JP2002241282A - Medicine for treating allergic dermatitis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine which is effective for allergic dermatitis such as allergic contact dermatitis and atopic dermatitis. SOLUTION: The medicine for treating dermatitis through a delayed-type allergic reaction is characterized by containing 3-(4- fluorophenylsufonamide)-1,2,3,4-tetrahydro-9-carbazolepropionic acid represented by the formula or its pharmaceutically acceptable salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the formula

[0002]

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3- (4-fluorophenylsulfonamido) -1,2,3,4-tetrahydro-9-
The present invention relates to an agent for treating dermatitis via delayed-type allergic reaction, particularly allergic contact dermatitis or atopic dermatitis, which comprises carbazole propionic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

The following general formula including the compound of the above formula (I)

[0005]

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Wherein R ¹ is hydrogen, halogen or C _1-
C ₄ - alkyl and represents; R ² is halogen, trifluoromethyl, trifluoromethoxy or C ₁ -C ₄ - alkyl by represents phenyl which is mono- or disubstituted; x is 1 or 2; y Represents 0 or 1, cycloalkano [1,2-b] indolesulfonamide or a salt thereof is used for platelet aggregation (platet aggregation).
aggregation) inhibition and thromboxane A ₂ antagonist _{(antigonizing thromboxane A 2: TXA 2} ) shows the effect, that thrombosis, thromboembolism, treatment of ischemia, or anti-asthmatic agents, and are useful as an antiallergic agent Is known (see Japanese Patent Publication No. 4-50301).

Further, (3R) -3- (4) in the above formula (I)
-Fluorophenylsulfonamide) -1,2,3,4
-Tetrahydro-9-carbazolepropionic acid [general name: Ramatroban; development number: BAY
u 3405] binds to TXA ₂ receptor of bronchial smooth muscle, U-466 is mimetics of TXA ₂
19 (9,11-methanoepoxy-pros
taglandin H ₂ ) or prostaglandin D ₂ has been reported to inhibit bronchial muscle contraction in humans and guinea pigs [Br. J. P
Pharmacol. 104, 1991, 585-585.
590 and 591-595].

In addition, guinea pigs are given Ramatroban (BAY
u-3405) to give U-4661
9 has also been reported to suppress airway constriction induced by and improve lung compliance [Br. J. Pha
rmacol. 104, 1991, 596-60.
Page 2]. Also, Ramatroban (BAY u 3405)
In a guinea pig experimental allergic rhinitis model,
Involvement of TXA ₂ has also been reported has the effect of improving the symptoms suspected [March 1993 Otolaryngology Allergy and Immunology Society, etc.].

[0009] Thus, compounds of the formula (I) (ramatroban) is antagonize TXA _2, asthma TXA ₂ involving, to be effective against allergic symptoms such as rhinitis is well known.

By the way, although TXA ₂ is a substance that is released from such results mast cells and inflammatory cells of allergic reactions, is known to be asthma is dominant chemical mediators in allergic reactions involving bronchoconstriction such as [ Eur. J. Pharmacol. , Vol. 117 (1
985) p. 373-375; Thorax, Vol. 41 (1986) p.
Ukotriens and Essential F
atty Acids, Vol. 35 (1989) 125
１３０130]. Then, in the allergic dermatitis, TXA ₂ and prostaglandin histamine than the chemical mediators [Eur. J. Pharm
acol. , Vol. 117 (1985), 337-345.
And lymphokines derived from lymphocytes are considered to be important.

The present inventors have found that the compound of the formula (I) (ramatroban), which was conventionally considered to be a TXA ₂ antagonistic inhibitor and thus was considered to be ineffective against allergic dermatitis, Surprisingly, they have found that they are also effective against allergic dermatitis, especially dermatitis via delayed allergic reaction, and have completed the present invention.

The compound of the formula (I) is a compound known per se, and can be produced, for example, by the method described in JP-B-4-50301. Compounds of formula (I) have one asymmetric carbon atom and R
It can exist in the form of -form, S-form or mixtures thereof (racemic), of which the R-form is preferred.

The pharmaceutically acceptable salts of the compounds of the formula (I) include, for example, alkali metal salts or alkaline earth metal salts such as sodium, potassium, magnesium and calcium salts; ammonium salts. A salt with an organic amine such as ethylamine, di- or triethylamine, di- or tri-ethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, and ethylenediamine.

The compound of formula (I) or a salt thereof is useful as a medicament for the treatment or prevention of dermatitis via delayed-type allergic reaction, in particular, contact dermatitis or atopic dermatitis. It can be administered to blood animals.

The administration can be carried out orally, parenterally or topically, and the dose is not particularly limited. The severity of the symptoms, age, weight, administration route, sex, judgment of a doctor, etc. Can vary over a wide range, but for adults it is usually 0.1-10 mg / kg / day,
It is convenient to administer preferably 0.5 to 7.5 mg / kg / day, more preferably 1 to 5 mg / kg / day once or several times a day.

The compound of the formula (I) or a salt thereof is administered depending on the administration route, for example, an oral administration preparation such as fine granules, granules, capsules, tablets, liquids and syrups; Parenteral preparations such as infusions, drops and suppositories; and topical (transdermal or transmucosal) preparations such as ointments, creams, cataplasms and sprays.

Formulation of the compound of formula (I) or a salt thereof
It can be carried out by formulating the compound of the formula (I) or a salt thereof with an additive according to a conventional method.

Examples of additives that can be used in the preparation of oral administration preparations include starches such as corn starch and potato starch, lactose, sucrose, glucose, mannitol and other sugars, calcium carbonate, synthetic aluminum silicate and the like. Salts, paraffin, wax, fats and oils such as higher fatty acids, excipients such as cellulose; starches such as corn starch, potato starch, lactose, sucrose, glucose, saccharides such as mannitol, dextrin,
Natural substances such as gum arabic, tragacanth, carrageenin, sodium alginate, and gelatin, cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose; and synthetic polymers such as polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol Disintegrators such as starches, low-substituted hydroxypropylcellulose and crystalline cellulose; lubricants such as magnesium stearate, talc and synthetic aluminum silicate; coloring agents such as various food colorings; Artificial sweeteners, acidulants such as organic acids,
Flavoring and flavoring agents such as mint oil; solubilizing agents such as various surfactants; stabilizers such as benzoic acid esters (in the case of liquids)
And the like.

Water is preferably used as a solvent in the case of a liquid preparation or an injection, and a buffer adjusted to an appropriate pH can be used if necessary, and various amino acids, saccharides, salts and the like can be used. Isotonic agents, solubilizers such as alcohols, polyethylene glycol, sodium lauryl sulfate, and polysorbate can be added.

Transdermal preparations such as ointments and creams include, as bases, emulsifiable / water-soluble bases such as hydrophilic ointment, water-absorbing ointment, lanolin hydrolyzate, hydrophilic petrolatum, lanolin, polyethylene glycol and the like; paraffin,
Oily bases such as simple ointment and white ointment can be used, and besides preservatives such as paraoxybenzoates, humectants such as glycerin, propylene glycol, butylene glycol, and surfactants Can be.

Also, a poultice comprising a compound of the formula (I) or a salt thereof supported on a film made of various materials may be suitably used.

Hereinafter, the present invention will be described in more detail with reference to Test Examples and Examples.

[0023]

EXAMPLES Test Example 1: Inhibitory effect on experimental contact dermatitis in mice Ramatroban was orally administered to mice using prednisolone and seratrodast as control agents, and the effect on experimental contact dermatitis was examined.

[Experimental animals] Slc: ddy male mice (SPF) (11 weeks old, weight 30-35)
g, Japan SLC Co., Ltd.) [Test drug] Ramatroban, control drug prednisolone (Wako Pure Chemical Industries, Ltd.) and 7- (3,5,6-trimethyl-1,
4-benzoquinone-2-yl) -7-phenylheptanoic acid (general name seratrodast; JP-A-63-101322)
In each of the publications and compound No. 5), those suspended in a 0.5% aqueous solution of methylcellulose (MC) were used. As the antigen, an ethanol solution and an olive oil solution of picryl chloride (Katayama Chemical Industry Co., Ltd.) were used.

[Experimental method] Asherson, GL and Ptak, W
According to the method described in (Immunology, 15, 405 (1968)), the abdomen of a shaved mouse was sensitized by applying 0.1 ml of a 7% picryl chloride / ethanol solution to the abdomen on the previous day, and 1%
One drop (about 15 μl) of a picryl chloride / olive oil solution was applied to the front and back of the left and right ears with a syringe to initiate the reaction. Twenty-four hours after the inoculation, the thickness of the ear was measured using the Upright Dial Gauge (Peacoc
k, Ozaki Seisakusho), and the edema rate was calculated from the difference in thickness before and after the induction.

The amount of the test drug is 10 m 1 hour before the induction of the reaction.
Oral administration was performed at 1 / kg. The mice were fasted for at least 18 hours before the administration of the test drug.

[Results] Ramatroban significantly suppressed edema at all doses. Significant suppression was also observed in the prednisolone-administered group and the seratrodast-administered group (Table 1).
reference).

[0028]

[Table 1]

Test Example 2: Inhibitory effect on experimental contact dermatitis in mice [Ramatroban topical administration test] Ramatroban was locally administered to mice, and the effect on experimental contact dermatitis was examined.

[Experimental animals] Slc: ddy male mice (SPF) (11 weeks old, weight 36-41)
g, Japan SLC, Inc.) [Test drug] Ramatroban was used as a 5% ethanol solution. The antigen is picryl chloride (Katayama Chemical Industry Co., Ltd.)
Were used in ethanol solution and olive oil solution.

[Experimental method] The abdomen of the mouse shaved the day before was sensitized by applying 0.1 ml of a 7% picryl chloride / ethanol solution to the abdomen. One drop on the front and back with a syringe (about 15 μl)
The reaction was initiated by application. Twenty-four hours after the induction, the thickness of the ear was measured using an Upright Dial Gauge (Peacock, Ozaki Seisakusho), and the edema rate was calculated from the difference in thickness before and after the induction.

The test drug was applied topically (ear drops) 10 μl twice, one hour before and 3 hours after the reaction.

[Results] Ramatroban significantly suppressed edema (see Table 2).

[0034]

[Table 2]

Test Example 3: Inhibitory Effect on Mouse Delayed Footpad Response Ramatroban was orally administered to mice using prednisolone and ketotifen as control drugs, and the effect on delayed footpad response was examined.

[Experimental animals] Crj: CD-1 (ICR) male mice (SPF) (5 weeks old, body weight 28-36 g, Charles River Japan Co., Ltd.) [Test drugs] Ramatroban, prednisolone (Wako Pure Chemical Industries, Ltd.) Kogyo Co., Ltd.) and ketotifen (Sigma) are all 0.5
% Sheep erythrocytes (hereinafter referred to as SRB) as an antigen.
C (abbreviated as Denka Seiken Co., Ltd.) was washed with physiological saline three times and then used as a suspension in physiological saline.

[Experimental Method] Two mice were placed in the left hind footpad
It was sensitized by injection of 25 μl of × 10 ⁷ SRBCs. Four days later, 2 × 10 ⁸ SRBCs (25 μl) were injected subcutaneously into the right hind footpad of the sensitized mice excluding the negative control group to induce a reaction.

Twenty-four hours after induction, the thickness of the right and left hind footpads
The thickness was measured using a thickness gauge (Ozaki Seisakusho), and the difference between the left and right was defined as swelling of the footpad.

Each of the test drugs was orally administered at a dose of 10 ml / kg twice in total, one hour before the induction of the reaction and 16 hours after the induction of the reaction.

[Results] No significant inhibition was observed in the ramatroban 10 mg / kg administration group and the ketotifen administration group as compared with the positive control group, but the ramatroban 30 mg / kg was observed.
Significant suppression was observed in the kg administration group and the prednisolone 10 mg / kg administration group (see Table 3).

[0041]

[Table 3]

Test Example 4: Inhibitory Effect on Mouse Delayed Footpad Reaction (2) Ramatroban was orally administered to mice using prednisolone as a control drug, and the effect on delayed footpad reaction was examined.

[Experimental animals] ddy male mice (body weight: 18 to 25 g, Japan SLC, Inc.) [Test drugs] Ramatroban was suspended in a 0.5% sodium carboxymethylcellulose (CMC-Na) aqueous solution. Using. Prednisolone (ac
etate) (Takeda Pharmaceutical Co., Ltd.). The antigen used was one obtained by washing sheep erythrocytes (hereinafter abbreviated as SRBC, oriental serum) and then diluting with Hanks' solution.

[Experimental Method] S was placed subcutaneously on the left hind footpad of a mouse.
It was sensitized by injection of 40 μl of RBC 2.5 × 10 ⁸ cells / ml. Five days later, SRBC (2.5 × 1) was subcutaneously injected into the right hind footpad.
( ⁰⁹ / ml 40 μl) to induce the reaction. 24
After hours, hind limb volume was measured with a plethysmometer (UNICOM), and the difference between the left and right hind limb volumes was defined as edema.

The test drug was orally administered at a dose of 10 ml / kg, twice each two hours before and 16 hours after the induction of the reaction.

[Results] Ramatroban significantly inhibited hind limb edema at a dose of 10 mg / kg, and prednisolone showed a decrease of 5 mg / kg.
It was significantly suppressed at mg / kg (see Table 4).

[0047]

[Table 4]

Claims (2)

[Claims] (1) Formula (1) Wherein 3- (4-fluorophenylsulfonamido) -1,2,3,4-tetrahydro-9-carbazolepropionic acid or a pharmaceutically acceptable salt thereof represented by Agent for treating dermatitis through delayed allergic reaction. 2. The treatment agent according to claim 1, wherein the dermatitis mediated by delayed allergic reaction is allergic contact dermatitis or atopic dermatitis.