# Patent

## Title
Organic compounds

## Abstract

The invention relates to organic compounds having the ability to reduce or suppress the onset of skin irritation induced by extraneous cause selected from the group of 2-heptylcyclopentanone, 2-ethoxynaphthalene; 2-methoxynaphthalene; 1-methoxy-4-(prop-1-enyl)benzene; 1-(cyclopropylmethyl)-4-methoxybenzene;




    
    
        wherein X, Y, and R1 to R11 have the same meaning as given in the description.
    
    


Furthermore the invention refers to compositions for topical application to the skin comprising them. It further relates to a method of reducing or suppressing the formation of skin irritation.

## Background
This is a Divisional patent application of copending patent application U.S. Ser. No. 12/066,518, which in turn is a patent application filed under 35 USC 371 of PCT/CH2006/000481.


The present invention relates to organic compounds having the ability to reduce or suppress the formation of skin irritation induced by extraneous causes, and to compositions comprising them for topical application to the skin. It further relates to a method of reducing or suppressing the onset of skin irritation by extraneous causes.
The human skin is constantly exposed to environmental stresses, such as heat and cold, air pollution, exceptionally dry air or exaggerated UV irradiation. A further form of stress can come from the application of cosmetic products or personal wash products.
For example, certain soap acids and some surfactants, in particular anionic and cationic surfactants, are known to stress the skin. Antiperspirant salts, such as aluminum salts and zirconium salts contained in antiperspirant products, retinol and derivatives thereof contained in anti-aging products, α-hydroxy acids such as glycolic acid or lactic acid contained in anti-wrinkle products are also known to stress the skin.
It is known from the art that prostaglandins are mediators being formed upon a wide variety of different forms of external stress applied to the human skin, which may become apparent in redness of the skin, particularly on normal, healthy skin. Thus there is a need for additives in topical application compositions, such as cosmetic products and personal wash products, which suppress or reduce the formation of prostaglandins, in particular prostaglandin E2 (PGE2).
Surprisingly the inventors have found that certain classes of chemical compounds, most of which are known as fragrance ingredients, have the ability to reduce or suppress the formation of prostaglandins in skin cells.
Thus the present invention refers in one aspect to the use of a compound for the preparation of topical skin care compositions for reduction of skin irritation, wherein the compound is selected from the list consisting of

    
    
        (a) compounds of the formula
    
    






    
    
        
        
            wherein
            R is hydrogen or isopropyl;
            R1 is methyl or ethyl; and R2 is C1-C6 alkyl or C2-C6 alkenyl; or
            R1 and R2 together with the carbon atom to which they are attached form a C5 or
            C6 cycloalkyl ring; and
            the dotted line together with the carbon carbon bond represents a single bond or a double bond;
        
        
        (b) compounds of the formula
    
    






    
    
        
        
            wherein Y is a C4-C7 hydrocarbon residue, e.g. cyclohexyl, n-hexyl, n-pentyl, iso-butyl, cis-3-hexen-1-yl, phenethyl, and 1-methyl-hex-3-en-1-yl;
        
        
        (c) compounds of the formula
    
    






    
    
        
        
            wherein
            R4 is methyl or ethyl and
            I) R3 is hydrogen and R5 is —CH2—O—R6, wherein R6 is methyl or isopropyl; or
            II) R3 is —C(O)—R7, wherein R7 is benzyl, and R5 is —CH2—CH═CH2,
        
        
        (d) compounds of the formula
    
    






    
    
        
        
            wherein
            R8 is methyl, C3-C4 alkyl, C3-C4 alkenyl, —(CH2)2-Ph, or —CH═CH-Ph;
            X is —CH═CH—CH2— or —(CH2)n—, wherein n is 1 or 2; and
            R9 is isobutyl or phenylethyl;
        
        
        (e) compounds of the formula
    
    






    
    
        
        
            wherein
            R10 is hydrogen or methyl; and
            R11 is a C3-C4 alkyl, e.g. isopropyl, isobutyl or tert-butyl,
        
        
        and
        (f) 2-heptylcyclopentanone, 2-ethoxynaphthalene, 2-methoxynaphthalene, 1-methoxy-4-(prop-1-enyl)benzene and 1-(cyclopropylmethyl)-4-methoxybenzene.
    
    


Particularly preferred is the use of compounds selected from the list consisting of 2-cyclohexylidene-2-phenylacetonitrile, 2-cyclopentylidene-2-phenylacetonitrile, 3-ethyl-2-phenylpent-2-enenitrile, 2-ethoxy-4-(isopropoxymethyl)phenol, 2-ethoxy-4-(methoxymethyl)phenol, phenethyl cinnamate, 4-allyl-2-methoxyphenyl 2-phenylacetate, n-hexyl salicylate, cis-3-hexen-1-yl salicylate, cyclohexylsalicylate (=cyclohexyl 2-hydroxybenzoate), amylsalicylate (=pentyl 2-hydroxybenzoate), isobutylsalicylate (=isobutyl 2-hydroxybenzoate), phenylethyl benzoate, benzyl 2-methylbut-2-enoate, 2-methyl-3-(4-isopropylphenyl)propanal, isobutyl benzoate, cinnamyl cinnamate, phenethyl salicylate, 2-methyl-3-(4-(2-methylpropyl)phenyl)propanal, 2-heptylcyclopentanone, 2-ethoxynaphthalene, 2-methoxynaphthalene, 1-methoxy-4-(prop-1-enyl)benzene, phenethyl pivalate, 1-(cyclopropylmethyl)-4-methoxybenzene, cinnamyl acetate, 3-(4-tert-butylphenyl)propanal, phenethyl 2-methylbutanoate, and phenethyl isobutyrate.
The availability of a greater number of compounds, which in addition to their odoriferous properties, have the ability to reduce or suppress the formation of skin irritation provides the perfumer with an adequate amount of molecules some of which posses quite varied odor notes, to create hedonically attractive fragrance compositions while providing reduction of skin irritation and/or redness reduction activity to the skin to which it is applied. In particular, the use of multiple perfume ingredients permits the design of hedonically attractive fragrance accords.
The actives for reducing skin irritation as hereinabove described may be combined with all known odorant molecules selected from the extensive range of natural products and synthetic molecules currently available, such as essential oils, alcohols, aldehydes and ketones, ethers and acetals, esters and lactones, macrocycles and heterocycles, and/or in admixture with one or more ingredients or excipients conventionally used in conjunction with odorants in fragrance compositions, for example, carrier materials, and other auxiliary agents commonly used in the art. Such ingredients are, for example, described in “Perfume and Flavor Materials of Natural Origin”, S. Arctander, Ed., Elizabeth, N.J., 1960; “Perfume and Flavor Chemicals”, S. Arctander, Ed., Vol. I & II, Allured Publishing Corporation, Carol Stream, USA, 1994; and “International cosmetic ingredient dictionary” 6th ed., The Cosmetic, Toiletry and Fragrance Association, Inc., Washington, 1995.
While lower concentrations of the active compound show an effect in a cell culture system, as can be seen from the examples, higher concentrations in personal care products are necessary to allow for an effective concentration on the human skin even if, for example part of the product may be removed by abrasion of clothes or may be diluted by sweat. Furthermore, the healthy skin acts as a barrier which limits the penetration of the active compounds. Generally, the concentration of active compound needed for efficaciousness on skin is from about 50 to 100 times higher than that needed in in-vitro tests. The usual perfume concentration in a topical cosmetic product is about 0.3 to 2% by weight. In general, the amount of actives applied is in the range of from 0.2 to 2% by weight, based on the end-product applied to the skin, the amounts applied usually being in the range of from 0.3 to 1% by weight.
Thus the present invention refers in a further aspect to fragrance compositions comprising at least 30 weight % based on the total fragrance composition of at least two actives for reducing skin irritation as hereinabove described.
Whereas some active compounds may be used in relatively high amounts in a fragrance composition others which are known to be very powerful odorants, such as NerolineTM and Propyl Diantilis, may be used only in smaller amounts in order to avoid negatively effecting the overall hedonic impression of the fragrance composition. In general, as the overall proportion of the active compound in the fragrance composition rises, so should the number of active compounds used. For example, a fragrance composition comprising more than 40 weight % of active compounds should preferably contain at least 4 different actives, a fragrance composition comprising more than 50 weight % of active compounds should preferably contain at least 5 different actives, and a fragrance compositions comprising more than 60 weight % of active compounds should preferably contain at least 6 different actives. Thus, in a further aspect the present invention refers to fragrance compositions comprising at least 30 weight % of at least three, four or five actives for reducing skin irritation. Optionally the fragrance composition according to the present invention comprises at least two, three or four actives of which are selected from a different group of compounds, namely group (a), (b), (c), (d), (e), and (f) as hereinabove described.
From a hedonic point of view the actives are selected from two different group of compounds. In particular embodiments are fragrance compositions comprising a compound of formula (a) and a compound of formula (b), and fragrance compositions comprising a compound of formula (c) and a compound of formula (d) or (d′). As can be seen from the examples, fragrance compositions which are both hedonically attractive and which have irritation reducing properties may be prepared, for example, if the composition comprises at least four active compounds, each of which is selected from a different group of compounds.
In an other embodiment the invention is directed to fragrance compositions comprising (a) at least one compound of the formula




    
    
        wherein
        R is hydrogen or isopropyl;
        R1 is methyl or ethyl; and R2 is C1-C6 alkyl or C2-C6 alkenyl; or
        R1 and R2 together with the carbon atom to which they are attached form a C5 or
        C6 cycloalkyl ring; and
        the dotted line together with the carbon carbon bond represents a single bond or a double bond;
    
    


(b) at least one compound of the formula




    
    
        wherein Y is a C4-C7 hydrocarbon residue, e.g. cyclohexyl, n-hexyl, n-pentyl, iso-butyl, cis-3-hexen-1-yl, phenethyl, and 1-methyl-hex-3-en-1-yl;
    
    


(c) at least one compound of the formula




    
    
        wherein
        R4 is methyl or ethyl and
        I) R3 is hydrogen and R5 is —CH2—O—R6, wherein R6 is methyl or isopropyl; or
        II) R3 is —C(O)—R7, wherein R7 is benzyl, and R5 is —CH2—CH═CH2; and
    
    


(d) at least one compound of the formula




    
    
        wherein
        R8 is methyl, C3-C4 alkyl, C3-C4 alkenyl, —(CH2)2-Ph, or —CH═CH-Ph;
        X is —CH═CH—CH2— or —(CH2)n—, wherein n is 1 or 2; and
        R9 is isobutyl or phenylethyl.
    
    


Furthermore, the present invention refers to topical skin care compositions, such as cosmetic products and personal wash products, comprising about 0.2 to about 3 weight %, preferably about 0.5 to about 2.5 weight % of a fragrance composition, the fragrance composition containing at least 30 weight % of at least two actives selected from the group (a), (b), (c), (d), (e), and (f) as hereinabove described, with the proviso that the topical skin care composition comprises at least 0.2 weight % of actives based on the total amount of the skin composition. In particular embodiments are topical skin care compositions wherein the fragrance composition containing a compound of formula (a) and a compound of formula (b), and topical skin care composition wherein the fragrance composition containing a compound of formula (c) and a compound of formula (d) or (d′).
In another aspect the present invention is directed to a method of reducing the onset of skin irritation by applying to the skin an effective amount of a topical skin care composition comprising a fragrance composition, the fragrance composition containing at least 30 weight % based on the total fragrance composition of at least two actives as defined hereinabove, with the proviso that the topical skin care composition comprises at least 0.2 weight % of actives based on the total amount of the skin composition.
An “effective amount” is generally achieved if about 5-50 mg/cm2 skin or about 0.05 to about 0.5 mm thick film of the topical skin product is applied to the skin.
As used within the meaning of the present invention the expression “at least 30 weight %” includes fragrance compositions comprising at least 35, 40 or even 45 or 50 weight % of at least two actives as defined hereinabove. The term “actives” and “active compounds” as used within the meaning of the present invention refers to all compounds selected from the list of compounds of formula (a), (b), (c), (d), (d′), (e) and 2-heptylcyclopentanone, 2-ethoxynaphthalene, 2-methoxynaphthalene, 1-methoxy-4-(prop-1-enyl)benzene and 1-(cyclopropylmethyl)-4-methoxybenzene.
Topical skin care compositions of the present invention may be divided into two classes of products, that is, cosmetic products and topical washing products, and may include but is not limited to antiperspirants, deodorants, day and night creams, shaving products, hand creams, body lotions, hair shampoo and conditioners, lipsticks, after-sun products, hand lotions, foundation creams, moisturizing creams, skin food, skin tonics, skin lightening products and overnight facial masks. The compositions may be in any form. These forms may include lotions, creams, sticks, roll-on formulations, mousses, aerosol sprays, pad-applied formulations, powders, tonics, and emulsions (oil-in-water, water-in-oil, or mixed emulsion systems).
The invention is now further described with reference to the following non-limiting examples. All of the amounts are given as percentage amounts by weight, unless otherwise indicated.


EXAMPLE 1
Screening for Compounds Protecting Keratinocytes Against Irritating Agents
Normal human epidermal keratinocytes (NHEK) were obtained from skin biopsies and maintained as described by Rheinwald and Green (cell, 6:331-344, 1975) in keratinocyte growth medium supplemented with 10% heat inactivated fetal calf serum at a humidity of 98% in a 5% carbon dioxide atmosphere. A confluent culture was trypsinated and adjusted to a density of 5×104 cells/ml. The cells were then seeded in the same medium but with only 1% fetal calf serum in 24 well plates and cultivated for a period of 48 h. A model irritating agent was then applied to the cells by adding calcimycin to a final level of 2.5 μM. The individual compounds, as listed below, dissolved in DMSO were added simultaneously. The final concentration of the compounds was 50 μM or 10 μM, the final DMSO concentration was adjusted to 1% (v/v). Parallel treatments received no calcimycin (non-irritated control) or calcimycin without compounds according to the present invention (irritated control). The DMSO concentration was adjusted to 1% in all these control treatments. After 24 h incubation, the supernatant of the cells was harvested, diluted 1:1 and added to an enzyme linked immunoassay kit for the specific detection of prostaglandin E2 as a marker of cellular irritation (Product #404110, Neogen corporation, Lexington Ky. 40505, USA). The prostaglandin levels in treated cell cultures were compared to the irritated and non-irritated control cultures in order to determine the relative inhibition of PGE2 formation. Results for the individual compounds are listed below.













relative inhibition in %



of PGE2 formation in



keratinocyte cultures at









Compound
50 μM
μM












PEONILE ® (2-cyclohexylidene-2-
93.3
92.4


phenylacetonitrile)


PROPYL DIANTILIS
90.9
95.1


(2-Ethoxy-4-(isopropoxymethyl)phenol)


METHYL DIANTILIS ®
n.d.
88.2


(2-Ethoxy-4-(methoxymethyl)phenol)


Phenethyl cinnamate
91.7
93.6


EUGENYL PHENYL ACETATE
96.6
99


(Phenyl 2-(4-allyl-2-methoxyphenyl)acetate)


n-Hexyl salicylate
82.9
91.6


cis-3-Hexen-1-yl salicylate
94.8
81.4


Cyclohexyl salicylate
97.4
76.6


Amyl salicylate
89.8
73.5


Isobutyl salicylate
69.1
73.1


Phenethyl benzoate
92.4
56.9


TIGLATE BENZYLE (benzyl 2-methylbut-2-
72.4
50.2


enoate)


CYCLAMEN ALDEHYDE TM
82.0
32


(2-Methyl-3-(4-isopropylphenyl)propanal)


Isobutyl benzoate
52.5
n.d.


Cinnamyl cinnamate
64.0
n.d.


Phenethyl salicylate
50.9
n.d.


SILVIAL ® (2-Methyl-3-(4-(2-
62.7
n.d.


methylpropyl)phenyl)propanal)


ALISMONE TM (2-heptylcyclopentanone)
92.4
47


NEROLINE TM CRIST (2-ethoxynaphthalene)
83
50.2


YARA YARA TM (2-methoxynaphthalene)
78
46


ANETHOLE (1-methoxy-4-(prop-1-
51
n.d.


enyl)benzene)


CENTIFOLYL TM (phenethyl pivalate)
39
n.d.


TOSCANOL ® (1-(cyclopropylmethyl)-4-
56.7
n.d.


methoxybenzene)


Cinnamyl acetate
47.8
n.d.


BOURGEONAL TM (3-(4-tert-
65.0
n.d.


butylphenyl)propanal)


ANATOLYL TM (phenethyl 2-
50.5
n.d.


methylbutanoate)


Phenethyl isobutyrate
44.8
n.d.


2-Cyclopentylidene-2-phenylacetonitrile
80.8
71.1


3-Ethyl-2-phenylpent-2-enenitrile
73.2
63.9





n.d. = not determined






Similar results as listed above were obtained by irritation of the cells either by UVB irradiation or exposure to the skin cells to irritating cationic surfactant benzalkonium chloride.
EXAMPLE 2
Fragrance Compositions with the Properties to Reduce or Suppress the Formation of Skin Irritation
2.1 Floral Fragrance Composition No. 1













parts by weight 1/100



















Peonile ®
18.90



Alismone TM
5.30



Cyclohexyl salicylate
12.10



Silvial ®
6.80



Toscanol ®
0.15



Floral fragrance base
56.75










2.2 Floral Fragrance Composition No. 2














parts by weight 1/100



















PEONILE ®
1.00



PROPYL DIANTILIS
0.01



Phenethyl cinnamate
0.20



Hexyl salicylate
40.00



cis-3-Hexen-1-yl salicylate
1.00



Amyl salicylate
3.00



NEROLINE TM
0.10



Floral fragrance base
54.69










2.3 Floral-Fruity Fragrance Composition No. 3














parts by



weight 1/900

















Citronellyl acetate
10


Cyclamen aldehyde TM*
3


Ambrettolide (oxacycloheptadec-10-en-2-one)
40


Ambrofix (CAS No. 6790-58-5) 10% in dipropyleneglycol
8


Bourgeonal TM*
30


Centifolyl TM*
45


Dihydromyrcenol (2,6-dimethyloct-7-en-2-ol)
8


Ethyllinalool (3,7-dimethyl-1,6-nonadien-3-ol)
45


Florol ® (tetrahydro-2-isobutyl-4-methyl-2H-pyran-4-ol)
25


Galaxolide ® (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-
12


hexamethyl-cyclopenta-gamma-2-benzopyran) 50%


dissolved in isopropylmyristate


Hedione ® (methyl 2-(3-oxo-2-pentylcyclopentyl)acetate)
250


Cis-3-hexenol 10% in dipropyleneglycol
3


Phenethyl isobutyrate*
25


Ethyl-2-methyl-butyrate 10% in dipropyleneglycol
3


Neroline TM* 10% in dipropyleneglycol
2


Orange essence brazil
15


Pomarose (5,6,7-trimethylocta-2,5-dien-4-one) 10%
3


in dipropyleneglycol


Prunella ® subst (compounded perfumery
3


base from Firmenich)


Cyclohexyl salicylate*
75


cis-3-Hexen-1-yl salicylate*
100


n-Hexyl salicylate*
20


Phenylethyl salicylate*
80


Silvial ®*
45


Tropional (2-methyl-3-(3,4-methylenedioxyphenyl)-
40


propanal)


Velvione ® (5-cyclohexadecen-1-one)
10





All ingredients marked with an * are active compounds having the ability to reduce or suppress the formation of skin irritation, as defined according to the present invention.


The fragrance composition No. 3 comprises 47 weight % of actives.






2.4 Floral-Fruity Fragrance Composition No. 4














parts by



weight 1/900

















Benzyl-acetate
14


2-Phenylethanol
200


Cyclamen aldehyde TM*
3


Bourgeonal TM*
3


Centifolyl TM*
80


Phenethyl-cinnamate*
25


Citronellol
25


1-(1,1-Dimethoxypropan-2-yl)benzene
8


Dione (2-[2-(3,3,5-trimethylcyclohexyl)-1-
3


ethanone]cyclopentanone) 10% in


dipropyleneglycol


Dipropyleneglycol
128


Gardenol (alpha-Methylbenzyl acetate)
5


Georgywood (1-(1,2,3,4,5,6,7,8-octahydro-1,1,7,8-
2


tetramethyl-naphthalen-7-yl)ethanone)


Geraniol
30


Hedione ®
70


Heliotropine
4


Indolene (8-(1H-indol-2-yl)-8-(1H-indol-3-yl)-2,6-
1


dimethyloctan-2-ol)


Isoraldeine 70 (mixture of 4/1-(2,6,6-trimethyl-
25


2-cyclohexen-1-yl)-3-methyl-3-buten-2-one)


Methyl diantilis ®*
25


Neroline TM*
1


Patchouli essential oil rectified (origin: Indonesia)
2


Peach pure (5-heptyl-dihydrofuran-2(3H)-one)
10


Pharaone (2-Cyclohexyl-1,6-heptadien-3-one) 1%
8


in dipropyleneglycol


Pomarose 10% in dipropyleneglycol
3


Rose oxide
7


Cyclohexyl salicylate*
45


cis-3-Hexenyl salicylate*
55


n-Hexyl salicylate*
20


Phenethyl salicylate*
80


Vanillin
5


Viridine (phenylacetaldehyde dimethyl acetal)
3


Ylang Ylang essential oil
10





All ingredients marked with an * are active compounds having the ability to reduce or suppress the formation of skin irritation, as defined according to the present invention.


The fragrance composition No. 3 comprises 37.4 weight % of actives.






2.5 Fresh, Woody Floral Fragrance Composition No. 5














parts by



weight 1/1000

















Azurone 10% in triethyl citrate
4


(7-(3-Methylbutyl)-2H-1,5-benzodioxepin-3(4H)-one)


Ethyl vanilline 10% in DPG
4


Evernyl TM (methyl 2,4-dihydroxy-3,6-dimethylbenzoate)
2


Fixolide
55


(1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalen-


2-yl)ethanone)


Florhydral ® (3-(3-isopropylphenyl)butanal)
5


Iso E super TM
250


(1-(2,3,8,8-tetramethyl-1,2,3,4,5,6,7,8-octahydro-


naphthalen-2-yl)ethanone)


Kephalis
30


(4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexanone)


Cyclohexal
80


Linalool (3,7-dimethylocta-1,6-dien-3-ol)
40


Patchouli essential oil
10


Peonil ®*
100


Diethyl phthalate
60


Radjanol TM (2-ethyl-4-(2,2,3-trimethyl-3-
50


cyclopenten-1-yl)-2-buten-1-ol)


Phenethyl salicylate*
100


cis-3-Hexen-1-yl salicylate*
55


n-Hexyl salicylate*
55


Serenolide TM (2-(1-(3,3-dimethylcyclohexyl)ethoxy)-2-
60


methylpropyl cyclopropanecarboxylate)


Velvione ®
40





All ingredients marked with an * are active compounds having the ability to reduce or suppress the formation of skin irritation, as defined according to the present invention.


The fragrance composition No. 5 comprises 31 weight % of actives.






2.6 Floral, Spicy, Green Fragrance Composition No. 6













parts by



weight 1/948
















Dimethyl benzyl carbinyl acetate
25


Linalyle acetate
70


Phenylethyl alcohol
75


Methyl anthranilate
3


Cosmone (3-methylcyclotetradec-5-enone)
40


Florol ® (2-isobutyl-4-methyltetrahydro-2H-pyran-4-ol)
70


Galbanum oil
35


Gardenol
15


Hedione ®
55


Indole 1% in dipropyleneglycol (DPG)
45


Isoraldeine 70
80


Methyl diantilis ®*
45


Nirvanolide TM (13-methyloxacyclopentadec-10-en-2-one)
45


Peche pure
3


Peonile ®*
55


EUGENYL PHENYL ACETATE*
20


Phenethyl salicylate*
100


Cis-3-Hexen-1-yl salicylate*
100


Vertofix coeur (methyl cedryl ketone)
55


Ylang Ylang essential oil
12





All ingredients marked with an * are active compounds having the ability to reduce or suppress the formation of skin irritation, as defined according to the present invention.


The fragrance composition No. 6 comprises 33.7 weight % of actives.






2.7 Floral, Rosy, Fruity Fragrance Composition No. 7














parts by



weight 1/825

















Benzyl-acetate
20


2-Phenylethanol
200


Phenethyl benzoate*
130


Centifolyl ®*
45


Cinnamyl cinnamate*
10


Phenyl ethyl cinnamate*
52


Citronellol
45


Dihydrofarnesal TM (3,7,11-trimethyldodeca-6,10-dienal)
20


Florhydral TM (3-(3-isopropylphenyl)butanal)
3


Hedione ®
150


Phenethyl isobutyrate*
25


Isoraldeine 70
45


Methyl diantilis ®*
45


Peche pure
10


Rose oxide
10


Vanillin
15





All ingredients marked with an * are active compounds having the ability to reduce or suppress the formation of skin irritation, as defined according to the present invention.


The fragrance composition No. 7 comprises 37.2 weight % of actives.






EXAMPLE 3
Effect of Fragrance Compositions on Keratinocyte Cultures
Keratinocytes were grown in 24 well plates and irritated with calcimycin as described in example 1. Fragrance compositions of example 2 were dissolved in DMSO and added to the cultures simultaneously. Inhibition of PGE2 formation was measured as described in example 1. The results are listed in Table 1.









TABLE 1









Relative inhibition in % of



PGE2 formation at 



different concentration



of test fragrance










12.5 ppm
6.25 ppm















Composition No. 1
79.0
42.4



Composition No. 2
82.6
85.6



Floral fragrance base
0
0










As can been seen from the figures in Table 1, about 80% reduction of PGE2 formation was observed at 12.5 ppm if a fragrance composition according to the present invention is applied, whereas using the floral fragrance base without actives, no measurable reduction of PGE2 formation was observed.
EXAMPLE 4
Irritation Reducing Effects of a Hydrogel on Reconstituted Epidermis
A hydrogel was prepared as follows:













INGREDIENT
SUPPLIER
INCI NAME
% W/W







CARBOPOL 980
Goodrich
Carbomer
0.50


PEMULEN TR1
Goodrich
Acrylate/C10-C30
0.20




Alkyl acrylate crosscopolymer


LUBRAGEL CG
Guardian
Polyglycerylmethacrylate &
0.50




Propylene glycol


UCON 75H450
Amerchol
PEG/PPG-17/6 copolymer
1.00


GLYCERIN
AMI
Glycerin
4.00


HEXYLENE GLYCOL

Hexylene Glycol
2.00


DEIONISED WATER

Water
qsq 100.00


GERMALL 115
Sutton
Imidazolidinyl Urea
0.60


SODIUM HYDROXIDE

Sodium Hydroxide
qsp pH = 5.50


10% in water


CREMOPHOR RH 40 BASF

PEG 40 Hydrogenated Castor oil
1.00









Glycerin and water were mixed, Carbopol 980 was dispersed, then Pemulen TR 1 and then the remaining ingredients were added.
Human reconstituted epidermis EpiDerm was purchased from Mattek (Ashland, USA). The cultures were exposed to a single Dose of 600 mJ UVB, and then either 50 mg phosphate buffered saline (PBS) or 50 mg of the above hydrogel was added on top of the individual EpiDerm cultures. After 24 h incubation, the culture medium beneath the air exposed EpiDerm cultures was sampled and analyzed for PGE2 as described in example 1. All skin samples retained 100% cellular viability throughout the experiment. Skin samples treated with a hydrogel containing the inventive perfume composition 1 from example 2 suppressed UVB induced PGE2 formation.











TABLE 2







level PGE2





per ml
t-test vs
t-test vs



culture medium
control
UVB irritation



















Control, no UVB
8.253
1.000



UVB 600 mJ, PBS treatment
42.143
0.003
1.000


UVB 600 mJ,
48.778
0.046
0.742


Hydrogel treatment


UVB 600 mJ,
12.135
0.384
0.001


Hydrogel containing 0.5%


(w/w) fragrance comp. No. 1









EXAMPLE 5
Antiperspirant with Reduced Irritation on Reconstituted Epidermis
An antiperspirant was formulated according the following formulation:













Weight %



















Water
67



Aluminium chlorohydrate
20



Glycerin
5



Sunflower oil
4



Steareth 2
3



Steareth-20
1










The following antiperspirant compositions had been prepared:

    
    
        I) antiperspirant & 1 weight % conventional perfume A
        II) antiperspirant & 0.5 weight % conventional perfume B
        III) antiperspirant & 0.5 weight % fragrance composition No. 1 (Ex. 2.1)
        IV) antiperspirant & 1 weight % fragrance composition No. 1 (Ex. 2.1)
    
    


50 mg of the resulting antiperspirant I)-IV) or 50 mg of PBS as control was added to Mattek skin cultures as described above, and after 24 h the level of PGE2 in the culture medium was determined according to the procedure described above. The results are shown in Table 3.










TABLE 3







Level of PGE2 in
t-test vs



culture medium
control




















PBS
12.54




Composition I)
35.49
0.002



Composition II)
27.66
0.011



Composition III)
16.05
0.302



Composition IV)
9.48
0.368










As can be seen from the results above, antiperspirants formulated with conventional perfumes (i.e. composition I) and II)) led to significantly enhanced PGE2 formation indicating an irritating nature of these products to the human skin, whereas upon treatment of EpiDerm with antiperspirants containing the inventive fragrance composition, no significantly enhanced PGE2 levels were detected. All epidermal cultures retained 100% of the cellular viability showing that all the products are not cytotoxic.

## Claims

1. A method of reducing the onset of skin irritation caused by either environmental stresses or by stresses caused by the application of chemical compounds to skin, by applying to the skin an effective amount of a topical skin care composition comprising both:
at least one (a) compound of the following formula




wherein
R is hydrogen or isopropyl;
R1 is methyl or ethyl; and R2 is C1-C6 alkyl or C2-C6 alkenyl; or
R1 and R2 together with the carbon atom to which they are attached form a C5 or C6 cycloalkyl ring; and
the dotted line together with the carbon carbon bond represents a single bond or a double bond;
and,


at least one (b) compound of the following formula



wherein Y is a C4-C7 hydrocarbon residue, wherein the total amount of both compound (a) and compound (b) is at least 0.2% wt. of the total amount of the topical skin care composition.

2. A method of reducing the onset of skin irritation caused by either environmental stresses or by stresses caused by the application of chemical compounds to skin, comprising the steps of:
(A) providing a topical skin care composition which includes a fragrance composition comprising both:
at least one (a) compound of the following formula




wherein
R is hydrogen or isopropyl;
R1 is methyl or ethyl; and R2 is C1-C6 alkyl or C2-C6 alkenyl; or
R1 and R2 together with the carbon atom to which they are attached form a C5 or C6 cycloalkyl ring; and
the dotted line together with the carbon carbon bond represents a single bond or a double bond;
and,

at least (b) one compound of the following formula




wherein Y is a C4-C7 hydrocarbon residue,

wherein the total amount of both compound (a) and compound (b) is at least 30% of the total weight of the fragrance composition present in the topical skin care composition; and,
(B) topically applying to the skin an amount of the topical skin composition which is effective for reducing skin irritation.

3. A method of reducing the formation of prostaglandins in skin cells by applying to the skin cells an effective amount of a topical skin care composition comprising a fragrance composition containing both:
at least one (a) compound of the following formula




wherein
R is hydrogen or isopropyl;
R1 is methyl or ethyl; and R2 is C1-C6 alkyl or C2-C6 alkenyl; or
R1 and R2 together with the carbon atom to which they are attached form a C5 or C6 cycloalkyl ring; and
the dotted line together with the carbon carbon bond represents a single bond or a double bond; and,
at least one (b) compound of the following formula





wherein Y is a C4-C7 hydrocarbon residue wherein the total amount of both compound (a) and compound (b) is at least 0.2% wt. of the total amount of the topical skin care composition.

4. A method of reducing the formation of prostaglandins in skin cells by applying to the skin cells an effective amount of a topical skin care composition comprising a fragrance composition containing both:
at least one (a) compound of the following formula




wherein
R is hydrogen or isopropyl;
R1 is methyl or ethyl; and R2 is C1-C6 alkyl or C2-C6 alkenyl; or
R1 and R2 together with the carbon atom to which they are attached form a C5 or C6 cycloalkyl ring; and
the dotted line together with the carbon carbon bond represents a single bond or a double bond; and,
at least one (b) compound of the following formula





wherein Y is a C4-C7 hydrocarbon residue wherein the total amount of both compound (a) and compound (b) is at least 30% wt. of the total amount of the fragrance composition present in the topical skin care composition.