Note: Descriptions are shown in the official language in which they were submitted.
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USE OF HYDROXY TETRAEEYDRO-NAPHTHALENE DERIVATIVES
The present invention relates to the use of hydroxy-tetrahydro-
naphthalenylurea derivatives which
are described in WO. 03/095420 as an active ingredient of pharmaceutical
preparations for the
treatment of diseases associated with VRl activity in new indications. The
hydroxy-tetrahydro-
naphthalenylurea derivatives of the present invention are used for the
prophylaxis and treatment of
diseases associated with VR1 activity, in particular for the treatment of
respiratory diseases or
disorders such as the conunon cold, cough, sneeze, bronchitis including acute
and chronic
bronchitis, bronchiolitis, rhinitis, allergic rhinitis, vasomotor rhinitis,
mucositis, sinusitis, allergy,
disorders associated with exogenous irritants such as tobacco smoke, smog,
high levels of
atmospheric SOz and noxious gases in the workplace, and airways
hyperreactivity, milk product
intolerance, Loffler's pneumonia, emphysema, cystic fibrosis, bronchiectasis,
pulmonary fibrosis,
pneumoconiosis, collagen vascular disease, granulomatous disease, laryngitis,
pharyngitis,
pneumonia, pleuritis, persistent asthma and chronic asthmatic bronchitis.
Vanilloid compounds are characterized by the presence of a vanillyl group or a
functionally
equivalent group. Examples of several vanilloid compounds or vanilloid
receptor modulators are
vanillin (4-hydroxy-3-methoxy-benzaldehyde), guaiacol (2-methoxy-phenol),
zingerone (4-/4-
hydroxy-3-methoxyphenyl/-2-butanon), eugenol(2-methoxy4-/2-propenyl/phenol),
and capsaicin
(8-methy-N-vanillyl-6-noneneamide).
Among others, capsaicin, the main pungent ingredient in "hot" chili peppers,
is a specific
neurotoxin that desensitizes C-fiber afferent neurons. Capsaicin interacts
with vanilloid receptors
(VRl), which are predominantly expressed in cell bodies of dorsal root ganglia
(DRG) or nerve
endings of afferent- sensory fibers including C-fiber nerve endings [Tominaga
M, Caterina MJ,
Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D:
The cloned
capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 21: 531-
543, 1998]. The
VRl receptor was recently cloned [Caterina MJ, Schumacher MA, Tominaga M,
Rosen TA,
Levine JD, Julius D: Nature 389: 816-824, (1997)] and identified as a
nonselective cation channel
with six transmembrane domains that is structurally related to the TRP
(transient receptor
potential) channel family. Binding of capsaicin to VRl allows sodium, calcium
and possibly
potassium ions to flow down their concentration gradients, causing initial
depolarization and
release of neurotransmitters from the nerve terminals. VRl can therefore be
viewed as a molecular
integrator of chemical and physical stimuli that elicit neuronal signals in a
pathological conditions
or diseases.
There are abundant of direct or indirect evidence that shows the relation
between VR1 activity and
diseases such as pain, ischaemia, and inflammatory diseases (e.g., WO 99/00115
and WO
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00/503 87). Further, it has been demonstrated that VRl transduces reflex
signals that are involved
in the overactive bladder of patients who have damaged or abnormal spinal
reflex pathways [De
Groat WC: A neurologic basis for the overactive bladder. Urology 50 (6A
Suppl): 36-52, 1997].
Desensitisation of the afferent nerves by depleting neurotransmitters using
VR1 agonists such as
capsaicin has been shown to give promising results in the treatment of bladder
dysfunction
associated with spinal cord injury and multiple sclerosis [(Maggi CA:
Therapeutic potential of
capsaicin-like molecules - Studies in animals and humans. Life Sciences 51:
1777-1781, 1992) and
(DeRidder D; Chandiramani V; Dasgupta P; VanPoppel H; Baert L; Fowler CJ:
Intravesical
capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center
study with long-term
followup. J. Urol. 158: 2087-2092, 1997)].
It is anticipated that antagonism of the VR1 receptor would lead to the
blockage of
neurotransmitter release, resulting in prophylaxis and treatment of the
condition and diseases
associated with VRl activity.
This invention relates to hydroxy-tetrahydro-naphthalenylurea derivatives
which are described in
WO 03/095420, and which are expressly incorporated as part of the description
of this invention,
for the treatment of respiratory diseases or disorders such as the common
cold, cough, sneeze,
bronchitis including acute and chronic bronchitis, bronchiolitis, rhinitis,
allergic rhinitis,
vasomotor rhinitis, mucositis, sinusitis, allergy, disorders associated with
exogenous irritants such
as tobacco smoke, smog, high levels of atmospheric SO2 and noxious gases in
the workplace, and
airways hyperreactivity, milk product intolerance, Loffler's pneumonia,
emphysema, cystic
fibrosis, bronchiectasis, pulmonary fibrosis, pneumoconiosis, collagen
vascular disease,
granulomatous disease, laryngitis, pharyngitis, pneumonia, pleuritis,
persistent asthma and chronic
azthmatic bronchitis.
Special selected compounds of WO 03/095420 which are named for this invention
for the
treatment of respiratory diseases or disorders such as the common cold, cough,
sneeze, bronchitis
including acute and chronic bronchitis, bronchiolitis, rhinitis, allergic
rhinitis, vasomotor rhinitis,
mucositis, sinusitis, allergy, disorders associated with exogenous irritants
such as tobacco smoke,
smog, high levels of atmospheric SO2 and noxious gases in the workplace, and
airways
hyperreactivity, milk product intolerance, Loffler's pneumonia, emphysema,
cystic fibrosis,
bronchiectasis, pulmonary fibrosis, pneumoconiosis, collagen vascular disease,
granulomatous
disease, laryngitis, pharyngitis, pneumonia, pleuritis, persistent asthma and
chronic asthmatic
bronchitis are compounds of formula (I), its tautomeric or stereoisomeric
form, or a salt thereof:
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O
HN'J~ N
H
HO
Z~
Z2
wherein
X represents
1 R2
R3
in which
Y represents a direc-t bond or
R5
R4
in which
and RZ independently represent hydrogen, chloro, bromo,'fluoro, cyclopentyl-
amino, trifluoromethyl, or trifluoromethoxy;
R3, R4 and RS each represent hydrogen; and
Zl and ZZ each represent hydrogen.
More preferably, said hydroxy-tetrahydro-naphthalenylurea derivative of the
formula (I) is selected
from the group consisting of: '
N [4-chloro-3-(trifluoromethyl)phenyl]-N-{7-hydroxy-5,6,7,8-tetrahydro-1
naphthalenyl)urea;
N-(3-chlorophenyl)-N'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea;
N-(7-hydroxy-5, 6, 7, 8-tetrahydro-l-naphthalenyl)-N'-[3-
(trifluoroimethyl)phenyl]urea;
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N-(7-hydroxy-5,6,7, 8-tetrahydro-l-naphthalenyl)-N'-[4-
(trifluoromethyl)phenyl]urea;
N-(3,4-dichlorophenyl)-N'-(7-hydroxy-5,6,7, 8-tetrahydro-l-naphthalenyl)urea;
N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-(7-hydroxy-5,6,7,8-tetrahydro-l-
naphthalenyl]urea;
N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[(7S)-7-hydroxy-5,6,7,8-tetrahydro-l-
naphthalenyl]urea;
N-[4-chloro-3 -(trifluoromethyl)phenyl]-N'-[(7R)-7-hydroxy-5, 6, 7, 8-
tetrahydro-l-
naphthalenyl]urea; .
N-(7-hydroxy-5, 6, 7, 8-tetrahydro-l-naphthalenyl)-N'-phenylurea;
N-(4-chlorophenyl)-N'-(7-hydroxy-5,6,7, 8-tetrahydro-l-naphthalenyl)urea;
N-(7-hydroxy-5,6,7,8-tetrahydro-l-naphthalenyl)-N'-[2-
(trifluoromethyl)phenyl]urea;
N-(7-hydroxy-5, 6,7, 8-tetrahydro-l-naphthalenyl)-N'-[4-
(trifluoromethyl)phenyl] urea;
N-(3,4-dichlorophenyl)-N'-(7-hydroxy-5,6,7, 8-tetrahydro-l-naphthalenyl)urea;
N-(7-hydroxy-5,6,7,8-tetrahydro-1 naphthalenyl)-N'-[4-
(trifluoromethoxy)phenyl]urea;
N-(7-hydroxy-5,6,7,8-tetrahydro-l-naphthalenyl)-N-[4-
(trifluoromethoxy)benzyl]urea;
N-(7-hydroxy-5,6,7,8-tetrahydro-l-naphthalenyl) N'-(2,4,6-
trimethoxybenzyl)urea;
N-(2, 6-difluorobenzyl)-N'-(7-hydroxy-5, 6, 7, 8-tetrahydro-l-
naphthalenyl)ureaz
N-[(7R)-7-hydroxy-5,6,7,8-tetrahydro-1 naphthalenyl] N-[4-
(trifluoromethyl)benzyl]urea;
N-[(7 S)-7-hydroxy-5,6,7, 8-tetrahydro-l-naphthalenyl]-N'-[4-
(trifluoromethyl)benzyl]urea;
N-[(7R)-7-hydroxy-5,6,7,8-tetrahydro-l-naphthalenyl]-N'-[4-
(trifluoromethoxy)benzyl]urea;
N=[(7S)-7-hydroxy-5,6,7,8-tetrahydro-l-naphthalenyl]-N'-[4-
(trifluoromethoxy)benzyl]urea;
N-[2-(4-chlorophenyl)ethyl]-N'-(7-hydroxy-5,6,7,8-tetrahydro-l-
naphthalenyl)urea; and
N-[3 -fluoro-4-(trifluoromethyl)benzyl] -N'-(7-hydroxy-5, 6, 7, 8-tetrahydro=l-
naphthalenyl)urea.
Furthermore the invention relates to the preparation of medicaments of hydroxy-
tetrahydro-
naphthalenylurea derivatives which are described in WO 03/095420 for the
treatment of
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respiratory diseases or disorders such as the common cold, cough, sneeze,
bronchitis including
acute and chronic bronchitis, bronchiolitis, rhinitis, allergic rhinitis,
vasomotor rhinitis, mucositis,
sinusitis, allergy, disorders associated with exogenous irritants such as
tobacco smoke, smog, high
levels of atmospheric SOz and noxious gases in the workplace, and airways
hyperreactivity, milk
product intolerance, Loffler's pneumonia, emphysema, cystic fibrosis,
bronchiectasis, pulmonary
fibrosis, pneumoconiosis, collagen vascular disease, granulomatous disease,
laryngitis, pharyngitis,
pneuinonia, pleuritis, persistent asthma and chronic asthmatic bronchitis.
Furthermore the invention relates to the preparation of medicaments of
compounds of formula (1),
its tautomeric or stereoisomeric form, or a salt thereof for the treatment of
respiratory diseases or
disorders such as the common cold, cough, sneeze, bronchitis including acute
and chronic
bronchitis, bronchiolitis, rhinitis, allergic rhinitis, vasomotor rhinitis,
mucositis, sinusitis, allergy,
disorders associated with exogenous irritants such as tobacco smoke, smog,
high levels of
atmospheric SO2 and noxious gases in the workplace, and airways
hyperreactivity, milk product
intolerance, Loffler's pneumonia, emphysema, cystic fibrosis, bronchiectasis,
pulmonary fibrosis,
pneumoconiosis, collagen vascular disease, granulomatous disease, laryngitis,
pharyngitis,
pneumonia, pleuritis, persistent asthma and chronic asthmatic bronchitis.
Preferably, the hydroxy-tetrahydro-naphthalenylurea derivatives which are
described in WO
03/095420 are used for the treatment of allergic rhinitis.
Preferably, the compounds of formula (I), its tautomeric or stereoisomeric
form, or a salt thereof,
are used for the treatment of allergic rhinitis.
The compounds of WO 03/095420 including the compounds of the forrnula (I) of
the present
iiivention can be,-but not limited to be, prepared by the methods described in
WO 03/095420.
When the compound shown by the fonnula (I) or a salt thereof has an asymmetric
carbon in the
structure, the use of their optically active compounds and racemic mixtures
are also included in the
scope of the present invention.
Typical salts of the compound shown by the formula (I) include salts prepared
by reaction of the
compounds of the present invention with a mineral or organic acid, or an
organic or inorganic
base. Such salts are known as acid addition and base addition salts,
respectively.
Acids to form acid addition salts include inorganic acids such as, without
limitation, sulfuric acid,
phosphoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid and the
like, and organic
acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic
acid, oxalic acid, p-
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bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic
acid, acetic acid, and
the like.
Base addition salts include those derived from inorganic bases, such as,
without limitation,
ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides,
carbonates,
bicarbonates, and the like, and organic bases, such as, without limitation,
ethanolainine,
triethylamine, tris(hydroxymethyl)aminomethane, and the like. Examples of
inorganic bases
include sodium hydroxide, potassiuin hydroxide, potassium carbonate, sodium
carbonate, sodium
bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and
the like.
The compound of the present invention or a salt thereof may form hydrates
and/or other solvates.
The use of those hydrates, and solvates are included in the scope of the
present invention.
The compound of the present invention may be administered in oral forms, such
as, without
limitation normal and enteric coated tablets, capsules, pills, powders,
granules, elixirs, tinctures,
solution, suspensions, syrups, solid and liquid aerosols and emulsions. They
may also be
administered in parenteral forms, such as, without limitation, intravenous,
intraperitoneal,
subcutaneous, intramuscular, and the like forms, well-known to those of
ordinary skill in the
pharmaceutical arts. The compounds of the present invention can be
administered in intranasal
form via topical use of suitable intranasal vehicles, or via transdermal
routes, using transdermal
delivery systems well-known to those of ordinary skilled in the art, or
perlingual or buccal or via
inhalation.
The dosage regimen with the use of the compounds of the present invention is
selected by one of
ordinary skill in the arts, in view of a variety of factors, including,
without limitation, age, weight,
sox, and medicaL.condition of the recipient, the severity of the condition to
be treated, the route of
administration, the level of metabolic and excretory function of the
recipient, the dosage form
employed, the particular compound and salt thereof employed.
The compounds of the present invention are preferably fonnulated prior to
administration together
with one or more pharmaceutically-acceptable excipients. Excipients are inert
substances such as,
without limitation carriers, diluents, flavoring agents, sweeteners,
lubricants, solubilizers,
suspending agents, binders, tablet disintegrating agents and encapsulating
material.
For oral administration, the active ingredient may be combined with an oral,
and non-toxic,
pharmaceutically-acceptable carrier, such as, without limitation, lactose,
starch, sucrose, glucose,
sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate,
calcium sulfate,
methyl cellulose, and the like; together with, optionally, disintegrating
agents, such as, without
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limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum,
alginic acid, and the like;
and optionally, binding agents, for example, without limitation, gelatin,
natural sugars, beta-
lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth,
sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes, and the like; and,
optionally, lubricating
agents, for example, without limitation, magnesium stearate, sodium stearate,
stearic acid, sodium
oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.
In powder forms, the carrier may be a finely divided solid which is in
admixture with the finely
divided active ingredient. The active ingredient may be mixed with a carrier
having binding
properties in suitable proportions and compacted in the shape and size desired
to produce tablets.
The powders and tablets preferably contain from about 1 to about 99 weight
percent of the active
ingredient which is the novel composition of the present invention. Suitable
solid carriers are
niagnesium carboxymethyl cellulose, low melting waxes, lactose, and cocoa
butter.
Sterile liquid formulations include suspensions, eniulsions, syrups and
elixirs. The active
ingredient can be dissolved or suspended in a pharmaceutically acceptable
carriers, such as sterile
water, sterile organic solvent, or a mixture of both sterile water and sterile
organic solvent.
The active ingredient can also be dissolved in a suitable organic solvent, for
exaniple, aqueous
propylene glycol. Other compositions can be made by dispersing the finely
divided active
ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in
a suitable oil.
For intranasal administration, the pharmaceutical compositions of this
invention may be
administered by nasal drops, by nasal aerosols, or as an inhaled powder.
Suitable nasal spra-y formulations of inventive compositions can be readily
prepared according to
techniques vvell known in the art of pharmaceutical formulation. For exainple,
the preparation of
solutions or emulsions are described by Achari et al., U.S. Pat. No. 6,
436,950 (supra), J. G. Nair
[Chapt. 39, Solutions, Emulsions, Suspensions and Extracts, pg. 721-752J] and
aerosols by J.
Sciarra and C. J. Sicarra [Chapt. 50, "Aerosols", pg. 963 to 979] in the
standard text: "Remington,
the science and practice of pharmacy," Alfonso R. Gennaro, Chairman of the
editorial board and
editor. 20th ed. Baltimore, Md. Lippincott Williams & Wilkins, 2000.
The compositions the active ingredient may be prepared as gels, liposomal
dispersions,
suspensions or emulsions in saline, employing benzyl alcohol, benzalkonium
chloride or other
suitable preservatives, absorption promoters such as cyclodextrins to enhance
bioavailability and
bioadhesives for prolonged contact, and/or other solubilizing or dispersing
agents known in the art.
Thus, a composition for administration to the intranasal surfaces is
particularly contemplated that
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comprises a solution of the active ingredient dissolved or dispersed in a
pharmaceutically
acceptable diluent (carrier). The solvent or wetting agent may be propylene
glycol (1,2-
propanediol) and a variety of aqueous carriers can be used, e.g. buffered
water, 0.9 percent saline,
buffered aqueous-ethanol solutions and the like. These compositions can be
sterilized by
conventional, well-known sterilization techniques, or can be sterile filtered.
The resulting solutions
can be packaged for use as is or mixed as an adjuvant to another medication.
The inventive embodiment compositions can contain pharmaceutically acceptable
auxiliary
substances as required to approximate physiological conditions, such as pH
adjusting and
buffering agents, tonicity adjusting agents, wetting agents and the like, for
example, sodium
acetate, sodium lactate, sodium chloride, potassium chloride, calcium
chloride, sorbitan
monolaurate, triethanolamine oleate, and the like.
Another form of intranasal administration is to administer the active
ingredient in powder form; by
itself or admixed to an inert carrier such as calcium carbonate or lactose.
Methods for preparing
spray dried powder with a hydrophilic excipient, e.g. povidone, lactose, and
delivering it using dry
powder nasal inhalers, have been described by Gordon et al. (U.S. Pat. No.
6,365,190) and are
incorporated herein by reference. The advantage of a powder method for
delivery is that it may
have a more prolonged action when administered in dry powder versus in soluble
forms, as the
nose has robust clearance mechanisms. The powder may be prepared in micronized
form, by re-
crystallization, by granulation, by drying, or by milling to a specified
particle size and thus to have
a high surface area for interaction with cold receptors. Methods for preparing
powders are well-
known to the art and have been reviewed by R. E. O'Connor and J. B. Schwartz
(Powders, Chapt.
37, pg. 681-699) in the standard text: "Remington, the science and practice of
pharmacy," Alfonso
R: Gennaro, Chairman of the editorial board and editor. 20th ed. Baltimore,
Md. Lippincott
Williams &Wilkins, 2000. To quote from this Chapter (pg. 688):
The formulation may be in unit dosage form, which is a physically discrete
unit containing aunit
dose, suitable for administration in human or other mammals. A unit dosage
form can be a capsule
or tablets, or a number of capsules or tablets. A "unit dose" is a
predetermined quantity of the
active compound of the present invention, calculated to produce the desired
therapeutic effect, in
association with one or more excipients. The quantity of active ingredient in
a unit dose may be
varied or adjusted from about 0.1 to about 1000 milligrams or more according
to the particular
treatment involved.
Typical oral dosages of the present invention, when used for the indicated
effects, will range from
about 0.01mg /kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to
30 mg/kg/day,
and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the
case of parenteral
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administration, it has generally proven advantageous to administer quantities
of about 0.001 to
100mg /kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of
the present
invention may be administered in a single daily dose, or the total daily dose
may be administered
in divided doses, two, three, or more times per day. Where delivery is via
transdermal forms, of
course, administration is continuous.
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EXA.MPLES
The effect of the compounds of the present invention were examined by the
assays and
pharmacological tests described in WO 03/095420.
The compounds of the present invention were prepared as described in WO
03/095420.
