JPH08104641A - Agent for suppressing production of il-5 - Google Patents

Abstract

PURPOSE: To obtain a medicine containing an erythromycin derivative, having strong IL-5 production suppressing action and useful for treating various kinds of allergic diseases. CONSTITUTION: This IL-5 production suppressor contains 3-O-(2-nitro-3,4,5,6- tetrafluoro)phenyl-5-O-de sosaminyl-6-O-methylerythronolide A or its acid addition salt as an active ingredient. The compound is further, properly blended with a conventional vehicle, a binder, a lubricant, a disintegrator, etc., and the blend is prepared in oral or parenteral administration form by an ordinary method. The compound is administered at a daily dose of 50-200mg/adult in 2-3 divided portions. The erthromycin A derivative is obtained by reacting 5-O- desosaminyl-6-O-methylerythronolide A in a solvent (e.g. THF) and reacting the compound with pentafluoronitrobenzene in the presence of a base (e.g. NaOH).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an IL-5 production inhibitor containing an erythroma machine A derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Interleukin 5 (IL-5) is known to be an important differentiation and growth factor for eosinophils that promotes allergic inflammation. Therefore, the IL-5 production inhibitor is considered to be useful for various allergic diseases (bronchial asthma, allergic rhinitis, atopic dermatitis, drug allergy, eosinophilic pneumonia, etc.).

Erythromycin is a clinically widely used antibiotic as a therapeutic agent for infectious diseases caused by Gram-positive bacteria, certain Gram-negative bacteria, mycoplasma and the like. Recently, it has been reported that erythromycin and roxithromycin have an IL-5 production inhibitory effect (The 5th Annual Meeting of the Japanese Society of Allergology Spring Clinical Conference,
424 (1993)), these IL-5 production inhibitory effects are not sufficient.

[0004]

An object of the present invention is to provide an excellent drug having a strong IL-5 production inhibitory action.

[0005]

Means for Solving the Problems As a result of various studies on the IL-5 production inhibitory action of the erythromycin A derivative, the present inventors have found that the following erythromycin A derivative has a strong IL-5 production inhibitory action, The present invention has been completed.

The present invention relates to 3-O- (2-nitro-3,4,
An IL-5 production inhibitor containing 5,6-tetrafluoro) phenyl-5-O-desosaminyl-6-O-methylerythronolide A or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

The pharmaceutically acceptable acid addition salts in the present invention include, for example, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate. , Succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluene Sulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, cystine salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinic acid Salts, oxalates, picrates, thiocyanates, undecanoates, acrylic acid polymer salts, carboxyvinyl polymer salts, etc. Rukoto can.

The compound according to the present invention can be produced, for example, as follows.

That is, 5-O-desosaminyl-6-O
-The compound according to the present invention can be produced by dissolving methylerythronolide A in a suitable solvent and reacting it with pentafluoronitrobenzene in the presence of a base. Here, the suitable solvent is acetone, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, dioxane or a mixed solvent thereof. The base is sodium hydride, sodium hydroxide, potassium hydroxide or the like. Reaction temperature is -20 ° C to 50
C., preferably 0 to 25.degree.

The compounds according to the invention can be administered orally or parenterally. The dosage form is tablets, capsules, granules, powders, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulation techniques (for example, It can be manufactured by the method prescribed in the 12th revised Japanese Pharmacopoeia. These dosage forms can be appropriately selected depending on the patient's symptoms, age and the purpose of treatment. In the production of various dosage forms, conventional excipients (eg, crystalline cellulose,
Use of starch, lactose, mannitol, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), lubricants (eg, magnesium stearate, talc, etc.), disintegrating agents (eg, carboxymethylcellulose calcium, etc.), etc. You can

The dose of the compound according to the present invention is 50 to 2000 mg for treating an adult, which is 2 times a day.
~ 3 divided doses are administered. This dose depends on the age of the patient,
The dose can be adjusted according to body weight and symptoms.

[0012]

INDUSTRIAL APPLICABILITY The compound according to the present invention exhibits a strong inhibitory action on IL-5 production, and is effective for humans and animals (including farm animals).
And is useful as an IL-5 production inhibitor. Therefore, the compound according to the present invention is a disease associated with IL-5 production,
For example, it is useful as a therapeutic agent for various allergic diseases.

[0013]

EXAMPLES Next, the present invention will be described in more detail with reference to production examples, examples and test examples. Production Example 3-O- (2-nitro-3,4,5,6-tetrafluor
B) Phenyl-5-O-desosaminyl-6-O-methyl
Preparation of erythronolide A 5-O-desosaminyl-6-O-methylerythronolide A 1.178 g (2 mmol) and pentafluoronitrobenzene 4.02 ml (10 mmol) and 60%
240 mg (6 mmol) of sodium hydride was added to 10 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform: methanol: aqueous ammonia = 19: 1: 0.1) to give 210 mg.
The title compound was obtained.

Mass (FAB) m / z; 783 [M
H] ^{+ 1} H-NMR (200 MHz, CDCl ₃ ) δ (pp
m); 2.25 (6H, s), 3.05 (3H, s).

Example 10 g of the compound obtained in Production Example, 550 g of lactose, 300 g of corn starch, 100 g of carboxymethylcellulose calcium and 30 g of polyvinylpyrrolidone were mixed well, granulated with ethanol by a conventional method, dried and then sized. To this, 10 g of magnesium stearate was added and mixed, and then a tablet of 100 mg was prepared by a conventional method.

Test Example The effect on mouse IL-5 production was examined by the following method (M. Hikida et al., Immunolog.
y Letters, 34, 297-302 (19
92)).

Mouse Th2 clone (D10.G4.1
Cells) were obtained from ATCC. Antigen presenting cell is C
1 × 10 ⁷ splenocytes of 3H / HeN mouse (8 weeks old, female)
50 μm by suspending the cells in 5 ml of RPMI-1640 medium.
The cells were incubated with g / ml of mitomycin C for 30 minutes at 37 ° C., washed 3 times with 50 ml of RPMI-1640 medium, and used. The cell culture medium was RPMI-1640 supplemented with 10% fetal bovine serum, 0.5 U of IL-2 (manufactured by Zenzyme), and 5 × 10 ⁻⁵ M of 2-mercaptoethanol.
Was used. The test compound was dissolved in DMSO and then diluted with cell culture medium to each concentration so that the final concentration of DMSO was 0.1%.

D1 on a 96-well plate (Corning)
0. G4.1 cells 4 × 10 ⁵ cells / ml, MMC
2 × 10 ⁶ cells / ml of treated antigen-presenting cells, 400 μg / ml of conalbumin (manufactured by Sigma) as an antigen,
50 μl / we each of cell culture medium dilutions of test compound
ll added (200 μl / well), 37 ° C 5%
It was cultured for 48 hours in a CO ₂ incubator. After the completion of the culture, the culture supernatant was collected, the cells were centrifuged, and the amount of IL-5 in the supernatant was measured with an IL-5EIA kit manufactured by ENDOGEN. The effect of the test compound was represented by the concentration of the drug that suppresses the IL-5 production amount by 50% (IC ₅₀ value) (Table 1).

[0019]

[Table 1]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication C07H 17/08 B (72) Inventor Tomoyuki 3-24-1 Takada, Toshima-ku, Tokyo Taisho product (72) Inventor Hirokazu Okuhira 5-19-17-206 Koishikawa, Bunkyo-ku, Tokyo

Claims (1)

[Claims] 1. 3-O- (2-nitro-3,4,5,6)
-Tetrafluoro) phenyl-5-O-desosaminyl-
An IL-5 production inhibitor comprising 6-O-methylerythronolide A or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.