JP2000351792A - Fifteen-membered macrolide compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new 15-membered macrolide antibiotic compound that shows antimicrobial activity against not only erythromycin-sensitive bacteria, but also against erythromycin-resistant bacteria. SOLUTION: This is a 15-membered ring macrolide represented by formula I (R1 is H, a 1-5C alkyl; R2 is pyridyl, pyrazinyl, thiazolyl; X is formula II) or its pharmaceutically acceptable salt, typically, 3-O-(2-pyridyl)-acetyl-5-O- desosaminyl-9-deoxo-9a-aza-9a-methyl-9a-homoerythronolide A. This compound is prepared by dissolving 2'-O-acetyl-5-O-desosaminyl-9-deoxo-9a-aza-9a-methyl-9a- homoerythnolide A in dichloromethane, adding 2-pyridyl acetate hydrochloride and 1-[3-(dimethylamino)propyl]-3-ethyl-carbodimide hydrochloride and 4- dimethylaminopyridine to the solution in order and stirring the resultant mixture at room temperature for 0.5 hour.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a 15-membered macrolide compound of an antibiotic.

[0002]

2. Description of the Related Art Erythromycin is a macrolide antibiotic widely used as a remedy for infectious diseases caused by gram-positive bacteria, mycoplasma and the like. However, erythromycin has the drawback that it is easily decomposed by acid in the stomach because it is unstable to acid, and its pharmacokinetics is not constant. Many derivatives have been investigated for the purpose of improving the instability to this acid. For example, it has been reported that a 6-O-methylerythromycin A derivative (U.S. Pat. No. 431803) has improved stability against acids and has better in vivo antibacterial activity upon oral administration than erythromycin. Furthermore, there is a report on an erythromycin 3-position acyl derivative aimed at expanding the antibacterial spectrum in addition to acid stability (US Pat. No. 4,328,334).

A 15-membered ring macrolide compound is reported in US Pat. No. 5,631,354.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a new antibiotic having antibacterial activity not only against conventional erythromycin-sensitive bacteria but also against erythromycin-resistant bacteria.

[0005]

The present inventors have conducted various studies on the antibacterial activity of erythromycin derivatives.
The inventors have found that certain 3-position ester derivatives among the 5-membered ring macrolide compounds have antibacterial activity against erythromycin-resistant bacteria, and completed the present invention. The present invention uses the formula

[0006]

Embedded image [Wherein, R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R ² represents a pyridyl group, a pyrazinyl group, or a thiazolyl group;

[0007]

Embedded image Or expression

[0008]

Embedded image Is shown. Or a pharmaceutically acceptable salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the number of carbon atoms is 1-
The alkyl group 5 is a methyl group, an ethyl group, a propyl group, a butyl group or a pentyl group. Pharmaceutically acceptable salts refer to salts used in chemotherapy and prevention of bacterial infections. They include, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid,
Tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid,
P-Toluenesulfonic acid, lauryl sulfate, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picrin Examples thereof include salts with acids such as acids, thiocyanic acid, undecanoic acid, acrylic acid polymers and carboxyvinyl polymers.

The compounds of the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules,
Powders, troches, ointments, suspensions, suppositories, injections and the like, which can be produced by conventional formulation techniques. The dosage is 10 times daily for treating adults.
0 to 1000 mg, which can be administered 2-3 times a day. This dosage can be appropriately increased or decreased depending on the age, weight and condition of the patient.

[0011]

The compound of the present invention has antibacterial activity against erythromycin-resistant bacteria as well as erythromycin-sensitive bacteria. Accordingly, the compounds of the present invention are useful as antimicrobial agents for the treatment of bacterial infections in humans and animals (including farm animals).

[0012]

Next, the present invention will be described in more detail with reference to examples. Example 1 3-O- (2-pyridyl) acetyl-5-O-desosaminyl-9-deoxo-9a-aza-9a-methyl-9a
-Production of homoerythronolide A (1) 2'-O-acetyl-5-O-desosaminyl-9-deoxo-9a-aza-9a-methyl-9a-homoerythronolide A0 described in U.S. Pat. No. 5,631,354. 0.7 g was dissolved in 7 ml of dichloromethane, and 2-pyridylacetic acid hydrochloride was added.
385 mg, 1- [3- (dimethylamino) propyl] -3
-Ethylcarbodiimide hydrochloride (425 mg) and 4-dimethylaminopyridine (135 mg) were sequentially added, and the mixture was stirred at room temperature for 0.5 hour. Dichloromethane is distilled off under reduced pressure.
A 2N aqueous sodium hydroxide solution and water were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of ammonium chloride and then with a saturated saline solution, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure and 2'-
O-acetyl-3-O- (2-pyridyl) acetyl-5
-O-desosaminyl-9-deoxo-9a-aza-9a
0.81 g of -methyl-9a-homoerythronolide A was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 2.08 (3H, s, 2′-OCO
CH ₃ ) (2) 0.81 g of the compound obtained in the above (1) was added to methanol 10m
and stirred at room temperature for 2 days. Under reduced pressure, methanol was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 20: 1: 0.1) to obtain 0.54 g of the title compound. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 2.29 (6H, s, 3′-N (C
H ₃ ) ₂ ), 2.36 (3H, s, 9a-NCH ₃ ), 3.92 & 3.99 (each 1H, e
ach d, 3-OCOCH _2- ), 5.39 (1H, dd, 3-H) ¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 40.4 (3′-N (C
H ₃ ) ₂ ), 43.2 (9a-NCH ₃ ) IonSprayMS m / z: 732.4 [M + Na] ⁺

Example 2 3-O- (3-pyridyl) acetyl-5-O-desosaminyl-9-deoxo-9a-aza-9a-methyl-9a
-Production of homoerythronolide A 2'-O-acetyl-5-O-desosaminyl-9-deoxo-9a-aza-9a-methyl-9a-homoerythronolide A 1 g, 3-pyridylacetic acid hydrochloride 824 mg, 1-
Using [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (910 mg) and 4-dimethylaminopyridine (193 mg), the reaction was carried out in the same manner as in (1) and (2) of Example 1 to give 0.62 g of the title compound. Obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 2.28 (6H, s, 3′-N (C
_{H 3) 2), 2.36 (} 3H, s, 9a-NCH 3), 3.70 & 3.78 (each 1H, e
ach d, 3-OCOCH _2- ), 5.39 (1H, dd, 3-H)

Example 3 3-O- (4-pyridyl) acetyl-5-O-desosaminyl-9-deoxo-9a-aza-9a-methyl-9a
-Production of homoerythronolide A 2'-O-acetyl-5-O-desosaminyl-9-deoxo-9a-aza-9a-methyl-9a-homoerythronolide A 0.5 g, 4-pyridylacetic acid hydrochloride 400 mg , 1
Using [440 mg of-[3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and 94 mg of 4-dimethylaminopyridine, the reaction was carried out in the same manner as (1) and (2) of Example 1, and 0.16 g of the title compound was obtained. I got ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 2.26 (6H, s, 3′-N (C
H ₃ ) ₂ ), 2.35 (3H, s, 9a-NCH ₃ ), 3.69 & 3.78 (each 1H, e
ach d, 3-OCOCH _2- ), 5.40 (1H, dd, 3-H)

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Akira Manaka 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. F-term (reference) 4C057 AA18 AA19 KK11 4C086 AA03 BC76 BC82 EA12 MA01 MA04 NA14 ZB35

Claims (1)

[Claims] (1) Formula (1) [Wherein, R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R ² represents a pyridyl group, a pyrazinyl group, or a thiazolyl group, and X represents a group represented by the formula: Or the formula Is shown. Or a pharmaceutically acceptable salt thereof.