JPH11116590A - 11-substituted erythromycin A derivatives - Google Patents

Abstract

(57) [Problem] To provide a new macrolide antibiotic having a strong antibacterial activity. SOLUTION: The general formula: (Wherein X may be the same or different and may be an amino group, an alkoxy group, a lower alkyl group, an arylthio group, an acyloxy group, an acyloxymethyl group, an acylamino group, an aminomethyl group, an alkoxycarbonyl group, an azide group, a hydroxyl group, Represents a methyl group, Y represents a hydrogen atom or a tetrahydropyranyl group which may have a substituent, n represents an integer of 0 to 4, and R ¹ represents an acyloxyimino group, a hydroxyimino group or an oxygen atom. And R ²
Represents a hydrogen atom or a methyl group, and R ³ represents a hydrogen atom or an acyl group. ) Or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to erythromycin A having a tetrahydropyranyl ring introduced at the 11-position and derivatives thereof.

[0002]

BACKGROUND OF THE INVENTION Erythromycin A is a gram-positive bacterium,
It is an antibiotic widely used as a remedy for infectious diseases caused by mycoplasma and the like. However, erythromycin A has a low acid stability and is degraded by gastric acid during oral administration, so it cannot achieve a constant pharmacokinetics and has insufficient antibacterial activity against Haemophilus influenzae, an important causative organism of respiratory infection. However, there still remain problems to be improved. To resolve these issues,
Many erythromycin derivatives have been produced so far. Among them, examples of introducing a new sugar into the structure of erythromycin include, for example, WO94 / 17088 and J. Antibi.
otics, 46, 813, 1993, report the synthesis of a compound in which cladinose at position 3 has been replaced with a new sugar. Also, a report of introducing a glucose at the 2'-position using a microbial conversion technique (J. Antibiotics, 49, 1110, 1996), synthesis of a compound in which a new sugar has been introduced into the oxime group at the 9-position of erythromycin And antibacterial activity (J. Antibiotics, 49, 103
6, 1996).

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a new antibiotic having a strong antibacterial activity against conventional erythromycin-sensitive bacteria.

[0004]

The present inventors have studied the synthesis of erythromycin derivatives and their antibacterial activity, and as a result, have found that a tetrahydropyranyl ring can be introduced at the 11-position of an erythromycin A derivative, which has not been reported before. Succeeded and completed the present invention.

That is, the present invention provides the following general formula:

[0006]

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(Wherein X may be the same or different, and may be amino, alkoxy, lower alkyl, arylthio, acyloxy, acyloxymethyl, acylamino, aminomethyl, alkoxycarbonyl, azido, hydroxyl A hydroxymethyl group,
Y is a hydrogen atom or a tetrahydropyranyl group which may have a substituent, n represents an integer of 0 to 4, R ¹ represents an acyloxyimino group, a hydroxyimino group or an oxygen atom, and R ² represents R ³ represents a hydrogen atom or an acyl group; ) Or a pharmaceutically acceptable salt thereof.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, an alkoxy group means, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-
1-5 carbon atoms such as butoxy and tert-butoxy groups
And an alkoxy group which may be substituted by an aromatic hydrocarbon such as an alkoxy group and a benzyloxy group. The lower alkyl group is, for example, a methyl group, an ethyl group, a propyl group,
An alkyl group having 1 to 5 carbon atoms such as an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group. The arylthio group includes, for example, a phenylthio group, a 4-biphenylthio group, a 1-naphthylthio group,
Fluorophenylthio group, 2-chlorophenylthio group,
A phenyl group such as a 3-methylphenylthio group, a halogen atom, an alkyl group having 1 to 5 carbon atoms or 1 carbon atom
And arylthio groups which may be substituted with an alkoxy group. The acyloxy group is, for example, an aliphatic or aromatic acyloxy group such as an acetoxy group, a propionyloxy group, a pivaloyloxy group, and a benzoyloxy group. The acyloxymethyl group is, for example, an aliphatic or aromatic acyloxymethyl group such as an acetoxymethyl group, a propionyloxymethyl group, a pivaloyloxymethyl group, and a benzoyloxymethyl group. Alkoxycarbonyl groups include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-
It is an alkoxycarbonyl group containing an alkoxy having 1 to 5 carbon atoms such as a butoxycarbonyl group. The acylamino group includes, for example, an alkanoyl group having 1 to 5 carbon atoms such as an acetylamino group, a propionylamino group, an isopropionylamino group, a butyrylamino group, an isobutyrylamino group, a sec-butyrylamino group, and a pivaloylamino group. It is an acylamide group. The optionally substituted tetrahydropyranyl group means a lower alkyl group, an alkoxy group, an acyloxy group, a hydroxyl group, an amino group, a substituted amino group, a tetrahydropyranyl group optionally substituted with an acylamino group, or the like. And
Includes cladinosyl, glucopyranosyl, rhamnopyranosyl, xylopyranosyl, arabinopyranosyl and the like.

When n is 2 or more, a plurality of Xs may be the same or different. In the present invention, a pharmaceutically acceptable salt means a salt that can be used as a chemotherapeutic and prophylactic agent for bacterial infection. They include, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid,
Maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, paratoluene Sulfonic 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, picric acid, thiocyanic acid, undecanoic acid, Examples thereof include salts with acids such as acrylic acid polymers and carboxyvinyl polymers.

The compound of the present invention can be produced, for example, by the following method.

Step A

[0012]

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(Wherein, Xn, Y and R ² have the same meanings as described above, and R ^{3 ′} represents an acyl group.) 5-O- (2′-O-acetyl) desosaminylerythrono as a raw material Ride A 9-acetoxime (1) can be produced by the method described in WO94 / 17088. In addition, the phenylsulfinyl-tetrahydropyranyl derivative (2) is obtained from Methods in Carbohydrat.
e Chemistry. VI, 218. (Academic Press), Journal of Industrial Chemistry, 67, 78 (1964), or J. Am. Chem. Soc., 73, 5273.
(1951) and the like.

In this step, phenylsulfinyl-tetrahydropyranyl derivative is added to 5-O- (2'-O-acetyl) desosaminylerythronolide A 9-acetoxime in the presence of an organic base and trifluoromethanesulfonic anhydride.
The desired compound (3) can be produced by reacting (2). This reaction can be performed in a solvent that does not participate in the reaction, such as dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, and toluene. As the organic base, 2,6-di-tert-butyl-4-methylpyridine, pyridine, triethylamine and the like can be used. The reaction temperature is -100C to 10C.
It can be performed at 0 ° C.

However, when X is a hydroxyl group or an amino group, or Y is a substituent having a hydroxyl group, it is preferable to carry out the above reaction after appropriately protecting. When synthesizing a compound in which part or all of X is an amino group, it can be derived from a compound having a corresponding protected amino group or azide group. The conversion of the azide group to an amino group by reduction is performed by treatment with a trialkylphosphine (eg, trimethylphosphine, triethylphosphine, etc.) or an arylphosphine (eg, triphenylphosphine), or by hydrogen reduction in the presence of palladium It can be carried out. This reaction can be performed at room temperature in an organic solvent such as tetrahydrofuran, dioxane, or methanol.

Step B

[0017]

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(Wherein, Xn, Y and R ² have the same meanings as described above, and R ^{3 ′} represents an acyl group.) Step B is a hydrolysis reaction of the compound (3), and is carried out by treatment with a base. Thus, compound (4) can be produced. As the base, 1,8-diazabicyclo [5,4,0] -7-undecene (DB
U), 1,5-diazabicyclo [4,3,0] -5-nonene (DBN), sodium carbonate, potassium carbonate and the like can be used. This reaction can be carried out in an organic solvent such as methanol or ethanol at -78 ° C to 100 ° C.

Step C

[0020]

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(Wherein, Xn, Y and R ² have the same meanings as described above.) Step C is a conversion reaction of compound (4) to compound (5),
The treatment can be performed by treating with an oxidizing agent (for example, manganese dioxide), sodium bisulfite, titanium trichloride, or the like. The reaction can be carried out in a solvent that does not participate in the reaction, such as dichloromethane, dichloroethane, or hydrated methanol. This reaction can be carried out in an organic solvent such as methanol or ethanol at -78 ° C to 100 ° C.

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.
1,0001,000 mg, which can be administered in two or three divided doses per day. This dosage can be appropriately increased or decreased depending on the age, weight and condition of the patient.

[0023]

The compound of the present invention has a strong antibacterial activity against erythromycin-sensitive bacteria. Therefore, the compounds of the present invention are useful as antibacterial agents for preventing and treating bacterial infections in humans and animals (including farm animals).

[0024]

Next, the present invention will be described in more detail with reference to examples. Example 1 5-O- (2′-O-acetyl) desosaminyl-11-O- [β
Production of -D- (3-azido-3-deoxy-2,4,6-tri-O-pivaloyl) glucopyranosyl] erythronolide A 9-acetoxime 3-azido-3-deoxy-1-phenyl under argon atmosphere 20 ml of anhydrous dichloromethane containing 1.13 g (2.0 mmol) of sulfinyl-2,4,6-tri-O-pivaloyl-D-glucopyranose and 0.447 g (2.2 mmol) of 2,6-di-t-butyl-4-methylpyridine
0.34 ml of trifluoromethanesulfonic anhydride in the solution
(2.0 mmol) was added dropwise at -78 ° C over 34 minutes, and the temperature was raised to -10 ° C over about 1 hour. Then, 5-O- (2'-O-acetyl)
Desosaminyl erythronolide A 9-acetoxime 0.675
g (1.0 mmol) in 10 ml of anhydrous dichloromethane at -78 ° C
For 15 minutes, the temperature was raised to -10 ° C in about 1 hour, and the mixture was stirred at the same temperature for 42 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred for 30 minutes, and the product was extracted with chloroform. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated, and the residue was subjected to column chromatography (Silica Gel).
CHCl ₃ / MeOH = 50/1 to 9/1) to give the title compound 0.
32 g were obtained. _{MS (FAB): C 54 H} 91 N 5 O 19, m / z, 1114 (M + H) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.06 (3H, s, COC
_{H 3), 2.17 (3H,} s, COCH 3), 2.26 (6H, s, 3'-N (CH 3) 2), 4.48
(1H, s, 11-H ), 5.93 (1H, d, J = 7.9Hz, 1 "-H) 13 C-NMR (100MHz, CDCl3) δ (ppm): 40.7 (3'-N (CH 3)
₂ ), 97.5 (1 ").

Example 2 5-O- (2'-O-acetyl) desosaminyl-11-O- [β-D- (3-amino-3-deoxy-2,4,6-tri-O-
Preparation of pivaloyl) glucopyranosyl] erythronolide A 9-acetoxime To a solution of 0.118 g (0.105 mmol) of the compound obtained in Example 1 in 4 ml of anhydrous tetrahydrofuran was added 1M of trimethylphosphine.
0.21 ml (0.21 mmol) of the solution was added, and the mixture was stirred at room temperature for 3 hours. Then, 0.2 ml of water was added, and the mixture was stirred at 50 ° C. for 4 hours.
The reaction solution was extracted with ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, filtration and concentration were performed, and the residue was purified by column chromatography (Silica Gel CHCl ₃ / MeOH = 25/1) to obtain the title compound (0.047 g). _{MS (FAB): C 54 H} 93 N 3 O 19, m / z, 1088 (M + H) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.06 (3H, s, COC
H ₃ ), 2.17 (3H, s, COCH ₃ ), 2.26 (6H, s, 3′-N (CH ₃ ) ₂ ) ¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 40.7 (3′- N (CH ₃ )
₂ ).

Example 3 5-O-desosaminyl-11-O- [β-D-
Preparation of (3-N-pivaloylamino-3-deoxy-4,6-di-O-pivaloyl) glucopyranosyl] erythronolide A 9-oxime In a solution of 248 mg (0.228 mmol) of the compound obtained in Example 2 in 9 ml of methanol, 130 mg (0.854 mmol) of 1,8-diazabicyclo [5,4,0] undec-7-ene was added, and the mixture was stirred at room temperature for 7 days. The reaction solution was concentrated, and the residue was purified by column chromatography (Silica Gel CHCl ₃ / MeOH / NH ₄ OH = 190/10/1) to obtain 34 mg of the title compound. MS (FAB): C50H89N3O17, m / z, 1004 (M + H) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.28 (6H, s, 3'-N
(CH ₃ ) ₂ ), 3.91 (1H, s, 11-H), 4.65 (1H, d, J = 7.6Hz, 1 "-H),
5.86 (1H, d, J = 9.5Hz, NHCO) 13 C-NMR (100MHz, CDCl 3) δ (ppm): 40.3 (3'-N (CH 3)
₂ ), 56.2 (3 "), 84.9 (11), 104.5 (1"), 169.8 (9), 175.9
(1).

Example 4 5-O- (2'-O-acetyl) desosaminyl-11-O- [L- (2,3,4-tri-O-pivaloyl) arabinopyranosyl] erythronolide A Preparation of 9-oxime 1-phenylsulfinyl-2,3,4-tri-O-pivaloyl-L-
The reaction was carried out in the same manner as in Example 1 using 663 mg (1.3 mmol) of arabinopyranose and 438 mg (0.65 mmol) of 2′-O-acetyl-5-O-desosaminylerythronolide A 9-acetoxime to give the title compound 103 mg were obtained. _{MS (FAB): C 53 H} 90 N 2 O 19, m / z, 1059 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.04 (3H, s, COC
H ₃ ), 2.12 (3H, s, COCH ₃ ), 2.25 (6H, s, 3'-N (CH ₃ ) ₂ ), 4.44
(1H, s, 11-H ), 5.44 (1H, d, J = 6.4Hz, 1 "-H) 13 C-NMR (100MHz, CDCl 3) δ (ppm): 40.7 (3'-N (C
_{H 3) 2), 76.4 (} 11), 98.1 (1 "), 173.1 (1), 180.1 (9).

Example 5 Preparation of 5-O- (2′-O-acetyl) desosaminyl-11-O- [L- (4 ″ -O-acetylclazinosyl) erythronolide A 9-oxime 4- O-acetyl-1-phenylsulfinyl cladinose 436
mg (1.34 mmol) and 450 mg (0.67 mmol) of 2'-O-acetyl-5-O-desosaminylerythronolide A 9-acetoxime
Using l), the reaction was carried out in the same manner as in Example 1 to give the title compound
85 mg were obtained. _{MS (FAB): C 43 H} 74 N 2 O 16, m / z, 875 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.08 (3H, s, COC
H ₃ ), 2.12 (3H, s, COCH ₃ ), 2.16 (3H, s, COCH ₃ ), 2.26 (6H, s,
3'-N (CH ₃ ) ₂ ), 3.38 (3H, s, 3 "-OCH ₃ ), 4.06 (1H, s, 11-H),
5.21 (1H, d, J = 4.9Hz, 1 "-H) 13 C-NMR (100MHz, CDCl 3) δ (ppm): 40.7 (3'-N (C
H ₃ ) ₂ ), 50.1 (3 "-OCH3), 79.4 (11), 98.3 (1"), 174.7 (1),
177.4 (9).

Example 6 3-O-α-clazinosyl-11-O-α-
Production of cladinosyl-5-O-desosaminyl-6-O-methylerythronolide A 9-oxime (1) 457 mg (1.40 mmol) of 4-O-acetyl-1-phenylsulfinyl cladinose and 3-O- (4 ''-O-acetyl) clazinosyl-5-O- (2'-O-acetyl) desosaminyl-6-O-methylerythronolide A 9-acetoxime 624 mg (0.70 mmo
Using l), the reaction was carried out in the same manner as in Example 1 to give 3-O- (4 ″ -O-acetyl) clazinosyl-11-O- (4 ′ ″-O-acetyl) clazinosyl-5-O- ( 624 mg of 2′-O-acetyl) desosaminyl-6-O-methylerythronolide A 9-acetoxime was obtained. SIMS (3-NBA + NaCl): C ₅₄ H ₉₂ N ₂ O ₂₀ , m / e 1111 (M + N
a) ⁺ .

(2) 270 mg of the compound obtained in the above (1) (0.
248 mmol) was deacetylated in the same manner as in Example 3 to obtain 113 mg of the title compound. _{MS (FAB): C 46 H} 84 N 2 O 16, m / e 921 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.32 (6H, s, 3'-N ( C
H ₃ ) ₂ ), 3.07 (3H, s, 6-OCH ₃ ), 3.32 (6H, s, 3 "-OCH ₃ &3"'-
_{OCH 3), 3.92 (1H,} s, 11-H), 5.01 (1H, d, J = 4.3Hz, 1 "'- H) 13 C-NMR (100MHz, CDCl 3) δ (ppm): 40.3 (3 '-N (C
H ₃ ) ₂ ), 49.5 (OCH ₃ ), 49.7 (OCH ₃ ), 50.4 (6-OCH ₃ ), 79.6
(11), 95.9 (1 "), 97.6 (1"'), 168.8 (9), 175.7 (1).

Example 7 3-O- (4 "-O-acetyl) clazino
Sil-5-O- (2'-O-acetyl) desosaminyl-6-O-methyl-11
-O- [α- (6-methoxycarbonyl) tetrahydropyran-2-
Yl] erythronolide A Preparation of 9-acetoxime 6-methoxycarbonyl-2-phenylsulfinyltetra
317 mg (1.18 mmol) of hydropyran and 3-O- (4 ''-O-acetate
(Tyl) cladinosyl-5-O- (2'-O-acetyl) desosaminyl-
6-O-methylerythronolide A 9-acetoxime 533mg
(0.60 mmol), and the reaction was carried out in the same manner as in Example 1.
57 mg of the title compound were obtained. MS (FAB): C₅₁H₅₆N_TwoO₁₉, m / e 1031 (M + H)^{+ 1} H-NMR (400 MHz, CDCl_Three) δ (ppm): 2.04 (3H, s, 2'-OCO
CH_Three), 2.10 (3H, s, 4 "-OCOCH_Three), 2.13 (3H, s, 9 = NOCOCH_Three), 2.2
9 (6H, s, 3'-N (CH_Three)_Two), 3.03 (3H, s, 6-OCH_Three), 3.34 (3H, s,
3 "-OCH_Three), 3.70 (3H, s, CO_TwoCH_Three), 4.00 (1H, s, 11-H), 5.37
(1H, d, J = 2.3Hz, 1 "'-H)¹³ C-NMR (100 MHz, CDCl_Three) δ (ppm): 40.7 (3'-N (CH_Three)
_Two), 49.2 (3 "-OCH_Three), 50.4 (6-OCH_Three), 51.8 (5 '' '-CO_Two C
H_Three), 80.4 (11), 100.0 (1 '' '), 176.0 (9).

Example 8 3-O-clazinosyl-5-O-desosaminyl-6-O-methyl-11-O- [α- (6-methoxycarbonyl)
Preparation of [tetrahydropyran-2-yl] erythronolide A 9-acetoxime Example 3 was obtained using 539 mg (0.523 mmol) of the compound obtained in Example 7.
Deacetylation was carried out in the same manner as in the above to give 30 mg of the title compound. _{MS (FAB): C 45 H} 80 N 2 O 16, m / z 905 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.30 (6H, s, 3'-N ( C
H ₃ ) ₂ ), 3.11 (3H, s, 6-OCH ₃ ), 3.33 (3H, s, 3 "-OCH ₃ ), 3.72
(3H, s, CO ₂ CH ₃ ) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm): 40.3 (3′-N (C
H ₃ ) ₂ ), 49.5 (3 "-OCH ₃ ), 50.6 (6-OCH ₃ ), 51.9 (5 '''-CO ₂ C
H ₃ ).

Example 9 Preparation of 3-O-clazinosyl-5-O-desosaminyl-6-O-methyl-11-O- (α-D-2-deoxyglucopyranosyl) erythronolide A 9-oxime (1) 2-deoxy-1-phenylsulfinyl-3,4,6-tri
-O-pivaloyl-D-glucopyranose 687mg (1.31mmol)
And 3-O- (4 ''-O-acetyl) clazinosyl-5-O- (2'-O-acetyl) desosaminyl-6-O-methylerythronolide A 9-
Using 438 mg (0.65 mmol) of acetoxime, the reaction was carried out in the same manner as in Example 1 to give 3-O- (4 ″ -O-acetyl) clazinosyl-5.
-O- (2'-O-acetyl) desosaminyl-6-O-methyl-11-O- [α
-D- (2-Deoxy-3,4,6-tri-O-pivaloyl) glucopyranosyl] erythronolide A 9-acetoxime 32 mg was obtained. _{MS (FAB): C 61 H} 106 N 2 O 21, m / z 1203 (M + H) +.

(2) 1.30 g of the compound obtained in the above (1) (0.
248 mmol) was deprotected in the same manner as in Example 3 to obtain 77 mg of the title compound. ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 2.37 (6H, s, 3′-N
_{(CH 3) 2), 3.09} (3H, s, 6-OCH 3), 3.32 (3H, s, 3 "-OCH 3), 3.
99 (1H, s, 11-H), 5.33 (1H, brs, 1 '''-H) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm): 40.3 (3'-N (CH ₃ )
_{2), 49.4 (3 "-OCH} 3), 50.7 (6-OCH 3), 99.8 (1 '''). Example 10 3-O-α- cladinosyl -11-O-alpha-cladinosyl -5-O Production of 1-desosaminylerythronolide A 9-oxime (1) 436 mg (1.34 mmol) of 4-O-acetyl-1-phenylsulfinyl cladinose and 5-O- (2′-O-acetyl) desosaminylerythroyl Nolide A 9-acetoxime 450 mg (0.6
7 mmol) and reacted in the same manner as in Example 1 to give 3-O-
(4``-O-acetyl) cladinosyl-11-O- (4 ''-O-acetyl)
273 mg of cladinosyl-5-O- (2'-O-acetyl) desosaminylerythronolide A 9-acetoxime was obtained.

(2) 214 mg of the compound obtained in the above (1) (0.
199 mmol) was deacetylated in the same manner as in Example 3 to obtain 119 mg of the title compound. _{MS (FAB): C 45 H} 82 N 2 O 16, m / z 907 (M + H) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.32 (6H, s, 3'-N
_{(CH 3) 2), 3.30} (3H, s, OCH 3), 3.32 (3H, s, OCH 3), 3.78 (1
H, s, 11-H) , 4.99 (1H, d, J = 3.8Hz, 1 '''- H) 13 C-NMR (125MHz, CDCl 3) δ (ppm): 40.5 (3'-N (C
H ₃ ) ₂ ), 49.5 (OCH ₃ ), 49.7 (OCH ₃ ), 79.9 (11), 97.8
(1 ''').

Example 11 3-O-α-clazinosyl-11-O-
Preparation of α-clazinosyl-5-O-desosaminyl-6-O-methylerythronolide A To a solution of 334 mg (0.363 mmol) of the compound obtained in Example 10 in 15 ml of anhydrous dichloromethane, 2.85 g of active manganese dioxide was added.
Was added and stirred at room temperature for 72 hours. After filtering the waste,
The residue obtained by distilling off the solvent was subjected to column chromatography.
(Silica Gel CHCl ₃ / MeOH = 20/1) to give 71 mg of the title compound. _{MS (FAB): C 46 H} 83 NO 16, m / z 906 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.30 (6H, s, 3'-N
(CH ₃ ) ₂ ), 3.06 (3H, s, 6-OCH ₃ ), 3.33 (3H, s, OCH ₃ ), 3.35
(3H, s, OCH ₃ ), 3.80 (1H, s, 11-H), 4.85 (1H, d, J = 4.3Hz,
1 '''-H) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm): 40.3 (3'-N (C
H ₃ ) ₂ ), 49.5 (OCH ₃ ), 49.7 (OCH ₃ ), 50.3 (6-OCH ₃ ), 97.2
(1 ''').

Example 12 Preparation of 11-O- (6-aminomethyltetrahydropyran-2-yl) -3-O-clazinosyl-5-O-desosaminyl-6-O-methylerythronolide A 9-oxime ( 1) 371 mg (1.4 mmol) of 6-azidomethyl-2-phenylsulfinyltetrahydropyran and 3-O- (4 "-O-acetyl) clazinosyl-5-O- (2'-O-acetyl) desosaminyl-6-
O-Methylerythronolide A 9-acetoxime 624mg (0.
7 mmol) to carry out a reaction in the same manner as in Example 1 to obtain 354 mg of a white powder compound. Then 624 mg of this product (0.6
2 mmol) was reduced in the same manner as in Example 2 to give 3-O- (4 ″ -O-acetyl) clazinosyl-5-O- (2′-O-acetyl) desosaminyl-6-O-methyl-11- 140 mg of O- (6-aminomethyltetrahydropyran-2-yl) erythronolide A 9-acetoxime was obtained.

(2) 170 mg of the compound obtained in the above (1) (0.
185 mmol) was deacetylated in the same manner as in Example 3 to obtain 19 mg of the title compound. _{MS: C 44 H 81 N 3} O 14, m / z 876 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.29 (6H, s, 3'-N
_{(CH 3) 2), 3.08} (3H, s, 6-OCH 3), 3.33 (3H, s, 3 "-OCH 3), 3.
98 (1H, s, 11- H), 5.18 (1H, brs, 1 '''- H) 13 C-NMR (125MHz, CDCl 3) δ (ppm): 40.3 (3'-N (C
H ₃ ) ₂ ), 47.1 (CH ₂ NH ₂ ), 49.5 (3 "-OCH ₃ ), 50.4 (6-OCH ₃ ), 8
0.6 (11), 99.5 (1 ''').

Test Example (In Vitro Antimicrobial Activity) Using a medium for susceptible disks (manufactured by Eiken Chemical Co., Ltd.), the in vitro antimicrobial activity of the compound of the present invention against various test bacteria was measured according to the MIC measurement method of the Japan Society for Chemotherapy. . The compounds of the present invention showed strong antibacterial activity.

[0040]

[Table 1]

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Shigeo Morimoto 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Takeo Kobori 3-27-14 Moridai, Atsugi-shi, Kanagawa (72) Inventor Takahisa Sugimoto 1780 Sanogawa, Fujino-cho, Tsukui-gun, Kanagawa Prefecture (72) Inventor Kenichi Goda 4-4-1 Nishi Onuma, Sagamihara City, Kanagawa Prefecture

Claims (1)

[Claims] 1. A compound of the general formula (Wherein X may be the same or different and may be an amino group, an alkoxy group, a lower alkyl group, an arylthio group, an acyloxy group, an acyloxymethyl group, an acylamino group, an aminomethyl group, an alkoxycarbonyl group, an azide group, a hydroxyl group, Represents a methyl group, Y represents a hydrogen atom or a tetrahydropyranyl group which may have a substituent, n represents an integer of 0 to 4, and R ¹ represents an acyloxyimino group, a hydroxyimino group or an oxygen atom. And R ²
Represents a hydrogen atom or a methyl group, and R ³ represents a hydrogen atom or an acyl group. Or a pharmaceutically acceptable salt thereof.