WO2002002066A1

WO2002002066A1 - Naphthomelanins, process for their preparation and compositions thereof

Info

Publication number: WO2002002066A1
Application number: PCT/IB2000/001616
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Individual
Current assignee: Individual
Priority date: 2000-07-05
Filing date: 2000-11-07
Publication date: 2002-01-10
Anticipated expiration: 2003-01-05
Also published as: ITMI20001513A0; IT1318610B1; ITMI20001513A1; AU2001211674A1

Abstract

The present invention relates to naphthomelanins obtainable by polymerization of polyhydroxynaphthalene monomers, alone or in combination or in conjunction with different dihydroxyaromatic co-monomers, to processes for the manufacture thereof either by chemical or enzymatic synthesis and to the use of said naphthomelanins in cosmetic compositions useful to protect the skin, the mucous membranes and hair against UV-radiation and ageing, as well as to the use of said naphthomelanins as polymer additives useful for coloring and protecting against polymer degradation by UV-radiation and oxidation.

Description

NAPHTHOMELANINS, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS THEREOF

FIELD OF THE INVENTION

The present invention relates to synthetic melanins having a naphthalene structure, hereinafter called naphthomelanins.

More particularly, the present invention relates to naphthomelanins obtainable by polymerization of polyhydroxynaphthalene monomers, alone or in combination or in conjunction with different dihydroxyaromatic co-monomers.

The invention also relates to processes for the manufacture of said naphthomelanins either by chemical or enzymatic synthesis.

The invention further relates to the use of said naphthomelanins in cosmetic compositions useful to protect the skin, the mucous membranes and hair against UV- radiation and ageing, as well as the use of said naphthomelanins as polymer additives useful for coloring and protecting against polymer degradation by UV-radiation and oxidation.

BACKGROUND OF THE INVENTION

Melanins are complex three-dimensional biopolymers with several biological functions including: photoreceptor shielding, thermoregulation, photoprotection, camouflage, metal chelation and free radical scavenging. The term melanin refers to a variety of highly irregular heteropolymers containing several structural moieties, such as free carboxy, amino, hydroxy, carbonyl, methoxy, biphenolic, indolic, quinoic groups and so on.

Eumelanins and phytomelanis are nitrogen-containing biopolymers derived from the rearrangement and polymerization of L-dopa and its metabolites in oxidative conditions, whereas allomelanins are yellow-reddish or brown-black melanins typically occuring in the plant kingdom and produced from nitrogen-free precursors. The allomelanins could be further classified as "phytomelanins" resulting from the polymerization of plant polyphenols; and melanin polymers comprising a naphthalene moiety, i.e. "micomelanins". Melanin pigments are often highly localized in individual plants in contrast to the more general distribution of the enzyme tyrosinase. This may be attributed either to the presence of inhibitors (ascorbic acid is of common occurrence) or to circumstances which, under normal conditions, prevent the enzyme and substrate having simultaneous access to oxygen and more probably to the fact that the final stages of melanogenesis does not require the presence of an enzyme. This situation breaks down on disruption of the cell structure and melanin formation can then proceed; alternatively injury to the tissue may result in oxidation of the inhibitor with consequent loss of inhibitory capacity. An example of ascorbic acid inhibition is seen in Stizolobium hassjoo, wherein blackening takes place most rapidly in the younger leaves, which have the lowest concentration of ascorbic acid. A study of melanin formation by a black mutant of the fungus Neurospora crassa it was possible to correlate increased pigmentation with increased tyrosinase activity, but was unable to demonstrate whether this was due to the presence of a larger amount of enzyme or to a partial block in the synthesis of a tyrosinase inhibitor. The inhibitor in this case may be a tbiol, as it was found that tyrosinase activity in Neurospora is dependent upon sulphur nutrition. The fungal pigments are in general wallbound and extracellular in nature and are formed by a radical process starting from diphenols (catechol, 1,8-dihydroxynaphthalene, glutamyl-3,4,-dihydroxybenzene). Fungi melanins containing naphthalene rings are typically produced by fungi such as Verticillus dahliae, Thielaviopsis basicola, Pyricularia oryzae, Wangiella dermatitis, Aspergillus niger as well as by a variety of imperfect fungi, ascomycetes and basidioumycetes. Other examples of polynaphthalene melanins are seen in the fungi Daldinia concentrica and Dahlia tubers, or those detected in the broom Sarothamnus scoparius.

Melanins containing naphthalene rings also appear in the tissue of some higher plants, such as in the shell of Juglans regia by the oxidative polymerization of juglone. Natural melanins comprising a naphthalene moiety derive from the condensation of 1,8-DHN, as this compound is the only known natural precursor thereof.

Said natural melanins can be obtained by an extraction procedure from fungi producing them, which is an expensive method, not suitable for large scale industrial application.

Melanins found increasing acceptance as ingredient in health care industry-' due to their photoprotective, anti-ageing, free radical scavenging, chelating and tanning properties. However, these materials are not currently available for industrial applications, so cosmetic and pharmaceutical applications are limited to the use of the commercially available brown-black eumelanins obtained by polymerization of 5,6-dihydroxymdole carboxylic acid (DHICA) and/or 5,6-dihydroxyindole (DFfl) and related indoles.

The antioxidant and dying properties of melanins could also be exploited in the manufacturing of polymer containing articles . BRIEF DESCRIPTION OF THE DRAWINGS

Some illustrative embodiments of the invention and examples of carrying out the invention, are described in detail hereinbelow, with reference to the accompanying drawing in which: FIG. 1 is a schematic view of two UV-visible spectra, i.e. of a pure naphthomelanin and a naphthomelanin copolymer, which is produced by copolymerization of a dihydroxynaphthalene with a polyphenol, respectively. DETAILED DESCRIPTION OF THE INVENTION

We have now surprisingly found out that melanins comprising naphthalene moieties may be produced from monomer different than 1 ,8-DHN.

In fact, we have ascertain that in oxidative conditions, the commercially available di- and tri-hydroxynaphthalenes submitted to oxidative reaction conditions yield naphthomelanins in a broad range of colors and molecular weights. This issue is particularly important as the synthetic process can be managed and controlled in order to obtain a specific color or antioxidant activity, thus achieving a melanin suitable for a variety of applications in the cosmetic or nutritional industries as well as in polymer manufacturing industries.

Therefore, according to one of its aspects the present invention relates to new synthetic naphthomelanins obtainable by polymerization of at least one monomer unit (a), and optionally one comonomer (b), wherein:

(a) is a polyhydroxynaphthalene or a quinone-derivative form thereof; and

(b) is a polyhydroxyaromatic compound other than (a).

According to the present invention, the term "naphthomelanins" designates a family of new chemical compounds, more specifically synthetic melanins comprising naphthalene moieties in their polymeric structure.

Said naphthomelanins are thus obtained by polymerization in oxidative conditions of polyhydroxynaphthalene monomers and optionally . of dihydroxyaromatic comonomers to yield homo- or ethero-polymers. According to a preferred embodiment, the invention concerns naphthomelanins obtainable by oxidation of at least one monomer (a), and optionally one co-monomer (b) as above, wherein (a) is a naphthalene derivative of formula (I):

wherein:

R independently represents hydrogen or an hydroxy group, the number of hydroxy groups being 2 or 3, provided that positions 1 and 8 are not simultaneously substituted by hydroxy groups, or of the quinone-derivatives thereof. hi oxidative conditions, the polyhydroxynaphthalenes of formula (I) are converted into the corresponding semiquinones and quinones, which afterward undergo either self-condensation or copolymerization with optionally different dihydroxyaromatic compound.

The naphthomelanins of the present invention are obtained by polymerization of suitable naphthalene precursors in presence of atmospheric oxygen, to afford naphthomelanins having a molecular weight comprised between 1x10 and 1x10 dalton.

There are several naphthalene precursors which are able to afford naphthomelanins which are especially contemplated within the scope of the present invention. Preferred naphthalene precursors are the commercially available dihydroxynaphthalenes, such as 1,4-dihydroxynaphthalenes (1,4-DHN), 1,5- dihydroxynaphthalenes (1,5-DHN), 1,6-dihydroxynaphthalenes (1,6-DHN), 2,7- dihydroxynaphthalenes (2,7-DHN), and their corresponding quinones.

In a further embodiment of the present invention "mixed-type" naphthomelanins are provided, which are produced by oxidative copolymerization of polyhydroxynphthlenes with dihydroxyaromatic comonomers, such as eumelanin precursors, plant polyphenols, anthraquinones and dihydroxyisoquinolines

Preferred eumelanin precursors for the present invention include the oxydation product of L-tyrosine and the L-dopa metabolites. Examples are L-dopa, D,L-dopa, 5,6-dihydroxyindole 3-carboxylic acid (DHICA), 5,6-dihydroxyindole (DHI), 3,4-dihydroxyphenylethylamine (dopamine), 3,4-dihydroxyphenylacetic acid (DOPA), Further eumelanin precursors for our purposes may include the neurocataecholammes, mainly formed by the adrenal medulla, such as epinephrine and norepfnephrine. Preferred plant polyphenols include the polyhydroxy compounds such as flavonoid and phytoalexines occurring in vegetal tissues. Examples of said compounds are quercetin, fisetin, fustin, luteolin, OPC, catechin, epicatechin, GC, GCG, EGC, EGCG, myricetin, dihydroquercetin, cyanidin, delphinidin, hydroxytyrosol, protocathechuic acid, protocathechuic aldehyde, gallic acid, tannic acid, and mixture thereof. Further polyphenols may include those plant diphenols which are biogenetically correlated with flavonoid, e.g. the benzyndenpyranones such as brazilin from brazilwood and sappanwood, and haematoxylin from logwood; or the isoflavones such as glycitein from soybean. Preferred anthraquinones for the present invention includes either synthetic or natural anthraquinones bearing two hydroxyl groups within the aromatic structure, e.g. alizarin and rhein.

Preferred dihydroxyquinolines for the present invention includes dihydroxy quinoline and isoquinoline The naphthomelanins of the present invention may be prepared from dihydroxynaphthols, with or without other dihydroxyaromatic comonomers, by a number of chemical or enzymatic polymerization procedures.

A preferred method of producing naphthomelanins is the chemical synthesis, by bubbling air or oxygen through an alkaline aqueous solution of the monomers at pH 10 or above (e.g. by 1 N sodium hydroxide, 2-3 N ammonia or other amines) during 12 to 48 hours (preferably 24 hours), at a temperature ranging from 10 to 90°C, preferably in the range of temperature from 20 to 30°C. The alkaline aqueous solution may comprise catalytic amounts of pro-oxidant metals, such as Cu^H', Fe^"1" , Ni , or Co^"1-1" solutions, for example at 5 to 20 mM concentrations. The amount of alkali depends on the chosen monomer, i.e. the strength and quantity of ionizable hydrogen atoms to be salified in order to achieve the full solubilization of the starting monomers. For strong alkali such as NaOH or KOH the optimum ratio with the melanin precursors is from 3:1 to 10:1 equivalents, whereas for weak alkali, such as ammoma, the optimum molar ratio is not less than 10:1. A fast polymerization procedure may also be carried out by using chemical oxidizing agents, such as hydrogen peroxide, hydrogen iodide, ammonium persulfate, potassium permanganate, or magnesium perchlorate. If such strong oxidants are employed, the naphthomelanin precursors may also be present as monohydroxylated (phenolic) form, and thereafter converted in situ to the corresponding diphenol compounds (the actual melanin monomers) in a "one-pot" oxidative polymerization reaction.

A further preferred method of producing naphthomelanins of the present invention is the enzymatic synthesis by suitable melanin-forming enzymes, such as tyrosinases, polyphenoloxidases (catechol oxidases), phenolases, (phenoloxidases), peroxidases, laccases, lypoxygenase, and mixture thereof.

The enzymatic process makes use of a stream of air or oxygen through a buffered aqueous solution of dihydroxynaphthols, eventually with polyphenols, during 12 to 48 hours or more, preferably at controlled temperature in presence of a suitable enzyme. In this case, the naphthomelanin will be produced in low concentration, due to their low solubility in water of the dihydroxynaphthols in their neutral (non-ionic) form.

Suitable enzymes for the synthesis of the naphthomelanin of the present invention may be obtained from several melanin-producing biological cells or tissues, such as:

(1) extracts of animal skins, e.g. horses, cattle, sheep, pigs, or any other such mammalian source; extracts of skins offish, amphibia, reptiles, birds;

(2) extracts of melanin-producing vegetal source, e.g. mushrooms, potatoes, bananas;

(3) extracts of melanin-producing invertebrate organisms, e.g. worms, arthropods; (4) extracts of melanin producing microorganism, e.g. bacteria and protozoans;

(5) extracts of any organisms in which genes for enzymes producing soluble melanin have been genetically cloned; and

(6) culture media of any organisms or cells which secrete enzymes for producing soluble melanin-such organisms or cells may or may not express cloned genes for the enzymes.

Some of the above mentioned enzymes are commercially available and the others can be prepared by known techniques.

Furthermore, the enzymes capable of actively synthesizing naphthomelanins may not necessarily have to be isolated from the organism producing thereof. More particularly when the used enzyme retains a significant hydroxylating activity, the starting monomers may be formed in situ from the corresponding monohydroxynaphthalenes ("pre-monomers") and monohydroxyaromatic compounds ("pre-comonomers"), as in the case of the chemical synthesis in presence of chemical oxidizing agents.

Illustrative examples of pre-monomers of naphthomelanins include α- and β- naphthol.

Illustrative examples of pre-comonomers of naphthomelanins include dihydrokaempferol, armadendrin, apigenin, p-hydroxybenzaldehyde, PHBA, tyrosol, p-coumaric acid, kaempferol, pelargonin, genistein, L-tyrosine, tyramine, 5-hydroxy- indole, 1-hydroxyanthraquinone, 5-hydroxyquinoline and 5-hydroxyisoquinoline.

The polymerization may be carried out in a standard fashion, i.e. by introducing all the monomers at once, as well as by separate or sequential polymerization of group of monomers, as to provide melanin "block co-polymers". The naphthomelanins of the invention may be used for their application either as the native solution or in solid form, the latter being obtained by a number of precipitation procedures known to those skilled in the art, for example by addition of an organic or mineral acid, e.g. HC1, H₂SO , acetic acid, glycolic acid, or L-tartaric acid; or by addition of water-soluble organic solvents, for example 2 volumes of acetone or ethanol; or by addition of divalent or trivalent metal salts, for example solution of ZnCl₂, MgCl₂, A1C1₃, or CaCl₂, thus forming insoluble metal complexes; or by mixed techniques.

Moreover, the naphthomelanins may be stabilized by stopping the polimerization by the addition of boric acid or salt thereof, which are added to the final reaction mixture to prevent further increase of the molecular weight.

Further modification to the structure of the naphthomelanin may be applied when desired in order to alter their chemical and physical properties, for instance to prepare their ester- or ether- derivatives. Esters of naphthomelanins can be prepared by standard acylation methods, such as by the reaction of the napthomelanin with acid chlorides or acid anhydrides in the presence of a base. The preparation of naphthomelanins by reaction with acid anhydrides in pyridine is particularly useful as described for the acylation of certain other lower molecular weight polyphenols by Thompson, et al., JCS, 1387 (1972), Fletcher, et al, JCS, 1628 (1977) and Hemingway, JCS, 1299 (1982).

Ethers can be prepared by standard etherification methods such as by reaction of the naphthomelanins with alkyl halides and alkyl tosylates in bases. Methyl ethers are readily prepared by diazomethane as disclosed in the etherification of certain other low molecular weight flavonoids by Thompson, JCS, 1387 (1972), Hemingway, JCS, 1299 (1982).

Contrary to natural naphthalene-containing melanins, the synthetic naphthomelanins of the invention are free from any impurity deriving from the natural source (such as for instance protein impurities that are complexed within the melanin molecule during its biosynthesis) and the synthetic process of the invention allows to obtain substantially pure naphthomelanins which are first at all reproducible products having a specific reproducible composition and which also avoid any possible allergy problem, as they are free from impurities that can cause immunitary responses, e.g. as vegetal/fungi proteins. The naphthomelanins may be isolated and/or purified by filtration, ultrafiltration, fractional sedimentation, freeze-drying, spray-drying, dialysis, centrifugation or combination thereof.

Alternatively, the naphthomelanins of the invention may be directly used as aqueous solutions, then complexed or compounded with suitable ingredients during the preparation of cosmetic or polymeric compositions. When the naphthomelanins are used in a soluble or suspended form in a fluid preparation, they are preferably associated with at least one part in weight of a suitable surfactant, such as cationic, anionic, amphoteric and non-ionic surfactants, in order facilitate the dispersion and stabilize the naphthomelanin during storage. The naphthomelanins of the present invention may be used in cosmetic preparations to provide protection against oxidative stress, due to the presence of the highly active moiety within the polymeric network.

In addition, the naphthomelanins of the present invention can be produced in a large variety of colors, thus being a valuable tool for producing cosmetic compositions for facial make-up and hair dyes, as well as in tanning, anti-sun, moisturizing-protecting compositions and toiletry preparations.

It is a further object of the present invention to provide cosmetic compositions comprising the aforementioned naphthomelanins. The cosmetic composition according to the invention may further comprise any cosmetically acceptable ingredients, for example those included in the INCI list drawn by the European Cosmetic Toiletry and Perfumery Association (COLIPA) issued in 96/335/EC "Annex to Commission Decision of 8 May 1996" and further modifications. Preferred cosmetic ingredient to be associated at the naphthomelanins in fluid cosmetic formulations are the surfactants, thus including anionic, cationic, nonionic and zwitterionic surfactants.

Among surfactants are particularly preferred those bearing a positive charge, thus capable of forming a ion pair with the substantially negatively charged naphthomelanins, therefore stabilized and maintained in a suspendedsolubilized form.

More preferably, the naphthomelanins in solution or precipitated form are premixed with one or more surfactant (e.g. soybean lecithin and mono- di-glycerides) prior the mixing with the rest of the formulation, to produce a stable color, an homogeneous appearance and enhancing stability and shelf life of the cosmetic formulations containing thereof.

The cosmetic composition of the invention can be formulated as a lotion, a fluid cream, a cream or a gel. The composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer. For example, a lotion or fluid cream can be packaged in a bottle or a roll-ball applicator, or a capsule, or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation. When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze- container, such as a tube or a lidded jar. In a further embodiment of the present invention the naphthomelanins are used to stabilize and dyes the plastic composition containing polymers.

Also, the naphthomelanins of the present invention may stabilize polymeric materials, thus preventing the oxidative degeneration and ageing by their addition during the manufacturing of article containing polymer, said of the naphthomelanins acting as non-leaking polymeric pigments (dyes) and being furthermore^' characterized by radical scavenger and UV-stabilizer activities.

The non-leaking properties are due to the polymeric structure of the naphthomelanins, whose proper dispersion onto a polymer o mix of polymers provide the coloring behaviour, thus coupled with an anti-ageing protection against polymer degradation.

Polymers which can be stabilized include, for example, the polymers of monoolefϊns and cuolefms, copolymers of monoolefins and diolefms with each other or with other vinyl or acryl monomers; polystyrene and copolymers of styrene or methylstyrene with dienes or acrylic derivatives, graft or block copolymers of styrene; halogen-containing polymers; polymers derived from α, β-unsaturated acids and derivatives thereof (polyacrylates and polymethacrylates, polyacrylamide and polyacrylonitrile) and their copolymers with other unsaturated monomers; polymers derived from unsaturated alcohols and amines, or acyl derivatives thereof or acetals thereof; homo- and co-polymers of cyclic ethers; polyacetals with or without ethylene oxide as comonomer; polyphenylene oxides and sulfides, and mixtures of polyphenylene oxides with polystyrene; polyurethanes; polyamides and copolyamides thereof and copolymers; polyureas, polyimides and polyamide-imides; polyesters; polycarbonates; polysulfones, polyethersulfones and polyetherketones; crosslinked polymers derived from aldehydes and phenols with ureas and melamines; drying and non-drying alkyd resins; unsaturated polyester resins; thermosetting acrylic resins; alkyd resins, polyester resins or acrylate resins; crosslmked epoxide resins; mixtures of polymers as mentioned above, for example PP/EPDM, Polyamide 6/EPDM or ABS, PVC/EVA, PVC/ABS, PVC/MBS, PC/ABS, PBTP/ABS. Also included are natural polymers, such as cellulose, rubber, gelatine and derivatives thereof which are chemically modified in a polymer homologous manner, such as cellulose esters and ethers; naturally occurring and synthetic organic materials which are pure monomeric compounds or mixtures of such compounds, for example mineral oils, animal and vegetable fats, oil and waxes, or oils, fats and waxes based on synthetic esters (e.g. phthalates, adipates, phosphates or trimellitates) and mixtures of synthetic esters with mineral oils in any weight ratios, which materials may be used as plasticizers for polymers or as textile spinning oils, as well as aqueous emulsions of such materials.

Also included are aqueous emulsions of natural or synthetic rubber, e.g. natural latex or lattices of carboxylated styrene/butadiene copolymers, soft and hard polysiloxanes; polyketimines in combination with unsaturated acrylic polyacetoacetate resins or with unsaturated acrylic resins; radiation curable compositions containing ethylenically unsaturated monomers or oligo ers and a polyunsaturated aliphatic oligomer; epoxymelamine resins such as light-stable epoxy resins crosslinked by an epoxy functional co-etherified high solids melamine resin, such as LSE-4103 (Monsanto).

In general, the naphthomelanins of the present invention are added to polymers in a proportion from about 0.01 to about 5% by weight of the final composition, although this proportion will vary with the particular substrate and application. An advantageous proportion is from about 0.5 to about 2%, and especially 0.1 to about 1%.

The naphthomelanins may readily be incorporated into the organic polymers by conventional techniques, at any convenient stage prior to the manufacture of shaped articles therefrom. For example, the naphthomelanins may be mixed with the polymer in dry powder form, or a suspension or emulsion or alkaline solution of the naphthomelanins may be mixed with a solution, suspension, or emulsion of the polymer.

The resulting stabilized polymer compositions of the invention may optionally also contain from about 0.01 to about 5%, preferably from about 0.025 to about 2%, and especially from about 0.1 to about 1% by weight of various conventional additives, such as those listed in WO0009604.

Examples of additives are the polymer antioxidants, thus including alkylated antioxidants (e.g. 2,6-di-t-butyl-4-methylphenol), alkylated hydroquinones (e.g. 2,5- di-tert-butyl-hydroquinone), hydroxylated thiodiphenyl ethers (e.g. 2,2'-thio-bis-(6- tert-butyl-4-methylphenol)), alkylidene-bisphenols (e.g. 2,2'-methylene-bis-(6-tert- butyl-4-methylphenol)), benzyl compounds (e.g. l,3,5-tri-(3,5-di-tert-butyl-4- hydroxybenzyl)-2,4,6-trimethylbenzene), acylaminophenols (e.g.4-hydroxy-lauric acid anilide), esters of β-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionic acid with alcohols and polyols, amides of β-(3,5-di-tertrbutyl-4-hydroxyphenyl)-propionic acid (e.g. N,N'-di-(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)-hexamethylenediamine), diarylamines (e.g. diphenylamine).

Other examples of additives are the UV absorbers and light stabilizers, thus including 2-(2'-Hydroxyphenyl)-benzotriazoles (e.g. the 5 '-methyl- derivative), 2- Hydroxy-benzophenones (e.g. the 4-hydroxy- derivative), esters of optionally substituted benzoic acids (e.g. phenyl salicylate), acrylates (e.g. α-cyano-β,β- diphenylacrylic acid ethyl ester), nickel compounds (e.g. nickel 1:1 complex of 2,2'- thio-bis-[4-(l,l,3,3-tetramethylbutyl)-phenol]), sterically hindered amines (e.g. bis- (2,2,6,6-tetramethylpiperidyl)sebacate), oxalic acid diamides (e.g. 4,4'-di-octyloxy- oxanilide), and hydroxyphenyl-s-triazines (e.g. 2,6-bis-(2,4-dimethylphenyl)-4-(2- hydroxy-4-octyloxyphenyl)-s-triazine).

Other examples of additives include metal deactivators (e.g. N,N'- diphenyloxalic acid diamide), phosphites and phosphonites (e.g. triphenyl phosphite), anti-peroxide agents (e.g. lauryl β-thiodipropionic acid), hydroxylamines (e.g. N,N-dibenzylhydroxylamine), nitrones (e.g. N-benzyl-alpha-phenyl nitrone), polyamide stabilizers (e.g. copper salts with iodides and/or phosphorus compounds and Mn(II) salts), basic co-stabilizers (e.g. melamine), nucleating agents (e.g. 4-tert- butyl-benzoic acid) fillers and reinforcing agents (e.g., glass fibers).

Other examples of polymer additives include plasticizers, lubricants, emulsifϊers, pigments, optical brighteners, flameproofmg agents, anti-static agents, blowing agents and tbiosynergists such as dilauryl thiodipropionate or distearyl thiodipropionate.

The following examples are preferred features of the invention but are not intended to limit it in any way. EXAMPLES

Method A - Chemical synthesis of naphthomelanins

A weighted amount of a total monomers is charged into a flat-bottom conical flask (500 ml) and solubilized in 200 ml of sodium hydroxide 1 N (the amount of sodium hydroxyde shall undergo minor variation according to the K_a and the number of acid centers within the molecule of each plant polyphenol, i.e. according to the quantity

'I and quality of ionizable hydrogen atom to be salified in order to achieve the full solubilization of the starting monomers).

The flask, placed in a thermostatic bath at 24°C, is equipped with an air pump (Silent Air^®, manufactured by Renn-Plax, Inc. in Taiwan R.O.C.) connected by a flexible hose to a disperser, which is placed at the bottom of the flask. The air is forced through the disperser and finely divided throughout the alkaline solution, which, for the oxidative polymerization, is kept under air bubbling for a time ranging from 12 to 48 hours at a temperature of 24°C. The water lost due to the evaporation caused by the stream of air was refilled from time to time in the reaction vessel. The reaction mixture readily develops colors, as melanins absorb widely throughout the ultraviolet and visible spectra (e.g., 220 to 600 nm), the final color of the rnelanm solution varying according to the monomer composition and, at less extent, to the reaction time. Absorbance of melanins was measured by spectrophotometric absorbance of a solution obtained by dissolving 4 mg of naphthomelanin in 100 ml of 0.1 N NaOH. The UV visible absorption spectrum was recorded on a spectrophotometer between the wavelength of 200-700 nm in 1 cm path length cuvette. The representative spectra (200-500 nm) of a selected number of naphthomelanins are shown in FIG 1 and 2, herewith attached. The aforementioned procedure were modified to provide further naphthomelanins, which are modified from the original homo- or etheropolymer under the circumstances described herewithafter.

Modification applicable to the method A i) The use of pro-oxidant transition metal ions, such as Cu÷÷, Nf", Co", Fe" to enhance oxidative polimerization.

In the next Examples, 1,25 mM Cu ^"1" solution is formed by solubilizing 20 mg

CuSO₄*2H₂O into 100 ml of the reaction mixture. ii) The use of weak bases instead of NaOH or KOH solutions.

In the next Examples, ammoma 2.5 N is used as alkalifying medium instead of sodium hydroxide. iii) The use of chemical oxidant, organic or inorganic peroxides.

In the next Examples, ammonium persulfates in 1:1 molar ratio as regard to the total pre-monomer content is added to the reaction mixture under high stirring to provide oxygen circulation, for 26 hours. At the end of reaction a dark naphthomelanin is obtained.

Method B - Enzymatic synthesis of the naphthomelanins

A weighted amount of a total plant polyphenols, calculated from the actual monomer content of the starting material, is charged into a flat-bottom conical flask (250 ml) and solubilized in 100 ml of a solution 20 mg of laccase at 0.8 LAMU/mg (Denilase^® II S, Novo Nordisk A/S, Bagsvaerd, Denmark) in phosphate buffer 50 mM at pH 6,5.

The solution is kept at a temperature of 37°C under high stirring by a magnetic bar, so to force hair circulation for 24 hours. At the end of reaction an insoluble naphthomelanin is obtained.

Modification appliable to both Methods A and B iv) The use of boric acid or its soluble salts to stop post-polymerization pathways. In the next Examples, boric acid is added 30 minutes before the end of the reaction at about 1:1 molar ratio with respect to the total amount of the starting monomer units. v) The use of anti-foaming agent during oxidative polymerization. In the next Examples, Dow Corning^® 2210 is added at 5-40 ppm into the reaction mixture.

Examples 1-20 - Synthesis of naphthomelanins

Following the standard procedure of Methods A and Bl or B2 and further modifications (from i to v), 100 ml of the solution of monomers or of mixed solution of monomers and aromatic comonomers, as shown in Table I, were submitted to oxidative polymerization by dispersed air to provide colored naphthomelanin solutions.

Each Example provided synthetic naphthomelanins which exhibit reproducible physical features, such as color, MW distribution and the UV-spectra, whose representative examples are shown in FIG. 2. The color of the synthetic naphthomelanins of Example 1-20 were analyzed by according a standardized procedure based on scanning of a small quantity of sample adsorbed onto a white paper and the analysis of the color composition.

A quantity of 0.1 ml of the solution were deposited on a filter paper (Whatmann N.3), thereafter the spot were dried at room temperature. The spots were scanned with HP ScannJet 4300C^® Pro (Hewlett Packard) set in a fixed mode for input, acquisition as 16.7 million colors photo, with an output set at customized resolution (x20), resolution area of 239 units, shadows at 6 units and medium tones at 2.2 units.

The spots were then analyzed in different point by the software WhatColor v3.21e by Hikaru Kakahara (Japan) with the dither scope set at 8 surrounding pixels for the analyze of the average color of the spot of naphthomelanins by chemical synthesis, where those by enzymatic synthesis where analized with a single pixel scope.

The value was given in decimal figure with the RGB composition of the 3 main colors, namely Red, Green and Blue. Example 1-22 were evaluated with the afore mentioned method to provide consistent color ranging from the more brown-black to red-purple, as shown in Table I.

EX_ Synthetic NaphthomelaniB L Synthetic Naphthomelanin Molar ratio Reaction- Method Solid RGB values

M o n o m e r >

(a) C o m o n o m e r (b) (a):(b) time Applied content (0.1 ml on paper) W f¹

N° Dihydroxynapht. (g) (mmol) Non-napht. aromatic (g) (mmol) (mol:mol) (h) (A,B, i-v) td (%) R G B

I—¹

1 1,4-DHN quinone 2,5 15,8 24 A-i,v 2,5% 142 82 63

2 1,6-DHN 2,5 15,6 24 A-i 2,5% 61 57 55

3 1,6-DHN 2,5 15,6 24 A 2,5% 80 71 66

4 1,6-DHN 1,0 6,2 L-dopa 1,5 7,6 3:4 24 A 1,0% 133 102 82

5 1,6-DHN 1,5 9,4 dopamine 1,0 5,3 2:1 24 A-i 1,5%. 126 96 79

6 1,6-DHN 1,3 8,1 2,7-DHN 1,3 8,1 1:1 24 A-i _. 1,3% 49 57 55

7 1,6-DHN 2,0 12,5 brazilwood 0,5 1,5 9:1 12 A-i,v 2,0% 75 67 65

8 1,6-DHN 1,5 9,4 alizarine 1,0 4,2 2:1 24 A-i,v 1,5% 84 71 66

9 1,6-DHN 2,5 15,6 fustic (40% sol.) 2,0 2,6 6:1 24 A-i 2,5%o 82 72 66

10 1,5-DHN 2,5 15,6 24 A 2,5% 67 59 57

11 1,5-DHN 1,3 7,8 24 A-i 1,3% 97 74 69

12 1,5-DHN 2,5 15,6 24 A-ii,v 2,5% 145 112 101

13 1,5-DHN 1,3 8,1 24 A-v 1,3% 103 85 77

14 1,5-DHN 2,5 15,6 2,7-DHN 1,3 8,1 2:1 24 A 2,5% 82 73 71

15 2,7-DHN 2,5 15,6 anthocyanins (20%) 10,0 5,6 3:1 24 A-i,v 2,5% 111 . 100 88

16 2,7-DHN 1,0 6,2 protocatechuic acid 1,5 9,7 3:4 24 A-i 1,0% 114 76 78

17 2,7-DHN 1,5 9,4 protocatechuic acid 1,5 9,7 1:1 12 A-i 1,5% 117 79 78

18 2,7-DHN 1,5 9,4 protocatechuic acid 1,0 6_b5 3:2 24 A 1,5% 99 72 74

19 2,7-DHN 1,0 6,2 pyrocatechol 1,0 9,1 3:4 24 A-i 1,0% 104 68 74

20 1,6-DHN 0,02 0,1 24 B 0,02% 67 63 64

21 1,6-DHN 2,0 12,5 lawsone 0,55 3,2 4:1 26 A-iv . 2,0% 78 66 52

22 1,6-DHN ISO 6,2 p-hydroxybenzoic ac. 0,9 6,5 1:1 26 A-iii 1,0% : 97 73 64

Applicative Examples 1-3 -Dermoprotective foundation 100 g of each foundations contain:

Appl. Ex. 1 Appl. Ex. 2 Appl. Ex. 3

Triethanolamine stearate 2.5 g 2.5 g 2.5 g

Glycerol mono- e distearate 0.4 g 0.4 g 0.4 g

Magnesium silicate 1.9 g 1.9 g 1.9 g

Pigment formed with the naphthomelanin of Example 6 (*) 14.0 g 10.0 g 3.7 g

Pigment formed with the naphthomelanin of Example 16 (*) 2.9 g 8.0 g -

Pigment foπned with the naphthomelanin of Example 21 (*) - 2,1 g 15.0 g

Titanium dioxide (rutile) 10.0 g 10.0 g 10.0 g

Miscela di PEG-6 e PEG-32 9.0 g 9.0 g 9.0 g

Nylon micronized 9.0 g 9.0 g 9.0 g

Cyclomethycone 13.0 g 13.0 g 13.0 g

Propylene glycol 5.0 g 5.0 g 5.0 g

Glycerine 4.5 g 4.5 g 4.5 g

Preservatives 0 5 g 0.5 g 0.5 g

Deionized water qb to 100 g qb to 100 g qb to 100 g

(*) In 100 ml of the solution of the naphthomelanin are suspended 13 g of alumina, the slurry is stirred and added with a solution of A1C1₃ 1M until pH 6-7. The slurry is then washed with demineralized water, filtrated, then dried, and the pigment is finally grinded. The fatty phase containing the oils and stearic acid and the aqueous phase containing triethanolamine are separately heated to 80 °C. The mixture is emulsified at 80°C and cooled slowly. During the cooling, the mixture of pigments, previously ground in propylene glycol and cyclomethicone are added. Applicative Example 4 - Polymer stabilization 100 ml of the 2.5% w/v alkaline solution of the naphytomelanin of Example 2 was added with 5 g polyvynilpyrrolidone (PVP, average MW = 15 kdalton, Fluka, Buch, CH) and precipitated with HC13,5 N until pH 3-4, then filtered and dried in an oven at 80°C to yield 13.6 g of naphthomelanimPVP mixture. A master batches was prepared by extruding 10% by weight of tne naphthomelanimPVP mixture with powdered LDPE (Riblene^® FF 29 V, Enichem, Milan, Italy) with a density of 0.921 g cm³ and a melt flow index (190°C/2.16 kg) of 0.60 g/10 min. Pure LDPE and the masterbatch at 20:1 w/w ratio were blended in a slow mixer and blow extruded at 200°C, to provide films of 150 um thickness. The films was exposed on the south-facing roof of a greenhouse in Como,

Italy. The greenhouse was treated once with 4% w/v of aqueous solution of metam- sodium (Vapam^®, Baslini SpA, Treviglio (BG), Italy) and monthly with 0.1 % of aqueous solution of permethrin (Sesmetrin^®, Bimex SpA, Isola (VI), Italy).

The degradation measured by FT-IR analysis gave a weather resistance of about 10^"2, expressed as the difference between the measured carbonyl absorptions of the films before and after 6 months of ageing.

It should be understood that the specific forms of the invention herein illustrated and described are intended to be representative only. Changes, including but not limited to those suggested in this specification, may be made in the illustrated embodiments without departing from the clear teachings of the disclosure.

Claims

1. Synthetic naphthomelanins obtainable by polymerization of at least one monomer unit (a), and optionally one comonomer (b), wherein:

(a) is a polyhydroxynaphthalene or a quinone-derivative form thereof; and

(b) is a dihydroxyaromatic compound other than (a), as well as their ester- or ether-derivatives.

2. Naphthomelanins according to Claim 1, wherein (a) is a polyhydroxynaphthalene of formula (I):

wherein:

R independently represents hydrogen or an hydroxy group, the number of hydroxy groups being 2 or 3, provided that positions 1 and 8 are not simultaneously substituted by hydroxy groups.

3. Naphthomelanins according to Claims 1 or 2, wherein the polyhydroxyaromatic compound is a plant polyphenol selected in the group consisting in quercetin, fisetin, fustin, luteolin, OPC, catechin, epicatechin, GC, GCG, EGC, EGCG, myricetin, dihydroquercetin, cyanidin, delphinidin, hydroxytyrosol, protocathechuic acid, protocathechuic aldehyde, gallic acid, tannic acid, pyrocatechol, pyrogallol and mixture thereof.

4. Naphthomelanins according to Claims 1 or 2, wherein the polyhydroxyaromatic compound is an eumelanin precursor selected in the group consisting in L-dopa, D,L-dopa, DHI, DHICA, dopamine and mixture thereof.

5. Naphthomelanins according to Claims 1 or 2, wherein the polyhydroxyaromatic compound is a anthraquinone selected from the group consisting in alizarin, rhein and mixture thereof.

6. Process for preparing naphthomelanins according to Claims 1 to 5 comprising bubbling air or oxygen through an alkaline aqueous solution of the corresponding monomers at pH 10 or higher, during 12 to 48 hours, at a temperature ranging from 10 to 90°C.

7. The process of Claim 6, further comprising catalytic amounts of pro- oxidant metal ions selected in the group consisting in Cu⁺⁺, Fe , Ni⁺⁺, Co^"1-1" and mixture thereof.

8. The process of Claims 6 or 7, wherein the chemical oxidizing agent is selected in the group consisting in hydrogen peroxide, hydrogen iodide, ammonium persulfate, potassium permanganate, magnesium perchlorate, and mixture thereof.

9. Process for preparing naphthomelanins according to Claims 1 to 5 comprising bubbling air or oxygen through an buffered aqueous solution of the corresponding monomers at pH from 9.5 to 4.5, during 12 to 48 hours, at a temperature ranging from 20 to 45°C and in presence of a suitable enzyme.

10. The process of Claim 9, wherein the enzyme is selected in the group consisting in tyrosinases, polyphenoloxidases, phenolases, peroxidases, laccases, lypoxygenase and mixture thereof.

1 L The process of Claims 8 to 10 wherein the monomer units (a) or (b)_a re formed in situ from monohydroxylated pre-momomers.

12. The process of Claim 11 wherein the pre-momomers are selected in the group consisting in α-naphthol, β-naphthol, dihydrokaempferol, armadendrin, p-hydroxybenzaldehyde, PHBA, tyrosol, p-coumaric acid, apigenin, kaempferol, pelargonin, genistein, tyrosine, tyramine, 5- hydroxy-indole, 2-hydroxy-anthraquinone, 5-hydroxy-quinoline, 5- hydroxy-quinoline and mixture thereof.

13. A cosmetic composition comprising as active ingredient at least one naphthomelanins according to Claims 1 to 5.

14. Cosmetic composition according to Claim 13, for facial make-up, hair dyes, tanning, anti-sun, toiletry, moisturizing and protecting the skin.

15. Use of naphthomelanins according to Claims 1 to 5 for facial make-up, hair dyes, tanning, anti-sun, toiletry, moisturizing and protecting the skin.

16. Stabilized polymer composition which comprises a polymer, a copolymer or a polymer blend and an effective stabilizing amount of an at least one naphthomelanins according to Claims 1 to 5.

17. Use of naphthomelanins according to Claims 1 to 5 for stabilizing a polymer, a copolymer or a polymer blend.