JPH11116592A - 4"-substituted erythromycin a derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a specific erythromycin A derivative introduced with a sugar residue or a tetrahydropyranyl group at 4" position, which is new and useful for the prevention and treatment of a bacterial infectious disease as a macrolide-based antibiotic material exhibiting a potent antibacterial effect. SOLUTION: This 4"-substituted erythromycin A derivative is expressed by formula I [X is hydroxyl, an alkoxyl, an alkoxycarbonyl, a lower alkanoyloxy, an aryl, an arylthio, an aminomethyl, an azidomethyl, etc.; (n) is 0-4 integer; R<1> is O or the formula: R<5> -O-N (R<5> is H or an acetyl); R<2> is H or acetyl; R<3> , R<4> are each OH or a carbonate by becoming one unit], and is useful as an antibacterial agent for the treatment and prevention of human and animal bacterial infectious diseases. The compound is obtained by reacting a compound of formula II (Me is methyl) with a tetrahydropyranyl derivative of formula III (Ph is phenyl), etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an antibiotic erythromycin A derivative.

[0002]

2. Description of the Related Art Erythromycin A is an antibiotic widely used as a therapeutic agent for infectious diseases caused by gram-positive bacteria, mycoplasma and the like. However, erythromycin A has a low acid stability and is decomposed by gastric acid during oral administration, so that a constant pharmacokinetics cannot be obtained.
There are still problems to be solved, such as insufficient antibacterial activity against Haemophilus influenzae, which is an important cause of respiratory infection. To solve these problems, many erythromycin derivatives have been produced.
Among them, examples of introducing a new sugar into the structure of erythromycin include, for example, WO94 / 17088 and J. Antibiot.
ics 46: 813, 1993 reports 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 reports on antibacterial activity (J. Antibiotics, 49, 1036,
1996).

[0003]

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

[0004]

The present inventors have studied the synthesis of an erythromycin derivative and its antibacterial activity. As a result, the present inventors have reported a sugar residue or tetrahydropyranyl group at the 4 "position of an erythromycin A derivative which has not been reported so far. And so on, and completed the present invention.

That is, the present invention provides

[0006]

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Wherein X may be the same or different and a hydroxyl group, a lower alkyl group, an alkoxy group, an alkoxycarbonyl group, a lower alkanoyloxy group, an aryl group, an arylthio group, an aminomethyl group, an azidomethyl group, R represents an acetylaminomethyl group or an N, N-dibenzylaminomethyl group; n represents an integer of 0 to 4;
¹ represents an oxygen atom or a formula R ⁵ —ON (wherein R ⁵ represents a hydrogen atom or an acetyl group), R ² represents a hydrogen atom or an acetyl group, and R ³ and R ⁴ each represent a hydroxyl group Or a carbonate group together. And a pharmaceutically acceptable salt thereof.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, a lower alkyl group means, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group,
It is an alkyl group having 1 to 5 carbon atoms such as an ert-butyl group. The alkoxy group means, for example, an alkoxy group having 1 to 5 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a benzyloxy group, Is an alkoxy group which may be substituted by the aromatic hydrocarbon. The alkoxycarbonyl group is, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, or the like. It is an alkoxycarbonyl group containing an alkoxy group of 5 to 5 in the group. A lower alkanoyloxy group is
For example, it is an alkanoyl group having 2 to 6 carbon atoms such as an acetoxy group, a propionyloxy group and a pivaloyloxy group. An aryl group is, for example, a phenyl group such as a phenyl group, a 4-biphenyl group, a 4-fluorophenyl group, a 3-methylphenyl group, a naphthyl group, an anthranyl group, a halogen atom, an alkyl group having 1 to 5 carbon atoms or a carbon atom. An aromatic hydrocarbon group which may be substituted with an alkoxy group having 1 to 5 atoms. The arylthio group includes, for example, a phenyl group such as a phenylthio group, a 4-biphenylthio group, a 1-naphthylthio group, a 4-fluorophenylthio group, a 2-chlorophenylthio group, and a 3-methylphenylthio group;
An arylthio group which may be substituted with a halogen atom, an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms.

In the present invention, a pharmaceutically acceptable salt means a salt used in chemotherapy and prevention of 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, paratoluenesulfonic acid, lauryl sulfate, malic acid, aspartic acid, glutamic acid, adipic acid, Cysteine, N-
Salts with acids such as acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, acrylic acid polymers, carboxyvinyl polymers, etc. be able to.

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

[0011]

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(Wherein, Xn, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above.) 5-O- (2′-O-acetyl) desosaminyl- which is a starting material of the present invention. 6-O-Methyl-erythronolide A 9-acetoxime or 5-O- (2'-O-acetyl) desosaminyl-6-O-methyl-erythronolide A is prepared according to the method described in U.S. Pat.No. 5,631,354. Can be manufactured. 5-O- (2′-O-acetyl) desosaminyl-6-O-methyl-erythronolide A 11,12-cyclic carbonate can be produced by the method described in WO94 / 17088. The phenylsulfinyl-tetrahydropyranyl derivative or the dihydropyran derivative is obtained from Methods in C
arbohydrate Chemistry, VI, 218, (Academic Press),
Journal of Industrial Chemistry, 67, 78 (1964), J. Am. Chem. Soc., 73, 52.
73 (1951).

Reaction of 2'-O-acetyl-6-O-methylerythromycin A 9-acetoxime (1) with phenylsulfinyl-tetrahydropyranyl derivative (2) in the presence of an organic base and trifluoromethanesulfonic anhydride Can produce the desired compound (3). As the organic base, 2,6-di-t-butyl-4-methylpyridine, pyridine, triethylamine and the like can be used. Further, using a dihydropyran derivative (2 ′) in the presence of an acid catalyst
The desired compound (3) can also be produced by reacting (1). As the acid catalyst, trifluoromethanesulfonic anhydride, camphorsulfonic acid, p-toluenesulfonic acid, boron trifluoride ether complex, copper trifluoromethanesulfonic acid, silver perchlorate, tin chloride and the like can be used. These reactions can be carried out in a solvent that does not participate in the reaction, such as dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, and toluene, at a reaction temperature of -100C to 100C.

In these reactions, for example, 2 ′
It is preferable to use a compound in which a hydroxyl group or a carbonyl group at the 9-position is protected in order to make the reaction proceed efficiently. In this case, the hydroxyl-protecting group of the product can be easily removed by subjecting it to a hydrolysis reaction. In particular,
When an acetoxy group is used as a protecting group for a hydroxyl group, a desired compound can be produced by treating with a base. 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 50 ° C. Also, 9
When the protecting group for the carbonyl group is an oxime group, the desired compound can be produced by subjecting to an elimination reaction. This reaction uses an oxidizing agent (for example, manganese dioxide), sodium bisulfite, sodium nitrite, titanium trichloride, and the like, and the reaction solvent may be performed in a solvent that does not participate in the reaction, such as dichloromethane, dichloroethane, or hydrated methanol. it can. The reaction can be carried out at a temperature of -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.

[0016]

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

[0017]

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

Example 1 3-O- [α-4 "-O- (4-O-acetylclazinosyl) clazinosyl] -5-O- (2'-O-acetyl) desosaminyl-6-O-methyl Production of erythronolide A 9-acetoxime Under an argon atmosphere, 4-acetyl-1-phenylsulfinyl cladinose 463 mg (1.42 mmol) and 2,6-di-t-butyl-4
To a solution of 323 mg (1.55 mmol) of 3-methylpyridine in 14 ml of anhydrous dichloromethane was added 242 trifluoromethanesulfonic anhydride.
μl (1.43 mmol) was added dropwise at −78 ° C. over 15 minutes.
Stirred for 0 minutes. Then, 5-O- (2'-O-acetyl) desosaminyl-3-O-clazinosyl-6-O-methylerythronolide
A solution of 601 mg (0.71 mmol) of A9-acetoxime in 7 ml of anhydrous dichloromethane was added dropwise at -78 ° C for 5 minutes, and the mixture was stirred for 45 minutes. An 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 = 100/1 ~
Purification by 50/1) gave 620 mg of the title compound. ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 2.03 (3H, s, COC
_{H 3), 2.12 (3H,} s, COCH 3), 2.17 (3H, s, COCH 3), 2.27 (6H, s,
3'-N (CH ₃ ) ₂ ), 3.00 (3H, s, 6-OCH ₃ ), 3.26 (3H, s, OCH ₃ ),
_{3.32 (3H, s, OCH 3} ), 4.81 (1H, d, J = 5.5Hz, 1 '''- H) 13 C-NMR (125MHz, CDCl 3) δ (ppm): 40.7 (3'-N ( C
H ₃ ) ₂ ), 49.2 (OCH ₃ ), 49.6 (OCH ₃ ), 50.8 (6-OCH ₃ ), 100.2
(1 '''), 177.6 (9).

Example 2 3-O- [α-4 "-O- (clazinosyl)
Preparation of Cladinosyl] -5-O-desosaminyl-6-O-methylerythronolide A 9-oxime In a solution of 620 mg (0.59 mmol) of the compound obtained in Example 1 in 34 ml of anhydrous methanol, 1,8-diazabicyclo [5, 348 mg of 4,0] -7-undecene was added, and the mixture was stirred at room temperature for 58 hours. The reaction mixture was concentrated, and the residue was subjected to column chromatography (Silica Ge
l, CHCl ₃ / MeOH = 100/1 to 10/1) to obtain 244 mg of the title compound. ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 2.30 (6H, s, 3′-N (C
H ₃ ) ₂ ), 3.11 (3H, s, 6-OCH ₃ ), 3.29 (6H, s, OCH ₃ X2), 4.77
(1H, d, J = 4.3Hz , 1 '''- H) 13 C-NMR (125MHz, CDCl 3) δ (ppm): 40.2 (3'-N (C
H ₃ ) ₂ ), 49.3 (OCH ₃ ), 49.7 (OCH ₃ ), 51.2 (6-OCH ₃ ), 175.5
(9).

Example 3 3-O- [α-4 "-O- (clazinosyl)
Preparation of cladinosyl] -5-O-desosaminyl-6-O-methylerythronolide A To a solution of 170 mg (0.185 mmol) of the compound obtained in Example 2 in 1.4 ml of 50% ethanol, 78 mg of sodium bisulfite and formic acid 1
8 μl was added and the mixture was stirred at 80 ° C. for 2 hours. 2.2 ml of water in the reaction solution
And diluted with 2N sodium hydroxide under ice-water cooling.
35 ml was added and the mixture was stirred for 2 hours. The product was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Thereafter, column chromatography (Silica Gel, CHCl ₃ / MeOH = 30 /
Purification according to 1) afforded 73 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): 2.29 (6H, s, 3'-N (C
H ₃ ) ₂ ), 3.05 (3H, s, 6-OCH ₃ ), 3.28 (3H, s, OCH ₃ ), 3.29 (3
_{H, s, OCH 3),} 4.76 (1H, d, J = 4.3Hz, 1 '''- H) 13 C-NMR (125MHz, CDCl 3) δ (ppm): 40.4 (3'-N (C
H ₃ ) ₂ ), 49.6 (OCH ₃ ), 49.7 (OCH ₃ ), 50.9 (6-OCH ₃ ), 89.2
(4 "), 100.5 (1 '''), 221.3 (9).

Example 4 5-O-desosaminyl-3-O- [4 "-O-
Production of (6-methoxycarbonyltetrahydropyran-2-yl) cladinosyl] -6-O-methylerythronolide A 9-oxime (1) 375 mg (1.40 mmol) of 2-methoxycarbonyl-6-phenylsulfinyltetrahydropyran and 5 -O- (2'-O-
Acetyl) desosaminyl-3-O-clazinosyl-6-O-methylerythronolide A 593 mg (0.71 mmol) of 9-acetoxime
And reacted in the same manner as in Example 1 to give 5-O- (2'-O-acetyl) desosaminyl-3-O- [4 "-O- (6-methoxycarbonyltetrahydropyran-2-yl) Cladinosyl] -6-O-methylerythronolide A 9-acetoxime 547 mg was obtained.

(2) Using the compound obtained in the above (1) in Example 2
Deacetylation was carried out in the same manner as in the above to give 73 mg of the title compound.

[0023] _{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 ), 3.10 (3H, s, 6-OCH ₃ ), 3.31 (3H, s, 3 "-OCH ₃ ), 3.75
(3H, s, CO ₂ CH ₃ ) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ (ppm): 40.3 (3′-N (C
_{H 3) 2), 49.6 (} 3 "-OCH 3), 51.2 (6-OCH 3), 52.2 (CO 2 C H 3).

Example 5 5-O-desosaminyl-3-O- [4 "-O-
Production of (tetrahydropyran-2-yl) clazinosyl] -6-O-methylerythronolide A (1) Under an argon atmosphere, 5-O- (2'-O-acetyl) desosaminyl-3-O-clazinosyl-6 -O-methylerythronolide A 896 mg (1.13 mmol) and 3,4-dihydro-2-H-pyran 504 m
g (6 mmol) and powdered molecular sieve 4A, 1.8 g of a solution of camphorsulfonic acid 30 in 40 ml of anhydrous dichloromethane.
0 mg (1.3 mmol) was added under ice-water cooling, and the mixture was stirred at room temperature for 45 hours. 0.22 ml of triethylamine was added to the reaction solution, and the solid was filtered and washed with chloroform. The filtrate was concentrated, and the residue was subjected to column chromatography (Silica Gel, CHCl ₃ / MeOH
= 200/1 to 10/1) to give 5-O- (2'-O-acetyl) desosaminyl-3-O- [4 "-O- (tetrahydropyran-2-yl) cladinosyl] -6- 425 mg of O-methylerythronolide A was obtained.

(2) 370 mg (0.4 mg) of the compound obtained in the above (1)
23 mmol) was deacetylated in the same manner as in Example 2 to obtain 240 mg of the title compound. _{MS (FAB): C 43 H} 77 NO 14, m / z 832 (M + H) + 1 H-NMR (300MHz, CDCl 3) δ (ppm): 2.28 (6H, s, 3'-N (C
_{H 3) 2), 3.04 (} 3H, s, 6-OCH 3), 3.31 (3H, s, 3 "-OCH 3).

Example 6 Preparation of 3-O- [4 "-O- (6-azidomethyltetrahydropyran-2-yl) clazinosyl] -5-O-desosaminyl-6-O-methylerythronolide A (1 ) 5-O- (2'-O-acetyl) desosaminyl-3-O-clazinosyl-6-O-methylerythronolide A 1.715 g (2.17mmo
l) and 2-azidomethyl-3,4-dihydro-2-H-pyran 0.834
g (6.51 mmol) and the reaction was carried out in the same manner as in Example 5 to give 3-O- [4 "-O- (6-azidomethyltetrahydropyran-2-yl) cladinosyl] -5-O- ( 1.1 g of 2'-O-acetyl) desosaminyl-6-O-methylerythronolide A was obtained.

(2) 0.631 g of the compound obtained in the above (1) (0.
677 mmol) was dissolved in 20 ml of anhydrous methanol, and the mixture was heated under reflux for 7 days. The reaction solution was concentrated, and the residue was purified by column chromatography (Silica Gel, CHCl ₃ / MeOH = 100/1 to 20/1) to obtain 0.406 g of the title compound. MS (FAB): m / z 887 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.29 (6H, s, 3'-N (C
_{H 3) 2), 3.06 (} 3H, s, 6-OCH 3), 3.33 (3H, s, 3 "-OCH 3).

Example 7 Preparation of 3-O- [4 "-O- (6-aminomethyltetrahydropyran-2-yl) clazinosyl] -5-O-desosaminyl-6-O-methylerythronolide A To a solution of 421 mg (0.47 mmol) of the compound obtained in Step 6 in 10 ml of anhydrous tetrahydrofuran was added 0.94 (0.94 mmol) of a 1M solution of trimethylphosphine and the mixture was stirred at room temperature for 2 hours, and 1.9 ml of water was added. The mixture was stirred at 50 ° C. for 3 hours, diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (Silica Gel, CHCl ₃ / MeOH / NH _4).
OH = 475/25/2) to give 360 mg of the title compound. MS (FAB): m / z 861 (M + H) + 1 H-NMR (300MHz, CDCl 3) δ (ppm): 2.29 (6H, s, 3'-N (C
_{H 3) 2), 3.04 (} 3H, s, 6-OCH 3), 3.31 (3H, s, 3 "-OCH 3).

Example 8 3-O- [4 "-O- (6-N, N-dibenzylaminomethyltetrahydropyran-2-yl) clazinosyl] -5-O-desosaminyl-6-O-methylerythrono Ride A
To a solution of 218 mg (0.25 mmol) of the compound obtained in Example 7 and 54 mg (0.49 mmol) of benzaldehyde in 6 ml of anhydrous dichloromethane was added 122 mg (0.5 mg) of sodium triacetoxyborohydride.
7 mmol) and stirred at room temperature for 23 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, 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,
Purification by CHCl ₃ / MeOH / NH ₄ OH = 475/25/2) gave 190 mg of the title compound.

[0030] MS (FAB): m / z 1041 (M + H) + 1 H-NMR (300MHz, CDCl 3) δ (ppm): 2.27 (6H, s, 3'-N (C
H ₃ ) ₂ ), 3.05 (3H, s, 6-OCH ₃ ), 3.28 (3H, s, 3 "-OCH ₃ ), 7.18
7.37.38 (10H, m, Ar-H).

Example 9 3-O- [4 "-O- (6-acetylaminomethyltetrahydropyran-2-yl) cladinosyl] -5-O-
Preparation of Desosaminyl-6-O-methylerythronolide A To a solution of 121 mg (0.139 mmol) of the compound obtained in Example 7 in 3 ml of anhydrous dichloromethane was added 23 mg (0.278 mmol) of sodium hydrogen carbonate.
l) and 28 mg (0.278 mmol) of acetic anhydride were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was subjected to column chromatography (Sili
ca Gel, CHCl ₃ / MeOH / NH ₄ OH = 485/15/2)
125 mg of the amide compound was obtained. Amide 125 mg in methanol 10 ml
And heated to reflux for 11 days. The solvent was distilled off, and the residue was subjected to column chromatography (Silica Gel, CHCl ₃ / EtOH).
/ NH ₄ OH = 450/3/1 to 500/10/2) (SK-265)
58 mg and (SK-266) 73 mg. SIMS (3-NBA + NaCl) : C 46 H 82 N 2 O 15, 925 (M + Na) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.01 (3H, s, COC
_{H 3), 2.29 (6H,} s, 3'-N (CH 3) 2), 3.04 (3H, s, 6-OCH 3), 3.3
0 (3H, s, 3 " -OCH 3).

Example 10 5-O- (2'-O-acetyl) desosaminyl-3-O- [4 "-O- (6-phenyltetrahydropyran-2-
Yl) Cladinosyl] -6-O-Methylerythronolide A Preparation of 5-O- (2'-O-acetyl) desosaminyl-3-O-clazinosyl-6
0.81 g (1.03 mmol) of -O-methylerythronolide A and 2-
Phenyl-3,4-dihydro-2H-pyran 0.41 g (2.56 mmol)
Was reacted in the same manner as in Example 5 to give the title compound
0.151 g was obtained. MS (FAB): m / z 950 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.05 (3H, s, COC
_{H 3), 2.29 (6H,} s, 3'-N (CH 3) 2), 3.01 (3H, s, 6-OCH 3), 3.3
8 (3H, s, 3 "-OCH ₃ ), 4.99 (1H, dd, J = 11.5,2.4Hz, 5 '''-H),
5.03 (1H, d, J = 4.3Hz, 1 '''- H), 7.24~7.36 (5H, m, Ar-H) 13 C-NMR (125MHz, CDCl 3) δ (ppm): 40.8 (3' -N (C
H ₃ ) ₂ ), 49.5 (3 "-OCH ₃ ), 50.5 (6-OCH ₃ ), 87.3 (4"), 100.
5 (1 ''').

Example 11 5-O- (2'-O-acetyl) desosaminyl-3-O- [4 "-O- (6-phenylthiotetrahydropyran
-2-yl) clazinosyl] -6-O-methylerythronolide A
Preparation of 5-O- (2'-O-acetyl) desosaminyl-3-O-clazinosyl-6
0.474 g (0.6 mmol) of -O-methylerythronolide A and 2-
Phenylthio-3,4-dihydro-2H-pyran 0.23 g (1.2 mmo
l) was reacted in the same manner as in Example 5 to obtain 63 mg of the title compound. MS (FAB): m / z 982 (M + H) + 1 H-NMR (500MHz, CDCl 3) δ (ppm): 2.02 (3H, s, COC
H ₃ ), 2.30 (6H, s, 3'-N (CH ₃ ) ₂ ), 3.00 (3H, s, 6-OCH ₃ ), 3.2
7 (3H, s, 3 " -OCH 3), 7.23~7.54 (5H, m, Ar-H).

Example 12 5-O-desosaminyl-3-O- {4 "-O
Preparation of-[α-L- (2,3,4-tri-O-methyl) rhamnopyranosyl] clazinosyl} -6-O-methylerythronolide A 11,12-cyclic carbonate 1-phenylsulfinyl-2,3 , 4-Tri-O-methyl-L-rhamnopyranose 251 mg (0.8 mmol) and 5-O- (2'-O-acetyl) desosaminyl-6-O-methylerythronolide A11,12-
The reaction was carried out in the same manner as in Example 1 using 326 mg (0.4 mmol) of cyclic carbonate to obtain 315 mg of a white powder compound. 260 mg of this white powder compound was deacetylated in the same manner as in Example 7, (2) to obtain 210 mg of the title compound. SIMS (3-NBA + NaCl) : C 48 H 83 NO 18, 984 (M + Na) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.26 (6H, s, 3'-N (C
H ₃ ) ₂ ), 3.00 (3H, s, 6-OCH ₃ ), 3.31 (3H, s, 3 "-OCH ₃ ), 3.48
_{(3H, s, OCH 3)} , 3.49 (3H, s, OCH 3), 3.50 (3H, s, OCH 3).

Example 13 5-O-desosaminyl-3-O- {4 "-O
-[β-L- (2,3,4-tri-O-methyl) xylopyranosyl] clazinosyl} -6-O-methylerythronolide A Preparation of 11,12-cyclic carbonate 1-phenylsulfinyl-2,3 240 mg (0.8 mmol) of 5,4-tri-O-methyl-L-xylopyranose and 5-O- (2′-O-acetyl) desosaminyl-6-O-methylerythronolide A11,12-
The reaction was carried out in the same manner as in Example 1 using 336 mg (0.4 mmol) of cyclic carbonate, followed by deacetylation as in (2) of Example 6 to obtain 272 mg of the title compound. SIMS (3-NBA + NaCl) : C 47 H 81 NO 18, 970 (M + Na) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.25 (6H, s, 3'-N (C
H ₃ ) ₂ ), 2.99 (3H, s, 6-OCH ₃ ), 3.32 (3H, s, 3 "-OCH ₃ ), 3.46
_{(3H, s, OCH 3)} , 3.53 (3H, s, OCH 3), 3.60 (3H, s, OCH 3).

Example 14 5-O-desosaminyl-3-O- {4 "-O
-[β-L- (2,3,4-tri-O-ethyl) xylopyranosyl] clazinosyl} -6-O-methylerythronolide A 11,12-cyclic carbonate 1-phenylsulfinyl-2,3,4 -Tri-O-ethyl-L-xylopyranose 272 mg (0.8 mmol) and 5-O- (2'-O-acetyl) desosaminyl-6-O-methylerythronolide A11,12-
The reaction was carried out in the same manner as in Example 1 using 326 mg (0.4 mmol) of cyclic carbonate to obtain 377 mg of a white powder compound. Subsequently, 150 mg of this white powder compound was deacetylated in the same manner as in Example 6, (2) to obtain 126 mg of the title compound. SIMS (3-NBA + NaCl) : C 50 H 87 NO 18, 1012 (M + Na) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.26 (6H, s, 3'-N (C
_{H 3) 2), 2.99 (} 3H, s, 6-OCH 3), 3.31 (3H, s, 3 "-OCH 3).

Example 15 5-O-desosaminyl-3-O- {4 "-O
-[α-L- (2,3,4-tri-O-methyl) arabinopyranosyl] clazinosyl} -6-O-methylerythronolide A Preparation of 11,12-cyclic carbonate 1-phenylsulfinyl 300 mg (1.0 mmol) of -2,3,4-tri-O-ethyl-L-arabinopyranose and 5-O- (2'-O-acetyl) desosaminyl-6-O-methylerythronolide A 11,12
-Using 408 mg (0.5 mmol) of cyclic carbonate,
After performing the reaction in the same manner as in Example 1, the obtained crude product was subjected to column chromatography (Silica Gel, CHCl3 / EtOH /
NH ₄ OH = 500/5/1) to give a white powdered compound (A) 1
50 mg and 100 mg of white powder compound (B) were obtained. Then
The white powder compound (A) was deacetylated in the same manner as in Example 6, (2) to obtain 112 mg of the title compound. MS (3-NBA + NaCl) : C 47 H 81 NO 18, 970 (M + Na) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.18 (6H, s, 3'-N (C
H ₃ ) ₂ ), 3.01 (3H, s, 6-OCH ₃ ), 3.31 (3H, s, 3 "-OCH ₃ ), 3.41
_{(3H, s, OCH 3)} , 3.50 (3H, s, OCH 3), 3.60 (3H, s, OCH 3). Example 16 5-O-desosaminyl-3-O- {4 "-O- [β-L- (2,3,
4-tri-O-methyl) arabinopyranosyl] clazinosyl} -6
Production of -O-methylerythronolide A 11,12-cyclic carbonate White powder compound (B) obtained in Example 15
Was deacetylated in the same manner as in Example 6, (2) to obtain 79 mg of the title compound. SIMS (3-NBA + NaCl) : C 47 H 81 NO 18, 970 (M + Na) + 1 H-NMR (400MHz, CDCl 3) δ (ppm): 2.26 (6H, s, 3'-N (C
H ₃ ) ₂ ), 3.00 (3H, s, 6-OCH ₃ ), 3.31 (3H, s, 3 "-OCH ₃ ), 3.44
_{(3H, s, OCH 3)} , 3.47 (3H, s, OCH 3), 3.49 (3H, s, OCH 3).

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

[0039]

[Table 1]

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Toshifumi Asaga 3- 24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Masato Kashimura 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Shigeo Morimoto 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] (1) Formula (1) [Wherein X may be the same or different and a hydroxyl group, a lower alkyl group, an alkoxy group, an alkoxycarbonyl group, a lower alkanoyloxy group, an aryl group, an arylthio group, an aminomethyl group, an azidomethyl group, an N-acetylaminomethyl A group or an N, N-dibenzylaminomethyl group, n represents an integer of 0 to 4, R ¹ represents an oxygen atom or a formula R ⁵ —O—N, wherein R ⁵ represents a hydrogen atom or an acetyl group. R ² represents a hydrogen atom or an acetyl group, and R ³ and R ⁴ each represent a hydroxyl group or a carbonate group. And a pharmaceutically acceptable salt thereof.