WO2006064366A1

WO2006064366A1 - 6- (1h-pyrazol-5-yl)-1, 3, 5-triazine derivatives and their use as protective agents against uv radiation

Info

Publication number: WO2006064366A1
Application number: PCT/IB2005/003931
Authority: WO
Inventors: Carles Trullas; Carles Pelejero; David Panyella; Jordi Corbera; Jorg Holenz
Original assignee: Isdin, S.A.
Priority date: 2004-12-16
Filing date: 2005-12-14
Publication date: 2006-06-22
Also published as: PE20060744A1; EP1833818A1; ES2264624B1; ES2264624A1; TW200637848A; UY29280A1; AR052818A1

Abstract

New triazine derivatives, procedures for their preparation and their use as protective agents against UV radiation. This invention relates to new triazine derivatives of general formula (I) and to procedures for making them. The physiochemical properties of said compounds allow them to be used as absorbent agents of UV radiation.

Description

6- ( 1H-PYRAZOL-5-YL) -1 , 3 , 5-TRIAZINE DERIVATIVES AND THEIR USE AS PROTECTIVE AGENTS AGAINST UV RADIATION

FIELD OF THE INVENTION

5 This invention is related with the cosmetic, dermatological and pharmaceutical fields. In particular, the present invention relates to new triazine derivatives whose physiochemical properties make them useful as protective agents against UV radiation, as well as to 0 their use for the manufacture of cosmetic, dermatological and pharmaceutical formulations which protect the skin, lips, nails and hair from UV radiation.

BACKGROUND OF THE INVENTION 5 Sunlight and ultraviolet radiation in particular can under certain circumstances give rise to harmful effects on the skin, occasioning pathological manifestations such as burns, photodermatosis and photo- ageing, among others. 0 The main agent responsible for such pathological manifestations is ultraviolet radiation, whose energy is inversely proportional to its wavelength. Thus, the shorter the wavelength the more powerful will be the radiation. Ultraviolet radiation can accordingly be 5 classified into UVC (200-290 nm) , UVB (290-320 nm) and UVA (320-400 nm) , with UVC waves being the most harmful, although they are absorbed by the ozone layer.

Against the damage that UV-A and UV-B radiation can cause, people have various natural protective systems 0 in their skins that either absorb or deflect the radiation, such as melanin, hair, the fatty layer of the skin, etc.

In this respect, solar filters are currently used in order to reduce the effects of solar radiation. Such 5 solar filters are compounds that are applied on the skin, lips, nails or hair and can be found in cosmetic, dermatological and pharmaceutical formulations as well as in other cosmetic products for protecting against solar radiation, preventing the decomposition of active ingredients or radiation-sensitive components.

Research has been carried out in recent years into compounds whose physiochemical properties make them more effective as solar filters.

An example of these might be document WO 03/075875, which discloses UV radiation absorbent compositions comprising a hydroxyphenyltriazine compound of general formula (1) :

in which Ri, R₂ and R₃ are, each independently of the others, Ci_i₈ alkyl, C2-₁₀ alkenyl or Ci_₄ phenylalkyl; and R₄ is hydrogen or C₁-C₅ alkyl.

Despite the great diversity of solar filters, there is a need for new compounds whose physiochemical properties make them suitable solar filters for offering simultaneous protection against UV-A and UV-B radiation.

DESCRIPTION OF THE INVENTION

A first aspect of the present invention is a triazine derivative of general formula (I) :

in which Ri represents a hydrogen atom; an optionally substituted cycloalkyl radical from 3 to 7 carbon atoms; an aryl radical optionally substituted with a group selected from aryl, halogen, alkoxy group containing from 1 to 6 carbon atoms and an alkyl group containing from 1 to 6 carbon atoms; an arylalkyl radical in which the alkyl group is an optionally substituted chain from 1 to 6 carbon atoms; a straight-chain or branched alkyl radical that has from 1 to 18 carbon atoms optionally substituted with a group selected from -SO₃M, -N(R₄J₃ ⁺ and a group of general formula (II)

n= 0 or 1 m= 0 , 1 , 2 , 3 or 4

R₅, Re, R₇, Re and Rg are the same as or different from each other and are selected from an optionally substituted alkyl radical from 1 to 6 carbon atoms, an alkoxy radical from 1 to 6 carbon atoms, an optionally substituted aryl radical and a -OSi (R₁₀) ₃ radical; Rio represents an alkyl radical from 1 to 6 carbon atoms, an alkoxy radical from 1 to 6 carbon atoms or an optionally substituted aryl radical; M is H, Na or K;

R₄ is an optionally substituted alkyl group; R₂ and R₃ are the same as or different from each other and are selected from hydrogen; an optionally substituted, straight-chain or branched alkyl radical that has from 1 to 4 carbon atoms; and an optionally substituted aryl radical; or

R₂ and R₃ are condensate with an optionally heterosubstituted mono- or polycyclic annular system; Ai is a radical of general formula (III) or (IV)

A₂ is a radical of general formula (III), (V) or (VI]

Ru represents a hydrogen atom; an optionally- substituted, straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 6 carbon atoms; a -OH radical;

R₁₂ represents a hydrogen atom; a hydroxyl radical; a

-COORi₅ radical; a -CONRi₆Ri₇ radical; an optionally substituted alkoxy radical from 1 to 18 carbon atoms; a phenoxy radical; a cycloalkyl radical having from 3 to 7 carbon atoms; a phenyl o naphtyl radical; a phenyl or naphtyl radical having 1 or 2 identical o different substituents, such as phenyl, chlorine, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a phenyl or a group of general formula (II) as defined above; Ri₅, Ri₆ and Ri₇ are the same as or different from each other and are selected from hydrogen, an optionally substituted, straight-chain or branched, alkyl radical from 1 to 18 atoms of carbon;

Ri₄ is H or -SO₃M, being M as defined above; Ri₃ and R' ₁₃ can be the same as or different from each other and are selected from hydrogen; an optionally substituted acyl radical from 1 to 18 carbon atoms; a straight-chain or branched, saturated or unsaturated, alkyl radical which contains from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a - SO₃M group or -N(R₄)₃ ⁺ group, where M and R₄ are as defined above, or a group of general formula (H)/ as defined above.

In a preferred embodiment, this invention relates to a triazine derivative of general formula (I) in accordance with the first aspect of the invention, in which:

Ri represents a hydrogen atom; an optionally substituted cycloalkyl radical of 3 to 7 carbon atoms; an aryl radical optionally substituted with a group selected from aryl, halogen, an alkoxy group containing from 1 to 6 carbon atoms and an alkyl group that contains from 1 to 6 carbon atoms; an arylalkyl radical in which the alkyl group is a chain from 1 to 6 carbon atoms optionally substituted; a straight-chain or branched alkyl radical, which has from 1 to 18 atoms of carbon, optionally substituted with a group of general formula (II)

m= 0, 1, 2, 3 or 4

R₅, Re, R₇, Rs and R₉ are the same as or different from each other and are selected from an optionally substituted alkyl radical having from 1 to 6 carbon atoms, an alkoxy radical from 1 to 6 carbon atoms, an optionally substituted aryl radical and a -OSi (Rio) ₃ radical;

Rio represents an alkyl radical from 1 to 6 carbon atoms, an alkoxy radical from 1 to 6 carbon atoms or an optionally substituted aryl radical;

R₂ and R₃ are the same as or different from each other and are selected from hydrogen; an optionally substituted, straight-chain or branched, alkyl radical which has from 1 to 4 carbon atoms; and an optionally substituted aryl radical; or

:iii) :iv) A₂ is a radical of general formula (III), (V) or (VI]

)

Rn represents a hydrogen atom; an optionally substituted, straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 6 atoms of carbon; an -OH radical;

Ri₂ represents a hydrogen atom; a hydroxyl radical; a -COORi₅ radical; a -CONRi₆Ri₇ radical; an optionally substituted alkoxy radical from 1 to 18 carbon atoms; a phenoxy radical; a cycloalkyl radical having from 3 to 7 carbon atoms; a phenyl o naphtyl radical; a phenyl or naphtyl radical having 1 or 2 identical o different substituents, such as phenyl, chlorine, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a phenyl or a group of general formula (II) as defined above; Ri₅, Ri₆ and Ri₇ are the same as or different from each other and are selected from hydrogen; an optionally substituted, straight-chain or branched, alkyl radical from 1 to 18 carbon atoms;

Ri₄ is H or -SO₃M, being M as defined above; Ri₃ and R₁₃' can be the same as or different from each other and are selected from hydrogen; an optionally substituted acyl radical from 1 to 18 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted by at least one -OH radical, a - SO₃M group, a -N(R₄)3⁺ group, being M and R₄ as defined above, or a group of general formula (II) as defined above.

In another preferred embodiment, the present invention relates to a triazine derivative of general formula (I), in accordance with the first aspect of the invention, in which

Ri represents a hydrogen atom; a straight-chain or branched alkyl radical having from 1 to 18 carbon atoms; a cycloalkyl radical from 3 to 7 carbon atoms; a phenyl or naphthyl radical; a phenyl or naphthyl radical that has 1 or 2 identical or different substituents, such as phenyl, chlorine, alkoxy from 1 to 6 carbon atoms, alkyl containing from 1 to 6 carbon atoms; a phenylalkyl radical in which the alkyl group is a chain from 1 to 6 carbon atoms;

R₂ represents a hydrogen atom; a straight-chain or branched alkyl radical, having from 1 to 4 carbon atoms; a phenyl or naphthyl radical; R₃ represents a hydrogen atom; a straight-chain or branched alkyl radical, having from 1 to 4 carbon atoms; a phenyl or naphthyl radical;

Ai is a radical of general formula (III) or (IV)

:III: (IV)

A₂ is a radical of general formula (III), (V) or (Vi;

in which

Rn represents a hydrogen atom; a straight-chain or branched, saturated or unsaturated, alkyl radical, containing from 1 to 6 carbon atoms; a -OH radical;

Ri₂ represents a hydrogen atom; a hydroxyl radical; a -COOR₁₅ radical; a -CONRi₆Ri₇ radical; an optionally substituted alkoxy radical from 1 to 18 carbon atoms; a phenoxy radical; a cycloalkyl radical having from 3 to 7 carbon atoms; a phenyl o naphtyl radical; a phenyl or naphtyl radical having 1 or 2 identical o different substituents, such as phenyl, chlorine, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a phenyl or a group of general formula (II) as defined above; Rχ₃ and R' ₁₃ are the same and represent a hydrogen atom; an acyl radical from 1 to 18 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical, containing from 1 to 18 carbon atoms, optionally substituted by at least one -OH radical or optionally substituted by a group of general formula (II) as defined above; and

R₁₄ is H.

In the present invention and unless explicitly stated otherwise, "optionally substituted" is taken to mean an alkyl, cycloalkyl, acyl, aryl or alkoxy radical, as defined above, which can be substituted in at least one position, said substituent being an alkyl, alkenyl, alkinyl, aryl, heteroaryl, alkoxide radical such as methoxide, ethoxide or butoxide, halogen such as chlorine or fluorine, nitro, amine, amide or silyl.

In a preferred embodiment of the first aspect of the invention, A₂ is selected from a compound of general formula (III) and one of general formula (V)

where Rn, R12, R13, R'13 and R14 are as defined above.

In another preferred embodiment of the first aspect of the invention Ri is a straight-chain or branched alkyl radical that has from 7 to 18 carbon atoms.

In yet another preferred embodiment of the first aspect of the invention, Ri is selected from hydrogen, methyl, phenyl and naphthyl optionally substituted in at least one position by a phenyl, chlorine, alkoxy or alkyl and phenylalkyl group; R₂ is selected from hydrogen, phenyl, naphthyl and methyl; R₃ is selected from hydrogen, phenyl, naphthyl, methyl and ethyl; Rn is selected from hydrogen, hydroxyl, methyl and ethyl; R₁₂ is selected from hydrogen, hydroxyl, methyl, ethyl, tert-butyl, benzyl, cyclohexyl, methoxyphenyl, biphenyl, -COOR15 and -CONR1₆R17; R1₃ and R'₁₃ are indistinctly selected from hydrogen, methyl, ethyl, propyl, butyl and 2-ethylhexyl; Ri₅ is selected from hydrogen, methyl, ethyl, propyl, butyl and 2-ethylhexyl; Ri₆ is selected from hydrogen, methyl, ethyl, propyl, butyl, t-butyl and 2-ethylhexyl; Ri₇ is selected from hydrogen, methyl, ethyl, propyl, butyl, t- butyl and 2-ethylhexyl; R₅ to R₉ are selected from methyl, ethyl, methoxy, ethoxy and phenyl; and Rio is selected from methyl, ethyl, methoxy, ethoxy and phenyl.

Advantageously, said derivative of general formula (I) according to the first aspect of the invention is selected from the group consisting of:

2, 4-bis (2, 4-dihydroxyphenyl) -6- (l-methyl-lH-pyrazol-5- yl) -1, 3, 5-triazine;

2,4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy]phenyl}-6- (1- methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine; - 2- [2, 4-bis (2-ethylhexyloxy)phenyl] -4- [4- (2- ethylhexyloxy) -2-hydroxyphenyl] -6- (l-methyl-lH-pyrazol-5- yl) -1, 3, 5-triazine;

2, 4-bis (2, 4-dihydroxyphenyl) -6 (l-phenyl-lH-pyrazol-5- yl) -1, 3, 5-triazine; - 2, 4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy]phenyl}-6- (1- phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine;

2, 4-bis [4- (butoxycarbonyl)phenylamino] -6- (1-methyl-IH- pyrazol-5-yl) -1, 3, 5-triazine;

2, 4-bis{4- [ (2-ethylhexyloxy) carbonyl]phenylamino}-6- (1- methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine;

2, 4-bis [4- (butoxycarbonyl)phenylamino] -6- (1-phenyl-lH- pyrazol-5-yl) -1, 3, 5-triazine;

2, 4-bis{4- [ (2-ethylhexyloxy) carbonyl]phenylamino}-6- (1- phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine; - 2- [ (4-butoxycarbonyl)phenylamino] -4, 6-bis (1-methyl-lH- pyrazol-5-yl) -1, 3, 5-triazine.

Surprisingly, the inventors of the present invention have found that the triazine derivatives of general formula (I) absorb in the ultraviolet radiation range of both type A and type B, thus making said derivatives useful as UV radiation absorbent agents while simultaneously provides effective protection against UV-A and UV-B radiation. Another aspect of this invention are the procedures of preparation of a triazine derivative in accordance with the first aspect of the invention.

In particular, the triazine derivatives of general formula I in which Ai is a radical of general formula (IV) and A₂ is a radical of general formula (V) as defined above:

in which R_i4= H and Ri, R₂, R₃, R₁₃ and R' ₁₃ have the meaning stated above, can be prepared as shown in Reaction Scheme 1.

REACTION SCHEME 1 to produce IA, where R_i4 = H (Ia]

(Ia)

Briefly, 2, 4-dichloro-6- (RiR₂R₃-pyrazol-5-yl) -1, 3, 5- triazine compounds of general formula (VIII) are prepared by lithiation of the pyrazol of general formula (VII) with n-BuLi in an inert solvent such as tetrahydrofuran and subsequent reaction with cyanuric chloride at a temperature ranging between -78°C and room temperature in accordance with the process described in the literature (J.K. Chakrabarti and D.E. Tupper, Tetrahedron, 31, 1879- 1882 (1975)) .

The 2, 4-bis-2, 4-dihydroxyphenyl-6- (RiR₂R₃-pyrazol-5- yl) -1, 3, 5-triazine of general formula (IX) is prepared by Friedel-Crafts acylation of resorcinol with 2, 4-dichloro- 6- (RiR₂R₃-pyrazol-5-yl) -1, 3, 5-triazine (VIII) in the presence of a Lewis acid, in particular aluminium chloride, in an inert solvent such as xylene (mixture of 5 isomers) and at a temperature between 60°C and 100⁰C, in accordance with the process disclosed in US patent 5.955.060.

The etherification of the p-hydroxyl groups that leads to the compounds of general formula (XI) is carried

10 out by alkylation of the compounds of general formula (IX) in the presence of a base, such as sodium hydroxide, cesium carbonate, potassium carbonate and potassium tert- butoxide, in an appropriate polar solvent such as 2- methoxyethanol, 2-ethoxyethanol, N,N-dimethylformamide and

15 ethanol, at a temperature ranging between 120°C and the boiling temperature of the solvent.

The trialkylated compounds of general formula (Ia) are obtained by alkylation of the compound of general formula (IX) or (XI), in the presence of a base, such as

20 potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and sodium t-butoxide, in a polar solvent such as 2-methoxyethanol, 2-ethoxyethanol, N,N- dimethylformamide and ethanol, and at a temperature ranging between 120°C and the boiling temperature of the

25 solvent.

The compounds of general formula (IA) in which Ri₄ is -SO₃M, being M as defined above, can be obtained, for example, following the procedures disclosed in US patent 6.090.370, and particularly in column 5, line 59-column 6,

30 line 8.

The compounds of general formula (I) in which a -SO₃M group has been inserted into an alkylic chain, being M as defined above, can be obtained, for example, following the procedures described in Lewin, G. et al., J. Nat. Prod.,

35 58 (1995) 12, 1840-1847. The compounds of general formula (I), in which a -

N(R₄)_S ⁺ group has been inserted into an alkylic chain, with

R₄ being as defined above, can be obtained, for example, following the procedures described in Sharma, M.L. et al., J. Indian Chem. Soc, 74(1997)4, 343-344.

In another embodiment of the second aspect of the invention, the triazine derivatives of general formula (I) in which Ai and A₂ are the same as each other and correspond to a radical of general formula (III) :

and in which Ri , R2 , R3 , I Rn and R_i2 have the meaning stated above, can be prepared aε 5 set out in Reaction Scheme 2 .

Briefly, the 2, 4-dichloro-6- (RiR₂R₃-pyrazol-5-yl) - 1, 3, 5-triazine of general formula (VIII) reacts with at least 2 equivalents of an aniline of formula (XIII) , in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide in a solvent such as dioxane or acetone, at a temperature ranging between 0⁰C and the boiling temperature of the solvent, preferably between room temperature and the boiling temperature of the solvent, and more preferably between 50°C and the boiling temperature of the solvent. In another embodiment, the triazine derivatives of general formula (I) in which Ai is a radical of general formula (III) and A₂ is a radical of general formula (V) :

in which R₁₄= H and R₁, R₂, R₃, Rn, Ri2, R13 and R'₁₃ have the meaning stated above, can be prepared according to the process disclosed in the US patent 3278534.

In yet another preferred embodiment, the triazine derivatives of general formula (I), in accordance with the first aspect of the invention, in which Ai is a radical of general formula (IV) and A₂ is a radical of general formula (VI ) :

and in which R_i4 is H and R₁, R₂, R3 and Ri₃ have the meaning stated above, can be prepared by following, for example, a method similar to that described for the triazine derivative (IA) . In yet another preferred embodiment of the third aspect of the invention, the triazine derivatives of general formula (I) in which Ai is a radical of formula (III) and A₂ is a radical of general formula (VI)

and in which Ri, R₂, R₃, Rn and R₁₂ have the meaning stated above, can be prepared as set out in Reaction Scheme 3 below:

RE

which comprises reacting a compound of general formula

(XIV) with a compound of general formula (XV) in the presence of a base and a polar solvent, said base being selected preferably from cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and potassium t-butoxide, and said polar solvent from 2- methoxyethanol, N,N-dimethylformamide, 2-ethoxyethanol and ethanol. As stated earlier, the triazine derivatives of general formula (I) according to the first aspect of this invention have physiochemical properties such as ultraviolet light absorption that allow them to be used as protective agents against UV radiation.

Also object of the present invention are, therefore, cosmetic, dermatological or pharmaceutical formulations that include one or more derivatives of general formula

(I), according to the first aspect of the invention, and at least one cosmetically, dermatologically or pharmaceutically acceptable vehicle or excipient.

In a preferred embodiment, said cosmetic, dermatological or pharmaceutical formulation further includes at least one organic, inorganic or organomineral filter against solar radiation.

In another preferred embodiment, said formulation also includes at least one active ingredient.

Said cosmetic, dermatological or pharmaceutical formulation can be adapted for application thereof onto the skin and lips in the form of: non-ionic vesicular dispersion, emulsion, cream, lotion, gel, aerosol, cream- gel, gel-cream, suspension, dispersion, ointment, powder, solid stick, foam, spray, oil and fluid, among others. Similarly, said formulation can be adapted for application thereof onto the hair in the form of a shampoo, lotion, gel, fluid, lacquer, foam, dye, emulsion, cream, spray, among others, and onto the nails in the form of a nail varnish, oil and gel, among others. The organic, inorganic and organomineral filters are chosen from ones acceptable under the country's legislation.

For example, the organic filters can be selected from those approved by the Council of the European Communities (Revised Text of European Directive 76/768/EEC Annexe-7, pages 76-81, published on 15.10.2003) and by the U.S. Food and Drug Administration (see, for example, "Food and Drugs, Sunscreen drug products for over the counter human use", title 21, volume 5 of the Code of Federal Regulations, as revised on 1 April 2004), such as: antranilates; derivatives of camphor; derivatives of dibenzoylmethane; derivatives of benzotriazoles; derivatives of diphenylacrylates; cinnamic derivatives; salycylic derivatives; triazine derivatives such as those described in patents EP-863145, EP-517104, EP-570838, EP- 796851, EP-775698 and EP-878469, derivatives of benzophenone; derivatives of benzalmalonate; derivatives of benzimidazole, imidizolines; derivatives of p- aminobenzoic acid; polymeric and silicone filters. The inorganic filters can be selected from a group that includes: metallic oxides as pigments, nanopigments, treated and untreated, such as dioxide of titanium (amorphous or crystalline) , iron, zinc, zirconium or cerium. Moreover, alumina and/or aluminium stearate are conventional coating agents. Examples of untreated metallic oxides as inorganic filters (uncoated) are described in patent applications EP518772 and EP518773.

The cosmetic, dermatological and pharmaceutical formulations of the present invention can additionally contain additives and adjuvants that can be selected from fatty acids, organic solvents, thickening agents, softening agents, antioxidants, opacifiers, stabilisers, emollients, hydroxyacids, anti-foaming agents, wetting agents, vitamins, fragrances, preservatives, surfactants, sequestering agents, polymers, propellants, acidifying or basifying agents, colorants, dyes, dihydroxyacetone, insect repellents or any other ingredient commonly used in cosmetic formulations, and particularly in the production of photoprotective compositions. Examples of substances/fatty acids include among others oils or waxes or mixtures thereof and can include fatty acids, fatty alcohols and esters of fatty acids. The oils are selected, advantageously, from animal, vegetable, mineral or synthetic oils and in particular from liquid petrolatum, liquid paraffin, volatile and non-volatile silicone oils, isoparaffins, polyalphaolefins or fluorated or perfluorated oils. Similarly, the waxes are selected, advantageously, from animal, vegetable, mineral or synthetic waxes known to the skilled in the art.

Examples of organic solvents include short-chain alcohols and polyoles.

The thickeners are selected, advantageously, from crosslinked polymers of acrylic acid, modified and unmodified carob gum rubbers, celluloses and xantan rubber, such as hydroxypropylated carob gum rubbers, methylhydroxyethylcellulose, hydroxypropylmethylcellulose or hydroxyethylcellulose.

In selecting the excipients, adjuvants, etc., a skilled in the art will ensure that they do not affect the activity of the triazine derivatives of general formula (I) in accordance with the invention.

Under a fourth aspect, the present invention relates to the use of a triazine derivative according to the first aspect of the invention in a cosmetic, dermatological or pharmaceutical formulation as a UV radiation filtering agent.

Under a fifth aspect, the present invention relates to the use of a triazine derivative according to the first aspect of the invention for the manufacture of a formulation for protecting the skin, lips and/or related tissues of a mammal against solar radiation.

Under a sixth aspect, the present invention relates to the use of at least one triazine derivative according to the first aspect of the invention for the manufacture of a formulation for the prevention, coadjuvant in the treatment or for the treatment of pathologies caused by ultraviolet radiation on the skin, lips and/or related tissues of a mammal, such as light- induced polymorphic eruptions, photoageing, actinic keratosis, vitiligo, solar urticaria, chronic actinic dermatitis, xeroderma pigmentosum. Preferably, said formulation is applied topically and, more preferably still, said mammal is a human. The properties of the triazine derivatives of general formula (I) make them also useful as photostabilisers of synthetic polymers and solar filters for textile fibres.

There follow below some examples by way of non- restrictive illustration of this invention.

EXAMPLES

Example 1 a) Synthesis of 2, 4-dichloro-β- (l-methyl-lH-pyrazol-5-yl) - 1,3, 5-triazine.

To a solution of 1-methyl-lH-ρyrazol (1.64 g, 20 mmol) in 25 mL of THF cooled to -60°C and under N₂ atmosphere, BuLi 2.5 M in hexane (8 mL, 20 mmol) is added and it is kept at -60°C for 40 min. Subsequently, this cooled mixture is added slowly to a solution of 2,4,6- trichloro-1, 3, 5-triazine (3.7 g, 20 mmol) maintaining the temperature below -45°C, and the resulting mixture is left under stirring for 18 hours at room temperature. The solvent is evaporated at low pressure and the residue is extracted twice with 40 mL of hexane. The hexane is removed at low pressure and the resulting solid is 5 purified by silica gel chromatography to yield 2,4- dichloro-6- (l-methyl-lH-pyrazol-5-yl) -1,3, 5-triazine (0.75 g, 3.26 mmol, 16%, white solid, m.p.= 101-105°C) and 2- chloro-4, 6-bis (l-methyl-lH-pyrazol-5-yl) 1, 3, 5-triazine as a by-product (0.22 g, 0.79 mmol, 4%, white solid, m.p.= 10 161-164°C) .

b) Synthesis of 2, 4-bis (2, 4-dihydroxyphenyl) -6- (1-methyl- lH-pyrazol-5-yl) -1, 3, 5-triazine

AICI₃ (0.64 g, 4.80 mmol) is slowly to a mixture of 2, 4-dichloro-6- (l-methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine (0.5 g, 2.17 mmol) and resorcinol (0.58 g, 4.77 mmol) in 25 20 mL of xylene heated to 40-50°C, added and the mixture is maintained at 8O⁰C for 2 hours. The solvent is decanted, the residue is washed with ethylic ether and decanted.

A solution of HCl 3N is added to the resulting crude 30 product, is left under stirring and the solid is filtered and washed with HCl 2N and water. The solid is treated with acetone and is filtered to yield 2, 4-bis (2,4- dihydroxyphenyl) -6- (l-methyl-lH-pyrazol-5-yl) -1, 3, 5- triazine (0.40 g, 1.08 mmol, yellow solid, m.p.> 300⁰C) . ¹H RMN (300 MHz, DMSOd₆) : 54.35 (s, 3H), 6.38 (d, J= 2.2 Hz, 2H), 6.50 (dd, J= 8.9 Hz, J'= 2.2 Hz, 2H), 7.17 (d, J= 1.9 Hz, IH), 7.64 (d, J= 1.9 Hz, IH), 8.20 (d, J= 8.9 Hz, 2H), 10.40-10.65 (m, 2H), 12,45-12.85 (m, 2H) .

c) Synthesis of 2, 4-bis{ [4- (2-ethylhexyloxy) -2- hydroxy]phenyl}-6- (l-methyl-lH-pyrazol-5-yl) -1, 3, 5- triazine

15 A mixture of 2, 4-bis (2, 4-dihydroxyphenyl) -6- (1- methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine (0.32 g, 0.86 mmol) and a 30% NaOH solution (0.24 g, 1.8 mmol) in 2- methoxyethanol (Methyl Cellosolve, 4 mL) is heated to 80°C for 30 minutes. A solution of 3- (bromomethyl) heptane (0.41

20 g, 2.12 mmol) in 2-methoxyethanol (Methyl Cellosolve, 1.2 mL) is then added slowly for 20 minutes, maintaining the reaction temperature at 80°C. Once addition has finished, the mixture is heated to 110-114⁰C for 16 hours, following the alkylation by TLC. Then a new solution of 3-

25 (bromomethyl) heptane (0.41 g, 2.12 mmol) in 2- methoxyethanol (Methyl Cellosolve, 1.2 mL) is added at this temperature and it is kept at 110-114°C for a further 16 hours. The solvent is evaporated and the residue is diluted in ethyl ether. The organic phase is washed with a

30 dilute solution of acetic acid and a dilute solution of NaHCO₃ and it is evaporated at low pressure. The resulting crude product is purified by silica gel chromatography to yield 2,4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy]phenyl}-6- (1- methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine (60 mg, 0.10 mmol,

35 12%, white solid, m.p.= 81-83°C) . ¹H RMN (300 MHz, CDCl₃) : δ θ.93 (m, 12H), 1.08-1.60 (m, 16H), 1.76 (m, 2H), 3.90 (d, J= 5.4 Hz, 4H), 4.44 (s, 3H), 6.47 (s, 2H), 6.54 (d, J= 9.1 Hz, 2H), 7.13 (s, IH), 7.59 (s, IH), 8.17 (m, 2H), 13.11 (m, 2H) . UV λmax= 302 nm ε =35000 M^"1 cm^"1, and λ.max= 356 nm ε

= 40000 M^"1 cm^"1 (Ethanol)

Example 2

Synthesis of 2- [2, 4-bis (2-ethylhexyloxy)phenyl] -4- [4- (2- ethylhexyloxy) -2-hydroxyphenyl] -6- (l-methyl-lH-pyrazol-5- yl) -1, 3, 5-triazine

A mixture of 2, 4-bis (2, 4-dihydroxyphenyl) -6- (1- methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine (0.48 g, 1.27 mmol) , potassium carbonate (0.52 g, 3.8 mmol) , potassium iodide (0.1 g, 0.60 mmol) and 3- (bromomethyl)heptane (0.74 g, 3.80 mmol) in N,N-dimethylformamide (25 mL) is heated to 130⁰C for one night. The solvent is evaporated at low pressure and the residue is diluted in ethyl acetate and washed with water. The organic phase is evaporated and the crude product is purified by silica gel chromatography to yield 2- [2, 4-bis (2-ethylhexyloxy)phenyl] -4- [4- (2- ethylhexyloxy) -2-hydroxy phenyl] -6- (l-methyl-lH-pyrazol-5- yl) -1, 3, 5-triazine (0.15 g, 0.21 mmol, 16%, white wax) . ¹H RMN (300 MHz, CDCl₃) : δ 0.65-1.03 (m, 18H), 1.05- 1.85 (m, 26H), 2.04 (m, IH), 3.92 (m, 4H), 4.05 (d, J= 6.6 Hz, 2H), 4.50 (s, 3H), 6.42-6.70 (m, 4H), 7.32 (d, J= 1.8 Hz, IH), 7.57 (d, J= 1.8 Hz, IH), 8.24 (d, J= 8.5 Hz, IH) , 8.39 (d, J= 8.9 Hz, IH), 13.64 (m, IH) . UV λ max= 292 rim ε =38000 M -1 cm ^x, and λ max= 339 nm ε =

34000 M A-I cm -^"1¹ (n-hexane )

Example 3 Synthesis of 2 , 4 -bis ( 2 , 4 -dihydroxyphenyl ) - 6- ( 1-phenyl-lH- pyrazol-5-yl ) -1 , 3 , 5-triazine

Resorcinol (1.4 g, 5.82 mmol) is dissolved in 70 mL of xylene at 40-50⁰C, 2, 4-dichloro-6- (1-phenyl-lH-pyrazol- 5-yl) -1,3, 5-triazine (1.7 g, 12.72 mmol) is added at this temperature and portions of AICI₃ (1.7 g, 12, 75 mmol) are then added quickly. The mixture is heated to 80-83⁰C and is kept at this temperature for 3 hours. The solution is cooled, the solvent is decanted and is added to a solution of HCl 2N (60 mL) and left under stirring, forming a yellowish solid which is filtered, washed with a solution of HCl 2N and dried. The resulting crude product is treated with acetone, filtered and washed with acetone to yield 2, 4-bis (2, 4-dihydroxyphenyl) -6- (1-phenyl-lH-pyrazol- 5-yl) -1,3, 5-triazine (1.47 g, 3.34 mmol, 57%, yellow solid, m.p.> 300⁰C) .

¹H RMN (300 MHz, DMSOd₆) : 6 6.30 (m, 4H), 7.35 (d, J= 1.9 Hz, IH), 7.49 (br s, 5H), 7.61 (d, J= 8.6 Hz, 2H), 7.91 (d, J= 1.9 Hz, IH), 10.44 (s, 2H), 12.36 (s, 2H) . Example 4

Synthesis of 2, 4-bis{ [4- (2-ethylhexyloxy) -2- hydroxy]phenyl}-6- (1-phenyl-lH-pyrazol-5-yl) -1,3,5- triazine

A mixture o

phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine (0.35 g, 0.80 mmol) and a 30% NaOH solution (0.24 g, 1.8 mmol) in 2- methoxyethanol (Methyl Cellosolve, 4 mL) is heated to 80°C for 30 minutes. A solution of 3- (bromomethyl) heptane (0.40 g, 2.07 mmol) in 2-methoxyethanol (Methyl Cellosolve, 1 mL) is then added slowly for 20 minutes maintaining the reaction temperature at 80⁰C. Once the addition is finished, the mixture is heated to 110-114°C for 16 hours following the alkylation by TLC. Afterwards, a new solution of 3- (bromomethyl) heptane (0.40 g, 2.07 mmol) in 2-methoxyethanol (Methyl Cellosolve, 1 mL) is added at this temperature and is kept at 110-114⁰C for a further 16 hours. The solvent is evaporated and the residue is diluted in ethyl ether. The organic phase is washed with a dilute solution of acetic acid and a diluted NaHCO₃ solution and is evaporated at low pressure. The resulting crude product is purified by silica gel chromatography to yield 2,4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy]phenyl}-6- (1- phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine (185 mg, 0.28 mmol, 28%, yellowish solid, m.p.= 81-84°C) .

¹H RMN (300 MHz, DMSO-d₆) : δ 0.88 (m, 12H), 1.20-1.45 (m, 16H), 1.66 (m, 2H), 3.90 (d, J= 5.9 Hz, 4H), 6.46 (m, 4H), 7.40 (d, J= 1.9 Hz, IH), 7.51 (br s, 5H), 7.69 (d, J= 9.7 Hz, 2H), 7.93 (d, J= 1.9 Hz, IH), 12,43 (m, 2H) . UV λ max= 302 nm ε =33000 M^"1 cm , and λ . max= 357 nm ε = 38000 M^"1 cm^"1 (Ethanol )

Example 5 Synthesis of 2, 4-bis [4- (butoxycarbonyl)phenylamino] -6- (1- methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine

A mixture of 2, 4-dichloro-6- (l-methyl-lH-pyrazol-5- yl) -1, 3, 5-triazine (0.23 g, 1 mmol) , butyl 4-aminobenzoate

(0.39 g, 2 mmol) and potassium carbonate (0.30 g, 2.17 mmol) in dioxane (15 mL) is heated at 90⁰C for 4 hours following the reaction by TLC. The solvent is evaporated at low pressure, the residue is diluted in methylene chloride and the organic phase is washed with water. The solvent is removed at low pressure and the resulting crude product is purified by silica gel chromatography to yield de 2, 4-bis [4- (butoxycarbonyl)phenylamino] -6- (1-methyl-lH- pyrazol-5-yl) -1, 3, 5-triazine (0.15 g, 0.27 mmol, 27%, white solid, m.p. =152-153°C)

¹H RMN (300 MHz, DMSO-d₆) : δ 0.93 (t, J= 7.4 Hz, 6H), 1.41 (m, 4H), 1.68 (m, 4H), 4.24 (t, J= 6.4 Hz, 4H), 4.30 (s, 3H), 7.06 (d, J= 1.6 Hz, IH), 7.54 (d, J= 1.6 Hz, IH), 7.93 (br s, 8H) , 10.28 (s, 2H) . ϋVλmax= 294 nm ε= 61000 M^'1 cm^"1 (methanol) . Example 6

Synthesis of 2, 4-bis{4- [ (2-ethylhexyloxy) carbonyl] phenylamino}-6- (l-methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine

A mixture of 2, 4-dichloro-6- (l-methyl-lH-pyrazol-5- yl) -1, 3, 5-triazine (0.23 g, 1 mmol) , 2-ethylhexyl 4- aminobenzoate (0.50 g, 2 mmol) and potassium carbonate

(0.30 g, 2.17 mmol) in dioxane (15 mL) is heated to 90⁰C for 4 hours following the reaction by TLC. The solvent is evaporated at low pressure, the residue is diluted in methylene chloride and the organic phase is washed with water. The solvent is removed at low pressure and the resulting crude product is purified by silica gel chromatography to yield 2, 4-bis{4- [ (2- ethylhexyloxy) carbonyl]phenylamino}-6- (1-methyl-lH- pyrazol-5-yl) -1, 3, 5-triazine (0.56 g, 0.85 mmol, 85%, thick oil) .

¹H RMN (300 MHz, DMSO-d₆) : δ 0.82-0.94 (m, 12H), 1.23- 1.46 (m, 16H), 1.67 (m, 2H), 4.17 (d, J= 4.4 Hz, 4H), 4.30 (s, 3H), 7.06 (br s, IH), 7.54 (d, J= 1.9 Hz, IH), 7.94 (br s, 8H), 10.29 (br s, 2H) .

UV λmax= 293 nm ε= 59000 M^'1 cm^"1 (methanol) . Example 7

Synthesis of 2, 4-bis [4- (butoxycarbonyl)phenylamino] -6- (1- phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine

A mixture of 2, 4-dichloro-6- (l-phenyl-lH-pyrazol-5- yl) -1, 3, 5-triazine (0.29 g, 1 mmol) , butyl 4-aminobenzoate (0.39 g, 2 mmol) and potassium carbonate (0.30 g, 2.17 mmol) in dioxane (15 mL) is heated to 90°C for 4 hours following the reaction by TLC. The solvent is evaporated at low pressure, the residue is diluted in methylene chloride and the organic phase is washed with water. The solvent is removed at low pressure and the resulting crude product is purified by silica gel chromatography to yield 2, 4-bis [4- (butoxycarbonyl)phenylamino] -6- (1-phenyl-lH- pyrazol-5-yl) -1, 3, 5-triazine (0.20 g, 0.33 mmol, 33%, beige solid, m.p. =131-133°C) .

¹H RMN (300 MHz, DMSO-d₆) : δ 0.94 (t, J= 7.3 Hz, 6H), 1.42 (m, 4H), 1.68 (m, 4H), 4.23 (t, J= 6.3 Hz, 4H), 7.09 (s, IH), 7.20-8.10 (m, 14H), 10.22 (m, 2H) .

¹H RMN (300 MHz, DMSO-d₆, 80°C):δ 0.96 (t, J= 7.3 Hz, 6H) , 1.45 (m, 4H) , 1.71 m. 4H) , 4.26 (t, J= 6.4 Hz, 4H),

7.08 (d, J= 1.9 Hz, IH), 7.34 (m, IH), 7.46 (m, 4H) 7.60 (m, 4H), 7.78 (m, 5H), 9.90 (s, 2H) .

UV λmax= 300 nm ε= 58000 M^"1 cm^"1 (ethanol) . Example 8

Synthesis of 2, 4-bis{4- [ (2-ethylhexyloxy) carbonyl]phenylamino}-6- (l-phenyl-lH-pyrazol-5-yl) -1, 3, 5- triazine

A mixture of 2, 4-dichloro-6- (l-phenyl-lH-pyrazol-5- yl)-l,3,5-triazine (0.30 g, 1.02 mmol) , 2-ethylhexyl A- aminobenzoate (0.51 g, 2.04 mmol) and potassium carbonate (0.30 g, 2.17 mmol) in dioxane (25 mL) is heated to 90°C for 4 hours following the reaction by TLC. The solvent is evaporated at low pressure, the residue is diluted in methylene chloride and the organic phase is washed with water. The solvent is removed at low pressure and the resulting crude product is purified by silica gel chromatography to yield de 2, 4-bis{4- [ (2-ethylhexyloxy) carbonyl]phenylamino}-6- (l-phenyl-lH-pyrazol-5-yl) -1, 3, 5- triazine (0.30 g, 0.42 mmol, 41%, beige solid, m.p.= 109- 110⁰C) .

¹H RMN (300 MHz, DMSO-d₆):δ 0.79-1.00 (m, 12H), 1.18- 1.43 (m, 16H), 1.66 (m, 2H), 4.15 (m, 4H), 7.09 (s, IH), 7.20-8.05 (m, 14H), 10.21 (m, 2H) .

¹H RMN (300 MHz, DMSO-d₆, 80⁰C) :δ 0.90-1.00 (m, 12H), 1.20-1.50 (m, 16H), 1.69 (m, 2H), 4.18 (d, J= 5.3 Hz, 4H), 7.08 (s, IH), 7.33 (m, IH), 7.45 (m, 4H), 7.59 (m, 4H), 7.77 (m, 5H) , 9.91 (s, 2H) . UV λmax= 300 nm ε= 59000 M^"1 cm^"1 (ethanol) . Example 9: Synthesis of 2= [ (4=butoxycarbonyl)phenylamino] 4, 6-bis (l-methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine

A mixture of 2-chloro-4, 6-bis (l-methyl-lH-pyrazol-5- yl) -1,3, 5-triazine (110 mg, 0.4 mmol) , butyl A- aminobenzoate (77 mg, 0.4 mmol) and potassium carbonate

(60 mg, 0.43 mmol) in dioxane 5 mL is heated to 90⁰C for 4 hours following the reaction by TLC. The solvent is evaporated at low pressure, the residue is diluted in methylene chloride and the organic phase is washed with water. The solvent is removed at low pressure and the resulting crude product is purified by silica gel chromatography to yield 2- [ (4-butoxycarbonyl)phenylamino] -

4, 6-bis (l-methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine (30 mg, 0.07 mmol, 18%, white solid, m.p.= 161-164°C) .

¹H RMN (300 MHz, CDCl₃) : δ 0.99 (t, J= 7.3 Hz, 3H),

1.49 (m, 2H), 1.77 (m.2H), 4.34 (t, J= 6.6 Hz, 2H), 4.40

(s, 6H), 7.23 (d, J= 1.9 Hz, 2H), 7.58 (d, J= 1.9 Hz, 2H),

7.68 (br s, IH), 7.75 and 8.10 (AB System, J_AB= 8.6 Hz, 4H) .

UV λmax= 296 nm ε= 49000 M^"1 cm^"1 (chlorophorm) .

Example 10: Formulation in oil

% W/W Mineral Oil (Liquid Paraffin) 59.85

Arlamol HD(Uniqema) (Isohexadecane) 16.00

Arlamol S7 (Uniqema) (cyclomethicone, PPG-I5, stearil ether) 16.00

ParsolMCX(DSM) (ethylhexyl methoxycinnamate) 5.00

Parfum 0.15 2,4-bis{ [4-(2-ethylhexyloxy)-2-hydroxy] phenyl]-6-(l-methyl-lH-pyrazol-5-yl)-1,3,5-triazine

Example 11: Formulation in form of oil/water cream

in weight

A) PEG-100 Stearate (Simulsol M59 (Seppic) ) 2.00 Glyceril Stearate (Cutina MS (Henkel) ) 1.00 Cetearyl Alcohol (Lanette 0 (Henkel) ) 2.50 Stearic Acid 5.00 Propylene glycol

Dicaprilate/dicaprate (Estol 1526 PDCC) 7.50 Triglyceride (Myritol 318 (Henkel) Caprillic/capric 3.00

Dimethicone (SF 18-350 (General Electric) 0.50 Tocopheryl Acetate 0.50

2,4-bis{ [4-(2-ethylhexyloxy)-2-hydroxy] phenyl]-6-(l-methyl-lH-pyrazol-5-yl)-1,3,5-triazine

B) Titanium Dioxide (and) Aluminium Hydroxide (and) Stearic Acid (MT-TlOO TV (Tayca) ) 4.00 Isohexadecane (Permethyl 101A (Presperse) 5.00 Cyclomethicone (SF 1204 (General Electric) 2.50

C) Water up to 100

Potassium Cethylphosphate (Amphisol K (Roche) ) 0 .50

D) PNC 30 (Sodium Acrylates/Crosslinked Polymer Vinyl Isodecanoate) 0 .15

E) Butylene glycol 1 50

ABIOL (Imidazolidinyl Urea) 0 30 Methylparaben 0 20 Propylparaben 0 • 10 F. Parfum 0 30

Example 12: Formulation in Gel form

% in weight

A) Ethanol ( 95° ) (CTFA : SD Alcohol ) 50 . 00 Klucel HF (CTFA: hydroxypropylcellulose ) 2 . 00

B) Ethanol ( 95 ° ) (CTFA: SD Alcohol ) 27 . 50 2, 4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy] phenyl] -6- (l-methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine

PARSOL® MCX (CTFA: octyl methoxycinnamate) 7.50

Uvinul M-40 (CTFA: 3-benzophenone) 4.00

Finsolv TN (CTFA: 12-15 Benzoate alcohols) 5.00

Fluid 556 Silicone (CTFA: Phenyl dimethicone) 1.00

C) Perfume, preservatives, deionised water c.s.p. 100 Example 13: Formulation in solid stick form

% in weight

A) 2,4-bis{ [4-(2-ethylhexyloxy)-2-hydroxy]phenyl}-6- (l-phenyl-lH-pyrazol-5-yl)-1,3,5-triazine 2.00

PARSOL MCX (CTFA: Octyl methoxycinnamate) 7.50

RICINOL (CTFA: Castor Oil) 7.50

Cutina HR (CTFA: Hydrogenated Castor Oil) 7.50 SATOL (CTFA: Oleilic Alcohol) purified and stabilised 20.00

Multiwax MH 180 (CTFA: Microcrystalline Wax) 30.00

Mineral Oil (30-40 ce) (CTFA) 7.35

Vaseline (CTFA: Petrolatum) 8.53

Silicone 200 Fluid (200 cs) (CTFA: Dimethicone) 3.50

Butilated Hydroxytoluene (CTFA: BHT) 0.02

Betacarotene (1% sol'n) 0.30

B ) d-PANTENOL ( CTFA : Panthenol ) 0 . 80 Propylenglycol (CTFA : Propylene glycol ) 3 . 00

C ) Parfum, preservatives, Vaseline c. s . p.100

Example 14 : Formulation in fluid form

% in weight A) 2, 4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy] phenyl} -6- (l-phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine 1 . 00

PARSOL® MCX (CTFA: Octyl Methoxycinnamate) 6.00

Uvinul M-40 (CTFA: 3-Benzophenone) 0.50

Silicone 344 Fluid (CTFA: Cyclomethicone) 45.00 Silicone Q2-1401 (CTFA: Cyclomethicone (and) Dimethicone) 20.00

Finsolv TN (CTFA: Ci₂-Ci₅ Alcohol benzoates) 10.00

Crodamol DA (CTFA: Diisopropyl adipate ) 15.50

B) Parfum, Finsolv TN c. s. p. 100

Example 15: Formulation in form of Water/Oil emulsion % in weight

A) Arlacel P135 (PEG-30 Dipolyhydroxystearate) 4.00

Arlamol HD (Isohexadecane) 6.00

Mineral Oil (Liquid Paraffin) 3.00

Tioveil 50 FCM (Titanium Dioxide, Alkyl Ci₂-Ci₅ benzoate Cyclomethicone, polyhydroxystearic acid, aluminium stearate, alumina) 12.00

2, 4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy] phenyl} -6- (l-phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine 6.00

B) Water up to 100.00

Pricerine 9091 (Glycerine) 3.00 MgSO₄ -7H₂O (Magnesium Sulphate) 0.70 Alpantha (Panthenol, Allantoin) 0.30 C) Kemaben 2 (Propylenglycol, diazolidinyl urea, methylparaben,

Propylparaben) 1.00

D) Parfum c.s Example 16; Formulation in cream for the prevention and/or coadjuvant use in the treatment of the melasma:

% in weight

Hydroquinone 4.00 Filter of the invention (for example, that of ex. 14)10.00

Parsol MCX (ethylhexyl methoxycinnamate) 6.00

Uvinul M-40 (benzophenone-3) 2.00

Parsol 1789 (butyl methoxydibenzoylmethane) 1.50

Evanescent base cream c.s.p. 100

Claims

1. A triazine derivative of general formula (I)

in which

Ri represents a hydrogen atom; an optionally substituted cycloalkyl radical from 3 to 7 carbon atoms; an aryl radical optionally substituted with a group selected from aryl, halogen, an alkoxy group containing from 1 to 6 carbon atoms and an alkyl group containing from 1 to 6 carbon atoms; an arylalkyl radical in which the alkyl group is an optionally substituted chain from 1 to 6 carbon atoms; a straight-chain or branched alkyl radical having from 1 to 18 carbon atoms optionally substituted by a group selected from -SO3M, -N (R₄) ₃ ^"1" and a group of general formula (II)

n= 0 or 1 m= 0, 1, 2, 3 or 4

R₅, Re, R₇, Rs and Rg are the same as or different from each other and are selected from an optionally substituted alkyl radical from 1 to 6 carbon atoms, an alkoxy radical from 1 to 6 carbon atoms, an optionally substituted aryl radical and a -OSi (Rio) ₃ radical;

M is H, Na or K;

R₄ is an optionally substituted alkyl group; R₂ and R₃ are the same as or different from each other and are selected from hydrogen; optionally substituted, straight-chain or branched, alkyl radical which has from 1 to 4 carbon atoms; and an optionally substituted aryl radical; or

(in: (IV)

A₂ is a radical of general formula (III), (V) or (VI)

)

Rn represents a hydrogen atom; an optionally substituted, straight-chain or branched, saturated or unsaturated, alkyl radical that contains from 1 to 6 carbon atoms; a -OH radical;

R₁₂ represents a hydrogen atom; a hydroxyl radical; a

-COOR₁₅ radical; a -CONRi₆Ri₇ radical; an optionally substituted alkoxy radical from 1 to 18 carbon atoms; a phenoxy radical; a cycloalkyl radical having from 3 to 7 carbon atoms; a phenyl o naphtyl radical; a phenyl or naphtyl radical having 1 or 2 identical o different substituents, such as phenyl, chlorine, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a phenyl or a group of general formula (II) as defined above;

Ri5, Ri6 ^and Ri7 are the same as or different from each other and are selected from hydrogen; an optionally substituted straight-chain or branched alkyl radical from 1 to 18 carbon atoms; Rχ₄ is H or -SO₃M, where M is as defined above;

R1₃ and R' ₁₃ can be the same as or different from each other and are selected from hydrogen; optionally substituted acyl radical having from 1 to 18 carbon atoms; straight-chain or branched, saturated or unsaturated, alkyl radical containing from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a - SO₃M group, a -N(R₄J₃ ⁺ group, where M and R₄ are as defined above, or a group of general formula (II) , as defined above.

2. Triazine derivative according to claim 1, in which:

Ri represents a hydrogen atom; an optionally substituted cycloalkyl radical from 3 to 7 carbon atoms; an aryl radical optionally substituted with a group selected from aryl, halogen, an alkoxy group containing from 1 to 6 carbon atoms and an alkyl group containing from 1 to 6 carbon atoms; an arylalkyl radical in which the alkyl group is an optionally substituted chain from 1 to 6 carbon atoms; a straight-chain or branched alkyl radical, which has from 1 to 18 carbon atoms optionally substituted with a group of general formula (II)

m= 0, 1, 2, 3 or 4 R5, Re, R7, Re and R9 ^are the same as or different from each other and are selected from an optionally substituted alkyl radical having from 1 to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms, an optionally substituted aryl radical and a -OSi (Rio) 3 radical;

Rio represents an alkyl radical from 1 to 6 carbon atoms, an alkoxy radical from 1 to 6 atoms of carbon or an optionally substituted aryl radical;

R₂ and R₃ are the same as or different from each other and are selected from hydrogen; an optionally substituted, straight-chain or branched, alkyl radical which has from 1 to 4 carbon atoms; and an optionally substituted aryl radical ; or

R2 and R₃ are condensate with an optionally heterosubstituted mono- or polycyclic annular system; Ai is a radical of general formula (III) or (IV)

(in: :iv)

A₂ is a radical of general formula (III), (V) or (VI)

Ru represents a hydrogen atom; an optionally substituted, straight-chain or branched, saturated or unsaturated, alkyl radical that contains from 1 to 6 carbon atoms; an -OH radical;

Ri₂ represents a hydrogen atom; a hydroxyl radical; a -COORi₅ radical; a -CONR₁₆R₁₇ radical; an optionally substituted alkoxy radical from 1 to 18 carbon atoms; a phenoxy radical; a cycloalkyl radical having from 3 to 7 carbon atoms; a phenyl 0 naphtyl radical; a phenyl or naphtyl radical having 1 or 2 identical 0 different substituents, such as phenyl, chlorine, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a phenyl or a group of general formula (II)

in which n= 0 or 1 m= 0, 1, 2, 3 or 4

R5, Re, R₇, R₈ and Rg are the same as or different from each other and are selected from an optionally substituted alkyl radical from 1 to 6 carbon atoms, an alkoxy radical from 1 to 6 carbon atoms, an optionally substituted aryl radical and a - OSi (Rio) 3 radical;

R₁₀ represents an alkyl radical from 1 to 6 carbon atoms, an alkoxy radical from 1 to 6 carbon atoms or an optionally substituted aryl radical;

Ri₅, Ri₆ and Ri₇ are the same as or different from each other and are selected from hydrogen; an optionally substituted, straight-chain or branched alkyl radical from 1 to 18 carbon atoms; M a H, Na or K atom;

R₄ an optionally substituted alkyl group; Ri₄ is H or -SO₃M, where M is as defined above; Ri₃ and R' ₁₃ can be the same as or different from each other and are selected from hydrogen; an optionally substituted acyl radical from 1 to 18 carbon atoms; a straight-chain or branched, saturated or unsaturated, alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a - SO₃M group, a -N(R₄J₃ ⁺ group, where M and R₄ are as defined above, or by a group of general formula (II) as defined above.

3. Triazine derivative of general formula (I) according to claim 1, in which:

Ri represents a hydrogen atom; a straight-chain or branched alkyl radical having from 1 to 18 carbon atoms; a cycloalkyl radical from 3 to 7 carbon atoms; a phenyl or naphthyl radical; a phenyl or naphthyl radical that has 1 or 2 identical or different substituents, such as phenyl, chlorine, alkoxy with 1 to 6 carbon atoms, alkyl containing from 1 to 6 carbon atoms; a phenylalkyl radical in which the alkyl group is a chain of 1 to 6 carbon atoms;

Ai is a radical of general formula (III) or (IV)

A₂ is a radical of general formula (III), (V) or (VI)

in which

Ri₂ represents a hydrogen atom; a hydroxyl radical; a -COORi₅ radical; a -CONRi₆Ri₇ radical; an optionally substituted alkoxy radical from 1 to 18 carbon atoms; a phenoxy radical; a cycloalkyl radical having from 3 to 7 carbon atoms; a phenyl o naphtyl radical; a phenyl or naphtyl radical having 1 or 2 identical o different substituents, such as phenyl, chlorine, alkoxy having from 1 to 6 carbon atoms, alkyl having from 1 to 6 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted with at least one -OH radical, a phenyl or a group of general formula (II) as defined above in wh

m=0, 1, 2, 3 or 4

R₅, R₆, R₇, R_Θ and R₉ represent independently an alkyl radical from 1 to 6 atoms of carbon, an alkoxy radical from 1 to 6 atoms of carbon, an aryl radical or a -OSi (Rio) ₃ radical, in which R₁₀ represents independently an alkyl radical from 1 to 6 atoms of carbon, an alkoxy radical of 1 to 6 atoms of carbon or an aryl radical;

Ri₃ and R' ₁₃ are the same and represent a hydrogen atom; an acyl radical from 1 to 18 carbon atoms; a straight-chain or branched, saturated or unsaturated alkyl radical, containing from 1 to 18 carbon atoms, optionally substituted by at least one -OH radical or optionally substituted by a group of general formula (II) as defined above; and

Ri₄ is H.

4. Derivative according to any of the preceding claims, in which A₂ is selected from a radical of general formula (III) a

where Rn, R_i2, Rj_.3, Ri3- and R₁₄ are as defined in any of claims 1-3.

5. Triazine derivative according to any of the preceding claims, which has the general formula (IA) :

in which Ri₄= H and Ri, R₂, R₃, R13 and R' 13 are as defined in any of the preceding claims.

6. Triazine derivative according to any of claims 1-4 that has the general form

7. Triazine derivative according to any of claims 1-4 that has the general formula (IC) :

8. Triazine derivative according to any of claims 1-4 that has the general formula (ID) :

9. Triazine derivative according to any of claims 1-4 that has the general formula (IE) :

10. Derivative according to any of the preceding claims, in which Ri is a straight-chain or branched alkyl radical that has from 7 to 18 atoms of carbon.

15 11. Derivative according to claim 10, in which R_x is selected from hydrogen, methyl, phenyl and naphthyl optionally at least substituted in one position with a phenyl, chlorine, alkoxy or alkyl and phenylalkyl group.

12. Derivative according to any of claims 1-9, in which R₂ 20 is selected from hydrogen, phenyl, naphthyl and methyl.

13. Derivative according to any of claims 1-9, in which R₃ is selected from hydrogen, phenyl, naphthyl, methyl and ethyl.

14. Derivative according to any of claims 1-9 in which Rn 25 is selected from hydrogen, hydroxyl, methyl and ethyl.

15. Derivative according to any of claims 1 to 9 in which R₁₂ is selected from hydrogen, hydroxyl, methyl, ethyl, tert-butyl, benzyl, cyclohexyl, methoxyphenyl, biphenyl, - COORi₅ and -CONRi₆Ri₇, where R₁₅, R₁₆ and Ri₇ are as defined

30 in any of claims 1-3.

16. Derivative according to any of claims 1-9, in which R₁₅ is selected from hydrogen, methyl, ethyl, propyl, butyl and 2-ethylhexyl.

17. Derivative according to any of claims 1-9, in which Ri₆ is selected from hydrogen, methyl, ethyl, propyl, butyl, tert-butyl and 2-ethylhexyl.

18. Derivative according to any of claims 1-9, in which 5 Ri₇ is selected from hydrogen, methyl, ethyl, propyl, butyl, t-butyl and 2-ethylhexyl.

19. Derivative according to any of claims 1-9, in which R₅ to Rg are selected from methyl, ethyl, methoxy, ethoxy and phenyl.

10 20. Derivative according to any of claims 1-9, in which Rio is selected from methyl, ethyl, methoxy, ethoxy and phenyl.

21. Derivative according to any of the preceding claims selected from the group consisting of:

15 - 2, 4-bis (2, 4-dihydroxyphenyl) -6- (l-methyl-lH-pyrazol-5- yl) -1, 3, 5-triazine;

2,4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy]phenyl}-6- (1- methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine;

2- [2, 4-bis (2-ethylhexyloxy)phenyl] -4- [4- (2-ethylhexy 20 loxy) -2-hydroxyphenyl] -6- (l-methyl-lH-pyrazol-5-yl) -1, 3, 5- triazine;

2, 4-bis (2, 4-dihydroxyphenyl) -6 (l-phenyl-lH-pyrazol-5- yl) -1, 3, 5-triazine;

2,4-bis{ [4- (2-ethylhexyloxy) -2-hydroxy]phenyl}-6- (1- 25 phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine;

2, 4-bis [4- (butoxycarbonyl)phenylamino] -6- (1-methyl-lH- pyrazol-5-yl) -1, 3, 5-triazine;

- 2, 4-bis{4- [ (2- (ethylhexyloxy) carbonyl]phenylamino}-6- (1- methyl-lH-pyrazol-5-yl) -1, 3, 5-triazine;

30 - 2, 4-bis [4- (butoxycarbonyl)phenylamino] -6- (1-phenyl-lH- pyrazol-5-yl) -1,3, 5-triazine;

2, 4-bis{4- [ (2-ethylhexyloxy) carbonyl]phenylamino}-6- (1- phenyl-lH-pyrazol-5-yl) -1, 3, 5-triazine;

2- [ (4-butoxycarbonyl)phenylamino] -4, 6-bis (1-methyl-IH- 35 pyrazol-5-yl) -1, 3, 5-triazine.

22. Process for preparing a triazine derivative of general formula (I) according to claim 1, in which Ai is a radical of general formula (IV)

and A₂ is a radical of general formula (V)

where Ri₄= H, which consists of the alkylation of a compound of general formula (XI) with a compound of general formula (XII)

(XI) where Ri, R₂, R₃, R₁₃ and R' ₁₃ are as defined in claim 1 and R₁₃ and R' ₁₃ being different from each other, in a basic medium that includes a polar solvent, said base preferably being selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate and potassium t-butoxide and said polar solvent from 2- methoxyethanol, 2-ethoxyethanol, N,N-dimethylformamide and ethanol.

23. Process according to claim 22, characterized in that the compound of general formula (XI) is obtained by alkylation of a compound of general formula (IX) with a compound of general formula (X)

where Ri, R₂, and R₁₃ are as defined in claim 1, in a basic medium that includes a polar solvent, said base being preferably selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate and potassium t-butoxide and said polar solvent from 2- methoxyethanol, 2-ethoxyethanol, N,N-dimethylformamide and ethanol, at a temperature ranging between 120°C and the boiling temperature of the solvent.

24. A process for preparing a triazine derivative of general formula (I) according to claim 1, in which A₁ is a radical of general formula (IV)

and A₂ is a radical of general formula (V)

where Ri₄= H, which consists of the alkylation of a compound of general formula (IX) with a compound of general formula (X) or (XII),

where Ri, R₂, R3, R13 and R' 13 are as defined in claim 1 and R₁₃ and R' ₁₃ are the same as each other, in a basic medium that includes a polar solvent, said base being preferably selected from sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate and potassium t-butoxide and said polar solvent from 2- methoxyethanol, 2-ethoxyethanol, N,N-dimethylformamide and ethanol.

25. Process according to claim 23 or 24, characterised in that the compound of general formula (IX) is obtained by acylation of 1, 3-dihydroxybenzene with a compound of general formula (VIII)

in which R₁, R₂ and R₃ are as defined in claim 1, in the presence of a Lewis acid and in an inert solvent, said Lewis acid being preferably trialuminium chloride and said inert solvent xylene.

26. Process for obtaining a compound of general formula (I) according to claim 1, in which Ai and A₂ are

5 where Rn and R₁₂ are as defined in claim 1, characterised in that it comprises reacting a compound of general formula (VIII) with a compound of general formula

15 (VIII) (XIII)

where Ri, R₂, R₃, Rn, R12 are as defined in claim 1, in the presence of a base which is preferably selected from potassium carbonate, sodium carbonate, cesium

20 carbonate, sodium and potassium hydroxide; and a polar solvent which is selected from acetone and dioxane, at a temperature ranging between 0°C and the boiling temperature of the solvent, preferably between room temperature and the boiling temperature of the solvent.

25 27. Process according to claim 26, in which said temperature ranges between 50°C and the boiling temperature of the solvent.

28. Process for obtaining a derivative of general formula (I) according to claim 1, in which

30 Ai is a radical of general formula (III)

35 and A₂ is a radical of general formula (VI)

that comprises reacting a compound of general formula (XIV) with a compound of general formula (XIII)

where Ri, R₂, R₃, R₄ and R₅ are as defined in claim 1; in the presence of a base and a polar solvent, said base being preferably selected from cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and potassium t-butoxide and said polar solvent from 2- methoxyethanol, N,N-dimethylformamide, 2-ethoxyethanol and ethanol.

29. Triazine derivative according to claim 1 that has the general formula (IX)

(IX) in which Ri, R₂ and R₃ have the meaning defined in claim 1.

10

30. Process for preparing a triazine derivative of general formula (IX) according to claim 29, characterised in that it is obtained from the reaction of a compound of general formula (VII), in which Ri, R₂ and R₃ have the meaning 15 defined above, with 2, 4, 6-trichloro-l, 3, 5-triazine

20

(VIII) to provide a compound of general formula (VIII), in which 25 Ri, R₂ and R₃ have the meaning defined above, and the subsequent acylation of 1, 3-dihydroxybenzene with said compound of general formula (VIII) in the presence of a Lewis acid, said Lewis acid being preferably trialuminium chloride.

30 31. Triazine derivative according to any of claims 1 to 22 and 29 for using as a UV radiation absorbing agent.

32. Cosmetic formulation that includes one or more derivatives according to any of claims 1 to 22 and 29 and at least one cosmetically acceptable vehicle or excipient.

33. Dermatological formulation that includes one or more derivatives according to any of claims 1 to 21 and 29 and at least one dermatologically acceptable vehicle or excipient.

5 34. Pharmaceutical formulation that includes one or more derivatives according to any of claims 1 to 21 and 29 and at least one pharmaceutically acceptable vehicle or excipient.

35. Formulation according to any of claims 32-34, which 10 further includes at least one organic, inorganic or organomineral filter against solar radiation.

36. Formulation according to any of claims 32-35 that further includes at least one active substance.

37. Use of a triazine derivative according to any of 15 claims 1 to 21 and 29 for the manufacture of a cosmetic, dermatological and/or pharmaceutical composition as a UV radiation filtering agent.

38. Use of a triazine derivative according to any of claims 1 to 21 and 29 for the manufacture of a formulation

20 for protecting the skin, lips and/or related tissues of a mammal against ultraviolet radiation.

39. Use of a triazine derivative according to any of claims 1 to 21 and 29 for the manufacture of a formulation for the prevention of, use as coadjuvant in the treatment

25 or for the treatment of pathologies caused by ultraviolet radiation in the skin, lips and/or related tissues of a mammal.

40. Use according to any of claims 37-39, in which said mammal is a human.

30 41. Use of a derivative according to any of claims 1 to 21 and 29 as a photostabiliser of synthetic polymers.

42. Use of a derivative according to any of claims 1 to 21 and 29 as an ultraviolet radiation filtering agent in textile fibres.

35