WO1997044031A1

WO1997044031A1 - Agent for treating allergic dermatitis

Info

Publication number: WO1997044031A1
Application number: PCT/JP1997/001687
Authority: WO
Inventors: Shuzo Sawada; Takashi Hironaka; Hiroichi Nagai
Original assignee: Bayer Yakuhin, Ltd.
Priority date: 1996-05-21
Filing date: 1997-05-20
Publication date: 1997-11-27
Also published as: AU2790697A; JP2002241282A

Abstract

An agent for treating dermatitis through a delayed type allergic reaction, comprising 3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropionic acid represented by formula (I), or a pharmaceutically acceptable salt thereof as an active ingredient. This agent is useful for curing or preventing allergic dermatitis, such as allergic contact dermatitis or atopic dermatitis.

Description

Details

Agent for treating allergic dermatitis

Technical field

The present invention uses the formula

3- (4-Fluorophenylsulfonamide) represented by C00H- 1,1,2,3,4-tetrahydro-9-potassium rubazolepropionic acid or a pharmaceutically acceptable salt thereof as an active ingredient The present invention relates to a therapeutic agent for dermatitis via delayed allergic reaction, particularly for allergic contact dermatitis or atopic dermatitis.

Background art

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

C00H wherein R ¹ represents hydrogen, halogen or C, -C ₄ -alkyl;, R ² is halogen, trifluoromethyl, trifluoromethoxy or (, ~ (: mono- or disubstituted by ₄ -alkyl) Fe that may be X represents 1 or 2, y represents 0 or 1, and cycloalkano [1,2-b] indolesulfonamide or a salt thereof inhibits platelet aggregation. and Tron Bokisan a 2挂抗_{_{(.antigonizing thromboxane a 2: TXA 2}} ) shows the effect, thrombosis, thromboembolism, treatment of ischemia, or anti-asthmatic agents, and are useful as anti-§ les Energy agent This is known (see Japanese Patent Publication No. 4-50301).

In addition, (3R) —3— (4-fluorophenylsulfonamide) -1,1,2,3,4-tetrahydro-1-9-potassium rubazolepropionic acid of the formula (I) [general name: Ramatroban ); Development number: BAY u 3405] binds to the TXA ₂ receptor in bronchial smooth muscle and is a mimetics of TXA ₂ U—46619 (9,11-one methanoepoxy—prostag 1 andin H ₂ ) or prostaglandin Has been reported to inhibit the contraction of human and guinea pig bronchial muscles induced by carcinoma D2 [Br. J. Pharmacol., 104, 1991, pp. 585-590 and Pp. 591-595]. Furthermore, pretreatment of guinea pigs with ramatroban (BAY u3405) has been reported to suppress U-46619-induced airway constriction and improve lung compliance [Br. J. Phar. ma co 1., 104, 1991, 596-602]. It has also been reported that lamatroban (BAY u3405) has an effect of improving various symptoms suspected of involving TXA _{2 in} a guinea pig experimental allergic rhinitis model [Otolaryngology in March 1993] Family immune allergy Thus, compounds of the formula (I) (ramatroban) is拮pile Ding eight _2, TXA ₂ is well known that there is effect against allergic symptoms such as asthma involved, rhinitis.

Incidentally, TX A ₂ is a substance released from etc. results mast cells or inflammatory cells Arerugi one reaction, it is known that asthma is a dominant chemical mediators in allergic reactions involving bronchoconstriction etc. [Eur. J. Pharmaco., Vol. 117 (1985), pp. 373-375; Thorax, Vol. 41 (1986), pp. 955-959], for allergic unilateral captive inflammation It is not considered to be an important chemical mediator for the onset [Prostaglandins, Leukotriens and Essential Fat Acids, 35 (1989) 125-130]. Then, Oite to allergic skin captive flame, Hisuta Mi emissions than TX A ₂ and prostaglandin as chemical mediators [Eu r. J. Ph a rma co l., The first Vol. 17 (1985) 337～ P. 345] and lymphokines derived from lymphocytes are considered to be important.

Disclosure of the invention

The present inventors have been conventionally Taukaiarufa ₂ competitive inhibitor, therefore, the formula for the § Les Energy dermatitis was thought to have no effect I spoon compound of (I) (ramatroban) However, surprisingly, they have found that they are also effective against allergic skin inflammation, especially skin inflammation 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 Japanese Patent Publication No. 50301/1992. Wear. The compounds of the formula (I) have one asymmetric carbon atom and can be present in the form of the R-form, the S-form or a mixture thereof (racemic), in particular the R-form It is suitable.

The pharmaceutically acceptable salt of the compound of the formula (1) includes, for example, sodium salt, potassium salt, magnesium salt, alkali metal salt such as calcium salt, and alkaline earth metal salt. Ammonium salts; salts with organic amines such as ethylamine, di or triethylamine, di or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, ethylenediamine and the like.

The compound of the formula (I) or a salt thereof is an agent for treating or preventing dermatitis via delayed (or type IV) allergic reaction, in particular, allergic contact dermatitis or atopic dermatitis. Can be administered to humans or warm-blooded animals other than humans.

Administration can be oral, parenteral, or topical, and the dosage is not particularly limited, and depends on the severity of the symptoms, age, weight, route of administration, sex, doctor's judgment, etc. It can vary over a wide range, but for adults, usually 0.1 to 10 mg Zkg gZ, preferably 0.5 to 7.SmgZkgZ, more preferably l Smg / kgZ one or more times It is convenient to administer in divided doses.

Upon administration, the compound of the formula (I) or a salt thereof may be administered depending on the administration route, for example, oral preparations such as fine granules, granules, capsules, tablets, liquids, syrups, etc .; injections, infusions Parenteral preparations such as suppositories, etc .: Can be formulated into topical (transdermal or transmucosal) preparations such as plasters, creams, cataplasms, sprays, etc. Formulation of the compound of the formula (I) or a salt thereof can be carried out by formulating the compound of the formula (I) or a salt thereof together with additives according to a conventional method.

Additives that can be used in the preparation of oral dosage forms include, for example, starches such as corn starch and potato starch, sugars such as lactose, sucrose, glucose, mannitol, inorganic salts such as calcium carbonate, and synthetic aluminum aluminum. , Paraffin, wax, oils and fats such as higher fatty acids, and excipients such as cellulosics; starches such as corn starch and potato starch; sugars such as lactose, sucrose, glucose, mannitol, dextrin, and arabic Natural substances such as rubber, tragacanth, carrageenin, sodium alginate, and gelatin; cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyquinpropylmethylcellulose, and carboxymethylcellulose sodium; Binders such as synthetic polymers such as lenglycol, polyvinylpyrrolidone, and polyvinyl alcohol: disintegrants such as starches, low-substituted hydroxypropylcellulose, and crystalline cellulose; magnesium stearate, talc, synthetic gay Lubricants such as aluminum phosphate;

Coloring agents such as various edible pigments; various natural and artificial sweeteners; acidulants such as organic acids; flavoring and flavoring agents such as heart oil; solubilizing agents such as various surfactants; benzoic acid esters, etc. And stabilizers (in the case of liquids).

Water is preferably used as a solvent when preparing a liquid or injection, and if necessary, a buffer adjusted to an appropriate pH can be used. In addition, various amino acids, sugars, and salts can be used. Etc. and solubilizing agents such as alcohols, polyethylene glycol, sodium lauryl sulfate, polysorbate, etc. Can be blended.

For transdermal preparations such as ointments and creams, the base may be an emulsion or water-soluble base such as hydrophilic ointment, water-absorbing ointment, lanolin hydrolyzate, hydrophilic cerin, lanolin, polyethylene glycol, etc. Oleaginous base such as petrolatum, vaseline, paraffin, simple ointment, white ointment, etc .; preservatives such as paraoxybenzoic acid esters; humectants such as glycerin, propylene glycol, and polyethylene glycol In addition, a surfactant and the like can be blended.

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

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

Example

Test Example 1: Inhibitory effect on experimental contact skin I »inflammation in mice

Ramatroban was orally administered to mice using prednisolone, sera trodust, and domitroban as control drugs, and the effect on experimental contact dermatitis was examined.

[Experimental animals]

Slc: ddy male mouse (SPF) (11 weeks old, weight 30-35g, Japan SLC, Inc.)

[Test drug]

Ramatroban, control prednisolone, seratrodast (AA-2414) and domitroban (S-1452) were all used in a 0.5% aqueous solution of methylcellulose (MC). Antigens include picryl chloride (Katayama Chemical Co., Ltd.) in ethanol and olive oil. Was used.

[experimental method]

According to the method of Asherson, GL and Pta W (Immunology, 15, 405 (1968)), the abdomen of the shaved mouse was sensitized by applying 7% picryl chloride in ethanol solution 0.1 ml to the abdomen the day before. Work 7 states that a drop of 1% picryl chloride oil solution (approx. 15/1) 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 an Upright Dial Gauge (Peacock, Ozaki Seisakusho), and the edema rate was calculated from the difference in thickness before and after the inoculation.

One hour before the induction of the reaction, the test drug was orally administered at a volume of 1 Om1Zkg. The mice were fasted for at least 18 hours before the administration of the test drug.

[Result]

Ramatroban significantly reduced edema at both doses. Significant suppression was also observed in the prednisolone-treated group, which was a positive control. Furthermore, Tron Bokisan A ₂ receptor antagonist is a canceller Torodasuto administered group and Dominion Toroba also significantly suppressed in the emission administration group was observed (see Table one 1).

These results, thromboxane A ₂ receptor antagonist is a shall be suggested to exhibit a common effect on the inhibition of skin «flame through the delayed allele formic first reaction.

Group dose Number of animals Edema rate (%) Inhibition rate

(mg / kg) (average soil S.E.)

Contoronore 10 29.0 + 4.8

(0.5% MC)

10 10 17.1 + 1.5 * 41.0 Ramat ί3 Knob 30 10 10.9 ± 1.2 ** 62.4

100 10 10.5 + 1.6 ** 63.8 Pre-dnisolone 50 10 6.6 + 1.4 ## 77.2 Sera torodast 30 10 10.1 Sat 1.2 ## 65.2 Dmit mouth pan 60 10 17.0 + 1. 41.4

% p 0.05, ** p 0.01 vs control (Dunnett's test),

## P 0.01 vs control (Aspin-Welch test) Test example 2: Suppressive effect on experimental contact dermatitis in mice [Ramatroban topical administration test]

Ramatroban was administered topically to mice, and its effect on experimental contact dermatitis was examined. [Experimental animals]

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

[Experimental method] 7% picryl chloride in ethanol Sensitize by applying 1 ml, and sensitize 7 A 1% picryl chloride / olive oil solution is applied to the left and right ears with 1 syringe (approximately 15 βΐ) to induce a reaction. I let it. Twenty-four hours after the challenge, 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 challenge.

The test drug was topically applied (ear drops) twice, 1 hour before and 3 hours after the reaction.

[Result]

Ramatroban significantly reduced edema (see Table 1-2).

Table 1 2

** p <0.01 (Student's st— test) Test Example 3: Inhibitory effect on delayed mouse foot type response

Ramatroban was orally administered to mice using prednisolone and ketotiphan as control drugs, and the effect on delayed foot reaction was examined.

[Experimental animals]

Crj: CD-I (ICR) male mouse (SPF) (5 weeks old, body weight 28-36 g, Charles Riva Japan Co., Ltd.)

[Test drug]

Ramatroban, prednisolone (Wako Pure Chemical Industries, Ltd.), and ketotiphan (Sigraa) are all suspended in 0.5% methylcellulose (MC) aqueous solution. The antigen used was a suspension of sheep erythrocytes (abbreviated as SRBC, Denka Seiken Co., Ltd.) washed with physiological saline three times and then suspended in physiological saline. .

[experimental method]

In the left hind leg foot of the mouse 2 <10 ⁷ 31¾8. 25 1 was injected to sensitize. 4 After that, 2 × 10 ⁸ SRBC 25〃1 were injected subcutaneously into the right hind limb of the sensitized mice excluding the negative control group to elicit a reaction.

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

Each dose of the test drug was orally administered at a dose of 10 ml / Zkg, 1 hour before and 16 hours after the induction of the reaction.

[Result]

No significant suppression was observed in the ramatroban 10 mg / kg group and the ketotifen group compared with the positive control group, but significant suppression was observed in the ramatroban 30 mg / kg group and prednisolone 1 Omg / kg group. Was observed (see Table 13).

Table 1 3

** p <0.01 vs negative control (Dunnett's test);

## p <0.01 vs Positive control (Dunnett 's test) Test example 4: Inhibitory effect on mouse delayed-type foot 醮 response

Ramatroban was orally administered to mice using blednisolone as a control drug, and the effect on delayed foot response was examined.

[Experimental animals]

ddy male mouse (body weight: 18-25 g, Japan SLC, Inc.) [Test drug]

Ramatroban used was suspended in a 0.5% sodium carboxymethylcellulose (CMC-Na) aqueous solution. As a control drug, an aqueous suspension of prednisolone (acetate) (Takeda Pharmaceutical Co., Ltd.) was used. The antigen used was one obtained by washing shed red blood cells (hereinafter, abbreviated as SRBC, oriental serum) and then diluting with Hanks' solution. [experimental method]

The mice were sensitized by subcutaneously injecting SRBC 2.5 × 10 ⁸ cells / ml 40〃1 into the left hind leg. After the 5th, SRBC (2.5 x 1 0 ⁹ cells / ml 40 ^ 1) were injected to elicit the response. Twenty-four hours later, hind limb volume was measured with a plethysmometer (UNICOM), and the difference between the left and right hind limb volumes was defined as edema.

Each dose of the test drug was orally administered at a dose of 10 m1 Zkg, 2 times before and 16 hours after the induction of the reaction.

[Result]

Ramatroban significantly inhibited hind limb edema at a dose of 1 OmgZkg, and prednisolone significantly inhibited it at 5 mg / kg (see Table 14).

Table 1 4

* p <0.05, ** pku 0 · 01 vs contronore (Dunnett's test)

Claims

The scope of the claims

1 set

3- (4-fluorophenylsulfonamide) represented by C00H-11,2,3,4-tetrahydro 9-potassium rubazolepropionic acid or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic agent for dermatitis mediated by 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.

3. A method for treating dermatitis via delayed allergic reaction, which comprises administering to a patient a compound of the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

4. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the treatment of dermatitis via delayed allergic reactions c.

5. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating captive inflammation via delayed allergic reactions.