was added drop-wise to the 10 mixture. The mixture was stirred at reflux up to 12 hours. The solvent was removed on a Rotavap, and the expected product was isolated. The structure of the dithiane was confirmed using mass spectroscopy, NMR and IR.

15 0H OH
HSCH2CH2SH
20
tohiene/-H20

(III-B)

25

SO

WO 2004/052316 PCT7EP2003/013704
Example 2
Cosmetic compositions within the scope of the invention were . prepared. 5
A base formulation shown in Table 3, below, was made by heating phase A ingredients to 70 to 85°C with stirring. Phase B ingredients were heated in a separate container to 70 to 85°C with stirring. Then, phase A was added into 10 phase B while both phases were kept at 70 to 85 °C. The
mixture was stirred for at least 15 minutes at 70 to 85°C then cooled.
A base formulation is shown in the table below.


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10

TABLE 5
a b
Inaredients %wt %wt Phase
Isostearyl Palmitate 6.00 6.00 A
C12-C15Alkyl Octanoate 3.00 3.00 A
PEG-100Stearate 2.00 2.00 A
Glyceryl Hydroxystearate 1.50 1.50 A
Stearyl Alcohol 1.50 1.50 A
Stearic acid 3.00 4.00 A
TEA, 99% 1.20 1.20 B
Dimethicone 1.00 1.00 A
Sorbitan Monostearate 1.00 1.00 A
Magnesium Aluminum Silicate 0.60 0.60 B
Vitamin E acetate 0.10 0.10 A
Cholesterol 0.50 0.50 A
Simethicone 0.01 0.01 B
Xanthan gum 0.20 0.20 B
Hydroxyethylcellulose 0.50 0.50 B
Propylparaben 0.10 0.10 B
Disodium EDTA 0.05 0.05 B
Butylated hydroxytolene 0.05 0.05 B
Compound of Formula III 0.05 2.00 B
Niacinamide 1.00 1.00 B
Metal oxide 2.50 5.00 B
Methylparaben 0.15 0.15 B
Water BAL* BAL* B
Total 100.00 100.00 B
*BAL means Balance.
Example 3
Additional cosmetic compositions within the scope of the invention were prepared.
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TABLE 6

Wt% Phase
water, Dl BALANCE A
disodium EDTA 0.05 A
magnesium aluminum silicate 0.6 A
methyl paraben 0.15 A
simethicone 0.01 A
butylene glycol 1,3 3.0 A
hydroxyethylcellulose 0.5 A
glycerine, USP 2.0 A
xanthan gum 0.2 A
triethanolamine 1.2 B
stearic acid 3.0 B
propyl paraben NF 0.1 B
glyceryl hydroxystearate 1.5 B
stearyl alcohol 1.5 B
isostearyl paimltate 6.0 B
C12-15 alcohols octanoate 3.0 B
dimethicone 1.0 B
cholesterol NF 0.5 B
sorbftan stearate 1.0 B
Micronlzed titanium dioxide 5.0 C
tocopheryl acetate 0.1 B
PEG-100 stearate 2.0 B
sodium stearoyl iactylate 0.5 B
hydroxycaprylic acid 0.1 C
Compound of Formula III 10.0 C
PARSOL MCX 2.4 C
alpha-bisabolol 0.2 C
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The composition of Example 3, was prepared as follows:
1. Heat Phase- A to 80°C
2. Heat Phase B to 75°C in a separate container
3. Add B to A and mix with heat off for 30 mins.
5 4. At 50°C add Phase C and mix for 10 mins.
Examples 4-11
A set of additional compositions useful in the methods of 10 the present invention were prepared within the scope of the present invention, and are listed in the table below.

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TABLE 7

Ingredients Phase Examples (wt %)
4 acid soap base 5 6 7 8 9 10 11
Stearic acid A 17.9 17.9 17.9 17.9 17.9 17.9 17.9 17.9
Sodium cetearyi sulfate* (emulsifier) A 2.2 1 1.5 2 3 2
Myrj59* (emulsifier) A 2 2 2 2 2 1
Span 60* (emulsifiers) A 2 2 2 2 2 1
Compound of Formula III B 0.05 0.05 2.0 2.0 3.5 3.5 5.0 10.0
Micronized Zinc Oxide B 2.50 5.00 5.00 2.50 2.50 5.00 2.50 5.00
KOH, 22% (form in situ soap with stearic acid) 2.20
Octyl methoxycinnamate 2.50 2.50 2.50 2.50
Water B BAL BAL BAL BAL BAL BAL BAL BAL
Glycerin |B 1 1 1 1 1 1 1 1
5 EXAMPLE 12 - Mushroom Tyrosinase Assay
Mushroom tyrosinase inhibition is indicative of reduction in melanin synthesis, thereby showing skin lightening effect. This experiment shows the efficacy of resorcinol derivatives 10 of the present invention.
Into- each well of a 96-well plate, 150 microliters of phosphate buffer (100 mM, pH 7.0), 10 microliters of L-DOPA (L-3, 4-Dihydroxyphenylalanine, 10 mM), and 20 microliters 15 of skin lightening agent (dissolved in ethanol, which is the
35"

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control) were added. Following an initial measurement of background absorbency at 475-nm 20 microliters of mushroom tyrosinase (Sigma T-7755; 6050 units/ml) was added and incubated at room temperature. 5
Absorbency is read at 475-nm over the following time points; 0, 2, 4, and 6.5 minutes. The data is plotted as 475-nm absorbency vs. time (minutes) and the slope of the line is calculated (AAbs 475nm/ min). In the Table below, data is 10 shown in terms of IC50, which is the concentration of active needed to reduce tyrosinase synthesis by 50 % versus the untreated ethanol control reaction.
TABLE 8. Mushroom Tyrosinase Assay Results
15
Compound IC50 (Concentration) Experiment 1 IC50 (Concentration) Experiment 2
4-Ethyl Resorcinol (Positive Control) 550 nano-M 400 nano-M
6-member Di-Thianyl Resorcinol 1.7 micro-M 1.0 micro-M
5-member Di-Thianyl Resorcinol 3.8micro-M 2.5 micro-M
The data show that the inventive compounds are substantially as effective or slightly less effective than 4-ethyl 20 resorcinol, both compounds having good skin lightening
effects. An advantage of the inventive compounds is that § they are relatively easy and cost-effective to manufacture^
It should be understood that the specific forms of the § 25 invention herein illustrated and described are intend*'
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representative only, changes, including but not limited to those suggested in this specification, may be made in the illustrated embodiments without departing from the clear teachings of the disclosure. Accordingly, reference should be made to the following appended claims in determining the full scope of the invention.

We claim:

1. A cosmetic composition comprising :
a. about 0.000001% to about 50% of a compound of general formula I

X

wherein
each A, and/or A2 independently is = H, COR, C02R, CONHR where R = C1 - C18 saturated or unsaturated hydrocarbon; and each Yi and/or Y2 independently is H, C1 - C18 saturated or unsaturated hydrocarbon, or OZ where Z = H, COR1, CO2R1 CONHR1 and wherein R1 = C1 - C18 unsaturated or saturated hydrocarbon; X is carbon, nitrogen, sulphur or oxygen; N is an integer between 0 and 2; and
b. a cosmetically acceptable carrier.
2. The cosmetic composition of claim 1, wherein the said compound is a compound of general formula II:

(II)

38

3. The cosmetic composition of claim 1 or claim 2, wherein the said compound is a
compound of formula III:
N
■(III)
4. The cosmetic composition of any of claims 1 to 3, wherein the compound
comprises about 0.00001% to about 10% of the composition.
5. The cosmetic composition of any of claims 1 to 4, optionally comprising a
sunscreen.
6. The cosmetic composition of any of the claims 1 to 5, wherein the hydroxy groups of the compound are esterified with an acid selected from ferulic acid, vanillic acid, sebacic acid, azaleic acid, benzoic acid, caffeic acid, coumaric acid, salicylic acid, cysteine, cystine, lactic acid, glycolic acid and mixtures thereof.
7. A compound of general formula II

39
wherein

each A1 and/or A2 independently is = H, COR, C02R, CONHR where R = C, C18 saturated or unsaturated hydrocarbon; and each Y1 and/or Y2 independently is H, Ci - Cis saturated or unsaturated hydrocarbon, or OZ where Z = H, COR1, C02R1 CONHR1 and wherein R1 = C1 - C18 unsaturated or saturated hydrocarbon. 8. A compound of claim 7, having the formula III:

9. The compound of claims 7 or 8, wherein the hydroxy groups of the compound are esterified with an acid selected from ferulic acid, vanillic acid, sebacic acid, azaleic acid, benzoic acid, caffeic acid, coumaric acid, salicylic acid, cysteine, cystine, lactic acid, glycolic acid and mixtures thereof.
10. A process for synthesizing 4-[2'~(1,3'- dithiacyclopentyl)] - 1, 3 -dihydroxybenzene, 4 - [2' - (1', 3' - dithiacyclohexyl)] - 1, 3 -dihydroxybenzene, 4 - [2' - (1', 3' - dithiacycloheptyl)] - 1, 3 -dihydroxybenzene, or mixtures thereof comprising:
reacting
(a) 2, 4 - dihydroxy benzaldehyde; with
(b) 1, 2 -Dimercaptoethane, 1, 3 - Dimercaptopropane, 1, 4 -Dimercaptobutane, or mixtures thereof, respectively;
40

in the presence of an acid catalyst;
wherein the acid catalyst is selected from methane sulfonic acid, p-toluene
sulfonic acid, sulfuric acid, hydrochloric acid, acidic resins and mixtures thereof.
Dated this 31st day of May 2005
Dr. Sanchita Ganguli Of S Majumdar&Co. Applicant's Agent
41