JP2906663B2 - 5-0-desosaminylerythronolide A derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel derivative of the antibiotic erythromycin, and more specifically, a novel derivative of 5-O-desosaminylerythronolide A and a pharmaceutically acceptable acid thereof. Related to addition salts.

BACKGROUND ART Erythromycin is an antibiotic widely used clinically as a therapeutic agent for infectious diseases caused by gram-positive bacteria, certain gram-negative bacteria, mycoplasma, and the like, and many derivatives of erythromycin have their biological and / or biological properties. Manufactured to improve pharmaceutical properties. 5-O-
For the 3-position ketone of desosaminyl erythronolide A, see Antimicrobial Agents and Chemotherapy Vol.
o.4, P479 (1974) and Journal of Medicinal Chemistry
As described in Vol. 17, No. 9, P953 (1974), these antibacterial activities are generally extremely weak. An object of the present invention is to provide a new antibiotic having a strong antibacterial activity.

DISCLOSURE OF THE INVENTION The present inventors have conducted various studies on the antibacterial activity of the 3-position ketone derivative of a 5-O-desosaminylerythronolide A derivative, and as a result, are included in the structural formula in EP-A-0487411. However, it has been found that 5-O-desosaminylerythronolide A derivatives, which have no specific description, have particularly strong antibacterial activity, and the present invention has been completed.

The present invention relates to 11-amino-3,11-dideoxy-3-oxo-5-O-desosaminyl-6-O-methylerythronolide A 11-N, 12-O-cyclic carbamates and pharmaceutically acceptable salts thereof. Acid addition salt.

As the pharmaceutically acceptable acid addition salt in the present invention,
For example, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinate, ethylsuccinate,
Lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluenesulfonate, lauryl sulfate, apple Acid, aspartate, glutamate,
Adipates, cysteines, hydrochlorides, hydrobromides,
Phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, carboxyvinyl polymer salt and the like can be mentioned.

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

[Production Method 1] Method using 6-O-methylerythromycin A as a starting material Step (1); 6-O-methylerythromycin A is first prepared by reacting 6-O-methylerythromycin A in an inert solvent with a compound of the formula R ₂ O (where R is an acetyl group Or a propionyl group), or an acid halide represented by the formula RX (where R is the same as described above and X represents a halogen atom) and a base at 0 ° C. 30
At 2 ° C. to protect the hydroxyl group at the 2 ′, 4 ″ position, (Wherein R is as defined above). Here, as a suitable inert solvent, dichloromethane, dichloroethane, acetone, pyridine and the like are used. As the acid anhydride or acid halide, acetic acid,
Anhydrides and halides of propionic acid and the like are used.
As the base, pyridine or 4-dimethylaminopyridine is used.

Step (2): Next, the compound (a) is reacted with 1,1′-carbonyldiimidazole and a base in a suitable solvent at room temperature to obtain a compound of the formula (b) (Wherein R is as defined above). Here, as a suitable solvent, N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, a mixed solvent thereof or the like is used. As the base, sodium hydride, potassium hydroxide, sodium bis-trimethylsilylamide and the like are used.

Step (3): Next, the compound (b) is reacted with ammonia and sodium hydride in an appropriate solvent to give 11,12
-Formula (c) of the cyclic carbamate body (Wherein R is as defined above). Here, the same solvent as in step (2) is used as a suitable solvent.

Step (4): Next, the compound (c) is reacted with an acid to obtain a compound of the formula (d) (Wherein R is as defined above). Here, the acid means hydrochloric acid, bromic acid, sulfuric acid and the like, preferably 0.5 to 2 N hydrochloric acid, and in some cases, a mixed solution with a lower alcohol such as methanol or ethanol is also used.

Step (5): Next, the compound (d) is treated in an inert solvent with chromic acid, chromic acid-pyridine, pyridinium chlorochromate, pyridinium dichromate, activated dimethyl sulfoxide or the like at -78 ° C to 30 ° C. Oxidation at C gives the 3-position ketone. Subsequently, in a lower alcohol or a hydrated lower alcohol, a base such as sodium hydrogen carbonate may be added here, and the reaction is carried out at 0 ° C. to 100 ° C., preferably at room temperature to 80 ° C. to remove the 2′-protecting group, Equation (e) Can be produced. Here, suitable inert solvents are the same as those used in step (1). As an activator for dimethyl sulfoxide, acetic anhydride, trifluoroacetic anhydride, oxalyl chloride, phosphorus pentoxide, pyridinesulfonic acid, pyridinetrifluoroacetic acid, 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl ) -3-Ethylcarbodiimide hydrochloride and the like are used. Here, as the lower alcohol, methanol, ethanol, propyl alcohol and the like are used.

[Production Method 2] Method using 5-O-desosaminyl-6-O-methylerythronolide A as a starting material Step (6); 5-O-desosaminyl-6-O-methylerythronolide A In an active solvent, R ₂ O (wherein,
R is the same as above. ) And optionally in the presence of a weak base such as sodium bicarbonate to protect only the 2'-hydroxyl group. Next, a reaction with a reagent such as phosgene dimer or phosgene trimer is performed in an inert solvent under ice cooling using a base. Click carbonate and benzyloxycarbonylation at the 3-position are carried out in the same vessel to obtain formula (f) (Wherein R is as defined above). Here, the inert solvent is the same as that used in the step (1). As the base, pyridine, collidine, N-methylpiperidine, N-methylmorpholine, triethylamine, dimethylaniline and the like are used.
Next, this compound is reacted in the same manner as in step (2) to obtain a compound of formula (g) (Wherein R is as defined above).

Step (7): The compound (g) is reacted in the same manner as in Step (3) to obtain an 11,12-cyclic carbamate. Next, 10% Pd-C and ammonium formate are added and stirred to remove the benzyloxycarbonyl group at the 3-position. Then, the compound of the present invention can be produced by reacting in the same manner as in step (5).

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 manufactured by conventional formulation techniques.
The dose is 1 mg / kg to 50 mg / kg, which is administered once a day to 3 mg / kg.
Administer in divided doses.

INDUSTRIAL APPLICABILITY The compound of the present invention has strong antibacterial activity against erythromycin-sensitive bacteria and some resistant bacteria, and has good absorbability in the body. 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).

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 (1) A solution of 500 g (0.668 mol) of 6-O-methylerythromycin A in 1 L of dichloromethane was added to 220.8 ml of acetic anhydride (2.3%).
4 mol) and 32.67 g (0.267 mol) of 4-dimethylaminopyridine were added and stirred at room temperature for 2 days. The reaction solution was washed with a dilute sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude crystals were crystallized from ethyl acetate to give 25.2'-di-O-acetyl-6-O-methylerythromycin A (485.2 g).

(2) 149.77 g (0.18 mol) of the compound obtained in the above (1) was
-225 ml of dimethylformamide and 375 of tetrahydrofuran
Dissolved in 1 ml of the mixture, 1,1'-carbonyldiimidazole 7
3.08 g (0.45 mol) was added. Under ice-cooling, 9.37 g (0.23 mol) of 60% sodium hydride was added at 5 to 7 ° C, and the mixture was stirred for 1 hour. It returned to room temperature and reacted for 2.5 hours. Extracted with ethyl acetate to give a colorless foamy 10,11-anhydro-2 ', 4 "-di-O-
Acetyl-12-O-imidazolylcarbonyl-6-O-
200.79 g of methylerythromycin A was obtained.

(3) A solution prepared by dissolving 200.79 g of the compound obtained in the above (2) in 400 ml of tetrahydrofuran is cooled with dry ice acetone in 500 ml of liquid ammonia and 200 ml of tetrahydrofuran.
And the mixture was stirred at room temperature for 2 days. Then 60%
2.16 g (0.054 mol) of sodium hydride was added and reacted for 3 hours. Extracted with ethyl acetate and obtained as a colorless crystalline powder of 11-amino-11-deoxy-2 ', 4 "-di-O-acetyl-6-O-
174.35 g of methyl erythromycin A 11-N, 12-O-cyclic carbamate was obtained.

(4) 174.35 g (0.20 mol) of the compound obtained in the above (3) was dissolved in a mixture of 700 ml of 2N hydrochloric acid and 350 ml of ethanol,
Stirred at room temperature for 20 hours. 4N sodium hydroxide solution 35
0 ml was added, and the precipitated crude crystals were collected by filtration and purified by silica gel column chromatography (elution solvent: hexane: acetone: triethylamine = 100: 50: 0.2) to give 2′-O
-Acetyl-11-amino-11-deoxy-5-O-desosaminyl-6-O-methylerythronolide A 11-N, 12
116.2 g of -O-cyclic carbamate was obtained.

(5) 110.84 g (0.16 mol) of the compound obtained in the above (4) was dissolved in 600 ml of dichloromethane, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.
76.68 g (0.40 mol) of hydrochloride and dimethyl sulfoxide 9
0.8 ml (1.28 mol) was added. Next, 77.25 g (0.40 mol) of pyridinium trifluoroacetate was added, and 1.5
Stirred for hours. After completion of the reaction, the dichloromethane layer was washed successively with a saturated saline solution and a saturated sodium hydrogen carbonate solution,
Dichloromethane was distilled off under reduced pressure. Residue in methanol 300m
and heated under reflux for 3 hours. The crude product obtained by distilling off methanol was purified by silica gel column chromatography (elution solvent; chloroform solution containing 1.5 to 8% methanol), and then crystallized from methanol to obtain 11-amino-3, 11-dideoxy-3-oxo-5
-O-desosaminyl-6-O-methylerythronolide
62.28 g of A 11-N, 12-O-cyclic carbamate was obtained as colorless crystals.

mp: 245~247 ℃ Mass (FAB) m / z: 613 [MH] + 1 H-NMR (300MHz, CDCl 3) δ (ppm): 1.32 (3H, s), 1.48
(3H, s), 2.29 (6H, s), 2.61 (3H, s) ¹³ C-NMR (75 MHz, CDCl ₃ ) δ (ppm): 40.3 [3′-N (C
_{H 3) 2], 49.4 (} 6-OCH 3), 158.0 (11-NCOO-12), 20
4.5 (C-3) Example 2 (1) Dissolve 11.78 g (0.02 mol) of 5-O-desosaminyl-6-O-methylerythronolide A in 100 ml of acetone and, under ice-cooling, 2.27 ml (0.024) of acetic anhydride. Mol) was added and 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 with a saturated sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was recrystallized from ether-n-hexane to give 2'-O-acetyl-5-O-desosaminyl-6-O-.
12.17 g of methylerythronolide A was obtained as a white powder.

mp: 158~160 ℃ Mass (FAB) m / z: 632 [MH] + 1 H-NMR (200MHz, CDCl 3) δ (ppm): 2.07 (3H, s), 2.26
(6H, s), 2.95 (3H, s), 3.26 (1H, s), 3.96 (1H, s) IR (KBr, cm ^-1 ): 3469,1750,1733,1693 (2) 42.5 g of a compound obtained in a similar manner (67.
3 mmol) was dissolved in 230 ml of dichloromethane, and cooled under ice-cooling.
81.4 ml (1.01 mol) of pyridine were added. At the same temperature, 20 ml of a dichloromethane solution of 20.2 ml (168 mmol) of trichloromethyl chloroformate was added dropwise, and after stirring for 3 hours, 72.7 ml (673 mmol) of benzyl alcohol was added dropwise over 30 minutes. After stirring at room temperature for 16 hours, ice chips were added little by little, and the pH was adjusted to 10 with a sodium hydroxide solution. Dichloromethane was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to 300 ml of the solvent. The precipitated crystals were collected by filtration, and 2'-O-acetyl-3-O-benzyloxycarbonyl-5-O-desosaminyl-6-methylerythronolide A 11,12-cyclic carbonate 38.
7 g were obtained.

Mass (FAB) m / z: 792 [MH] + 1 H-NMR (300MHz, CDCl 3) δ (ppm): 1.49 (3H, s), 2.07
(3H, s), 2.25 (6H, s), 2.99 (3H, s), 4.70 (1H, s), 5.
21 (2H, s), 7.35 to 7.46 (5H, m) IR (KBr, cm- ¹ ): 1821, 1746, 1715, 1267, 1241 (3) 10 g (12.6 mmol) of the compound obtained in the above (2) To
N, N-dimethylformamide-tetrahydrofuran (1:
1) Dissolve in 100 ml and add 1,1'-carbonyldiimidazole 8.
18 g (50.4 mmol) and 1.11 g of 60% sodium hydride
(27.8 mmol) was added and the mixture was stirred at room temperature for 0.5 hour. Tetrahydrofuran was distilled off under reduced pressure, water was poured into the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and 2'-O-acetyl-10,11-anhydro-3-O-benzyloxycarbonyl-12-O- as a white foam was obtained.
Imidazolylcarbonyl-5-O-desosaminyl-6
11.5 g of O-methylerythronolide A was obtained.

(4) 5 g (5.9 mmol) of the compound obtained in the above (3) was dissolved in 50 ml of acetonitrile-5 ml of tetrahydrofuran,
After adding 3 ml of 5% aqueous ammonia and stirring at room temperature for 4 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: acetone = 3: 1) to obtain 1.8 g of a cyclic carbamate.
Then, the mixture was heated in methanol for 2 hours to obtain 0.95 g of a compound from which the acetyl group at the 2′-position was removed.

(5) 0.85 g (1.14 mmol) of the compound obtained in the above (4)
Was dissolved in 10 ml of methanol, 0.17 g (20% by weight) of 10% Pd-C and 358 mg (5.70 mmol) of ammonium formate were added, and the mixture was stirred at room temperature for 0.5 hour. After filtration of the reaction solution, the filtrate was concentrated, then methanol was distilled off under reduced pressure, water was poured into the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 0.64 g of a compound having a hydroxyl group at the 3-position.

(6) Of these, 0.6 g (0.98 mmol) was dissolved in 6 ml of acetone, 0.15 ml (2.28 mmol) of acetic anhydride was added, and the mixture was stirred at room temperature for 1.5 hours. Then, acetone was distilled off under reduced pressure.
Post-treatment was conducted in the same manner as in the above (5), and 0.58 g of 2'-O
-An acetyl form was obtained.

(7) 0.29 g (0.44 mmol) of the compound obtained in the above (6)
Was dissolved in 3 ml of dichloromethane, and dimethyl sulfoxide was dissolved.
0.3 ml (4.23 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.254 g (1.
32 mmol) and 0.256 g (1.33 mmol) of pyridinium trifluoroacetate were added, and the mixture was stirred at room temperature for 1 hour. A 2N sodium hydroxide solution and water were added to the reaction solution, and extracted with dichloromethane. Post-processing was performed in the same manner as in the above (5). After the solvent was distilled off, 10 ml of methanol was added to the obtained residue, and the mixture was heated under reflux for 2 hours. The methanol was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: methanol: 25% aqueous ammonia = 30: 1: 0.1). Dichloromethane-n
-By crystallization from a mixed solvent of hexane, 11-
Amino-3,11-dideoxy-3-oxo-5-O-desosaminyl-6-O-methylerythronolide A 11-N, 12
0.16 g of -O-cyclic carbamate was obtained.

Test Example 1 (In Vitro Antibacterial Activity) The in vitro antibacterial activity of the compound of the present invention against various test bacteria was measured using a medium for susceptible disks (manufactured by Eiken Chemical Co., Ltd.) in accordance with the MIC measurement method of the Japan Society for Chemotherapy. Comparative drug 1: 3
-Deoxy-11- {2- [methyl (benzyl) amino]
Ethyl {amino-3-oxo-5-O-desosaminyl-
6-O-methylerythronolide A 11-N, 12-O-cyclic carbamate (described in EP 0 474 711), comparative drug 2: 3-deoxy-3-oxo-5-O-
Desosaminyl-6-O-methylerythronolide A 11,1
2-Cyclic carbonate (European patent 0874711)
Comparative drug 3: 6-O-methylerythromycin A and comparative drug 4: azithromycin. The result is expressed as MIC value (minimum inhibitory concentration of microbial growth mcg / ml),
The results are shown in Table 1.

Test Example 2 (In Vivo Antibacterial Activity) The protective effect of the compound of the present invention against the infectious bacteria (S. aureus Smith4) was evaluated for mice (ICR strain, male, 4 weeks old, group 8)
), Comparative Drug 1, Comparative Drug 2 and Comparative Drug 3
(Comparative drugs were the same as those used in Test Example 1). After infecting bacteria (S. aureus Smith4) were cultured for 18 hours, mice were intraperitoneally inoculated with 0.5 ml of a 5% mucin-containing physiological saline diluted with a heart infusion medium. One hour after the bacterial inoculation, the drug was suspended in 5% gum arabic and orally administered, and the viability was determined for 7 days. The results are shown in Table 2.

Test Example 3 (Mouse Serum Concentration) The concentration of the compound of the present invention in mouse serum was measured. The test was performed using ICR mice (male, 4 weeks old, 10 mice per group) using Comparative Drug 2 and Comparative Drug 3 (Comparative drugs were the same as those used in Test Example 1). Mice were orally administered with a drug suspended in 5% gum arabic, and blood was collected over time to separate serum. The measurement of the drug concentration in the serum was performed by the paper disk method using M. luteus ATCC9341 as a test bacterium. Table 3 shows the results.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Shigeo Morimoto 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 24-24 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical (56) References JP-A-4-290893 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07H 17/00 C07H 17/08 A61K 31/70-31 / 71 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) 11-amino-3,11-dideoxy-3-oxo-5-O-desosaminyl-6-O-methylerythronolide A 11-N, 12-O-cyclic carbamate and pharmaceutically acceptable salts thereof Acid addition salts