JP2009519267A - Diarylureas for treating inflammatory skin, eye and / or ear diseases - Google Patents

Abstract

  The present invention relates to 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy}-for treating inflammatory skin, eye and / or ear diseases. It relates to a pharmaceutical composition comprising pyridine-2-carboxylic acid methylamide, optionally in combination with at least one further therapeutic agent.

Description

  The present invention relates to 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy}-for treating inflammatory skin, eye and / or ear diseases. It relates to a pharmaceutical composition comprising pyridine-2-carboxylic acid methylamide, optionally in combination with at least one further therapeutic agent.

  Diarylurea compounds, for example 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridine-2-carboxylic acid methylamide described for example in US20050038080 are VEGFR It is a potent anti-cancer and anti-angiogenic agent having a variety of activities including inhibitory activity against PDGFR, raf, p38 and / or flt-3 kinase signaling molecules. These diarylurea compounds have been previously characterized as having various activities including inhibition of Raf / MEK / ERK pathway, raf kinase, p38 kinase, VEGFR kinase, PDGFR kinase. These activities and their use in the treatment of various diseases and conditions are disclosed, for example, in WO 2005/009961.

Contact dermatitis is one of the most frequently occurring inflammatory skin, eye and / or ear diseases, for example a type of intolerance to external toxins (SA Buecher, Kontaktdermatitis, Schweiz Med Forum, 2001, 18 , 458), which can be distinguished into allergic contact dermatitis and toxic irritation. Allergic contact dermatitis is a type IV reaction according to Coombs and Gell, which requires specific sensitization to certain environmental substances (D. Belsito, J. Allergy Clin. Immunol. 2000, 105 , 409). Irritant contact dermatitis is a primary inflammation of the skin that responds to chemical or physical stimuli for no immune reason (H. Loeffler et la., Die irritative Kontaktdermatitis, Hautarzt, 2000, 51 , 203) . Standard treatment for contact dermatitis is topical application of glucocorticoid followed by protective skin treatment (eg, hydration or fatty cream). Recent therapeutic agents are pimecrolimus and tacrolimus, the latter also used for the treatment of atopic dermatitis and psoriasis.

2,4-Dinitrofluorobenzene-a highly sensitizing substance-is known to activate ERK1 / 2 and MAPK signaling pathways in antigen-presenting dendritic cells, from mouse skin Extracted (TS Matos, J. Dermatol. Sci. 2005, 39 , 113).

  The present invention provides a pharmaceutical composition for treating inflammatory skin, eye and / or ear diseases comprising a compound of formula I and optionally at least one additional therapeutic agent.

  The present invention provides a method of treatment that treats inflammatory skin, eye and / or ear disorders more effectively compared to current therapies and is therefore superior to current therapies. The present invention can be used, for example, by administering diarylurea compounds of formula I and optionally further therapeutic agents, their pharmaceutically acceptable salts, their derivatives and the like.

  Compounds having the structure of formula I, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, metabolites and prodrugs thereof are in diastereomeric forms (isolated and stereoisomers). Collectively referred to herein as “compounds of formula I”, including both body mixtures).

Formula (I) is as follows:

  Where the plural form of a word such as a compound, salt, etc. is used herein, this is taken to mean also a singular compound, salt, and the like.

  The invention also relates to useful forms of the compounds disclosed herein, such as pharmaceutically acceptable salts, metabolites, and prodrugs. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. For pharmaceutically acceptable salts, the principal compound that functions as a base is reacted with an inorganic or organic acid to give a salt such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, Those obtained by forming salts of maleic acid, succinic acid and citric acid are included. Pharmaceutically acceptable salts also include those where the main compound functions as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium and choline salts. One skilled in the art will further recognize that acid addition salts of the claimed compounds can be made by reacting the compound with a suitable inorganic or organic acid in any of a number of known ways. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with a suitable base in a variety of known ways.

  Representative salts of the compounds of the present invention include conventional non-toxic salts and quaternary ammonium salts formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphor Acid salt, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptane Acid salt, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, picoate Phosphate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, trifluoromethanesulfonate, and undecanoate.

  Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. In addition, basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl and dibutyl; and diamyl sulfate, long chain halogens. Chlorides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aryl or aralkyl halides such as benzyl and phenethyl bromide, and other mono-substituted halogenated aralkyls or multi-substituted halogenated aralkyls Can be quaternized with these substances.

  For the purposes of the present invention, a solvate is in the form of a compound in which solvent molecules form a complex in the solid state, including but not limited to ethanol and methanol. Hydrates are a special form of solvates where the solvent molecule is water.

Certain pharmacologically active substances can be further modified with labile functional groups that are cleaved after in vivo administration to yield the parent active substance and a pharmaceutically inert derivatizing group. These derivatives, commonly referred to as prodrugs, are used, for example, to alter the physicochemical properties of the active substance, target the active substance to a specific tissue, and the pharmacokinetic and pharmacodynamic properties of the active substance And unwanted side effects can be reduced. Prodrugs of the present invention include, for example, esters of suitable compounds of the present invention that are well tolerated and pharmaceutically acceptable esters, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Including alkyl esters. Additional esters such as phenyl-C ₁ -C ₅ alkyl may be used, but methyl esters are preferred.

Methods that can be used to synthesize other prodrugs are described in the following review on this subject and are incorporated herein by reference for a description of these synthetic methods:
Higuchi, T .; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems.ACS Symposium Series.American Chemical Society: Washington, DC (1975).
Roche, EB Design of Biopharmaceutical Properties through Prodrugs and Analogs.American Pharmaceutical Association: Washington, DC (1977).
・ Sinkula, AA; Yalkowsky, SH J Pharm Sci. 1975, 64, 181-210.
・ Stella, VJ; Charman, WN Naringrekar, VH Drugs 1985, 29, 455-473.
・ Bundgaard, H., ed.Design of Prodrugs.Elsevier: New York (1985).
・ Stella, VJ; Himmelstein, KJJ Med. Chem. 1980, 23, 1275-1282.
・ Han, HK; Amidon, GL AAPS Pharmsci 2000, 2, 1- 11.
・ Denny, WA Eur. J. Med. Chem. 2001, 36, 577-595.
・ Wermuth, CG in Wermuth, CG ed.The Practice of Medicinal Chemistry Academic Press: San Diego (1996), 697-715.
Balant, LP; Doelker, E. in Wolff, ME ed.Burgers Medicinal Chemistry And Drug Discovery John Wiley & Sons: New York (1997), 949-982.

  Metabolites of compounds of the present invention include oxidized derivatives of compounds of formula I wherein one or more nitrogens are replaced with hydroxy groups; it is referred to in the art as 1-oxo-pyridine. Derivatives in which the nitrogen atom of the pyridine group is in the oxide form, or derivatives having a hydroxy substituent, referred to in the art as 1-hydroxy-pyridine, are included.

General Preparation Methods The compounds of the present invention may be prepared by use of known chemical reactions and methods described, for example, in the following published international application WO2005 / 009961.

Further therapeutic agents The compounds of formula I according to the invention can be combined with further therapeutic agents such as anti-inflammatory agents and / or known drugs for the treatment of inflammatory skin, eye and / or ear diseases.

  Further therapeutic agents according to the present invention include corticosteroids such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methylprednisolone and cortisol; retinoids such as acitretin; cyclosporine, methotrexate, fumaric acid, efalizumab, etanercept, onecelpt, Examples include, but are not limited to, adalimumab, infliximab, pimecrolimus, tacrolimus, efomycin, elaiophyllin, and parapoxvirus ovis.

  Preference is given to corticosteroids, such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methylprednisolone and cortisol; pimecrolimus and / or tacrolimus.

Indications The compounds and combinations according to the invention can be used for the manufacture of a medicament for the treatment of inflammatory skin, eye and / or ear diseases. The present invention also relates to the treatment of inflammatory skin, eye and / or ear diseases comprising administering an effective amount of at least one compound of formula I and optionally at least one further therapeutic agent according to the present invention. Provide a method. An “effective amount” is the amount of a compound that is useful to achieve the desired result, eg, to treat a disease or condition. Any subject can be treated according to the present invention, eg, invertebrates, vertebrates, mammals (eg, humans; non-human primates; monkeys; livestock, eg, cattle, pigs and sheep; dogs; cats; rodents; Rats; mice; guinea pigs) and birds (eg, chickens; turkeys; and ducks).

  Diseases according to the invention include contact dermatitis such as irritant or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid lupus erythematosus, ocular inflammatory diseases such as keratitis, uveitis or retina Inflammation, and inflammatory diseases of the ear, such as, but not limited to, otitis media.

  Preferred are contact dermatitis such as irritant or allergic contact dermatitis, atopic dermatitis, discoid lupus erythematosus, ocular inflammatory diseases such as keratitis, uveitis or retinitis, and otic Inflammatory diseases such as otitis media. More preferably, contact dermatitis, such as irritant or allergic contact dermatitis, is mentioned as a disease according to the present invention.

  The invention also relates to the treatment and / or prevention of contact dermatitis caused by contact with skin sensitizers. A skin sensitizer is any substance that can cause an allergic reaction after repeated exposure to it. Examples of contact dermatitis and sensitizers include, for example, neonatal contact dermatitis (eg, diapers; metals; fragrances; wool; polyester; cosmetics; antibiotics such as neomycin and penicillin, antihistamines and corticosteroids Medicinal creams); intercalation; dermatitis due to napkin; dermatitis due to cosmetics (eg fragrance; formaldehyde; balsam; flavoring; spices; fixatives such as balsam, benzyl salicylate and synthetic musk; methyl cinnamate; antioxidant Lanolin; sunscreen; surfactants such as lauryl sulfate and coconut diethanolamide; oils; creams; powders; deodorants and antiperspirants containing zinc salts, aluminum salts, zirconium preparations; Hexachlorophene and hydroxyquino Hair dyes such as phenylenediamine, toluenediamine, nitro-PPD, p-aminodiphenylamine, resorcinol and pyrogallol; hair paints such as shellac, benzoin and cyclohexanone-formaldehyde resins; hair creams and gels; hair lotions Quinine, resorcinol and hexamidine isethionate; hair cleansing agents such as azo dyes, hydroxyquinolines and zinc pyrithium; hair sprays such as lanolin, shellac or gum arabic; hair shampoos, For example, tars, salicylic acid, resorcin, quinine sulfate, detergent, azo dyes, hydroxyquinolines, pyrithione zinc, quina, lanolin, paraben, p-phenylenediamine; hair Dyes such as p-toluenediamine, resorcinol, pyrogallol and musk; lip preparations (eg lipstick azo dyes, quinazoline yellow and colored and flavoring preparations; flavoring agents (eg mustard, cinnamon, vanilla, allspice) Adhesives such as rubber chemicals, acrylates, diphenyl-thiourea; epoxy resins; topical drugs such as benzoyl peroxide and parabens; phenothiazines; hydroxyquinolines; formaldehyde; toothpaste and mouthwash; E.g. fluorine, antiseptics, essential oils and flavors); dermatitis from clothing (e.g. dyes; finishings; spandex; mercaptobenzothiazole; formaldehyde; chromate; tannins, paraphenylenediamine) Soap remnants); dermatitis due to detergent (detergent; surfactant; sulfonated oil; wetting agent; emulsifier; perborate; phosphate; bleach; fragrance; quaternary ammonium compound; soda ash Dermatitis caused by plants (eg grass; shrubs; certain “toxic” plant oils such as poison ivy, oak and urushi; beeswax; poplar resin; cinnamic acid ester; garlic, eg diallyl disulfide; essential oil; cinnamon oil; Oil; lemon oil; vanilla; furocourmaines; pollen; epoxy resin; dermatitis due to urushi; dermatitis due to paint; dermatitis due to metal (eg chromium; nickel, eg nickel sulfate and nickel ammonium sulfate; gold salt) And platinum; mercury such as mercury salts, mercurochrome, phenylmercuric borate, phenylmercuric acetate and red Of mercury; arsenic and arsenic salts; white gold; gold chloride; iodine); included seborrheic dermatitis; dermatitis shoes; skin by stocking dermatitis. Any of the substances listed above can cause contact dermatitis.

  The invention also treats inflammatory reactions, symptoms or diseases of the skin, eye or ear with immune cells comprising dendritic cells (eg, contact sensitizers have been shown to cause maturation of DC cells) and And / or prevention.

  The compounds according to the invention can be routinely tested for their ability to treat and / or prevent inflammatory conditions of the invention. There are numerous in vivo and vitro models of inflammatory symptoms. For example, hairless guinea pigs (eg, Miyauchi and Horio, J. Dermatol., 1992 Mar; 19 (3): 140-5); those induced in the ears of BALB / c mice using dinitrofluorobenzene (eg Bhol and Schecter, Br. J. Dermatol. 2005 Jun; 152 (6): 1235-42); hairless mouse model. See also Knight and Breheny, Altern Lab Anim. 2002 Jan-Feb; 30 (1): 7-22.

  The present invention also relates to ocular inflammatory conditions, diseases and disorders. These include, but are not limited to, eye infections, immune disorders and inflammation associated with allergies. Uveitis is an example of an autoimmune disease that affects the eyes. Examples of autoimmune diseases that affect the eyes include, for example, giant cell arteritis (associated with rheumatic polymyalgia); iritis (associated with ankylosing spondylitis); scleritis (with rheumatoid arthritis) Related); and dry eyes (associated with Sjogren's syndrome). Reactive arthritis can also be associated with ocular inflammation, including uveitis and conjunctivitis. See, for example, Colmegna et al., Clin Microbiol Rev. 2004 Apr; 17 (2): 348-369.

  Other examples of inflammatory eye conditions that can be treated according to the present invention include allergic conjunctivitis, infectious conjunctivitis, blepharitis and red eye.

  Chronic uveitis can be associated with a heterogeneous group of diseases including arthritis, sarcoidosis and Behcet's syndrome. Intermediate uveitis can be associated with multiple sclerosis, sarcoidosis, syphilis, Lyme disease and ocular lymphoma. Posterior uveitis (also known as choroiditis and chorioretinitis) is associated with a number of systemic diseases, including sarcoidosis, syphilis, Behcet's syndrome and Forked-Koyanagi-Harada syndrome, as well as sympathetic ophthalmitis and shotlet choroiditis May be associated with purely ocular syndromes.

  Models of ocular inflammation are well known in the art and include the rabbit model; an experimental model of allergic conjunctivitis to ragweed in guinea pigs (eg Merayo-Lloves et al., Curr Eye Res. 1995 Jun; 14 (6) : 487-94).

Administration The compounds or drug combinations of the invention can be administered, for example, orally, parenterally, enterally, intravenously, intraperitoneally, externally, transdermally (eg, any standard patch, bandage or bandage In the eye, nasal cavity, topically, parenterally, eg aerosol, inhalation, subcutaneously, intramuscularly, buccal, sublingual, rectal, vagina, intraarterial And can be administered in any form by any effective route, including in the subarachnoid space and the like. They can be administered alone or in combination with any active or inactive ingredient.
Preference is given to oral and / or topical administration.

The compounds or drug combinations of the present invention can be converted into conventional formulations in a known manner, these being liquid or solid formulations such as, but not limited to, normal and enteric coated tablets, capsules, pills, Powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols, creams, ointments, gels, ear drops, eye drops, and emulsions.
Examples of solid formulations for oral administration are described in US Provisional Application No. 60 / 605,752.

  The combinations of the present invention can be administered at any time and in any effective form. For example, the compounds can be administered simultaneously, eg, as a single composition or dosage unit (eg, a pill or solution containing both compositions), or they can be administered as separate compositions, but Can be administered simultaneously (eg, one drug is administered intravenously and the other is administered orally or intramuscularly). Drugs can also be administered sequentially at different times. The substance can be formulated in conventional manner to achieve the desired release rate over an extended period of, for example, 12 hours, 24 hours. This can be achieved by using substances with suitable metabolic half-lives and / or their derivatives and / or by using controlled release formulations.

  Drug combinations can be synergistic if, for example, the cooperative action of the drugs is such that the combined effect is greater than the algebraic sum of their individual effects. Thus, a small amount of drug is administered, for example to reduce toxicity or other adverse or undesirable effects, and / or use the same amount used when the substance is administered alone However, greater efficacy can be achieved.

The compounds or drug combinations of the present invention can be further combined with any other suitable additive or pharmaceutically acceptable carrier. Such additives include any of the materials already mentioned, as well as any of those conventionally used, e.g., Remington: The Science and Practice of Pharmacy (Gennaro and Gennaro, eds, 20th edition, Lippincott Williams & Wilkins, 2000); Theory and Practice of Industrial Pharmacy (Lachman et al., Eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia of Pharmaceutical Technology (Swarbrick and Boylan, eds., 2nd edition, Marcel Dekker, 2002) are included. These may be referred to herein as “pharmaceutically acceptable carriers” to indicate that they can be combined with an active drug and safely administered to a subject for therapeutic purposes.

  In addition, the compounds or drug combinations of the present invention can be administered with other active agents or other therapeutic agents utilized in the treatment of any of the diseases and / or conditions described above.

The present invention also provides a combination of at least one compound of formula I and at least one other therapeutic agent as described above, useful for the treatment of a disease or disorder. For purposes of the present invention, “combination” includes the following:
A single composition or dosage form containing at least one compound of formula I and at least one other therapeutic agent as described above;
A combination pack containing at least one compound of formula I to be administered simultaneously or sequentially and at least one other therapeutic agent as described above;
-Comprising at least one compound of formula I and at least one other therapeutic agent as described above packaged separately as a unit dose or as independent unit doses, which are administered simultaneously or sequentially A kit with or without instructions; and
The separation of at least one compound of formula I and at least one other therapeutic agent as described above which, when administered simultaneously or sequentially, cooperates to achieve a therapeutic effect, eg treatment of the same disease. Independent dosage form.

  The dosage of each substance in the combination can be selected with reference to other diseases and / or disease types and / or disease states to provide the desired therapeutic activity. For example, the active agents in the combination can be present and administered in a fixed combination. “Fixed combination” is intended herein to mean a pharmaceutical form in which the ingredients are present in a fixed ratio that provides the desired efficacy. These amounts can be routinely determined for a particular patient, where various parameters (eg, disease type, patient age, disease state, patient health, etc.) are selected to select an appropriate dose. , Body weight, etc.) or the amount can be relatively standard.

  The amount of active ingredient administered will depend on the particular compound and unit used, the mode and time of administration, the duration of treatment, age, sex, and general condition of the patient being treated, the nature and extent of the condition being treated, drug metabolism And can vary widely depending on considerations such as the rate of excretion, possible drug combinations and drug-drug interactions.

  Preferred is an amount of a compound of formula I of 20 to 2000 mg, preferably 40 to 800 mg, more preferably 50 to 600 mg.

  Particularly preferred is 20 to 3000 mg, preferably 50 to 1500, more preferably 60 to 1000 mg of 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] in the pharmaceutical composition. The amount of -3-fluorophenoxy} -pyridine-2-carboxylic acid methylamide.

  In another embodiment of the invention, the compound of the formula I is administered in combination with at least one further therapeutic agent in an amount that can be determined by the person skilled in the art according to his professional judgment.

  The pharmaceutical composition according to the invention is administered once or more per day, preferably up to 3 times, more preferably up to 2 times a day. Preference is given to administration by the oral route. In each administration, the number of tablets or capsules taken at the same time should not exceed two.

  Nevertheless, it may be advantageous to deviate from the specified amounts depending on the body weight, the individual's behavior with respect to the active ingredient, the type of formulation and the time or interval between administrations. For example, it may be sufficient to make less than the above-mentioned minimum amount, while in other cases the specified upper limit must be exceeded. If administered in relatively large amounts, it may be desirable to divide these into several individual doses over the day.

  The combination can include an effective amount of at least one compound of Formula I and at least one other therapeutic agent as described above, which has greater therapeutic efficacy than when either compound is used alone. Achieve. A combination is useful for the treatment of inflammatory skin, eye and / or ear disease when no therapeutic effect is observed when each substance is used alone, or when an enhanced effect is observed when the combination is administered. possible.

  The relative ratio of each compound in the combination can also be selected based on their respective mechanism of action and the biology of the disease. The relative ratios of each compound can vary widely, and the present invention allows the amount of compound of formula I and the other therapeutic agent to be routinely adjusted so that one is present in a greater amount, inflammatory skin, eye And / or combinations for treating ear diseases.

  The release of one or more substances of the combination may provide the desired therapeutic activity when required, when in a single dosage form, combination pack, kit, or in a separate, independent dosage form. It can also be controlled to provide.

  Preferred is a combination comprising a compound of formula I and at least one corticosteroid. More preferably comprising 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridine-2-carboxylic acid methylamide and at least one corticosteroid. Use a combination.

Example:
Example 1: Reduction of ear edema in a mouse model of allergic contact dermatitis In female BALB / c mice (n = 10 / group), topical abdominal application of oxazolone (3% in ethanol; Sigma, St. Louis) , MO, USA), and allergic contact dermatitis (ACD) is induced by systemic sensitization using oxazolone and subsequent oxazolone induction (2% in ethanol) on the 6th day.

  Test compound 4 {4- [3- (4-Chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridine-2-carboxylic acid methylamide in ethanol (100%) 1% or 3 % Concentration and administered topically to the auricle 30 minutes after induction. Ear swelling is measured using a modified device (Kaefer, Villingen-Schwenningen, D; Taschendickenmessgeraet J15 measuring diameter 6.35 mm, applied pressure 0.35 N). Measurements are performed before induction and 24 hours after induction. Topical treatment with 4 {4- [3- (4-Chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridine-2-carboxylic acid methylamide was significant relative to vehicle control animals. (** p <0.0001; Mann-Whitney U test (test compound 3% vs vehicle), Table 1).

Table 1

Claims (10)

A compound of formula I or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite thereof, for the manufacture of a medicament for the treatment of inflammatory skin, eye and / or ear diseases; Use of a prodrug or diastereoisomer, wherein the compound of formula I is

Is used.   Treatment of eye inflammatory diseases such as irritant or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid lupus erythematosus, keratitis, uveitis or retinitis, and ear inflammatory diseases such as otitis media The use according to claim 1 for.   2. At least one treatment selected from the group consisting of at least one compound of formula I according to claim 1 and an anti-inflammatory agent and a known drug for the treatment of inflammatory skin, eye and / or ear diseases. Combinations containing agents.   The additional therapeutic agent is selected from the group consisting of corticosteroids, retinoids, cyclosporine, methotrexate, fumaric acid, efalizumab, etanercept, oneserpt, adalimumab, infliximab, pimecrolimus, tacrolimus, efomycin, elaiophyrin and parapoxvirus Ovis The combination according to claim 2.   Use of a combination according to any of claims 3 to 4 for the manufacture of a medicament for the treatment of inflammatory skin, eye and / or ear diseases.   Treatment of eye inflammatory diseases such as irritant or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid lupus erythematosus, keratitis, uveitis or retinitis, and ear inflammatory diseases such as otitis media 6. Use according to claim 5 for.   A pharmaceutical composition comprising the combination according to any one of claims 3 to 4.   8. A pharmaceutical composition according to claim 7 for the treatment of inflammatory skin, eye and / or ear diseases. A method of treating inflammatory skin, eye and / or ear disease in a subject in need of treatment of inflammatory skin, eye and / or ear disease comprising an effective amount of a compound of formula I or a pharmaceutical thereof Administering an acceptable salt, polymorph, solvate, hydrate, metabolite, prodrug or diastereoisomer, wherein the compound of formula I is

Is that way.   9. The compound of claim 8, wherein the compound of formula I is combined with at least one therapeutic agent selected from the group consisting of anti-inflammatory agents and known drugs for the treatment of inflammatory skin, eye and / or ear diseases. Method.