JPH08175991A - Agent for treating allergic dermatitis - Google Patents

Abstract

PURPOSE: To obtain a treating agent for warm-blooded animals, containing a specific carbazole ring compound as an active ingredient, and useful for treating and preventing atopic dermatitis, eczema, urticaria, skin pruritus, contact dermatitis, prurigo, etc. CONSTITUTION: This treating agent contains 3-(4-fluorophenylsulfonamido)-1,2,3,4- tetrahydro-9-carbazolepropuionic acid (preferably R-type) or its salt such as the alkali (alkaline earth) metal salt, a-monium salt or organic amine salt as an active ingredient. The compound is usually orally, parenterally, percutaneously or transmucosally administered at a dose of 0.5-10mg/kg/day (preferably 1-5mg/kg/day) in one to several portions a day.

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-
It relates to a therapeutic agent for allergic dermatitis, which comprises carbazolepropionic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

The following general formulas, including the compounds of the above formula (I),

[0005]

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In the formula, R ¹ is hydrogen, halogen or C _1- .
Represents C ₄ -alkyl; R ² represents halogen, trifluoromethyl, trifluoromethoxy or phenyl which may be mono- or disubstituted by C ₁ -C ₄ -alkyl; x represents 1 or 2; y Represents 0 or 1, and the cycloalkano [1,2-b] indolesulfonamide or salt thereof represented by
egation) inhibitory action and thromboxane A ₂ antagonism (ant
igonizing thromboxane A ₂ : TXA ₂ ) action, and is known to be useful as a treatment for thrombosis, thromboembolism, ischemia, or as an anti-asthma agent and anti-allergic agent (Japanese Patent Publication No. 4-50301). (See the official gazette).

Further, (3R) -3- (4) of the above formula (I)
-Fluorophenylsulfonamide) -1,2,3,4
-Tetrahydro-9-carbazole propionic acid (BA
Yu 3405) binds to TXA ₂ receptor of bronchial smooth muscle, U-466 is mimetics of TXA ₂
19 (9,11-methanoepoxy-pros
It has been reported to suppress the contraction of human and guinea pig bronchial muscles induced by taglandin H ₂ ) or prostaglandin D ₂ [Br. J.
Pharmacol. , 104, 1991, 585
~ 590 and 591-595]. Furthermore, by pre-treating guinea pigs with BAY u 3405, U-
It has also been reported to inhibit 46619-induced airway contraction and improve lung compliance [Br.
J. Pharmacol. , 104, 1991, 5
96-602]. BAY u 3405 was also tested in the guinea pig experimental allergic rhinitis model using TXA.
It is also reported to have an effect of improving various symptoms in which the involvement of ₂ is suspected. [March 1993 Otolaryngology Immunoallergic Society, etc.].

Thus, the compound of formula (I) (BA
Y u 3405) is antagonize TXA _2, asthma TXA ₂ is involved, to be effective against allergic symptoms such as rhinitis is well known.

[0009] By the way, TXA ₂ is a substance released from mast cells and inflammatory cells as a result of allergic reaction, and it is known that TXA ₂ is a predominant chemical mediator in allergic reactions involving bronchoconstriction such as asthma [ Eur. J. Pharmacol. , Volume 117 (1
985) pp. 373-375; Thorax, Vol. 41 (1986) 955-959, etc.], and is considered to be not an important chemical mediator for the development of allergic dermatitis [Prostalandins, Le.
ukotriens and Essential A
Cids, Volume 35 (1989) 125-130
page]. Then, in the allergic dermatitis, TXA ₂ and prostaglandin histamine than the chemical mediators [Eur. J. Pharmaco
l. , 117 (1985) pp. 337-345].
Also, lymphokines derived from lymphocytes are considered to be important.

The present inventors have previously proposed that the compound is a compound of formula (I) (BAY) which was previously considered to be a TXA ₂ antagonistic inhibitor and was therefore considered to have no effect on allergic dermatitis.
u3405) was surprisingly found to be effective against allergic dermatitis, and completed the present invention.

The compound of formula (I) is a compound known per se, and can be produced, for example, by the method described in Japanese Patent Publication No. 4-50301. The compounds of formula (I) have one asymmetric carbon atom and R
It can exist in the form of -form, S-form or a mixture thereof (racemic form), among which the R-form is preferred.

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

The compound of the formula (I) or a salt thereof is used for treating or preventing allergic dermatitis, more specifically, atopic dermatitis, eczema, dermatitis, urticaria, pruritus dermatitis, contact. It can be administered to humans or warm-blooded animals other than humans as a drug for treating or preventing dermatitis, prurigo and the like.

The administration can be carried out orally, parenterally or locally, and the dose thereof is not particularly limited, and the severity of symptoms, age, body weight, administration route, sex, judgment of a doctor, etc. It can be varied over a wide range depending on, but in the case of adults, it is usually 0.5-10 mg / kg / day,
Preferably, 1 to 5 mg / kg / day is conveniently administered once or several times a day.

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

Formulation of a compound of formula (I) or a salt thereof comprises
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 production of orally administered preparations include starches such as corn starch and potato starch, sugars such as lactose, sucrose, glucose and mannitol, inorganic substances such as calcium carbonate and synthetic aluminum silicate. Excipients such as salts, paraffins, waxes, fats and oils such as higher fatty acids, and celluloses; starches such as corn starch and potato starch; sugars such as lactose, sucrose, glucose and mannitol; dextrins;
Natural substances such as gum arabic, tragacanth, carrageenin, sodium alginate and gelatin, cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose, synthetic polymers such as polyethylene glycol, polyvinylpyrrolidone and polyvinyl alcohol. Binders; starches, low-substituted hydroxypropyl cellulose, crystalline cellulose, and other disintegrators; magnesium stearate, talc, synthetic aluminum silicate, and other lubricants; various food dyes and other coloring agents; Artificial sweeteners, acidulants such as organic acids,
Flavoring agents such as peppermint oil; solubilizing agents such as various surfactants; stabilizers such as benzoic acid esters (in the case of liquid preparations)
Etc.

Water is preferably used as a solvent in the case of a liquid preparation or an injectable preparation, and if necessary, a buffer solution adjusted to an appropriate pH may be used, and various amino acids, sugars, salts and the like may be used. A tonicity agent and a solubilizing agent such as alcohols, polyethylene glycol, sodium lauryl sulfate, and polysorbate can be added.

In the percutaneous preparations such as ointments and creams, as its base, hydrophilic ointment, water-absorbing ointment, lanolin hydrolyzate, hydrophilic petrolatum, lanolin, water-soluble bases such as polyethylene glycol, and petrolatum, paraffin,
An oily base such as a single ointment or a white ointment can be used, and a preservative such as paraoxybenzoic acid esters, a moisturizer such as glycerin, propylene glycol, butylene glycol, and a surfactant, etc. should be added. You can

Also, poultices prepared by supporting the compound of formula (I) or a salt thereof on a film made of various materials can be preferably used.

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

[0022]

EXAMPLES BAY u 3405 has the formula (I) above.
Means a compound.

Test Example 1 : Inhibitory effect on biphasic allergic skin reaction in mice Balb / c mice were passively sensitized by intravenous administration of 1 ml of mouse anti-dinitrophenol monoclonal IgE antibody. After 24 hours, 25 μl of 0.15% dinitrofluorobenzene was applied to the front and back of both auricles of the mouse to induce the reaction. Ear thickness was measured using a dial thickness gauge before, 1 hour and 24 hours after the dinitrofluorobenzene challenge.
The results were expressed as the percentage increase in ear thickness after challenge 1 and 24 hours after the dinitrofluorobenzene challenge value. 1,10 mg / kg BAY u
3405 was administered orally 1 hour before antigen challenge. As a control drug, 2 mg / kg of ketotifen and 10
Prednisolone at mg / kg was administered orally. The results are shown in Table 1. As can be seen from Table-1, BAY u 3
405 1 and 10 mg / kg, ketotifen 2 m
g / kg and 10 mg / kg of prednisolone significantly suppressed the increase in ear thickness 1 hour after antigen challenge.
On the other hand, as for the ear swelling 24 hours after the challenge, B
10 mg / kg of AY u 3405 and 10 mg / kg of prednisolone showed a significant inhibitory effect. These results show that BAY u 3405 suppresses both immediate and delayed allergic skin reactions.

Table 2 shows toxicity data of BAY u 3405.

[0025]

[Table 1]

[0026]

[Table 2]

Formulation Example 1 : Capsule 100 g of finely ground compound of formula (I) 250 g of corn starch, 260 g of lactose and microcrystalline cellulose 216
g with polyvinyl pyrrolidone 25,
It was granulated with an aqueous solution containing 20 g and then dried. The granulate was screened and mixed with 4 g magnesium stearate. This mixture was filled in a capsule so as to contain 425 mg to prepare a capsule containing 50 mg of the drug per capsule.

Formulation Example 2 : Tablets The granulate produced as in Example 1 was screened and mixed with 4 g of magnesium stearate. The mixture was compressed into tablets weighing 425 mg having a diameter of 11 mm.

Formulation Example 3 : Fine Granules 50 g of finely ground compound of formula (I) 450 g D-mannitol, 363 g lactose and 100 g microcrystalline cellulose.
And the mixture was granulated with an aqueous solution containing 35 g of hydroxypropyl cellulose and then dried. The granules were screened and the coarse granules were crushed and mixed again. Further, it was mixed with 2 g of light anhydrous silicic acid to produce a fine granule.

Formulation Example 4 : Dry syrup formulation White sugar 94 obtained by pulverizing 50 g of finely pulverized compound of formula (I)
0 g, tragacanth powder 3 g, anhydrous citric acid 2 g and sodium citrate 3 g were mixed, and this mixture was granulated with an aqueous solution containing 3 g of hydroxypropyl cellulose and then dried. The granules were sieved and the coarse granules were crushed and mixed again to produce a dry syrup.

Formulation Example 5 : Injectable agent To a suitable amount of water for injection, 24 g of 0.1N sodium hydroxide, 1 g of sodium citrate and 9 g of sodium chloride were added and dissolved, and further 1 g of the compound of the formula (I) was dissolved. Next, the pH is adjusted to 7.5 by adding about 1.3 g of 1N hydrochloric acid, and the volume is adjusted to 1 liter with water for injection. This aqueous solution was sterilized by filtration through a membrane filter and then filled in an ampoule to prepare an injection.

Formulation Example 6 : Emulsifying ointment (cream) To 1 g of finely pulverized compound of formula (I), a small amount of Japanese Pharmacopoeia hydrophilic ointment was added to thoroughly grind, and further, Japanese Pharmacopoeia hydrophilic ointment was gradually added to a total amount of 100 g. And kneaded well to obtain an emulsion ointment with uniform quality.

Formulation Example 7 : Ointment To 1 g of the finely pulverized compound of formula (I), a small amount of Japanese Pharmacopoeia white petrolatum was added to thoroughly grind it, and further, Japanese Pharmacopoeia white petrolatum was gradually added to bring the total amount to 100 g. An ointment was produced with equal quality.

Claims (1)

[Claims] (1) Formula (1) 3- (4-fluorophenylsulfonamido) -1,2,3,4-tetrahydro-9-carbazolepropionic acid or a pharmaceutically acceptable salt thereof represented by A therapeutic agent for allergic dermatitis.