Note: Descriptions are shown in the official language in which they were submitted.
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DIARYL UREA FOR TREATING DIABETIC NEUROPATHY
The present invention relates to pharmaceutical compositions for treating
diabetic neuropathy
comprising 4 {4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-
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.
Diabetic neuropathy also called painful diabetic neuropathy is a common
diabetes related
phenomenon. Pain as syndrome of neuropathy may be seen in as many as one third
of all patients
with diabetes. Neuropathic pain is difficult to manage and the available
treatment options rarely
provide total relief (C.F. Corbett, The Diabetes Educator, Vol. 31, 2005, 4,
523-540). Its cause is
unclear and it does not respond well to traditional pain therapies (R.A. Malik
(2003) Treat.
Endocrinol. 2(6), 339-400).
Recent advancements in the diagnosis of neuropathic pain include methods that
can distinguish
between neuropathic and non-neuropathic pain. In the absence of treatment,
nerve damage may
progress while pain diminishes. Symptom mangament treatment is available and
includes the use
of analgesics (NSAIDs), antidepressants (e.g. selective serotonin reuptake
inhibitors, tricyclic
antidepressants), anticonvulsants, capsicain topical cream, nexiletine, as
well as physical or
mechanical therapy such as electrical stimulation, acupuncture, magnet therapy
or topical use of
polyurethane films.
As demonstrated recently (S.A Price et al. (2004) Diabetes, 53, 1851-1856)
treatment of diabetic
animals with SB 239063, fidarestat or insulin prevent reduction in both motory
and sensory nerve
conduction velocity. Reduced nerve conduction velocity (NCV) is an established
hallmark of
diabetic neuropathy.
The present invention provides pharmaceutical compositions for treating
diabetic neuropathy
comprising a compound of formula I and optionally at least one further
therapeutic agent.
The present invention provides a therapeutic method which do not only reduce
the neuropathic
pain of patients more effectively compared to current therapies but also
provides a therapeutic
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method for the reconstitution of nerve functions. The therapeutic method
according to the
invention is superior to current therapies. Therefore the present invention
can be used e.g: by
administering a diary) 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:
F3 O
CI \ O N,CH3
O
N~N / N H
H H
F
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
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and the quatemary 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
dicyclohexylamine 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-Cl-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:
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= 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 ofMedicinal 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 analgesics, anti-depressants, anti-diabetics,
glucose controlling agents,
neuroprotective agents, anticonvulsants, anesthesics, anti-inflammatory agents
or capsaicin.
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Examples of analgesics include, but are not limited to, NSAID (non-steroidal
antiinflammatory
drugs), COX-1- or COX-2-inhibitors etc..
Examples of NSAID include, but are not limited to, e.g. aceclofenac,
acetaminophen, o-acetyl-
salicylic acid, alclofenac, alminprofen, amfenac, ampiroxicam,
amtolmetinguacil, anirolac,
antrafenin, azapropazon, benorilat, bermoprofen, bindarit, bromfenac,
bucloxsaure, bucolom,
bufexamac, bumadizon, butibufen, butixirat, carbasalat calcium, carprofen,
cinmetacin,
cinnoxicam, clidanac, clobuzarit, deboxamet, dexibuprofen, dexketoprofen,
diclofenac, diflunisal,
eltenac, enfenamsaure, etersalat, etodolac, etofenamat, feclobuzon, felbinac,
fentiazac, fepradinol,
flobufen, floctafenin, flufenam acid, flunoxaprofen, flurbiprofen,
flurbiprofen axetil, furpfenac,
furprofen, glucametacin, ibufenac, ibuprofen, indobufen, indometacin,
indometazin franesil,
indoprofen, ketoprofen, ketorolac, lobenzarit, lonazolac, lornoxicam,
loxoprofen, mefenam acid,
meloxicam, mesalazin, mofezolac, nabumeton, naproxen, niflumic, olsalazin,
oxaprozin,
pelubiprofen, phenylbutazon, pimeprofen, pirazolac, piroxicam, pirprofen,
pranoprofen, prifelon,
prinomid, proglumetacin, proquazon, protizin acid, romazarit, salicylamide,
salicylic acid,
salmistein, salnacedin, salsalat, sulindac, suprofen, talniflumat, tenidap,
tenosal, tenoxicam,
tepoxalin, tiaprofensaure, tiaramid, tilnoprofen arbamel, timegadin,
tinoridin, tolfenam acid,
tolmetin, ufenamat, ximoprofen, zaltoprofen and zoliprofen.
Preference is given to an NSAID selected from the group consisting of
acetaminophen, o-
acetylsalicylic acid, clidanac, diclofenac, flurbiprofen, ibuprofen,
ketoprofen and sulindac. More
preferably o-acetylsalicylic acid is used as NSAID.
Examples of anesthesics include, but are not limited to, e.g. melixetine,
lidocaine and benzocaine.
Preference is given to melixetine.
Examples of anti-depressants include, but are not limited to, e.g. selective
serotonin reuptake
inhibitors and tricyclic anti-depressants such as duloxetine, trazodone and
venlafaxine.
Examples of anticonvulsants include, but are not limited to, e.g. gabapentin,
lamotrigine,
amitriptyline and pregabalin.
Examples of anti-diabetic agents include, but are not limited to, e.g.
insuline, CB-1 antagonists
such as rimonabant or SLV-319, 5HT uptake inhibitors such as sibutramin,
ilpase inhibitors such
as orlistat or ALT-962, CNTF agonists such as axokine, DGAT inhibitors such as
BAY 74-4113,
DPP IV inhibitors such as vildagliptin, sitagliptin, saxagliptin, LAF-237, MK-
0431 or BMS-
477118, GLP-1 analogues such as exenatide, betatropin, BIM-51077, CJC-1131 or
liraglutide,
PPAR ay agonists such as BAY 62-9069, BAY 68-2959, tesaglitazar, muraglitazar,
ONO-5129,
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LY-510929, LY-519818, GW-677954, TAK-559, naveglitazar or AVE-0847, PPAR y
agonists
such as pioglitazone, rosiglitazone, R-483, balaglitazone, rivoglitazone or
TAK-654. Preference is
given to BAY 74-4113, BAY 62-9069, BAY 68-2959, rimonabant, SLV-319,
pioglitazone,
rosiglitazone, orlistat, tesaglitazar, muraglitazar and exenatide.
Indications -
The compounds and combinations according to the present invention can be used
for manufacture
of a medicament for treating diabetic neuropathy. Also the present invention
provides methods of
treating diabetic neuropathy, 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. Diabetic neuropathy is also known as
painful diabetic neuropathy.
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 patch), 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 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, solution,
suspensions, syrups, solid and liquid aerosols and emulsions.
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.
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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); Theorv and Practice of Industrial
Pharmacy (Lachman et
al., eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia of
Pharmaceutical
TechnoloQV (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.
Other therapies according to the invention include, but are not limited to,
physical or mechanical
therapy such as electrical stimulation, acupuncture, magnet therapy or topical
use of polyurethane
films.
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
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-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 behavior 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
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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 diabetic
neuropathy, 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 diabetic
neuropathy 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 NSAID.
More preferably a combination comprising 4{4-[3-(4-chloro-3-
trifluoromethylphenyl)-ureido]-3-
fluorophenoxy}-pyridine-2-carboxylic acid methylamide and at least one NSAID
is used. Most
preferably a combination comprising 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-
ureido]-3-
fluorophenoxy}-pyridine-2-carboxylic acid methylamide and o-acetylsalicylic
acid is used.
