Note: Descriptions are shown in the official language in which they were submitted.
CA 02255842 1999-02-26
- SPECIFICATION
ROSACEA TREATING AGENT
Technical Field
The present invention relates to a treating agent
for rosacea.
Backgrround Art
Rosacea is, while rare among colored races,
common among races with a light-colored skin, especially
white races, and many cases occur among them. It is
divided according to the symptoms into the first degree
(telangiectatic rosacea on the forehead, cheeks, dorsum
nasi), the second degree (acne rosacea, coexistence of
follicular papules and pustules), and the third degree
(rhinophyma, dark red tumor and dilated pore on apex
nasi) . It starts with facial flush (redness) and
eventually involves serious impairment of appearance,
developing papules, pustules, rhinophyma, and tumor on
apex nasi. It is also accompanied by seborrhea or
enhancement of feeling of heat on the face due to
emotional stress or change of environmental temperature.
Thus, these symptoms give a patient mental and physical
suffering.
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For the time being, the real cause of rosacea is
unknown (Hifuka Chiryo Handbook, pp. 380-381, Nanzando
(1987) and Gerd Plewing, Albert M. Kligman, ACNE arid
ROSACEA, 2nd, Completely Revised and Enlarged Edition,
pp. 431-454, Springer-Verlag (1993)). Rosacea is apt to
be confused with acne, what is called pimple,
classificationally. Rosacea, which can coexist with
acne, essentially differs from acne. It is
characterized by facial flush due to vascularization and
proceeds with acne rosacea and tumor on apex nasi. A
digestive disease, hypertension, Demodex folliculon~,
emotional stress, hereditary predisposition, etc. have
been pointed out as a conceivable cause of rosacea,
which has not been ascertained yet.
Therefore, there is no drug established as a
remedy for rosacea, and the only method available now is
symptomatic treatment, such as administration of
minocycline or tetracycline antibiotics for the
treatment of delayed skin diseases, use of metronidazole
(anthelmintic), removal of mental stress, dietetic
treatment, and supplemental concomitant use of vitamin
BZ or B6.
Accordingly, it has been keenly demanded to study
and develop more useful treating agents for rosacea.
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An object of the present invention is to provide
a useful rosacea treating agent.
Disclosure of the Invention
The inventor of the present invention has
conducted extensive study to develop a rosacea treating
agent in the light of the above circumstances, and found
as a result that at least one compound selected from the
group consisting of benzoheterocyclic derivatives
represented by the following formula (1):
O
X / COOH
N \ I NJ (1)
HO
R
wherein R represents a lower alkyl group; and X
represents a halogen atom,
and salts thereof is suitable as an active ingredient of
a rosacea treating agent. The present invention has
been completed based on this finding.
That is, the present invention relates to a
rosacea treating agent comprising at least one selected
from the group consisting of the above benzoheterocyclic
derivatives represented by formula (1) and salts
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thereof as an active ingredient; use of at least one
selected from the above compounds for preparing a
rosacea treating agent; and a method for treating
rosacea comprising using at least one selected from the
above compounds.
The benzoheterocyclic derivatives represented by
formula (1) or salts thereof are known from, e.g.,
Japanese Patent Publication No. 41127/89, which teaches
details of a method for preparing these compounds and
usefulness of the compounds as antimicrobial agents.
However, it is unpredictable even for one skilled
in the art whether or not these benzoheterocyclic
derivatives and their salts are effective for treating
rosacea that has been considered baffling and difficult
to cure.
The rosacea treating agent according to the
present invention is effective even for treating
intractable rosacea on which conventional antibiotics
such as minocycline do not work, healing rosacea active
papules, active pustules, erythema, and active
efflorescence, and suppressing telangiectasia. It has
low toxicity, causing little side effect, and is of long
duration.
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In another aspect, the present invention provides a
rosacea treating composition comprising a benzoheterocyclic
compound represented by the following formula (1):
X ~aH
(1)
HO
rt
wherein R represents an alkyl group having 1 to 6
carbon atoms; and X represents a halogen atom, or a salt
thereof, and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides use
of a benzoheterocyclic compound represented by formula (1) or
a salt thereof for preparing a rosacea treating composition.
In another aspect, the present invention provides use
of the rosacea treating composition of the present invention
for treating rosacea.
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Hest F~abodiments for Carrving~ Out the Invention
The rosacea treating agent according to the
present invention comprises at least one selected from
the group consisting of the above benzoheterocyclic
derivatives represented by formula (1) and salts thereof
as an active ingredient.
In formula (1), the lower alkyl group represented
by R includes straight-chain or branched alkyl groups
having 1 to 6 carbon atoms, such as methyl, ethyl,
propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl
groups. The halogen atom represented by X includes a
fluorine atom, a chlorine atom, a bromine atom, and an
iodine atom.
Of the compounds represented by formula (1) , (~) -
9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-
1-oxo-1H,5H-benzo[i,j]-quinolizine-2-carboxylic acid is
particularly preferred.
The compound represented by formula (1) can be
easily converted into acid-addition salts thereof by the
reaction with a pharmaceutically acceptable acid. The
acid includes inorganic acids, such as hydrochloric acid,
sulfuric acid, phosphoric acid, and hydrobromic acid;
and organic acids, such as oxalic acid, malefic acid,
fumaric acid, malic acid, tartaric acid, citric acid,
and benzoic acid. The compounds represented by formula
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(1) can easily be converted into salts thereof by the
reaction with a pharmaceutically acceptable alkaline
compound. The alkaline compound includes sodium
hydroxide, calcium hydroxide, potassium hydroxide,
sodium carbonate, and potassium hydrogencarbonate.
The compound represented by formula (1) of the
present invention and salts thereof can be easily
isolated and purified by ordinary separation means, such
as solvent extraction, dilution, recrystallization,
column chromatography, preparative thin layer
chromatography, and the like.
In using the compound represented by formula (1)
and salts thereof as a rosacea treating agent, they are
generally compounded into pharmaceutical compositions
together with pharmaceutically acceptable carriers which
are commonly employed in preparing drugs of dose form
conformable to the method of administration. Suitable
carriers which can be used include diluents or
excipients, such as fillers, extenders, binders, wetting
agents, disintegrants, surfactants, lubricants, etc.
The rosacea treating agent can have various
dosage forms in accordance with the purpose of the
therapy. Typical dosage forms include tablets, pills,
powders, liquid preparations, suspensions, emulsions,
granules, capsules, suppositories, injectable
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preparations (solutions, suspensions, etc.); sprays,
such as inhalations and aerosol for external use;
liquids for topical application, lotions, .gels, oily
ointments; emulsified ointments, such as O/W hydrophilic
ointments and W/O water-absorbent ointments; water-
soluble ointments, creams, liniments, cataplasms, pastes,
plasters, external preparation such as emulsions, and
sheets.
If the pharmaceutical composition is formulated
into tablets, a wide range of carriers known in the art
can be used. Examples of suitable carriers include
excipients such as lactose, white sugar, sodium chloride,
glucose, urea, starch, calcium carbonate, kaolin,
crystalline cellulose, and silicic acid; binders such as
water, ethanol, propanol, simple syrup, a glucose
solution, a starch solution, a gelatin solution,
carboxymethyl cellulose, shellac, methyl cellulose,
potassium phosphate, and polyvinylpyrrolidone;
disintegrants such as dried starch, sodium alginate,
agar powder, laminaria powder, sodium hydrogencarbonate,
calcium carbonate, polyoxyethylene sorbitan fatty acid
esters, sodium laurylsulfate, glycerol monostearate,
starch, and lactose; disintegration inhibitors such as
white sugar, stearin, cacao butter, and hydrogenated
oils; absorption promoters such as quaternary ammonium
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bases and sodium laurylsulfate; humectants such as
glycerol and starch; adsorbents such as starch, lactose,
kaolin, bentonite, and colloidal silicic. acid; and
lubricants such as purified talc, stearic acid salts,
boric acid powder, and polyethylene glycol. The tablets,
if desired, can be coated tablets having a general coat,
such as sugar-coated tablets, gelatin-coated tablets,
enteric coated tablets, film-coated tablets, double-
layered coated tablets, or multilayered coated tablets.
In formulating into pills, carriers well known in the
art can be used widely. Examples of suitable carriers
are excipients such as glucose, lactose, starch, cacao
butter, hardened vegetable oils, kaolin, and talc;
binders such as gum arabic powder, tragacanth powder,
gelatin, and ethanol; and disintegrants such as
laminaria and agar. In formulating into suppositories,
carriers well known in the art can be used widely.
Examples are polyethylene glycol, cacao butter, higher
alcohols, higher alcohol esters, gelatin, and
semisynthetic glycerides. Capsules are generally
prepared by mixing the active ingredient with the above-
enumerated various carriers and packing the mixture into
hard gelatin capsules or soft capsules. Solutions,
emulsions or suspensions as injectable preparations are
preferably sterilized and made isotonic with blood. In
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preparing these preparations, all diluents customarily
used in the art, such as water, ethanol, Macrogol,
propylene glycol, ethoxylated isostearyl alcohol,
polyoxylated isostearyl alcohol, and polyoxyethylene
sorbitan fatty acid esters, can be used. Sodium
chloride, glucose or glycerol may be incorporated into
the injectable preparation in an amount sufficient for
making it isotonic. The injectable preparations can
contain general dissolution aid, buffers, pain-
alleviating agents, and the like. The pharmaceutical
compositions can contain coloring agents, preservatives,
perfumes, flavors, sweeteners, and other drugs. In
formulating the pharmaceutical composition into pastes,
creams or gels , a wide variety of diluents known in the
art can be used. Examples are white petrolatum,
paraffin, glycerol, cellulose derivatives, polyethylene
glycol, silicone, and bentonite.
Bases which can be used for an external
preparation comprise an oily base or a mixture of two or
more oily bases or a water-soluble base or a mixture of
two or more water-soluble bases. Examples of suitable
bases are fats and oils such as peanut oil, sesame oil,
soybean oil , safflower oil , avocado oil , sunflower oil ,
corn oil, rape seed oil, cotton seed oil, castor oil,
camellia oil, palm oil, olive oil, poppy seed oil,
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coconut oil, beef tallow, lard, and lanolin; modified
fats and oils prepared by subjecting the above-described
fats and oils to a chemical change such as
hydrogenation; mineral oils such as vaseline, paraffin,
silicone oil, and squalane; higher fatty acid esters,
higher fatty acid alcohols and waxes such as isopropyl
myristate, N-butyl myristate, isopropyl linolate, propyl
ricinoleate, isopropyl ricinoleate, isobutyl ricinoleate,
heptyl ricinoleate, diethyl sebacate, diisopropyl
adipate, cetyl alcohol, stearyl alcohol, white beeswax,
cetaceum, Japan wax, lanolin, carnauba wax, and shellac
wax; higher fatty acids such as stearic acid, oleic acid
and palmitic acid; mono-, di- and triglyceride mixtures
of saturated or unsaturated fatty acids having 12 to 18
carbon atoms; polyhydric alcohols such as ethylene
glycol, polyethylene glycol, propylene glycol,
polypropylene glycol, glycerol, butyl alcohol,
pentaerythritol, sorbitol, and mannitol; gum such as gum
arabic, gum benzoin, guaiac resin, ad gum tragacanth;
naturally occurring water-soluble polymers such as
gelatin, starch, casein, dextrin, pectin, sodium pectin,
sodium alginate, methyl cellulose, ethyl cellulose,
carboxymethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, nitrocellulose, and crystalline
cellulose; synthetic water-soluble polymers such as
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polyvinyl alcohol, polyvinyl methyl ether,
polyvinylpyrrolidone, sodium polyacrylate, carboxyvinyl
polymers, and polyethyleneimine; nonionic, anionic,
amphoteric or cation surfactants; ethanol, isopropyl
alcohol, and the like.
These external preparations, if desired, can
contain various known bases such as excipients, binders,
lubricants, and disintegrants. If desired, they can
also contain oily materials such as various fats and
oils, waxes, hydrocarbons, fatty acids, higher alcohols,
ester oils and metallic soaps, animal or vegetable
extracts, pharmaceutically effective components such as
vitamins, hormones, and amino acids, surfactants,
coloring matters, dyes, pigments, perfumes, antiseptics,
antimicrobial agents, humectants, thickeners,
antioxidants, sequestering agents, ultraviolet absorbers,
ultraviolet scattering agents, or any other known
components and additives as long as the effects of the
present invention are not impaired.
The amount of the active compound to be
incorporated into the rosacea treating agent of the
present invention is not particularly limited and can
vary over a wide range. A suitable effective amount is
usually from about 1 to 705 by weight based on the total
composition.
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There is no particular restriction on the manner
of using the rosacea treating agent, and the treating
agent can be administered by routes suitable for the
particular forms of the preparation, the age, sex or
other conditions of patients, the symptoms, and the like.
For example, the tablets, pills, liquid preparations,
suspensions, emulsions, granules and capsules are orally
administered. The injectable preparations are
intravenously administered either alone or together with
ordinary auxiliary agents such as glucose and amino
acids. As required, the injectable preparations can be
singly administered intramuscularly, intracutaneously,
subcutaneously or intraperitoneally. The suppositories
are administered intrarectally, and the external
preparations are applied onto the skin.
The dosage of the rosacea treating agent of the
present invention is appropriately selected according to
the administration route, the age, sex or other
conditions of a patient, the symptoms, etc. Usually, a
preferred dose of the active compound is about 0.2 to
100 mg/kg body weight in 3 or 4 divided doses per day.
An external preparation is applied once or twice a day
at a dose of about 10 mg of the active compound per day.
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Examples
The present invention will now be illustrated in
greater detail by way of formulation examples and
pharmacological test example.
Formulation Example 1
Compound of formula (I) 200 mg
Glucose 250 mg
Injectable distilled water appropriate amount
Total 5 ml
The compound of formula (1) and glucose were
dissolved in injectable distilled water, and the
solution was put into a 5 ml-volume ampule. After
substitution with nitrogen, the solution was sterilized
by autoclaving at 121°C for 15 minutes to obtain an
injection having the above composition.
Formulation Example 2
Compound of formula (1) 100 g
Avicel (trade name, a product of 40 g
Asahi Chemical Industry Co., htd.)
Corn starch 30 g
Magnesium stearate 2 g
Hydroxypropylmethyl cellulose 10 g
* Trade-mar k
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Polyethylene glycol-6000 3 g
Castor oil 40 g
Ethanol . 40 g
The compound of the invention, Avicel, corn
starch, and magnesium stearate were mixed, ground, and
punched using a pestle of sugar coating R=10 mm. The
resulting tablets were coated with a film coating agent
comprising hydroxypropyl methyl cellulose, polyethylene
glycol-6000, castor oil and ethanol to obtain film-
coated tablets.
Formulation Exams 3
(~)-9-Fluoro-6,7-dihydro-8-(4- 2 g
hydroxy-1-piperidyl)-5-methyl-1-oxo-
1H,5H-benzo[i,j]quinolizine-2-
carboxylic acid
Purified lanolin 5 g
White beeswax 5 g
White petrolatum 88 g
Total 100 g
White beeswax was liquefied by heating, and the
compound of the invention, purified lanolin and white
petrolatum were added thereto. After once heated to
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liquefy, the mixture was stirred till it began to
solidify to obtain an ointment of the above composition.
Formulation Example 4
Cream:
(~)-9-Fluoro-6,7-dihydro-8-(4- 1.0 g
hydroxy-1-piperidyl)-5-methyl-1-oxo-
1H,SH-benzo[i,j]quinolizine-2-
carboxylic acid
White petrolatum 10.0 g
Light liquid paraffin 9.0 g
Stearyl alcohol 4.0 g
Polyoxyethylene cetyl ether 3.0 g
Concentrated glycerin 10.0 g
Purified water and the like appropriate amount
Total 100.0 g
Formulation
Component I:
White petrolatum 10.0 g
Light liquid paraffin 9.0 g
Stearyl alcohol 4.0 g
Cetanol 4.0 g
Polyoxyethylene cetyl ether 3.0 g
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Component II:
(~) -9-Fluoro-6, 7-dihydro-8- (4- 1. 0 g
hydroxy-1-piperidyl)-5-methyl-1-oxo- .
1H,5H-benzo[i,j]quinolizine-2-
carboxylic acid
Glycerin 10.0 g
Di ( ~i-hydroxyethyl ) amine 0 . 1 g
Purified water 58.9 g
An external preparation in cream form was
obtained in the same manner as in Formulation Example 4.
Formulation Example 6
Ointment:
White petrolatum 73.54
g
Light liquid paraffin 10.0 g
Cetanol 5.0 g
Cholesterol 4.0 g
()-9-Fluoro-6,7-dihydro-8-(4- 1.0 g
hydroxy-1-piperidyl)-5-methyl-1-oxo-
1H,5H-benzo[i,j]quinolizine-2-
carboxylic acid
Sodium hydroxide 0.112
g
Propylene glycol 5.0 g
Di ((3-hydroxyethyl) amine 0 . g
2
Disodium edetate 0.1 g
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Purified water 1.048 g
Formulation
Component I:
White petrolatum 6.5 g
Light liquid paraffin 6.0 g
Stearyl alcohol 2.5 g
Cetanol 2.5 g
Polyoxyethylene cetyl ether 2.0 g
Component II:
()-9-Fluoro-6,7-dihydro-8-(4- 1.0 g
hydroxy-1-piperidyl)-5-methyl-1-oxo-
1H,5H-benzo[i,j]quinolizine-2-
carboxylic acid
Sodium hydroxide 0.112 g
Di ((3-hydroxyethyl) amine 0 . 36
g
Purified water 79.028
g
Component I was heated to about 80C to melt.
Separately, component II was mixed, dissolved, and
heated to about 80C. The heated components I and II
were mixed and cooled to obtain an external preparation
in emulsion form.
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Formulation Exaa~le 8
Lotion:
()-9-Fluoro-6,7-dihydro-8-(4- . 1.0 g
hydroxy-1-piperidyl)-5-methyl-1-oxo-
1H,5H-benzo[i,j]quinolizine-2-
carboxylic acid
Isopropyl alcohol 62.4 g
Propylene glycol 2.5 g
Tri ((3-hydroxyethyl) amine 0 . g
4
Sodium hydroxide 0.2 g
Purified water appropri ate
amount
Total 1000 ml
A cream prepared in accordance with Formulation
Example 4, which contained 1~ of (~)-9-fluoro-6,7-
dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H,5H-
benzo[i,j]-quinolizine-2-carboxylic acid, was applied to
the face of 13 rosacea patients suffering from facial
flush and 15 or more active pustules or papules on their
face twice a day. Of the 13 cases, 11 had received
medical treatment With minocycline (6 cases),
metronidazole (5 cases), oxytetracycline (2 cases),
erythromycin (2 cases), tetracycline (1 case), benzoyl
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peroxide (1 case) , zinc acetate (1 case) , doxycycline (1
case) , fluocinonide (1 case) , nystatin (1 case) or white
petrolatum (1 case) .
After 12 weeks from the start of the treatment
with the cream, the physician in charge judged the
degree of overall improvement in the patients on cream
therapy based on 5 scales of cure, remarkable
improvement, improvement, no change, and aggravation.
As a result, of 13 cases 2 cases (15.4 of the total)
were judged as cure and 9 cases (69.2 of the total) as
remarkable improvement, proving that the rate of
improvement reached 84.6. There were only 2 cases
(15.4 of the total) judged as no change.
It is seen from these results that the rosacea
treating agent according to the present invention brings
about improvement on rosacea symptoms, exhibiting
effectiveness even on those patients who had not been
cured completely by previous therapy.
Industrial Agnlicability
The benzoheterocyclic derivatives of formula (1)
and salts thereof are useful as a rosacea treating agent
that is effective even on baffling and intractable
rosacea which cannot be cured completely by conventional
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antibiotics such as minocycline, has low toxicity,
causes little side effect, and is of long duration.
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