JPH0853355A - Il-5 production-inhibiting agent - Google Patents

Abstract

PURPOSE:To obtain the subject agent containing a specific erythromycin A derivative as an active ingredient, excellent in the interleukin-5 production- inhibiting action, and useful for the therapy of various allergic diseases such as bronchial asthma, allergic rhinitis, and atopic dermatitis. CONSTITUTION:This agent contains 3-0-(2,4-difluorophenyl)aminocarbonyl-5-0- desosaminyl-6-0-methylerythronolide A 11, 12-cyclic carbonate of formula I or its acid adduct salt as an active ingredient. The compound of formula I is obtained e.g. by reacting a compound of formula II with a compound of the formula: R<1>X (R<1> is an acryl; X is a 1ogen), converting the obtained compound of formula III into a compound of formula IV with a reagent such as phosgene dimer in the presence of a base such as pyridine, reacting the compound of formula IV with 2,4-difluorophenylisocyanate, and subsequently removing the protecting group from the 2'-position of the produced compound.

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 suppressor is considered to be useful for allergic diseases (bronchial asthma, allergic rhinitis, atopic dermatitis, drug allergy, eosinophilic pneumonia).

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 action (The 5th Annual Meeting of the Japanese Society of Allergology Spring Meeting)
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- (2,4-difluorophenyl) aminocarbonyl-5-O-desosaminyl-6.
An IL-5 production inhibitor comprising -O-methylerythronolide A 11,12-cyclic carbonate or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.

Examples of the pharmaceutically acceptable acid addition salt in the present invention include acetate, propionate, butyrate,
Formate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate Salt, ethane sulfonate, 2-hydroxyethane sulfonate,
Benzenesulfonate, paratoluenesulfonate, lauryl sulfate, malate, aspartate, glutamate, adipate, cystine salt, hydrochloride, hydrobromide, phosphate, sulfate, iodine Hydrochloride, nicotinate, oxalate, picrate, thiocyanate,
Examples thereof include undecanoate, acrylic acid polymer salt, carboxyvinyl polymer salt and the like.

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

[0009]

Embedded image

Step (1): 5-O-desosaminyl-6-
O-methylerythronolide A (a) in an inert solvent,
An acid anhydride represented by the formula R ¹ ₂ O (wherein R ¹ represents an acyl group) or a formula R ¹ X (wherein R ¹ is the same as the above, and X is an arbitrary halogen atom) A compound represented by the formula (b) (in the formula, R ¹ is the same as the above) can be obtained by reacting an acid halide represented by the formula) with a base at 0 ° C to 30 ° C. . Here, suitable inert solvents include dichloromethane, dichloroethane, acetone,
Pyridine, ethyl acetate, tetrahydrofuran and the like are used. As the acid anhydride or acid halide, acetic acid,
Propionic acid, benzoic acid, anhydrides of pyridinecarboxylic acid and halides are used. As the base, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, triethylamine, pyridine, tributylamine and the like are used.

Step (2); the compound obtained in step (1) is
Formula (c) (wherein R ⁵ is the same as defined above) using a reagent such as phosgene dimer, trichloromethyl chloroformate or phosgene trimer and a base such as pyridine in a suitable inert solvent under ice cooling. A compound represented by can be obtained. Here, the suitable inert solvent is the same as that used in the step (1).

Step (3): The compound obtained in Step (2) is reacted with 2,4-difluorophenylisocyanate in the presence of a base such as pyridine in an inert solvent, followed by heating in a lower alcohol such as methanol. The 2'-position can be deprotected according to to produce the compound of the present invention represented by the formula (d). Here, as the inert solvent, N, N-dimethylformamide, N-methylpiperidone, tetrahydrofuran, acetonitrile, a mixed solvent thereof or the like is used.

The compounds of the present 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, starch, lactose, mannitol, etc.), binders (eg,
Hydroxypropyl cellulose, polyvinylpyrrolidone, etc.), lubricants (eg magnesium stearate,
Talc, etc.), a disintegrating agent (eg, carboxymethyl cellulose calcium, etc.), etc. can be used.

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.

[0015]

INDUSTRIAL APPLICABILITY The compound of the present invention exhibits a strong IL-5 production inhibitory action and is useful as an IL-5 production inhibitor in humans and animals (including farm animals). Therefore, the compound of the present invention is useful for diseases caused by IL-5 production, and various allergic diseases (bronchial asthma, allergic rhinitis,
It is useful for atopic dermatitis, drug allergy, and eosinophilic pneumonia.

[0016]

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

Production Example 3-O- (2,4-difluorophenyl) aminocarbo
Nyl-5-O-desosaminyl-6-O-methylerythro
Nolide A 11,12-of cyclic carbonate
Production (1) 11.78 g (0.02 mol) of 5-O-desosaminyl-6-O-methylerythronolide A was dissolved in 100 ml of acetone, and 2.27 ml of acetic anhydride under ice cooling.
(0.024 mol) was added, and the mixture was stirred at room temperature for 6 hours. Acetone was distilled off under reduced pressure, and the residue was extracted with dichloromethane. The dichloromethane layer was washed successively with saturated sodium hydrogen carbonate solution and then saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ether-n-hexane to give a white powder of 2'-O-acetyl-5-O-desosaminyl-6-O.
12.17 g of methyl erythronolide A were obtained. mp; 158~160 ℃ Mass (FAB) m / z; 632 [MH] + 1 H-NMR (200MHz, CDCl 3) δ (pp
m); 2.07 (3H, s), 2.26 (6H, s),
2.95 (3H, s), 3.26 (1H, s), 3.9
6 (1H, s) IR (KBr, cm ^-1 ); 3469,1750,173
3,1693.

(2) 50 g (8) of the compound obtained in the above (1)
4.8 mmol) was dissolved in 500 ml of dichloromethane, and 102.6 ml (1.27 mol) of pyridine under ice cooling.
Was added. At the same temperature, 40 ml of a solution of 25.4 ml (212 mmol) of trichloromethyl chloroformate in dichloromethane was added dropwise, and the mixture was stirred for 5.5 hours. Cold water and saturated sodium hydrogen carbonate solution were added little by little to the reaction solution, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed successively with saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; acetone: n-hexane: triethylamine = 6 to 10: 1).
0: 0.2) to give 2'-O-acetyl-5-O-desosaminyl-6-O- as a white foam.
41.93 g of methyl erythronolide A 11,12-cyclic carbonate was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ (pp
m); 2.05 (3H, s), 2.25 (6H, s),
2.92 (3H, s), 4.57 (1H, d, J = 9H
z), 4.74 (1H, s), 4.75 (1H, dd,
J = 10 Hz, 9 Hz), 5.13 (1 H, dd, J =
12 Hz, 2 Hz) (3) 450 mg (0.68) of the compound obtained in (2) above
5 mmol) in 10 ml of tetrahydrofuran,
2,4-difluorophenyl isocyanate 0.41m
1 (3.425 mmol) and pyridine 0.08 ml
(1.028 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine, concentrated, and then purified by silica gel column chromatography (eluting solvent: chloroform: methanol: 25% aqueous ammonia = 20: 1: 0.1). The obtained compound was dissolved in 5 ml of methanol and heated under reflux for 5 hours. Methanol was distilled off under reduced pressure to obtain 40 mg of the title compound as a white foamy substance. ¹ H-NMR (200 MHz, CDCl ₃ ) δ (pp
m); 1.30 (3H, s), 2.22 (6H, s),
3.03 (3H, s), 4.03 (1H, d, J = 7H
z), 4.76 (1H, s), 5.02 (1H, d, J
= 9 Hz), 6.82 to 6.95 (2H), 7.18
(1H, brs), 8.02 to 8.15 (1H).

Example 10 g of the compound obtained in Production Example, 550 g of lactose, 300 g of corn starch, 100 g of calcium carboxymethyl cellulose 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).

[0023]

[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- (2,4-difluorophenyl)
IL-5 production inhibitor containing aminocarbonyl-5-O-desosaminyl-6-O-methylerythronolide A 11,12-cyclic carbonate or a pharmaceutically acceptable acid addition salt thereof as an active ingredient