Note: Descriptions are shown in the official language in which they were submitted.
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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-trifluoromethylphenyl}ureido]-3-
fluorophenoxy}-
pyridine-2-carboxylic acid methylamide as described e.g. in US 20050038080 are
potent anti-
cancer 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.
Bucher, Kontaktdermatitis,
, 458) which can be differentiated in an allergic contact dermatitis
Schweiz Med Forum, 2001, 18
and a toxic irritative one. The allergic contact dermatitis is a type IV
reaction according to Coombs
and Gell 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.
Loffler et la., Die irritative Kontaktdermatitis, Hautarzt, 2000, 51 203). 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. Sci. 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.
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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 V.
Formula (I) is as follows:
CF3 O
CI O O N~ICH3
H
N
N N
H H
F (I)
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.
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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 pharma-
cologically 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.
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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 ofProdrugs. 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.
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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.
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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; emulsifiers; perborates; phosphates; bleaches; perfumes;
quatemary 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 amnionium sulfate; gold salts an d 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.
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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, Altem Lab Anim. 2002 Jan-Feb;30(1):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 chorioretiriitis) 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.
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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 compo-
sition 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
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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
Technolo~y (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.
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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 nietabolism 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
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ear diseases where the amounts of the formula I 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 cortico-
steroid 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 J15
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 (** p<0.0001; Mann-Withney-u-Test
(test compound
3% vs. vehicle), table 1).
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Table I
Mouse # not challenged vehicle Test compound 1% Test compound 3%
1 0,2 0,6 0,42 0,25
2 0,21 0,38 0,33 0,25
3 0,21 0,57 0,36 0,35
4 0,21 0,55 0,36 0,27
0,23 0,52 0,43 0,23
6 0,21 0,43 0,3 0,3
7 0,2 0,45 0,41 0,4
8 0,21 0,47 0,36 0,33
9 0,22 0,37 0,39 0,3
0,19 0,47 0,47 0,25
mean 0,21 0,48 0,38 0,29
SD 0,01 0,08 0,05 0,05
