Amarousiaxanthin A esters and their uses

Abstract

The present invention relates to compounds of formula (I) or stereoisomers thereof, in particular amarousiaxanthin A acetate. The present invention also relates to processes for the preparation of these compounds, compositions containing them and their medical and cosmetic uses.

Description

[Technical field]

[0001] The present invention relates to amarousiaxanthin A esters, processes for their preparation, compositions containing them and their medical and cosmetic uses. [Background technology]

[0002] Amarousiaxanthin A (ACX) is a compound found in the culture of Marousium priciferum ( Amaroucium pliciferum ACX is one of the major metabolites of fucoxatin after oral administration in mice, and the postulated metabolism is deacetylation of fucoxatin (FCX) to fucoxatinol and subsequent translocation to ACX in the liver (Drug Metab Dispos, 2004, 32, 205-211).

[0003] The wide range of applications of fucoxanthin (FCX), especially as an antioxidant, antiobesity, antidiabetic, and anticancer agent, is well known in the literature (Int J Mol Sci, 2013, 14, 13763-13781, Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865, 158618), whereas ACX was recently reported to significantly suppress hepatic oxidative stress, inflammation, and fibrosis in rodent models (Biochem Biophys Res Commun, 2020, 528, 305-310), making this compound a highly promising candidate.

[0004] FCX is widely distributed in brown algae, diatoms and dinoflagellates and is commercially available from natural extracts. Unfortunately, ACX or its derivatives only exist in small amounts in nature, so there is no direct source. Until now, ACX has been obtained from natural extracts after laborious purification steps or by very long chemical synthesis, which has the risk of low overall yields and incomplete control of the chiral center (Org Lett, 2013, 15, 5310-5313).

[0005] Thus, there is a need for ACX prodrugs that can be synthesized in good yields without isomerization of the chiral center and that convert directly to ACX after administration without the formation of intermediate metabolites as seen with FCX administration. Summary of the Invention

[0006] The present inventors have unexpectedly found that ACX esters, especially acetate esters, spontaneously convert to ACX and its cis isomer in the body. The esters can be easily obtained from commercially available fucoxanthin in a one-pot, one-step synthesis, and are fully converted without the risk of isomerization of the chiral center. The acetate esters can also be used as precursors of ACX to obtain pure ACX, further ACX ester derivatives or other fucoxanthin metabolites.

[0007] Thus, in a first aspect, the present invention provides a compound of formula (I): [ka] (Wherein, R is a straight or branched chain C 1 -C 4 alkyl) or a stereoisomer thereof.

[0008] In a second aspect, the present invention provides a method for preparing a compound as defined in the first aspect, comprising the steps of: a) Formula (II) or (IIa): [ka] with an oxidizing agent, preferably selected from the group consisting of tetra-n-propylammonium perruthenate (TPAP) and 2-iodoxybenzoic acid (IBX), optionally in the presence of a co-oxidizing agent, preferably N-methylmorpholine N-oxide (NMO), to produce a compound of formula (III) or (IIIa): [ka] obtaining a compound of b) reacting a compound of formula (III) or (IIIa) with SiO 2 in the presence of a base, preferably a base selected from the group consisting of N-methylmorpholine and triethylamine; 2 to obtain a compound of formula (I) or (Ia) wherein R is methyl; and c) R is a straight or branched chain C 2 -C 4 In the case of compounds of formula (I) or (Ia) which is alkyl, c1) Treating a compound of formula (I) or (Ia) in which R is methyl with an esterase, preferably a lipase, to give a compound of formula (IV) or (IVa): [ka] and c2) coupling a compound of formula (IV) or (IVa) with a compound of formula (V): R-COOH (V) (Wherein, R is a straight or branched chain C 2 -C 4 (It is alkyl) with a carboxylic acid of formula (I) or (Ia): [ka] (Wherein, R is a straight or branched chain C 2 -C 4 alkyl) To obtain the compound The present invention relates to a method comprising the steps of:

[0009] A third aspect relates to the use of a compound of the first aspect for the manufacture of a composition comprising amaroussiaxanthin A, and / or amaroussiaxanthin A and paracentrone.

[0010] A fourth aspect relates to a method for producing amaroussiaxanthin A, comprising treating a compound of the first aspect with an esterase, preferably a lipase.

[0011] A fifth aspect relates to a compound of the first aspect and a compound of formula (VI), preferably formula (VIa): [ka] (Wherein, R is a straight or branched chain C 2 -C 4 alkyl, preferably methyl. Preferably, the compound has formula (VIa), preferably wherein R is methyl.

[0012] A sixth aspect relates to a pharmaceutical composition comprising a compound of the first aspect or a composition of the fifth aspect.

[0013] A seventh aspect relates to a compound of the first aspect, a composition of the fifth aspect or a pharmaceutical composition of the sixth aspect for use in medicine.

[0014] An eighth aspect relates to the compound of the first aspect, the composition of the fifth aspect or the pharmaceutical composition of the sixth aspect for use in the treatment and / or prevention of a disease selected from the group consisting of cancer, cardiovascular disease, gut microbiota imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia related disease, ageing related disorder, lipid related disease, glucocorticoid induced muscle atrophy, bone related disease, eye disease, angiogenesis related disease, psoriasis, eczema, atopic dermatitis, and thyroid related disorder.

[0015] A ninth aspect relates to a food, functional cosmetic, functional food, or cosmetic composition comprising a compound of the first aspect or a composition of the fifth aspect.

[0016] A tenth aspect relates to a cosmetic method for preventing and / or reducing skin aging and / or ameliorating the adverse cosmetic effects of aging, comprising administering to a subject in need thereof a compound of the first aspect, or a composition of the fifth aspect, or a food, functional cosmetic, functional food or cosmetic composition of the ninth aspect. [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows the plasma concentrations of amaroussiaxanthin A following oral delivery of amaroussiaxanthin A acetate. Description of the Invention

[0018] Compounds of formula (I) The first aspect of the present invention relates to a compound of formula (I): [ka] (Wherein, R is a straight or branched chain C 1 -C 4 alkyl) or a stereoisomer thereof.

[0019] The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having 1 to 4 carbon atoms and attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, iso-butyl, and sec-butyl. Preferably, the alkyl is methyl.

[0020] The term "stereoisomers" refers to compounds composed of the same atoms bonded in the same series of bonds, but with different, incompatible three-dimensional structures.

[0021] In a preferred embodiment, the compound of the present invention has formula (Ia): [ka] (wherein R is as previously defined). It is a compound of the formula:

[0022] In a preferred embodiment, the compound of the invention is a compound of formula (I) where R is methyl.

[0023] In a more preferred embodiment, the compound of the present invention is a compound of formula (Ia) where R is methyl, i.e., amarouthiaxanthin A acetate.

[0024] Methods for preparing compounds of formula (I) A second aspect of the present invention relates to a method for preparing a compound as defined in the first aspect, comprising the steps of: a) Formula (II) or (IIa): [ka] with an oxidizing agent, preferably selected from the group consisting of tetra-n-propylammonium perruthenate (TPAP) and 2-iodoxybenzoic acid (IBX), optionally in the presence of a co-oxidizing agent, preferably N-methylmorpholine N-oxide (NMO), to produce a compound of formula (III) or (IIIa): [ka] obtaining a compound of b) reacting a compound of formula (III) or (IIIa) with SiO 2 in the presence of a base, preferably a base selected from the group consisting of N-methylmorpholine and triethylamine; 2 to obtain a compound of formula (I) or (Ia) wherein R is methyl; and c) R is a straight or branched chain C 2 -C 4 In the case of compounds of formula (I) or (Ia) which is alkyl, c1) Treating a compound of formula (I) or (Ia) in which R is methyl with an esterase, preferably a lipase, to give a compound of formula (IV) or (IVa): [ka] and c2) coupling a compound of formula (IV) or (IVa) with a compound of formula (V): R-COOH (V) (Wherein, R is a straight or branched chain C 2 -C 4 (It is alkyl) with a carboxylic acid of formula (I) or (Ia): [ka] (Wherein, R is a straight or branched chain C 2 -C 4 alkyl) To obtain the compound The present invention relates to a method comprising the steps of:

[0025] When step a) is carried out with a compound of formula (II), a compound of formula (III) is obtained in this step, a compound of formula (I) in which R is methyl is obtained in step b), a compound of formula (IV) is obtained in step c1), where R is C 2 -C 4 The alkyl compound (I) is obtained in step c2).

[0026] When step a) is carried out with a compound of formula (IIa), a compound of formula (IIIa) is obtained in this step, a compound of formula (Ia) in which R is methyl is obtained in step b), a compound of formula (IVa) is obtained in step c1), in which R is C 2 -C 4 The alkyl compound of formula (Ia) is obtained in step c2).

[0027] The oxidizing agent in step a) may be any suitable oxidizing agent capable of providing a compound of formula (III) or (IIIa). Examples of oxidizing agents are tetra-n-propylammonium perruthenate (TPAP) and 2-iodoxybenzoic acid (IBX), preferably TPAP.

[0028] In step a), a co-oxidant may also be used. An example of a suitable co-oxidant is N-methylmorpholine N-oxide (NMO).

[0029] Preferably, step a) is carried out using TPAP as oxidant and NMO as co-oxidant.

[0030] The reaction of step a) is preferably carried out in an organic solvent such as dichloromethane, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran or mixtures thereof, preferably dichloromethane.

[0031] The reaction of step a) is preferably carried out at a temperature in the range of 15°C to 35°C.

[0032] The amount of the oxidizing agent used in step a) is preferably 0.01 to 0.5 mol, more preferably 0.05 to 0.2 mol, per 1 mol of the compound of formula (II) or (IIa).

[0033] When present, the amount of co-oxidant used in step a) is preferably from 1.5 to 5 mol, more preferably from 1.5 to 2.5 mol, per mol of compound of formula (II) or (IIa).

[0034] Step a) is preferably carried out with the removal of water, for example, 4 Å molecular sieves can be used in step a).

[0035] In another embodiment, step a) is carried out without removing water.

[0036] Preferably, step a) is carried out for 0.5 to 5 hours.

[0037] Step a) provides a compound of formula (III) or (IIIa). When step a) is carried out using a compound of formula (II), a compound of formula (III) is obtained in this step. When step a) is carried out using a compound of formula (IIa), a compound of formula (IIIa) is obtained in this step.

[0038] The next step of the process comprises reacting a compound of formula (III) or (IIIa) with SiO in the presence of a base, preferably a base selected from the group consisting of N-methylmorpholine and triethylamine. 2 to obtain a compound of formula (I) or (Ia) wherein R is methyl.

[0039] The compounds of formula (III) or (IIIa) are obtained in step a).

[0040] SiO used in step b) 2 The amount of is preferably 10 to 50 mol per 1 mol of the compound of formula (II) or (IIa).

[0041] Step b) is carried out in the presence of a base. Examples of suitable bases are N-methylmorpholine, trimethylamine, N,N-diisopropylethylamine and mixtures thereof, preferably N-methylmorpholine.

[0042] The amount of base used in step b) is preferably 0.1 to 5 mol per mol of the compound of formula (II) or (IIa).

[0043] In a particular embodiment, step a) is carried out in the presence of NMO as a co-oxidant, yielding N-methylmorpholine as a by-product, which is then used as a base in step b).

[0044] Thus, in a particular embodiment, steps a) and b) are carried out in one pot.

[0045] The reaction of step b) is preferably carried out in an organic solvent such as dichloromethane, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran or mixtures thereof, preferably dichloromethane.

[0046] The reaction of step b) is preferably carried out at a temperature in the range of 15°C to 35°C.

[0047] Preferably, step b) is carried out for 0.5 to 24 hours.

[0048] Step b) provides a compound of formula (I) or (Ia) where R is methyl. When step b) is carried out with a compound of formula (III), this step provides a compound of formula (I) where R is methyl. When step b) is carried out with a compound of formula (IIIa), this step provides a compound of formula (Ia).

[0049] When the target compound of the process of the present invention is a compound of formula (I) or (Ia) in which R is methyl, step c) is not carried out.

[0050] The compound of the present invention is a compound in which R is a straight or branched chain C2 -C 4 For compounds of formula (I) or (Ia) that are alkyl, step c) is carried out. Step c) comprises steps c1) and c2).

[0051] Step c1) is to treat a compound of formula (I) or (Ia) in which R is methyl with an esterase, preferably a lipase, to obtain a compound of formula (IV) or (IVa): [ka] The aim is to convert it into a compound of the formula:

[0052] The compounds of formula (IV) or (IVa) are obtained in step b).

[0053] Any esterase can be used that can obtain compound (IV) or (IVa) from the compound of formula (I) or (Ia), respectively. Examples of esterases are lipase and cholesterol esterase, preferably lipase.

[0054] Step c1) is preferably carried out in the presence of an emulsifier, such as sodium taurocholate, sodium dodecyl sulfate or hydrates thereof.

[0055] Preferably, step c1) is carried out in an aqueous solvent, preferably at a pH of 6.5 to 7.5, more preferably step c1) is carried out in phosphate buffered saline (PBS).

[0056] The reaction of step c1) is preferably carried out at a temperature in the range of 30°C to 45°C.

[0057] Preferably, step c1) is carried out for 2 to 24 hours.

[0058] Step c1) provides a compound of formula (IV) or (IVa). When step c1) is carried out using a compound of formula (I), a compound of formula (IV) is obtained in this step. When step c1) is carried out using a compound of formula (Ia), a compound of formula (IVa) is obtained in this step.

[0059] The next step of the process of the present invention is to couple a compound of formula (IV) or (IVa) to a compound of formula (V): R-COOH (V) (Wherein, R is a straight or branched chain C 2 -C 4 (It is alkyl) with a carboxylic acid of formula (I) or (Ia): [ka] (Wherein, R is a straight or branched chain C 2 -C 4 alkyl) The step c2) is to obtain the compound represented by the formula:

[0060] The compounds of formula (IV) or (IVa) are obtained in step c1).

[0061] The coupling agent used in step c2) may be any suitable coupling agent known in the art for esterifying a carboxylic acid with an alcohol. Examples of suitable coupling agents are carbodiimides, preferably dicyclohexylcarbodiimide (DDC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide (EDC) or salts thereof. The esterification reaction in step c2) is carried out in the presence of DMAP.

[0062] Preferably, 1-2 mol of coupling agent per mol of carboxylic acid (V) are used in step c2).

[0063] Preferably, 0.01-0.5 mol of DMAP per mol of carboxylic acid of formula (V) is used in step c2).

[0064] Preferably, 1 to 2 mol of compound of formula (IV) or (IVa) are used in step c2) per mol of carboxylic acid of formula (V).

[0065] Preferably, step c2) is carried out in an organic solvent such as dichloromethane, N,N-dimethylformamide or a mixture thereof.

[0066] The reaction of step c2) is preferably carried out at a temperature in the range of 0°C to 30°C.

[0067] Preferably, step c2) is carried out for 1 to 15 hours.

[0068] Step c2) produces a linear or branched C 2 -C 4 When step c2) is carried out with a compound of formula (IV), a compound of formula (I) or (Ia) is obtained in which R is selected from the group consisting of linear or branched C 2 -C 4 In this step, a compound of formula (I) is obtained, in which R is selected from the group consisting of straight or branched chain C alkyl. When step c2) is carried out with a compound of formula (IVa), 2 -C 4 A compound of formula (Ia) selected from the group consisting of alkyl is obtained in this step.

[0069] In a preferred embodiment, in the method of the present invention, The oxidizing agent in step a) is TPAP; Step a) is carried out in the presence of a co-oxidant, The co-oxidant in step a) is NMO; and / or The base in step b) is N-methylmorpholine.

[0070] In another preferred embodiment, steps a) and / or b) of the process of the invention are carried out in the presence of water, in particular with more than 0.05 mol of water per mol of compound of formula (II) or (IIa), thereby obtaining a reaction between a compound of formula (I) or (Ia) and a compound of formula (VI) or (VIa): [ka] (Wherein, R is a straight or branched chain C 2 -C 4 alkyl, preferably methyl), preferably a compound of formula (VIa), preferably a mixture of compounds of formula (VIa) where R is methyl.

[0071] Alternatively, the compound of formula (VI) or (VIa) can be obtained by heating the compound of formula (I) or (Ia) at 60-90°C in the presence of water. In one embodiment, step a) is carried out in the presence of water. In another embodiment, step a) is carried out without the presence of water. To avoid the presence of water in step a), a water removing agent such as 4 Å molecular sieves can be used. In another embodiment, step b) is carried out in the presence of water. In another embodiment, step b) is carried out without the presence of water. To avoid the presence of water in step a), a water removing agent such as 4 Å molecular sieves can be used. In another embodiment, both steps a) and b) are carried out in the presence of water. In another embodiment, both steps a) and b) are carried out without the presence of water. To avoid the presence of water in steps a) and b), a water removing agent such as 4 Å molecular sieves can be used.

[0072] The term "presence of water" refers to an amount of water between 0.1% and 100% by volume, preferably 100% by volume. This amount of water is determined with respect to the solvent present in the reaction medium, without taking into account the water removed by the water removal agent.

[0073] A third aspect relates to the use of a compound of the first aspect for the preparation of a composition comprising amaroussiaxanthin A, and / or amaroussiaxanthin A and paracentrone.

[0074] The compounds of formula (I) or (Ia) of the first aspect, preferably compounds of formula (Ia), preferably where R is methyl, can be used for the preparation of amarouthiaxanthin A. Amarouthiaxanthin A can be obtained, for example, by carrying out steps a), b) and c1) of the process of the invention as described above.

[0075] The compound of formula (I) or (Ia) of the first aspect, preferably the compound of formula (Ia), preferably R is methyl, can be used as described above for the preparation of the compound of formula (VI) or (VIa), preferably the compound of formula (VIa), preferably R is methyl (i.e. paracentrone acetate). The compound of formula (VI) or (VIa), preferably the compound of formula (VIa), preferably R is methyl, can be obtained, for example, by carrying out step a) and / or b) of the process of the invention in the presence of water as described above. This process gives a mixture of the compound of formula (I) or (Ia) and the compound of formula (VI) or (VIa), preferably the compound of formula (Ia) and the compound of formula (VIa), preferably R is methyl.

[0076] The compounds of formula (I) or (Ia) of the first aspect, preferably compounds of formula (Ia), preferably where R is methyl, can be used for the preparation of amarouthiaxanthin A and paracentrone. Amarouthiaxanthin A and paracentrone can be obtained, for example, by carrying out steps a), b) and c1) of the process of the invention as described above, said steps a) and / or b) being carried out in the presence of water.

[0077] A fourth aspect relates to a process for the preparation of amaroussiaxanthin A, comprising treating a compound of formula (I) or (Ia) of the first aspect, preferably a compound of formula (Ia), preferably where R is methyl, with an esterase, preferably a lipase. Specific conditions are as described above for steps a), b) and c1) of the process of the invention.

[0078] A further aspect relates to a process for the preparation of paracentrone, which comprises treating a compound of formula (VI) or (VIa) as above, preferably a compound of formula (VIa), preferably where R is methyl, with an esterase, preferably a lipase. Specific conditions are described above for step c1) of the process of the invention.

[0079] composition A fifth aspect relates to a composition comprising a compound of formula (I) or (Ia) of the first aspect, preferably a compound of formula (Ia), preferably where R is methyl, and a compound of formula (VI) or (VIa) as described above, preferably a compound of formula (VIa), preferably where R is methyl.

[0080] In a particular embodiment, the amount of the compound of formula (I) or (Ia) in the composition of the fifth aspect is from 10 to 99.9% by weight, preferably from 40 to 99% by weight, based on the total weight of the composition.

[0081] In a particular embodiment, the amount of compound of formula (VI) or (VIa) in the composition of the fifth aspect is from 1 to 60% by weight relative to the total weight of the composition.

[0082] A sixth aspect relates to a pharmaceutical composition comprising a compound of formula (I) or (Ia) of the first aspect, preferably a compound of formula (Ia), preferably where R is methyl, or a composition of the fifth aspect.

[0083] The term "pharmaceutical composition", as used herein, relates to a composition comprising at least a combination provided by the present invention together with a pharma- ceutically acceptable carrier.

[0084] As used interchangeably herein, "pharmacologically acceptable vehicle", "pharmacologically acceptable carrier", "pharmacologically acceptable diluent" or "pharmacologically acceptable excipient" refers to any conventional non-toxic solid, semi-solid or liquid filler, diluent, encapsulating agent or formulation auxiliary. A pharma-ceutically acceptable carrier is essentially non-toxic to a recipient at the dosage and concentration employed and is compatible with the other ingredients of the formulation. The number and nature of the pharma-ceutically acceptable carriers depend on the desired mode of administration. Pharmaceutically acceptable carriers are known and can be prepared by methods well known in the art. They are involved in carrying or transporting the subject chemicals from one organ or part of the body to another without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Examples of materials that can function as pharma- ceutically acceptable carriers include: (a) sugars (e.g., lactose, glucose, and sucrose), (b) starches (e.g., corn starch and potato starch), (c) cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), (d) powdered tragacanth, (e) malt, (f) gelatin, (g) talc, (h) excipients (e.g., suppository waxes), (j) glycols (e.g., propylene glycol), (k) glycerides (e.g., propylene glycol), (m) glycerides (e.g., glycerides), (n ... Examples of suitable non-toxic compatible substances include, for example, glycerol, sorbitol, mannitol, and polyethylene glycol), (k) polyols (e.g., glycerin, sorbitol, mannitol, and polyethylene glycol), (1) esters (ethyl oleate and ethyl laurate), (m) agar, (n) buffers (e.g., magnesium hydroxide and aluminum hydroxide), (o) alginic acid, (p) pyrogen-free water, (q) isotonic saline, (r) Ringer's solution, (s) ethyl alcohol, (t) phosphate buffer, and (u) other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifying agents, and lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, release agents, coating agents, sweetening agents, flavorings, and perfuming agents, preservatives, and antioxidants may also be present in the composition.Examples of pharma- ceutically acceptable antioxidants include (a) water-soluble antioxidants (e.g., ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, or sodium sulfite), (b) oil-soluble antioxidants (e.g., ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, or α-tocopherol), and (c) metal chelators (e.g., citric acid, ethylenediamine tetraacetate (EDTA), sorbitol, tartaric acid, or phosphoric acid).

[0085] More preferably, the pharmaceutical formulation comprises a vehicle or carrier suitable for topical or oral administration.

[0086] Depending on the particular mode of administration, the pharmaceutical preparations may be formulated into tablets, pills, capsules, sachets, granules, powders, suspensions, emulsions, anhydrous or aqueous topical preparations and solutions.

[0087] Pharmaceutically acceptable carriers or vehicles are well known to those skilled in the art and are readily available to the public. Preferably, the pharma-ceutically acceptable carrier or vehicle is chemically inert to the active formulation and its components, and has no detrimental side effects or toxicity under the conditions of use.

[0088] In some embodiments, the pharmaceutical formulation is adapted as a delivery system for delivering a therapeutic agent orally, parenterally, or intravenously into the circulatory system of a subject.

[0089] In cases other than intravenous administration, the composition may contain small amounts of wetting agents, emulsifying agents, or pH buffering agents. The composition may be a liquid solution, suspension, emulsion, gel, polymer, or sustained release formulation. The composition may be formulated with conventional binders and carriers as known in the art. The formulation may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharide, cellulose, magnesium carbonate, and other inert carriers with well-established functionality in pharmaceutical manufacturing. Various delivery systems are known and can be used to administer the therapeutic agent of the present invention, including encapsulation in liposomes, microparticles, microcapsules, and the like.

[0090] If necessary, the combination or pharmaceutical composition of the present invention is formulated in a composition that also contains a solubilizer and a local anesthetic to improve pain at the injection site.Generally, the components are mixed together separately or in a unit dosage form and supplied in a sealed container such as an ampoule or sachet indicating the amount of active agent, for example, as a lyophilized powder or water-free concentrate.When the composition is administered by infusion, it can be dispensed using an infusion bottle containing pharmaceutical grade sterile water or saline.When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed before administration.

[0091] Preparations suitable for oral administration include liquid solutions dissolved in diluents such as water or saline; capsules, sachets, tablets, lozenges, each containing a predetermined amount of the combination of the present invention; powders; suspensions in suitable liquids; and emulsions.Liquid dosage forms for oral administration can include pharma-ceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, including inert diluents commonly used in the art, such as water.These compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweeteners, flavorings and flavorings.

[0092] The solid dosage forms for oral administration include conventional capsules, sustained release capsules, conventional tablets, sustained release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, suspensions, powders, granules and gels.In these solid dosage forms, the active compound can be mixed with at least one inert excipient such as sucrose, lactose or starch.Such dosage forms can also contain additional substances other than inert diluents, such as magnesium stearate, as is common practice.In the case of capsules, tablets, effervescent tablets and pills, the dosage forms can also contain buffering agents.Tablets and pills can be prepared with enteric coating.

[0093] Parenteral preparations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, e.g., water for injections, immediately prior to use.

[0094] The pharmaceutical composition of the present invention can be administered by topical, transdermal or subcutaneous routes. Examples of topical or transdermal administration include, but are not limited to, iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic gradient, occlusive dressing, microinjection, needleless injection by pressure, microelectrical patch and any combination thereof. In any case, the excipients are selected according to the pharmaceutical dosage form selected.

[0095] Injectable preparations, for example, aqueous or oily suspensions, sterile injections can be formulated according to known techniques using suitable dispersants, wetting agents and / or suspending agents.Among the recognized vehicles and solvents that can be used, water, Ringer's solution and isotonic sodium chloride solution are included.Sterile oils are also conventionally used as solvents or suspending media.

[0096] In certain preferred embodiments of the present invention, the pharmaceutical composition of the present invention is administered by topical route.For topical administration, the pharmaceutical composition of the present invention can be formulated as cream, gel, lotion, liquid, pomade, spray solution, dispersion, solid bar, emulsion, microemulsion and the like, which can be formulated according to conventional method using suitable excipients such as emulsifier, surfactant, thickener, colorant and combination of two or more thereof.

[0097] Furthermore, the pharmaceutical compositions of the present invention can be administered in the form of a transdermal patch or iontophoresis device. Suitable transdermal patches are well known to those of ordinary skill in the art.

[0098] Several drug delivery systems are known and can be used to administer the combination of the present invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules, nanoparticles, nanocapsules and the like.The required dose can be administered as a single unit or in sustained release form.In certain preferred embodiments of the present invention, the pharmaceutical composition is encapsulated in liposomes.

[0099] Sustained release forms and suitable materials and methods for their manufacture are well known in the state of the art.In one embodiment of the present invention, the orally administrable form of the combination according to the present invention further comprises at least one coating or matrix in sustained release form.Coatings or sustained release matrices include, but are not limited to, natural polymers, semi-synthetic or synthetic water-insoluble, modified waxes, oils and fats, fatty alcohols, fatty acids, natural, semi-synthetic or synthetic plasticizers, or combinations of two or more thereof.Enteric coatings can be applied using conventional methods known to those skilled in the art.

[0100] Another aspect relates to a food, functional cosmetic, nutraceutical, or cosmetic composition comprising a compound of the first aspect or a composition of the fifth aspect.

[0101] As used herein, the term "food" is any substance or product, solid or liquid, natural or processed, of whatever nature, which, by its characteristics, use, composition, preparation and state of storage, can normally or ideally be used for some of the following purposes: a) for the normal nutrition of humans or animals or as a luxury food, or b) as a nutritional product in the special case of human or animal food (feed). The term "food" includes natural materials and final products of any origin, which are suitable for animal diet, either separately or conveniently mixed with each other.

[0102] Ready-to-eat foods are those that do not require dilution, for example, with an aqueous solution suitable for consumption. In principle, the ingredients present in ready-to-eat foods are balanced and, as a person skilled in the art would expect, no additional ingredients need to be added to the food to make it ready to eat. Concentrated foods are those in which one or more ingredients are present in a higher concentration than in cooked foods and therefore require dilution, for example, with an aqueous solution suitable for consumption, in order to be used. Non-limiting examples of food products provided by the present invention include dairy products and derivatives, such as fermented milk, yogurt, kefir, curd, cheese, butter, ice cream, milk-based desserts, etc., and non-dairy products, such as baked goods, cakes and pastries, cereals, chocolates, jams, juices, other fruit derivatives, oils and margarines, prepared foods, etc.

[0103] As used herein, the term "functional cosmetics" refers to products suitable for use on the human or animal body, including one or more functional cosmetics (functional cosmetics, dermopharmaceuticals or active cosmetics), i.e., topical hybrid products with cosmetic-pharmaceutical characteristics (therefore, they are intermediate between non-cosmetics and drugs) that contain higher, more effective concentrations of active ingredients that act on the skin, hair and / or nails of the user. Specific examples of functional cosmetics include essential oils, ceramides, enzymes, minerals, peptides, vitamins, etc.

[0104] As used herein, the term "functional food" refers to a product suitable for human or animal use that contains one or more natural products that have a therapeutic action associated with providing a health benefit or preventing or alleviating a disease, including dietary supplements that are provided in a non-food matrix (e.g., capsules, powders, etc.) of concentrated natural bioactive products normally present (or not) in foods, and that exert a health benefit greater than that which regular foods may have when ingested in doses higher than those present in those foods. Thus, the term "functional food" includes isolated or purified foods, as well as additives or food supplements provided in dosage forms normally used orally, such as capsules, tablets, sachets, drinkable files, etc., such products providing a physiological benefit or protection against disease, generally chronic disease. Optionally, the functional food provided by the present invention may contain, in addition to xanthophylls, one or more functional foods (products or substances related to the prevention or alleviation of disease), such as flavonoids, omega-3 fatty acids, etc., and / or one or more prebiotics (non-digestible food ingredients that stimulate the activity and / or growth of probiotics), such as oligofructose, pectin, inulin, galactooligosaccharides, lactulose, human milk oligosaccharides, dietary fiber, etc.

[0105] As used herein, the term "nutritional composition" of the present invention relates to a food that beneficially affects one or more functions of the body so as to provide better health and wellness. Thus, such a nutritional composition may be intended for the prevention and / or treatment of a disease or a causative agent of a disease. Thus, the term "nutritional composition" of the present invention can be used as a synonym for functional food or food for a specific nutritional purpose, or medical food. Nutritional compositions are similar to conventional foods and are consumed as part of a normal diet.

[0106] The term "cosmetic composition" or "personal care composition" as used herein refers to a composition comprising one or more products suitable for use in the personal hygiene of humans or animals, or for enhancing natural beauty or altering the appearance of the human or animal body without affecting its structure or function, providing such an effect. Optionally, the cosmetic composition provided by the present invention may contain, in addition to the combination of the present invention, one or more cosmetic or cosmetic products, i.e., substances or mixtures intended to be in contact with the external parts of the human or animal body (e.g., the epidermis, hair system, nails, lips, etc.), or the teeth and buccal mucosa, for the exclusive or primary purpose of cleaning them, perfume them, altering their appearance, protecting them, keeping them in good condition, or correcting body odor. Specific examples of cosmetically acceptable vehicles include products included in the INCI (International Nomenclature of Cosmetic Ingredients) list. Cosmetic or personal care compositions include products such as balms, pads, pomades, creams, oils, surfactants, moisturizers, plant extracts, vitamins, antioxidants, sunscreens, fragrances, preservatives, etc. Specific examples include moisturizers, botanical extracts, vitamins, antioxidants, and sunscreens.

[0107] The components as described herein above are preferably provided in a cosmetic composition that can be formulated into creams, gels, lotions, oils, ointments, powders, sticks, cakes, or other forms that can be applied topically. The resulting cosmetic composition can be in the form of a liquid, solid, semi-solid, dispersion, suspension, solution, or emulsion, and can be either aqueous-based or anhydrous. The cosmetic composition of the present invention can also be in the form of a color cosmetic composition, such as foundation makeup, mascara, lip color, blush, eye shadow, etc. Certain other derivatives are lipophilic in nature and are likely to be found in the oil phase of an emulsion. The combination of the present invention is preferably found in the aqueous phase of an emulsion or is encapsulated in the aqueous phase in liposomes.

[0108] As used herein, the term "cosmetically effective amount" refers to the amount of a compound (i.e., the combination of the present invention) sufficient to provide a desired effect, which is generally determined, among other things, by the characteristics of the compound itself and the cosmetic effect to be achieved.The dosage to obtain a cosmetically effective amount also depends on various factors such as, for example, the age, weight, sex or tolerance of an animal, preferably a mammal, more preferably a human.

[0109] In a particular embodiment of the invention, the cosmetic composition of the invention is administered by topical route. Suitable formulations for topical administration of the composition of the invention have been detailed in relation to the pharmaceutical composition of the invention and apply equally to the cosmetic composition of the invention.

[0110] In some cases, the cosmetic composition of the present invention is incorporated into a fabric, nonwoven fabric or medical device, including, but not limited to, bandages, gauze, T-shirts, pantyhose, socks, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bed covers, towelettes, adhesive patches, non-adhesive patches, occlusive patches, micro-electrical patches and face masks.

[0111] medical use Cancer (Satomi Y, Anticancer Res. 2017;37(4):1557-62; Meresse S et al., Int J Mol Sci. 2020 Dec 4;21(23); Peng J et al., Mar Drugs. 2011 Oct 10;9(10):1806-28), cardiovascular diseases, hypertension, portal hypertension, pulmonary arterial hypertension, hyperglycemia, diabetes (type 2), insulin resistance, liver protection and lipid management-related diseases (Peng J et al., Mar Drugs. 2011 Oct 10;9(10):1806-28), metabolic syndrome and diabetes prevention (Maeda H. J Oleo Sci. 2015 Jan 20;64(2):125-32), coronary atherosclerotic heart disease, rheumatoid arthritis and as anti-angiogenesis (Meresse S et al., Int J Mol Sci. 2020 Dec 4;21(23)), gut microbiota imbalance, glaucoma, diabetic retinopathy, angiogenesis-related diseases, hereditary hemorrhagic telangiectasia and psoriasis (Xiao H et al., Mar Drugs. 2020 Dec 11;18(12)), as anti-inflammatory, anaphylactic shock, sepsis, cytokine storm (Su et al., Front Pharmacol., 2019, DOI: 10.3389 / fphar.2019.00906), lupus, sarcoidosis, chronic obstructive pulmonary disease (COPD), asthma, primary biliary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis, ulcerative colitis (Li X et al., Aging (Albany NY). 2021; 13:2655-2667; Yang YP et al., Nat Prod Res. 2020 Jun; 34(12):1791-1795; Zheng J et al., Mar Drugs. 2019;17(10):552; Yang X et al., J Environ Pathol Toxicol Oncol. 2019;38(3):229-238; Takatani N et al., Biochem Biophys Res Commun. 2020 Jul 23; 528(2) 305-310; Su et al., Front Pharmacol., 2019, DOI: 10.3389 / fphar.2019.00906), fibrosis (Xiao H et al., Mar Drugs. 2020 Dec 11;18(12); Ma SY et al. Eur J Pharmacol. 2017 Sep 15;811:199-207), as an antibacterial agent (Karpinski TM, Adamczak A. Fucoxanthin-An Antibacterial Carotenoid. Antioxidants (Basel). 2019 Jul 24;8(8)), as a neuroprotectant (Hu L et al. Biomed Pharmacother. 2018 Oct;106:1484-9), gout and kidney stones (Wang et al., Journal of King Saud University - Science. 2020 Apr; 32(3) 1896-1901), aging-related disorders (Guvatova Z et al., Mech Ageing Dev. 2020 Jul;189:111260; Chen, S.-J. et al., Mar. Drugs 2021, 19, 114), glucocorticoid-induced muscle atrophy (Zhiyin L et al. Biomed Pharmacother. 2021 Apr 14;139:111590), bone health (Walsh PJ et al. Mar Drugs. 2019 Feb 28;17(3)), age-related macular degeneration (Chen SJ et al. Mar Drugs. 2021 Feb 18;19(2)), eczema, atopic dermatitis and pruritus (Natsume C et al. Int J Mol Sci. 2020 Mar 22;21(6)), and thyroid-related diseases (Yang The utility of ACX for treating and / or preventing various pathologies, such as inflammatory bowel disease, osteoporosis, and osteoarthritis, has been described in the prior art.

[0112] Furthermore, the ACX esters of formula (I) or (Ia) are prodrugs of ACX and are naturally converted to ACX and its cis-isomer in the body. Therefore, the esters of the present invention are suitable for the treatment and prevention of the same diseases as those reported for ACX.

[0113] Thus, in another aspect, the present invention relates to a compound of formula (I) or (Ia) of the first aspect, a composition of the fifth aspect or a pharmaceutical composition of the sixth aspect for use in medicine.

[0114] In another aspect, the present invention relates to a compound of formula (I) or (Ia) of the first aspect, a composition of the fifth aspect or a pharmaceutical composition of the sixth aspect for use in the treatment and / or prevention of a disease selected from the group consisting of cancer, cardiovascular disease, gut microbiota imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia related disease, ageing related disorder, lipid related disease, glucocorticoid induced muscle atrophy, bone related disease, eye disease, angiogenesis related disease, psoriasis, eczema, atopic dermatitis, and thyroid related disorder.

[0115] In another aspect, the present invention relates to the use of a compound of formula (I) or (Ia) of the first aspect, a composition of the fifth aspect or a pharmaceutical composition of the sixth aspect in the manufacture of a medicament for the treatment and / or prevention of a disease selected from the group consisting of cancer, cardiovascular disease, gut microbiota imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia related disease, ageing related disorder, lipid related disease, glucocorticoid induced muscle atrophy, bone related disease, eye disease, angiogenesis related disease, psoriasis, eczema, atopic dermatitis, and thyroid related disorder.

[0116] In a further aspect, the present invention relates to a method for the treatment and / or prevention of a disease selected from the group consisting of cancer, cardiovascular disease, gut microbiota imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia related disease, ageing related disorder, lipid related disease, glucocorticoid induced muscle atrophy, bone related disease, eye disease, angiogenesis related disease, psoriasis, eczema, atopic dermatitis, and thyroid related disorder, comprising administering to a subject in need thereof a compound of formula (I) or (Ia) of the first aspect, a composition of the fifth aspect or a pharmaceutical composition of the sixth aspect.

[0117] The terms "prevention", "preventing" or "prevent" as used herein relate to the administration of the combination according to the present invention or a medicament comprising said combination to a subject who has not been diagnosed as possibly having a disease, but who is normally expected to develop said disease or is at high risk of said disease. Prevention is intended to avoid the appearance of said disease. Prevention may be complete (e.g., the total absence of disease). Prevention may also be partial, for example, such that the occurrence of a disease in a subject is less than would have occurred without the administration of the composition of the present invention. Prevention also refers to a reduction in susceptibility to a pathological condition.

[0118] The term "treatment", as used herein, refers to any type of therapy aimed at terminating, preventing, ameliorating or reducing susceptibility to a condition as described herein. In a preferred embodiment, the term treatment relates to the prophylactic treatment of a disorder or condition as defined herein (i.e., treatment to reduce susceptibility to a condition). Thus, "treatment", "treating" and their equivalent terms refer to obtaining a desired pharmacological or physiological effect and are directed to any treatment of a pathological condition or disorder in a mammal, including a human. The effect may be preventive in that it completely or partially prevents the disorder or its symptoms, and / or therapeutic in that it partially or completely cures the disorder and / or side effects caused by the disorder. That is, "treatment" includes (1) preventing the occurrence or recurrence of a disorder in a subject; (2) inhibiting the disorder, such as arresting its onset; (3) halting or terminating the disorder or at least a symptom associated therewith, such that the host is no longer afflicted by the disorder or its symptoms, e.g., regressing the disorder or its symptoms by restoring or repairing a lost, deficient, or defective function or by stimulating an inefficient process; or (4) alleviating, relieving, or ameliorating the disorder or its associated symptoms, where amelioration is used broadly to refer to at least a reduction in the magnitude of a parameter.

[0119] The term "cancer," as used herein, refers to a disease characterized by uncontrolled cell division (or increased survival or resistance to apoptosis) and the ability of said cells to invade other adjacent tissues (infiltration), spread via lymphatic and blood vessels to other areas of the body where they are not normally localized (metastasis), circulate in the bloodstream, and then invade normal tissues elsewhere in the body. Tumors are classified as benign or malignant depending on whether they spread by invasion and metastasis; benign tumors are tumors that cannot spread by invasion or metastasis, i.e., they only grow locally, and malignant tumors are tumors that can spread by invasion and metastasis. As used herein, the term cancer includes, but is not limited to, the following types of cancer: breast cancer; biliary tract cancer; bladder cancer; brain cancer, including glioblastoma, particularly glioblastoma multiforme, and medulloblastoma; cervical cancer; head and neck cancer; choriocarcinoma; colon cancer, colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; blood cancer neoplasms, including acute lymphocytic and myeloid leukemia; T-cell acute lymphoblastic leukemia / lymphoma; hairy cell leukemia; chronic myelogenous leukemia, multiple myeloma; AIDS-related leukemia and adult T-cell leukemia / lymphoma; intraepithelial neoplasms, including Bowen's disease and Paget's disease; liver cancer, hepatoma; lung cancer, pleural mesothelioma; Hodgkin's disease and lymphoma. These include lymphomas, including lymphocytic lymphomas; neuroblastomas; oral cancers, including squamous cell carcinomas; parotid gland cancers; ovarian cancers, including those arising from epithelial, stromal, germ and mesenchymal cells; pancreatic cancer; prostate cancer; kidney cancer, upper renal cancer; rectal cancer; sarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma; skin cancers, including melanoma, Merkel cell carcinoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma; cervical cancer, endometrial cancer; testicular cancers, including seminoma, non-seminoma (teratoma, choriocarcinoma), stromal tumors, and germ cell tumors; thyroid cancers, including thyroid adenocarcinoma and medullary carcinoma; and renal cancers, including adenocarcinoma and Wilms' tumor. Other cancers will be known to those skilled in the art. In certain embodiments, the cancer is gastric cancer, duodenal cancer, liver cancer, blood cancer, breast cancer, glioma, bladder cancer, pancreatic cancer, prostate cancer, colorectal cancer, cervical cancer, nasopharyngeal cancer, lung cancer, renal cancer, metastatic cancer, melanoma, sarcoma, nervous system cancer or skin cancer.

[0120] In certain embodiments, the cardiovascular disease is hypertension, portal hypertension, pulmonary arterial hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome or coronary atherosclerosis.

[0121] In certain embodiments, the inflammatory disease is anaphylactic shock, sepsis, or cytokine storm.

[0122] In certain embodiments, the autoimmune disease is lupus, sarcoidosis, chronic obstructive pulmonary disease, asthma, primary biliary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis, and ulcerative colitis.

[0123] "Fibrosis" as used herein refers to the formation of excess fibrous connective tissue in an organ or tissue during repair or reaction processes. Fibrosis may be a benign condition, but the present invention preferably relates to fibrosis in a pathological condition. In a particular embodiment, the fibrosis is liver fibrosis, renal fibrosis, pulmonary fibrosis, myocardial fibrosis, interstitial fibrosis, IGG4-associated fibrosis, scleroderma or retroperitoneal fibrosis.

[0124] In certain embodiments, the neurological disease is Parkinson's disease, Alzheimer's disease, dementia, depression or cerebral ischemia.

[0125] In certain embodiments, the hyperuricemia-related disease is rheumatoid arthritis, gout, or kidney stones.

[0126] In certain embodiments, the lipid-related disease is obesity, cholesterol, triglyceridemia, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

[0127] In certain embodiments, the bone-related disease is bone loss.

[0128] In certain embodiments, the eye disease is glaucoma, diabetic retinopathy or age-related macular degeneration.

[0129] In certain embodiments, the angiogenesis-related disease is hemorrhagic telangiectasia.

[0130] beauty method The utility of ACX compounds in preventing and / or reducing skin aging and / or ameliorating the adverse cosmetic effects of aging has been described in the prior art (Peng J et al. Mar Drugs. 2011 Oct 10;9(10):1806-28; Kang SY et al. J Cosmet Sci. 2020;71(2):53-64.). As explained above, the ACX esters of formula (I) or (Ia) are spontaneously converted in the body to ACX and its cis isomer. Thus, the esters of the present invention are suitable for use in the same cosmetic methods as reported for ACX.

[0131] Thus, in another aspect, the present invention relates to a cosmetic method for preventing and / or reducing skin ageing and / or ameliorating the adverse cosmetic effects of ageing, comprising administering to a subject in need thereof a compound of formula (I) or (Ia) of the first aspect, preferably formula (Ia), preferably wherein R is methyl, a composition of the fifth aspect, or a food, functional cosmetic, functional food or cosmetic composition of the ninth aspect.

[0132] As used herein, the term "cosmetic method" refers to a method used to enhance the appearance of the skin of a subject. Cosmetic compositions used in the cosmetic methods of the present invention include skin care creams, lotions, powders, lipsticks, eye and facial makeup, towelettes, gels, deodorants, hand sanitizers, baby products, bath oils, bubble baths, bath salts, butters, and many other types of products.

[0133] Skin aging is a multifactorial process that affects almost all aspects of its biology and function and is caused by both intrinsic (e.g., time, genetic factors, hormones) and extrinsic factors (e.g., UV exposure, pollution, cigarette smoke). Skin aging also occurs due to aging.

[0134] Cellular senescence is a proliferation arrest that occurs as a result of various damaging stimuli, including DNA damage, telomere shortening and dysfunction, or oncogenic stress. Senescent cells have pleiotropic effects on development, tissue aging and regeneration, inflammation, wound healing, and tumor suppression. Senescent cells are characterized by an inability to proliferate, resistance to apoptosis, and secretion of factors that promote inflammation and tissue deterioration.

[0135] In human skin, senescent keratinocytes and fibroblasts appear to accumulate with age, and senescent cells express a wide range of genes with pleiotropic effects, including degradative enzymes, growth factors, and inflammatory cytokines.

[0136] "Adverse cosmetic effects of aging," as used herein, refers to the characteristics of intrinsic or chronological aging, exemplary non-limiting visible signs of which include thinning and dryness of the skin, fine wrinkles, loss of elasticity, pigmentation disorders, gray hair, and hair loss.

[0137] "Skin aging," as used herein, refers to the state of aging, and in particular to damage to epidermal cells of human skin resulting from partial damage or complete destruction of cells, toxic by-products of oxygen metabolism, free radical pathological mechanisms, or conversion of imide bonds to amide bonds in collagen and / or elastin caused by photodamage and general aging.

[0138] The cosmetic methods of the present invention are intended to reduce epidermal cells in humans, thereby reducing skin aging, including by reducing or inhibiting aging, including one or more effects such as increasing the vascularity of the underlying skin, increasing the rate of cell replication and desquamation to produce a more youthful appearance, increasing collagen synthesis and homogeneity, slowing skin atrophy and thinning of the epidermis and dermis, and reversing photodamage or other regenerative effects.

[0139] The combinations of the present invention may be administered in a cosmetically effective amount.

[0140] The term "cosmetically effective amount" as used herein refers to an amount of the compound or composition of the present invention that is sufficient to provide a desired effect, and is generally determined, among other things, by the characteristics of the compound itself and the cosmetic effect to be achieved. The dosage to obtain a cosmetically effective amount also depends on various factors such as age, weight, sex or tolerance of the animal, preferably a mammal, more preferably a human.

[0141] In a particular preferred embodiment of the cosmetic method of the present invention, the cosmetic composition of the present invention is administered by topical route. Sufficient formulations for topical administration of the combination of the present invention are detailed in relation to the cosmetic composition of the present invention and apply equally to the cosmetic method of the present invention.

[0142] In some cases, the cosmetic composition of the present invention is incorporated into a fabric, nonwoven fabric or medical device, including, but not limited to, bandages, gauze, T-shirts, pantyhose, socks, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bed covers, towelettes, adhesive patches, non-adhesive patches, occlusive patches, micro-electrical patches and face masks.

[0143] The present invention is as follows. [1] The above formula (I) (wherein R is a straight or branched chain C 1 -C 4 alkyl) or a stereoisomer thereof. [2] The compound according to the above-mentioned [1], represented by the above-mentioned formula (Ia) (R is as defined in the above-mentioned [1]). [3] The compound according to the above [1] or [2], wherein R is methyl. [4] A method for producing the compound according to any one of the above [1] to [3], a) reacting a compound of formula (II) or (IIa) above with an oxidizing agent, preferably selected from the group consisting of tetra-n-propylammonium perruthenate (TPAP) and 2-iodoxybenzoic acid (IBX), optionally in the presence of a co-oxidizing agent, preferably N-methylmorpholine N-oxide (NMO), to obtain a compound of formula (III) or (IIIa) above; b) reacting the compound of formula (III) or (IIIa) with SiO 2 in the presence of a base, preferably a base selected from the group consisting of N-methylmorpholine and triethylamine; 2 to obtain a compound of formula (I) or (Ia) above, wherein R is methyl; and c) R is a straight or branched chain C 2 -C 4 In the case of the compounds of formula (I) or (Ia) above which is alkyl, c1) converting a compound of formula (I) or (Ia) above, in which R is methyl, into a compound of formula (IV) or (IVa) above, by treating it with an esterase, preferably a lipase; and c2) coupling a compound of the above formula (IV) or (IVa) with a coupling agent, preferably a carbodiimide, more preferably a carbodiimide selected from the group consisting of dicyclohexylcarbodiimide (DDC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide (EDC) or a salt thereof, in the presence of 4-(dimethylamino)pyridine (DMAP), to form a compound of the above formula (V) (wherein R is a straight or branched C 2 -C 4 esterification with a carboxylic acid of formula (I) or (Ia) above, where R is a straight or branched chain C 2 -C 4 to obtain a compound of formula (1) selected from the group consisting of alkyl A method comprising: [5] The oxidizing agent in step a) is TPAP; step a) is carried out in the presence of a co-oxidant, the co-oxidant in step a) is NMO; and / or The base in step b) is N-methylmorpholine; The method described in [4] above. [6] The method according to [4] or [5] above, wherein step a) and / or b) is carried out in the presence of water, and thereafter, a mixture of a compound according to any one of [1] to [3] above and a compound of formula (VI), preferably formula (VIa) (wherein R is defined as any one of [1] to [3] above) is obtained. [7] Use of the compound according to any one of [1] to [3] above for the manufacture of a composition containing amarousiaxanthin A, and / or amarousiaxanthin A and paracentrone. [8] A method for producing amaroussiaxanthin A, comprising treating the compound according to any one of the above [1] to [3] with an esterase, preferably a lipase. [9] A composition comprising the compound according to any one of the above [1] to [3] and the compound according to the above [6] of formula (VI), preferably formula (VIa).

[10] A pharmaceutical composition comprising the compound according to any one of the above [1] to [3] or the composition according to the above [9].

[11] The compound according to any one of the above [1] to [3], the composition according to the above [9] or the pharmaceutical composition according to the above

[10] for use in medicine.

[12] The compound according to any one of [1] to [3] above, the composition according to [9] above, or the pharmaceutical composition according to

[10] above for use in the treatment and / or prevention of a disease selected from the group consisting of cancer, cardiovascular disease, imbalance of gut flora, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia-related disease, aging-related disorder, lipid-related disease, glucocorticoid-induced muscle atrophy, bone-related disease, eye disease, angiogenesis-related disease, psoriasis, eczema, atopic dermatitis, and thyroid-related disorder.

[13] the cancer is gastric cancer, duodenal cancer, liver cancer, blood cancer, breast cancer, glioma, bladder cancer, pancreatic cancer, prostate cancer, colorectal cancer, cervical cancer, nasopharyngeal cancer, lung cancer, kidney cancer, metastatic cancer, melanoma, sarcoma, nervous system cancer, or skin cancer; the cardiovascular disease is hypertension, portal hypertension, pulmonary arterial hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome or coronary atherosclerosis; the inflammatory disease is anaphylactic shock, sepsis, or cytokine storm; the autoimmune disease is lupus, sarcoidosis, chronic obstructive pulmonary disease, asthma, primary biliary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis and ulcerative colitis; the fibrosis is hepatic fibrosis, renal fibrosis, pulmonary fibrosis, myocardial fibrosis, interstitial fibrosis, IGG4-associated fibrosis, scleroderma, or retroperitoneal fibrosis; the neurological disease is Parkinson's disease, Alzheimer's disease, dementia, depression or cerebral ischemia; the hyperuricemia-related disease is rheumatoid arthritis, gout, or kidney stones; the lipid-related disease is obesity, cholesterolemia, triglyceridemia, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease; the bone-related disease is bone loss; the eye disease is glaucoma, diabetic retinopathy or age-related macular degeneration; and / or The angiogenesis-related disease is hemorrhagic telangiectasia. A compound, composition or pharmaceutical composition for use according to

[12] above.

[14] A food, functional cosmetic, functional food, or cosmetic composition comprising the compound according to any one of [1] to [3] above or the composition according to [9] above.

[15] A cosmetic method for preventing and / or reducing skin aging and / or ameliorating the adverse cosmetic effects of aging, comprising administering to a subject in need thereof a compound described in any of [1] to [3] above, a composition described in [9] above, or a food, functional cosmetic, functional food or cosmetic composition described in

[14] above. The following examples represent specific embodiments of the present invention and are not intended to limit the scope of the invention as defined herein. EXAMPLES

[0144] Analysis method nuclear magnetic resonance (NMR) NMR spectra were obtained on a Varian 400 MHz or 500 MHz machine. 1 H chemical shifts are expressed relative to the deuterated solvent.

[0145] Example 1 Synthesis of Amaroussiaxanthin A Acetate Fucoxatin (1 equiv.), NMO monohydrate (2 equiv.) and freshly dried 4 Å molecular sieves are dissolved in dichloromethane (DCM). TPAP (0.12 equiv.) is added at room temperature. When the reaction has reached complete conversion (>97%), the reaction is diluted with SiO 2 (30 equiv.) is added. The reaction is stirred at room temperature until complete conversion. The reaction is filtered and dried over SiO 2 The filtrate was dissolved in 5% aqueous Na 2 S 2 O 3 The organic layer is washed twice with brine and 2 SO 4 Dry at 40° C., filter and evaporate to dryness. Dry the residue using high vacuum to give the desired compound as a red solid.

[0146] 1 H-NMR (400MHz, CDCl 3) δ 7.10 (d, J = 10.9 Hz, 1H), 6.83 - 6.50 (m, 5H), 6.45 (d, J = 11.6 Hz, 1H), 6.35 (d, J = 15.0 Hz, 1H), 6.27 (d, J = 11.7 Hz, 1H), 6.13 (d, J = 11.5 Hz, 1H), 6.05 (s, 1H), 5.84 (s, 2H), 5.44 - 5.33 (m, 1H), 3.05 (d, J = 15.0 Hz, 1H), 2.92 (d, J = 15.0 Hz, 1H), 2.47 (d, J = 18.1 Hz, 1H), 2.38 - 2.24 (m, 2H), 2.04 (s, 3H), 1.99 (m, 7H), 1.95 (s, 3H), 1.90 (d, J = 1.0 Hz, 3H), 1.81 (s, 3H), 1.51 (t, J = 12.2 Hz, 1H), 1.40 (m, 8H), 1.14 - 1.02 (m, 9H).

[0147] Example 2: Synthesis of paracentrone acetate Amarousiaxanthin A acetate is mixed with water and heated to 70°C. When the reaction stops, it is cooled and extracted with dichloromethane. The organic layer is dried, filtered and evaporated to dryness. The resulting residue is treated with SiO 2 Purification by column chromatography gives the desired compound as a brown solid.

[0148] Paracentrone acetate: 1 H-NMR (500 MHz, CDCl 3) δ 7.14 (dd, J = 10.7, 1.2 Hz, 1H), 6.77 - 6.53 (m, 5H), 6.42 - 6.30 (m, 2H), 6.26 (d, J = 11.5 Hz, 1H), 6.12 (dd, J = 11.4, 1.0 Hz, 1H), 6.06 (d, J = 7.2 Hz, 1H), 5.38 (m, 1H), 2.36 (s, 3H), 2.31 - 2.25 (m, 1H), 2.03 (s, 3H), 2.02 - 1.96 (m, 6H), 1.93 (d, J = 0.9 Hz, 3H), 1.81 (t, J = 3.6 Hz, 3H), 1.50 (m, 1H), 1.44 - 1.39 (m, 1H), 1.36 (d, J = 15.3 Hz, 6H), 1.09 - 1.03 (m, 3H).

[0149] Example 3. Synthesis of Amarousiaxanthin A Acetate Using Various Oxidizing Agents The same procedure was followed as in Example 1, except that TPAP and NMO were replaced with IBX, Dess-Martin Periodinane and Swern oxidation. The results are summarized in the table below. [Table 1]

[0150] Example 4 Synthesis of Amaroussiaxanthin A Amarousiaxanthin A acetate (1 eq.) and sodium taurocholate (30 eq.) are dissolved in MeOH. The solvent is evaporated to dryness. The residue is dissolved in phosphate buffered saline (PBS, pH 7) and lipase (1340 U / mg compound) is added. The reaction is shaken at 37° C. until maximum conversion (approximately 80%). The reaction is quenched with MeOH and Et 2 Extract the aqueous layer with EtO and brine until no color is visible in the organic layer. 2 The mixture is extracted with SiO. The combined organic layers are dried, filtered and evaporated to dryness. The residue is 2 Purification by column chromatography gives amaroussiaxanthin A as a red solid and recovers unreacted amaroussiaxanthin A acetate.

[0151] 1 H-NMR (500 MHz, acetone) δ 7.53 (dd, J = 10.8, 1.1 Hz, 1H), 6.93 - 6.81 (m, 2H), 6.80 - 6.67 (m, 3H), 6.52 (d, J = 11.6 Hz, 1H), 6.36 (dd, J = 17.7, 13.4 Hz, 2H), 6.16 (dd, J = 11.4, 1.0 Hz, 1H), 6.02 (s, 1H), 5.91 (s, 1H), 5.74 - 5.69 (m, 1H), 4.28 - 4.17 (m, 1H), 3.61 (d, J = 1.6 Hz, 1H), 3.48 (d, J = 5.1 Hz, 1H), 3.21 (q, J = 15.5 Hz, 2H), 2.80 (d, J = 1.6 Hz, 3H), 2.78 - 2.75 (m, 1H), 2.62 (d, J = 17.6 Hz, 1H), 2.21 - 2.11 (m, 2H), peak under acetone, 2.02 (s, 2H), 1.99 (s, 2H), 1.94 (t, J = 3.3 Hz, 2H), 1.91 (m, 1H), 1.89 - 1.83 (m, 5H), 1.40 - 1.24 (m, 7H), 1.07 - 0.98 (m, 6H).

[0152] Example 5 Conversion of Amaroussiaxanthin A Acetate to Amaroussiaxanthin after Oral Absorption Immunocompetent mice of the Hsd:ICR (CD-1) strain (female, 6-7 weeks old, from ENVIGO) were housed under pathogen-free conditions at constant temperature (20-22 °C) and relative humidity (45-65%) with a light / dark cycle (12 h). Sterile water and food were available ad libitum.

[0153] Amarousiaxanthin A acetate (ACX-Ac) was dissolved in a suitable vehicle at 1 mg / mL and sterilized by filtration. Animals were weighed and then assayed to determine the appropriate volume of distribution at 10 mL / kg. Formulations were administered intragastrically once at 10 mg / kg. Blood was collected at various time points as shown in Table 1. Blood was extracted from the facial vein or by intracardiac puncture (endpoint) in recipients containing 5 μL of 0.5 M EDTA.

[0154] Blood samples were analyzed by HPLC-MS / MS according to a proprietary analytical method to determine the ACX concentration in each sample.Non-compartmental pharmacokinetic analysis was performed using individual plasma concentrations versus sampling time with PKPlus® software version 2.0 (Simulations Plus, Lancaster, CA 93534, USA).

[0155] [Table 2]

[0156] ACX-Ac was not detectable in plasma samples when administered orally. The absorption of ACX was subsequently analyzed (Figure 1). The estimated maximum observed plasma concentration (Cmax) was determined to be 9.35 μM, and the area under the concentration-time curve (AUCt) was calculated to be 80.59 μM h.

Claims

1. Formula (I): 【Chemistry 1】 (Wherein R is a straight or branched chain C １ -C ４ alkyl) or a stereoisomer thereof.

2. Formula (Ia): 【Chemistry 2】 where R is as defined in claim 1. The compound according to claim 1.

3. 3. The compound of claim 1 or 2, wherein R is methyl.

4. A process for producing a compound according to claim 1 or 2, comprising the steps of: a) a compound of formula (II) or (IIa): 【Chemistry 3】 is reacted with an oxidizing agent selected from the group consisting of tetra-n-propylammonium perruthenate (TPAP) and 2-iodoxybenzoic acid (IBX), optionally in the presence of a co-oxidizing agent, N-methylmorpholine N-oxide (NMO), to produce a compound of formula (III) or (IIIa): 【Chemistry 4】 obtaining a compound of b) reacting a compound of formula (III) or (IIIa) with SiO in the presence of a base selected from the group consisting of N-methylmorpholine and triethylamine. ２ to obtain a compound of formula (I) or (Ia) wherein R is methyl; and c) R is a straight or branched chain C ２ -C ４ In the case of compounds of formula (I) or (Ia) which is alkyl, c1) treating a compound of formula (I) or (Ia) in which R is methyl with an esterase to obtain a compound of formula (IV) or (IVa): 【Chemistry 5】 and c2) reacting a compound of formula (IV) or (IVa) with a compound of formula (V): R-COOH (V) (Wherein R is a straight or branched chain C ２ -C ４ is alkyl) with a carboxylic acid of formula (I) or (Ia): 【Chemistry 6】 (Wherein R is a straight or branched chain C ２ -C ４ alkyl) To obtain the compound A method comprising:

5. The method of claim 4, wherein the esterase is a lipase.

6. The method of claim 4 , wherein the coupling agent is a carbodiimide.

7. 7. The method of claim 6, wherein the carbodiimide is selected from the group consisting of dicyclohexylcarbodiimide (DDC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide (EDC) or a salt thereof.

8. The oxidizing agent in step a) is TPAP; step a) is carried out in the presence of a co-oxidant, said co-oxidant being NMO; and / or The base in step b) is N-methylmorpholine; The method according to claim 4.

9. Steps a) and / or b) are carried out in the presence of water, followed by reacting a compound according to claim 1 with a compound of formula (VI): 【Chemistry 7】 (wherein R is defined in claim 1).

5. The process of claim 4, wherein a mixture of compounds of the formula:

10. Steps a) and / or b) are carried out in the presence of water, followed by reacting a compound according to claim 2 with a compound of formula (VIa): 【Chemistry 8】 (wherein R is defined in claim 2).

5. The process of claim 4, wherein a mixture of compounds of the formula:

11. 3. Use of a compound according to claim 1 or 2 for the preparation of a composition comprising amarouthiaxanthin A, and / or amarouthiaxanthin A and paracentrone.

12. 3. A method for producing amaroussiaxanthin A, comprising treating a compound according to claim 1 or 2 with an esterase.

13. The process according to claim 12, wherein the esterase is a lipase.

14. The compound of claim 1 and formula (VI): 【Chemistry 9】 (wherein R is defined in claim 1). A composition comprising a compound of formula (I).

15. The compound of claim 2 and formula (VIa): 【Chemistry 10】 (wherein R is defined in claim 2). A composition comprising a compound of formula (I).

16. 16. A pharmaceutical composition comprising a compound according to claim 1 or a composition according to claim 14 or 15.

17. 16. A composition according to claim 14 or 15 for use in medicine.

18. The composition according to claim 14 or 15 for use in the treatment and / or prevention of a disease selected from the group consisting of cancer, cardiovascular disease, gut flora imbalance, inflammatory disease, autoimmune disease, fibrosis, bacterial infection, neurological disease, hyperuricemia-related disease, ageing-related disorder, lipid-related disease, glucocorticoid-induced muscle atrophy, bone-related disease, eye disease, angiogenesis-related disease, psoriasis, eczema, atopic dermatitis, and thyroid-related disorder.

19. the cancer is gastric cancer, duodenal cancer, liver cancer, blood cancer, breast cancer, glioma, bladder cancer, pancreatic cancer, prostate cancer, colorectal cancer, cervical cancer, nasopharyngeal cancer, lung cancer, renal cancer, metastatic cancer, melanoma, sarcoma, nervous system cancer, or skin cancer; The cardiovascular disease is hypertension, portal hypertension, pulmonary arterial hypertension, hyperglycemia, type 2 diabetes, insulin resistance, metabolic syndrome or coronary atherosclerosis; the inflammatory disease is anaphylactic shock, sepsis, or cytokine storm; the autoimmune disease is lupus, sarcoidosis, chronic obstructive pulmonary disease, asthma, primary biliary cholangitis, sclerosing cholangitis, autoimmune hepatitis, inflammatory bowel disease, Crohn's disease, multiple sclerosis or ulcerative colitis; The fibrosis is hepatic fibrosis, renal fibrosis, pulmonary fibrosis, myocardial fibrosis, interstitial fibrosis, IGG4-associated fibrosis, scleroderma, or retroperitoneal fibrosis; The neurological disease is Parkinson's disease, Alzheimer's disease, dementia, depression or cerebral ischemia; The hyperuricemia-related disease is rheumatoid arthritis, gout, or kidney stones; the lipid-related disease is obesity, cholesterolemia, triglyceridemia, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease; the bone-related disease is bone loss; the eye disease is glaucoma, diabetic retinopathy or age-related macular degeneration; and / or The angiogenesis-related disease is hemorrhagic telangiectasia.

20. The composition of claim 18.

20. 16. A food, functional cosmetic, functional food, or cosmetic composition comprising a compound according to claim 1 or a composition according to claim 14 or 15.

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