EP1962828A1 - Diaryl urea for treating inflammatory skin, eye and/or ear diseases - Google Patents

Diaryl urea for treating inflammatory skin, eye and/or ear diseases

Info

Publication number
EP1962828A1
EP1962828A1 EP06829328A EP06829328A EP1962828A1 EP 1962828 A1 EP1962828 A1 EP 1962828A1 EP 06829328 A EP06829328 A EP 06829328A EP 06829328 A EP06829328 A EP 06829328A EP 1962828 A1 EP1962828 A1 EP 1962828A1
Authority
EP
European Patent Office
Prior art keywords
eye
diseases
compound
ear
inflammatory
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06829328A
Other languages
German (de)
French (fr)
Inventor
Olaf Weber
Bernd Riedl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer Healthcare AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Priority to EP06829328A priority Critical patent/EP1962828A1/en
Publication of EP1962828A1 publication Critical patent/EP1962828A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising 4 ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophen- oxy ⁇ -pyridine-2-carboxylic acid methylamide optionally combined with at least one additional therapeutic agent.
  • Diaryl urea compounds e.g. 4 ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyI)-ureido]-3-fluorophenoxy ⁇ - pyridine-2-carboxylic acid methylamide as described e.g. in US 20050038080 are potent anticancer and anti-angiogenic agents that possess various activities, including inhibitory activity on the VEGFR, PDGFR, raf, p38, and/or flt-3 kinase signaling molecules.
  • diaryl urea compounds have been previously characterized as having various activities, including for inhibiting the Raf/MEK/ERK pathway, raf kinase, p38 kinase, VEGFR kinase, PDGFR kinase. These activities and their use in treating various diseases and conditions are disclosed in, e.g., WO 2005/009961.
  • Contact dermatitis is one of the most frequently occurred inflammatory skin, eye and/or ear diseases and is a kind of intolerance against e.g. external toxins (S.A. B ⁇ cher, Kunststoffdermatitis, für Med Forum, 2001, 18, 458) which can be differentiated in an allergic contact dermatitis and a toxic irritative one.
  • the allergic contact dermatitis is a type IV reaction according to Coombs and GeIl und requires a specific sensitisation against specific environmental substances (D. Belsito, J. Allergy Clin. Immunol. 2000, 105, 409).
  • the irritative contact dermatitis is a primary inflammation of the skin in response to chemical or physical stimuli without immune reasons (H.
  • the present invention provides pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising a compound of formula I and optionally at least one further therapeutic agent.
  • the present invention provides a therapeutic method which treat inflammatory skin, eye and/or ear diseases more effectively compared to current therapies and therefore is superior to current therapies.
  • the present invention can be used e.g. by administering a diaryl urea compound of formula I and optionally a further therapeutic agent, pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, metabolites and prodrugs.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts,” J. Pharm. ScI 1977, 66, 1-19.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, mangnesium, ammonium, and choline salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl- sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylprop
  • 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 dicyclo- hexylamine and N-methyl-D-glucamine.
  • basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aryl or aralkyl halides like benzyl and phenethyl bromides and others monosubstituted aralkyl halides or polysubstituted aralkyl halides.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibut
  • Solvates for the purposes of the invention are those forms of the compounds where solvent molecules form a complex in the solid state and include, but are not limited to for example ethanol and methanol. Hydrates are a specific form of solvates, where the solvent molecule is water.
  • Certain pharmacologically active agents can be further modified with labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharmacologically inactive derivatizing group.
  • These derivatives commonly referred to as prodrugs, can be used, for example, to alter the physicochemical properties of the active agent, to target the active agent to a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce undesirable side effects.
  • Prodrugs of the invention include, e.g., the esters of appropriate compounds of this invention that are well-tolerated, pharmaceutically acceptable esters such as alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-Ci-C 5 alkyl may be used, although methyl ester is preferred.
  • the metabolites of the compounds of this invention include oxidized derivatives of the compounds of formula I, wherein one or more of the nitrogens are substituted with a hydroxy group; which includes derivatives where the nitrogen atom of the pyridine group is in the oxide form, referred to in the art as 1-oxo-pyridine or has a hydroxy substituent, referred to in the art as 1 -hydroxy- pyridine.
  • the compounds of the invention may be prepared by use of known chemical reactions and procedures as described e.g. in the following published international application WO 2005/009961. Further therapeutic agents
  • the compounds of formula I according to the present invention can be combined with further therapeutic agents such as anti-inflammatory and/or known drugs for the therapy of inflammatory skin, eye and/or ear diseases.
  • the further therapeutic agents according to the invention include, but are not limited to, corticosteroids such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methylpred- nisolone and Cortisol; retinoids such as acitretin; cyclosporine, methothrexat, fumaric acid, efali- Kursab, etanercept, onecerpt, adalimumab, infliximab, pimecrolimus, tacrolimus, efomycin, elaiophyllin and parapoxvirus ovis.
  • corticosteroids such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methylpred- nisolone and Cortisol
  • retinoids such as acitretin
  • cyclosporine methothrexat
  • fumaric acid efali- Kurs
  • corticosteroids such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methylprednisolone and Cortisol; pimecrolimus and/or tacrolimus.
  • the compounds and combinations according to the present invention can be used for manufacture of a medicament for treating inflammatory skin, eye and/or ear diseases.
  • the present invention provides methods of treating inflammatory skin, eye and/or ear diseases, comprising administering effective amounts of at least one compound of formula I and optionally at least one further therapeutic agent according to the invention.
  • An "effective amount" is the quantity of the compound that is useful to achieve the desired result, e.g., to treat the disease or condition.
  • Any subject can be treated in accordance with the present invention, including, e.g., invertebrates, vertebrates, mammals (e.g., humans; non-human primates; monkeys; livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats; mice; guinea pigs), and birds (e.g., chicken; turkey; and ducks).
  • mammals e.g., humans; non-human primates; monkeys; livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats; mice; guinea pigs
  • birds e.g., chicken; turkey; and ducks.
  • Diseases according to the present invention include, but are not limited to, contact dermatitis such as irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythema- todes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
  • contact dermatitis such as irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythema- todes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
  • contact dermatitis such as irritative or allergic contact dermatitis, atopic dermatitis, discoid Lupus erythematodes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media. More preferably contact dermatitis such as irritative or allergic contact dermatitis is to be mentioned as disease according to the invention.
  • the present invention also relates to the treatment and/or prophylaxis of contact dermatitis that is produced by contact with skin sensitizers.
  • a skin sensitizer is any agent that can cause an allergic reaction after repeated exposure to it.
  • contact dermatitis and the sensitizing agent include, e.g., neonatal contact dermatitis (e.g., diapers; metals; perfumes; wool; polyester; cosmetic preparations; medicated creams containing antibiotics, such as neomycin and penicillin, antihistamines, and corticosteroids); intertrigo; napkin dermatitis; cosmetic dermatitis (e.g.
  • perfumes such as formaldehyde; balsams; flavoring agents; spices; fixatives, such as balsams, benzyl salicylates, and synthetic musk; methyl cinnamate; antioxidants; lanolins; sunscreens; detergents, such as lauryl ether sulfate, and coconut diethanolamide; oils; creams; powders; deodorants and antiperspirants, containing zinc salts, aluminum salts, zirconium preparations; chlorinated phenols, hexachlorophene, and hydroxyquinolines; hair dyes, such as phenylenediamine, toluenediamine, nitro-PPD, p-aminodiphenylamine, resorcinol and pyrogallol; hair lacquers, such as shellac, benzoin, and cyclohexanone-formaldehyde resin ; hair creams and gels; hair lotions, such as quinine, resorcinol,
  • the present invention also relates to treating and/or preventing any skin, eye, or ear inflammatory response, condition, or disease associated with immune cells, including dendritic cells (e.g., contact sensitizers have been shown to trigger DC cell maturation.
  • dendritic cells e.g., contact sensitizers have been shown to trigger DC cell maturation.
  • Compounds according to the present invention can be tested for their ability to treat and/or prevent inflammatory conditions of the present invention routinely.
  • the present invention also relates to inflammatory conditions, diseases, and disorders of the eye. These include, but are not limited to, inflammation associated with ocular infection, immune disorders, and allergy.
  • Uveitis is an example of an autoimmune disease that affects the eye.
  • autoimmune conditions that affect the eye include, but are not limited to, e.g., giant cell arteritis (associated with polymyalgia rheumatica); LTDis (associated with ankylosing spondylitis); scleritis (associated with rheumatoid arthritis); and dry eyes (associated with Sjogren's syndrome).
  • Reactive arthritis can also be associated with eye inflammation, including uveitis and conjunctivitis.
  • inflammatory eyes conditions that can be treated in accordance with 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 also known as choroiditis and chorioretinitis
  • Posterior uveitis can be associated with many systemic diseases, including sarcoidosis, syphilis, Behcet's syndrome, and Vogt Koyanagi Harada syndrome, as well as purely ocular syndromes such as sympathetic ophthalmia and birdshot chorioretinopathy.
  • Models of eye inflammation are well-known in the art, including rabbit models; experimental model of allergic conjunctivitis to ragweed in guinea pig (e.g., Merayo-Lloves et al., Curr Eye Res. 1995 Jun; 14(6):487-94. Administration
  • Compounds or drug combinations of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patches, plasters or bandages), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. They can be administered alone, or in combination with any ingredient(s), active or inactive.
  • any effective route including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patches, plasters or bandages), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathe
  • Compounds or drug combinations of the present invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations e.g. without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols, cremes, ointments, gels, ear drops, eye drops and emulsions.
  • liquid or solid formulations e.g. without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols, cremes, ointments, gels, ear drops, eye drops and emulsions.
  • the combinations of the present invention can be administered at any time and in any effective form.
  • the compounds can be administered simultaneously, e.g., as a single composition or dosage unit (e.g., a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (e.g., where one drug is administered intravenously and the other is administered orally or intramuscularly).
  • the drugs can also be administered sequentially at different times.
  • Agents can be formulated conventionally to achieve the desired rates of release over extended period of times, e.g., 12-hours, 24-hours. This can be achieved by using agents and/or their derivatives which have suitable metabolic half-lives, and/or by using controlled release formulations.
  • the drug combinations can be synergistic, e.g., where the joint action of the drugs is such that the combined effect is greater than the algebraic sum of their individual effects.
  • reduced amounts of the drugs can be administered, e.g., reducing toxicity or other deleterious or unwanted effects, and/or using the same amounts as used when the agents are administered alone, but achieving greater efficacy.
  • Compounds or drug combinations of the present invention can be further combined with any other suitable additive or pharmaceutically acceptable carrier.
  • additives include any of the substances already mentioned, as well as any of those used conventionally, such as those described in 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).
  • pharmaceutically acceptable carriers can be referred to herein as “pharmaceutically acceptable carriers” to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes.
  • compounds or drug combinations of the present invention can be administered with other active agents or other therapies that are utilized to treat any of the above-mentioned diseases and/or conditions.
  • the present invention provides also combinations of at least one compound of Formula I and at least one other therapeutic agent mentioned above useful in treating a disease or disorder.
  • “Combinations” for the purposes of the invention include:
  • compositions or dosage forms which contain at least one compound of Formula I and at least one other therapeutic agent mentioned above;
  • kits which comprise at least one compound of Formula I and at least one other therapeutic agent mentioned above packaged separate from one another as unit dosages or as independent unit dosages, with or without instructions that they be administered concurrently or sequentially;
  • each agent of the combination can be selected with reference to the other and/or the type of disease and/or the disease status in order to provide the desired therapeutic activity.
  • the active agents in the combination can be present and administered in a fixed combination.
  • "Fixed combination” is intended here to mean pharmaceutical forms in which the components are present in a fixed ratio that provides the desired efficacy. These amounts can be determined routinely for a particular patient, where various parameters are utilized to select the appropriate dosage (e.g., type of disease, age of patient, disease status, patient health, weight, etc.), or the amounts can be relatively standard.
  • the amount of the administered active ingredient can vary widely according to such considerations as the particular compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.
  • an amount of 4 ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]- 3-fluorophenoxy ⁇ -pyridine-2-carboxylic acid methylamide in the pharmaceutical composition from 20 to 3000 mg, preferably from 50 to 1500, more preferably from 60 to 1000 mg.
  • the compound of formula I is administered in combination with at least one further therapeutic agent in an amount that those of ordinary skill in the art can determine by their professional judgement.
  • the pharmaceutical composition according to the invention is administered one or more, preferably up to three, more preferably up to two times per day. Preference is given to an administration via the oral route. With each administration the number of tablets or capsules taken in at the same time should not exceed two.
  • the combination can comprise effective amounts of at least one compound of Formula I and at least one other therapeutic agent mentioned above, which achieves a greater therapeutic efficacy than when either compound is used alone.
  • the combination can be useful to treat inflammatory skin, eye and/or ear diseases, where the therapeutic effect is not observed when the agents are used alone, or where an enhanced effect is observed when the combination is administered.
  • the relative ratios of each compound in the combination can also be selected based on their respective mechanisms of action and the disease biology.
  • the relative ratios of each compound can vary widely and this invention includes combinations for treating inflammatory skin, eye and/or ear diseases where the amounts of the formula 1 compound and the other therapeutic agent can be adjusted routinely such that either is present in higher amounts.
  • the release of one or more agents of the combination can also be controlled, where appropriate, to provide the desired therapeutic activity when in a single dosage form, combination pack, kit or when in separate independent dosage forms.
  • Example 1 Reduction of ear edemas in an allergic contact dermatitis mouse model
  • ACD Allergic contact dermatitis
  • test compound 4 ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy ⁇ -pyridine- 2-carboxylic acid methylamide is prepared at concentrations of 1% or 3% in Ethanol (100%) and administered locally to the ear pinna 30 minutes after the challenge.
  • Ear swelling is measured using a modified device (Kafer, Villingen-Schwenningen, D; Taschendickenmessgerat Jl 5 measuring diameter of 6,35 mm adapted pressure of 0,35 N). Measurement is performed before and 24 hours after challenge.
  • Topical treatment with 4 ⁇ 4-[3-(4-chloro-3-trifluoromethylphenyl)- ureido]-3-fluorophenoxy ⁇ -pyridine-2-carboxylic acid methylamide results in a significant reduction vs. the vehicle controlled animals (** pO.OOOl; Mann-Withney-u-Test (test compound 3% vs. vehicle), table 1).

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophen- oxy}-pyridine-2-carboxylic acid methylamide optionally combined with at least one additional therapeutic agent.

Description

DIARYL UREA FOR TREATING INFLAMMATORY SKIN. EYE AND/OR EAR DISEASES
The present invention relates to pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophen- oxy}-pyridine-2-carboxylic acid methylamide optionally combined with at least one additional therapeutic agent.
Diaryl urea compounds e.g. 4{4-[3-(4-chloro-3-trifluoromethylphenyI)-ureido]-3-fluorophenoxy}- pyridine-2-carboxylic acid methylamide as described e.g. in US 20050038080 are potent anticancer and anti-angiogenic agents that possess various activities, including inhibitory activity on the VEGFR, PDGFR, raf, p38, and/or flt-3 kinase signaling molecules. These diaryl urea compounds have been previously characterized as having various activities, including for inhibiting the Raf/MEK/ERK pathway, raf kinase, p38 kinase, VEGFR kinase, PDGFR kinase. These activities and their use in treating various diseases and conditions are disclosed in, e.g., WO 2005/009961.
Contact dermatitis is one of the most frequently occurred inflammatory skin, eye and/or ear diseases and is a kind of intolerance against e.g. external toxins (S.A. Bϋcher, Kontaktdermatitis, Schweiz Med Forum, 2001, 18, 458) which can be differentiated in an allergic contact dermatitis and a toxic irritative one. The allergic contact dermatitis is a type IV reaction according to Coombs and GeIl und requires a specific sensitisation against specific environmental substances (D. Belsito, J. Allergy Clin. Immunol. 2000, 105, 409). The irritative contact dermatitis is a primary inflammation of the skin in response to chemical or physical stimuli without immune reasons (H. Lδffler et Ia., Die irritative Kontaktdermatitis, Hautarzt, 2000, 5J_, 203). The standard therapy of the contact dermatitis is a local application of glucocorticoids followed by an protective skin care (e.g. hydrating or fatty cremes). Recent therapeutic agents are pimecrolimus and tacrolimus which latter is also used for the treatment of atopic dermatitis and psoriasis.
It is known that 2,4-dinitrofluorbenzene - a highly sensitising agent - activates the ERK 1/2 and the MAPK signal pathway in antigen presenting dendritic cells which were extracted from mice skin (T.S. Matos, J. Dermatol. ScL 2005, 39, 113).
The present invention provides pharmaceutical compositions for treating inflammatory skin, eye and/or ear diseases comprising a compound of formula I and optionally at least one further therapeutic agent. The present invention provides a therapeutic method which treat inflammatory skin, eye and/or ear diseases more effectively compared to current therapies and therefore is superior to current therapies. The present invention can be used e.g. by administering a diaryl urea compound of formula I and optionally a further therapeutic agent, pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.
The compounds with the structure of formula I, pharmaceutically acceptable salts, polymorphs, solvates, hydrates metabolites and prodrugs thereof, including diastereoisomeric forms (both isolated stereoisomers and mixtures of stereoisomers) are collectively referred to herein as the "compounds of formula I".
Formula (I) is as follows:
(D
Where the plural form of the word compounds, salts, and the like, is used herein, this is taken to mean also a single compound, salt, or the like.
The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, metabolites and prodrugs. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. ScI 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, mangnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods. Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are 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, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl- sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, 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 dicyclo- hexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aryl or aralkyl halides like benzyl and phenethyl bromides and others monosubstituted aralkyl halides or polysubstituted aralkyl halides.
Solvates for the purposes of the invention are those forms of the compounds where solvent molecules form a complex in the solid state and include, but are not limited to for example ethanol and methanol. Hydrates are a specific form of solvates, where the solvent molecule is water.
Certain pharmacologically active agents can be further modified with labile functional groups that are cleaved after in vivo administration to furnish the parent active agent and the pharmacologically inactive derivatizing group. These derivatives, commonly referred to as prodrugs, can be used, for example, to alter the physicochemical properties of the active agent, to target the active agent to a specific tissue, to alter the pharmacokinetic and pharmacodynamic properties of the active agent, and to reduce undesirable side effects. Prodrugs of the invention include, e.g., the esters of appropriate compounds of this invention that are well-tolerated, pharmaceutically acceptable esters such as alkyl esters including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters. Additional esters such as phenyl-Ci-C5 alkyl may be used, although methyl ester is preferred. Methods which can be used to synthesize other prodrugs are described in the following reviews on the subject, which are incorporated herein by reference for their description of these synthesis methods:
• Higuchi, T.; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems. ACS Symposium Series. American Chemical Society: Washington, DC (1975).
• Roche, E. B. Design of Biopharmaceutical Properties through Prodrugs and Analogs. American Pharmaceutical Association: Washington, DC (1977).
• Sinkula, A. A.; Yalkowsky, S. H. JPharm Sci. 1975, 64, 181-210.
• Stella, V. J.; Charman, W. N. Naringrekar, V. H. Drugs 1985, 29, 455-473.
• Bundgaard, H., ed. Design of Prodrugs. Elsevier: New York (1985).
• Stella, V. J.; Himmelstein, K. J. J. Med. Chem. 1980, 23, 1275-1282.
• Han, H-K; Amidon, G. L. AAPS Pharmsci 2000, 2, 1 - 11.
• Denny, W. A. Eur. J. Med. Chem. 2001, 36, 577-595.
• Wermuth, C. G. in Wermuth, C. G. ed. The Practice of Medicinal Chemistry Academic Press: San Diego ( 1996), 697-715.
• Balant, L. P.; Doelker, E. in Wolff, M. E. ed. Burgers Medicinal Chemistry And Drug Discovery John Wiley & Sons: New York (1997), 949-982.
The metabolites of the compounds of this invention include oxidized derivatives of the compounds of formula I, wherein one or more of the nitrogens are substituted with a hydroxy group; which includes derivatives where the nitrogen atom of the pyridine group is in the oxide form, referred to in the art as 1-oxo-pyridine or has a hydroxy substituent, referred to in the art as 1 -hydroxy- pyridine.
General Preparative Methods
The compounds of the invention may be prepared by use of known chemical reactions and procedures as described e.g. in the following published international application WO 2005/009961. Further therapeutic agents
The compounds of formula I according to the present invention can be combined with further therapeutic agents such as anti-inflammatory and/or known drugs for the therapy of inflammatory skin, eye and/or ear diseases.
The further therapeutic agents according to the invention include, but are not limited to, corticosteroids such as aldosterone, hydrocortisone, dexamethasone, prednisolone, methylpred- nisolone and Cortisol; retinoids such as acitretin; cyclosporine, methothrexat, fumaric acid, efali- zumab, etanercept, onecerpt, 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 present invention can be used for manufacture of a medicament for treating inflammatory skin, eye and/or ear diseases. Also the present invention provides methods of treating inflammatory skin, eye and/or ear diseases, comprising administering effective amounts of at least one compound of formula I and optionally at least one further therapeutic agent according to the invention. An "effective amount" is the quantity of the compound that is useful to achieve the desired result, e.g., to treat the disease or condition. Any subject can be treated in accordance with the present invention, including, e.g., invertebrates, vertebrates, mammals (e.g., humans; non-human primates; monkeys; livestock, such as cows, pigs, and sheep; dogs; cats; rodents; rats; mice; guinea pigs), and birds (e.g., chicken; turkey; and ducks).
Diseases according to the present invention include, but are not limited to, contact dermatitis such as irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythema- todes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
Preference is given to contact dermatitis such as irritative or allergic contact dermatitis, atopic dermatitis, discoid Lupus erythematodes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media. More preferably contact dermatitis such as irritative or allergic contact dermatitis is to be mentioned as disease according to the invention. The present invention also relates to the treatment and/or prophylaxis of contact dermatitis that is produced by contact with skin sensitizers. A skin sensitizer is any agent that can cause an allergic reaction after repeated exposure to it. Examples of contact dermatitis and the sensitizing agent include, e.g., neonatal contact dermatitis (e.g., diapers; metals; perfumes; wool; polyester; cosmetic preparations; medicated creams containing antibiotics, such as neomycin and penicillin, antihistamines, and corticosteroids); intertrigo; napkin dermatitis; cosmetic dermatitis (e.g. perfumes; formaldehyde; balsams; flavoring agents; spices; fixatives, such as balsams, benzyl salicylates, and synthetic musk; methyl cinnamate; antioxidants; lanolins; sunscreens; detergents, such as lauryl ether sulfate, and coconut diethanolamide; oils; creams; powders; deodorants and antiperspirants, containing zinc salts, aluminum salts, zirconium preparations; chlorinated phenols, hexachlorophene, and hydroxyquinolines; hair dyes, such as phenylenediamine, toluenediamine, nitro-PPD, p-aminodiphenylamine, resorcinol and pyrogallol; hair lacquers, such as shellac, benzoin, and cyclohexanone-formaldehyde resin ; hair creams and gels; hair lotions, such as quinine, resorcinol, and hexamidine isethionate; hair detergents, such as azo dyes, hydroxyquinolines, and zinc pyrithium; hair sprays, such as lanolin, shellac, or gum Arabic; hair shampoos, such as tars, salicylic acid, resorcin, quinine sulfate, detergent, azo dyes, hydroxyquinolines, zinc pyrithium, cinchona, lanolin, paraben, p-phenylenediamine; hair dyes, such as p-toluenediamine, resorcinol, pyrogallol, and musk; lip preparations (e.g., rouge azo dyes, quinazoline yellow, and coloring and flavoring preparations; flavoring agents (e.g., mustard, cinnamon, vanilla, allspice, oil of juniper, and cloves; adhesives, such as rubber chemicals, acrylates, diphenyl-thiourea; epoxy resin; topical medications, such as benzoyl peroxide and parabens; phenothiazine; hydroxyquinolines; formaldehyde; tooth and mouthwashes, such as fluorine, antiseptics, essential oils, and flavorings); clothing dermatitis (e.g., dyes; finishings; spandex; mercaptobenzothiazole; formaldehyde; chromate; tannin, paraphenylene diamine; remnants of soaps); detergent dermatitis (detergents; surface-acting agents; sulphonated oils; wetting agents; emulsifϊers; perborates; phosphates; bleaches; perfumes; quaternary ammonium compounds; soda ash; plant dermatitis (e.g., grass; shrubs; oils of certain "poisonous" plants such as poison ivy, oak, and sumac; beeswax; poplar resin; cinnamic acid ester; garlic, such as diallyldissulphide; essential oils; cinnamon oil; clove oil; lemon oil; vanilla; furocourmaines; pollens; epoxy resin); rhus dermatitis; lacquer dermatitis; metal dermatitis (e.g., chromium; nickel, such as nickel sulfate and nickel ammonium sulfate; gold salts and platinum; mercury, such as mercuric salts, mercurochrome, phenyl mercuric borate, phenyl mercuric acetate, and red mercuric sulfide; arsenic and arsenic salts; white gold; chloride gold; iodine); shoe dermatitis; stocking dermatitis; seborrheic dermatitis. Any of the agents listed above can cause contact dermatitis. The present invention also relates to treating and/or preventing any skin, eye, or ear inflammatory response, condition, or disease associated with immune cells, including dendritic cells (e.g., contact sensitizers have been shown to trigger DC cell maturation.
Compounds according to the present invention can be tested for their ability to treat and/or prevent inflammatory conditions of the present invention routinely. A number of in vivo and vitro models exist for inflammatory conditions. See, e.g., hairless guinea pig (e.g., Miyauchi and Horio, J. Dermatol., 1992 Mar; 19(3): 140-5); induced on ears of BALB/c mice using dinitrofluorobenzene (e.g., 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(l):7-22.
The present invention also relates to inflammatory conditions, diseases, and disorders of the eye. These include, but are not limited to, inflammation associated with ocular infection, immune disorders, and allergy. Uveitis is an example of an autoimmune disease that affects the eye. Examples of autoimmune conditions that affect the eye include, but are not limited to, e.g., giant cell arteritis (associated with polymyalgia rheumatica); iritis (associated with ankylosing spondylitis); scleritis (associated with rheumatoid arthritis); and dry eyes (associated with Sjogren's syndrome). Reactive arthritis can also be associated with eye inflammation, including uveitis and conjunctivitis. See, e.g., Colmegna et al., Clin Microbiol Rev. 2004 Apr; 17(2): 348- 369. Other examples of inflammatory eyes conditions that can be treated in accordance with 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 also known as choroiditis and chorioretinitis) can be associated with many systemic diseases, including sarcoidosis, syphilis, Behcet's syndrome, and Vogt Koyanagi Harada syndrome, as well as purely ocular syndromes such as sympathetic ophthalmia and birdshot chorioretinopathy. Models of eye inflammation are well-known in the art, including rabbit models; experimental model of allergic conjunctivitis to ragweed in guinea pig (e.g., Merayo-Lloves et al., Curr Eye Res. 1995 Jun; 14(6):487-94. Administration
Compounds or drug combinations of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patches, plasters or bandages), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. They can be administered alone, or in combination with any ingredient(s), active or inactive.
Preference is given to an oral and/or topical administration.
Compounds or drug combinations of the present invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations e.g. without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups, solid and liquid aerosols, cremes, 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, e.g., as a single composition or dosage unit (e.g., a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (e.g., where one drug is administered intravenously and the other is administered orally or intramuscularly). The drugs can also be administered sequentially at different times. Agents can be formulated conventionally to achieve the desired rates of release over extended period of times, e.g., 12-hours, 24-hours. This can be achieved by using agents and/or their derivatives which have suitable metabolic half-lives, and/or by using controlled release formulations.
The drug combinations can be synergistic, e.g., where the joint action of the drugs is such that the combined effect is greater than the algebraic sum of their individual effects. Thus, reduced amounts of the drugs can be administered, e.g., reducing toxicity or other deleterious or unwanted effects, and/or using the same amounts as used when the agents are administered alone, but achieving greater efficacy.
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 substances already mentioned, as well as any of those used conventionally, such as those described in 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). These can be referred to herein as "pharmaceutically acceptable carriers" to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes.
In addition, compounds or drug combinations of the present invention can be administered with other active agents or other therapies that are utilized to treat any of the above-mentioned diseases and/or conditions.
The present invention provides also combinations of at least one compound of Formula I and at least one other therapeutic agent mentioned above useful in treating a disease or disorder. "Combinations" for the purposes of the invention include:
- single compositions or dosage forms which contain at least one compound of Formula I and at least one other therapeutic agent mentioned above;
- combination packs containing at least one compound of Formula I and at least one other therapeutic agent mentioned above to be administered concurrently or sequentially;
- kits which comprise at least one compound of Formula I and at least one other therapeutic agent mentioned above packaged separate from one another as unit dosages or as independent unit dosages, with or without instructions that they be administered concurrently or sequentially; and
- separate independent dosage forms of at least one compound of Formula I and at least one other therapeutic agent mentioned above which cooperate to achieve a therapeutic effect, e.g., treatment of the same disease, when administered concurrently or sequentially.
The dosage of each agent of the combination can be selected with reference to the other and/or the type of disease and/or the disease status in order 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 here to mean pharmaceutical forms in which the components are present in a fixed ratio that provides the desired efficacy. These amounts can be determined routinely for a particular patient, where various parameters are utilized to select the appropriate dosage (e.g., type of disease, age of patient, disease status, patient health, weight, etc.), or the amounts can be relatively standard. The amount of the administered active ingredient can vary widely according to such considerations as the particular compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.
Preference is given to an amount of the compound of formula I from 20 to 2000 mg, preferably from 40 to 800 mg, more preferably from 50 to 600 mg.
Particular preference is given to an amount of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]- 3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide in the pharmaceutical composition from 20 to 3000 mg, preferably from 50 to 1500, more preferably from 60 to 1000 mg.
In another embodiment of the invention the compound of formula I is administered in combination with at least one further therapeutic agent in an amount that those of ordinary skill in the art can determine by their professional judgement.
The pharmaceutical composition according to the invention is administered one or more, preferably up to three, more preferably up to two times per day. Preference is given to an administration via the oral route. With each administration the number of tablets or capsules taken in at the same time should not exceed two.
Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on body weight, individual behaviour toward the active ingredient, type of preparation and time or interval over which the administration is effected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases. In the case of administration of relatively large amounts, it may be advisable to divide these into several individual doses over the day.
The combination can comprise effective amounts of at least one compound of Formula I and at least one other therapeutic agent mentioned above, which achieves a greater therapeutic efficacy than when either compound is used alone. The combination can be useful to treat inflammatory skin, eye and/or ear diseases, where the therapeutic effect is not observed when the agents are used alone, or where an enhanced effect is observed when the combination is administered.
The relative ratios of each compound in the combination can also be selected based on their respective mechanisms of action and the disease biology. The relative ratios of each compound can vary widely and this invention includes combinations for treating inflammatory skin, eye and/or ear diseases where the amounts of the formula 1 compound and the other therapeutic agent can be adjusted routinely such that either is present in higher amounts.
The release of one or more agents of the combination can also be controlled, where appropriate, to provide the desired therapeutic activity when in a single dosage form, combination pack, kit or when in separate independent dosage forms.
Preference is given to a combination comprising a compound of formula I and at least one corticosteroid. More preferably a combination comprising 4{4-[3-(4-chloro-3-trifluoromethylphe- nyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide and at least one corticosteroid is used.
Examples:
Example 1: Reduction of ear edemas in an allergic contact dermatitis mouse model
Allergic contact dermatitis (ACD) is induced in female BALB/c mice (n=10/group) via systemic sensibilisation by means of topical abdominal application of Oxazolon (3% in Ethanol; Sigma, St. Louis, MO, USA) and subsequent Oxazolon challenge after 6 days at the ear pinna (2% in Ethanol).
The test compound 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine- 2-carboxylic acid methylamide is prepared at concentrations of 1% or 3% in Ethanol (100%) and administered locally to the ear pinna 30 minutes after the challenge. Ear swelling is measured using a modified device (Kafer, Villingen-Schwenningen, D; Taschendickenmessgerat Jl 5 measuring diameter of 6,35 mm adapted pressure of 0,35 N). Measurement is performed before and 24 hours after challenge. Topical treatment with 4{4-[3-(4-chloro-3-trifluoromethylphenyl)- ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide results in a significant reduction vs. the vehicle controlled animals (** pO.OOOl; Mann-Withney-u-Test (test compound 3% vs. vehicle), table 1).
Table 1

Claims

What we claim :
1. Use of a compound of formula I or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite, prodrug or diastereoisomeric form thereof, for manufacture of a medicament for treatment of inflammatory skin, eye and/or ear diseases,
wherein said compound of formula I is:
2. The use of claim 1 for the treatment of irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythematodes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
3. Combination comprising at least one compound of formula I as defined in claim 1 and at least one therapeutic agent selected from the group consisting of anti-inflammatory agents and known drugs for the therapy of inflammatory skin, eye and/or ear diseases.
4. Combination of claim 2 wherein the further therapeutic agent is selected from the group consisting of corticosteroids, retinoids, cyclosporine, methothrexat, fumaric acid, efalizumab, etanercept, onecerpt, adalimumab, infliximab, pimecrolimus, tacrolimus, efomycin, elaiophyllin and parapoxvirus ovis.
5. Use of the combination of any of claims 3 to 4 for manufacture of a medicament for treatment of inflammatory skin, eye and/or ear diseases.
6. The use of claim 5 for the treatment of irritative or allergic contact dermatitis, psoriasis, atopic dermatitis, discoid Lupus erythematodes, inflammatory diseases of the eye such as keratitis, uveitis or retinitis, and inflammatory diseases of the ear such as Otitis media.
7. Pharmaceutical composition comprising a combination as defined in any of claims 3 to 4.
8. Pharmaceutical composition of claim 7 for the treatment of inflammatory skin, eye and/or ear diseases.
A method for treating inflammatory skin, eye and/or ear diseases in a subject in need thereof comprising administering effective amounts of a compound of formula I or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite, prodrug or diastereoisomeric form thereof
wherein said compound of formula I is:
10. The method 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 therapy of inflammatory skin, eye and/or ear diseases.
EP06829328A 2005-12-15 2006-12-06 Diaryl urea for treating inflammatory skin, eye and/or ear diseases Withdrawn EP1962828A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06829328A EP1962828A1 (en) 2005-12-15 2006-12-06 Diaryl urea for treating inflammatory skin, eye and/or ear diseases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP05027468 2005-12-15
EP06016368 2006-08-04
PCT/EP2006/011692 WO2007068382A1 (en) 2005-12-15 2006-12-06 Diaryl urea for treating inflammatory skin. eye and/or ear diseases
EP06829328A EP1962828A1 (en) 2005-12-15 2006-12-06 Diaryl urea for treating inflammatory skin, eye and/or ear diseases

Publications (1)

Publication Number Publication Date
EP1962828A1 true EP1962828A1 (en) 2008-09-03

Family

ID=37806056

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06829328A Withdrawn EP1962828A1 (en) 2005-12-15 2006-12-06 Diaryl urea for treating inflammatory skin, eye and/or ear diseases

Country Status (4)

Country Link
EP (1) EP1962828A1 (en)
JP (1) JP2009519267A (en)
CA (1) CA2633414A1 (en)
WO (1) WO2007068382A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2805874A1 (en) * 2010-07-19 2012-01-26 Bayer Healthcare Llc Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
KR20140048218A (en) * 2011-06-28 2014-04-23 바이엘 헬스케어 엘엘씨 Topical ophthalmological pharmaceutical composition containing regorafenib
UY35183A (en) * 2012-12-21 2014-07-31 Bayer Healthcare Llc TYPICAL OPHTHALMOLOGICAL PHARMACEUTICAL COMPOSITION CONTAINING REGORAFENIB

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1663978B1 (en) * 2003-07-23 2007-11-28 Bayer Pharmaceuticals Corporation Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007068382A1 *

Also Published As

Publication number Publication date
WO2007068382A1 (en) 2007-06-21
CA2633414A1 (en) 2007-06-21
JP2009519267A (en) 2009-05-14

Similar Documents

Publication Publication Date Title
AU2024227546A1 (en) Neuroactive steroids and their methods of use
WO2000002542A2 (en) Agents with an antidepressive effect containing pramipexol and an additional antidepressant drug
WO2017111069A1 (en) Antipruritic
EP1962828A1 (en) Diaryl urea for treating inflammatory skin, eye and/or ear diseases
WO2007068381A1 (en) Diaryl ureas for treating inflammatory skin, eye and/or ear diseases
JP2009062316A (en) Skin care preparation for external application containing furan fatty acid or derivative thereof
JP7321435B2 (en) Composition for treatment of atopy or pruritus containing N-acetyl or N-acylamino acid
FR2915100A1 (en) USE OF 4-CYCLOPROPYLMETHOXY-N- (3,5-DICHLORO-1-OXYDO-PYRIDIN-4-YL) -5- (METHOXY) PYRIDINE-2-CARBOXALIDE FOR THE TREATMENT OF PARKINSON'S DISEASE-RELATED MOTOR DISORDERS
US20080255238A1 (en) Composition containing a thiourea derivative for preventing or treating pruritic or irritant skin diseases
WO2005075023A1 (en) Use of epothilones in the treatment of neuronal connectivity defects such as schizophrenia and autism
RU2426540C1 (en) Anti-inflammatory and anti-allergic medication and based on it pharmaceutical composition
JP7257091B2 (en) Dementia treatment and preventive drug
JP7498475B2 (en) Treatment for multiple myeloma
AU2018258970B2 (en) Idalopirdine-based combinatorial therapies of Alzheimer's disease
WO1999025382A1 (en) Pharmaceutical combination of a cyclooxygenase-2 inhibitor
US20210236445A1 (en) Baclofen and acamprosate based therapy of alzheimer's disease in patients having lost responsiveness to acetylcholinesterase inhibitor therapy
JP2025500088A (en) Novel synergistic combinations based on FENM and acetylcholinesterase inhibitors - Patent Application 20070123333
JPS6092216A (en) Antirheumatic agent
JPS5935365B2 (en) Liver disease treatment drug
CH639072A5 (en) 2-[ alpha -(p-Chlorophenoxy)isobutyrate] of 2,6-pyridinedimethanol and process for its preparation
JP2013170165A (en) Amyotrophic lateral sclerosis prevention therapeutic agent
HK1138204B (en) Prophylactic or therapeutic agent for alopecia
HK1138204A1 (en) Prophylactic or therapeutic agent for alopecia

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080715

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

17Q First examination report despatched

Effective date: 20090527

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090701