TW201325590A - 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid for the treatment psoriasis - Google Patents

Abstract

The present invention provides 2-[(3, 5-difluoro-3'-methoxy-1, 1'-biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable salt or N-oxide or solvate or deuterated derivative thereof, for use in the treatment of psoriasis.

Description

2-[(3,5-Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid for psoriasis treatment

The present invention provides 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid (2-[ for psoriasis treatment) (3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid), or a pharmaceutically acceptable salt thereof or an N-oxide or a solvent Solvent or deuterated derivative.

Psoriasis is a common, chronic, inflammatory disease of the skin. Psoriasis affects approximately 3% of the population in the UK (Laws, P M et al., Clinical, Cosmetic and Investigational Dermatology 2010: 3, 25-37) and is the most prevalent immunological disease in adults. It is a disabling disease with significant social, psychological and economic consequences. At present, psoriasis cannot be cured and patients need to face lifelong treatment. The impact of psoriasis on quality of life is reported to be comparable to that observed in other chronic conditions such as diabetes and depression. Epidemiological studies indicate that psoriasis is often associated with other chronic inflammatory diseases such as arthritis or colitis.

The first episode of psoriasis can occur at any age, but usually begins in post-puberty or early adulthood. The period is uncertain but usually lasts for a lifetime. Clinical conditions are not necessarily, but in most cases, psoriasis is a chronic remission and recurrent disease.

The diagnosis of psoriasis is clinical and usually does not require histopathology to confirm. Most of the characteristic lesions contain chronic, impulsive, plaque-like dark red scaly plaques, especially on the extensor and scalp of the extremities.

Psoriasis is a clinically heterogeneous disease characterized by varying degrees of severity and extensive combination in different patients. Clinically, there are mild to moderate conditions (3%-10%) covering 3% of the surface area of the skin from skin plaques, and up to more than 10% of the severely affected conditions of the body surface area.

According to the US National Psoriasis Foundation, there are psoriasis in the form of: Plaque Psoriasis or Psoriasis vulgaris: the most common form of illness, accounting for 85-90 % example. The main symptoms include floating, inflamed lesions covered with white scales. Plaque psoriasis can be found throughout the skin of the body, more often on the scalp, limbs, knees and torso. This condition can occur in children and usually lasts for life.

- Guttate Psoriasis: The main symptoms include small, spotted spots with some scales. It can be found on the body's torso, legs and arms.

- Inverse Psoriasis: The main symptoms include smooth inflammatory lesions without scales. It can be found on the skin wrinkles, armpits, and groin of the body.

- Erthrodermic Psoriasis: The main symptoms include severe redness and swelling of the skin. It can be found throughout the body.

- Psoriatic arthritis: The main symptoms include swelling and inflammation of the joint, which occurs in 10% of patients with psoriasis. It can be found on the knees, hips, elbows, spine, hands and feet of the body.

- Scalp Psoriasis: Scalp psoriasis is usually in the form of plaque. Scalp psoriasis is present in 50% of patients with psoriasis.

- Nail Psoriasis: The main symptoms include depression, discoloration, and shedding of fingernails and toenails. Nail psoriasis usually occurs due to inflammation of the skin around the nails.

A wide range of treatments for psoriasis treatment, including topical, systemic phototherapy (ultraviolet light) and biotherapy (Laws, PM et al., Clinical, Cosmetic and Investigational Dermatology 2010: 3, 25-37) .

The treatment regimen cleans the skin, but the recurrence is quite frequent and many patients require repeated treatment. This exacerbates the importance of considering the risk of treatment - the performance of the benefits. In general, the preferred local treatment is greater than the systemic treatment because the skin can be treated locally by treating the desired site of the attack directly, thereby avoiding or at least attenuating the underlying systemic side effects.

In the treatment of mild to moderate psoriasis, topical treatments are usually optimal and have several options to choose from. This includes salicylic acid, steroids (clobetasol, bethametasone), vitamin D analogs (calcipotriol) , retinoids (tazarotene), dithranol, coal tar extracts or any combination of these agents (Murphy et al., JEADV 2011, 25, [Suppl.4], 3-8).

Corticosteroid alone or in combination with a vitamin D analog (betamethasone dipropionate) is the most effective treatment for psoriasis. However, long-term use of corticosteroids may be associated with poor skin conditions such as skin atrophy and shrinkage. Other major problems are the rapid immune response (tachiphylaxis) or the reduction in the benefits of corticosteroids over prolonged use.

In addition, the most common side effect of calcipotriol is the irritation mainly on the face and the rub. If a large amount of calcipotriol is administered, the absorption of this vitamin D analog may cause hypercalcemia (Lebwohl M et al., Ann Rheum Dis 2005; 64 [Suppl II]: ii83-ii86).

Systemic treatments include fumaric acid esters (FAEs), methotrexate (MTX) or cyclosporine A, and biological agents (ustekinumab, infliximab) Resistance (infliximab), adalimumab (adalimumab). As expected, systemic therapy is associated with high-risk side effects: cyclosporine is nephrotoxic and strongly immunosuppressive, while methotrexate is hepatotoxic (Lebwohl M et al., Ann Rheum Dis 2005; 64 [Suppl II ]: ii83-ii86).

In the market, Leflunomide (5-methyl-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarbamamine (4-Isoxazolecarboxamide, 5-me thyl- N-[4-(trifluoromethyl)phenyl]-); CAS RN 75706-12-6) is currently the only dihydroorotate dehydrogenase (DHODH) inhibitor. It is approved by the European Medicines Agency (EMA) for systemic treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Leflunomide is a pre-driving drug for teriflunomide that is converted to an active metabolite.

The benefits of leflunomide in psoriasis have not been extensively studied as in rheumatoid arthritis (RA). The effect of leflunomide on joint psoriasis and/or psoriasis vulgaris was studied in a randomized controlled trial, 3 open trials, and 2 case reports (Affleck, AG et al., Arch Dermatol) 2008, 144: 2, 1642-1643). Although the results varied between trials, a total of 190 patients with joint psoriasis and psoriasis vulgaris were treated with flumetide for 24 weeks during the third trial and were observed to be mild to Moderate cattle Among the people in the skin, it has only moderate benefits compared to placebo (Jones, P. BB. et al., Open Access Rheumatology: Research and Reviews, 2010: 2, 53-71). In all trials, the dose of leflunomide tested on patients with psoriasis was the same as for rheumatoid arthritis, and higher doses may be required in psoriasis. This drug is like Remicade for two diseases but has a higher dose on psoriasis than rheumatoid arthritis.

In addition, patients with psoriasis treated with leflunomide showed severe adverse effects, particularly hepatotoxicity. Leflunomide is not recommended for patients with evidence of hepatitis B or hepatitis C or severe liver abnormalities. Patients treated with leflunomide require regular laboratory monitoring of liver function tests. In the case of psoriasis patients with high sensitivity to hepatotoxicants, the extent to which hepatotoxicity of leflunomide may be ruled out may be excluded from the use of high doses (Curtis JR et al., Ann Rheum Dis, 2010, 69(1): 43-47).

The high degree of variability in psoriasis and its individual manifestations in patients make it difficult to choose the most appropriate treatment. Alternative treatments that best avoid the side effects of current therapies are needed for the disease system.

Surprisingly, the purified human enzyme and peripheral blood mononuclear cell in the test tube test is also 2-[(DHDH inhibitor) of DHDH inhibitor. The 3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid exhibits a higher potential than leflunomide. In addition, 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid was evaluated for hepatotoxicity in comparison with leflunomide. The extent of plasma transaminases and bilirubin was not shown in the in vivo test mode in mice, wherein the test compounds were administered by the intraperitoneal route to maximize liver exposure.

In other words, 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid Local skin application can reduce epidermal hyperplasia and dermal inflammation and is therefore quite useful in the treatment of psoriasis.

The present invention therefore provides 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid for the treatment of psoriasis, or a pharmaceutically acceptable Accepted salts or nitrogen oxides or solvates or deuterated derivatives.

The invention further relates to a topical composition for the treatment of psoriasis comprising 2-[(3,5-difluoro-3'-methoxy-1,1', alone or in combination with one or more active ingredients. -biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable salt thereof or an oxynitride or solvate or deuterated derivative.

The invention further relates to a method for treating a patient suffering from psoriasis comprising an effective amount of 2-[(3,5-difluoro-3'-methoxy) administered alone or in combination with one or more active ingredients. -1,1'-biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable salt thereof or an oxynitride or solvate or deuterated derivative thereof, is affected by the skin of the patient region.

The invention further relates to the use of 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable thereof Use of a salt or an oxynitride or solvate or a deuterated derivative for the manufacture of a medicament for the treatment of psoriasis.

Figure 1 depicts the proliferation of areas of the rat's dorsal skin under uninduced (vehicle), induction (tissue polypeptide antigen (TPA)), and treated (tissue polypeptide antigen + 1% active ingredient) Evaluation.

Figure 2 shows images of histopathological evaluation of uninduced (excipient), induced (tissue polypeptide antigen), and treated (tissue polypeptide antigen + 1% active ingredient) epidermis collected on day 8. In all images, magnification = 100x.

The present invention provides 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid for the treatment of psoriasis, or a pharmaceutically acceptable thereof a salt or an oxynitride or solvate or a deuterated derivative. In particular, it is used for the treatment of plaque psoriasis or psoriasis vulgaris, drip psoriasis, reversal psoriasis, erythrodermic psoriasis, joint psoriasis, scalp psoriasis and nail psoriasis.

2-[(3,5-Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid and its manufacturing process are in International Patent Application No. WO 2008/077639 Described in A1.

WO 2010/102826 A1 describes 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid L-arginine (L-arginine ), meglumine, or tromethamine salts.

As used herein, the term "treatment" means a treatment for a disease or condition in a human patient, which comprises: (a) avoiding the occurrence of a disease or condition, that is, a preventive treatment of the patient; (b) Improve the disease or physical condition, that is, cause the disease or physical condition of the patient to subside; (c) suppress the disease or physical condition, that is, slow down the disease or physical condition of the patient; or (d) reduce the patient's condition Symptoms of illness or physical condition.

As used herein, the pharmaceutically acceptable salts of the vocabulary encompass pharmaceutically acceptable salts of acids or bases. Pharmaceutically acceptable acids include inorganic acids such as, for example, hydrochloric acid, sulphuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, hydrogen Hydroiodic acid; and an organic acid, for example, citric acid, Fumaric acid, maleic acid, malic acid, mandelic acid, ascorbic acid, oxalic acid, succinic Acid), tartaric acid, benzoic acid, acetic acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, cyclohexylaminosulfonate Cyclohexylsulfamic acid (cyclamic acid) or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (eg, sodium or potassium) and alkaline earth metal (eg, calcium or magnesium) hydroxides; and organic bases, for example, alkyl amines, aralkyl amines ( Arylalkyl amines), as well as heterocyclic amines.

Other preferred salts according to the invention are quaternary ammonium compounds wherein the equivalent of the negative ion (X-) is associated with the positive charge of the nitrogen atom. X- can be an anion of various inorganic acids, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or organic Anion of an acid, such as acetate, maleate, fumarate, citrate, oxalate, succinate ), tartrate, malate, mandelate, trifluoroacetate, methanesulphonate, and p-toluenesulphonate. Preferably, X- is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate, or trifluoroacetate. More preferably, X- is a chloride, bromide, trifluoroacetate or methanesulfonate.

When used herein, an easily available oxidizing agent is used, and nitrogen oxides are formed from tertiary basic amines or tertiary imines present in the molecule.

As used herein, the term solvate means more than a stoichiometric or non-stoichiometric solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol. (2-propanol) or the like which is combined by non-covalent intermolecular attraction. When the solvent is water, the vocal hydrate is used in place of the solvate.

As used herein, a lexical deuterated derivative encompasses a compound of the invention wherein at least one hydrogen atom at a particular position is substituted with deuterium. Rhodium (D or 2H) is a stable hydrogen isotope which is present in nature at a content of 0.015 mol%.

Hydroquinone exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. The exchange (calibration) reaction may be holistic or partial.

In general, the deuterated derivative of the compound of the present invention has an isotope enrichment factor for each hydrazine present on the compound at a position designated as a potential position for deuteration (the ratio between the isotope content of this isotope and the natural content, That is, the calibration percentage of the hydrazine in the molecule at a given position is at least 3500 (52.5% 氘 calibration).

In a preferred embodiment, the isotope enrichment factor is at least 5000 (75% guanidine). In a more preferred embodiment, the isotope enrichment factor is at least 6333.3 (95% 氘 calibration). In the preferred embodiment, the isotope enrichment factor is at least 6633.3 (99.5% 氘 calibration). It should be understood that the isotopically enriched factor lines present in each of the locations designated as the deuteration sites are independent of other deuteration sites.

Isotopic enrichment factors can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry (MS) and nuclear magnetic resonance (NMR).

In a particular embodiment, 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid is in the form of a free acid, that is, No additional salts are formed.

In other embodiments, 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid is L-arginine, meglumine Or in the form of a trimethylolamine salt, that is, 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotine Acid, methylamine salt; 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid, trishydroxymethylmethylamine salt Or 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid, L-arginine; and pharmaceutically acceptable Solvate.

In general, 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable salt thereof or The nitrogen oxides or solvates or deuterated derivatives are administered in a suitable form for oral, inhalation, topical, transdermal, transmucosal, transrectal, transdermal or injectable administration.

Preferably, 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable salt thereof or The nitrogen oxides or solvates or deuterated derivatives are administered topically.

As used herein, topical administration describes the route of introduction of a drug into the body where the drug is applied to the skin (skinically) for partial (topical) effects with little or no systemic drug absorption.

Topical composition

The invention further relates to a topical composition for the treatment of psoriasis with a pharmaceutically acceptable excipient or carrier comprising 2-[(3,5-difluoro-3'-methoxy-1,1) '-Biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable salt thereof or an oxynitride or solvate or deuterated derivative; in particular, for plaque psoriasis or vulgaris Psoriasis, drip-like psoriasis, inverted psoriasis, erythrodermic psoriasis, joint psoriasis, scalp psoriasis and nail psoriasis.

An excipient or carrier means a carrier material suitable for transdermal administration, and includes any such materials known in the art, for example, any liquid, gel, solvent, liquid diluent, solubilizing agent, etc., which does not The other ingredients in the composition react in a toxic form. Examples of suitable vectors can be found in Martindale-The complete drug reference, 32nd edition, 1999.

Suitable pharmaceutically acceptable carriers or excipients according to the invention are water, petroleum hydrocarbons (petroleum, paraffin and wax), animal and vegetable fats and oils, fatty acids, fatty alcohols, nonionic interfacial activity Agents, natural waxes, enamel resins and polyols, or mixtures thereof.

Suitable petroleum hydrocarbons according to the present invention, that is, petroleum, paraffin and wax derived from crude oil are hard paraffin, liquid paraffin (liquid petrol or paraffin oil), light soft paraffin (light soft paraffin (Light) Liquid Petrolatum) or paraffinum Perliquidium, white wax (white petrolatum), yellow soft paraffin (yellow petrolatum), macrocrystalline paraffin waxes (mainly containing saturated C ₁₈ -C ₃₀ hydrocarbons and a small amount of a mixture of isoalkanes and naphthenes having a molecular weight comprised between 250 and 450 g/mol, although solid at room temperature, having a relatively small melting point typically comprised between 40oC and 60oC) Microcrystalline paraffines waxes (comprising C ₄₀ -C ₅₅ compounds, which contain a large number of isoparins and naphtenes with long alkyl side chains in addition to linear hydrocarbon molecules, isoalkanes The microcrystalline, microcrystalline wax has an average molecular weight encompassing between 500 and 800 g/mol, is solid at room temperature and has a melting point between 60 ° C and 90 ° C, or a mixture thereof.

Preferred petroleum hydrocarbons are hard paraffin, liquid paraffin, light paraffin wax, white wax or mixtures thereof, and particularly preferably liquid paraffin, white wax or a mixture thereof.

Suitable animal or vegetable fats and oils according to the invention are linear with a chain length of from 1 to 30 carbon atoms And/or esters of branched and saturated and/or unsaturated alkanecarboxylic acids with linear and/or branched, saturated and/or unsaturated alcohols having a chain length of from 1 to 30 carbon atoms; Or an ester of a linear carboxylic acid with a linear and/or branched, saturated and/or unsaturated alcohol having a chain length of from 1 to 30 carbon atoms.

These oils are preferably selected from isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, hard N-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl, stearic acid (stearate), isobornyl stearate, isodonyl isononanoate, 2-ethylhexyl laurate, 2-ethylhexyl palmitate 2-ethylhexyl palmitate), 2-ethylhexyl cocoate, 2-hexyldecyl stearate, 2-ethylhexylisostearate (2- Ethylhexyl isostearate), 2-octyldodecyl palmitate, cetyl palmitate, oleyl oleate, oleyl erucate , a group consisting of erucyl oleate, erucyl erucate, and the synthesis of these esters, Synthetic and natural mixtures, such as jojoba oil (jojoba oil) (having a single C ₁₈ -C ₂₄ chains unsaturated carboxylic acid monomer (monounsaturated monocarboxylic acids) and having a single C ₁₈ -C ₂₄ long-chain unsaturated mono alcohol of a natural mixture of esters.

Other suitable oils of the saturated alkanoic acid and alcoholic ester form are fatty acid methyl esters, preferably C ₆ - which may be wholly or partially hydrogenated from fats and oils of animals and plants. C ₂₄ fatty acid methyl esters, such as cotton, safflower, coconut, rapeseed, linseed, palm, palm kernel, sunflower ), oil (olein), olive, olive pomace, castor oil, tallow, soy, tall oil, etc., as well as purification or synthesis Fatty acids, such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid (palmitic acid) (cetylic acid)), palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid, oleic acid , ricinoleic acid, elaidic acid, petroselinic acid, linoleic acid Acid), linolenic acid, arachidic acid, gadoleic acid, behenic acid, and erucic acid, and mixtures thereof.

Other suitable animal or vegetable fats and oils according to the invention are fatty acid triglycerides, in particular linear and/or branched, saturated chains having a chain length of from 6 to 24 carbon atoms, preferably from 10 to 18 carbon atoms. And/or triglycerin esters of unsaturated alkanecarboxylic acids. The fatty acids at different positions of the esterified glycerol may vary, thus producing a large number of possible combinations comprising positional combinations. The location of the different fatty acids in the natural triglyceride is not random but depends on the original fat. The simpler triglyceride is constructed from a single fatty acid.

The fatty acid triglyceride may preferably be selected from the group consisting of, for example, synthetic, semi-synthetic and natural oils. As an example, animal fats and oils are like tallow, lard, bone oil, aquatic animal fats and oils (fish, for example Squid, squid or sardine; whales; etc.; and vegetable fats and oils like avocado oil, almond oil, hazelnut oil, babassu palm oil , borage oil, peanut oil (peanut oil), canola oil, hemp oil, milk thistle oil, safflower oil, chufa oil, coconut oil , rapeseed oil, black cumin oil, wheat germ oil, sunflower oil, linseed oil, macadamia nut oil ) corn oil, walnut oil, olive oil and its by-products such as olive pomace oil, palm oil and fractions such as palm olein ( Palm olein) and palm stearin, evening primrose oil, rosehip oil, castoroil, rice bran oil, apricot kernel oil , cottonseed oil, pumpkinseed oil, palm kernel oil and fractions such as palm kernel olein and palm kernel stearin, grape seed oil (grape seed oil), sesame oil, soy oil, cocoa butter, butter Oil (shea butter) and so on.

Particularly preferred are vegetable fats and oils as described above.

The fatty acids suitable for use in accordance with the invention are C ₆ -C ₂₄ fatty acids derived from vegetable and animal fats and oils, as previously described, such as cotton, safflower, coconut, rapeseed, linseed which may be wholly or partially hydrogenated. , palm, palm kernel, sunflower, oil, olive, olive fruit, castor oil, butter, soybean, tall oil, etc., and purified or synthetic fatty acids like acid, caprylic acid, citric acid, lauric acid, myristic acid, Hexadetaic acid (palmitic acid), palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid, oleic acid, ricinoleic acid, oleic acid, apisic acid, linoleic acid, linseed oil Acid, arachidic acid, oleic acid, eucalyptus acid, and sinapic acid, or an industrial grade mixture thereof. Preferred are lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, 2-ethylhexanoic acid, oleic acid, ricinoleic acid, and eucalyptus acid, particularly derived from plant sources. Or a mixture of fatty acids.

The fatty alcohols suitable for use according to the invention are C ₆ -C ₂₄ fatty acids derived from vegetable and animal fats and oils, as previously described, such as cotton, safflower, coconut, rapeseed, flax, which may be wholly or partially hydrogenated. Kernel, palm, palm kernel, sunflower, oil, olive, olive fruit, castor oil, butter, soybean, tall oil, etc., and purified or synthetic fatty alcohols such as caproyl alcohol, capryl alcohol , capric alcohol, lauryl alcohol, myristyl alcohol, palmytil (cetyl) alcohol, palmitolyl alcohol, stearyl Alcohol), isostearyl alcohol, 2-octyldodecanol, 2-ethylhexanoyl alcohol, oleyl alcohol, ricinolealcohol ), elaidyl alcohol, petroselinic alcohol, linoleyl alcohol, linolenyl alcohol, arachidyl alcohol, gadoleyl alcohol, eucalyptus Behenyl alcohol and sinyl alcohol (erucyl a Lcohol) or its industrial grade mixture is like cetostearyl alcohol. Preferred are lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleol, stearyl alcohol, isostearyl alcohol, 2-ethylhexanol, oleyl alcohol, ricinoleic alcohol and eucalyptus alcohol, especially from plant sources. , or an industrial grade mixture thereof such as a fatty alcohol of cetearyl alcohol.

Suitable nonionic surfactants according to the invention are acetoglycerides; diacetylated monoglycerides; monoethylidene monoglyceride and acetylated monoglycerides; monoglycerol Esters and glycerides (such as glyceryl monobehenate, glyceryl dibehenate, glyceryl monooleate, glyceryl dioleate (glyceryl) Dioleate), glyceryl monostearate, glyceryl distearate, glyceryl monopalmitosteareate or glyceryl dipalmitosteareate; Ethylene glycol or propylene glycol and C ₆ -C ₂₂ fatty acid esters (such as ethylene glycol monopalmitostearate, ethylene glycol monostearate (ethylene glycol) Monostearate), propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dioctyl decyl ester (prop Ethylene glycol dicaprylocaprate), propylene glycol monopalmitostearate, propylene glycol monostearate or propylene glycol alginate; polyoxyethylene alkyl ethers ) [n-alcohols such as lauryl alcohol, oleyl alcohol, myristyl alcohol, palmitol and stearyl alcohol glycol ethers (polyoxyethylene glycol ethers); like polyethylene glycol cetyl hard Macrogol cetostearyl ethers (polyoxyl 6 cetostearyl ether, polyoxyethylene (20) polyoxyl 20 cetostearyl ether or polyoxyethylene (25) Polyoxyl 25 cetostearyl ether, macrogol cetearyl ethers (such as polyoxyl 2 cetyl ether, polyoxyethylene (polyoxyethylene) 10)-polyoxyl 10 cetyl ether or polyoxyl 20 cetyl ether, macrogol lauryl ethers (like polyoxyethylene (2) ) polyoxyl 2 lauryl ether, polyoxyethylene (4) Polyoxyl 4 lauryl ether, polyoxyl 9 lauryl ether or polyoxyl 23 lauryl ether, polyethylene glycol stearyl ether Macrogol stearyl ethers) (such as polyoxyl 2 stearyl ether, polyoxyl 10 stearyl ether, polyoxyethylene (21) ten Polyoxyl 21 stearyl ether or polyoxyl 100 stearyl ether, or macrogol oleyl ethers (like polyoxyethylene ( 2) polyoxyl 2 oleyl ether, polyoxyl 10 oleyl ether or polyoxyl 20 oleyl ether; polyethylene glycol single Macrogol monomethyl ethers (polyethylene glycol monomethyl ethers) have a nominal average molecular weight ranging from 300 to 10,000, preferably from 320 to 4,000, more preferably from 350 to 1,000. Such as polyoxyethylene glycol (1000) monohexadecyl ether); menfegol; nonoxinols (eg nonoxynol ether (9) (nonoxinol 9), nonoxinol 10 or nonoxinol 11; octoxinols (eg oxtoxinol 9) ); poloxamers (copolymers of polyoxyethylene and polyoxypropylene, such as poloxamer (188) or poloxamer (188)); polyoxyl castor oils ( Such as polyoxyethylene (35) castor oil); polyoxyl hydrogenated castor oil (such as polyoxyethylene (40) hydrogenated castor oil); polyoxyl stearates (polyoxyl stearates) (hard fat Acidic ethoxylated derivatives such as polyoxyethylene (2) stearate, polyoxyethylene (4) stearate, polyoxyethylene (6) stearate, polyoxyethylene (8) ) stearate, polyoxyethylene (12) stearate, polyoxyethylene (20) stearate, polyoxyethylene (40) stearate, polyoxyethylene (50) stearate, Polyoxyethylene (100) stearate, polyoxyethylene (150) stearate, polyoxyl 4 distearate, polyoxyethylene (8) distearate , polyoxyethylene (12) distearate, polyoxyethylene (32) distearate or polyoxyethylene (150) distearate); polyoxyethylene sorbitan fatty acid esters (eg, polysorbate 20, polysorbate (40), poly Sorbitol ester (60), polysorbate (65), polysorbate (80) or polysorbate (85)); propylene glycol diacetate (PGDA, propylene oxide) ) a reaction product with acetic acid); sorbitan esters (such as sorbitan monolaurate, sorbitan mono-oleate, sorbitan monopalmitate) Sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate or sorbitan tristearate Sorbitan tristearate and sucrose esters.

Preferred nonionic surfactants according to the invention are monoglycerides and diglycerides (e.g., glyceryl monobehenate, glyceryl dibehenate, glyceryl monooleate, glycerol dioleate, mono-hard Glyceryl glyceride, glyceryl distearate, glycerol monopalmitate or glyceryl palmitate); esters of ethylene glycol or propylene glycol with C ₆ -C ₂₂ fatty acids (like ethylene glycol) Palm stearic acid, ethylene glycol monostearate, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dioctyl decyl ester, propylene glycol monopalmitic acid, propylene glycol monostearate or propylene glycol alginate ); alkyl polyoxyethylene ethers [glycols such as lauryl alcohol, oleyl alcohol, myristyl alcohol, palmitol and stearyl alcohol glycol ethoxylates; like polyethylene glycol cetearyl ether ( Polyoxyethylene (6) cetearyl ether, polyoxyethylene (20) cetearyl ether or polyoxyethylene (25) cetearyl ether), polyethylene glycol cetyl ether (like polyoxygen) Ethylene (2) cetyl, polyoxyethylene (10) hexadecane or polyoxyethylene (20) cetyl), ethylene glycol lauryl ether (such as polyoxyethylene (2) lauryl ether, polyoxygen Ethylene (4) Laurel , polyoxyethylene (9) lauryl ether) or polyoxyethylene (23) lauryl ether), polyethylene glycol stearyl ether (such as polyoxyethylene (2) stearyl ether, polyoxyethylene (10 ) octadecyl ether, polyoxyethylene (21) stearyl ether or polyoxyethylene (100) stearyl ether), or polyethylene glycol oleyl ether (such as polyoxyethylene (2) oil Alcohol ether, polyoxyethylene (10) oleyl alcohol ether or polyoxyethylene (20) oleyl alcohol ether)]; polyoxyethylene sorbitan fatty acid ester (such as polysorbate (20), polysorbate ( 40), polysorbate (60), polysorbate (65), polysorbate (80) or polysorbate (85)); propylene glycol diacetate (PGDA, propylene oxide and acetic acid reaction And sorbitan esters (such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleic acid) Ester, sorbitan trioleate or sorbitan tristearate).

Suitable natural waxes according to the present invention are candelilla wax, carnauba wax, Japan wax, esparto wax, cork wax, gar. Guaruma wax, rice wax, sugar cane wax, ouricury wax, montan wax, beeswax, shellac wax Shellac wax), espermaceti, wool lanolin (wax), uropygial fat wax, ceresin waxes, peat waxes, ozokerite ), as well as chemical processing waxes (hard waxes), for example, montan wax esters, waxes obtained by the Fischer-Tropsch process, hydrogenated jojoba wax (jojoba) Waxes) and synthetic waxes.

The applicable enamel resin according to the present invention is a cyclic and/or linear oxime resin which can be constructed by a monomer which is generally characterized in that the structural elements are:

Wherein the halogen atoms may be substituted by the same or different alkyl or aryl groups, and are generally represented by the R ₁ -R ₄ groups.

The linear oxime resin having a oxirane monomer according to the present invention is generally characterized in that the structural elements are:

Wherein the ruthenium atoms may be substituted by the same or different alkyl or aryl groups, generally represented by R ₁ -R ₄ groups (meaning that the number of different groups is not necessarily limited to 4), and m may be selected from 2 to The value of 200,000.

Suitable cyclic silicones according to the invention are generally characterized in that the structural elements are:

Wherein the ruthenium atoms may be substituted by the same or different alkyl or aryl groups, generally represented by R ₁ -R ₄ groups (meaning that the number of different groups is not necessarily limited to 4), and n may be selected from 3/2 A value of up to 20. The numerical value of n indicates that the oxoalkyl group present in the ring may be singular.

Specific examples include a cyclic methyl siloxane having the formula [(CH ₃ ) ₂ SiO] _x wherein x is 3-6 or ((CH ₃ ) ₂ SiO[(CH ₃ ) ₂ SiO a short chain linear methyl siloxanes of the formula _y Si(CH ₃ ) ₃ wherein y is 0-5.

Some suitable cyclomethoxanes are hexamethylcyclotrisiloxanes (D3), solids with a boiling point of 134oC and chemical formula [(Me ₂ )SiO] ₃ ; octamethylcyclotetrasiloxane (octamethylcyclotetrasiloxane) , D4), which has a boiling point of 176oC, a viscosity of 2.3 mm ² /s, and a chemical formula of [(Me ₂ )SiO] ₄ ; decamethylcyclopentasiloxane (D5) (cyclomethicone) )), having a boiling point of 210oC, a viscosity of 3.87 mm ² /s, and a chemical formula of [(Me ₂ )SiO] ₅ ; and (dodecamcthylcyclohexasiloxane, D6) having a boiling point of 245 ° C, a viscosity of 6.62 mm ² /s, and a chemical formula [(Me ₂ ) SiO] ₆ .

Some suitable short-chain linear methyl oxiranes are hexamethyldisiloxane (MM) having a boiling point of 100 ° C, a viscosity of 0-65 mm ² /s, and a chemical formula of Me ₃ SiOMe ₃ ; octamethyltriazine Octamethyltrisiloxane (MDM) having a boiling point of 152 ° C, a viscosity of 1.04 mm ² /s, and a chemical formula of Me ₃ SiOMe ₂ SiOSiMe ₃ ; decamethyltetrasiloxane (MD2M) having a boiling point of 194 ° C and a viscosity of 1.53 mm ² /s and the chemical formula Me ₃ SiO(MeSiO) ₂ SiMe ₃ ; dodecamethylpentasiloxane (MD3M) having a boiling point of 229 ° C, a viscosity of 2.06 mm ² /s and a chemical formula of Me ₃ SiO(Me ₂ SiO) ₃ SiMe ₃ ; tetradecamethylhexasiloxane (MD4M) having a boiling point of 245 ° C, a viscosity of 2.63 mm ² /s, and a chemical formula of Me ₃ SiO(Me ₂ SiO) ₄ SiMe ₃ ; Hexanecamethylheptasiloxane (MD5M) having a boiling point of 270 ° C, a viscosity of 3.24 mm ² /s, and a chemical formula of Me ₃ SiO(Me ₂ SiO) ₅ SiMe ₃ .

In addition, long-chain linear methyl oxane may also be included, such as phenyltrimethicone, bis(phenylpropyl)dimethicone, Dimethicone, dimethiconol, cyclomethicone (octametilciclotetrasiloxane), hexamethine Hexamethylcyclotrisiloxane, poly(dimethylsiloxane), cetyldimethicone, and behenyloxypolydimethyloxane (behenoxy dimethicone).

Further, according to the present invention, a mixture of cyclopolydimethyloxane and isotridecyl isononanoate and cyclopolydimethyloxane and isooctyl stearate (2-ethylhexyl isostearate) ) is also suitable for the resin.

Polyols suitable for use in accordance with the present invention are preferably water-soluble polyols, such as polyhydric alcohols having two or more hydroxyl groups in the molecule.

Specific examples may include ethylene glycol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, Hexane glycol, dipropylene glycol, polyethylene with an average molecular weight between 100 and 1000 Polyethylene glycol, glucose, fructose, galactose, mannose, ribose, erythrose, maltose, maltitol ), maltotriose, sucrose, xylitol, sorbitol, threitol, erythritol, glycerol, Polyglycerol and starch alcohols. Preferred polyols according to the invention are ethylene glycol, propylene glycol, 1,3-butanediol, 1,4-butanediol, hexanediol, dipropylene glycol, having a weight between 100 and 1000. The average molecular weight of polyethylene glycol, glycerin, polyglycerol, and mixtures thereof.

Particularly preferred polyols in accordance with the invention are 1,3-butanediol, 1,4-butanediol, hexanediol, dipropylene glycol, glycerin, and mixtures thereof.

The pH of the topical composition according to the present invention generally falls within the acceptable range for topical administration, and is preferably in the range of from 3.0 to 9.0, more preferably in the range of from 3.5 to 7.5.

In a preferred embodiment, the topical composition according to the present invention is in the form of an emulsion, gel, oil gel, ointment, paste, suspension, detergent, foam, spray, aerosol or solvent. to make.

The viscosity of the topical composition according to the invention will depend on the form of the composition. For example, in the case of an emulsion, a DIN-Rotations Rheometer (Paar Physica) at 20 ° C; a Measuring System Z 3 DIN; D = 57.1 The viscosity measured by s is usually in the range of 2,000 to 15,000 mPa.s, preferably in the range of 2,500 to 10,000 mPa.s, and more preferably in the range of 3,000 to 7,000 mPa.s. In the case of gels, the German standard rotary rheometer (Paphy physics) is used at 20 ° C; the measurement system Z 3 DIN; D = 57.2 / s measured viscosity is usually in the range of 300 to 1500 mPa.s, It is preferably in the range of 500 to 1200 mPa.s, more preferably in the range of 600 to 900 mPa.s. Within the scope.

The topical composition according to the present invention may optionally further comprise, selected from the group consisting of (a) antibiotics, (b) antifungal agents, (c) antihistamine agents, (d) Antimetabolites, (e) corticosteroids, (f) immunosuppressants, (g) nonsteroidal anti-inflammatory drugs (NSAIDs), (h) vitamin A One or more active ingredients of the group consisting of vitamin A analogues and (i) vitamin D analogues.

Examples of antibiotics for use in the context of the present invention include, but are not limited to, aclarubicin, actinomycin D, amrubicin, liposome annamycin. , adhamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, softening Galarubicin, idarubicin, mitomycin C, mupiricin, nemorubicin, neocarzinostatin , peplomycin, pirarubicin, rebeccamycin, retapamulin, stimalamer, streptozotocin Streptozocin), valrubicin, zinostatin, and combinations thereof.

Examples of antifungal agents useful in the context of the present invention include, but are not limited to, amphotericin B, bifonazole, caspofungin, clotrimazole, echinococcus Echinocandin B, econazole, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole ), Posaconazole, ravuconazole, terbinafine, tioconazole, voriconazole, and combinations thereof.

Examples of antihistamines useful in the context of the present invention include, but are not limited to, clemastine, diphenhydramine, benadryl, doxylamine, and chloride. Loratadine, desloratadine, fexofenadine, pheniramine, cetirizine, ebastine, HCl Promethazine, chlorpheniramine, levocetirizine, olopatadine, quetiapine, meclizine, tea phenyl sea Dimenhydrinate, embramine, dimethindene, dexchlorpheniramine, cimetidine, famotidine, ranitidine (ranitidine), nizatidine, roxatidine, lafutidine, A-349,821, ABT-239, ciproxifan, clobenpropit, radix Histamine protein, thioperamide, JNJ 7777120, VUF-6002 and combination.

Examples of antimetabolites useful in the context of the present invention include, but are not limited to, methotrexate; 6-mercaptopuhne riboside; mercaptopurine alone or with formazan tetrahydrofolate ( Leucovorin), tegafur, UFT, doxifluhdine, carmofur, cytarabine, cytarabine ocfosfate ), enocitabine, S-1, Alimta (premetrexed disodium (LY231514, MTA)), Gemzar (gemcitabine, EIi Lilly), gludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine Clofarabine), decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, nitrogen mustard Acid (melphalan), nairabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pyridinium Pelitrexol, raltitrexed, thapine, trimetrexate, vidarabine, vincristine, vinorelbine , N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thienylcarbenyl -L-glutamic acid (N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid a combination of 5-fluorouracil (5-FUuracil, 5-FU); And combinations thereof. A preferred antimetabolite is a killing cancer ingot and 5-fluorouracil, and particularly preferably 5-fluorouracil.

Examples of corticosteroids and glucocorticoids useful in the context of the present invention include, but are not limited to, prednisolone, methylprednisolone, dexamethasone cipecilate, naphthalene Naflocort, deflazacort, halopedone, acetate, budesonide, beclomethasone dipropionate, hydrogenated steroid Hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, vinegar Nylon (methylprednisolone aceponate), dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, aclomethasone dipropionate (alclometasone dipropionate), halometasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, cyclossophylline Ciclesonide, butixocort propionate, RS-85095, CGP-13774, GW-250495, dehydrocortisone, NO-Prednisolone, Ai Epinol ester (etiprednol dicloacetate), QAE-397, 7beta-OH-EPIA, RPR-106541, deprodone propionate, fluticasone propionate, fluticasone furoate, propionic acid halide Halobetasol propionate, iotepredol etabonate, betamethasone butyrate propionate, flunisolide Prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone, doubling Betamethasone dipropionate, 21-chloro-11 β-hydroxy-17 α-[2-(methylsulfonyl)ethoxycarbonyl]-4-pregnene-3,20-dione ( 21-Chloro-11beta-hydroxy-17alpha-[2-(methylsulfanyl)acetoxy]-4-pre, deisobutyrylciclesonide, hydrocortisone acetate, hydrocortisone amber Sodium (hydrocortisone sodium succinate), prednisolone sodium phosphate, and hydrocortisone probutate, prednisone Prednisolone sodium metasulfobenzoate, clobetasol propionate and combinations thereof. Preferred corticosteroids and glucocorics are prednisolone, prednisolone, quercetin, betamethasone propionate and its derivatives, esters, salts and mixtures, and combinations thereof.

Examples of suitable immunosuppressive agents include, but are not limited to, imiquimod, picemolimus, tacrolimus, cyclosporine A, anti-TNF agents (anti -TNF agents) and combinations thereof. A preferred immunosuppressive agent is imiquimod.

Examples of non-steroidal anti-inflammatory agents useful in the context of the present invention include, but are not limited to, oxicams, piroxicam, meloxicam, isoxicam, and Tenoxicam, sudoxicam, CP-14, 304, salicylates, aspirin (acetylsalicylic acid), double water Disalcid, benorilate, trilisate, sorprin, diflunisal, fendosal, acetic acid derivatives Fins), aceclofenac, diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoke Acid (isoxepac), furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, Clindanac, oxepinac, felbinac, etodolac, ketorolac, fenama Tes), mefenamic acid, meclofenamic, flufenamic, niflumic, tolfenamic acids, propionic acid Derivatives, ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, pyridoxine (piketoprofen), fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin , pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen, pyrazoles, base Phenylbutazone, oxyphenbutazone, feprazone, azapropazone, trimethazone and its derivatives, esters, salts and mixtures, And its combination. Preferred non-steroidal anti-inflammatory agents are aspirin (acetamidine salicylic acid), aceclofenac, di-chlorophene and its derivatives, esters, salts and mixtures, and combinations thereof. A more preferred non-steroidal anti-inflammatory agent is diclofenac sodium.

Examples of vitamin A analogs for use in the context of the present invention include, but are not limited to, acitretin, adapalene, alitretinoin, bexarotene, fendi A. Fenretinide, isotretinoin, retinal, retinol, tazarotene, tretinoin and its derivatives, esters, salts Classes and mixtures, and combinations thereof. Preferred vitamin A analogs are valsaratin, tazarotene and retinoic acid.

Examples of vitamin D analogs for use in the context of the present invention include, but are not limited to, alfacalcidol, calcipotriol, calcitriol, dihydrotachysterol-2 , doxercalciferol, holecalciferol, 22-oxacalcitriol, paracalcitol, seocalcitol (EB) 1089)), his bone alcohol (tacalcitrol) and its compositions.

The topical composition according to the present invention more optionally comprises other conventional pharmaceutically and/or cosmetically acceptable additives such as, for example, anti-irritants, antioxidants, buffers (buffering). Agents (pH adjusting agents), chelating agents, emollients, penetration enhancing agents, preservative agents, solubilizing agents ), thickening agents, wetting agents, and the like, or mixtures thereof.

Examples of suitable anti-irritants are aloe vera, chamomile, alpha-bisabolol, cola nitida extract, green tea extract, Tea tree oil, licoric extract, batyl alcohol (α-octadecyl glyceryl ether), squalyl alcohol (α-9-ten) Selachyl alcohol (α-9-octadecenyl glyceryl ether), chimyl alcohol (α-hexadecyl glyceryl ether), panthenol , allantoin, caffeine or other xanthines, glycyrrhizic acid and its derivatives, and mixtures thereof.

The antioxidant used may be any antioxidant suitable or customary for cosmetic and/or dermatological use. Suitable antioxidants are preferably small tolerated doses (e.g., pmol to μmol/kg) selected from the group consisting of amino acids (e.g., glycine, histidine, tyrosine, tryptamine). Tryptophan) and its derivatives, imidazoles (such as 4-urocanic acid) and derivatives thereof, peptides such as D, L-carnosine, D-carnosine, L-carnosine and its derivatives (such as antherine), carotenoids, carotenes (such as alpha-carotene, beta-carotene, beta-carotene, Lycopene and its derivatives, lipoic acid and its derivatives (such as dihydrolipoic acid), aurothioglucose, propylthiouracil and Other thiols (eg, thioredoxin, glutathione, cysteine, cystine, cystamine, and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and its auryl, Palmitoyl, oleyl, γ-linoleyl, cholesteryl and its glycerides, and its salts, dilauryl thiodipropionate, thio Distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and Sulphoximine compounds (eg, buthionine sulphoximines, homocysteine sulphoximine, buthionine sulphones, 5- a group consisting of 6-, 7-methionine (penta-, heptathionine sulphoximine), and according to the invention, a (metal) chelating agent (for example, an alpha-hydroxy fatty acid (α-) is also suitable. Hydroxy fatty acids), palmitic acid, phytic acid, lactoferrin, alpha-hydroxy acids (eg, citric acid, lactic acid, malic acid), rot Humic acid, bile acid, bile extracts, bilirubin , biliverdin, EDTA, EGTA and its derivatives, unsaturated fatty acids and their derivatives (such as γ-linolenic acid, linoleic acid, oleic acid) ), folic acid and its derivatives, ubiquinone and ubiquinol and its derivatives, vitamin C and its derivatives (eg ascorbyl palmitate, magnesium ascorbyl phosphate) Mg ascorbyl phosphate), ascorbyl acetate, tocopherols and their derivatives (eg vitamin E acetate), and benzoin coniferyl benzoate ( Coniferylbenzoate), rutinic acid and its derivatives, ferulic acid and its derivatives, butylated hydroxytoluene, butylated hydroxyanisole, norbin Nordihydroguaiac resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose And its derivatives, zinc and its derivatives (such as ZnO, ZnSO ₄ ), selenium and its derivatives (such as selenium methionine), stilbene (stilbenes) and its derivatives (such as two Stirbene oxide, trans-stilbene oxide and derivatives thereof, salts (esters, esters, ethers, saccharides, nucleotides, nuclei) Glycosides, peptides and lipids).

Any pharmaceutically acceptable buffering agent for adjusting the pH of the topical composition to an acceptable level for topical administration may be used in accordance with the present invention, preferably in the range of from 3.0 to 9.0, more preferably from 3.5 to Within the scope of 7.5. For example, a pharmaceutically acceptable acid contained in the composition, such as acetic acid, citric acid, fumaric acid, phosphoric acid, hydrochloric acid, lactic acids, or nitric acids, or the like, or a mixture thereof. It will also be understood that some of the compositions of the present invention may have a desired range of pH values without the inclusion of pH adjusting agents specifically for this purpose. However, in general, an acidic buffer system is present in the composition to achieve a desired pH. The acidic buffer system includes an acidulant and a buffer. Suitable acidifying agents which will be known to those of ordinary skill in the art include, for example, acetic acid, citric acid, fumaric acid, hydrochloric acid, phosphoric acid, lactic acid, nitric acid, and the like, and mixtures thereof. Suitable buffer will Also well known to those of ordinary skill in the art, and examples include potassium metaphosphate, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate (sodium) Citrate), etc., and mixtures thereof.

Suitable emollients for use in the compositions of the present invention include, for example, dodecane, squalane, cholesterol, isohexadecane, isodecyl isononanoate (isononyl isononanoate), PPG Ethers, petrolatum, lanolin, safflower oil, castor oil, coconut oil, cottonseed oil, palm oil, palm oil, peanut oil, soybean oil, polyol carboxylate (polyol carboxylic acid esters), derivatives thereof, and the like, and combinations thereof.

Examples of suitable permeability enhancers may include, for example, dimethylsulfoxide (DMSO), N-methyl pyrrolidine, dimethyl formamide (DMF), urine. Allantoin, urazole, N,N-dimethylacetamide (DMA), decylmethylsulfoxide, polyethylene glycol single laurel Polyethylene glycol monolaurate, propylene glycol, propylene glycol monolaurate, glycerol monolaurate, lecithin, 1-substituted nitrogen heterocycle 1-substituted azacycloheptan-2-ones, especially 1-n-dodecylcyclazacycloheptan-2-one, alcohols , glycerin, hyaluronic acid, transcutol, and the like, and mixtures thereof. Certain oil components (eg, certain vegetable oils, such as safflower oil, cottonseed oil, and corn oil) may also exhibit enhanced penetration characteristics.

An example of a preservative suitable for avoiding microbial contamination is an alkyl paraben. (alkylparabens), especially methylparaben, propylparaben and butylparaben; hydroxychloroaniline; positive soap (benzethonium) Chloride; benzoic acid; benzyl alcohol; sodium benzoate; bronopol; butylated hydroxy toluene; butylated hydroxyanisole ; cetyltrimium bromide; chlorobutanol; chlorocresol; chlorhexidine; dehydroacetic acid; ethylenediamine tetraacetic Acid); paraben esters; phenylethylalcohol; phenol; phenoxyethanol; sorbic acid; potassium sorbate; . The amount of preservative used will generally vary depending upon the preservative selected.

An example of a co-solvent is a nonionic surfactant such as at least one of the following groups: 1 to 30 moles of ethylene oxide and/or 0 to 5 moles of propylene oxide. a product of a linear C ₈ -C ₂₂ fatty alcohol, a C ₁₂ -C ₂₂ fatty acid, and an alkyl phenols having 8 to 15 carbon atoms; an alkyl group having 8 to 22 carbons in the alkyl group; / or algoglycosides (oligoglycosides) and its ethoxy analogs; 1 to 15 moles of ethylene oxide and processed products of castor oil and / or hydrogenated castor oil; 15 to 60 moles of ethylene oxide Processed product with castor oil and/or hydrogenated castor oil; part with hydroxycarboxylic acids containing 12 to 22 carbons of unsaturated or saturated, linear or branched fatty acids and/or containing 3 to 18 carbon atoms Esterified glycerol and/or sorbitan, and processed products thereof having 1 to 30 moles of ethylene oxide; alkoxylated glycerides and alkoxylated glycerine, partially esterified Polyglycerol (average degree of self condensation (2 to 8)), polyethylene glycol (polyethyle) Ne glycol) (weight average molecular weight 400 to 5000), trimethylolpropane, pentaerythritol, sugar alcohols (eg sorbitol), alkyl glucosides (eg methyl Methyl glucoside, butyl glucoside, lauryl glucoside, and saturated and/or unsaturated, linear or branched fatty acids and/or containing 12 to 22 carbons a mixture of polyglucosides (for example, cellulose) of 3 to 18 carbon hydroxycarboxylic acids and processed products thereof having 1 to 33 moles of ethylene oxide; pentaerythritol, fatty acids, citric acid and fatty alcohols Mixed esters, and/or fatty acids containing 6 to 22 carbons, methyl glucose and polyols, preferably mixed esters of glycerol or polyglycerol; Trialkyl phosphates, and mono-, di- and/or tri-PEG-alkyl phosphates and salts thereof; block copolymers, for example, poly Ethylene glycol (30) dipolyhydroxystearate (Poly Ethyleneglycol-30 Dipolyhydroxystearate); polymer emulsifiers; polyalkylene glycols and alkyl glyceryl ethers. A particularly preferred co-solvent is the addition of 1 to 30 moles of ethylene oxide and/or 0 to 5 moles of propylene oxide to a linear C ₈ -C ₂₂ fatty alcohol such as lauryl alcohol, myristyl alcohol, cetyl alcohol. (palmitol), stearyl alcohol, oleyl alcohol and castor oil or an industrial grade mixture thereof is a product of cetearyl alcohol or palmitoleyl alcohol.

The thickener or viscosity-enhancing agent may generally comprise a pharmaceutical composition for thickening the liquid. While any suitable thickening agent may be included in the compositions of the present invention, when a preferred thickening agent is used, it comprises one or more acacia, algionic acid, bentonite, card Carbomer, carboxymethylcellulose calcium or sodium carboxymethylcellulose (carboxymethylcellulose sodium), cetostearyl alcohol, methyl cellulose, ethylcellulose, glycerin, gelatin and guar gum, hydroxy Hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone , propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, starch tragacanth, and xanthan gum (xanthan gum), and any combination thereof. Preferred thickeners are glycerin, hydroxypropyl methylcellulose and xanthan gum, and any combination thereof.

Examples of wetting agents (chemicals that increase liquid diffusion and permeability characteristics by reducing surface tension) comprise one or more cationic surfactants, such as benzalkonium chloride; nonionic surfactants ( Non-ionic surfactants, such as polyoxyethylene and polyoxypropylene block copolymers; polyoxyethylene fatty acid glycerides and oils (such as polyoxyethylene (6) Caprylic/capric acid and polyoxyethylene (6) caprylic/capric mono- and diglycerides), polyoxyethylene (40) hydrogenated castor oil (polyoxyethylene (40) hydrogenated Castor oil); polyoxyethylene sorbitan esters, such as polysorbate (20) and polysorbate (80); propylene glycol fatty acid esters, such as propylene glycol lauric acid Propylene glycol laureate; glyceryl fatty acid esters, such as glyceryl monostearate; sorbitol Anhydride esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, and sorbitan monostearate; glyceryl fatty acid esters, for example Glyceryl monostearate; anionic surfactants, such as sodium lauryl sulphate, sodium lauryl ether sulphate; or fatty acids and their salts, like It is oleic acid, sodium oleate and triethanolamine oleate.

The invention also provides a method for treating a patient suffering from psoriasis; in particular, a method for treating plaque psoriasis or psoriasis vulgaris, drip psoriasis, reversal psoriasis, erythroderma psoriasis, joint Method for treating patients with psoriasis, scalp psoriasis and nail psoriasis; it comprises administering an effective amount of 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl) An amino]nicotinic acid, or a pharmaceutically acceptable salt thereof or an oxynitride or solvate or deuterated derivative, or a topical composition as defined in the above, to the affected area of the skin of the patient .

In general, the affected area of the skin affected by psoriasis is selected from the group consisting of eyelids, ears, mouth and lips, skin wrinkles, hands and feet, and nails. The skin at these locations varies and requires different treatments.

The method of using the topical composition of the present invention is to apply it to completely cover the affected area to form an occlusive barrier. The amount required depends on the size of the lesion.

The present invention relates more to a 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable salt thereof Or the use of nitrogen oxides or solvates or deuterated derivatives for the manufacture of medicaments for the treatment of psoriasis, in particular for the manufacture of plaque psoriasis or psoriasis vulgaris, psoriasis psoriasis, reversal psoriasis - erythrodermic psoriasis, joint psoriasis, scalp psoriasis and nail psoriasis treatment.

The following examples are given to provide a clear enough and complete description of the present invention to those of ordinary skill in the art, and as set forth in the foregoing part of the specification, are not to be construed as limiting the scope of the invention.

example Example 1 Epidermal hyperplasia

The epidermal hyperplasia rat model was used to test the pharmaceutical activity of 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid.

Animals and reactants

Wistar rats (200-250 g) were obtained from Edinburgh (Sant Feliu de Codines, Spain) and were calibrated in all procedures with standard feed under standard light/light cycle. Feeding under the food. TPA (12-O-tetradecanoylphorbol-13-acetate) was purchased from Sigma Chemical Co., and a stock solution of 10 mg/ml was prepared under acetone.

method

On the first morning, shaving the back of each animal (n=5) revealed at least three bare skin areas of 2 x 2 sq cm. After six hours, acetone (excipient) or phorbol ester solution (100 μL/mL) in acetone was applied to the skin of three 2x2 sqcm areas which were shaved by using 200 μL of a silicone pad. Area A in which acetone (excipient) was accepted, and areas B and C in which phorbol ester was received. After the application of phorbol ester for 24 hours, the active ingredient 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid solution (in acetone) 1%) is applied to zone C while the remaining zone accepts acetone. Treatment with 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid or C daily Ketone for 7 days. Six hours after the last treatment, the animals were sacrificed and their skin lines were excised and treated with histopathological examination using H/E staining.

Proliferation was assessed by blind test pathology based on index 0 (normal skin thickness, 2-3 layers) to 3 (significant skin hyperplasia, epidermis > 8 cell layer).

result

There were no results visible to the naked eye during the experiment. Figure 1 shows the excipient, phorbol ester or active ingredient 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-) as indicated in the experimental procedure paragraph. The histopathological index of the test for the skin area treated with amino]nicotinic acid. Repeated acetone application (excipients) induces slight hyperplasia. However, phorbol ester is applied topically by topical application of 1% active ingredient 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotine once a day. Acid and induce a moderate hyperplasia.

Figure 2 shows uninduced (excipient) collected on day 8, A map; induction (phorbol ester), panel B; and treated (phorbol ester + 1% active ingredient, after 7 applications) , C map of the skin tissue evaluation. In all the figures, the magnification = 100x.

An increase in the thickness of the skin infiltrated along the periphery of the vascular surface in the phorbol ester-inducing region along the slightly blood vessel was confirmed (panel B). Treatment with 1% 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid offsets the induction by phorbol ester Hyperplasia and inflammation (Figure C).

In addition, phorbol ester induces a slight infiltration of perivascular mononuclear spheres, including macrophages, lymphocytes, and mastocytes (B), which are 1%2-[(3,5) -Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid was greatly reduced after topical treatment (panel C).

These results indicate that topical application of 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid counteracts the effect of phorbol ester. Phorbol ester is a type that is applied to rodent skin A phorbol ester that induces hyperplasia, inflammation, and edema on the skin, which summarizes the biochemical and tissue aberrations of some psoriasis skin (Risk B et al., Journal of Cell Science 1998; 111, 1395-1404).

Therefore, the results show that 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid is quite useful in the treatment of psoriasis.

Modifications that do not affect, alter, alter or modify the necessary aspects of the compounds, combinations or pharmaceutical compositions are encompassed within the scope of the invention.

Claims (9)

2-[(3,5-Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid for the treatment of psoriasis, or a pharmaceutically acceptable salt thereof a class or an oxynitride or solvate or a deuterated derivative. 2-[(3,5-Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid as described in claim 1, wherein the 2- [(3,5-Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid is in the form of a free acid. 2-[(3,5-Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid as described in claim 1, wherein the 2- [(3,5-Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid is L-arginine, meglumine or trimethylolmethamine The form of the class. 2-[(3,5-Difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino] as described in any one of claims 1 to 3 Nicotinic acid, wherein the 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid is administered topically. A 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl) group for use in the treatment of psoriasis in combination with a pharmaceutically acceptable excipient or carrier A topical pharmaceutical composition of an amino]nicotinic acid or a pharmaceutically acceptable salt thereof or an oxynitride or solvate or deuterated derivative. The topical composition according to claim 5, wherein the topical composition further comprises: (a) an antibiotic, (b) an antifungal agent, (c) a primary antihistamine, (d) Primary metabolite, (e) a corticosteroid, (f) an immunosuppressive agent, (g) a non-steroidal anti-inflammatory agent (NSAIDs), (h) a vitamin A analog, and (i) a vitamin D One or more active ingredients of the group consisting of. The topical composition according to claim 5, wherein the topical composition further comprises an anti-irritant, an antioxidant, a buffer, a chelating agent, and an emollient a osmotic adjuvant, a preservative, a co-solvent, a thickener, a wetting agent or a mixture thereof. A method for treating a patient suffering from psoriasis comprising administering an effective amount of 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino] Nicotinic acid, or a pharmaceutically acceptable salt thereof, or an oxynitride or solvate or deuterated derivative, or a topical composition as defined in any one of claims 5 to 7 To the skin affected area of the patient. One using 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid, or a pharmaceutically acceptable salt thereof or oxynitride Use of a substance or solvate or a deuterated derivative for the manufacture of a medicament for the treatment of psoriasis.