Benzylidenenorcamphor derivatives

The invention relates to the use of benzylidenenorcamphor derivatives of the formula I ##STR2## wherein Phe is a phenyl group which is unsubstituted or substituted by 1 to 5 hydroxyl, alkyl or alkoxy groups, preferably having 1 to 10 C atoms, and
n is 1 or 2,
as sunscreen filters, and also novel compounds of the formula I, processes for their preparation and their use in cosmetic preparations, in particular for protection from solar radiation, and in pharmaceutical preparations for the prophylactic treatment of inflammations and allergies of the skin or certain types of cancer.
BACKGROUND OF THE INVENTION
As is known, the skin has a sensitive reaction to solar rays, which can produce ordinary sunburn or erythema, but also more or less pronounced burns.
Solar rays, however, also have other adverse effects: they cause the skin to lose its elasticity and to form wrinkles and thus lead to premature ageing. Dermatoses can sometimes also be observed. In the extreme case, skin cancer occurs in some people.
It is also desirable to protect hair against photochemical damage in order to prevent changes of color shades, bleaching or damage of the mechanical type.
It is known that the components contained in cosmetic preparations are not always sufficiently photostable and decompose under the action of light rays.
As is known, the most dangerous part of solar rays are the ultraviolet rays having a wavelength of less than 400 nm It is also known that, owing to the presence of the ozone layer of the earth's atmosphere, which absorbs some of the solar radiation, the lower limit of the ultraviolet rays which reach the earth's surface is about 280 nm.
It thus appears desirable to make available compounds which can absorb UV rays in a wavelength range from 280 to 400 nm, i.e. also UV-B rays having a wavelength between 280 and 320 nm, which play a decisive part in the formation of photoerythema, and also UV-A rays having a wavelength between 320 and 400 nm, which bronze the skin but can also age it, favor the elicitation of an erythema reaction or increase this reaction in certain people or can even cause phototoxic or photoallergic reactions.
The sunscreen filters customary today in cosmetics are divided into UVA and UVB filters. While good filters are obtained in the UVB range (280-320 nm) using substances such as Eusolex.RTM.6300 or Eusolex.RTM.232, those used in the UVA range (320-400 nm) have drawbacks.
The benzylidenecamphor derivative Eusolex.RTM.6300 has, e.g., an absorption of about 1 at 305 nm.
Dibenzoylmethanes such as Parsol.RTM.1789 or Eusolex.RTM.8020 are not of unlimited stability under UV irradiation, which on the one hand reduces the filter effectiveness with time and on the other hand can favor photosensitization of the skin in isolated cases. The benzophenones which are likewise used as UVA filters are of only limited solubility in the oils used in cosmetics. Further, they have a relatively low absorption. On the other hand, only a few water-soluble UVA filters are currently known, the UV absorption of which, however, is low.
Similar biscamphorylidenemethylphenyls are known e.g., from EP 0 390 682; however, these have comparatively low absorption values in the UVA range.
W. Bowman et al, Tetrahedron 48 (33), 6883-96, 1992, described, inter alia, the preparation and epoxidation of the following norcamphor derivatives: ##STR3##
R=H, Cl or OCH.sub.3
There is no indication there that such compounds can be used as sunscreen filters.
SUMMARY OF THE INVENTION
It has been found that norcamphor compounds of the formula I, wherein Phe is a phenyl group which is unsubstituted or substituted by 1 to 5 hydroxyl, alkyl or alkoxy groups, in particular a mono- or unsubstituted phenyl group, have outstanding UVB filter properties (n=1), and outstanding UVA filter properties (n=2). Their solubility in the oils used in cosmetics is very good, such that use concentrations up to at least 10% of the preparation are possible even in complicated formulations.
The compounds according to the invention furthermore have an unusual advantageous photostability to UV radiation, which by far exceeds the stability of previously known UV filter substances. They are suitable, in particular, as UVB or UV wide-spectrum filters.
If the absorption in the UVA range has a minimum, this is not a disadvantage since a UVA filter can be additionally incorporated in the formulation without problems.
Furthermore, the compounds of the formula I can also be used for the prophylactic treatment of inflammations and allergies of the skin and for the prevention of certain types of cancer; e.g., those associated with exposure to the skin.
Apart from their good properties as filters, the compounds according to the invention are distinguished by a good thermal and photochemical stability.
These compounds furthermore have the advantage of being non-toxic and non-irritant and completely harmless to the skin.
They disperse uniformly in the conventional cosmetic carriers and can in particular form a continuous film in fatty carriers. They can be applied to the skin in this way in order to form an effective protective film.
The invention thus relates to the use of the compound of the formula I as a sunscreen filter, and also to the compounds of the formula I, the following compounds being excluded: ##STR4## wherein R is H, Cl or OCH.sub.3. Particular preference is given to compounds wherein Phe is 1,4-phenyl substituted by 1 or 2 alkyl groups having 1 or 2 C atoms.
If n=1, Phe is a phenyl group which is unsubstituted or substituted by 1-5 substituents. If n=2, Phe is a phenylene group which is unsubstituted or substituted by 1-4 substituents.
Phe is preferably a phenyl group of the formula (n=1) ##STR5## or a phenylene group of the formula (n=2) ##STR6##
In this formula, R is preferably a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl or 1,1,3,3-tetramethyl-butyl radical, methoxy, ethoxy, or 2-ethylhexyloxy radical or hydrogen, preferably hydrogen. m is 1 to 5, preferably 1 or 2.
The phenyl or phenylene group is preferably unsubstituted or substituted by two alkoxy groups having 1 to 8 C atoms, in particular by methoxy, ethoxy or 2-ethylhexyloxy groups.
Preferred compounds of the formula I are those of the formulae I1 to I15, A being a group of the formula ##STR7## and R being alkyl or alkoxy having 1 to 10 C atoms. ##STR8##
Among these, the compounds of the formulae I1, I2, I5, I6, I7, I8 and I11 are particularly preferred.
The compounds of the formula I are obtained, e.g., by reacting
Phe--(CHO).sub.n II
wherein Phe and n have the meaning indicated, with norcamphor in the presence of a base or of a Lewis acid.
The reaction may be carried out in an inert diluent, preferably a protic solvent, in particular an alcohol, such as e.g. methanol, ethanol, isopropanol or tert-butanol or an aprotic solvent, such as diethyl ether, toluene or cyclohexane or mixtures of the solvents mentioned. The bases employed are preferably alkali metal alkoxides, such as e.g. sodium methoxide, sodium ethoxide or potassium tert-butoxide. The Lewis acids employed are preferably borane compounds.
The reaction can be carried out at temperatures of 0.degree. C. to the boiling point of the reaction mixture, preferably at 25.degree. to 60.degree. C.
If n=1, preferably 0.8 to 1.2 mol of norcamphor are employed, relative to 1 mol of compound of the formula II, for the preparation.
If n=2, preferably 1.6 to 2.4 mol of norcamphor are employed, relative to 1 mol of compound of the formula II, for the preparation.
The aldehydes of the formula II are known or are prepared according to known methods.
Norcamphor is known and commercially available.
The invention also relates to the above-described process for the preparation of the novel compounds of the formula I.
The invention further relates to a cosmetic preparation, which contains an effective amount of at least one compound of the above formula I in a cosmetically acceptable carrier.
The cosmetic composition according to the invention can be used as an agent for the protection of the human. epidermis or of the hair or as a sunscreen composition.
The invention further relates to a process for the protection of the skin and natural or sensitized hair from solar rays by the application of an effective amount of at least one compound of the formula I to the skin or the hair.
"Sensitized hair" means hair which has been subjected to a permanent wave treatment or a coloring or bleaching process.
The invention further relates to a colored or uncolored light-stabilized cosmetic preparation which comprises an effective amount of at least one benzylidenenorcamphor compound of the above formula I.
If the cosmetic composition according to the invention is an agent for the protection of human epidermis against UV rays, it may be formulated in any of the various forms customarily used for such agents. Thus, it can be present, in particular, in the form of oily or oily-alcoholic lotions, emulsions, such as a cream or as a milk, in the form of oily-alcoholic, oily-aqueous or aqueous-alcoholic gels or as solid sticks or be formulated as an aerosol.
It can contain cosmetic adjuvants which are customarily used in this type of composition, such as e.g. thickeners, softeners, moisturizing agents, surface-active agents, preservatives, agents against foam formation, perfumes, waxes, lanolin, propellants, colorants and/or pigments which color the composition itself or the skin, and other ingredients usually used in cosmetics.
Preferably, the compound of the formula I is contained in such compositions in an amount from 0.5 to 10%,particularly preferably 1 to 8%, in particular 1 to 5%, relative to the total weight of the cosmetic composition for the protection of human epidermis.
Solubilizing agents which can be used in the compositions include oil, wax or other fatty substances, a lower monoalcohol or a lower polyol or mixtures, thereof. Particularly preferred are monoalcohols or polyols including ethanol, i-propanol, propylene glycol, glycerol and sorbitol.
A preferred embodiment of the invention is an emulsion which is present as a protective cream or milk and, apart from the compound of the formula I, comprises fatty alcohols, fatty acid esters, in particular triglycerides of fatty acids, fatty acids, lanolin, natural or synthetic oils or waxes and emulsifiers in the presence of water.
Further preferred embodiments are oil lotions based on natural or synthetic oils and waxes, lanolin, fatty acid esters, in particular triglycerides of fatty acids, or oily-alcoholic lotions based on a lower alcohol, such as ethanol, or on a glycol, such as propylene glycol, and/or on a polyol, such as glycerol, and oils, waxes and fatty acid esters, such as triglycerides of fatty acids.
The cosmetic composition according to the invention can also be present as an alcoholic gel which comprises one or more lower alcohols or polyols, such as ethanol, propylene glycol or glycerol, and a thickener, such as silica. The oily-alcoholic gels additionally contain natural or synthetic oil or wax.
The solid stick compositions preferably contain natural or synthetic waxes and oils, fatty alcohols, fatty acid esters, lanolin and other fatty substances.
The invention also relates to cosmetic sunscreen compositions which contain at least one compound of the formula I and other UVB and/or UVA filters.
In this case, the amount of the filter of the formula I is preferably about 1.0 and 8.0% by weight, based on the total weight of the sunscreen composition.
If a composition is formulated as an aerosol, the customary propellants may be used, such as alkanes, fluoroalkanes and chlorofluoroalkanes.
If the composition according to the invention is to protect natural or sensitized hair from UV rays, it can be present as a shampoo, lotion, gel or emulsion for rinsing out, the particular formulation being applied before or after shampooing, before or after coloring or bleaching, or before, or after permanent waving; or the composition is present as a lotion or gel for hairdressing and handling, as a lotion or gel for brushing or setting a water-wave, as a hair lacquer, permanent wave composition, or coloring Or bleaching composition for the hair. Apart from the compound according to the invention, this composition can contain various adjuvants used in this type of composition, such as surface-active agents, thickeners, polymers, softeners, preservatives, foam stabilizers, electrolytes, organic solvents, silicone derivatives, oils, waxes, anti-grease agents, colorants and/or pigments which color the composition itself or the hair or other ingredients customarily used for hair care. For such application, the composition preferably contains 10 to 50% by weight of the compound of the formula I.
The present invention also relates to cosmetic compositions which contain at least one compound of the formula I as an agent for protection from UV-rays, which also acts as an antioxidant. These compositions include hair products, such as hair lacquers, water-wave lotions for setting the hair, optionally for handling or easier hairdressing, shampoos, coloring shampoos, hair coloring compositions, make-up products, such as nail varnish, creams and oils for skin treatment, make-up (foundation) and lipsticks; skin care compositions, such as bath oils or creams; and other cosmetic compositions which, with respect to their components, can raise problems with photostability and/or oxidation in the course of storage. Preferably, compositions of this type contain 10 to 50% by weight of a compound of the formula I.
The invention furthermore relates to a method for the protection of cosmetic compositions from UV rays and oxidation, an effective amount of at least one compound of the formula I being added to these compositions.
The invention further relates to the use of the compounds of the formula I as sun filters having a large width of absorption in a wavelength range from 320 to 400 nm.
The invention further relates to the use of compounds of the formula I as cosmetic products.
As already mentioned above, in the course of its investigations, the inventors have additionally found that the compounds of the formula I have a significant pharmacological activity in the area of the preventive treatment of inflammations and skin allergies.
Therefore, the invention also relates to the use of the compounds of the formula I as medicaments.
The invention further relates to a pharmaceutical composition which contains an effective amount of at least one compound of the formula I as active compound in a non-toxic carrier or excipient.
The pharmaceutical composition according to the invention can be administered orally or topically.
For oral administration, the pharmaceutical composition may be present in the form of pastilles, gelatine capsules, coated tablets or as a syrup, suspension, solution, emulsion, etc. For topical administration it is present as an ointment, cream, hair-cream, solution, lotion, gel, spray, suspension, etc.
This composition can contain inert or pharmacodynamically active additives, in particular hydrating agents, antibiotics, steroids or non-steroidal anti-inflammatory agents, carotenoids and agents against psoriasis.
This composition can also contain flavor-enhancing agents, preservatives, stabilizers, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifiers, local anaesthetics, buffers, etc.
It can additionally be formulated in a manner known per se in delayed-release form or in a form in which the active compound is rapidly released.
Even without further details, it is assumed that a person skilled in the art can utilize the above description to the widest extent. The preferred embodiments are therefore only to be understood as a descriptive disclosure which is by no means limited in any way.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications, cited above and below, and of corresponding German Application No. P 44 26 216.7, filed Jul. 23, 1994, are hereby incorporated by reference.

EXAMPLES
The following examples are representative of the present invention.
Example 1 ##STR9##
A suspension of 80 mmol (8.8 g) of norcamphor and 120 mmol of sodium methoxide (21.5 g of a 30% solution) in 100 ml of toluene are stirred at 50.degree. C. for 30 min. 50 mmol (6.7 g) of terephthalaldehyde are then added dropwise and the mixture is refluxed for 1 h. It is then cooled to room temperature and 175 ml of water are added. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are extracted by shaking with HCl solution, washed with water until neutral, dried, filtered and concentrated in a rotary evaporator.
Chromatography with toluene/ethyl acetate 98:2 afforded a crude product which for further purification was recrystallized from isopropanol.
7.9 g=62%
Elemental analysis:
calculated: C:83.01 H:6.92 O:10.07
found: C:83.05 H:6.94 O:10.01
UV (ethanol, c=1 mg/100 ml): .lambda..sub.max =350 nm
The spectra correspond to the expected compound.
Example 2 ##STR10## A suspension of 40 mmol (4.4 g) of norcamphor and 60 mmol of sodium methoxide in 50 ml of toluene is stirred at 50.degree. C. for 30 min. 50 mmol (6.0 g) of 4-methylbenzaldehyde are then added dropwise and the mixture is refluxed. After customary working-up and chromatography, 5.85 g=69% of the product are obtained.
Elemental analysis:
calculated: C:84.90 H:7.55 O:7.55
found: C:84.94 H:7.57 O:7.49
UV (Ethanol, c=1 mg/100 ml): .lambda..sub.max =294 nm, E=1.05
The following is prepared analogously
Example 3 ##STR11## UV (Ethanol, c=1 mg/100 ml): .lambda..sub.max =290 nm, E=1.12
Example 4
Sunscreen cream (W/O)
______________________________________ %______________________________________A Compound from Example 1 (1) 3.00 Arlacel 581 (2) 7.00 Paraffin highly liquid (Item No. 7174) (1) 6.00 Arlamol S 7 (2) 2.00 Lunacera M (3) 5.00 Dow Corning 344 (4) 4.00 Miglyol 812 (5) 2.00 Oxynex 2004 (Item No. 6940) (1) 0.05B Glycerol (Item No. 4093) (1) 2.00 Magnesium sulfate heptahydrate (Item No. 5882) (1) 0.17 Preservative q.s. Water, demineralized to 100.00______________________________________
Preparation:
Heat phase A to 75.degree. C. and phase B to 80.degree. C. Slowly stir phase B into phase A. Homogenize. Cool with stirring. If desired perfume at 40.degree. C.
Suppliers:
(1) E. Merck, Darmstadt
(2) ICI, Essen
(3) LW Fuller, Luneburg
(4) Dow Corning, Dusseldorf
(5) Huls Troisdorf AG, Witten
Example 5
Sunscreen cream (O/W)
______________________________________ %______________________________________A Compound from Example 2 (1) 3.00 Emulsifier E 2155 (2) 8.00 Stearic acid (Item No. 671) (1) 2.00 Paraffin liquid (Item No. 7162) (1) 6.00 Pariffin non-caking (Item No. 7158) (1) 6.00 Cetyl alcohol (Item No. 989) (1) 2.50 Miglyol 812 (3) 9.50 Abil AV 200 (2) 0.50 Cetyl palmitate (Item No. 15419) (1) 5.50 Tocopherol acetate (Item No. 500952) (1) 0.05 Glycerol (Item No. 4093) (1) 3.00 1,2-Propanediol (Item No. 7478) (1) 2.00 Karion F liquid (Item No. 2993) (1) 5.00 Allantoin (Item No. 1015) (1) 0.25 Triethanolamine (Item No. 8377) (1) 0.50 Preservative q.s. Water, demineralized to 100.00______________________________________
Preparation:
Heat phase A to 75.degree. C. and phase B to 80.degree. C. Slowly stir phase B into phase A. Homogenize. Cool with stirring. If desired perfume at 40.degree. C.
Suppliers:
(1) E. Merck, Darmstadt
(2) Th. Goldschmidt, Essen
(3) Huls Troisdorf AG, Witten
Example 6
Sunscreen milk (W/O)
______________________________________ %______________________________________A Compound from Example 3 (1) 3.00 Pionier L-15 (2) 19.00 Paraffin highly viscous (Item No. 7160) (1) 15.00B Glycerol (Item No. 4093) (1) 5.00 Magnesium sulfate heptahydrate (Item No. 5882) (1) 0.50 Preservative q.s. Water, demineralized to 100.00______________________________________
Preparation:
Heat phase A to 75.degree. C. and phase B to 80.degree. C. Slowly stir phase B into phase A. Homogenize. Cool with stirring. If desired perfume at 40.degree. C.
Suppliers:
(1) E. Merck, Darmstadt
(2) Hansen & Rosenthal, Hamburg
Example 7
Sunscreen milk (O/W)
______________________________________ %______________________________________A Compound from Example 2 (1) 3.00 Eumulgin B 1 (2) 3.00 Cutina MD (2) 8.00 Miglyol 812 (3) 7.00B Glycerol (Item No. 4093) (1) 5.00 Preservative q.s. Water, demineralized to 100.00______________________________________
Preparation:
Heat phase A to 75.degree. C. and phase B to 80.degree. C. Slowly stir phase B into phase A. Homogenize. Cool with stirring. If desired perfume at 40.degree. C.
Suppliers:
(1) E. Merck, Darmstadt
(2) Henkel, Dusseldorf
(3) Huls Troisdorf AG, Witten
Example 8
Sunscreen oil
______________________________________ %______________________________________A Compound from Example 1 (1) 3.00 Arlatone T (2) 2.00 Miglyol 812 (3) 16.00 Cetiol B (4) 22.50 Isopropyl myristate (4) 7.50 Paraffin highly liquid (Item No. 4174) (1) 48.85 Oxynex 2004 (Item No. 6940) (1) 0.05B Perfume oil (5) 0.10______________________________________
Preparation:
Heat phase A to 70.degree. C. with stirring until all components are dissolved, stir until cold and add phase B at 40.degree. C.
Suppliers:
(1) E. Merck, Darmstadt
(2) ICI, Essen
(3) Huls Troisdorf AG, Witten
(4) Henkel, Dusseldorf
(5) Haarmann & Reimer, Holzminden
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Number	Name	Date
4656029	Grollier et al.	Apr 1987
4710584	Lang et al.	Dec 1987
5004594	Richard et al.	Apr 1991
5178852	Forestier et al.	Jan 1993

Benzylidenenorcamphor derivatives

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